"Not ready to throw in the towel": perceptions of physical activity held by older adults in Stockholm and Dublin.
The aim of this qualitative study was to explore and describe the perceptions of physical activity held by older urban Swedish and Irish adults. Qualitative interviews were carried out with 30 people age 65 years and older (mean age 74.5), of whom 15 were living in Dublin and 15 were living in Stockholm. The "thematic framework" approach was used to analyze the data. Three central themes were identified regarding people's perceptions of physical activity: physical activity as self-expression, physical activity as interaction, and physical activity as health promotion. Participants' perceptions of physical activity tended to relate to their perceived level of physical activity, regardless of their cultural background. Certain culture-specific motivators and barriers to exercise were also identified. Less active Irish men were more likely to underestimate the health-promoting benefits of exercise.


Multicenter randomized clinical trial of supervised exercise therapy with or without feedback versus walking advice for intermittent claudication.
The initial treatment for intermittent claudication is supervised exercise therapy (SET). Owing to limited capacity and patient transports costs of clinic-based SET, a concept of SET provided by local physiotherapists was developed. We hypothesized that provision of daily feedback with an accelerometer in addition to SET would further increase walking distance. This multicenter randomized trial was set in vascular surgery outpatient clinics and included 304 patients with intermittent claudication. Patients were randomized to exercise therapy in the form of "go home and walk" advice (WA), SET, or SET with feedback. Local physiotherapists provided SET. The primary outcome measure was the change in absolute claudication distance. Secondary outcomes were the change in functional claudication distance and results on the Walking Impairment Questionnaire (WIQ) and Short-Form 36 (SF-36) Health Survey after 12 months. In 11 centers, 102, 109, and 93 patients were included, respectively, in the WA, SET, and SET with feedback groups, and data for 83, 93, and 76, respectively, could be analyzed. The median (interquartile range) change in walking distance between 12 months and baseline in meters was 110 (0-300) in the WA group, 310 (145-995) in the SET group, and 360 (173-697) in the SET with feedback group (P < .001 WA vs SET). WIQ scores and relevant domains of the SF-36 improved statistically significantly in the SET groups. SET is more effective than WA in improving walking distance, WIQ scores, and quality of life for patients with intermittent claudication. Additional feedback with an accelerometer did not result in further improvement. SET programs should be made available for all patients with intermittent claudication.


A meta-analysis on the impact of alcohol dependence on short-term resting-state heart rate variability: implications for cardiovascular risk.
Alcohol dependence is associated with an increased likelihood of cardiac events. Reductions in heart rate variability (HRV) may be one mechanism linking dependence with these events. HRV may also be related to poor social functioning and the lack of impulse control commonly observed in alcohol-dependent individuals. However, prior studies on the impact of alcohol dependence on HRV have reported contradictory findings highlighting the need for a meta-analysis. Studies comparing short-term HRV in alcohol-dependent populations and healthy controls who were nondependent were considered for meta-analysis. Only studies reporting findings from participants without cardiovascular disease were included in the analysis. Meta-analyses were based on 6 articles that fulfilled inclusion criteria, comprising a total of 177 alcohol-dependent participants and 216 nondependent participants. Alcohol-dependent participants displayed reduced HRV (Hedges' g = -0.6, p > 0.001) in comparison with nondependent participants. No differences were observed between the summary effect sizes obtained from different HRV domains (Q = 1.19, p = 0.55). Alcohol dependence is associated with reduced HRV, an effect associated with a medium effect size. Findings highlight the importance of monitoring alcohol-dependent patients for cardiac disease and emphasize the need for cardiovascular risk reduction strategies in these patients.


Evaluation of drug interactions and dosing in 484 neurological inpatients using clinical decision support software and an extended operational interaction classification system (Zurich Interaction System).
The current study aimed at identifying and quantifying critical drug interactions in neurological inpatients using clinical decision support software (CDSS). Reclassification of interactions with a focus on clinical management aimed to support the development of CDSS with higher efficacy to reduce overalerting and improve medication safety in clinical practice. We conducted a cross-sectional study in consecutive patients admitted to the neurology ward of a tertiary care hospital. We developed a customized interface for mass analysis with the CDSS MediQ, which we used for automated retrospective identification of drug interactions during the first day of hospitalization. Interactions were reclassified according to the Zurich Interaction System (ZHIAS), which incorporates the Operational Classification of Drug Interactions (ORCA). Dose adjustments for renal impairment were also evaluated. In 484 patients with 2812 prescriptions, MediQ generated 8 "high danger," 518 "average danger," and 1233 "low danger" interaction alerts. According to ZHIAS, 6 alerts involved contraindicated and 33 alerts involved provisionally contraindicated combinations, and 327 alerts involved a conditional and 1393 alerts involved a minimal risk of adverse outcomes. Thirty-five patients (6.2%) had at least one combination that was at least provisionally contraindicated. ZHIAS also provides categorical information on expected adverse outcomes and management recommendations, which are presented in detail. We identified 13 prescriptions without recommended dose adjustment for impaired renal function. MediQ detected a large number of drug interactions with variable clinical relevance in neurological inpatients. ZHIAS supports the selection of those interactions that require active management, and the effects of its implementation into CDSS on medication safety should be evaluated in future prospective studies.


Lymph node ratio predicts recurrence in papillary thyroid cancer.
Lymph node metastasis occurs in 20%-50% of patients presenting for initial treatment of papillary thyroid cancer (PTC). The significance of lymph node metastases remains controversial, and the aim of this study is to determine how the lymph node ratio (LNR) may predict the likelihood of disease recurrence. We conducted a retrospective review of patients undergoing total thyroidectomy for PTC at our institution from 2005 to 2010. A total LNR (positive nodes to total nodes) and central lymph node ratio (cLNR) was calculated. Regression was used to determine a threshold LNR that best predicted recurrence. Multivariate logistic regression then determined the influence of LNR on recurrence while accounting for other known predictors of recurrence. Kaplan-Meier analysis and the log-rank test were used to compare differences in disease-free survival. Of the 217 patients undergoing total thyroidectomy for PTC, 69 patients had concomitant neck dissections. Sixteen (23.2%) patients developed disease recurrence. When disease-free survival functions were compared, we found that patients with a total LNR ≥0.7 (p < .01) or a cLNR ≥0.86 (p = .04) had significantly worse disease-free survival rates than patients with ratios below these threshold values. Considering other known predictors of recurrence, we found that LNR was significantly associated with recurrence (odds ratio: 19.5, 95% confidence interval: 4.1-22.9; p < .01). Elevated total LNR and cLNR are strongly associated with recurrence of PTC after initial operation. LNR in PTC is a tool that can be used to determine the likelihood of the patient developing recurrent disease and inform postoperative follow-up.


Horizontal acquisition of multiple mitochondrial genes from a parasitic plant followed by gene conversion with host mitochondrial genes.
Horizontal gene transfer (HGT) is relatively common in plant mitochondrial genomes but the mechanisms, extent and consequences of transfer remain largely unknown. Previous results indicate that parasitic plants are often involved as either transfer donors or recipients, suggesting that direct contact between parasite and host facilitates genetic transfer among plants. In order to uncover the mechanistic details of plant-to-plant HGT, the extent and evolutionary fate of transfer was investigated between two groups: the parasitic genus Cuscuta and a small clade of Plantago species. A broad polymerase chain reaction (PCR) survey of mitochondrial genes revealed that at least three genes (atp1, atp6 and matR) were recently transferred from Cuscuta to Plantago. Quantitative PCR assays show that these three genes have a mitochondrial location in the one species line of Plantago examined. Patterns of sequence evolution suggest that these foreign genes degraded into pseudogenes shortly after transfer and reverse transcription (RT)-PCR analyses demonstrate that none are detectably transcribed. Three cases of gene conversion were detected between native and foreign copies of the atp1 gene. The identical phylogenetic distribution of the three foreign genes within Plantago and the retention of cytidines at ancestral positions of RNA editing indicate that these genes were probably acquired via a single, DNA-mediated transfer event. However, samplings of multiple individuals from two of the three species in the recipient Plantago clade revealed complex and perplexing phylogenetic discrepancies and patterns of sequence divergence for all three of the foreign genes. This study reports the best evidence to date that multiple mitochondrial genes can be transferred via a single HGT event and that transfer occurred via a strictly DNA-level intermediate. The discovery of gene conversion between co-resident foreign and native mitochondrial copies suggests that transferred genes may be evolutionarily important in generating mitochondrial genetic diversity. Finally, the complex relationships within each lineage of transferred genes imply a surprisingly complicated history of these genes in Plantago subsequent to their acquisition via HGT and this history probably involves some combination of additional transfers (including intracellular transfer), gene duplication, differential loss and mutation-rate variation. Unravelling this history will probably require sequencing multiple mitochondrial and nuclear genomes from Plantago. See Commentary: http://www.biomedcentral.com/1741-7007/8/147.


On the significance of electroconvulsive therapy in the treatment of severe mental diseases.
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. During the last decades, numerous international medical societies including the Austrian and the German Association for Psychiatry (ÖGPP 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. 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. 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.


Semiclassical theory to optical resonant modes of a transparent dielectric spheroidal cavity.
We study the resonant scattering of light by a transparent dielectric spheroid. We try to understand the features of the resonant modes of a spheroidal optical cavity. In this way, we use an analogy between optics and quantum mechanics. Through this analogy it is possible to interpret resonances as quasibound states of light. Using semiclassical methods such as the WKB method and a uniform asymptotic expansion for spheroidal radial functions, we developed algorithms that permit us to calculate the resonance position as well as the resonance width.


Comparison of Euryarchaea strains in the guts and food-soil of the soil-feeding termite Cubitermes fungifaber across different soil types.
Termites are an important component of tropical soil communities and have a significant effect on the structure and nutrient content of soil. Digestion in termites is related to gut structure, gut physicochemical conditions, and gut symbiotic microbiota. Here we describe the use of 16S rRNA gene sequencing and terminal-restriction fragment length polymorphism (T-RFLP) analysis to examine methanogenic archaea (MA) in the guts and food-soil of the soil-feeder Cubitermes fungifaber Sjostedt across a range of soil types. If these MA are strictly vertically inherited, then the MA in guts should be the same in all individuals even if the soils differ across sites. In contrast, gut MA should reflect what is present in soil if populations are merely a reflection of what is ingested as the insects forage. We show clear differences between the euryarchaeal communities in termite guts and in food-soils from five different sites. Analysis of 16S rRNA gene clones indicated little overlap between the gut and soil communities. Gut clones were related to a termite-derived Methanomicrobiales cluster, to Methanobrevibacter and, surprisingly, to the haloalkaliphile Natronococcus. Soil clones clustered with Methanosarcina, Methanomicrococcus, or rice cluster I. T-RFLP analysis indicated that the archaeal communities in the soil samples differed from site to site, whereas those in termite guts were similar between sites. There was some overlap between the gut and soil communities, but these may represent transient populations in either guts or soil. Our data do not support the hypothesis that termite gut MA are derived from their food-soil but also do not support a purely vertical transmission of gut microflora.


Is NHS dentistry in crisis? 'Traffic light' maps of dentists distribution in England and Wales.
BACKGROUND: 'Traffic light' (red-yellow-green) maps are potentially powerful tools for 'at a glance' problem detection, for optimising resource allocation/reallocation, setting priorities, and targeting interventions to areas most in need. The maps can be also used for administrative area comparisons and performance monitoring over time. Interactive Web versions of the maps can be generated with many handy features to further empower organisations and decision makers. Methodological issues to consider when creating 'traffic light' maps include hue thresholding, data timeliness and stability of administrative boundaries. RESULTS: We used 'traffic light' maps to study the distribution of dentists per 1,000 population in all 304 English Primary Care Trusts (PCTs) and 22 Welsh Local Health Boards (LHBs) using datasets of dentist numbers per PCT (as at 31 December 2002) and LHB (as at 26 February 2004) from the Dental Practice Board, and 2001 Census population figures for PCTs and LHBs from the Office for National Statistics. The overall NHS dentists per 1,000 population figures for England (0.374) and Wales (0.359) are low compared to many other countries, with less than 0.3 dentist per 1,000 people available to 24.1% of the total population of England (81 PCTs or 26.6% of all PCTs) and 26.1% of the total population of Wales (6 LHBs or 27.3% of all LHBs). A general shortage of NHS dentists can be observed at a glance across England and Wales on all the 'traffic light' maps in our study, even on those using a more "tolerant" classification and an additional orange-yellow class. The distribution of NHS dentists in England and Wales was also found to be not uniform, with some PCTs/LHBs, especially those located in some of the deprived or less populated urban and rural communities, suffering significantly more shortage of dentists than others (see http://healthcybermap.org/PCT/dentists/). These results confirm recent media reports of a shortage of NHS dentists in various parts of England and Wales. CONCLUSION: Suitable programmes are urgently needed to increase the numbers of NHS dentists across England and Wales. We have included a set of recommendations to dental health policymakers and planners, in addition to ideas for further work.


Expression of the receptor tyrosine kinase KIT in mature beta-cells and in the pancreas in development.
In the pancreas, ligands of receptor tyrosine kinases (RTKs) are thought to be implicated in the development and function of the islets of Langerhans, which represent the endocrine part of the pancreas. In a previous study, we randomly screened by reverse transcriptase-polymerase chain reaction for RTKs expressed in the embryonic pancreas. One cDNA fragment that was cloned during this screen corresponded to the KIT receptor. The objective of the present study was to analyze the pattern of Kit expression in the pancreas. We demonstrated that Kit is expressed and functional in terms of signal transduction in the insulin-producing cell line INS-1. Indeed, upon treatment with the KIT ligand (KITL), the extracellular signal-regulated protein kinase was phosphorylated, and the expression of early responsive genes was induced. We also demonstrated that Kit mRNAs are present in fetal and adult rat islets. We next used mice that had integrated the lacZ reporter gene into the Kit locus. In these mice, beta-galactosidase (beta-gal) served as a convenient marker for expression of the endogenous Kit gene. Kit was found to be specifically transcribed in beta-cells (insulin-expressing cells), whereas no expression was found in other endocrine cell types or in the exocrine tissue. Interestingly, not all mature beta-cells expressed Kit, indicating that Kit is a marker of a subpopulation of beta-cells. Finally, by following beta-gal expression in the pancreas during fetal life, we found that at E14.5, Kit is expressed in both insulin- and glucagon-expressing cells present at that stage, and also in a specific cell population present in the epithelium that stained negative for endocrine markers. These data suggest that these Kit-positive/endocrine-negative cells could represent a subpopulation of endocrine cell precursors.


Serum Mac-2 binding protein is a novel biomarker for chronic pancreatitis.
To determine the efficacy of Mac-2 binding protein (Mac-2bp) for diagnosis of chronic pancreatitis. Fifty-nine healthy volunteers (HV), 162 patients with chronic pancreatitis (CP), and 94 patients with pancreatic ductal adenocarcinoma (PDAC) were enrolled in this study. We measured serum Mac-2bp using our developed enzyme-linked immunosorbent assay kit. Additional biochemical variables were measured using an automated analyzer (including aminotransferase, alanine aminotransferase, γ-glutamyltransferase, alkaline phosphatase, triglyceride, C-reactive protein, and amylase levels) or chemiluminescent enzyme immunoassay (carbohydrate antigen 19-9 and carcinoembryonic antigen). The ability of Mac-2bp to predict CP diagnosis accurately was assessed using receiver operating characteristic (ROC) analyses. Serum Mac-2bp levels were significantly increased in CP patients compared to HV (P < 0.0001) and PDAC patients (P < 0.0001). Area under the ROC curve values of Mac-2bp for the discrimination of CP from HV and PDAC were 0.727 and 0.784, respectively. Multivariate analyses demonstrated that serum Mac-2bp levels were independent determinants for CP diagnosis from HV and PDAC patients. Immunohistological staining showed that Mac-2bp was expressed faintly in the pancreas tissues of both CP and PDAC patients. Serum aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, alkaline phosphatase, and triglyceride levels were significantly higher in patients with CP or PDAC. Serum Mac-2bp levels were highly correlated with protein levels of alanine aminotransferase, γ-glutamyltransferase, and C-reactive protein, but not amylase, suggesting that the damaged liver produces Mac-2bp. Measurement of serum Mac-2bp may be a novel and useful biomarker for CP diagnosis as well as liver fibrosis in the general population.


Nanofiber-reinforced decellularized amniotic membrane improves limbal stem cell transplantation in a rabbit model of corneal epithelial defect.
Human amniotic membrane (AM) offers unique advantages as a matrix to support the transplantation of limbal stem cells (LSCs) due to its inherent pro-regenerative and anti-inflammatory properties. However, the widespread use of AM in clinical treatments of ocular surface disorders is limited by its weak mechanical strength and fast degradation, and high cost associated with preserving freshly isolated AM. Here we constructed a composite membrane consisting of an electrospun bioabsorbable poly(ε-caprolactone) (PCL) nanofiber mesh to significantly improve the ultimate tensile strength, toughness, and suture retention strength by 4-10-fold in comparison with decellularized AM sheet. The composite membrane showed extended stability and conferred longer-lasting coverage on wounded cornea surface compared with dAM. The composite membrane maintained the pro-regenerative and immunomodulatory properties of dAM, promoted LSC survival, retention, and organization, improved re-epithelialization of the defect area, and reduced inflammation and neovascularization. This study demonstrates the translational potential of our composite membrane for stem cell-based treatment of ocular surface damage. STATEMENT OF SIGNIFICANCE: Human decellularized amniotic membrane (dAM) has been widely shown as a biodegradable and bioactive matrix for regenerative tissue repair. However, the weak mechanical property has limited its widespread use in the clinic. Here we constructed a composite membrane using a layer of electrospun poly(ε-caprolactone) (PCL) nanofiber mesh to reinforce the dAM sheet through covalent interfacial bonding, while retaining the unique bioactivity of dAM. In a rabbit model of limbal stem cell (LSC) deficiency induced by alkaline burn, we demonstrated the superior property of this PCL-dAM composite membrane for repairing damaged cornea through promoting LSC transplantation, improving re-epithelialization, and reducing inflammation and neovascularization. This new composite membrane offers great translational potential in supporting stem cell-based treatment of ocular surface damage.


Dendritic and mast cell involvement in the inflammatory response to primary malignant bone tumours.
A chronic inflammatory cell infiltrate is commonly seen in response to primary malignant tumours of bone. This is known to contain tumour-associated macrophages (TAMs) and lymphocytes; dendritic cells (DCs) and mast cells (MCs) have also been identified but whether these and other inflammatory cells are seen commonly in specific types of bone sarcoma is uncertain. In this study we determined the nature of the inflammatory cell infiltrate in 56 primary bone sarcomas. Immunohistochemistry using monoclonal antibodies was employed to assess semiquantitatively CD45+ leukocyte infiltration and the extent of the DC, MC, TAM and T and B lymphocyte infiltrate. The extent of the inflammatory infiltrate in individual sarcomas was very variable. A moderate or heavy leukocyte infiltrate was more commonly seen in conventional high-grade osteosarcoma, undifferentiated pleomorphic sarcoma and giant cell tumour of bone (GCTB) than in Ewing sarcoma, chordoma and chondrosarcoma. CD14+/CD68+ TAMs and CD3+ T lymphocytes were the major components of the inflammatory cell response but (DC-SIGN/CD11c+) DCs were also commonly noted when there was a significant TAM and T lymphocyte infiltrate. MCs were identified mainly at the periphery of sarcomas, including the osteolytic tumour-bone interface. Our findings indicate that, although variable, some malignant bone tumours (e.g. osteosarcoma, GCTB) are more commonly associated with a pronounced inflammatory cell infiltrate than others (e.g. chondrosarcoma. Ewing sarcoma); the infiltrate is composed mainly of TAMs but includes a significant DC, T lymphocyte and MC infiltrate. Tumours that contain a heavy inflammatory cell response, which includes DCs, TAMs and T lymphocytes, may be more amenable to immunomodulatory therapy. MCs are present mainly at the tumour edge and are likely to contribute to osteolysis and tumour invasion.


Linking brains and brawn: exercise and the evolution of human neurobiology.
The hunting and gathering lifestyle adopted by human ancestors around 2 Ma required a large increase in aerobic activity. High levels of physical activity altered the shape of the human body, enabling access to new food resources (e.g. animal protein) in a changing environment. Recent experimental work provides strong evidence that both acute bouts of exercise and long-term exercise training increase the size of brain components and improve cognitive performance in humans and other taxa. However, to date, researchers have not explored the possibility that the increases in aerobic capacity and physical activity that occurred during human evolution directly influenced the human brain. Here, we hypothesize that proximate mechanisms linking physical activity and neurobiology in living species may help to explain changes in brain size and cognitive function during human evolution. We review evidence that selection acting on endurance increased baseline neurotrophin and growth factor signalling (compounds responsible for both brain growth and for metabolic regulation during exercise) in some mammals, which in turn led to increased overall brain growth and development. This hypothesis suggests that a significant portion of human neurobiology evolved due to selection acting on features unrelated to cognitive performance.


SU-E-J-23: Prostate Bed Motion Study Using Surgical Clips Based on Daily CBCT.
To study prostate-bed motion after prostatectomy using the surgical clips as a surrogate. On the treatment planning CT, surgical clips within the PTV are identified and contoured. They are also identified and contoured in each daily CBCT. The center of mass (COM) coordinates for each clip within the native reference frame of each image set of CT and CBCT are recorded. Each CBCT (for daily image guidance) is registered to the planning CT based on the pelvic bony structure. The resulted 3D transformation matrix is used to convert the clip coordinates in the CBCT to the planning CT reference frame. Difference between the converted COM coordinates and the one in planning CT is taken as the rigid motion of the prostate bed relative to the pelvic bony structure during the course of radiation therapy. The motion data are then analyzed using statistical error analysis and quantified by the commonly defined M (average over all fractions and all patients), S (stdev of averages per patient, the systematic motion), and s (root mean square of stdev per patient, the random motion). Among a large pool of patients, seven patients were selected for this retrospective study, each with 3 to 11 identifiable clips and 17 to 26 CBCT sets. The total number of clips is 44 and total daily CBCT sets 160. In the (right-left, anterio-posterior, foot-head) directions, the M values are (0.2 mm, 0.4 mm, -0.6 mm), S (0.2, 2.5, 3.2), and s (1.7, 2.6, 2.1). Relative to the bony pelvic structure, the prostate bed motion characteristics are similar to that of intact prostate, as summarized in Table 2 of Rasch et al 2005 ('Target Definition in Prostate, Head, and Neck.' Semin Radiat Oncol 15:136-145).


Strategies for high-altitude adaptation revealed from high-quality draft genome of non-violacein producing Janthinobacterium lividum ERGS5:01.
A light pink coloured bacterial strain ERGS5:01 isolated from glacial stream water of Sikkim Himalaya was affiliated to Janthinobacterium lividum based on 16S rRNA gene sequence identity and phylogenetic clustering. Whole genome sequencing was performed for the strain to confirm its taxonomy as it lacked the typical violet pigmentation of the genus and also to decipher its survival strategy at the aquatic ecosystem of high elevation. The PacBio RSII sequencing generated genome of 5,168,928 bp with 4575 protein-coding genes and 118 RNA genes. Whole genome-based multilocus sequence analysis clustering, in silico DDH similarity value of 95.1% and, the ANI value of 99.25% established the identity of the strain ERGS5:01 (MCC 2953) as a non-violacein producing J. lividum. The genome comparisons across genus Janthinobacterium revealed an open pan-genome with the scope of the addition of new orthologous cluster to complete the genomic inventory. The genomic insight provided the genetic basis of freezing and frequent freeze-thaw cycle tolerance and, for industrially important enzymes. Extended insight into the genome provided clues of crucial genes associated with adaptation in the harsh aquatic ecosystem of high altitude.


μ-opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization.
We have compared the ability of a number of μ-opioid receptor (MOPr) ligands to activate G proteins with their abilities to induce MOPr phosphorylation, to promote association of arrestin-3 and to cause MOPr internalization. For a model of G protein-coupled receptor (GPCR) activation where all agonists stabilize a single active conformation of the receptor, a close correlation between signaling outputs might be expected. Our results show that overall there is a very good correlation between efficacy for G protein activation and arrestin-3 recruitment, whereas a few agonists, in particular endomorphins 1 and 2, display apparent bias toward arrestin recruitment. The agonist-induced phosphorylation of MOPr at Ser(375), considered a key step in MOPr regulation, and agonist-induced internalization of MOPr were each found to correlate well with arrestin-3 recruitment. These data indicate that for the majority of MOPr agonists the ability to induce receptor phosphorylation, arrestin-3 recruitment, and internalization can be predicted from their ability as agonists to activate G proteins. For the prototypic MOPr agonist morphine, its relatively weak ability to induce MOPr internalization can be explained by its low agonist efficacy.


Reactivity of Grubbs' catalysts with urea- and amide-substituted olefins. Metathesis and isomerization.
[Chemical reaction: see text] The reactions of a series of urea- and amide-substituted olefins with Grubbs' catalysts are presented. Depending on the substrate's nature, the formation of either cross-metathesis or isomerization products is observed. To favor the cross-metathesis products, the reactions have been carried out using a wide range of experimental conditions. Upon addition of monophenyl phosphoester to these reactions, the isomerization of the olefins is completely suppressed and the cross-metathesis products are obtained in up to 60% yield.


Coupled catastrophes: sudden shifts cascade and hop among interdependent systems.
An important challenge in several disciplines is to understand how sudden changes can propagate among coupled systems. Examples include the synchronization of business cycles, population collapse in patchy ecosystems, markets shifting to a new technology platform, collapses in prices and in confidence in financial markets, and protests erupting in multiple countries. A number of mathematical models of these phenomena have multiple equilibria separated by saddle-node bifurcations. We study this behaviour in its normal form as fast-slow ordinary differential equations. In our model, a system consists of multiple subsystems, such as countries in the global economy or patches of an ecosystem. Each subsystem is described by a scalar quantity, such as economic output or population, that undergoes sudden changes via saddle-node bifurcations. The subsystems are coupled via their scalar quantity (e.g. trade couples economic output; diffusion couples populations); that coupling moves the locations of their bifurcations. The model demonstrates two ways in which sudden changes can propagate: they can cascade (one causing the next), or they can hop over subsystems. The latter is absent from classic models of cascades. For an application, we study the Arab Spring protests. After connecting the model to sociological theories that have bistability, we use socioeconomic data to estimate relative proximities to tipping points and Facebook data to estimate couplings among countries. We find that although protests tend to spread locally, they also seem to 'hop' over countries, like in the stylized model; this result highlights a new class of temporal motifs in longitudinal network datasets.


Red blood cell distribution width is increased in patients with psoriasis vulgaris: A retrospective study on 261 patients.
Circulating inflammatory cytokines and markers are increased in patients with psoriasis. Recent studies have shown that a higher red blood cell distribution width (RDW) is associated with disease activity in various disorders. Our objective was to investigate whether RDW is increased in psoriasis patients, and to evaluate its possible association with disease severity. We conducted a retrospective study of psoriasis patients seen in a university hospital in South Korea. Information about demographics, hematological parameters and disease severity were collected. Statistical analysis was performed using Student's t-test, multivariable logistic regression, Fisher's exact test and Spearman's rank correlation coefficient analysis as appropriate. A total of 261 psoriasis patients and 102 healthy controls were included in our study. The mean RDW value was significantly increased in psoriasis patients compared with healthy control (P = 0.037). Compared with mild psoriasis patients (Psoriasis Area and Severity Index [PASI], <7), moderate to severe patients (PASI, ≥7) showed significantly higher RDW values (P = 0.044). However, RDW did not show significant correlation with PASI (P = 0.358). When patients were divided into two groups according to their RDW value (<14.6% and ≥14.6%), the mean value of PASI was not significantly different (P = 0.219). Patients with psoriasis showed increased RDW values compared with healthy controls. It was also higher in the moderate and severe disease group than the mild group. Though this is only a pilot study, it is possible that RDW value can reflect the inflammatory status of psoriasis patients.


[Evaluation of a nutritional intervention to reduce cholesterol levels in patients with coronary artery disease].
The mainstay of cholesterol reduction therapy is the diet. But the lack of compliance and prescription problems limit its usefulness. To compare the effectiveness of a nutritional intervention given by a nutritionist with the usual recommendations given by a physician to reduce the LDL cholesterol levels in patients with coronary artery disease, treated at the Regional public hospital in Temuco. One hundred and forty patients with coronary heart disease (last acute episode at least three months before), without nutritional interventions nor cholesterol-lowering drugs, who gave informed consent, were randomized to receive either instructions by their physician or to take part in a nutritional program. The nutritional intervention consisted in five educational sessions, adapted from the NCEP and from a program of the Nutrition Department of the Catholic University of Chile. Patients randomized to the medical intervention received the standard written recommendations about diet. Lipid profile was measured before the intervention and after a three and twelve months follow up. After one year the group on the nutritionalprogram reduced LDL cholesterol by 11.1% (p=0.03). There were no changes in the medical group. However, only 10% patients on the nutritional intervention group and 8% of those with medical recommendations achieved LDL cholesterol levels less than 100 mg/dl. There were no changes in triglycerides, weight or body mass index during the period. Although this nutritional intervention proved to be more effective than usual medical instructions, most patients on secondary prevention did not achieve acceptable LDL cholesterol levels.


Comparative radiographic assessment of root canal obturation quality: manual verses rotary canal preparation technique.
To compare the technical quality of root canal obturation in relation to rotary and manual root canal preparation techniques. Cross sectional, analytical study. The Aga Khan University Hospital Karachi from January till December 2011. Data was retrospectively retrieved by periapical radiographs of 60 root canal treated molars for assessment of obturation quality. Data was divided into two groups, 30 radiographs in each group. Group 1 and 2 teeth were prepared with rotary and manual canal preparation technique respectively followed by obturartion with cold lateral condensation technique. Postobturation radiographs were assessed to evaluate technical quality of obturation in term of length, density and taper of root filling. Mann Whitney-U and Chi- square test was applied to compare the difference in technical quality of obturation between two canal preparation techniques. Amongst Thirty molar prepared with rotary instruments, 27 had achieved acceptable length, 25 had adequate density and 27 had achieved adequate taper. Amongst 30 molars prepared manually, 18 had achieved acceptable length, 14 had adequate density and 12 had adequate taper. Radiographic technical quality of the obturation (length, density and taper) was better with rotary technique as compared to manual canal preparation technique.


Temperature and ultrasound sensitive gatekeepers for the controlled release of chemotherapeutic drugs from mesoporous silica nanoparticles.
With the advent of smart biomaterials, environmental stimuli have always been the trigger for targeted drug delivery. Conventional routes of drug administration suffer from serious drawbacks like first pass metabolism, less patient compliance and the requirement of trained personnel. Of the many well-established non-conventional routes, transdermal drug delivery systems (TDDSs) seem to be promising as they do not enter directly into the bloodstream and hence, side effects can significantly be reduced. Researchers around the world are trying to incorporate environmental sensitivity into TDDSs. Herein, we report the design and fabrication of a dual sensitive TDDS: (tetrahydropyranyl methacrylate-co-amino ethyl methacrylate)-grafted-mesoporous silica nanoparticles, (THPMA-co-AEMA)-g-MSNs, that could simultaneously sense temperature and an external stimulus - ultrasound (US). Temperature sensitivity was imparted by the conformational changes adopted by the system above and below the lower critical solution temperature (LCST). Below the LCST (4 °C), the polymer would exist as linear chains allowing drug molecules to enter the mesopores of silica, and at physiological temperatures the copolymer collapses preventing premature drug leakage. This sensitivity could be complemented by the inclusion of mechanophores like tetrahydropyran (THP), which could cleave bonds on exposure to US. At physiological temperatures, the TDDS can be placed at malignant sites and on US exposure, the chemotherapeutic agents could be leached out, resulting in better targeting, efficient drug release and minimal side effects. US can act as a potential penetration enhancer making it ideal even for targeting internal organs. All reaction procedures were monitored with the aid of FTIR, XRD, 1H NMR and FE-SEM techniques. Temperature sensitivity was analysed by encapsulating 5-flurouracil (5-FU) and analysing with a UV-Visible spectrophotometer. US sensitivity was monitored as a function of scattering light intensity. Pore opening and closure was verified by nitrogen adsorption isotherms. The dual responsiveness of the material was confirmed by confocal images of the sample before and after exposure to US. The physiological acceptance and practical efficacy of the material in real life situations were confirmed by histological studies on rat skin, MTT assay in HeLa cell lines and in vivo CAM assay. The results suggest the potential applicability of the material in site selective transdermal delivery of chemotherapeutic drugs.


Implementation and evaluation of a teacher intervention program on classroom communication.
Background: Media frequently report on overall work-place challenges in Swedish schools, including teachers' working conditions, their well-being, and students' declining results. Language is the key to success in every school subject. Therefore, optimal language learning environments are important. Poor sound environments affect teachers' vocal health, their general well-being, and students' performance. To provide better conditions for teachers and students, it is necessary to combine optimized room acoustics with other preventive measures such as vocal training and evidence-based tools to improve classroom communication. Teachers play a key role in the classroom and need knowledge and skills in communicative strategies to ensure first-class communication. The purpose of this study is to explore the effects of an intervention program for primary-school teachers comprising strategies for enhanced language learning and interactions in the classroom, with focus on teachers' verbal and body communication (voice, gaze, and gesture).Methods: Teachers (n = 25) from seven schools teaching in school year 3-6 participated. Assessments were made pre/post intervention and at 5-weeks and 3-months follow-up. The assessments included teachers' self-assessments (questionnaires) of vocal health, self-efficacy, stress, burnout, and psychosocial work-environment.Results: The main results were significant decrease in voice problems at the 3-months follow-up and significant decrease of both stress and degree of burnout at 5-weeks follow-up. Self-efficacy score had increased significantly at 5-week follow-up.Conclusion: It can be concluded that the intervention program improves teachers' self-reported vocal health, decreases their perception of stress, and degree of burnout whilst increasing their sense of self-efficacy in classroom management.


Embryonic stem cell differentiation: a chromatin perspective.
Embryonic stem (ES) cells hold immense promise for the treatment of human degenerative disease. Because ES cells are pluripotent, they can be directed to differentiate into a number of alternative cell-types with potential therapeutic value. Such attempts at "rationally-directed ES cell differentiation" constitute attempts to recapitulate aspects of normal development in vitro. All differentiated cells retain identical DNA content, yet gene expression varies widely from cell-type to cell-type. Therefore, a potent epigenetic system has evolved to coordinate and maintain tissue-specific patterns of gene expression. Recent advances show that mechanisms that govern epigenetic regulation of gene expression are rooted in the details of chromatin dynamics. As embryonic cells differentiate, certain genes are activated while others are silenced. These activation and silencing events are exquisitely coordinated with the allocation of cell lineages. Remodeling of the chromatin of developmentally-regulated genes occurs in conjunction with lineage commitment. Oocytes, early embryos, and ES cells contain potent chromatin-remodeling activities, an observation that suggests that chromatin dynamics may be especially important for early lineage decisions. Chromatin dynamics are also involved in the differentiation of adult stem cells, where the assembly of specialized chromatin upon tissue-specific genes has been studied in fine detail. The next few years will likely yield striking advances in the understanding of stem cell differentiation and developmental biology from the perspective of chromatin dynamics.


Measures of physical performance and risk for progressive and catastrophic disability: results from the Women's Health and Aging Study.
Physical performance measures can predict incident disability, but little research has assessed and compared how these measures predict progressive and rapid-onset (catastrophic) disability. The authors evaluated the ability of upper and lower extremity performance measures to predict progressive and catastrophic disability in activities of daily living (ADL), mobility, and upper extremity function. The incidence of progressive and catastrophic disability was assessed semiannually during a 3-year period in 884 women participating in the Women's Health and Aging Study I. Four-meter walking speed, balance, and chair stands tests were used to evaluate lower extremity function. The putting-on-blouse test, the Purdue pegboard test, and grip strength were used to assess upper extremity function. Summary performance scores (SPS) for the lower and upper extremities were calculated. Among participants in whom disability developed, those who reported no difficulty in the previous year were defined as cases of catastrophic disability, and those who previously reported little or some difficulty were considered to be cases of progressive disability. Cox proportional hazard regression analyses were used to evaluate the association of performance measures and time to incident disability. The predictive ability of performance measures was compared using receiver-operator characteristic curves. All lower and upper extremity measures, with the exception of grip strength, significantly predicted the onset of progressive ADL disability, but only walking speed was significantly associated with the onset of catastrophic ADL disability. The chair stands test, walking speed, and the lower extremity SPS were significantly associated with the onset of both progressive and catastrophic mobility disability. Only lower extremity individual tests and SPS significantly predicted the onset of both progressive and catastrophic upper extremity disability. The receiver-operator characteristic curves for ADL and mobility disability showed that all performance measures evaluated had a greater predictive ability for progressive than for catastrophic incident disability. This finding was not consistent for upper extremity disability. The areas under the curve for walking speed and lower extremity SPS were very similar, ranging from 0.58 to 0.81 and from 0.57 to 0.85, and the predictive ability of these two measures was the greatest for all disability outcomes assessed. Physical performance measures of lower extremity and, in particular, walking speed and lower extremity SPS are valuable tools to predict different forms of disability, especially those with a progressive onset.


Voltage-gated potassium channel antibodies in limbic encephalitis.
We found voltage-gated potassium channel (VGKC) antibodies in 4 of 15 patients with limbic encephalitis (LE). Two patients with idiopathic LE had high VGKC antibody levels (>800 pM; controls <100 pM), that fell in parallel with a clinical response to immunotherapy. Two patients with lower VGKC antibodies (170 pM, 300 pM) had lung cancer (radiological evidence only in one) and the LE improved with immunotherapy in one. The other 11 patients without VGKC antibodies had paraneoplastic LE and eight onconeural antibodies (Hu in 6; Ma2 in 2). VGKC antibodies do not unambiguously discriminate between idiopathic or paraneoplastic LE but probably indicate a good response to immunotherapy.


Effect of Once-Weekly Exenatide in Patients With Type 2 Diabetes Mellitus With and Without Heart Failure and Heart Failure-Related Outcomes: Insights From the EXSCEL Trial.
Once-weekly exenatide (EQW) had a neutral effect on hospitalization for heart failure (HHF) in the EXSCEL study (Exenatide Study of Cardiovascular Event Lowering), with no differential treatment effect on major adverse cardiac events by baseline heart failure (HF) status. EQW's effects on secondary end points based on HHF status have not been reported. The objective was to explore the effects of EQW on secondary end points in patients with and without baseline HF and test the effects of EQW on recurrent HHF events. The prespecified analysis of the randomized controlled EXSCEL trial, which enrolled patients with type 2 diabetes mellitus with and without additional cardiovascular disease, analyzed EQW effects on all-cause death, each major adverse cardiac event component, first HHF, and repeat HHF, by baseline HF status (regardless of ejection fraction). A subgroup analysis of the population stratified by preserved or reduced baseline ejection fraction was performed. Of 14 752 EXSCEL participants, 2389 (16.2%) had HF at baseline. Compared with those without HF at baseline, patients with preexisting HF were older, and more likely to be male and white, with a higher burden of other cardiovascular diseases. Overall, those assigned to EQW had a lower incidence of all-cause death (hazard ratio [HR], 0.86 [95% CI, 0.77-0.97]) and the composite outcome of all-cause death or HHF (HR, 0.89 [95% CI, 0.80-0.99]). When stratified by presence or absence of baseline HF, there was no observed reduction in all-cause death with EQW with baseline HF (HR, 1.05 [95% CI, 0.85-1.29]), while the risk of mortality was reduced with EQW in the no-HF group (HR, 0.79 [95% CI, 0.68-0.92]) with an interaction P value of 0.031. The reduction in all-cause death or HHF seen with EQW in patients without baseline HF (HR, 0.81 [95% CI, 0.71-0.93]) was not seen in patients with baseline HF (HR, 1.07 [95% CI, 0.89-1.29]; interaction P=0.015). First, plus recurrent, HHF was reduced in the exenatide group versus placebo (HR, 0.82 [95% CI, 0.68-0.99]; P=0.038). In EXSCEL, the use of EQW in patients with or without HF was well tolerated, but benefits of EQW on reduction in all-cause death and first hospitalization for HF were attenuated in patients with baseline HF. https://www.clinicaltrials.gov. Unique identifier: NCT01144338.


Comparison between near retinoscopy and cycloplegic retinoscopy in the refraction of infants and children.
We investigated the validity of replacing cycloplegic retinoscopy with a noncycloplegic, "near" retinoscopy technique. We refracted a group of 31 infants (less than 2 years) and 43 children (greater than 2 years) with both techniques, grading our level of confidence in the result. Near retinoscopy gave on average a less hypermetropic result than cycloplegic retinoscopy by 0.39 D. The difference was significant in infants and for low levels of examiner confidence. However, a repeatability study showed that much of the variability in the infant group could be attributed to the poor repeatability of either retinoscopy technique. Agreement between the two techniques is improved by changing the suggested adjustment factor from 1.25 to 1.00 D for children and to 0.75 D for infants.


Entropy and volume change of dissociation in tobacco mosaic virus probed by high pressure.
Virus dissociation and inactivation by high pressure have been extensively studied in recent decades. Pressure-induced dissociation of viral particles involves a reduction in the Gibbs free energy of dissociation and a negative change in volume. In this work, we investigated the combined effect of high pressure and temperature on the dissociation of tobacco mosaic virus (TMV). We assumed the presence of two states of TMV with different tendencies to dissociate. Thus one form presents a low tendency (L) and the other a high tendency (H) to dissociate. Based on the model described here, the L-H transition was favored by an increase in pressure and a decrease in temperature. The volume change of dissociation was pressure- and temperature-dependent, with a highly negative value of -80 mL/mol being recorded at 0 °C and atmospheric pressure. The entropy and enthalpy of dissociation were very temperature- and pressure-dependent, with values of entropy of 450 to -1300 kJ/mol and values of enthalpy of 5.5 × 10(4) to 2.4 × 10(4) kJ/mol. The dissociation of TMV was enthalpy-driven at all temperatures and pressures investigated. Based on these findings, we conclude that the model presented allows accurate predictions of viral dissociation behavior in different experimental conditions.


A first look at multiple institutional affiliations: a study of authors in Germany, Japan and the UK.
This study sheds light on the unexplored phenomenon of multiple institutional affiliations using scientific publications. Institutional affiliations are important in the organisation and governance of science. Multiple affiliations may alter the traditional framework of academic employment and careers and may require a reappraisal of institutional assessment based on research outcomes of affiliated staff. Results for authors in three major science and technology nations (Germany, Japan and the UK) and in three fields (biology, chemistry, and engineering) show that multiple affiliations have at least doubled over the past few years. The analysis proposes three major types of multiple affiliations that depend on the structure of the research sector and its international openness. Highly internationalised and higher education-centred affiliations are most common for researchers in the UK whereas Germany and Japan have stronger cross-sector affiliation patterns. International multiple affiliations are, however, still more common in Germany compared to Japan which is characterised by a domestic, cross-sector affiliation distribution. Moreover, multiple affiliation authors are more often found on high impact papers, particularly in the case of authors from Japan and Germany in the fields of biology and chemistry.


Intake of Novel Red Clover Supplementation for 12 Weeks Improves Bone Status in Healthy Menopausal Women.
Objective. To investigate the effect by which daily consumption of a novel red clover (RC) extract influences bone health, inflammatory status, and cardiovascular health in healthy menopausal women. Design. A 12-week randomized, double-blinded, placebo-controlled trial involving 60 menopausal women receiving a daily dose of 150 mL RC extract containing 37.1 mg isoflavones (33.8 mg as aglycones) or placebo. Methods. Bone parameters were changes in bone mineral density (BMD), bone mineral content (BMC), and T-score at the lumbar spine and femoral neck. Bone turnover (CTx) and inflammatory markers were measured in plasma and finally blood pressure (BP) was evaluated. Results. RC extract had positive effect on bone health, and only the women receiving the placebo experienced a decline in BMD (p < 0.01) at the lumbar spine. T-score at the lumbar spine only decreased in the placebo group (p < 0.01). CTx decreased in the RC group with -9.94 (±4.93)%, although not significant. Conclusion. Daily consumption of RC extract over a 12-week period was found to have a beneficial effect on bone health in menopausal women based on BMD and T-score at the lumbar spine and plasma CTx levels. No changes in BP or inflammation markers were found and no side effects were observed.


Intermuscular coherence in Parkinson's disease: effects of subthalamic nucleus stimulation.
It remains unclear how high frequency stimulation of the subthalamic nucleus (STN) improves parkinsonism. We hypothesized that stimulation may affect the organization of the cortical drive to voluntarily activated muscle. Normally this is characterized by oscillations at 15-30 Hz, manifest in coherence between muscles in the same frequency band. We therefore investigated the effects of STN stimulation on electromyographic (EMG) activity in co-contracting distal arm muscles in nine subjects with Parkinson's disease off drugs. Without stimulation, coherence between EMG signals was diminished at 15-30 Hz compared with nine controls. STN stimulation increased coherence in the 15-30 Hz band, so that it approached that in healthy subjects. The results suggest that STN stimulation facilitates the normal cortical drive to muscles.


Biomarkers Related to Carotid Intima-Media Thickness and Plaques in Long-Term Survivors of Ischemic Stroke.
Lifestyle risk factors, inflammation and genetics play a role in the development of atherosclerosis. We therefore studied Fc gamma receptor (FcγR) polymorphisms, interleukin (IL)-10 polymorphisms and other biomarkers related to carotid intima-media thickness (cIMT) in patients with ischemic stroke at a young age. Patients were evaluated 12 years after stroke occurrence. Patients (n = 232) 49 years of age or younger with an index stroke between 1988 and 1997 were retrospectively selected. Blood samples were taken at a first follow-up 6 years after the stroke. At a second follow-up, additional arterial events were registered for 140 patients, new blood samples were taken, and measurements of cIMT and blood pressure (BP) were performed. Unadjusted logistic regression analysis showed that cIMT ≥1 mm was associated with age, male gender, additional arterial events, BP, cholesterol, sedimentation rate, haemoglobin, triglycerides, creatinine, glycolysed haemoglobin (HbA1c) and FcγRIIIB-NaII/NaII. Adjusted backward stepwise logistic regression showed significance for age (odds ratio (OR) 1.13, 95% confidence interval (CI) 1.04 to1.23, p = 0.003), male gender (OR 4.07, 95% CI 1.15 to 14.5, p = 0.030), HbA1c (OR 6.65, 95% CI 1.21 to 36.5, p = 0.029) and FcγRIIIB-NaII/NaII (OR 3.94, 95% CI 1.08 to 14.3, p = 0.037). In this long-term follow-up study of patients with ischemic stroke at a young age, FcγRIIIB-NaII/NaII was identified as a possible contributing factor for cIMT ≥1 mm together with known risk factors, such as age, male gender, systolic BP, additional arterial events and HbA1c.


Introductory experiments on ligand liposomes as delivery agents for boron neutron capture therapy.
Liposomes are, when coupled to receptor ligands, candidates for receptor mediated delivery of boron for tumour therapy since they have capacity to deliver large amounts of boron per receptor interaction. With EGF-liposomes we present a pegylated ligand liposome delivery vehicle, containing water soluble boronated phenanthridine, WSP1, or water soluble boronated acridine, WSA1, for EGFR targeting. In the case of WSA1 a ligand dependent uptake was obtained and the boron uptake was as good as if free WSA1 was given. No ligand dependent boron uptake was seen for WSP1 containing liposomes. Thus, WSA1 is a candidate for further studies. Approximately 10(5) boron atoms were in each liposome. A critical assessment indicates that after optimization up to 10(6) boron atoms can be loaded. Since it is known that, for therapeutic effect, approximately 10(8)-10(9) boron atoms are needed in a single tumour cell it is realized that 10(2)-10(3) receptor interactions are needed to meet the demand. Tests applying cultured glioma cells indicate, without optimization of the delivery conditions, a boron uptake in the ppm range, which is necessary for successful BNCT. Thus, it seems possible to kill micro-invasive tumour cells with targeted liposomes if the delivery conditions are optimal.


Intrinsic pathway-mediated apoptosis in elastase-induced aneurysms in rabbits.
The pathophysiology of saccular aneurysms is complex and multifactorial. The aim of the present study was to understand the mechanism of apoptosis in an elastase-induced aneurysm model in rabbits. Elastase-induced saccular aneurysms were created at the origin of the right common carotid artery in 20 rabbits. Aneurysm samples were harvested at 2 and 12 weeks after creation. Expression of apoptosis-associated proteins, including caspases and bcl-2 proteins, were assessed by Western blot analysis (n = 5 at both time points). Terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling (TUNEL) staining, which indicates the presence of apoptosis, was performed in tissue sections (n = 5 at both time points). The unoperated contralateral common carotid artery was used as a control. Expression of active caspase-3, the final executioner of apoptosis, and caspase-9, the mediator of the intrinsic mitochondrial pathway, was observed in aneurysms at 2 weeks, whereas the expression of activated caspase-8, the mediator of the extrinsic death receptor pathway, was absent at both time points. Expression of antiapoptotic proteins, Bcl-2 and phospho-Bad, was down-regulated in aneurysms compared with controls at 2 weeks. None of these proteins were differentially expressed at 12 weeks. These results were confirmed by the presence of TUNEL-positive cells in some aneurysms at the early time point. In this study of elastase-induced aneurysms in a rabbit model, activation of apoptosis is mediated predominantly by the Bcl-2-mediated intrinsic pathway through the activation of caspase-9.


Preclinical Evaluation of Antiurolithiatic Activity of Viburnum opulus L. on Sodium Oxalate-Induced Urolithiasis Rat Model.
The aim of the present research is to evaluate the antiurolithiatic effect of the various extracts prepared from the fruits of Viburnum opulus L., in regard to its ethnobotanical record. To induce urolithiasis, 70 mg/kg sodium oxalate was injected to the rats which were housed individually in metabolic cages. The test materials were applied during 7 days. Biochemical (urine and serum parameters), histopathological and antioxidant (TBARs, TSH and GSH) assays were conducted. The urine samples were examined by light microscope for the determination of the calcium oxalate crystals. Lyophilized juice of V. opulus (LJVO) and lyophilized commercial juice of V. opulus (LCJVO) exerted potential antiurolithiatic activity which was attributed to its diuretic effect along with the inhibitory action on the oxalate levels and free radical production. We also determined the chlorogenic acid content of the LJVO by high-performance liquid chromatography (HPLC). Chlorogenic acid was determined by using Supelcosil LC-18 (250 × 4.6 mm, 5 µm) column and acetonitrile: water: 0.2% o-phosphoric acid as a mobile phase. The chlorogenic acid content of V. opulus was found to be 0.3227 mg/mL in fruit juice. The results obtained in this study have provided a scientific evidence for the traditional usage of V. opulus on passing kidney stones in Turkish folk medicine.


Search for the centrally active component of Icacina trichantha tuber.
The chloroform extract of Icacina trichantha tuber was obtained after defatting with petroleum ether by overnight maceration. The extract gave a yield of 0.67% w/w after drying in a hot air oven at 40 °C. The dried residue was extracted with 50% methanol and gave a yield of 4.8% w/w. An extract of the freshly dried tuber with 50% methanol gave a yield of 4.98% w/w. The chloroform extract potentiated pentobarbitone induced sleeping time in mice dose-dependently. It also induced significant analgesia and muscle relaxant effects in mice. Mice poisoned with a convulsive dose (100 mg/kg) of pentylenetetrazole were significantly (60%) protected by the chloroform extract. Proportionate doses of the extracts based on their percentage yields were comparatively tested for analgesia in mice and the results obtained showed that the chloroform fraction alone exhibited almost the entire CNS activity.


Multisensory contributions to the perception of motion.
The ability to process motion is crucial for coherent perception and action. While the majority of studies have focused on the unimodal factors that influence motion perception (see, for example, the other chapters in this Special Issue), some researchers have also investigated the extent to which information presented in one sensory modality can affect the perception of motion for stimuli presented in another modality. Although early studies often gave rise to mixed results, the development of increasingly sophisticated psychophysical paradigms are now enabling researchers to determine the spatiotemporal constraints on multisensory interactions in the perception of motion. Recent findings indicate that these interactions stand over-and-above the multisensory interactions documented previously for static stimuli, such as the oft-cited 'ventriloquism' effect. Neuroimaging and neuropsychological studies are also beginning to elucidate the network of neural structures responsible for the processing of motion information in the different sensory modalities, an important first step that will ultimately lead to the determination of the neural substrates underlying these multisensory contributions to motion perception.


Eslicarbazepine and the enhancement of slow inactivation of voltage-gated sodium channels: a comparison with carbamazepine, oxcarbazepine and lacosamide.
This study aimed at evaluating the effects of eslicarbazepine, carbamazepine (CBZ), oxcarbazepine (OXC) and lacosamide (LCM) on the fast and slow inactivated states of voltage-gated sodium channels (VGSC). The anti-epileptiform activity was evaluated in mouse isolated hippocampal slices. The anticonvulsant effects were evaluated in MES and the 6-Hz psychomotor tests. The whole-cell patch-clamp technique was used to investigate the effects of eslicarbazepine, CBZ, OXC and LCM on sodium channels endogenously expressed in N1E-115 mouse neuroblastoma cells. CBZ and eslicarbazepine exhibit similar concentration dependent suppression of epileptiform activity in hippocampal slices. In N1E-115 mouse neuroblastoma cells, at a concentration of 250 μM, the voltage dependence of the fast inactivation was not influenced by eslicarbazepine, whereas LCM, CBZ and OXC shifted the V0.5 value (mV) by -4.8, -12.0 and -16.6, respectively. Eslicarbazepine- and LCM-treated fast-inactivated channels recovered similarly to control conditions, whereas CBZ- and OXC-treated channels required longer pulses to recover. CBZ, eslicarbazepine and LCM shifted the voltage dependence of the slow inactivation (V0.5, mV) by -4.6, -31.2 and -53.3, respectively. For eslicarbazepine, LCM, CBZ and OXC, the affinity to the slow inactivated state was 5.9, 10.4, 1.7 and 1.8 times higher than to the channels in the resting state, respectively. In conclusion, eslicarbazepine did not share with CBZ and OXC the ability to alter fast inactivation of VGSC. Both eslicarbazepine and LCM reduce VGSC availability through enhancement of slow inactivation, but LCM demonstrated higher interaction with VGSC in the resting state and with fast inactivation gating.


High Frequency of Detection by PCR of Viral Nucleic Acid in The Blood of Infants Presenting with Clinical Myocarditis.
Specific viruses are associated with pediatric myocarditis, but the prevalence of viral DNAemia detected by blood polymerase chain reaction (PCR) is unknown. We evaluated the prevalence of known cardiotropic viruses (enterovirus, adenovirus, human herpesvirus 6, and parvovirus B19) in children with clinical myocarditis (n = 21). Results were compared to pediatric controls with similar viral PCR testing. The majority of positive PCR (89 %) was noted in children ≤12 months of age at diagnosis compared to older children. Infant myocarditis patients (8/10) had increased the prevalence of PCR positivity compared to infant pediatric controls (4/114) (p < 0.0001). Other than age, patient characteristics at diagnosis were similar between PCR-positive and PCR-negative patients. Both PCR-negative myocarditis infants had clinical recovery at follow-up. Of the PCR-positive myocarditis infants, 4 had clinical recovery, 2 developed chronic cardiomyopathy, 1 underwent heart transplant, and 1 died. Infants with clinical myocarditis have a high rate of blood viral positivity, which is higher compared to older children with myocarditis and healthy infant controls. Age-related differences in PCR positivity may be due to differences in host and/or virus characteristics. Our findings suggest that viral blood PCR may be a useful diagnostic tool and identify patients who would potentially benefit from virus-specific therapy.


Self-Regulation and Executive Function Longitudinally Predict Advanced Learning in Preschool.
While the early years are often regarded as a critical period for establishing and supporting the developmental trajectories of delayed and typically developing children, they also represent a critical time for advanced learners. Yet to support advanced learners, a better understanding of sources and mechanisms of precocious early learning is needed. While there is ample research separately indicating importance of executive functions (EFs) and self-regulation for learning more broadly, it remains unclear whether, which, and to what extent EFs and/or self-regulation might account for the incidence of advanced learning in the prior-to-school years. The current study sought to investigate the EFs and self-regulation of 214 3- to 5-year old preschoolers, to better understand the profile of these abilities amongst advanced compared to non-advanced learners. Measures of self-regulation, EF and academic learning were taken at the start of the final pre-school year, and academic learning was assessed again at the end of the year. Results indicated that consistently advanced learning was predicted by socio-demographic factors (age, socioeconomic context), stronger cognitive development (combined EFs, cognitive aspects of self-regulation), yet lower behavioral self-regulation ratings. Results thus identify a profile of cognitive and behavioral characteristics of advanced early learners, which potentiates early identification and helps to clarify the nature and underpinnings of advanced early learning. It also raises questions about whether lower levels of behavioral self-regulation might constrain learning (e.g., difficulty remaining within the structures and sequences of the situation) or is a hallmark that is promotive of learning (e.g., convergent thinking, creativity).


Erinacine A Prevents Lipopolysaccharide-Mediated Glial Cell Activation to Protect Dopaminergic Neurons against Inflammatory Factor-Induced Cell Death In Vitro and In Vivo.
Hericium erinaceus (HE) is a common edible mushroom consumed in several Asian countries and considered to be a medicinal mushroom with neuroprotective effects. Erinacine A (EA) is a bioactive compound in Hericium erinaceus mycelium (HEM) that has been shown to have a neuroprotective effect against neurodegenerative diseases, e.g., Parkinson's disease (PD). Although the etiology of PD is still unclear, neuroinflammation may play an important role in causing dopaminergic neuron loss, which is a pathological hallmark of PD. However, glial cell activation has a close relationship with neuroinflammation. Thus, this study aimed to investigate the anti-neuroinflammatory and neuroprotective effects of EA on lipopolysaccharide (LPS)-induced glial cell activation and neural damage in vitro and in vivo. For the in vitro experiments, glial cells, BV-2 microglial cells and CTX TNA2 astrocytes were pretreated with EA and then stimulated with LPS and/or IFN-γ. The expression of proinflammatory factors in the cells and culture medium was analyzed. In addition, differentiated neuro-2a (N2a) cells were pretreated with EA or HEM and then stimulated with LPS-treated BV-2 conditioned medium (CM). The cell viability and the amount of tyrosine hydroxylase (TH) and mitogen-activated protein kinases (MAPKs) were analyzed. In vivo, rats were given EA or HEM by oral gavage prior to injection of LPS into the substantia nigra (SN). Motor coordination of the rats and the expression of proinflammatory mediators in the midbrain were analyzed. EA pretreatment prevented LPS-induced iNOS expression and NO production in BV-2 cells and TNF-α expression in CTX TNA2 cells. In addition, both EA and HEM pretreatment significantly increased cell viability and TH expression and suppressed the phosphorylation of JNK and NF- κB in differentiated N2a cells treated with CM. In vivo, both EA and HEM significantly improved motor dysfunction in the rotarod test and the amphetamine-induced rotation test and reduced the expression of TNF-α, IL-1β and iNOS in the midbrain of rats intranigrally injected with LPS. The results demonstrate that EA ameliorates LPS-induced neuroinflammation and has neuroprotective properties.


Pain and its clinical associations in individuals with cystic fibrosis: A systematic review.
Pain is recognized as a clinical complication in cystic fibrosis (CF), but the prevalence, characteristics and clinical associations of this co-morbidity have not been systematically reviewed. Electronic searches of six databases were performed. For inclusion in phase 1, studies reported a pain prevalence rate in CF and/or its clinical associations. For phase 2, included studies reported the measurement properties of validity, reliability and responsiveness of an instrument assessing pain in CF. Two independent reviewers rated the quality of evidence (phase 1) and the measurement properties using the 4-point COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist (phase 2). Of the 400 studies identified in the literature, 16 met the inclusion criteria for phase 1 and 5 for phase 2. The mean (SD) quality score (of 16) was 11.8 (2.3). The pooled prevalence of pain in adults with CF was 77% (95% confidence interval (CI): 57%-92%) and in children was 42% (95% CI: 0%-91%). Common regions of pain included back, abdomen, chest and limbs. In children and adults, pain was associated with a poorer quality of life (QOL) and significant interference with treatments. Measurement properties of three instruments (Brief Pain Inventory, Multidimensional Pain Inventory, Daily Pain Assessment-CF) were construct validity and criterion-predictive validity, with variable findings based on 'fair' to 'good' quality studies. Pain is a common problem in both children and adults with CF. It has negative clinical associations with QOL and the ability to successfully undertake treatment. Further research exploring the measurement properties of instruments assessing pain is required.


Information and care: A relational approach.
This article explores how the provision of information about dementia impacts on carers and the caring relationships in which they are involved. Narrative interviews were undertaken with 25 carers who had undertaken the Alzheimer's Society - run Carer Information and Support Programme in one of seven sites across London and the South East. Thematic analysis identified two major themes relating to the impact of information on carer and caring relationships ('understanding and care' and 'emotional impact of information'), and another theme relating to the context within which the information was provided and shared ('relational practices in information-giving and receiving'). Findings suggest that while information, particularly in the form of new knowledge about how dementia progresses, helps to improve understanding and increase confidence, competence and a sense of security and achievement in caring practices, it can also confound and complicate caring practices in ways that reflect and reinforce previously difficult relationships. Providing information in the context of carers' support was important for most participants but others were less able to benefit from this, especially where they felt unrecognised or where the timing of information felt inappropriate to their needs. Our analysis complements and extends previous scholarship emphasising the relational nature of care by showing how information can both enhance and complicate care relationships, depending on both specific care contexts and on how carers experience the context of information provision.


Divergent brain gene expression profiles between alternative behavioural helper types in a cooperative breeder.
Juveniles of the cooperatively breeding cichlid fish Neolamprologus pulcher either consistently provide help in form of alloparental egg care ("cleaners") or consistently abstain from helping ("noncleaners"). These phenotypes are not based on heritable genetic differences. Instead, they arise during ontogeny, which should lead to differences in brain structure or physiology, a currently untested prediction. We compared brain gene expression profiles of cleaners and noncleaners in two experimental conditions, a helping opportunity and a control condition. We aimed to identify (a) expression differences between cleaners and noncleaners in the control, (b) changes in gene expression induced by the opportunity and (c) differences in plasticity of gene expression between cleaners and noncleaners. Control cleaners and noncleaners differed in the expression of a single gene, irx2, which regulates neural differentiation. During the opportunity, cleaners and noncleaners had three upregulated genes in common, which were implicated in neuroplasticity, hormonal signalling and cell proliferation. Thus, the stimulus in the opportunity was sufficiently salient. Cleaners also showed higher expression of seven additional genes that were unique to the opportunity. One of these cleaner-specific genes is implicated in neuropeptide metabolism, indicating that this process is associated with cleaning performance. This suggests that the two types employed different pathways to integrate social information, preparing them for accelerated reaction to future opportunities. Interestingly, three developmental genes were downregulated between the control and the opportunity in cleaners only. Our results indicate that the two behavioural types responded differently to the helping opportunity and that only cleaners responded by downregulating developmental genes.


Inflammation in the Pathophysiology and Therapy of Cardiometabolic Disease.
The role of chronic inflammation in the pathogenesis of type 2 diabetes mellitus and associated complications is now well established. Therapeutic interventions counteracting metabolic inflammation improve insulin secretion and action and glucose control and may prevent long-term complications. Thus, a number of anti-inflammatory drugs approved for the treatment of other inflammatory conditions are evaluated in patients with metabolic syndrome. Most advanced are clinical studies with IL-1 antagonists showing improved β-cell function and glycemia and prevention of cardiovascular diseases and heart failure. However, alternative anti-inflammatory treatments, alone or in combinations, may turn out to be more effective, depending on genetic predispositions, duration, and manifestation of the disease. Thus, there is a great need for comprehensive and well-designed clinical studies to implement anti-inflammatory drugs in the treatment of patients with metabolic syndrome and its associated conditions.


Age-related changes in cortical connectivity influence the neuromodulatory effects of transcranial electrical stimulation.
Transcranial electrical stimulation (tES) is a potentially viable tool for boosting cognitive performance in aging. However, most knowledge on tES effects is based on studies involving young adults. Here, we applied tES (transcranial random noise stimulation [tRNS] as an effective stimulation and anodal transcranial direct current stimulation [atDCS] as a "control" stimulation) to the visual cortex during visual perceptual learning (VPL) in healthy young and older individuals. Moreover, we measured transcranial magnetic stimulation-evoked potentials to investigate the neurophysiological underpinnings of tES effects. We found that only the tRNS in the young, but not in the older, subjects modulated VPL, by decreasing performance. Transcranial magnetic stimulation-evoked potentials revealed age-related changes in connectivity, that is, a stronger activation of the prefrontal cortex after visual cortex stimulation, and a stronger modulation of the prefrontal cortex after VPL in the older subjects. These results may indicate that task performance in older adults relies on the recruitment of a wider network and a crucial contribution of the anterior portion of the brain, which may dramatically influence tES effects in aging.


Extracting and visualizing physiological parameters using dynamic contrast-enhanced magnetic resonance imaging of the breast.
An analysis procedure is presented that enables the acquisition and visualization of physiologically relevant parameters using dynamic contrast-enhanced magnetic resonance imaging. The first stage of the process involves the use of a signal model that relates the measured magnetic resonance signal to the contrast agent concentration. Since the model requires knowledge of the longitudinal relaxation time T(1), a novel optimization scheme is presented which ensures a reliable measurement. Pharmacokinetic modelling of the observed contrast agent uptake is then performed to obtain physiological parameters relating to microvessel leakage permeability and volume fraction and the assumptions made in the derivation of these parameters are discussed. A simple colour representation is utilized that enables the relevant physiological information to be conveyed to the clinician in a visually efficient and meaningful manner. A second representation, based on vector maps, is also devised and it is demonstrated how this can be used for malignant tumour segmentation. Finally, the procedure is applied to 14 pre- and post-chemotherapy breast cases to demonstrate the clinical value of the technique. In particular, the apparent improved representation of tissue vascularity when compared to conventional methods and the implications for this in treatment assessment are discussed.


Structure of the enabled/VASP homology 1 domain-peptide complex: a key component in the spatial control of actin assembly.
The Enabled/VASP homology 1 (EVH1; also called WH1) domain is an interaction module found in several proteins implicated in actin-based cell motility. EVH1 domains bind the consensus proline-rich motif FPPPP and are required for targeting the actin assembly machinery to sites of cytoskeletal remodeling. The crystal structure of the mammalian Enabled (Mena) EVH1 domain complexed with a peptide ligand reveals a mechanism of recognition distinct from that used by other proline-binding modules. The EVH1 domain fold is unexpectedly similar to that of the pleckstrin homology domain, a membrane localization module. This finding demonstrates the functional plasticity of the pleckstrin homology fold as a binding scaffold and suggests that membrane association may play an auxiliary role in EVH1 targeting.


Elevated NCOR1 disrupts a network of dietary-sensing nuclear receptors in bladder cancer cells.
Increasingly invasive bladder cancer cells lines displayed insensitivity toward a panel of dietary-derived ligands for members of the nuclear receptor superfamily. Insensitivity was defined through altered gene regulatory actions and cell proliferation and reflected both reduced receptor expression and elevated nuclear receptor corepressor 1 (NCOR1) expression. Stable overexpression of NCOR1 in sensitive cells (RT4) resulted in a panel of clones that recapitulated the resistant phenotype in terms of gene regulatory actions and proliferative responses toward ligand. Similarly, silencing RNA approaches to NCOR1 in resistant cells (EJ28) enhanced ligand gene regulatory and proliferation responses, including those mediated by peroxisome proliferator-activated receptor (PPAR) gamma and vitamin D receptor (VDR) receptors. Elevated NCOR1 levels generate an epigenetic lesion to target in resistant cells using the histone deacetylase inhibitor vorinostat, in combination with nuclear receptor ligands. Such treatments revealed strong-additive interactions toward the PPARgamma, VDR and Farnesoid X-activated receptors. Genome-wide microarray and microfluidic quantitative real-time, reverse transcription-polymerase chain reaction approaches, following the targeting of NCOR1 activity and expression, revealed the selective capacity of this corepressor to govern common transcriptional events of underlying networks. Combined these findings suggest that NCOR1 is a selective regulator of nuclear receptors, notably PPARgamma and VDR, and contributes to their loss of sensitivity. Combinations of epigenetic therapies that target NCOR1 may prove effective, even when receptor expression is reduced.


Ongoing hydrothermal activities within Enceladus.
Detection of sodium-salt-rich ice grains emitted from the plume of the Saturnian moon Enceladus suggests that the grains formed as frozen droplets from a liquid water reservoir that is, or has been, in contact with rock. Gravitational field measurements suggest a regional south polar subsurface ocean of about 10 kilometres thickness located beneath an ice crust 30 to 40 kilometres thick. These findings imply rock-water interactions in regions surrounding the core of Enceladus. The resulting chemical 'footprints' are expected to be preserved in the liquid and subsequently transported upwards to the near-surface plume sources, where they eventually would be ejected and could be measured by a spacecraft. Here we report an analysis of silicon-rich, nanometre-sized dust particles (so-called stream particles) that stand out from the water-ice-dominated objects characteristic of Saturn. We interpret these grains as nanometre-sized SiO2 (silica) particles, initially embedded in icy grains emitted from Enceladus' subsurface waters and released by sputter erosion in Saturn's E ring. The composition and the limited size range (2 to 8 nanometres in radius) of stream particles indicate ongoing high-temperature (>90 °C) hydrothermal reactions associated with global-scale geothermal activity that quickly transports hydrothermal products from the ocean floor at a depth of at least 40 kilometres up to the plume of Enceladus.


NADH photo-oxidation is enhanced by a partially purified lambda-crystallin fraction from rabbit lens.
In the rabbit lens, high levels of reduced nicotinamide adenine dinucleotide (NADH) can function as a near-ultraviolet light (near-UV) filter, an effect apparently achieved by specific nucleotide binding to lambda-crystallin. The present investigation asks whether lambda-crystallin enhances NADH photo-oxidation by superoxide radicals produced via a photosensitization reaction of near-UV with NADH. Lambda-crystallin was partially purified from rabbit lens soluble fraction by a two-step gel filtration and affinity column chromatography procedure. NADH solutions with or without partially purified lambda-crystallin were subjected to near-UV irradiation or exposed to superoxide generated enzymatically by the xanthine/xanthine oxidase system. NADH oxidation was determined by assaying the decrease of absorbance at 340 nm. When irradiated with near-UV, free NADH was oxidized very little in the absence of lambda-crystallin. In contrast, NADH photo-oxidation was rapidly initiated in the presence of partially purified lambda-crystallin. This lambda-crystallin-enhanced NADH photo-oxidation was totally inhibited by adding superoxide dismutase. We also found that lambda-crystallin largely increased NADH oxidation by a superoxide that is generated enzymatically. These results indicate that NADH bound to lambda-crystallin rapidly reacts with superoxides. The reactivity of bound NADH with superoxide was almost equivalent to that of ascorbic acid. However, lambda-crystallin-enhanced NADH oxidation exceeded the superoxide levels generated by NADH photosensitization and xanthine/xanthine oxidase. We conclude that NADH binding to lambda-crystallin enhances NADH photo-oxidation through a radical chain reaction mechanism that is initiated by superoxides generated by NADH photosensitization and propagated by another superoxide from the molecule oxygen. High concentrations of NADH bound to lambda-crystallin may be beneficial to the rabbit lens in scavenging the low amounts of superoxide produced by near-UV absorption, since oxygen tension in the lens is very low. We also discuss the function of near-UV-filtering and the anti-photo-oxidation systems in other vertebrate lenses.


Compressive-force induced activation of apo-calmodulin in protein signalling.
Mechanical force plays a critical role in the relationship between protein structure and function. Force manipulation by Atomic Force Microscope can be significant and trigger chemical and biological activities of proteins. Previously we have reported that Apo-CaM undergoes through a spontaneous tertiary structural rupture under a piconewton compressive force. Here we have observed that the ruptured Apo-CaM molecules can be available to bind with C28W peptide, a typical protein signalling activity that only a Ca2+-activated CaM has. This behaviour is both unexpected and profound, as CaM in its Ca2+-non-activated form has a closed structure which does not presumably allow the molecule to bind to target peptides. In this experiment, we demonstrate that both chemical activation and force activation can play a vital role in biology, such as the cell-signalling protein dynamics and function.


Alternating current electrokinetic separation and detection of DNA nanoparticles in high-conductance solutions.
In biomedical research and diagnostics, it is a significant challenge to directly isolate and identify rare cells and potential biomarkers in blood, plasma and other clinical samples. Additionally, the advent of bionanotechnology is leading to numerous drug delivery approaches that involve encapsulation of drugs and imaging agents within nanoparticles, which now will also have to be identified and separated from blood and plasma. Alternating current (AC) electrokinetic techniques such as dielectrophoresis (DEP) offer a particularly attractive mechanism for the separation of cells and nanoparticles. Unfortunately, present DEP techniques require the dilution of blood/plasma, thus making the technology less suitable for clinical sample preparation. Using array devices with microelectrodes over-coated with porous hydrogel layers, AC electric field conditions have been found which allow the separation of DNA nanoparticles to be achieved under high-conductance (ionic strength) conditions. At AC frequencies in the 3000 Hz to 10,000 Hz range and 10 volts peak-to-peak, the separation of 10-microm polystyrene particles into low field regions, and 60-nm DNA-derivatized nanoparticles and 200-nm nanoparticles into high-field regions was carried out in 149 mM 1xPBS buffer (1.68 S/m). These results may allow AC electrokinetic systems to be developed that can be used with clinically relevant samples under physiological conditions.


Responses of the aphids Phorodon humuli and Rhopalosiphum padi to sex pheromone stereochemistry in the field.
Gynoparous female and male damson-hop aphids, Phorodon humuli (Schrank), were caught in the field by water traps that were releasing the sex pheromone of this species, (1RS,4aR,7S,7aS)-nepetalactol. No behavioral activity was elicited by (4aS,7S,7aR)-nepetalactone, the major sex pheromone component of other aphid species such as Megoura viciae Buckton, even though olfactory cells were found in the secondary rhinaria on the third antennal segment of P. humuli that responded strongly to this compound. Gynoparous female P. humuli in the field responded less strongly to (1R,4aS,7S,7aR)-nepetalactol, the sex pheromone of the bird cherry-oat aphid, Rhopalosiphum padi (L.), than they did to the (4aR,7S,7aS)-nepetalactols, but males responded only to the latter. The (4aR,7S,7aS)-nepetalactone showed no electrophysiological activity so was not used in field trials. Releasing either the (4aS,7S,7aR)-nepetalactone or the (1R,4aS,7S,7aR)-nepetalactol with the (4aR,7S,7aS)-nepetalactols did not inhibit the response of P. humuli gynoparous females and males to the latter. Males of R. padi responded as strongly to the (4aR,7S,7aS)-nepetalactols as they did to (1R,4aS,7S,7aR)-nepetalactol. Males of P. humuli and R. padi responded positively to an increased concentration of the (4aR,7S,7aS)-nepetalactols released from two vials compared with that from a single vial, as did P. humuli (in one of two experiments) and R. padi to the (1RS,4aR,7S,7aS)- and (1R,4aS,7S,7aR)-nepetalactols when released together.


A New Recombinant PACAP-Derived Peptide Efficiently Promotes Corneal Wound Repairing and Lacrimal Secretion.
A new recombinant pituitary adenylate cyclase-activating polypeptide (PACAP)-derived peptide, MPAPO, which has higher stability and PAC1-specific potency, was generated. The actions of MPAPO on corneal wound repairing and lacrimal secretion were examined. MPAPO was prepared and identified by gene recombination, high-performance liquid chromatography (HPLC), and electrospray ionization mass spectrometry (ESI-MS). Stability assay was performed by HPLC-ESI-MS. PAC1-specific binding and potency assays were performed using PAC1-CHO cells. C57BL/6 mice and Japanese white rabbits were respectively used to analyze the effects of MPAPO on corneal wound repairing and lacrimal fluid secretion. Tetrazolium-based colorimetric assay (MTT), immunofluorescence, gene microarrays, and Western blot assay were performed to measure the effects of MPAPO on corneal epithelial cell proliferation, synapse growth, and gene differential expression of trigeminal ganglion cells. As compared with the wild PACAP, the in vitro stability and PAC1-specific potency of MPAPO with four mutations (M17L, L27K and M, K, respectively, added to the N- and C-terminus) were increased approximately 31- and 2-fold, respectively. MPAPO can significantly promote the proliferation of mouse corneal epithelium cells and the synapse growth of trigeminal ganglion cells. In experimental animals, MPAPO performed a complete corneal epithelial wound closure in 30 hours and significantly inhibited corneal neovascularization, and the effects were obviously stronger than for wild PACAP and recombinant bovine (rb)-bFGF (an anti-corneal wound drug). Furthermore, MPAPO can increase the lacrimal secretion, which may efficiently improve dry eye. MPAPO may represent a promising external therapeutic peptide for corneal wound repairing or dry eye.


Benfotiamine in the treatment of diabetic polyneuropathy--a three-week randomized, controlled pilot study (BEDIP study).
The aim of the study was to evaluate the efficacy of benfotiamine administered over three weeks (allithiamine; a lipid-soluble vitamin B1 prodrug with high bioavailability) to patients with diabetic polyneuropathy in a randomized, placebo-controlled, double-blind, two-center pilot study. Forty inpatients (23 male, 18 female, age range 18 - 70 years) with a history of type 1 or 2 diabetes and polyneuropathy of not longer than two years, were included in the study. Twenty Patients received two 50 mg benfotiamine tablets four times daily and 20 patients received placebo over the three-week study period. Two clinical units were involved with 10 patients receiving placebo and 10 patients benfotiamine in each. The neuropathy score according to Katzenwadel et al. [1987] was used to evaluate symptoms of polyneuropathy, vibration perception threshold and both the physician's and the patient's own assessment were documented. A statistically significant (p = 0.0287) improvement in the neuropathy score was observed in the group given active drug when compared to the placebo-treated controls. There was no statistically significant change observed in the tuning fork test. The most pronounced effect on complaints was a decrease in pain (p = 0.0414). More patients in the benfotiamine-treated group than in the placebo group considered their clinical condition to have improved (p = 0.052). No side effects attributable to benfotiamine were observed. The differences between the groups cannot be attributed to a change in metabolic parameters since there were no significant alterations in the HbA1 levels and blood sugar profiles. The body mass index of the two groups did not differ. This pilot investigation (BEDIP Study) has confirmed the results of two earlier randomized controlled trials and has provided further evidence for the beneficial effects of benfotiamine in patients with diabetic neuropathy.


Response to the US FDA LeadCare Testing Systems Recall and CDC Health Alert.
On May 17, 2017, the Food and Drug Administration issued a safety recall for the Magellan Diagnostics' LeadCare Testing Systems due to the potential for inaccurately low blood lead test results when used with venous blood samples. Concurrently, the Centers for Disease Control and Prevention (CDC) issued a health alert with retesting recommendations for specific high-risk populations. The purpose of the CDC retesting recommendations was to help identify high-risk individuals so that those potentially impacted by falsely low test results could be retested and receive appropriate follow-up care. The CDC's Lead Poisoning Prevention Program sought to understand how the recall and recommendations impacted state and local public health agencies. Childhood lead poisoning prevention programs (CLPPPs) in state and local public health agencies collect blood lead test results for children and had a lead role in identifying children for retesting. Case studies are presented that highlight the experiences of 4 state CLPPPs in responding to the recall and recommendations. Collectively, the case studies point to several lessons learned, including the importance of (1) having a well-functioning surveillance system in place prior to a serious incident; (2) having a clear understanding of the roles partners play in the continuum of care for children potentially exposed to lead; and (3) ensuring effective communications with all staff, both internal and external, to public health agencies that have a role in responding to a serious incident. The ability to respond to public health emergencies or other serious incidents takes the combined effort of federal, state, and local public health agencies as well as others in the health care delivery system. The CDC will continue to support state and local lead poisoning prevention programs so that they have the information and tools they need to address and prevent the health effects of lead exposures in communities.