An outbreak of leptospirosis among kayakers in Brittany, North-West France, 2016.
In September 2016, a cluster of seven kayakers with clinical symptoms of leptospirosis with onset since July 2016 was reported to French health authorities. Human and animal investigations were undertaken to describe the outbreak, identify the likely place and source of infection and implement necessary control measures. We identified 103 patients with clinical symptoms of leptospirosis between 1 June and 31 October 2016 who lived in the Ille-et-Vilaine district in Brittany. Of these, 14 (including the original seven) reported contacts with the river Vilaine during the incubation period and were defined as outbreak cases: eight were confirmed by serology tests or PCR and six were probable without a laboratory confirmation for leptospirosis. All 14 cases were kayakers. Three distinct contamination sites were identified on a 30 km stretch of the river Vilaine. Nine cases reported having skin wounds while kayaking. None were vaccinated against leptospirosis. The outbreak was attributed to Leptospira kirschneri serogroup Grippotyphosa. Animal investigations did not allow identifying the possible reservoir. Leptospirosis outbreaks associated with freshwater sports are rare in temperate climates. The prevention of such outbreaks requires control of potential animal reservoirs in zones such as the Vilaine valley and that kayakers adopt the recommended individual prevention measures.


Associations of Ambient Temperature with Mortality Rates of Cardiovascular and Respiratory Diseases in Taiwan: A Subtropical Country.
We conducted a time-series analysis of daily ambient temperature and all-cause, cardiovascular, and respiratory disease mortality in Taiwan, which is generally neither extremely hot nor cold. Data on all-cause daily mortality rates (excluding accidents, suicide, and homicide), and mortality rates due to respiratory and cardiovascular diseases between 2008 and 2010 were obtained from the Taiwan Death Registry. The daily temperature for that period was averaged from 33 monitoring stations nationwide. A generalized least square model was constructed to assess the relationship between the time-series trends of temperature and mortality, and the cross-correlation function was used to determine the possible time lag for the effect of temperature on mortality. As the average temperature increased, the daily all-cause (β = -0.006) and respiratory disease (β = -0.012) mortality rates decreased. On the other hand, an inverse relationship (β = -0.028) between average daily temperature and cardiovascular disease mortality was observed only for a temperature between 12.91 °C and 26.36 °C. The time lag for all-cause and cardiovascular disease mortality was similar at 4-6 days, while the lag for respiratory disease was longer at 13-16 days. We found inverse associations between average temperature and all-cause and respiratory mortality. An inverse association between temperature and cardiovascular disease mortality was observed only from 12.91 °C to 26.36 °C.


Optimal chemotactic responses in stochastic environments.
Although the "adaptive" strategy used by Escherichia coli has dominated our understanding of bacterial chemotaxis, the environmental conditions under which this strategy emerged is still poorly understood. In this work, we study the performance of various chemotactic strategies under a range of stochastic time- and space-varying attractant distributions in silico. We describe a novel "speculator" response in which the bacterium compare the current attractant concentration to the long-term average; if it is higher then they tumble persistently, while if it is lower than the average, bacteria swim away in search of more favorable conditions. We demonstrate how this response explains the experimental behavior of aerobically-grown Rhodobacter sphaeroides and that under spatially complex but slowly-changing nutrient conditions the speculator response is as effective as the adaptive strategy of E. coli.


Neuroprotection by melatonin on astrocytoma cell death.
Glial cells play an active role in the homeostatic regulation of the central nervous system (CNS). Astrocytes, the most abundant glial cell types in the brain, provide mechanical and metabolic support for neurons. The regulation of astrocyte apoptosis, therefore, is important for physiological and pathological processes in the CNS. Melatonin is a neurohormone that regulates target cells via binding to specific high-affinity plasma membrane receptors, MT1/MT2. In addition to regulating circadian rhythms, melatonin has recently attracted much interest for its potential regulation of cell apoptosis. We recently showed that melatonin antagonizes apoptosis on U937 cells via intersecting signal transduction events involving binding to MT1/MT2 and activation of lipoxygenase. Here we describe the neuroprotective potential of melatonin, showing that melatonin significantly reduces damage-induced apoptosis in astrocytoma cells. The mechanism of protection is different from that shown in U937 cells, because it does not involve MT1/MT2 or lipoxygenase; likewise, Ca(2+) influx is not involved. Intriguingly, inhibition of phospholipase C (PLC) with neomycin reverses melatonin protection, suggesting that a PLC-dependent signal transduction, different from that triggered by MT1/MT2, is involved in the antiapoptotic pathway of melatonin.


A chemical and genetic approach to the mode of action of fumagillin.
Previous mode of action studies identified methionine aminopeptidase 2 (MetAP-2) as the target of the antiangiogenic natural product fumagillin and its drug candidate analog, TNP-470. We report here that TNP-470-mediated MetAP-2 inhibition blocks noncanonical Wnt signaling, which plays a critical role in development, cell differentiation, and tumorigenesis. Consistent with this finding, antisense MetAP-2 morpholino oligonucleotide injection in zebrafish embryos phenocopies gastrulation defects seen in noncanonical Wnt5 loss-of-function zebrafish mutants. MetAP-2 inhibition or depletion blocks signaling downstream of the Wnt receptor Frizzled, but upstream of Calmodulin-dependent Kinase II, RhoA, and c-Jun N-terminal Kinase. Moreover, we demonstrate that TNP-470 does not block the canonical Wnt/beta-catenin pathway. Thus, TNP-470 selectively regulates noncanonical over canonical Wnt signaling and provides a unique means to explore and dissect the biological systems mediated by these pathways.


Mechanoluminescent, Air-Dielectric MoS2 Transistors as Active-Matrix Pressure Sensors for Wide Detection Ranges from Footsteps to Cellular Motions.
Tactile pressure sensors as flexible bioelectronic devices have been regarded as the key component for recently emerging applications in electronic skins, health-monitoring devices, or human-machine interfaces. However, their narrow range of sensible pressure and their difficulty in forming high integrations represent major limitations for various potential applications. Herein, we report fully integrated, active-matrix arrays of pressure-sensitive MoS2 transistors with mechanoluminescent layers and air dielectrics for wide detectable range from footsteps to cellular motions. The inclusion of mechanoluminescent materials as well as air spaces can increase the sensitivity significantly over entire pressure regimes. In addition, the high integration capability of these active-matrix sensory circuitries can enhance their spatial resolution to the level sufficient to analyze the pressure distribution in a single cardiomyocyte. We envision that these wide-range pressure sensors will provide a new strategy toward next-generation electronics at biomachine interfaces to monitor various mechanical and biological phenomena at single-cell resolution.


Experiencing and perceiving visual surfaces.
A theoretical framework is proposed to understand binocular visual surface perception based on the idea of a mobile observer sampling images from random vantage points in space. Application of the generic sampling principle indicates that the visual system acts as if it were viewing surface layouts from generic not accidental vantage points. Through the observer's experience of optical sampling, which can be characterized geometrically, the visual system makes associative connections between images and surfaces, passively internalizing the conditional probabilities of image sampling from surfaces. This in turn enables the visual system to determine which surface a given image most strongly indicates. Thus, visual surface perception can be considered as inverse ecological optics based on learning through ecological optics. As such, it is formally equivalent to a degenerate form of Bayesian inference where prior probabilities are neglected.


Peripapillary retinal nerve fiber layer thickness in hyperopic children.
To evaluate the relationship between the spherical equivalent (SE)/axial length and peripapillary retinal nerve fiber layer (RNFL) thickness profile measured using Stratus optical coherence tomography (OCT) in hyperopic children. One hundred and sixty-four children with hyperopia were analyzed in the study. Subjects were divided into three groups according to their SE values: +3.00 D ≥ SE ≥ +0.50 D were designated as the low hyperopia group, +6.00 D ≥ SE ≥ +3.25 D as moderate hyperopia group, and +9.50 D ≥ SE ≥ 6.25 D as high hyperopia group. RNFL thickness measurements were taken from the superior, inferior, nasal, and temporal quadrants in the peripapillary region by Stratus OCT. Axial length, visual acuity, and SE values were also determined for all patients. There were 62 patients in the low hyperopia group, 60 patients in the moderate hyperopia group, and 42 patients in the high hyperopia group. The groups were similar concerning age and gender. The moderate and high hyperopia groups had lower mean BCVAs than low hyperopic group (both p < 0.001). SE and axial length were significantly different among all three groups (all p < 0.001). There were significant differences between low and high hyperopia groups concerning the mean RNFL thickness and the RNFL thicknesses of inferior and nasal quadrants (p = 0.045, p = 0.008, p = 0.03, respectively). However, when magnification attributable to SE/axial length is taken into account, the RNFL thickness differences disappear. We have demonstrated that when measured using the Stratus OCT, which does not take magnification into account, measurements erroneously indicate that children with high hyperopia had thicker RNFLs in inferior and nasal quadrants than children with low hyperopia. The current Stratus OCT normative database may be misleading for correct diagnosis of glaucoma in highly hyperopic children.


Metformin delays neurological symptom onset in a mouse model of neuronal complex I deficiency.
Complex I (also known as NADH-ubiquinone oxidoreductase) deficiency is the most frequent mitochondrial disorder present in childhood. NADH-ubiquinone oxidoreductase iron-sulfur protein 3 (NDUFS3) is a catalytic subunit of the mitochondrial complex I; NDUFS3 is conserved from bacteria and essential for complex I function. Mutations affecting complex I, including in the Ndufs3 gene, cause fatal neurodegenerative diseases, such as Leigh syndrome. No treatment is available for these conditions. We developed and performed a detailed molecular characterization of a neuron-specific Ndufs3 conditional KO mouse model. We showed that deletion of Ndufs3 in forebrain neurons reduced complex I activity, altered brain energy metabolism, and increased locomotor activity with impaired motor coordination, balance, and stereotyped behavior. Metabolomics analyses showed an increase of glycolysis intermediates, suggesting an adaptive response to the complex I defect. Administration of metformin to these mice delayed the onset of the neurological symptoms but not of neuronal loss. This improvement was likely related to enhancement of glucose uptake and utilization, which are known effects of metformin in the brain. Despite reports that metformin inhibits complex I activity, our findings did not show worsening a complex I defect nor increases in lactic acid, suggesting that metformin should be further evaluated for use in patients with mitochondrial encephalopathies.


ACTH Prevents Deficits in Fear Extinction Associated with Early Life Seizures.
Early life seizures (ELS) are often associated with cognitive and psychiatric comorbidities that are detrimental to quality of life. In a rat model of ELS, we explored long-term cognitive outcomes in adult rats. Using ACTH, an endogeneous HPA-axis hormone given to children with severe epilepsy, we sought to prevent cognitive deficits. Through comparisons with dexamethasone, we sought to dissociate the corticosteroid effects of ACTH from other potential mechanisms of action. Although rats with a history of ELS were able to acquire a conditioned fear learning paradigm and controls, these rats had significant deficits in their ability to extinguish fearful memories. ACTH treatment did not alter any seizure parameters but nevertheless was able to significantly improve this fear extinction, while dexamethasone treatment during the same period did not. This ACTH effect was specific for fear extinction deficits and not for spatial learning deficits in a water maze. Additionally, ACTH did not alter seizure latency or duration suggesting that cognitive and seizure outcomes may be dissociable. Expression levels of melanocortin receptors, which bind ACTH, were found to be significantly lower in animals that had experienced ELS than in control animals, potentially implicating central melanocortin receptor dysregulation in the effects of ELS, and suggesting a mechanism of action for ACTH. Taken together, these data suggest that early treatment with ACTH can have significant long-term consequences for cognition in animals with a history of ELS independently of seizure cessation and may act in part through a CNS melanocortin receptor pathway.


Empirical Bayes Estimation of Coalescence Times from Nucleotide Sequence Data.
We demonstrate the advantages of using information at many unlinked loci to better calibrate estimates of the time to the most recent common ancestor (TMRCA) at a given locus. To this end, we apply a simple empirical Bayes method to estimate the TMRCA. This method is both asymptotically optimal, in the sense that the estimator converges to the true value when the number of unlinked loci for which we have information is large, and has the advantage of not making any assumptions about demographic history. The algorithm works as follows: we first split the sample at each locus into inferred left and right clades to obtain many estimates of the TMRCA, which we can average to obtain an initial estimate of the TMRCA. We then use nucleotide sequence data from other unlinked loci to form an empirical distribution that we can use to improve this initial estimate.


Peripheral mucociliary clearance with high-frequency chest wall compression.
We investigated the effects of high-frequency chest wall compression (HFCWC) on peripheral and tracheal mucus clearance in anesthetized spontaneously breathing dogs. HFCWC was achieved by oscillating the pressure in a thoracic cuff with a piston pump. Regional lung retention of a technetium-99m sulfur colloid aerosol was monitored with a gamma camera. A peripheral mucus clearance index (PMCI) was defined for each region of interest. The tracheal mucus clearance rate (TMCR) was determined by bronchoscopic visualization of marker particle transport. Phase I: In seven dogs, 30 min of HFCWC at 13 Hz with peak cuff pressure (Pcuff) 100-120 cmH2O was found to significantly enhance PMCI in regions immediately under the cuff. (delta PMCI = 24.4 +/- 4.6 in the basal peripheral region.) Phase II: Because of subpleural hemorrhage in phase I, the effect of HFCWC on TMCR at various Pcuff levels was studied in five dogs. The enhancement of TMCR by HFCWC reached a plateau level at Pcuff = 50 cmH2O. Phase III: HFCWC at 13 Hz with Pcuff = 50-60 cmH2O was found to significantly enhance PMCI in five dogs without the consequence of hemorrhage. Correlations were found between the enhancement of PMCI and TMCR by HFCWC. These results demonstrate that HFCWC is effective in enhancing both peripheral and central mucus clearance in dogs and safe when moderate pressures are applied.


Serum lipids four weeks after acute myocardial infarction are a valid basis for lipid lowering intervention in patients receiving thrombolysis.
To compare serum concentrations of total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, and triglycerides four weeks after acute myocardial infarction with baseline levels measured within 24 hours after onset of symptoms. A prospective study including 141 patients with acute myocardial infarction who were admitted to the coronary care unit at a general hospital. Fasting serum concentrations of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides. In patients receiving thrombolytic therapy, no significant differences were found in serum lipids four weeks after admission compared to values estimated within 24 hours from onset of symptoms. In patients not receiving thrombolytic therapy, total cholesterol and low density lipoprotein cholesterol showed a minor increase four weeks after admission compared to values obtained within 24 hours after onset of symptoms. High density lipoprotein cholesterol and triglycerides remained unchanged. In patients with acute myocardial infarction receiving thrombolytic therapy, serum lipids measured four weeks after onset of infarction are reasonably valid estimates of baseline lipid levels and may be used to decide about lipid lowering interventions. This information can be a basis for actions against hyperlipidaemia early after hospital discharge when the patient is highly motivated to change lifestyles and is still in close contact with a cardiologist or other physician.


Resistance in Alternaria alternata to SDHI Fungicides Causes Rare Disease Outbreak in Peach Orchards.
Alternaria rot, caused by Alternaria alternata, was observed in commercial peach orchards in South Carolina. Single-spore isolates formed two phenotypically different culture morphologies on two artificial media. Isolates highly resistant (HR) to boscalid were also HR to penthiopyrad. Among isolates HR and medium resistant (MR) to boscalid and penthiopyrad, we detected isolates that were MR to fluopyram and HR to fluxapyroxad. Sequence analysis of succinate dehydrogenase (sdh) genes sdhB, sdhC, and sdhD revealed that resistant phenotypes were associated with point mutations leading to amino acid substitutions. In particular, H277Y/R in the SDHB and H134R in SDHC were consistently associated with the boscalid HR phenotype. The highest effective concentration that inhibits growth by 50% (EC50) values to penthiopyrad were conferred by H134R and D123E, whereas H134R conferred low resistance and MR to fluxapyroxad. A previously undescribed mutation, G79R, was identified in our collection conferring HR to both boscalid and penthiopyrad. The point mutations associated with highest EC50 values to all four FRAC 7 fungicides were H277L and H134R. The outbreak of Alternaria rot demonstrates that fungicide programs containing "medium to high-risk fungicides" may promote disease outbreaks by secondary pathogens that typically are outcompeted or controlled effectively, while still controlling the primary target disease.


The Energy Expenditure of Free-Living Physical Activities in Primary Schoolchildren.
The aim of this study is to establish the energy expenditure (EE) of a range of child-relevant activities and to compare different methods of estimating activity MET. 27 children (17 boys) aged 9 to 11 years participated. Participants were randomly assigned to 1 of 2 routines of 6 activities ranging from sedentary to vigorous intensity. Indirect calorimetry was used to estimate resting and physical activity EE. Activity metabolic equivalent (MET) was determined using individual resting metabolic rate (RMR), the Harrell-MET and the Schofield equation. Activity EE ranges from 123.7± 35.7 J/min/Kg (playing cards) to 823.1 ± 177.8 J/min/kg (basketball). Individual RMR, the Harrell-MET and the Schofield equation MET prediction were relatively similar at light and moderate but not at vigorous intensity. Schofield equation provided a better comparison with the Compendium of Energy Expenditure for Youth. This information might be advantageous to support the development of a new Compendium of Energy Expenditure for Youth.


Management and spectrum of complications in patients undergoing surgical debridement for pancreatic necrosis.
Patients who undergo pancreatic necrosectomy frequently develop complications and often have high mortality rates. These patients are best cared for at specialized centers to minimize morbidity, manage complex complications, and reduce mortality. We present a review of our experience and describe the spectrum of complications encountered in managing of these difficult patients. A registry of patients undergoing pancreatic necrosectomy during a 7-year period was analyzed for preoperative clinical scoring systems (Acute Physiology and Chronic Health Evaluation [APACHE] II and APACHE III scores), patient characteristics related to necrosectomy, and morbidity and mortality. Twenty-nine patients underwent necrosectomy. Indications for surgery were consistent with those previously described. There were 27 complications in 22 patients. Sixteen complications were early (less than 3 weeks after surgery) and 14 were late. The mortality rate was 14 per cent. All deaths were in patients transferred from outside institutions, some after extended time periods. Temporary percutaneous catheter drainage of abscesses before transfer and definitive surgery appeared to reduce mortality in transferred patients. There was a statistically significant correlation between mean maximal preoperative APACHE III score, but not APACHE II score, and the number of postoperative intensive care unit days (rho = 0.52, P = 0.004). We describe our experience managing patients with infected pancreatic necrosis that required operative necrosectomy. We found that more severely ill patients (higher APACHE III scores) had longer intensive care unit stays, but the initial severity of their illness did not increase mortality. If patients with infected pancreatic necrosis are referred to specialized centers, preoperative pretransfer percutaneous drainage may serve to temporarily control sepsis.


Benchmarking parameter-free AMaLGaM on functions with and without noise.
We describe a parameter-free estimation-of-distribution algorithm (EDA) called the adapted maximum-likelihood Gaussian model iterated density-estimation evolutionary algorithm (AMaLGaM-ID[Formula: see text]A, or AMaLGaM for short) for numerical optimization. AMaLGaM is benchmarked within the 2009 black box optimization benchmarking (BBOB) framework and compared to a variant with incremental model building (iAMaLGaM). We study the implications of factorizing the covariance matrix in the Gaussian distribution, to use only a few or no covariances. Further, AMaLGaM and iAMaLGaM are also evaluated on the noisy BBOB problems and we assess how well multiple evaluations per solution can average out noise. Experimental evidence suggests that parameter-free AMaLGaM can solve a wide range of problems efficiently with perceived polynomial scalability, including multimodal problems, obtaining the best or near-best results among all algorithms tested in 2009 on functions such as the step-ellipsoid and Katsuuras, but failing to locate the optimum within the time limit on skew Rastrigin-Bueche separable and Lunacek bi-Rastrigin in higher dimensions. AMaLGaM is found to be more robust to noise than iAMaLGaM due to the larger required population size. Using few or no covariances hinders the EDA from dealing with rotations of the search space. Finally, the use of noise averaging is found to be less efficient than the direct application of the EDA unless the noise is uniformly distributed. AMaLGaM was among the best performing algorithms submitted to the BBOB workshop in 2009.


The in vitro cytotoxicity of eluates from dentin bonding resins and their effect on tyrosine phosphorylation of L929 cells.
The aim of this study was to examine the relationship between the monomers eluted from dentin-bonding systems and their cytotoxicities, and to investigate the biochemical effect of the monomers on tyrosine phosphorylation, especially relating to the cell growth activity, of L929 cells in vitro. The primers, uncured or cured adhesives (3M and Kuraray) were tested to determine the cytotoxicity of confluent L929 cells cultured by Eagle's MEM medium supplemented with 10% FCS. The area of cells affected by the eluted monomers were evaluated with an image analyzer and the concentrations of monomers eluted into the medium were measured with high performance liquid chromatography (HPLC) after 24h incubation. The protein composition of the stimulated cells was compared by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and tyrosine phosphorylation was detected by Western blot. The primer and uncured adhesives revealed variable cytotoxicities. 2-hydroxyethyl-methacrylate (HEMA) was the major component eluted from uncured primers and adhesives. Small amounts of triethylene glycol dimethacrylate (TEGDMA) were also detected from the uncured adhesives. The cytotoxicities of the adhesives decreased as photo activation time increased. The amount of monomers eluted from the cured adhesives was almost undetectable and did not reach a sufficient concentration to suppress cell viability or cell growth. The cytotoxicities of the primers and adhesives correlated well with the amounts of either HEMA or TEGDMA eluted. Moreover, a high concentration of HEMA (4 mg/ml medium) affected intracellular tyrosine phosphorylation, which is related to cellular activities. Although the monomers present in dentin bonding resins are cytotoxic to L929 cells, the amount from cured bonding resin is very small and does not provide a cytotoxic dose. This data does however suggest that clinical exposure to the uncured primers and adhesives of dentin bonding resins should be minimized.


Differences in case-mix can influence the comparison of standardised mortality ratios even with optimal risk adjustment: an analysis of data from paediatric intensive care.
The publication of clinical outcomes for consultant surgeons in 10 specialties within the NHS has, along with national clinical audits, highlighted the importance of measuring and reporting outcomes with the aim of monitoring quality of care. Such information is vital to be able to identify good and poor practice and to inform patient choice. The need to adequately adjust outcomes for differences in case-mix has long been recognised as being necessary to provide 'like-for-like' comparisons between providers. However, directly comparing values of the standardised mortality ratio (SMR) between different healthcare providers can be misleading even when the risk-adjustment perfectly quantifies the risk of a poor outcome in the reference population. An example is shown from paediatric intensive care. Using observed case-mix differences for 33 paediatric intensive care units (PICUs) in the UK and Ireland for 2009-2011, SMRs were calculated under four different scenarios where, in each scenario, all of the PICUs were performing identically for each patient type. Each scenario represented a clinically plausible difference in outcome from the reference population. Despite the fact that the outcome for any patient was the same no matter which PICU they were to be admitted to, differences between the units were seen when compared using the SMR: scenario 1, 1.07-1.21; scenario 2, 1.00-1.14; scenario 3, 1.04-1.13; scenario 4, 1.00-1.09. Even if two healthcare providers are performing equally for each type of patient, if their patient populations differ in case-mix their SMRs will not necessarily take the same value. Clinical teams and commissioners must always keep in mind this weakness of the SMR when making decisions.


Electrochemical characterization of plutonium in n-tributyl phosphate.
This work investigates the electrochemical behavior of Pu(iv) and Pu(vi) complexes in n-tributylphosphate (TBP) as an entry to the electrochemical characterization of these complexes in organic extractants related to nuclear fuel reprocessing. Glassy carbon electrodes were used to show that Pu(iv) and Pu(vi) complexes display a reversible electrochemical reduction wave in TBP previously equilibrated with aqueous nitric acid solution. We investigated the reduction of Pu(iv) and Pu(vi) nitrato complexes extracted into TBP, with the aim to get thermodynamic (formal potential) and kinetic (diffusion coefficient) information about Pu(iv)/Pu(iii) and Pu(vi)/Pu(v) redox couples in the TBP medium. The formal potentials of the two redox couples were respectively 0.510 ± 0.005 and 0.478 ± 0.005 V per SCE in TBP equilibrated with 3 mol L-1 nitric acid at room temperature. The diffusion coefficient values of Pu(iv) and Pu(vi) species were estimated to be 0.72 × 10-6 and 0.77 × 10-6 cm2 s-1 respectively. Also, the Pu(iv) reduction showed a Nernstian dependence on the logarithm of nitric acid concentration in the organic phase, featuring the exchange of nitrates upon reduction of Pu(iv).


Nanotechnology in stem cells research: advances and applications.
Human beings suffer from a myriad of disorders caused by biochemical or biophysical alteration of physiological systems leading to organ failure. For a number of these conditions, stem cells and their enormous reparative potential may be the last hope for restoring function to these failing organ or tissue systems. To harness the potential of stem cells for biotherapeutic applications, we need to work at the size scale of molecules and processes that govern stem cells fate. Nanotechnology provides us with such capacity. Therefore, effective amalgamation of nanotechnology and stem cells - medical nanoscience or nanomedicine - offers immense benefits to the human race. The aim of this paper is to discuss the role and importance of nanotechnology in stem cell research by focusing on several important areas such as stem cell visualization and imaging, genetic modifications and reprogramming by gene delivery systems, creating stem cell niche, and similar therapeutic applications.


Ischemic colitis has a worse prognosis when isolated to the right side of the colon.
In general, ischemic colitis has a very good prognosis, but there is concern that when ischemia affects the right side of the colon in an isolated fashion, the prognosis may not be so favorable. The aim of this study was to compare the clinical features and outcomes of ischemia isolated to the right side of the colon with those of ischemia involving other areas of the colon. A retrospective study was undertaken of patients with colon ischemia hospitalized at the Moses and Weiler Divisions of the Montefiore Medical Center during the interval 1998-2005. Patients were identified using computerized searches of ICD-9 codes for colon ischemia and were divided into two groups: those with isolated right colon ischemia (IRCI) and those with colon ischemia not involving the right colon in an isolated fashion (non-IRCI). Only patients with biopsy-proven ischemic colitis were entered into our study. A total of 273 cases of biopsy-proven ischemic colitis were identified, of which 71 (26.0%) were isolated to the right side. Of these IRCI cases, 59.2% had an unfavorable outcome compared with 17.3% of cases of non-ICRI: 54.9% of IRCI patients required surgery compared with 10.9% of non-IRCI patients; mortality in patients with IRCI was 22.5% compared with 11.9% in patients with non-IRCI. A total of 273 cases of biopsy-proven ischemic colitis were identified of which 71 (26.0%) involved only the right side. Patients with IRCI had a worse outcome than those with colon ischemia involving other colon regions, including a fivefold need for surgery and a twofold mortality.


Two-Year Outcomes with a Magnetically Levitated Cardiac Pump in Heart Failure.
In an early analysis of this trial, use of a magnetically levitated centrifugal continuous-flow circulatory pump was found to improve clinical outcomes, as compared with a mechanical-bearing axial continuous-flow pump, at 6 months in patients with advanced heart failure. In a randomized noninferiority and superiority trial, we compared the centrifugal-flow pump with the axial-flow pump in patients with advanced heart failure, irrespective of the intended goal of support (bridge to transplantation or destination therapy). The composite primary end point was survival at 2 years free of disabling stroke (with disabling stroke indicated by a modified Rankin score of >3; scores range from 0 to 6, with higher scores indicating more severe disability) or survival free of reoperation to replace or remove a malfunctioning device. The noninferiority margin for the risk difference (centrifugal-flow pump group minus axial-flow pump group) was -10 percentage points. Of 366 patients, 190 were assigned to the centrifugal-flow pump group and 176 to the axial-flow pump group. In the intention-to-treat population, the primary end point occurred in 151 patients (79.5%) in the centrifugal-flow pump group, as compared with 106 (60.2%) in the axial-flow pump group (absolute difference, 19.2 percentage points; 95% lower confidence boundary, 9.8 percentage points [P<0.001 for noninferiority]; hazard ratio, 0.46; 95% confidence interval [CI], 0.31 to 0.69 [P<0.001 for superiority]). Reoperation for pump malfunction was less frequent in the centrifugal-flow pump group than in the axial-flow pump group (3 patients [1.6%] vs. 30 patients [17.0%]; hazard ratio, 0.08; 95% CI, 0.03 to 0.27; P<0.001). The rates of death and disabling stroke were similar in the two groups, but the overall rate of stroke was lower in the centrifugal-flow pump group than in the axial-flow pump group (10.1% vs. 19.2%; hazard ratio, 0.47; 95% CI, 0.27 to 0.84, P=0.02). In patients with advanced heart failure, a fully magnetically levitated centrifugal-flow pump was superior to a mechanical-bearing axial-flow pump with regard to survival free of disabling stroke or reoperation to replace or remove a malfunctioning device. (Funded by Abbott; MOMENTUM 3 ClinicalTrials.gov number, NCT02224755 .).


How do the biologics fit into the current DMARD armamentarium?
Most disease modifying antirheumatic drugs (DMARD) are discontinued within 5 years because of loss of clinical efficacy or toxicity. As a result, there has been a concerted effort to develop new immunomodulatory agents, particularly biological agents, that block the putative proinflammatory cytokines. Among the agents developed thus far, inhibitors of tumor necrosis factor (TNF) have shown perhaps the greatest promise as therapeutic agents for rheumatoid arthritis (RA). Two TNF-blocking agents, etanercept (Enbrel) and infliximab (Remicade), have been approved in the US and more recently in Europe, for the treatment of patients with RA. The results of randomized placebo controlled trials have shown that both agents significantly decrease the intensity of synovitis and prevent or retard the progression of cartilage destruction, especially when combined with methotrexate. Their side effect profiles appear to be acceptable, although rare cases of lupus-like diseases and of severe infections have been reported. Although the early clinical experience with these agents has been encouraging, their longterm safety and continuing efficacy in the general population with RA, as well as in high risk patient subsets (i.e., patients with malignancies or chronic infections), remain to be determined. In addition, the costs of these newer agents must be justified on clinical grounds. Because of the questions still surrounding these new treatment principles, several consensus conferences have been held in Europe and the US to address the role of the new biologicals in the current RA armamentarium.


Placental nutrient supply and fetal growth.
This review considers mechanisms by which transfer across the placenta takes place and how the capacity of the placenta to supply nutrients relates to fetal growth and vice versa. Blood flow through both uterine and umbilical circulations of the placenta, the structural properties of the placental exchange barrier and its related diffusional permeability, and the expression and activity of a wide range of transporter proteins in the syncytiotrophoblast, the transporting epithelium of the placenta, all need to be taken into account in considering placental supply capacity. We discuss the evidence that each of these factors affects, and is affected by, fetal growth rate and consider the regulatory mechanisms involved, with a particular focus on data that has emerged from study of the system A amino acid transporter. We consider that future work will build on the considerable foundation of knowledge regarding placental transfer mechanisms, as well as the other aspects of placental structure and function, to develop new diagnostic and therapeutic strategies for pregnancy complications, such as fetal growth restriction or overgrowth.


Reversal of hyperglycemic preconditioning by angiotensin II: role of calcium transport.
Myocardial cell death is an important contributor to the development of diabetic cardiomyopathy. It has been proposed that diabetes-mediated upregulation of the renin-angiotensin system leads to oxidative stress, the trigger for cardiomyocyte death and contractile dysfunction. However, the adverse effect of ANG II on the diabetic heart may extend beyond the development of the cardiomyopathy. ANG II also alters specific modulators of ischemic injury, such as PKC and calcium transport. Therefore, the present study examined the effect of ANG II on hyperglycemic preconditioning, a glucose-mediated condition associated with the elevation of PKC activity and alterations in calcium transport that render the cell resistant to hypoxia. Exposure of the glucose-treated cell to ANG II during the prehypoxic period blocked glucose-mediated cardioprotection. The reversal of hyperglycemic preconditioning was associated with enhanced accumulation of Ca(2+) during hypoxia, an effect prevented by inhibition of the Na(+)/ H(+) exchanger and the T-type Ca(2+) channel. The inhibitors of hypoxia-mediated Ca(2+) accumulation also blocked the reversal of hyperglycemic preconditioning by ANG II. Thus ANG II and glucose treatment exert opposite actions on the Na(+)/ H(+) exchanger and the T-type Ca(2+) channel. Because those transporters are involved in hypoxia-mediated apoptosis, they are logical candidates for the beneficial effects of high glucose and the adverse effects of ANG II on the hypoxic cardiomyocyte.


Age at menarche and lung function: a Mendelian randomization study.
A trend towards earlier menarche in women has been associated with childhood factors (e.g. obesity) and hypothesised environmental exposures (e.g. endocrine disruptors present in household products). Observational evidence has shown detrimental effects of early menarche on various health outcomes including adult lung function, but these might represent spurious associations due to confounding. To address this we used Mendelian randomization where genetic variants are used as proxies for age at menarche, since genetic associations are not affected by classical confounding. We estimated the effects of age at menarche on forced vital capacity (FVC), a proxy for restrictive lung impairment, and ratio of forced expiratory volume in one second to FVC (FEV1/FVC), a measure of airway obstruction, in both adulthood and adolescence. We derived SNP-age at menarche association estimates for 122 variants from a published genome-wide meta-analysis (N = 182,416), with SNP-lung function estimates obtained by meta-analysing three studies of adult women (N = 46,944) and two of adolescent girls (N = 3025). We investigated the impact of departures from the assumption of no pleiotropy through sensitivity analyses. In adult women, in line with previous evidence, we found an effect on restrictive lung impairment with a 24.8 mL increase in FVC per year increase in age at menarche (95% CI 1.8-47.9; p = 0.035); evidence was stronger after excluding potential pleiotropic variants (43.6 mL; 17.2-69.9; p = 0.001). In adolescent girls we found an opposite effect (-56.5 mL; -108.3 to -4.7; p = 0.033), suggesting that the detrimental effect in adulthood may be preceded by a short-term post-pubertal benefit. Our secondary analyses showing results in the same direction in men and boys, in whom age at menarche SNPs have also shown association with sexual development, suggest a role for pubertal timing in general rather than menarche specifically. We found no effect on airway obstruction (FEV1/FVC).


Differential regulation of cellular tropism and sensitivity to soluble CD4 neutralization by the envelope gp120 of human immunodeficiency virus type 1.
Using recombinant and mutant viruses generated between two human immunodeficiency virus type 1 isolates that display differences in cell tropism and sensitivity to soluble CD4 neutralization, we show that these two properties of the virus are regulated by different mechanisms. Whereas there is an association between V3 loop conformation and a particular cellular tropism, soluble CD4 neutralization sensitivity appears to be determined by amino acid differences in the C2 domain of the envelope gp120 that modulate the stability of gp120-gp41 association. Our findings further illustrate the importance of functional interactions among different regions of the envelope gp120 in regulating the biological phenotypes of human immunodeficiency virus and suggest that additional probing of the V3 loop with monoclonal antibodies may identify specific structural features of this loop that determine cell tropism.


Lifestyle counseling and supplementation with flaxseed or walnuts influence the management of metabolic syndrome.
A healthy lifestyle may ameliorate metabolic syndrome (MetS); however, it remains unclear if incorporating nuts or seeds into lifestyle counseling (LC) has additional benefit. A 3-arm, randomized, controlled trial was conducted among 283 participants screened for MetS using the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian Americans. Participants were assigned to a LC on the AHA guidelines, LC + flaxseed (30 g/d) (LCF), or LC + walnuts (30 g/d) (LCW) group. After the 12-wk intervention, the prevalence of MetS decreased significantly in all groups: -16.9% (LC), -20.2% (LCF), and -16.0% (LCW). The reversion rate of MetS, i.e. those no longer meeting the MetS criteria at 12 wk, was not significantly different among groups (LC group, 21.1%; LCF group, 26.6%; and LCW group, 25.5%). However, the reversion rate of central obesity was higher in the LCF (19.2%; P = 0.008) and LCW (16.0%; P = 0.04) groups than in the LC group (6.3%). Most of the metabolic variables (weight, waist circumference, serum glucose, total cholesterol, LDL cholesterol, apolipoprotein (Apo) B, ApoE, and blood pressure) were significantly reduced from baseline in all 3 groups. However, the severity of MetS, presented as the mean count of MetS components, was significantly reduced in the LCW group compared with the LC group among participants with confirmed MetS at baseline (P = 0.045). Our results suggest that a low-intensity lifestyle education program is effective in MetS management. Flaxseed and walnut supplementation may ameliorate central obesity. Further studies with larger sample sizes and of longer duration are needed to examine the role of these foods in the prevention and management of MetS.


[Association between physical violence, consumption of alcohol and other drugs, and bullying among Brazilian adolescents].
This study aimed to identify the association between alcohol and drug consumption and bullying on the one hand and involvement in situations of physical violence among adolescents 13 to 15 years in public and private schools in State capitals and the Federal District of Brazil. The study analyzed data from the National School Health Survey (PeNSE) for the year 2009. Data analysis used logistic regression. Prevalence of involvement in physical violence was 12.9% more common in boys than girls. Both genders showed associations between physical violence or being a victim of bullying and use of illegal drugs, plus the heightened effect of the combined consumption of alcohol and other drugs. In boys, alcohol consumption showed a significant association with physical violence. Having the father or both parents living at home was inversely associated with physical violence in girls. Knowledge of factors associated with physical violence among adolescents is important for supporting health promotion strategies and a culture of peace, thereby counteracting the idea of taking teenage violence for granted.


Crosstalk of Signaling Mechanisms Involved in Host Defense and Symbiosis Against Microorganisms in Rice.
Rice is one of the most important food crops, feeding about half population in the world. Rice pathogens cause enormous damage to rice production worldwide. In plant immunity research, considerable progress has recently been made in our understanding of the molecular mechanisms underlying microbe-associated molecular pattern (MAMP)-triggered immunity. Using genome sequencing and molecular techniques, a number of new MAMPs and their receptors have been identified in the past two decades. Notably, the mechanisms for chitin perception via the lysine motif (LysM) domain-containing receptor OsCERK1, as well as the mechanisms for bacterial MAMP (e.g. flg22, elf18) perception via the leucine-rich repeat (LRR) domain-containing receptors FLS2 and EFR, have been clarified in rice and Arabidopsis, respectively. In chitin signaling in rice, two direct substrates of OsCERK1, Rac/ROP GTPase guanine nucleotide exchange factor OsRacGEF1 and receptor-like cytoplasmic kinase OsRLCK185, have been identified as components of the OsCERK1 complex and are rapidly phosphorylated by OsCERK1 in response to chitin. Interestingly, OsCERK1 also participates in symbiosis with arbuscular mycorrhizal fungi (AMF) in rice and plays a role in the recognition of short-chitin molecules (CO4/5), which are symbiotic signatures included in AMF germinated spore exudates and induced by synthetic strigolactone. Thus, OsCERK1 contributes to both immunity and symbiotic responses. In this review, we describe recent studies on pathways involved in rice immunity and symbiotic signaling triggered by interactions with microorganisms. In addition, we describe recent advances in genetic engineering by using plant immune receptors and symbiotic microorganisms to enhance disease resistance of rice.


Bending Rules in Graphene Kirigami.
The three-dimensional shapes of graphene sheets produced by nanoscale cut-and-join kirigami are studied by combining large-scale atomistic simulations with continuum elastic modeling. Lattice segments are selectively removed from a graphene sheet, and the structure is allowed to close by relaxing in the third dimension. The surface relaxation is limited by a nonzero bending modulus which produces a smoothly modulated landscape instead of the ridge-and-plateau motif found in macroscopic lattice kirigami. The resulting surface shapes and their interactions are well described by a new set of microscopic kirigami rules that resolve the competition between bending and stretching energies.


An approach to peptide-based ATP receptors by a combination of random selection, rational design, and molecular imprinting.
Random selection, rational design and molecular imprinting were cooperatively utilized to develop peptide-based ATP synthetic receptors. In this fusion strategy, combinatorial chemistry was utilized for screening a precursor peptide useful for construction of ATP receptors, and rational design was employed in modification of the selected precursor peptide for higher affinity and selectivity. Finally, molecular imprinting was used for pre-organizing the conformation of the precursor peptide as complementary to a target molecule ATP. The fusion strategy appeared to have advantage to sole use of the individual strategy: (1) a low hit-rate of combinatorial chemistry will be improved by customizing a higher order structure of a selected peptide by molecular imprinting, (2) combinatorial chemistry allows us to semi-automatically select components of water-compatible synthetic receptors, (3) rational design improves the selected peptide sequence for better molecularly imprinted receptors. A peptide consisting of a randomly selected sequence and a rationally designed sequence (Resin-Lys-Gly-Arg-Gly-Lys-Gly-Gly-Gly-Glu-Lys-Tyr-Leu-Lys-NHAc) was designed and synthesized as a precursor peptide. The rational design was made according to the sequence of the adenine binding site of biotin carboxylase. The on-beads peptide was cross-linked with dimethyl adipimidate in the presence of ATP. In the saturation binding tests, the cross-linked on-beads peptide showed 5.3 times higher affinity compared to the non-cross-linked peptide with the same sequence. Furthermore, the cross-linked peptide showed improved selectivity; the ratios of binding constants, K((ATP))/K((ADP)) and K((ATP))/K((GTP)), were increased from 2.4 to 19, and from 0.8 to 10, respectively. It would be notable that the peptide without the rationally designed sequence showed no discrimination between ATP and GTP (K((ATP))/K((GTP)) as 0.9), suggesting that the rationally designed site was successfully engaged for recognition of the adenine base.


Cell Proliferation and Cytotoxicity Assays.
Cell viability is defined as the number of healthy cells in a sample and proliferation of cells is a vital indicator for understanding the mechanisms in action of certain genes, proteins and pathways involved cell survival or death after exposing to toxic agents. Generally, methods used to determine viability are also common for the detection of cell proliferation. Cell cytotoxicity and proliferation assays are generally used for drug screening to detect whether the test molecules have effects on cell proliferation or display direct cytotoxic effects. Regardless of the type of cell-based assay being used, it is important to know how many viable cells are remaining at the end of the experiment. There are a variety of assay methods based on various cell functions such as enzyme activity, cell membrane permeability, cell adherence, ATP production, co-enzyme production, and nucleotide uptake activity. These methods could be basically classified into different categories: (I) dye exclusion methods such as trypan blue dye exclusion assay, (II) methods based on metabolic activity, (III) ATP assay, (IV) sulforhodamine B assay, (V) protease viability marker assay, (VI) clonogenic cell survival assay, (VII) DNA synthesis cell proliferation assays and (V) raman micro-spectroscopy. In order to choose the optimal viability assay, the cell type, applied culture conditions, and the specific questions being asked should be considered in detail. This particular review aims to provide an overview of common cell proliferation and cytotoxicity assays together with their own advantages and disadvantages, their methodologies, comparisons and intended purposes.


Colposcopy is not necessary to assess the risk to the cervix in HIV-positive women: an international cohort study of cervical pathology in HIV-1 positive women.
The objectives of this prospective multicentre international cohort study are to describe the characteristics of a cohort of HIV-1 positive women and determine the best management system by comparing cervical pathology according to results of cytology, colposcopy and human papillomavirus (HPV) testing at baseline and throughout follow-up. A. Cohorts of known HIV-positive women were recruited from 6 hospital-based European centres and a community-based South African centre. Following registration, women were reviewed every 6 months to undergo cervical surveillance including cytology, colposcopy, histopathology and HPV testing, using the HPV hybrid capture assay. Independent risk factors for the incidence of cytological abnormality and acquisition/clearance of HPV infection during follow up were identified. A total of 1,534 women were recruited, 400 of which were from South Africa. At baseline, among European women, 66% had normal cytology and half were HPV negative and among South African women, 45% had normal cytology and one third (32%) were HPV negative. The sensitivity of cytology (>/=ASCUS) matched with that of colposcopy to detect CIN2+. Rate of detection of high grade CIN at 2 years was similar in European and South African women (11 and 9.3%, respectively). Cytology and HPV testing alone were each sufficiently sensitive as a screening test at 2 yearly intervals. Our data confirm the high prevalence of low-grade cytological abnormalities and high-risk HPV infection. Cytology appears to be sufficient for cervical surveillance, with HPV testing being less specific with poor positive predictive value. There appears to be no additional benefit from routine colposcopy.


Surface expression of ASIC2 inhibits the amiloride-sensitive current and migration of glioma cells.
Gliomas are primary brain tumors with a complex biology characterized by antigenic and genomic heterogeneity and a propensity for invasion into normal brain tissue. High grade glioma cells possess a voltage-independent, amiloride-inhibitable, inward Na+ current. This current does not exist in normal astrocytes or low grade tumor cells. Inhibition of this conductance decreases glioma growth and cell migration making it a potential therapeutic target. Our previous results have shown that the acid-sensing ion channels (ASICs), members of the epithelial Na+ channel (ENaC)/degenerin (DEG) family of ion channels are part of this current pathway. We hypothesized that one member of the ENaC/DEG family, ASIC2, is retained intracellularly and that it is the lack of functional expression of ASIC2 at the cell surface that results in hyperactivity of this conductance in high grade gliomas. In this study we show that the chemical chaperone, glycerol, and the transcriptional regulator, sodium 4-phenylbutyrate, inhibit the constitutively activated inward current and reduce cell growth and migration in glioblastoma multiforme. The results suggest that these compounds induce the movement of ASIC2 to the plasma membrane, and once there, the basally active inward current characteristic of glioma cells is abolished by inherent negative regulatory mechanisms. This in turn compromises the ability of the glioma cell to migrate and proliferate. These results support the hypothesis that the conductance pathway in high grade glioma cells is comprised of ENaC/DEG subunits and that abolishing this channel activity promotes a reversion of a high grade glioma cell to a phenotype resembling that of normal astrocytes.


Effect of immediate and delayed dentin sealing on the fracture strength, failure type and Weilbull characteristics of lithiumdisilicate laminate veneers.
Adhesion on dentin is less reliable than on enamel, which could affect the durability of laminate veneers (LV). Immediate dentin sealing (IDS) is suggested instead of delayed dentin sealing (DDS) to overcome hypersensitivity and prevent debonding from dentin. This study evaluated the effect of IDS and DDS on the durability of Li2Si2O5 laminate veneers in vitro. Window preparations were made on the labial surfaces of sound maxillary central incisors (N=50). They were randomly divided into five groups: Group 1: Enamel only+H3PO4+Adhesive (control); Group 2: <1/4 dentin+H3PO4+DDS (2 weeks later); Group 3: Complete dentin+H3PO4+DDS (2 weeks later); Group 4: <1/4 dentin+H3PO4+IDS; Group 5: Complete dentin+H3PO4+IDS. Li2Si2O5 laminate veneers (e.max Press) were bonded to the labial surfaces of the teeth with adhesive resin cement (Variolink Veneer). IDS layers were silicacoated (CoJet System) and silanized (ESPE-Sil). The teeth with their bonded laminates were thermocycled (10.000× cycles) and then subjected to static loading (1mm/min). Failure type and location after debonding were classified. Data were analyzed using ANOVA and Tukey's post hoc test (α=0.05). Two-parameter Weibull distribution values including the Weibull modulus, scale (m) and shape (0), values were calculated. Mean fracture strength (N) per group in descending order was as follows: Group 5 (576±254), Group 4 (478±216), Group 1 (473±159), Group 2 (465±186), and Group 3 (314±137). The presence of complete dentin exposure sealed with DDS after 2 weeks on the bonded surface (Group 3) resulted in significantly lower fracture strength results than those in group 5 with IDS (p=0.034). Weibull distribution presented higher shape (0) for Group 1 (3.67), than those of other groups (2.51-2.89). Failure types were predominantly adhesive failure between the cement and the laminate veneer in Groups 1, 2, 4 whereas Group 3 presented more often complete adhesive failures between the cement and dentin. In Group 5, failures showed some IDS and cement with or without ceramic fracture attached on the tooth. When laminate veneers are bonded to a large dentin substrate, application of immediate dentin sealing improves adhesion and thereby, the fracture strength of Li2Si2O5 laminate veneers.


Changes in Rous sarcoma virus RNA secondary structure near the primer binding site upon tRNATrp primer annealing.
Predicted secondary-structure elements encompassing the primer binding site in the 5' untranslated region of Rous sarcoma virus (RSV) RNA play an integral role in multiple viral replications steps including reverse transcription, DNA integration, and RNA packaging (A. Aiyar, D. Cobrinik, Z. Ge, H. J. Kung, and J. Leis, J. Virol. 66:2464-2472, 1992; D. Cobrinik, A. Aiyar, Z. Ge, M. Katzman, H. Huang, and J. Leis, J. Virol. 65:3864-3872, 1991; J. T. Miller, Z. Ge, S. Morris, K. Das, and J. Leis, J. Virol. 71:7648-7656, 1997). These elements include the U5-Leader stem, U5-IR stem-loop, and U5-TPsiC interaction region. Limited digestion of the 5' untranslated region of wild-type and mutant RSV RNAs with structure- and/or sequence-specific RNases detects the presence of the U5-Leader stem and the U5-IR stem-loop. When a tRNATrp primer is annealed to wild-type RNAs in vitro, limited nuclease mapping indicates that the U5-IR stem becomes partially unwound. This is not observed when mutant RNAs with altered U5-IR stem-loop structures are substituted for wild-type RNAs. The U5-Leader stem also becomes destabilized when the tRNA primer is annealed to either wild-type or mutant RNA fragments. Nuclease mapping studies of tRNATrp, as well as the viral RNA, indicate that the U5-TPsiC helix does form in vitro upon primer annealing. Collectively, these data suggest that the various structural elements near the RSV primer binding site undergo significant changes during the process of primer annealing.


Repair of common bile duct injury with the round and falciform ligament after clip necrosis: case report.
Occasionally, as abdominal surgeons, we are confronted with common bile duct injury noted during video laparoscopic or open cholecystectomy. Usually this is solved by endoscopic retrograde cholangiopancreatography (ERCP) sphincterotomy and stent, or enteric bypass, suture repair and tube drainage. However, after such procedures, there is a significant number of patients with postoperative stenosis. Another alternative to repair common bile duct injury and correct postoperative stenosis is using the round and falciform ligament as circumferencial patch. Due to their closeness to the common bile duct and their adequate blood supply, they make a perfect autologous biological graft.


Dietary supplement use by adolescents.
To review the use, benefits and adverse effects of the main dietary supplements consumed by adolescents. The literature review was performed using MEDLINE and LILACS databases (1997-2008). We analyzed 377 articles, and 52 of them were selected as references. Consumption of dietary supplements is widely spread among adolescents. This habit has often been detected in pediatric and adolescent medicine clinics. Most of the time, the use of supplements is motivated by the search of the ideal body. Other reasons for this practice are: attempt to compensate for an inadequate diet, increase immunity, prevent diseases, improve athletic performance and overcome their own athletic limits. The dietary supplements most frequently used and for which there is little evidence of beneficial effects in healthy adolescents are: proteins, amino acids, beta-hydroxy-beta-methylbutyrate, microelements, carnitine, creatine, vitamins, caffeine, and bicarbonate. This dietary supplementation may be beneficial for competitive athletes who do not have a balanced diet after a specific dietary deficiency has been detected. The unrestrained consumption of dietary supplements should be avoided, since, besides the lack of evidence that such practice will lead to improvement of performance, it exposes adolescents to several adverse effects. Balanced nutrition, with intake of essential energy and nutrients is usually enough to achieve good athletic performance. The use of dietary supplements must be allowed only for selected cases in which specific nutritional deficiencies are identified.


Effectiveness and safety of chemotherapy combined with dendritic cells co-cultured with cytokine-induced killer cells in the treatment of advanced non-small-cell lung cancer: a systematic review and meta-analysis.
Lung cancer, particularly non-small-cell lung cancer (NSCLC) is the leading cause of cancer mortality. Chemotherapy combined dendritic cells co-cultured with cytokine-induced killer cells (DC-CIK) immunotherapy has been applied in advanced NSCLC patients' treatment, but couldn't provide consistent beneficial results. Therefore, it is necessary to evaluate the efficiency and safety of combination therapy to promote the application. A literature search for randomized controlled trials of NSCLC was conducted in PubMed database. Before meta-analysis was performed, studies were evaluated heterogeneity. Pooled risk ratios (RRs) were estimated and 95% confidence intervals (CIs) were calculated using a fixed-effect model. Sensitivity analysis was also performed. Six eligible trials were enrolled. Efficiency and safety of chemotherapy followed by DC-CIK immunotherapy (experimental group) and chemotherapy alone (control group) were compared. 1-year overall survival (OS) (P = 0.02) and progression free survival (PFS) (P = 0.005) in the experimental group were significantly increased compared with the control. Disease control rate (DCR) (P = 0.006) rose significantly in experimental group. However, no significant differences between the two groups were observed in 2-year OS (P = 0.21), 2-year PFS (P = 0.10), overall response rate (ORR) (P = 0.76) and partial response (PR) (P = 0.22). Temporary fever, anemia, leukopenia and nausea were the four major adverse events (AEs) treated by chemotherapy. The incidence of anemia, leukopenia and nausea in the experimental group was obviously lower than the control group. Temporary fever rate was higher in experimental group than that in the control, but could be alleviated by taking sufficient rest. Chemotherapy combined with DC-CIK immunotherapy showed superiority in DCR, 1-year OS and PFS, and no more AEs appeared, however, there was no significant improvement in ORR, PR, 2-year OS and PFS. As a whole, the combination therapy is safer but modest in efficacy for advanced NSCLC patients.


Associations between insulin action and integrity of brain microstructure differ with familial longevity and with age.
Impaired glucose metabolism and type 2 diabetes have been associated with cognitive decline, dementia, and with structural and functional brain features. However, it is unclear whether these associations differ in individuals that differ in familial longevity or age. Here, we investigated the association between parameters of glucose metabolism and microstructural brain integrity in offspring of long-lived families ("offspring") and controls; and age categories thereof. From the Leiden Longevity Study (LLS), 132 participants underwent an oral glucose tolerance test (OGTT) to assess glycemia [fasted glucose and glucose area-under-the-curve (AUC)], insulin resistance [fasted insulin, AUCinsulin, and homeostatic model assessment of insulin resistance (HOMA-IR)], and pancreatic Beta cell secretory capacity (insulinogenic index). 3 Tesla MRI and Magnetization Transfer (MT) imaging MT-ratio (MTR) peak-height was used to quantify differences in microstructural brain parenchymal tissue homogeneity that remain invisible on conventional MRI. Analyses were performed in offspring and age-matched controls, with and without stratification for age. In the full offspring group only, reduced MTR peak-height in gray and white matter was inversely associated with AUCinsulin, fasted insulin, HOMA-IR and insulinogenic-index (all p < 0.01). When dichotomized for age (≤65 years and >65 years): in younger controls, significantly stronger inverse associations were observed between MTR peak-height and fasted glucose, AUCglucose, fasted insulin, AUCinsulin and HOMA-IR in gray matter; and for AUCglucose, fasted insulin and HOMA-IR in white matter (all P-interaction < 0.05). Although the strength of the associations tended to attenuate with age in the offspring group, the difference between age groups was not statistically significant. Thus, associations between impaired insulin action and reduced microstructural brain parenchymal tissue homogeneity were stronger in offspring compared to controls, and seemed to diminish with age.


New perspectives in the study of the Earth's magnetic field and climate connection: The use of transfer entropy.
The debated question on the possible relation between the Earth's magnetic field and climate has been usually focused on direct correlations between different time series representing both systems. However, the physical mechanism able to potentially explain this connection is still an open issue. Finding hints about how this connection could work would suppose an important advance in the search of an adequate physical mechanism. Here, we propose an innovative information-theoretic tool, i.e. the transfer entropy, as a good candidate for this scope because is able to determine, not simply the possible existence of a connection, but even the direction in which the link is produced. We have applied this new methodology to two real time series, the South Atlantic Anomaly (SAA) area extent at the Earth's surface (representing the geomagnetic field system) and the Global Sea Level (GSL) rise (for the climate system) for the last 300 years, to measure the possible information flow and sense between them. This connection was previously suggested considering only the long-term trend while now we study this possibility also in shorter scales. The new results seem to support this hypothesis, with more information transferred from the SAA to the GSL time series, with about 90% of confidence level. This result provides new clues on the existence of a link between the geomagnetic field and the Earth's climate in the past and on the physical mechanism involved because, thanks to the application of the transfer entropy, we have determined that the sense of the connection seems to go from the system that produces geomagnetic field to the climate system. Of course, the connection does not mean that the geomagnetic field is fully responsible for the climate changes, rather that it is an important driving component to the variations of the climate.


Intravenous glial growth factor 2 (GGF2) isoform of neuregulin-1β improves left ventricular function, gene and protein expression in rats after myocardial infarction.
Recombinant Neuregulin (NRG)-1β has multiple beneficial effects on cardiac myocytes in culture, and has potential as a clinical therapy for heart failure (HF). A number of factors may influence the effect of NRG-1β on cardiac function via ErbB receptor coupling and expression. We examined the effect of the NRG-1β isoform, glial growth factor 2 (GGF2), in rats with myocardial infarction (MI) and determined the impact of high-fat diet as well as chronicity of disease on GGF2 induced improvement in left ventricular systolic function. Potential mechanisms for GGF2 effects on the remote myocardium were explored using microarray and proteomic analysis. Rats with MI were randomized to receive vehicle, 0.625 mg/kg, or 3.25 mg/kg GGF2 in the presence and absence of high-fat feeding beginning at day 7 post-MI and continuing for 4 weeks. Residual left ventricular (LV) function was improved in both of the GGF2 treatment groups compared with the vehicle treated MI group at 4 weeks of treatment as assessed by echocardiography. High-fat diet did not prevent the effects of high dose GGF2. In experiments where treatment was delayed until 8 weeks after MI, high but not low dose GGF2 treatment was associated with improved systolic function. mRNA and protein expression analysis of remote left ventricular tissue revealed a number of changes in myocardial gene and protein expression altered by MI that were normalized by GGF2 treatment, many of which are involved in energy production. This study demonstrates that in rats with MI induced systolic dysfunction, GGF2 treatment improves cardiac function. There are differences in sensitivity of the myocardium to GGF2 effects when administered early vs. late post-MI that may be important to consider in the development of GGF2 in humans.


Triple-responsive inorganic-organic hybrid microcapsules as a biocompatible smart platform for the delivery of small molecules.
We designed novel hybrid inorganic/organic capsules with unique physicochemical features enabling multimodal triggering by physical (UV light, ultrasound) and chemical (enzymatic treatment) stimuli. Notably, the UV- and ultrasound response was achieved by a synergetic combination of TiO2 and SiO2 nanostructures which were in situ deposited into the polymer shell of microcapsules during sol-gel synthesis. This results in the formation of a composite hybrid shell with enhanced mechanical stability. Such sol-gel modification reduces the permeability of the capsule shell to allow for small molecule encapsulation. At the same time, these hybrid capsules consist of degradable polypeptides and polysaccharides and can be decomposed in response to enzymatic reaction. Upon employing different modes of treatment (UV-light, ultrasound or enzymatic degradation) we can stimulate different mechanisms of cargo release at desired times. Importantly, such capsules have been shown to be non-cytotoxic and can be internalized into human mesenchymal stem cells (MSCs) and cervical cancer cell lines (HeLa) revealing intracellular degradation. This work demonstrates that our hybrid capsules possess a triple stimuli-responsive effect, which is of capital importance for the future design and application of multimodal responsive platforms to improve externally stimulated release of bioactive compounds and their healthcare performance.


Molecular variation in chloroplast DNA regions in ancestral species of wheat.
Restriction map variation in two 5-6-kb chloroplast DNA regions of five diploid Aegilops species in the section Sitopsis and two wild tetraploid wheats, Triticum dicoccoides and Triticum araraticum, was investigated with a battery of four-cutter restriction enzymes. A single accession each of Triticum durum, Triticum timopheevi and Triticum aestivum was included as a reference. More than 250 restriction sites were scored, of which only seven sites were found polymorphic in Aegilops speltoides. No restriction site polymorphisms were detected in all of the other diploid and tetraploid species. In addition, six insertion/deletion polymorphisms were detected, but they were mostly unique or species-specific. Estimated nucleotide diversity was 0.0006 for A. speltoides, and 0.0000 for all the other investigated species. In A. speltoides, none of Tajima's D values was significant, indicating no clear deviation from the neutrality of molecular polymorphisms. Significant non-random association was detected for three combinations out of 10 possible pairs between polymorphic restriction sites in A. speltoides. Phylogenetic relationship among all the plastotypes (plastid genotype) suggested the diphyletic origin of T. dicoccoides and T. araraticum. A plastotype of one A. speltoides accession was identical to the major type of T. araraticum (T. timopheevi inclusively). Three of the plastotypes found in the Sitopsis species are very similar, but not identical, to that of T. dicoccoides, T. durum and T. aestivum.


Structural bioinformatics-based design of selective, irreversible kinase inhibitors.
The active sites of 491 human protein kinase domains are highly conserved, which makes the design of selective inhibitors a formidable challenge. We used a structural bioinformatics approach to identify two selectivity filters, a threonine and a cysteine, at defined positions in the active site of p90 ribosomal protein S6 kinase (RSK). A fluoromethylketone inhibitor, designed to exploit both selectivity filters, potently and selectively inactivated RSK1 and RSK2 in mammalian cells. Kinases with only one selectivity filter were resistant to the inhibitor, yet they became sensitized after genetic introduction of the second selectivity filter. Thus, two amino acids that distinguish RSK from other protein kinases are sufficient to confer inhibitor sensitivity.


Brain dynamics of post-task resting state are influenced by expertise: Insights from baseball players.
Post-task resting state dynamics can be viewed as a task-driven state where behavioral performance is improved through endogenous, non-explicit learning. Tasks that have intrinsic value for individuals are hypothesized to produce post-task resting state dynamics that promote learning. We measured simultaneous fMRI/EEG and DTI in Division-1 collegiate baseball players and compared to a group of controls, examining differences in both functional and structural connectivity. Participants performed a surrogate baseball pitch Go/No-Go task before a resting state scan, and we compared post-task resting state connectivity using a seed-based analysis from the supplementary motor area (SMA), an area whose activity discriminated players and controls in our previous results using this task. Although both groups were equally trained on the task, the experts showed differential activity in their post-task resting state consistent with motor learning. Specifically, we found (1) differences in bilateral SMA-L Insula functional connectivity between experts and controls that may reflect group differences in motor learning, (2) differences in BOLD-alpha oscillation correlations between groups suggests variability in modulatory attention in the post-task state, and (3) group differences between BOLD-beta oscillations that may indicate cognitive processing of motor inhibition. Structural connectivity analysis identified group differences in portions of the functionally derived network, suggesting that functional differences may also partially arise from variability in the underlying white matter pathways. Generally, we find that brain dynamics in the post-task resting state differ as a function of subject expertise and potentially result from differences in both functional and structural connectivity. Hum Brain Mapp 37:4454-4471, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.


Change of wrist motion before and after fixation of the distal radioulnar joint and resection of the distal ulna in a cadaveric model.
Recent study suggests the distal radioulnar joint (DRUJ) plays a role in flexion and extension of the wrist. We examined the range of motion (ROM) of the wrist before and after DRUJ fixation and distal ulnar resection in a cadaveric model. Twenty fresh cadaveric human wrists were transected and treated with two sequential interventions: (a) DRUJ fixation, and (b) distal ulnar resection. The angle of maximum flexion and extension of the wrist was measured before and after the procedures. Maximum force to the wrist was determined before the procedures using a digital pressure monitor. The mean maximum wrist flexion ROM was 84.2° before the procedures. The ROM decreased to 82.5° after DRUJ fixation, and significantly increased to 88.2° after subsequent resection of the distal ulna. The mean maximum wrist extension ROM before the procedures was 73.5°. The ROM decreased to 71.6° after DRUJ fixation, and significantly increased to 77.1° after subsequent resection of the distal ulna. Motion of the wrist is affected by DRUJ. This study suggests that the DRUJ might contribute to the ROM in flexion and extension of the wrist.


Theory-Driven Interventions in Psychoneuroimmunology and HIV-1 Infection.
Psychoneuroimmunology (PNI) is a rapidly evolving multidisciplinary field founded on the premise that psychosocial factors, the central nervous system, and the immune system are intimately linked. Following publication of scientific evidence supporting this link, a number of animal and human studies have been published, both inside and outside the area of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome. These studies support the existence of bidirectional feedback mechanisms operating between the brain and the immune system. To date, however, there is no all-encompassing model that predicts individual differences in the relationship among psychosocial factors, immunologic measures, and clinical disease progression in HIV type 1 (HIV-1) infection. This variability in human response has been explained by a number of cofactors (host as well as environmental) that appear to accelerate the course of the disease. Since psychosocial factors are highly amenable to behavioral interventions, several models for intervention research have been proposed to evaluate whether such interventions can enhance immune functioning, thereby curtailing disease progression. Examination of these interventions in the context of PNI and HIV-1 infection, however, is rather limited. Therefore, researchers and clinicians must not only consider conceptualizations and paradigms in this area of research, but also focus on empirically testable, theory-driven models that allow for the unique characteristics of individual patients.


Early DNA methylation changes in children developing beta cell autoimmunity at a young age.
Type 1 diabetes is a chronic autoimmune disease of complex aetiology, including a potential role for epigenetic regulation. Previous epigenomic studies focused mainly on clinically diagnosed individuals. The aim of the study was to assess early DNA methylation changes associated with type 1 diabetes already before the diagnosis or even before the appearance of autoantibodies. Reduced representation bisulphite sequencing (RRBS) was applied to study DNA methylation in purified CD4+ T cell, CD8+ T cell and CD4-CD8- cell fractions of 226 peripheral blood mononuclear cell samples longitudinally collected from seven type 1 diabetes-specific autoantibody-positive individuals and control individuals matched for age, sex, HLA risk and place of birth. We also explored correlations between DNA methylation and gene expression using RNA sequencing data from the same samples. Technical validation of RRBS results was performed using pyrosequencing. We identified 79, 56 and 45 differentially methylated regions in CD4+ T cells, CD8+ T cells and CD4-CD8- cell fractions, respectively, between type 1 diabetes-specific autoantibody-positive individuals and control participants. The analysis of pre-seroconversion samples identified DNA methylation signatures at the very early stage of disease, including differential methylation at the promoter of IRF5 in CD4+ T cells. Further, we validated RRBS results using pyrosequencing at the following CpG sites: chr19:18118304 in the promoter of ARRDC2; chr21:47307815 in the intron of PCBP3; and chr14:81128398 in the intergenic region near TRAF3 in CD4+ T cells. These preliminary results provide novel insights into cell type-specific differential epigenetic regulation of genes, which may contribute to type 1 diabetes pathogenesis at the very early stage of disease development. Should these findings be validated, they may serve as a potential signature useful for disease prediction and management.


Breast cancer risk factors differ between Asian and white women with BRCA1/2 mutations.
The prevalence and penetrance of BRCA1 and BRCA2 (BRCA1/2) mutations may differ between Asians and whites. We investigated BRCA1/2 mutations and cancer risk factors in a clinic-based sample. BRCA1/2 mutation carriers were enrolled from cancer genetics clinics in Hong Kong and California according to standardized entry criteria. We compared BRCA mutation position, cancer history, hormonal and reproductive exposures. We analyzed DNA samples for single-nucleotide polymorphisms reported to modify breast cancer risk. We performed logistic regression to identify independent predictors of breast cancer. Fifty Asian women and forty-nine white American women were enrolled. BRCA1 mutations were more common among whites (67 vs. 42 %, p = 0.02), and BRCA2 mutations among Asians (58 vs. 37 %, p = 0.04). More Asians had breast cancer (76 vs. 53 %, p = 0.03); more whites had relatives with breast cancer (86 vs. 50 %, p = 0.0003). More whites than Asians had breastfed (71 vs. 42 %, p = 0.005), had high BMI (median 24.3 vs. 21.2, p = 0.04), consumed alcohol (2 drinks/week vs. 0, p < 0.001), and had oophorectomy (61 vs. 34 %, p = 0.01). Asians had a higher frequency of risk-associated alleles in MAP3K1 (88 vs. 59 %, p = 0.005) and TOX3/TNRC9 (88 vs. 55 %, p = 0.0002). On logistic regression, MAP3K1 was associated with increased breast cancer risk for BRCA2, but not BRCA1 mutation carriers; breast density was associated with increased risk among Asians but not whites. We found significant differences in breast cancer risk factors between Asian and white BRCA1/2 mutation carriers. Further investigation of racial differences in BRCA1/2 mutation epidemiology could inform targeted cancer risk-reduction strategies.


Mid-urethral sling operations for stress urinary incontinence in women.
Urinary incontinence is a very common and debilitating problem affecting about 50% of women at some point in their lives. Stress urinary incontinence (SUI) is a predominant cause in 30% to 80% of these women imposing significant health and economic burden on society and the women affected. Mid-urethral sling (MUS) operations are a recognised minimally invasive surgical treatment for SUI. MUS involves the passage of a small strip of tape through either the retropubic or obturator space, with entry or exit points at the lower abdomen or groin, respectively. This review does not include single-incision slings. To assess the clinical effects of mid-urethral sling (MUS) operations for the treatment of SUI, urodynamic stress incontinence (USI) or mixed urinary incontinence (MUI) in women. We searched: Cochrane Incontinence Specialised Register (including: CENTRAL, MEDLINE, MEDLINE In-Process, ClinicalTrials.gov) (searched 26 June 2014); Embase Classic (January 1947 to Week 25 2014); WHO ICTRP (searched 30 June 2014); reference lists. Randomised or quasi-randomised controlled trials amongst women with SUI, USI or MUI, in which both trial arms involve a MUS operation. Two review authors independently assessed the methodological quality of potentially eligible studies and extracted data from included trials. We included 81 trials that evaluated 12,113 women. We assessed the quality of evidence for outcomes using the GRADE assessment tool; the quality of most outcomes was moderate, mainly due to risk of bias or imprecision.Fifty-five trials with data contributed by 8652 women compared the use of the transobturator route (TOR) and retropubic route (RPR). There is moderate quality evidence that in the short term (up to one year) the rate of subjective cure of TOR and RPR are similar (RR 0.98, 95% CI 0.96 to 1.00; 36 trials, 5514 women; moderate quality evidence) ranging from 62% to 98% in the TOR group, and from 71% to 97% in the RPR group. Short-term objective cure was similar in the TOR and RPR groups (RR 0.98, 95% CI 0.96 to 1.00; 40 trials, 6145 women). Fewer trials reported medium-term (one to five years) and longer-term (over five years) data, but subjective cure was similar between the groups (RR 0.97, 95% CI 0.87 to 1.09; 5 trials, 683 women; low quality evidence; and RR 0.95, 95% CI 0.80 to 1.12; 4 trials, 714 women; moderate quality evidence, respectively). In the long term, subjective cure rates ranged from 43% to 92% in the TOR group, and from 51% to 88% in the RPR group.MUS procedures performed using the RPR had higher morbidity when compared to TOR, though the overall rate of adverse events remained low. The rate of bladder perforation was lower after TOR (0.6% versus 4.5%; RR 0.13, 95% CI 0.08 to 0.20; 40 trials, 6372 women; moderate quality evidence). Major vascular/visceral injury, mean operating time, operative blood loss and length of hospital stay were lower with TOR.Postoperative voiding dysfunction was less frequent following TOR (RR 0.53, 95% CI 0.43 to 0.65; 37 trials, 6200 women; moderate quality evidence). Overall rates of groin pain were higher in the TOR group (6.4% versus 1.3%; RR 4.12, 95% CI 2.71 to 6.27; 18 trials, 3221 women; moderate quality evidence) whereas suprapubic pain was lower in the TOR group (0.8% versus 2.9%; RR 0.29, 95% CI 0.11 to 0.78); both being of short duration. The overall rate of vaginal tape erosion/exposure/extrusion was low in both groups: 24/1000 instances with TOR compared with 21/1000 for RPR (RR 1.13, 95% CI 0.78 to 1.65; 31 trials, 4743 women; moderate quality evidence). There were only limited data to inform the need for repeat incontinence surgery in the long term, but it was more likely in the TOR group than in the RPR group (RR 8.79, 95% CI 3.36 to 23.00; 4 trials, 695 women; low quality evidence).A retropubic bottom-to-top route was more effective than top-to-bottom route for subjective cure (RR 1.10, 95% CI 1.01 to 1.19; 3 trials, 477 women; moderate quality evidence). It incurred significantly less voiding dysfunction, and led to fewer bladder perforations and vaginal tape erosions.Short-and medium-term subjective cure rates between transobturator tapes passed using a medial-to-lateral as opposed to a lateral-to-medial approach were similar (RR 1.00, 95% CI 0.96 to 1.06; 6 trials, 759 women; moderate quality evidence, and RR 1.06, 95% CI 0.91 to 1.23; 2 trials, 235 women; moderate quality evidence). There was moderate quality evidence that voiding dysfunction was more frequent in the medial-to-lateral group (RR 1.74, 95% CI 1.06 to 2.88; 8 trials, 1121 women; moderate quality evidence), but vaginal perforation was less frequent in the medial-to-lateral route (RR 0.25, 95% CI 0.12 to 0.53; 3 trials, 541 women). Due to the very low quality of the evidence, it is unclear whether the lower rates of vaginal epithelial perforation affected vaginal tape erosion (RR 0.42, 95% CI 0.16 to 1.09; 7 trials, 1087 women; very low quality evidence). Mid-urethral sling operations have been the most extensively researched surgical treatment for stress urinary incontinence (SUI) in women and have a good safety profile. Irrespective of the routes traversed, they are highly effective in the short and medium term, and accruing evidence demonstrates their effectiveness in the long term. This review illustrates their positive impact on improving the quality of life of women with SUI. However, a brief economic commentary (BEC) identified three studies suggesting that transobturator may be more cost-effective compared with retropubic. Fewer adverse events occur with employment of a transobturator approach with the exception of groin pain. When comparing transobturator techniques of a medial-to-lateral versus a lateral-to-medial insertion, there is no evidence to support the use of one approach over the other. However, a bottom-to-top route was more effective than top-to-bottom route for retropubic tapes.A salient point illustrated throughout this review is the need for reporting of longer-term outcome data from the numerous existing trials. This would substantially increase the evidence base and provide clarification regarding uncertainties about long-term effectiveness and adverse event profile.


Protein overload-induced NF-kappaB activation in proximal tubular cells requires H(2)O(2) through a PKC-dependent pathway.
Abnormal traffic of proteins through the glomerular capillary has an intrinsic toxicity that results in tubular dysfunction and interstitial inflammation. It has been previously shown that in porcine proximal tubular cells high concentrations of albumin activated NF-kappaB, which is responsible for the enhanced synthesis of the inflammatory chemokine RANTES. This study investigates whether reactive oxygen species (ROS) served as second messengers in protein overload-induced NF-kappaB activation. Human proximal tubular cells (HK-2) were incubated (5 to 60 min) with human albumin and IgG (1 to 30 mg/ml). Both proteins induced a rapid or significant increase in hydrogen peroxide (H(2)O(2)) production at 5 min and persisting at 60 min. This effect was dose-dependent. The contribution of H(2)O(2) in regulating NF-kappaB activation was evaluated by using the antioxidants dimethyl-thiourea and pyrrolidine dithiocarbamate in protein-overloaded HK-2 cells. Both agents, by preventing H(2)O(2) generation, induced human albumin or IgG inhibited NF-kappaB activation. Stimulation of HK-2 with exogenous H(2)O(2) resulted in the activation of a NF-kappaB subunit pattern similar to that obtained after protein challenge. Specific inhibitors of protein kinase C (PKC) activity significantly prevented H(2)O(2) production and consequent NF-kappaB activation, suggesting that ROS generation in HK-2 cells occurs downstream of PKC activation. Either antioxidants or PKC inhibitor almost completely abolished the upregulation of the monocyte chemoattractant protein-1 gene induced by excess albumin, as evaluated by real-time PCR, thus supporting a role for PKC and ROS as critical signals for the expression of NF-kappaB-dependent inflammatory genes. To identify the enzymatic sources responsible for the increased H(2)O(2) production, the effect of dyphenyleneiodonium, an inhibitor of the membrane NADP(H) oxidase, was studied, as was the effect of rotenone, which blocks complex I of the mitochondrial respiratory chain. It was found that both agents significantly reduced the exaggerated H(2)O(2) induced by protein overload. These data indicate that exposure to excess proteins in proximal tubular cells induces the formation of ROS, which are responsible for NF-kappaB activation and consequent induction of NF-kappaB-dependent inflammatory signals.


Pharmacodynamic response to ionized calcium during acute sepsis.
Ionized Ca (Ca2+) is essential for maintaining physiologic functioning in the cardiovascular system (CVS). Sepsis affects the CVS by several mechanisms and is associated with decreased serum Ca2+. The pharmacodynamic response of the CVS to serum Ca2+ alteration was compared in acutely septic and nonseptic dogs at serum Ca2+ levels of 50%, 100%, 150% and 200% of normal baseline values. Serum Ca2+ alterations caused similar changes in both groups, although finite differences existed between septic and nonseptic subjects. Ca manipulation produced limited differences in the response of mean arterial pressure, cardiac output, left ventricular dP/dtmax, systemic (SVR) and pulmonary (PVR) vascular resistance between septic and nonseptic subjects. PVR and SVR demonstrated opposite responses during hypocalcemia; PVR was lower than baseline in both groups, whereas SVR was higher at the 50% level. No difference was evident for total oxygen consumption (VO2) or heart rate. In view of the limited differences in response and the failure to improve systemic VO2, serum Ca2+ supplementation does not afford any additional benefit in this experimental model of acute sepsis.


Violent and nonviolent video games differentially affect physical aggression for individuals high vs. low in dispositional anger.
Although numerous experiments have shown that exposure to violent video games (VVG) causes increases in aggression, relatively few studies have investigated the extent to which this effect differs as a function of theoretically relevant individual difference factors. This study investigated whether video game content differentially influences aggression as a function of individual differences in trait anger. Participants were randomly assigned to play a violent or nonviolent video game before completing a task in which they could behave aggressively. Results showed that participants high in trait anger were the most aggressive, but only if they first played a VVG. This relationship held while statistically controlling for dimensions other than violent content on which game conditions differed (e.g. frustration, arousal). Implications of these findings for models explaining the effects of video games on behavior are discussed.


Treatment Patterns of Multimorbid Patients with Rheumatoid Arthritis: Results from an International Cross-sectional Study.
To describe the treatment profile of multimorbid patients with rheumatoid arthritis (RA) in contrast to patients with RA only. COMORA (Comorbidities in Rheumatoid Arthritis) is a cross-sectional, international study assessing morbidities, outcomes, and treatment of patients with RA. Patients were grouped according to their multimorbidity profile assessed by a counted multimorbidity index (cMMI). Treatment for RA was categorized as use of biologic disease-modifying antirheumatic drugs (bDMARD), in particular tumor necrosis factor inhibitors (TNFi), synthetic DMARD (sDMARD) use only, nonsteroidal antiinflammatory drug (NSAID) use, and corticosteroid use. Logistic regression models were performed to determine the OR of bDMARD, TNFi, sDMARD, NSAID, or corticosteroid use based on a patient's cMMI and global region after adjusting for age, disease activity, disease duration, educational level, and previous DMARD therapy. Out of 3920 patients, 32.7% received bDMARD; 59.9% sDMARD only, 51.1% used concomitant NSAID, and 54.8% used corticosteroid. Regional differences were observed with the most frequent use of bDMARD in the United States (46.5%) and lowest in North Africa (9%). After adjusting for confounders in logistic regression, the OR for bDMARD use was reduced for each additional morbidity (OR 0.89, 95% CI 0.83-0.96). Similar results were found for TNFi (OR 0.91, 95% CI 0.84-0.99), whereas the OR for use of sDMARD was increased (1.13, 95% CI 1.05-1.22). No significant change of OR was found for NSAID or corticosteroid use. In this study, the odds of bDMARD use decreases 11% for each additional chronic morbid condition after adjustment for regional differences, disease activity, and other covariates.


Soft regulations in pharmaceutical policy making: an overview of current approaches and their consequences.
It is a challenge to improve public health within limited resources. Pharmaceutical policy making is a greater challenge due to conflicting interests between key stakeholder groups. This paper reviews current and future strategies to help improve the quality and efficiency of care, with special emphasis on demand-side controls for pharmaceutical prescribing. A large number of different educational, organizational, financial and regulatory strategies have been applied in pharmaceutical policy making. However, the effectiveness of most strategies has not been thoroughly evaluated and there is evidence that the behaviour of healthcare professionals is difficult to influence with traditional methods. During the last decades, new modes of governing and new governing constellations have also appeared in healthcare. However, relationships between those who regulate and those regulated are often unclear. New approaches have recently been introduced, including extensive dissemination strategies for guidelines and extensive quality assessment programmes where physicians' performances are measured against agreed standards or against each other. The main components of these 'soft regulations' are standardization, monitoring and agenda setting. However, the impact of these new modes on health provision and overall costs is often unknown, and the increased focus on monitoring may result in a higher conformity and uniformity that may not always benefit all key stakeholders. Alongside this, a substantial growth of auditing associations controlling a diminishing minority of people actually performing the tasks may be costly and counter-productive. As a result, new effective strategies are urgently needed to help maintain comprehensive healthcare without prohibitively raising taxes or insurance premiums. This is especially important where countries are faced with extreme financial problems. Healthcare researchers may benefit from researching other areas of society. However, any potential strategies initiated must be adequately researched, debated and evaluated to enhance implementation. We hope this opinion paper is the first step in the process to develop and implement new demand-side initiatives building on existing 'soft regulations'.