Secreted semaphorin 5A suppressed pancreatic tumour burden but increased metastasis and endothelial cell proliferation.
Our earlier reports demonstrated that membrane-bound semaphorin 5A (SEMA5A) is expressed in aggressive pancreatic cancer cells and tumours, and promotes tumour growth and metastasis. In this study, we examine whether (1) pancreatic cancer cells secrete SEMA5A and (2) that secreted SEMA5A modulates certain phenotypes associated with tumour progression, angiogenesis and metastasis through various other molecular factors and signalling proteins. In this study, we show that human pancreatic cancer cell lines secrete the extracellular domain (ECD) of SEMA5A (SEMA5A-ECD) and overexpression of mouse Sema5A-ECD in Panc1 cells (not expressing SEMA5A; Panc1-Sema5A-ECD; control cells - Panc1-control) significantly increases their invasion in vitro via enhanced ERK phosphorylation. Interestingly, orthotopic injection of Panc1-Sema5A-ECD cells into athymic nude mice results in a lower primary tumour burden, but enhances the micrometastases to the liver as compared with Panc1-control cells. Furthermore, there is a significant increase in proliferation of endothelial cells treated with conditioned media (CM) from Panc1-Sema5A-ECD cells and a significant increase in microvessel density in Panc1-Sema5A-ECD orthotopic tumours compared with those from Panc1-control cells, suggesting that the increase in liver micrometastases is probably due to increased tumour angiogenesis. In addition, our data demonstrate that this increase in endothelial cell proliferation by Sema5A-ECD is mediated through the angiogenic molecules - interleukin-8 and vascular endothelial growth factor. Taken together, these results suggest that a bioactive, secreted form of Sema5A-ECD has an intriguing and potentially important role in its ability to enhance pancreatic tumour invasiveness, angiogenesis and micrometastases.


Association between apolipoprotein E polymorphism and Alzheimer disease in Tehran, Iran.
Epsilon 4 allele of apolipoprotein E (APOE-epsilon4) is a major risk factor for Alzheimer's disease (AD). The association of APOE allele frequencies with AD remains unknown in developing countries. We examined the frequency of APOE alleles in 105 patients with AD and 129 cognitively normal subjects of similar age and sex (control group), in Tehran, Iran. The APOE-epsilon4 allele frequency was significantly higher in the AD subjects than in the control group (21% versus 6.2%, p < 0.001). In addition, the OR for APOE-epsilon4 heterozygous and homozygous subjects were 3.2 (p = 0.001) and 12.75 (p = 0.01), respectively. The OR was not uniform across age groups. The AD subjects carrying one or two APOE-epsilon4 allele showed earlier age-at-onset (p < 0.001). These data suggest that the APOE-epsilon4 allele increase the risk for AD in Tehran population in a dose and age-dependent manner. Although the APOE-epsilon2 allele frequency was lower in the AD subjects than in the control group (0.95% versus 2.7%, p = 0.15), APOE-epsilon2 was not associated with the onset of AD in Tehran's population. The OR for epsilon2 allele in AD subjects was 0.34 (p = 0.21). The genotype frequencies for epsilon3, epsilon4, and epsilon2 alleles in control subjects were 91.2, 6.1, and 2.7%, respectively. These values were similar to that reported for Turkish, Greece, Japanese, Spanish, and Moroccan populations, but they were significantly different from the reported values for the other ethnic populations. This observation emphasizes the importance of geographical location and ethnical background of the subjects in the study of APOE genotypes and their association with AD.


Elongation/Termination Factor Exchange Mediated by PP1 Phosphatase Orchestrates Transcription Termination.
Termination of RNA polymerase II (Pol II) transcription is a key step that is important for 3' end formation of functional mRNA, mRNA release, and Pol II recycling. Even so, the underlying termination mechanism is not yet understood. Here, we demonstrate that the conserved and essential termination factor Seb1 is found on Pol II near the end of the RNA exit channel and the Rpb4/7 stalk. Furthermore, the Seb1 interaction surface with Pol II largely overlaps with that of the elongation factor Spt5. Notably, Seb1 co-transcriptional recruitment is dependent on Spt5 dephosphorylation by the conserved PP1 phosphatase Dis2, which also dephosphorylates threonine 4 within the Pol II heptad repeated C-terminal domain. We propose that Dis2 orchestrates the transition from elongation to termination phase during the transcription cycle by mediating elongation to termination factor exchange and dephosphorylation of Pol II C-terminal domain.


NLRX1 negatively regulates TLR-induced NF-κB signaling by targeting TRAF6 and IKK.
Tight regulation of NF-κB signaling is essential for innate and adaptive immune responses, yet the molecular mechanisms responsible for its negative regulation are not completely understood. Here, we report that NLRX1, a NOD-like receptor family member, negatively regulates Toll-like receptor-mediated NF-κB activation. NLRX1 interacts with TRAF6 or IκB kinase (IKK) in an activation signal-dependent fashion. Upon LPS stimulation, NLRX1 is rapidly ubiquitinated, disassociates from TRAF6, and then binds to the IKK complex, resulting in inhibition of IKKα and IKKβ phosphorylation and NF-κB activation. Knockdown of NLRX1 in various cell types markedly enhances IKK phosphorylation and the production of NF-κB-responsive cytokines after LPS stimulation. We further provide in vivo evidence that NLRX1 knockdown in mice markedly enhances susceptibility to LPS-induced septic shock and plasma IL-6 level. Our study identifies a previously unrecognized role for NLRX1 in the negative regulation of TLR-induced NF-κB activation by dynamically interacting with TRAF6 and the IKK complex.


Large-scale synthesis and functionalization of hexagonal boron nitride nanosheets.
A simple and inexpensive method to functionalize hexagonal boron nitride (hBN) was achieved by using an acid mixture of phosphoric and sulphuric acid. This functionalization induced the exfoliation of the layered structure of hBN into monolayer to few-layer sheets where the sizes of the sheets were dependent on the parent hBN powder used. Exfoliated hBN was shown to be stable in solvents such as ethanol, acetone, deionized water and isopropyl alcohol, and this stability was linked to sulfur functionalization that was induced during the exfoliation process. Further evidence of the functionalization was observed using transmission electron spectroscopy (TEM) and X-ray photoelectron spectroscopy (XPS). By deconvoluting the high resolution peaks for B 1s, the bonding of boron to oxygen and sulfur was confirmed. The exfoliated hBN nanosheets were crystalline as confirmed from X-ray diffraction and they also exhibited an optically active defect related to sulfur functionalization at 320 nm (3.9 ± 0.1 eV).


Comparison of analytical methods to detect instability of etanercept during thermal stress testing.
The aim was comparing the capability of a set of analytical methods to detect physical instability (focus on aggregation and structural changes) of etanercept during thermal stress testing as early as possible. Pre-filled syringes of Enbrel® 50mg from three batches were thermally stressed for one week at 50°C. Samples were taken at days 0, 1, 2, 3, 4 and 7, and analyzed with high-performance liquid size exclusion chromatography (HP-SEC), SDS-PAGE gel electrophoresis, dynamic light scattering (DLS), light obscuration, extrinsic fluorescence (Bis-ANS), far-UV circular dichroism (CD) spectroscopy, second derivative UV spectroscopy (UV), and enzyme-linked immunosorbent assay (ELISA). Thermal stress resulted in the formation of small soluble aggregates (HP-SEC, DLS) which were in part covalent (SDS-PAGE), and conformationally changed (Bis-ANS, CD, UV). No significant increase in subvisible particles was detected by light obscuration. An apparent increase in TNF-α binding to etancercept in the stressed formulations was found by ELISA. The three batches were comparable when unstressed, but showed slight differences in aggregation tendency. Bis-ANS fluorescence was most sensitive with respect to early-stage detection of heat-induced instability of etanercept (significant changes already at day 1), followed by HP-SEC (day 2) and DLS (day 3). This points towards a degradation mechanism involving exposure of hydrophobic patches due to partial unfolding followed by aggregation.


Suppression of mesangial proliferative glomerulonephritis development in rats by inhibitors of cAMP phosphodiesterase isozymes types III and IV.
Excessive mesangial cell (MC) proliferation is a hallmark of many glomerulopathies. In our recent study on cultured rat MC (Matousovic, K., J.P. Grande, C.C.S. Chini, E.N. Chini, and T.P. Dousa. 1995. J. Clin. Invest. 96:401-410) we found that inhibition of isozyme cyclic-3',5'-nucleotide phosphodiesterase (PDE) type III (PDE-III) suppressed MC mitogenesis by activating cAMP-dependent protein kinase (PKA) and by decreasing activity of mitogen-activated protein kinase (MAPK). We also found that inhibition of another PDE isozyme, PDE-IV, suppresses superoxide generation in glomeruli (Chini, C.C.S., E.N. Chini, J.M. Williams, K. Matousovic, and T.P. Dousa. 1994. Kidney Int. 46:28-36). We thus explored whether administration in vivo of the selective PDE-III antagonist, lixazinone (LX), together with the specific PDE-IV antagonist, rolipram (RP), can attenuate development of mesangioproliferative glomerulonephritis (MSGN) induced in rats by anti-rat thymocyte serum (ATS). Unlike the vehicle-treated MSGN rats, rats with MSGN treated with LX and RP did not develop proteinuria and maintained normal renal function when examined 5 d after injection of ATS. In PAS-stained kidneys from PDE-antagonists-treated MSGN-rats the morphology of glomeruli showed a reduction in cellularity compared with control rats with ATS. Compared with MSGN rats receiving vehicle, the MSGN rats receiving PDE-antagonists had less glomerular cell proliferation (PCNA delta -65%), a significantly lesser macrophage infiltration (delta -36% ED-1) and a significant reduction of alpha-smooth muscle actin expression by activated MC; in contrast, immunostaining for platelet antigens and laminin were not different. The beneficial effect of PDE inhibitors was not due to a moderate decrease (approximately -20%) in systolic blood pressure (SBP); as a similar decrease in SBP due to administration of hydralazine, a drug devoid of PDE inhibitory effect, did not reduce severity of MSGN in ATS-injected rats. We conclude that antagonists of PDE-III and PDE-IV administered in submicromolar concentrations in vivo to ATS-injected rats can decrease the activation and proliferation of MC, inhibit the macrophage accumulation, and prevent proteinuria in the acute phase of MSGN. We propose that PDE isozyme inhibitors act to block (negative "crosstalk") the mitogen-stimulated intracellular signaling pathway which controls MC proliferation due to activating of the cAMP-PKA pathway. These results suggest that antagonists of PDE-111 and IV may have a suppressive effect in acute phases or relapses of glomerulopathies associated with MC proliferations.


Unexplained bleeding as primary clinical complaint in dogs infected with Angiostrongylus vasorum.
Unexplained bleeding was the primary clinical complaint in 15 dogs diagnosed with A. vasorum and was observed in the mouth, as external bleeding, as large subcutaneous hematoma, as hemoptysis, in the brain, post ovariectomy, as epistaxis, in the anterior ocular chamber and on a tracheal intubation tube. In 8 dogs the cause of bleeding initially was suspected to be a minor trauma or a surgical complication, and various surgical approaches had been undertaken to eliminate the problem. In only 3 dogs respiratory signs were observed before the bleeding prompted referral. The median time elapsed between the first recognized clinical signs attributed to A. vasorum until diagnosis was 2 weeks (range1 day to 4 months). Four dogs died, 3 on the day of admission and 1 dog 4 days after admission. Suspected causes of death were respiratory failure and cerebral hemorrhage in 2 dogs each. Four dogs had been pre-treated with NSAIDs; of these, 2 dogs developed severe hemoptysis (1 died), 1 dog developed brain hemorrhage (and died), and 1 dog developed a large subcutaneous hematoma with marked anemia. Bleeding at various sites may be the only recognized abnormality in A. vasorum infection. Without a high index of suspicion, the diagnosis and appropriate therapy may be delayed to the point of a fatal outcome. Tests of coagulation were quite variable and the cause of bleeding likely multifactorial.


Core-shell nanostructured nanoparticle films as chemically sensitive interfaces.
This paper reports the results of an investigation of vapor molecule sorption at different types of nanostructured nanoparticle films. Core-shell nanoparticles of two different core sizes, AU2-nm and Au5-nm, and molecular linkers of two different binding properties, 1,9-nonanedithiol and 11-mercaptoundecanoic acid, are utilized as building blocks for constructing chemically sensitive interfaces. The work couples measurements of two different transducers, interdigitated microelectrodes and quartz crystal microbalance, to determine the correlation of the electronic resistance change and the mass loading with vapor sorption. The responses to vapor sorption at these nanostructured interfaces are demonstrated to be dependent on the core size of nanoparticles and the chemical nature of linking molecules. The difference of molecular interactions of vapor molecules at the nanostructured interface is shown to have a significant impact on the response profile and sensitivity. For the tested vapor molecules, while there are small differences for the sorption of nonpolar and hydrophobic vapor molecules, there are striking differences for the sorption of polar and hydrophilic vapor molecules at these nanostructured interfacial materials. The implication of the findings to the delineation of design parameters for constructing core-shell nanoparticle assemblies as chemically sensitive interfacial materials is also discussed.


Predictors of the short-term responder rate of Electroconvulsive therapy in depressive disorders--a population based study.
The aim of the present study is to investigate the responder rate of Electroconvulsive therapy, ECT, in clinical routine work and to define clinical characteristics predictive of response to ECT. The main hypothesis is that the responder rate of ECT might be lower in clinical routine than in controlled trials. This is a population-based study of all patients (N = 990) treated with ECT for depressive disorders, between 2008-2010 in eight hospitals in Sweden. Patients with Clinical Global Impression-Improvement scores of 1 or 2 (much improved) within one week after ECT were considered responders to ECT. The predictive values of single clinical variables were tested by means of chi-squared tests and the relative importance was tested in a logistic regression analysis. The responder rate was 80.1%. A higher proportion of older patients (>50 years) responded (84.3% vs. 74.2%, p < 0.001). Psychotically depressed patients responded better (88.9% vs. 81.5% for severely depressed and 72.8% for mildly depressed, p < 0.001). There were no significant differences in responder rates between patients suffering from bipolar, first or recurrent major depressive syndromes, or a depressive episode of schizoaffective disorder. Patients with personality disorder had a lower responder rate (66.2% vs. 81.4%, p < 0.001). Also, outpatients had a lower responder rate (66.3%) compared to inpatients (83.4%, p < 0.001). In the logistic regression analysis, inpatient status, psychotic symptoms, absence of schizoaffective disorder and older age were independent factors associated with response to ECT. This study focuses exclusively on the short term responder rate with ECT in clinical practice. Similarly to results from controlled trials a high responder rate is reported. Older patients, more severely ill patients, psychotically ill patients and patients without personality disorders had the highest responder rates. Inpatients may have better outcome with ECT than outpatients.


The Development of an Open Hardware and Software System Onboard Unmanned Aerial Vehicles to Monitor Concentrated Solar Power Plants.
Concentrated solar power (CSP) plants are increasingly gaining interest as a source of renewable energy. These plants face several technical problems and the inspection of components such as absorber tubes in parabolic trough concentrators (PTC), which are widely deployed, is necessary to guarantee plant efficiency. This article presents a system for real-time industrial inspection of CSP plants using low-cost, open-source components in conjunction with a thermographic sensor and an unmanned aerial vehicle (UAV). The system, available in open-source hardware and software, is designed to be employed independently of the type of device used for inspection (laptop, smartphone, tablet or smartglasses) and its operating system. Several UAV flight missions were programmed as follows: flight altitudes at 20, 40, 60, 80, 100 and 120 m above ground level; and three cruising speeds: 5, 7 and 10 m/s. These settings were chosen and analyzed in order to optimize inspection time. The results indicate that it is possible to perform inspections by an UAV in real time at CSP plants as a means of detecting anomalous absorber tubes and improving the effectiveness of methodologies currently being utilized. Moreover, aside from thermographic sensors, this contribution can be applied to other sensors and can be used in a broad range of applications where real-time georeferenced data visualization is necessary.


Oxidative stability and consumer acceptance of fish oil fortified nutrition bars.
Oat and soy-based nutrition bars were fortified with 4 levels of fish oil (0, 6, 12, or 18 g per approximately 600 g batch), representing 0%, 20%, 40%, or 60% replacement of canola oil. The commercially available purified fish oil was not emulsified nor encapsulated, and contained tocopherols. Baked nutrition bars were evaluated for proximate composition, water activity, alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic (DHA) content, and consumer acceptance using a 9-point hedonic scale. The bars were sealed in opaque bags and stored in a stability chamber at 25 °C and 50% relative humidity for 10 wk to assess oxidative stability. There were no significant (P > 0.05) differences in proximate composition, water activity, or ALA levels among treatments. EPA and DHA levels were significantly (P < 0.05) different among treatments, averaging 178.1 mg/serving (20-FO), 488.3 mg/serving (40-FO), and 664.6 mg/serving (60-FO), but none changed during storage. Headspace hexanal and propanal levels decreased over time but were not significantly different among treatments until week 10. Peroxide values were not significantly different except between the control and 60-FO bars. Low values obtained for these analyses suggest negligible oxidation in the bars. Consumer acceptance scores did not differ significantly between the control and lowest fortification level (20-FO), ranging from 6.4 to 6.6 for aroma, texture, flavor, and overall acceptability. These results suggest that nonemulsified, nonencapsulated fish oil can successfully replace canola oil in intermediate moisture nutrition bars to provide EPA and DHA levels as high as 178 mg/serving without affecting consumer acceptability or oxidative stability. Omega-3 fatty acid rich fish oil has been shown to have numerous health benefits, but there are limitations to its use in shelf-stable food products. In this study, nutrition bars were successfully fortified with nonencapsulated, nonemulsified fish oil to deliver 178 mg EPA and DHA per 35 g serving. The fortified bars were oxidatively stable over 10 wk and acceptable to consumers.


The mini-PET in pediatric peritoneal dialysis: a useful tool to predict volume overload?
Cardiovascular disease (CVD) in patients on chronic peritoneal dialysis (PD) is a major cause of death and is closely linked to hypertension and volume overload. The mini-Pet has been proposed as a useful tool to evaluate free-water transport (FWT) and characterize ultrafiltration across the peritoneum. Knowledge regarding FWT could be of great value to predict volume overload in PD patients. Our objective in this study was to characterize FWT through the peritoneum in children on PD. We studied clinically stable patients with >2 months on PD. Exclusion criteria were a peritonitis episode up to 2 months prior to entrance into the study and active nephrotic syndrome. A 1-h mini-peritoneal equilibration test (mini-PET) was performed with 3.86 % glucose. Calculations (see text for full definitions) were: Dip Na (Na dial min60 - Na dial min1), Dip D/PNa (D/PNa60 - D/PNa1), total Na removal (NaR = total Na dial60 - Na dial1), ultrafiltration small pores [(UFSP = NaR × 1,000)/Nap], and FWT (UF-UFSP). Peritoneal equilibration test (PET), left ventricular mass index (LVMI, g/m(2)), daily UF, and residual renal function were evaluated. Pearson's correlation coefficient was used to establish correlation between variables. Sixteen patients were included, with a mean age of 11.8 ± 3.8 years. Free water transport normalized to body surface area (BSA) (FWTn) was 133.9 ± 85.7 ml/m(2); creatinine dialysate-to-plasma (D/P) and glucose dialysate at X dwell time-to-0 dwell time (Dx/D0) ratios were 0.38 ± 0.1 and 0.65 ± 0.09, respectively. LVMI was 46.6 ± 14.8 g/m(2); 2-h creatinine D/P and glucose Dx/D0 showed no correlation with FWTn, UF, and LVMI. FWTn showed a significant inverse correlation with LVMI (r 0.58, p 0.02). This study characterized FWT in PD children through the mini-PET. Left ventricular hypertrophy showed a high prevalence in this group, and a significant correlation between LVMI and FWT was found. FWT could be a useful tool to evaluate UF in PD children.


No-guard-interval coherent optical OFDM with self-tuning receiver.
We propose and experimentally demonstrate a no-guard-interval (No-GI) coherent optical orthogonal frequency division multiplexed (CO-OFDM) system that uses Fractionally-Spaced Time-Domain Equalizers (FS-TDE) to simultaneously demultiplex and equalize each subcarrier. Least-mean-squares algorithms (LMS) tune each FS-TDE to a subcarrier. A short unique training sequence is transmitted on each subcarrier, allowing each FS-TDE to lock onto its subcarrier. After the initial training, the adaptive blind equalizers remain tuned to their respective subcarriers. Unlike previous systems, this system does not require digital filtering or mixing of each subcarrier to baseband, so is more computationally efficient. Error-free transmission was measured over 800 km of fiber with a three-subcarrier 30 Gb/s system and a five-subcarrier 33.33 Gb/s system. The required OSNRs for a BER of 10(-3) were 8.6 dB and 9.3 dB respectively, which are within 1.5 dB of the theoretical limit for coherent systems.


Anterior iliac crest bone graft harvesting using the corticocancellous reamer system.
To evaluate the anterior iliac crest bone graft harvesting procedure using a corticocancellous acetabular reamer system. A total of 390 bone grafting procedures were reviewed using retrospective chart review. Two hundred twenty procedures were performed using the reamer system, and 170 were performed using traditional techniques (cortical strip, tricortical wedge, and cancellous trap door grafts). The Hospital for Special Surgery, New York, New York. Operative cases involving an anterior iliac crest bone graft procedure between January 1, 1991 and February 28, 1998. Complications were organized by the categories major, intermediate, and minor. Statistical analysis included assessment of comorbidity to determine risk factors that may be associated with a propensity for complications. Of the 390 patients reviewed, 13.1 percent (51 of 390) developed a total of seventy-one complications. Of the seventy-one complications, forty were reamer-associated and thirty-one were traditional method-associated complications. As compared with the traditional group, major morbidity was lower in the reamer group (0.9 percent [2 of 220] as compared with 1.8 percent [3 of 170] [ p = 0.4]). Intermediate and minor morbidity were slightly higher in the reamer group than in the traditional group (5.9 percent [13 of 220] as compared with 5.3 percent [9 of 170] [ p = 0.7] and 9.5 percent [21 of 220] as compared with 7.1 percent [12 of 170] [ p = 0.4], respectively). Of the forty reamer-associated complications, 90 percent (36 of 40) resolved within ninety days (average 36.6 days). Of the thirty-one traditional method-associated complications, 74.2 percent (23 of 31) were resolved by 90 days (average 50.6 days). Using logistical regression analysis obesity (body mass index) ( p = 0.03) and smoking ( p = 0.03) were correlated with development of a complication. Furthermore, if a patient was obese and a smoker, the analysis predicted an 83 percent chance of developing a complication. The reamer technique was found to be safe and efficacious while producing a large amount of autogenous corticocancellous bone graft. Overall complication rates for the reamer and the traditional groups were comparable. The corticocancellous reamer system represents an effective option for bone graft harvesting.


UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) binds to alpha-actinin 1: novel pathways in skeletal muscle?
Hereditary inclusion body myopathy (HIBM) is a rare neuromuscular disorder caused by mutations in GNE, the key enzyme in the biosynthetic pathway of sialic acid. While the mechanism leading from GNE mutations to the HIBM phenotype is not yet understood, we searched for proteins potentially interacting with GNE, which could give some insights about novel putative biological functions of GNE in muscle. We used a Surface Plasmon Resonance (SPR)-Biosensor based assay to search for potential GNE interactors in anion exchanged fractions of human skeletal muscle primary culture cell lysate. Analysis of the positive fractions by in vitro binding assay revealed alpha-actinin 1 as a potential interactor of GNE. The direct interaction of the two proteins was assessed in vitro by SPR-Biosensor based kinetics analysis and in a cellular environment by a co-immunoprecipitation assay in GNE overexpressing 293T cells. Furthermore, immunohistochemistry on stretched mouse muscle suggest that both GNE and alpha-actinin 1 localize to an overlapping but not identical region of the myofibrillar apparatus centered on the Z line. The interaction of GNE with alpha-actinin 1 might point to its involvement in alpha-actinin mediated processes. In addition these studies illustrate for the first time the expression of the non-muscle form of alpha-actinin, alpha-actinin 1, in mature skeletal muscle tissue, opening novel avenues for its specific function in the sarcomere. Although no significant difference could be detected in the binding kinetics of alpha-actinin 1 with either wild type or mutant GNE in our SPR biosensor based analysis, further investigation is needed to determine whether and how the interaction of GNE with alpha-actinin 1 in skeletal muscle is relevant to the putative muscle-specific function of alpha-actinin 1, and to the muscle-restricted pathology of HIBM.


Optogenetic mimicry of the transient activation of dopamine neurons by natural reward is sufficient for operant reinforcement.
Activation of dopamine receptors in forebrain regions, for minutes or longer, is known to be sufficient for positive reinforcement of stimuli and actions. However, the firing rate of dopamine neurons is increased for only about 200 milliseconds following natural reward events that are better than expected, a response which has been described as a "reward prediction error" (RPE). Although RPE drives reinforcement learning (RL) in computational models, it has not been possible to directly test whether the transient dopamine signal actually drives RL. Here we have performed optical stimulation of genetically targeted ventral tegmental area (VTA) dopamine neurons expressing Channelrhodopsin-2 (ChR2) in mice. We mimicked the transient activation of dopamine neurons that occurs in response to natural reward by applying a light pulse of 200 ms in VTA. When a single light pulse followed each self-initiated nose poke, it was sufficient in itself to cause operant reinforcement. Furthermore, when optical stimulation was delivered in separate sessions according to a predetermined pattern, it increased locomotion and contralateral rotations, behaviors that are known to result from activation of dopamine neurons. All three of the optically induced operant and locomotor behaviors were tightly correlated with the number of VTA dopamine neurons that expressed ChR2, providing additional evidence that the behavioral responses were caused by activation of dopamine neurons. These results provide strong evidence that the transient activation of dopamine neurons provides a functional reward signal that drives learning, in support of RL theories of dopamine function.


The Problem of Expertise in Knowledge Societies.
This paper puts forward a theoretical framework for the analysis of expertise and experts in contemporary societies. It argues that while prevailing approaches have come to see expertise in various forms and functions, they tend to neglect the broader historical and societal context, and importantly the relational aspect of expertise. This will be discussed with regard to influential theoretical frameworks, such as laboratory studies, regulatory science, lay expertise, post-normal science, and honest brokers. An alternative framework of expertise is introduced, showing the limitations of existing frameworks and emphasizing one crucial element of all expertise, which is their role in guiding action.


Use of paracetamol for suicide and non-fatal poisoning in the UK and France: are restrictions on availability justified?
To investigate the relationship between the availability of paracetamol and its use for overdose and suicide. Analysis of routinely collected information on time trends for paracetamol suicides, non-fatal overdoses, and sales. England and Wales and France. There were strong correlations between trends in paracetamol sales in the UK and trends in non-fatal paracetamol overdose in Oxford between 1976 and 1993 (Spearman's r = 0.86; 95% confidence interval (CI) 0.54, 0.96) and between paracetamol sales and non-fatal overdoses in France between 1974 and 1990 (r = 0.99; 95% CI 0.97, 1.00). Sales figures were also correlated with paracetamol related suicides in both England and Wales, 1983-91 (r = 0.72; 95% CI 0.11, 0.94) and France, 1974-90 (r = 0.79; 95% CI 0.50, 0.92). Similarly strong relationships were observed between trends in non-fatal overdoses and suicide by paracetamol poisoning in England and Wales (r = 0.85; 95% CI 0.61, 0.95) and France (r = 0.79; 95% CI 0.50, 0.92). It is estimated that approximately 32,000 overdoses involving paracetamol occur annually in England and Wales. Fatality rates from paracetamol overdose were four times as high in England and Wales (0.4%, 95% CI 0.38, 0.46) as in France (0.1%, 95% CI 0.06, 0.17). Trends towards greater availability of paracetamol are paralleled by increases in its use for both non-fatal overdose and suicide. Paracetamol related morbidity and mortality seem to be less frequent in France where the quantity of paracetamol in a single purchase is limited. Although not conclusive, these data add to a body of evidence which suggests that restrictions in the quantity of paracetamol available as a single purchase in the UK may reduce suicide and liver failure related to paracetamol.


Morphological Features Extracted by AI Associated with Spatial Transcriptomics in Prostate Cancer.
Prostate cancer is a common cancer type in men, yet some of its traits are still under-explored. One reason for this is high molecular and morphological heterogeneity. The purpose of this study was to develop a method to gain new insights into the connection between morphological changes and underlying molecular patterns. We used artificial intelligence (AI) to analyze the morphology of seven hematoxylin and eosin (H&E)-stained prostatectomy slides from a patient with multi-focal prostate cancer. We also paired the slides with spatially resolved expression for thousands of genes obtained by a novel spatial transcriptomics (ST) technique. As both spaces are highly dimensional, we focused on dimensionality reduction before seeking associations between them. Consequently, we extracted morphological features from H&E images using an ensemble of pre-trained convolutional neural networks and proposed a workflow for dimensionality reduction. To summarize the ST data into genetic profiles, we used a previously proposed factor analysis. We found that the regions were automatically defined, outlined by unsupervised clustering, associated with independent manual annotations, in some cases, finding further relevant subdivisions. The morphological patterns were also correlated with molecular profiles and could predict the spatial variation of individual genes. This novel approach enables flexible unsupervised studies relating morphological and genetic heterogeneity using AI to be carried out.


Beneficial effects of Lycium barbarum polysaccharide on spermatogenesis by improving antioxidant activity and inhibiting apoptosis in streptozotocin-induced diabetic male mice.
Spermatogenic dysfunction is one of the major secondary complications of diabetes. L. barbarum polysaccharide (LBP) has long been considered to possess anti-apoptotic activities and antioxidant, anti-inflammatory and fertility-enhancing properties in traditional medical practices in China. The aim of the current study was to seek out scientific evidence to determine if LBP also contributes to the recovery from spermatogenic dysfunction in diabetic individuals. We investigated whether the oral administration of LBP in streptozotocin (STZ)-induced type-1 diabetic male mice would reverse spermatogenic dysfunction and improve histological damage in testes. After the oral administration of LBP (10, 20 or 40 mg kg-1, respectively), sildenafil citrate (5 mg kg-1) or saline for 62 consecutive days, the sperm parameters were analyzed. Macroscopic and microscopic changes in the reproductive organs, including their weight, and photomicroscope and electronmicroscope images were also assessed. In addition, the antioxidant capacity and levels of malondialdehyde in the testes were determined according to the instructions provided with the assay kits and the expression of the apoptosis-related proteins, Caspase-3, Bax and Bcl-2, in the testes was analyzed using western-blot analysis. LBP treatment of diabetic mice considerably recovered the sperm parameters, increased the weight of the reproductive organs, ameliorated their histological appearance and increased antioxidant enzyme activity to different degrees. Moreover, our data also showed a marked decrease in Caspase-3 expression and an increase in the ratio of Bcl-2/Bax 43 after LBP administration (40 mg kg-1) when compared to the diabetic group. These results demonstrate that LBP exerts protective effects on diabetes induced male spermatogenic dysfunction, which is likely to be mediated through increasing antioxidant enzyme activities and inhibiting cell death.


Protein disorder prediction: implications for structural proteomics.
A great challenge in the proteomics and structural genomics era is to predict protein structure and function, including identification of those proteins that are partially or wholly unstructured. Disordered regions in proteins often contain short linear peptide motifs (e.g., SH3 ligands and targeting signals) that are important for protein function. We present here DisEMBL, a computational tool for prediction of disordered/unstructured regions within a protein sequence. As no clear definition of disorder exists, we have developed parameters based on several alternative definitions and introduced a new one based on the concept of "hot loops," i.e., coils with high temperature factors. Avoiding potentially disordered segments in protein expression constructs can increase expression, foldability, and stability of the expressed protein. DisEMBL is thus useful for target selection and the design of constructs as needed for many biochemical studies, particularly structural biology and structural genomics projects. The tool is freely available via a web interface (http://dis.embl.de) and can be downloaded for use in large-scale studies.


A new distance measure for model-based sequence clustering.
We review the existing alternatives for defining model-based distances for clustering sequences and propose a new one based on the Kullback-Leibler divergence. This distance is shown to be especially useful in combination with spectral clustering. For improved performance in real-world scenarios, a model selection scheme is also proposed.


Review: Plasma renin and the incidence of cardiovascular disease.
Whether renin is involved in the onset of coronary heart disease (CHD) remains unclear. A case-control study in 1972, suggesting a causal association between renin and CHD, has now been followed by three prospective studies. One was based on 1,717 hypertensive subjects in a Work-Site Program in New York. The main results showed an increased risk of CHD the higher the renin level. A second study in occupational groups in North West London, UK, recruited 803 white men not selected according to blood pressure, and found no association. A possible exception was in the minority of those with similar blood pressure levels to participants in the Work-Site Program, in whom the incidence of CHD was higher according to the renin level, but not significantly so. The third study was in Framingham Offspring and included 3,532 participants also not selected according to blood pressure. As in the UK study, there was no clear association between renin and risk of CHD in all participants, or in this study in those with raised blood pressure. The authors considered their results consistent with those of the UK study in finding "no association of renin with overall risk of CHD". Besides the three epidemiological studies, dealing explicitly with renin, other studies in which it has been one of several variables considered have also not found convincing evidence of its involvement in CHD. There is, therefore, little support for the hypothesis that high renin levels increase the risk of CHD, with the possible but uncertain exception of those with raised blood pressure.


Plasma DNA Analysis in Prostate Cancer: Opportunities for Improving Clinical Management.
Molecular characterization of tumors could be important for clinical management. Plasma DNA obtained noninvasively as a liquid biopsy could be widely applicable for clinical implementation in biomarker-based treatment strategies. Prostate cancer is a disease with variable clinical outcomes and molecular features and therefore presents multiple opportunities for biomarker-based treatment optimization. Tissue analysis may not be representative of the lethal clone in localized disease or of intrapatient, intermetastases heterogeneity; fresh tissue is often challenging to obtain by biopsy of metastasis, whereas archival samples may not represent current disease and may be of insufficient quality. Plasma DNA is of variable tumor-to-normal fraction that requires accurate estimation using sensitively measured genomic events. In plasma with sufficient tumor content, the spectrum of genomic aberrations closely resembles tissue and could be used to molecularly characterize patients in real time. In this review we discuss the opportunities for improving clinical management by using plasma DNA analysis in different clinical scenarios across the disease spectrum, from detection of prostate cancer and disease relapse to treatment response prediction, response assessment, and interrogation of treatment resistance in metastatic prostate cancer. Combinational strategies may incorporate other modalities, including circulating tumor cells, circulating microRNA, and extracellular vesicles analysis, which could help to achieve more accurate characterization. There are many opportunities for plasma DNA analyses to change clinical management. However, there are challenges that need to be addressed to clinically implement a test, including the development of accurate, fit for purpose, and technically reproducible assay, followed by prospective validation in a large cohort of patients.


The effect of ondansetron and meperedin on preventing shivering after off-pump coronary artery bypass graft.
One of the most common complications of operation and anesthesia is shivering. The purpose of this study was to compare the effectiveness of Ondanseton and Meperedine in preventing shivering after off-pump coronary artery bypass graft (OPCAB). In this double-blind randomized clinical trial, the sample consisted of 90 patients, who were candidates of CABG under general anesthesia. These patients were assigned to three groups, each containing 30 subjects: meperedine group (A), ondansetron group (B) and control group (C). Group (A) received 0.4 mg/Kg/IV of meperedine, group (B) received 8mg/IV of ondansetron and group (C) received Normal Saline. All these drugs were injected 15 minutes before the end of surgery. After the end of surgery, the intubated patients were transferred to the ICU and their body temperature was assessed through eardrum by a specialist who was blind to the research. The incidence of shivering in groups A, B, and C was 46.48%, 31.18%, and 60.83%, respectively (P=<0.01). The incidence of shivering was 64.4% in males and 35.6% in females (P=0.222). Also, the amount of incidence of shivering up to 3 hours after surgery was 75.87 % (P=0.064). Bradycardia was 3.3% in group (A) and 0.0 % in group (B). Other variables (myoclonus, seizure and rash) showed no statistically significant difference (P=0.353). According to the findings, it was demonstrated that ondansetron is more effective in preventing shivering after Off-pump CABG than meperedine.


Safety reporting on implantation of autologous adipose tissue-derived stem cells with platelet-rich plasma into human articular joints.
Adipose tissue-derived stem cells (ADSCs), a type of mesenchymal stem cells (MSCs), have great potential as therapeutic agents in regenerative medicine. Numerous animal studies have documented the multipotency of ADSCs, showing their capabilities to differentiate into tissues such as muscle, bone, cartilage, and tendon. However, the safety of autologous ADSC injections into human joints is only beginning to be understood and the data are lacking. Between 2009 and 2010, 91 patients were treated with autologous ADSCs with platelet-rich plasma (PRP) for various orthopedic conditions. Stem cells in the form of stromal vascular fraction (SVF) were injected with PRP into various joints (n = 100). All patients were followed for symptom improvement with visual analog score (VAS) at one month and three months. Approximately one third of the patients were followed up with third month magnetic resonance imaging (MRI) of the injected sites. All patients were followed up by telephone questionnaires every six months for up to 30 months. The mean follow-up time for all patients was 26.62 ± 0.32 months. The follow-up time for patients who were treated in 2009 and early 2010 was close to three years. The relative mean VAS of patients at the end of one month follow-up was 6.55 ± 0.32, and at the end of three months follow-up was 4.43 ± 0.41. Post-procedure MRIs performed on one third of the patients at three months failed to demonstrate any tumor formation at the implant sites. Further, no tumor formation was reported in telephone long-term follow-ups. However, swelling of injected joints was common and was thought to be associated with death of stem cells. Also, tenosinovitis and tendonitis in elderly patients, all of which were either self-limited or were remedied with simple therapeutic measures, were common as well. Using both MRI tracking and telephone follow ups in 100 joints in 91 patients treated, no neoplastic complications were detected at any ADSC implantation sites. Based on our longitudinal cohort, the autologous and uncultured ADSCs/PRP therapy in the form of SVF could be considered to be safe when used as percutaneous local injections.


Assessment of Selective and Universal Screening for Suicide Risk in a Pediatric Emergency Department.
According to National Patient Safety Goal 15.01.01, all individuals being treated or evaluated for behavioral health conditions as their primary reason for care in hospitals and behavioral health care organizations accredited by The Joint Commission should be screened for suicide risk using a validated tool. Existing suicide risk screens have minimal or no high-quality evidence of association with future suicide-related outcomes. To test the association between results of the Ask Suicide-Screening Questions (ASQ) instrument in a pediatric emergency department (ED), implemented through selective and universal screening approaches, and subsequent suicide-related outcomes. In this retrospective cohort study at an urban pediatric ED in the United States, the ASQ was administered to youths aged 8 to 18 years with behavioral and psychiatric presenting problems from March 18, 2013, to December 31, 2016 (selective condition), and then to youths aged 10 to 18 years with medical presenting problems (in addition to those aged 8-18 years with behavioral and psychiatric presenting problems) from January 1, 2017, to December 31, 2018 (universal condition). Positive ASQ screen at baseline ED visit. The main outcomes were subsequent ED visits with suicide-related presenting problems (ie, ideation or attempts) based on electronic health records and death by suicide identified through state medical examiner records. Association with suicide-related outcomes was calculated over the entire study period using survival analyses and at 3-month follow-up for both conditions using relative risk. The complete sample was 15003 youths (7044 47.0%] male; 10209 [68.0%] black; mean [SD] age, 14.5 [3.1] years at baseline). The follow-up for the selective condition was a mean (SD) of 1133.7 (433.3) days; for the universal condition, it was 366.2 (209.2) days. In the selective condition, there were 275 suicide-related ED visits and 3 deaths by suicide. In the universal condition, there were 118 suicide-related ED visits and no deaths during the follow-up period. Adjusting for demographic characteristics and baseline presenting problem, positive ASQ screens were associated with greater risk of suicide-related outcomes among both the universal sample (hazard ratio, 6.8 [95% CI, 4.2-11.1]) and the selective sample (hazard ratio, 4.8 [95% CI, 3.5-6.5]). Positive results of both selective and universal screening for suicide risk in pediatric EDs appear to be associated with subsequent suicidal behavior. Screening may be a particularly effective way to detect suicide risk among those who did not present with ideation or attempt. Future studies should examine the impact of screening in combination with other policies and procedures aimed at reducing suicide risk.Appeared originally in JAMA Netw Open 2019; 2:e1914070.


Computed tomography of temporal bone pneumatization: 2. Petrosquamosal suture and septum.
The degree of visualization of the petrosquamosal (Körner's) septum on high-resolution axial computed tomography (CT) in 141 temporal bones (100 subjects) was analyzed. The superior and inferior parts of the septum were assessed separately and were seen in 75% and 41% of cases, respectively. There was no relation between the size of Körner's septum and pneumatization. The clinical relevance of this finding is discussed. The CT features of the ventral petrosquamosal suture also were investigated. The crista tegmentalis, a contribution of the petrosal tegmen to the mandibular fossa, was seen on CT as a polypoid excrescence projecting from the ventrolateral petrous pyramid. This knowledge is useful in the radiographic analysis of the course of longitudinal fractures of the petrous bone.


Acetylcholinesterase inhibitors in MG: to be or not to be?
Myasthenia gravis (MG) is an autoimmune disorder usually caused by antibodies against either the acetylcholine receptor (AChR) or muscle-specific tyrosine kinase (MuSK) at the neuromuscular junction. Neuromuscular transmission failure results in muscle fatigue and weakness that can be treated symptomatically with acetylcholinesterase inhibitors (AChEIs). Long-term treatment with nonselective AChEIs may have considerable drawbacks; thus, this medication is ideally tapered when strength improves. Patients with AChR antibodies respond beneficially to treatment, whereas patients with MuSK antibodies generally do not. Recently, the selective AChEI EN101, which specifically targets the isoform of "read-through" AChE (AChE-R), has been developed and may be of importance for symptomatic relief in AChR-antibody seropositive MG. This article is a review of the mechanisms, therapeutic effects, and drawbacks, with both old and new AChEIs in MG.


A review of the volatiles from the healthy human body.
A compendium of all the volatile organic compounds (VOCs) emanating from the human body (the volatolome) is for the first time reported. 1840 VOCs have been assigned from breath (872), saliva (359), blood (154), milk (256), skin secretions (532) urine (279), and faeces (381) in apparently healthy individuals. Compounds were assigned CAS registry numbers and named according to a common convention where possible. The compounds have been grouped into tables according to their chemical class or functionality to permit easy comparison. Some clear differences are observed, for instance, a lack of esters in urine with a high number in faeces. Careful use of the database is needed. The numbers may not be a true reflection of the actual VOCs present from each bodily excretion. The lack of a compound could be due to the techniques used or reflect the intensity of effort e.g. there are few publications on VOCs from blood compared to a large number on VOCs in breath. The large number of volatiles reported from skin is partly due to the methodologies used, e.g. collecting excretions on glass beads and then heating to desorb VOCs. All compounds have been included as reported (unless there was a clear discrepancy between name and chemical structure), but there may be some mistaken assignations arising from the original publications, particularly for isomers. It is the authors' intention that this database will not only be a useful database of VOCs listed in the literature, but will stimulate further study of VOCs from healthy individuals. Establishing a list of volatiles emanating from healthy individuals and increased understanding of VOC metabolic pathways is an important step for differentiating between diseases using VOCs.


Spatial distribution of organic functional groups supported on mesoporous silica nanoparticles: a study by conventional and DNP-enhanced 29Si solid-state NMR.
Solid-state NMR spectroscopy, both conventional and dynamic nuclear polarization (DNP)-enhanced, was employed to study the spatial distribution of organic functional groups attached to the surface of mesoporous silica nanoparticles via co-condensation and grafting. The most revealing information was provided by DNP-enhanced two-dimensional 29Si-29Si correlation measurements, which unambiguously showed that post-synthesis grafting leads to a more homogeneous dispersion of propyl and mercaptopropyl functionalities than co-condensation. During the anhydrous grafting process, the organosilane precursors do not self-condense and are unlikely to bond to the silica surface in close proximity (less than 4 Å) due to the limited availability of suitably arranged hydroxyl groups.


The prognostic significance of computerised tomography findings in women with liver metastases from breast cancer.
While computerised tomography (CT) is used for diagnosis and assessing response to treatment little work has been performed on the prognostic significance of the CT findings in women with liver metastases. The aim of this study was to assess if the CT findings in women diagnosed with liver metastases at the time of first presentation with metastatic breast cancer have any prognostic significance. The staging CT scans of 78 consecutive women diagnosed with liver metastases at the time of first presentation of metastatic breast cancer were reviewed independently by two radiologists who were blinded to survival and the histological features of the tumour. The number and enhancement characteristics of liver metastases, whether metastases were solitary, multiple or diffuse, the diameter of the largest and the sum of the diameter of the five largest lesions, an estimate of % involvement (<10%, 10-50%, >50%), and the presence of metastases at other sites were assessed. HER-2 and ER status and histological grade of the patient's primary breast cancer were also recorded. Survival was ascertained from hospital records. The prognostic significance of these factors was assessed in a univariate and multivariate fashion. At univariate analysis, number of liver metastases, sum of the diameter of the five largest lesions, percentage estimated involvement, presence of ascites, chest metastases and HER-2 status were significantly associated with reduced survival. Liver metastasis pattern (i.e. whether discrete or multiple), enhancement characteristics, ER status and histological grade were not associated with a significant outcome. At multivariate analysis estimated percentage liver involvement and the presence of chest metastases retained prognostic significance. Estimated percentage involvement was reproducible with 90% concordance between the two observers. The CT appearances of patients with liver metastases at first presentation with metastatic breast cancer provide prognostic information which may be clinically useful.


Self-reported snoring and risk of cardiovascular disease among postmenopausal women (from the Women's Health Initiative).
Habitual snoring may be associated with cardiovascular disease (CVD); however, limited evidence exists among women. We investigated whether frequent snoring is a predictor of coronary heart disease (CHD) and stroke among 42,244 postmenopausal women participating in the Women's Health Initiative Observational Study. Participants provided self-reported information regarding snoring habits at baseline (1993 to 1998) and were followed up for outcomes through August 2009. Physician adjudicators confirmed CHD (defined as myocardial infarction, CHD death, revascularization procedures, or hospitalized angina) and ischemic stroke. Cox proportional hazards models were used to evaluate whether snoring frequency is a significant predictor of the adjudicated outcomes. We observed 2,401 incident cases of CHD during 437,899 person-years of follow-up. After adjusting for age and race, frequent snoring was associated with incident CHD (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.39 to 1.70) and stroke (HR 1.41, 95% CI 1.19 to 1.66), and all CVD (HR 1.46, 95% CI 1.34 to 1.60). In fully adjusted models that included CVD risk factors such as obesity, hypertension, and diabetes, frequent snoring was associated with a more modest increase in incident CHD (HR 1.14, 95% CI 1.01 to 1.28), stroke (HR 1.19, 95% CI 1.02 to 1.40), and CVD (HR 1.12, 95% CI 1.01 to 1.24). In conclusion, snoring is associated with a modest increased risk of incident CHD, stroke, and CVD after adjustment for CVD risk factors. Additional studies are needed to elucidate the mechanisms by which snoring might be associated with CVD risk factors and outcomes.


The impact of a pay-for-performance system on timing to hip fracture surgery: experience from the Lazio Region (Italy).
A tariff modulation mechanisms has been introduced in some Italian regions with the aim of reducing inappropriate admissions and improving quality of care. In response to a regional act, hospitals in Lazio adopted a clinical pathway for elderly patients with hip fracture and introduced a compensation system based on the quality of health care, as in a pay-for-performance model. The objective of the present study was to compare the proportion of surgery for hip fracture performed within 48 hours of admission among Lazio hospitals according to different payment systems, before and after the implementation of the regional act. A retrospective cohort study of patients aged 65 years and over, residing in the Lazio region and admitted to an acute care hospital for hip fracture before (1 July 2008 - 30 June 2009) and after (1 July 2010 - 30 June 2011) the pay-for-performance act. The proportion of surgeries performed within 48 h of hospital arrival was calculated. An adjusted multivariate regression analysis was applied to assess the effect of hospital payment type on the likelihood of surgery within 48 h of hospital arrival. The share of patients with hip fracture that had surgery within 48 hours was 11.7% before the introduction of the pay-for-performance act and 22.2% after. The proportion of early hip fracture operations increased after the pay-for-performance act, regardless of hospital payment type. The largest increase of surgery within 48 h occurred in private hospitals (adjusted Relative Risk = 2.80, p < 0.001). The introduction of a compensation system based on health care quality is associated with improved quality of care for elderly patients with hip fracture, especially in hospitals that only use the Diagnosis Related Group system.


Two pharmacologically and kinetically distinct transient potassium currents in cultured embryonic mouse hippocampal neurons.
Transient potassium currents in mammalian central neurons influence both the repolarization of single action potentials and the timing of repetitive action potential generation. How these currents are integrated into neuronal function will depend on their specific properties: channel availability at the resting potential, activation threshold, inactivation rate, and current density. We here report on the voltage-gated transient potassium currents in embryonic mouse hippocampal neurons dissected at embryonic days 15-16 and grown in dissociated cell culture for up to 3 d. Two transient potassium currents, A-current and D-current, were isolated based on steady state inactivation and sensitivity to 4-aminopyridine (4-AP) and dendrotoxin (DTx). A-current had an activation threshold of approximately -50 mV and was half-inactivated at approximately -81 mV. A-current relaxations at voltages between -40 and +40 mV could be fit by single exponential functions with time constants of 20-25 msec; these time constants showed little sensitivity to voltage. In contrast, D-current had an activation threshold of between -40 and -30 mV and was half-inactivated at approximately -22 mV. D-current inactivation was voltage dependent; time constants of fitted exponential functions ranged from approximately 7 sec at -40 mV to 200 msec at +40 mV. A slower component of inactivation was also evident. D-current was preferentially blocked by 4-AP (100 microM) and DTx (1 microM). Operationally, A- and D-currents could be cleanly separated based on conditioning pulse potential and 4-AP sensitivity. Total transient potassium current amplitude increased during the time that neurons were in culture (recordings were made between 2 hr after dissociation and 3 d in culture). When normalized for cell capacitance (an index of membrane area), A-current density (pA/pF) decreased and D-current density increased, even during a period between days 1 and 3 when total transient current density remained constant. This observation suggests that A- and D-currents may be reciprocally modulated. Since blockade of D-current (with 100 microM 4-AP) increased both action potential duration and repetitive firing in response to constant current stimulation, long-term modulation of the A-current:D-current ratio may affect the excitability of hippocampal neurons.


Plasmonic enhancement of SERS measured on molecules in carbon nanotubes.
We isolated the plasmonic contribution to surface-enhanced Raman scattering (SERS) and found it to be much stronger than expected. Organic dyes encapsulated in single-walled carbon nanotubes are ideal probes for quantifying plasmonic enhancement in a Raman experiment. The molecules are chemically protected through the nanotube wall and spatially isolated from the metal, which prevents enhancement by chemical means and through surface roughness. The tubes carry molecules into SERS hotspots, thereby defining molecular position and making it accessible for structural characterization with atomic-force and electron microscopy. We measured a SERS enhancement factor of 106 on α-sexithiophene (6T) molecules in the gap of a plasmonic nanodimer. This is two orders of magnitude stronger than predicted by the electromagnetic enhancement theory (104). We discuss various phenomena that may explain the discrepancy (including hybridization, static and dynamic charge transfer, surface roughness, uncertainties in molecular position and orientation), but found all of them lacking in enhancement for our probe system. We suggest that plasmonic enhancement in SERS is, in fact, much stronger than currently anticipated. We discuss novel approaches for treating SERS quantum mechanically that appear promising for predicting correct enhancement factors. Our findings have important consequences on the understanding of SERS as well as for designing and optimizing plasmonic substrates.


Stochastic resonance as dithering
A direct correspondence is demonstrated between the phenomenon of "stochastic resonance" in static nonlinear systems and the dithering effect well known in the theory of digital waveform coding. It is argued that many static systems displaying stochastic resonance are forms of dithered quantizers, and that the existence or absence of stochastic resonance in such systems can be predicted from the effects of "dither averaging" upon their transfer characteristics. Also, results are introduced regarding stochastic resonance in certain nonlinear systems with memory (e.g., hysteretic systems).


Use of radio-frequency-pulse surface acoustic wave profilometry for passband engineering of acousto-optic tunable filters.
One can determine the acoustic profile of an acousto-optic tunable filter (AOTF) either by measuring the intensity of a laser diffracted off the surface of an AOTF by the surface acoustic wave (SAW) or by measuring the optical output power of an AOTF as a short burst of rf energy is launched down the device. This rf-burst technique (also called pulse probing) is compared with the established optical diffraction SAW profilometry technique. We demonstrate the usefulness of rf-burst profilometry to measure the acousto-optic coupling as a function of position along an AOTF interaction region. Such a probe can be used to make adjustments to the acousto-optic coupling in real time to achieve passband shape modification in complex AOTF structures.


Emergent collective organization of bone cells in complex curvature fields.
Individual cells and multicellular systems respond to cell-scale curvatures in their environments, guiding migration, orientation, and tissue formation. However, it remains largely unclear how cells collectively explore and pattern complex landscapes with curvature gradients across the Euclidean and non-Euclidean spectra. Here, we show that mathematically designed substrates with controlled curvature variations induce multicellular spatiotemporal organization of preosteoblasts. We quantify curvature-induced patterning and find that cells generally prefer regions with at least one negative principal curvature. However, we also show that the developing tissue can eventually cover unfavorably curved territories, can bridge large portions of the substrates, and is often characterized by collectively aligned stress fibers. We demonstrate that this is partly regulated by cellular contractility and extracellular matrix development, underscoring the mechanical nature of curvature guidance. Our findings offer a geometric perspective on cell-environment interactions that could be harnessed in tissue engineering and regenerative medicine applications.


Comparison of single distance phase retrieval algorithms by considering different object composition and the effect of statistical and structural noise.
Phase retrieval is a technique for extracting quantitative phase information from X-ray propagation-based phase-contrast tomography (PPCT). In this paper, the performance of different single distance phase retrieval algorithms will be investigated. The algorithms are herein called phase-attenuation duality Born Algorithm (PAD-BA), phase-attenuation duality Rytov Algorithm (PAD-RA), phase-attenuation duality Modified Bronnikov Algorithm (PAD-MBA), phase-attenuation duality Paganin algorithm (PAD-PA) and phase-attenuation duality Wu Algorithm (PAD-WA), respectively. They are all based on phase-attenuation duality property and on weak absorption of the sample and they employ only a single distance PPCT data. In this paper, they are investigated via simulated noise-free PPCT data considering the fulfillment of PAD property and weakly absorbing conditions, and with experimental PPCT data of a mixture sample containing absorbing and weakly absorbing materials, and of a polymer sample considering different degrees of statistical and structural noise. The simulation shows all algorithms can quantitatively reconstruct the 3D refractive index of a quasi-homogeneous weakly absorbing object from noise-free PPCT data. When the weakly absorbing condition is violated, the PAD-RA and PAD-PA/WA obtain better result than PAD-BA and PAD-MBA that are shown in both simulation and mixture sample results. When considering the statistical noise, the contrast-to-noise ratio values decreases as the photon number is reduced. The structural noise study shows that the result is progressively corrupted by ring-like artifacts with the increase of structural noise (i.e. phantom thickness). The PAD-RA and PAD-PA/WA gain better density resolution than the PAD-BA and PAD-MBA in both statistical and structural noise study.


Selective ORAI1 Inhibition Ameliorates Autoimmune Central Nervous System Inflammation by Suppressing Effector but Not Regulatory T Cell Function.
The function of CD4(+) T cells is dependent on Ca(2+) influx through Ca(2+) release-activated Ca(2+) (CRAC) channels formed by ORAI proteins. To investigate the role of ORAI1 in proinflammatory Th1 and Th17 cells and autoimmune diseases, we genetically and pharmacologically modulated ORAI1 function. Immunization of mice lacking Orai1 in T cells with MOG peptide resulted in attenuated severity of experimental autoimmune encephalomyelitis (EAE). The numbers of T cells and innate immune cells in the CNS of ORAI1-deficient animals were strongly reduced along with almost completely abolished production of IL-17A, IFN-γ, and GM-CSF despite only partially reduced Ca(2+) influx. In Th1 and Th17 cells differentiated in vitro, ORAI1 was required for cytokine production but not the expression of Th1- and Th17-specific transcription factors T-bet and RORγt. The differentiation and function of induced regulatory T cells, by contrast, was independent of ORAI1. Importantly, induced genetic deletion of Orai1 in adoptively transferred, MOG-specific T cells was able to halt EAE progression after disease onset. Likewise, treatment of wild-type mice with a selective CRAC channel inhibitor after EAE onset ameliorated disease. Genetic deletion of Orai1 and pharmacological ORAI1 inhibition reduced the leukocyte numbers in the CNS and attenuated Th1/Th17 cell-mediated cytokine production. In human CD4(+) T cells, CRAC channel inhibition reduced the expression of IL-17A, IFN-γ, and other cytokines in a dose-dependent manner. Taken together, these findings support the conclusion that Th1 and Th17 cell function is particularly dependent on CRAC channels, which could be exploited as a therapeutic approach to T cell-mediated autoimmune diseases.


Implementing Goal Mama: Barriers and Facilitators to Introducing Mobile Health Technology in a Public Health Nurse Home-Visiting Program.
The present study explores barriers and facilitators experienced by public health nurses introducing a mobile health technology platform (Goal Mama) to the Nurse-Family Partnership home-visiting program. Goal Mama is a HIPAA-compliant goal-coaching and visit preparation platform that clients and nurses use together to set and track goals. Forty-two nurses across five sites, including urban, suburban, and rural communities, piloted the platform with clients for 6 months. The mixed method, QUAL+quan pilot evaluation focused on deeply understanding the implementation process. Data were analyzed via iterative content analysis and multivariate regression analysis, and triangulated to identify salient findings. Over 6 months of use participants identified critical areas for product and implementation improvement, but still viewed the platform favorably. Key opportunities for improving sustained use revolved around supporting the technological and programmatic integration needed to lower key barriers and further facilitate implementation.


Rapid film-based determination of antibiotic susceptibilities of Mycobacterium tuberculosis strains by using a luciferase reporter phage and the Bronx Box.
Detecting antibiotic resistance in Mycobacterium tuberculosis is becoming increasingly important with the global recognition of drug-resistant strains and their adverse impact on clinical outcomes. Current methods of susceptibility testing are either time-consuming or costly; rapid, reliable, simple, and inexpensive methods would be highly desirable, especially in the developing world where most tuberculosis is found. The luciferase reporter phage is a unique reagent well-suited for this purpose: upon infection with viable mycobacteria, it produces quantifiable light which is not observed in mycobacterial cells treated with active antimicrobials. In this report, we describe a modification of our original assay, which allows detection of the emitted light with a Polaroid film box designated the Bronx Box. The technique has been applied to 25 M. tuberculosis reference and clinical strains, and criteria are presented which allow rapid and simple discrimination among strains susceptible or resistant to isoniazid and rifampin, the major antituberculosis agents.


You have to make something of all that rubbish, do you? An empirical investigation of the social process of qualitative research.
In this article, we examine participants' talk about qualitative research. We provide empirical support for post-structural theorizations of the interview and propose three distinct but related dimensions of qualitative research: emotional, purposive/relational, and epistemic/ontological. In this study, participants often became upset but constructed participation as enjoyable and cathartic. The purpose of participation was to assist the communities to which one belonged. Participation was an active, reflexive practice that reconstructed the self and changed knowledge about one's self. This latter epistemic/ontological dimension of participation appeared to be the most compelling for participants, but it is also the hardest to observe, with implications for how we consider the costs and benefits of participation. We suggest two practical measures for researchers and institutional review boards to consider in light of our findings: routinely asking questions about the research experience in qualitative studies and reformulating patient information statements to particularize them to qualitative research.


THE SIGNIFICANCE OF THE SYNOVIAL VILLUS AND THE CILIARY PROCESS AS FACTORS IN THE LOCALIZATION OF BACTERIA IN THE JOINTS AND EYES OF RABBITS.
1. Histological examination of sections of the eyes and joints of large numbers of rabbits injected with hemolytic streptococci has clearly demonstrated that when arthritis or cyclitis occurs, the synovial villi and ciliary processes are the most frequent and usually the primary sites of inflammation. 2. By special methods for demonstration of bacteria, it has been shown that bacteria which found lodgement in either an eye or a joint were demonstrable first in the vessels of ciliary processes or synovial villi. 3. A localized synovitis or iridocyclitis is brought about by the localization of bacteria in the synovial villus and ciliary process. 4. These experiments, which give a clearer insight into the pathogenesis of infectious arthritis and iritis, explain why both may occur in association with certain infectious diseases.


Effect of Mikania glomerata (Asteraceae) leaf extract combined with anti-venom serum on experimental Crotalus durissus (Squamata: Viperidae) envenomation in rats.
Crotalic envenomation represents the highest number of deaths when compared to other snakebite envenomations of medical interest. Crotalic venom has important characteristics such as neurotoxicity, myotoxicity, nephrotoxicity, and clotting and hemolytic action. We evaluated the clinical and laboratory aspects of Crotalus durissus terrificus experimental envenomation in Wistar rats treated with antivenom and the aqueous extract of the plant Mikania glomerata. The animals were divided into three groups: Group C (control); Group VS-venom and antivenom; Group VSM-venom, antivenom and aqueous extract of M. glomerata. Crotalic poison caused clinical and laboratory alterations in Wistar mice. Significant clinical alterations were: temperature decrease, edema in the venom inoculated member, sedation and a locomotion decrease in groups VS and VSM when compared with group C. A faster recovery from sedation was observed only for animals of group VSM when compared to VS. There was an increase in the number of leukocytes, neutrophils and creatine kinase in the VS and VSM groups, compared to group C. Wistar rats showed a high resistance to crotalic venom. Additional studies with different doses, time of treatment, different administration methods and histopathological and immunological studies are necessary to understand the action of M. glomerata in crotalic accidents.


Establishing Live-Cell Single-Molecule Localization Microscopy Imaging and Single-Particle Tracking in the Archaeon Haloferax volcanii.
In recent years, fluorescence microscopy techniques for the localization and tracking of single molecules in living cells have become well-established and are indispensable tools for the investigation of cellular biology and in vivo biochemistry of many bacterial and eukaryotic organisms. Nevertheless, these techniques are still not established for imaging archaea. Their establishment as a standard tool for the study of archaea will be a decisive milestone for the exploration of this branch of life and its unique biology. Here, we have developed a reliable protocol for the study of the archaeon Haloferax volcanii. We have generated an autofluorescence-free H. volcanii strain, evaluated several fluorescent proteins for their suitability to serve as single-molecule fluorescence markers and codon-optimized them to work under optimal H. volcanii cultivation conditions. We found that two of them, Dendra2Hfx and PAmCherry1Hfx, provide state-of-the-art single-molecule imaging. Our strategy is quantitative and allows dual-color imaging of two targets in the same field of view (FOV) as well as DNA co-staining. We present the first single-molecule localization microscopy (SMLM) images of the subcellular organization and dynamics of two crucial intracellular proteins in living H. volcanii cells, FtsZ1, which shows complex structures in the cell division ring, and RNA polymerase, which localizes around the periphery of the cellular DNA. This work should provide incentive to develop SMLM strategies for other archaeal organisms in the near future.


Ovarian cancer statistics, 2018.
In 2018, there will be approximately 22,240 new cases of ovarian cancer diagnosed and 14,070 ovarian cancer deaths in the United States. Herein, the American Cancer Society provides an overview of ovarian cancer occurrence based on incidence data from nationwide population-based cancer registries and mortality data from the National Center for Health Statistics. The status of early detection strategies is also reviewed. In the United States, the overall ovarian cancer incidence rate declined from 1985 (16.6 per 100,000) to 2014 (11.8 per 100,000) by 29% and the mortality rate declined between 1976 (10.0 per 100,000) and 2015 (6.7 per 100,000) by 33%. Ovarian cancer encompasses a heterogenous group of malignancies that vary in etiology, molecular biology, and numerous other characteristics. Ninety percent of ovarian cancers are epithelial, the most common being serous carcinoma, for which incidence is highest in non-Hispanic whites (NHWs) (5.2 per 100,000) and lowest in non-Hispanic blacks (NHBs) and Asians/Pacific Islanders (APIs) (3.4 per 100,000). Notably, however, APIs have the highest incidence of endometrioid and clear cell carcinomas, which occur at younger ages and help explain comparable epithelial cancer incidence for APIs and NHWs younger than 55 years. Most serous carcinomas are diagnosed at stage III (51%) or IV (29%), for which the 5-year cause-specific survival for patients diagnosed during 2007 through 2013 was 42% and 26%, respectively. For all stages of epithelial cancer combined, 5-year survival is highest in APIs (57%) and lowest in NHBs (35%), who have the lowest survival for almost every stage of diagnosis across cancer subtypes. Moreover, survival has plateaued in NHBs for decades despite increasing in NHWs, from 40% for cases diagnosed during 1992 through 1994 to 47% during 2007 through 2013. Progress in reducing ovarian cancer incidence and mortality can be accelerated by reducing racial disparities and furthering knowledge of etiology and tumorigenesis to facilitate strategies for prevention and early detection. CA Cancer J Clin 2018;68:284-296. © 2018 American Cancer Society.


Stereoselective actions of S-nitrosocysteine in central nervous system of conscious rats.
This study examined whether the stereoselective actions of S-nitrosocysteine (SNC) in the central nervous system involves the activation of stereoselective SNC recognition sites. We examined the effects produced by intracerebroventricular injection of the L- and D-isomers of SNC (L- and D-SNC) on mean arterial blood pressure, heart rate, and vascular resistances in conscious rats. We also examined the hemodynamic effects produced by intracerebroventricular injections of 1) L-cystine, the major non-nitric oxide (NO) decomposition product of L-SNC, 2) the parent thiols L- and D-cysteine, and 3) the bulky S-nitrosothiol L-S-nitroso-gamma-glutamylcysteinylglycine [L-S-nitrosoglutathione, (L-SNOG)]. Finally, we examined the decomposition of L- and D-SNC and L-SNOG to NO on their addition to brain homogenates. The intracerebroventricular injection of L-SNC (250-1,000 nmol) produced falls in mean arterial pressure, increases in heart rate, and a dose-dependent pattern of changes in hindquarter, renal, and mesenteric vascular resistances. The intracerebroventricular injections of D-SNC, L-cystine, and L-SNOG produced only minor effects. The intracerebroventricular injection of L-cysteine produced pressor responses and tachycardia, whereas D-cysteine was inactive. L- and D-SNC decomposed equally to NO on addition to brain homogenates. L-SNOG decomposed to similar amounts of NO as L- and D-SNC. These results suggest that SNC may activate stereoselective SNC recognition sites on brain neurons and that S-nitrosothiols of substantially different structure do not stimulate these sites. These recognition sites may be stereoselective membrane-bound receptors for which L-SNC is the unique ligand.


Comparison of Early Treatment Diabetic Retinopathy Study Standard 7-Field Imaging With Ultrawide-Field Imaging for Determining Severity of Diabetic Retinopathy.
Moderate to substantial agreement between Early Treatment Diabetic Retinopathy Study (ETDRS) 7-field imaging and ultrawide-field (UWF) imaging has been suggested in single-center studies. Comparing images obtained by multiple centers could increase confidence that UWF images can be used reliably in place of ETDRS imaging in future clinical trials. To compare diabetic retinopathy (DR) severity from modified ETDRS 7-field imaging and UWF imaging. This preplanned, cross-sectional analysis included modified ETDRS 7-field images obtained using the Diabetic Retinopathy Clinical Research Network acquisition protocol and UWF images obtained captured with the Optos 200Tx system (Optos, PLC) from adult participants (≥18 years old) with type 1 or type 2 diabetes. Both image types were evaluated by trained graders masked to clinical data. Data collection occurred from February 2015 to December 2015, and data analysis from June 2016 to December 2017. Agreement between UWF images, UWF images masked to include only the ETDRS 7-field area, and ETDRS 7-field images were calculated using κ statistics. A total of 764 eyes from 385 participants were included; participants had a median (IQR) age of 62.2 (53.6-69.2) years, 194 (50.4%) were women, and 256 (66.5%) were white. Of 742 eyes with both ETDRS 7-field images and UWF masked images graded, 359 (48.4% [95% CI, 44.4%-52.4%]) eyes had exact agreement, and 653 eyes (88.0% [95% CI, 85.2%-90.3%]) agreed within 1 step (weighted κ, 0.51 [95% CI, 0.44-0.58]). After open adjudication by an independent senior grader of all images with more than a 2-step discrepancy, perfect agreement was found in 435 eyes (59.0% [95% CI, 55.1%-62.8%]) and agreement within 1 step in 714 eyes (96.9% [95% CI, 95.1%-98.0%]; κ, 0.77 [95% CI, 0.73-0.82]). Ability of the imaging modalities to detect retinopathy severity in an individual eye was considered similar in 59 eyes (50.9% [95% CI, 41.3%-60.4%]), better for ETDRS 7-field imaging in 22 eyes (19.0% [95% CI, 12.5%-27.7%]), and better for UWF-masked images in 31 eyes (26.7% [95% CI 18.8%-36.5%]). Comparing UWF masked and unmasked images, 94 of 751 eyes (12.5%) had DR graded as at least 1 step more severe on UWF unmasked images vs UWF masked images. Predominantly peripheral DR lesions were present in 308 of 751 eyes (41.0%); this suggested increased DR severity by 2 or more steps in 34 eyes (11.0%). Imaging by the ETDRS 7-field and UWF imaging systems have moderate to substantial agreement when determining the severity of DR within the 7 standard fields. Disparities in an individual eye are equivalently distributed between imaging modalities and can be better or worse on 1 or the other. Longitudinal follow-up will evaluate the primary outcome of this study to determine if peripheral retinal findings are associated with future retinopathy outcomes.


Ulcerative Colitis Remission Status After Induction With Mesalazine Predicts Maintenance Outcomes: the MOMENTUM Trial.
This study assessed the efficacy of maintenance treatment with multimatrix mesalazine following achievement of complete or partial remission after induction treatment with high-dose multimatrix mesalazine. In this phase 3b/4, open-label, multicentre, prospective, single-arm study, patients with mild-to-moderate ulcerative colitis were treated with multimatrix mesalazine 4.8g/day once daily for 8 weeks [induction phase]. At Week 8, those who achieved complete or partial remission, based on predefined clinical and endoscopic criteria, were eligible to receive 12 months of multimatrix mesalazine 2.4g/day once daily maintenance therapy. The primary endpoint was the proportion of patients in complete remission at Month 12. A total of 717 patients received induction treatment; 25.9% and 39.3% of patients achieved complete and partial remission, respectively, at Week 8. A total of 461 patients entered the maintenance phase. The likelihood of remaining in/achieving complete remission at Month 12 was higher for patients who entered the maintenance phase in complete remission compared with those who began maintenance in partial remission [47.8% vs 26.0%; p < 0.001]. At Month 12, mucosal healing [endoscopy score ≤ 1] was demonstrated in 76.4% [139/182] and 63.5% [176/277] of those who were in complete and partial remission, respectively, at the end of induction. Patients achieving complete remission before dose reduction were more likely to remain in remission at Month 12.


Emerging Tick-Borne Diseases.
Increases in tick-borne disease prevalence and transmission are important public health issues. Efforts to control these emerging diseases are frustrated by the struggle to control tick populations and to detect and treat infections caused by the pathogens that they transmit. This review covers tick-borne infectious diseases of nonrickettsial bacterial, parasitic, and viral origins. While tick surveillance and tracking inform our understanding of the importance of the spread and ecology of ticks and help identify areas of risk for disease transmission, the vectors are not the focus of this document. Here, we emphasize the most significant pathogens that infect humans as well as the epidemiology, clinical features, diagnosis, and treatment of diseases that they cause. Although detection via molecular or immunological methods has improved, tick-borne diseases continue to remain underdiagnosed, making the scope of the problem difficult to assess. Our current understanding of the incidence of tick-borne diseases is discussed in this review. An awareness of the diseases that can be transmitted by ticks in specific locations is key to detection and selection of appropriate treatment. As tick-transmitted pathogens are discovered and emerge in new geographic regions, our ability to detect, describe, and understand the growing public health threat must also grow to meet the challenge.


Promoting quality improvement and achieving measurable change: the lead states initiative.
Along with the development of a national voluntary accreditation program for public health departments that holds quality improvement as its core goal, the application of quality improvement in public health has been gaining momentum. The 16 states participating in the Multi-State Learning Collaborative: Lead States in Public Health Quality Improvement (MLC) represent best practices in these activities. The MLC brings together partnerships in 16 US states to prepare for accreditation and implement quality-improvement practices. The grantee states are managing quality-improvement teams of local and state health department representatives and other partners. These teams, called mini-collaboratives, are working collectively to implement quality-improvement techniques to make measurable change on identified public health issues, or target areas. The work of the MLC seems to show that state and local-health departments and their key partners have the leadership, will and interest to apply quality improvement tools, and methods to solving public health problems and to raising the standard of public health practice. This article describes the history, current status, and lessons learned from the work of the MLC.


Association of osteoarthritis risk factors with knee and hip pain in a population-based sample of 29-59 year olds in Denmark: a cross-sectional analysis.
This study aimed to a) describe the prevalence of knee and hip osteoarthritis risk factors in a population of 29-59 year old individuals, b) estimate the association between persistent knee/hip pain and osteoarthritis risk factors, and c) describe the prevalence of osteoarthritis risk factors, including specific biomechanical risk factors, in individuals with prolonged persistent knee or hip pain. Participants completed the "Early Detection and Prevention" pilot study questionnaire, including items on presence of knee/hip pain within the last month and osteoarthritis risk factors. Individuals reporting knee/hip problems completed a second questionnaire, including items about most problematic joint and specific biomechanical osteoarthritis risk factors. After describing the prevalence of persistent knee/hip pain and osteoarthritis risk factors among respondents stratified for sex and age, logistic regression was used to estimate the strength of associations between osteoarthritis risk factors and presence of knee/hip pain. The prevalence of prolonged persistent pain (i.e. knee/hip pain reported at both questionnaires) and osteoarthritis risk factors among respondents with prolonged persistent knee and hip pain, were described. Two thousand six hundred sixty-one respondents completed the first survey. The one-month prevalence of persistent knee/hip pain was 27%. Previous knee/hip injury was associated with persistent knee/hip pain for both sexes in all age groups, while a family history of osteoarthritis was associated with persistent knee/hip pain in all age groups except for 29-39 year old men. A higher BMI was associated with persistent knee/hip pain in 40-59 year old women, and 50-59 year old men. Eight hundred sixty seven respondents completed the second questionnaire. Knee/hip injuries and surgeries were more common in individuals with prolonged persistent knee than hip pain. Knee/hip pain within the last month was frequent among individuals aged 29-59 years. Multiple known osteoarthritis risk factors were associated with presence of knee/hip pain. Joint injury and previous surgery were more common in individuals with knee than hip pain. The results support the notion that joint injury and overweight during early adulthood are signs of a trajectory towards symptomatic osteoarthritis later in life and may help earlier identification of groups at high risk of future symptomatic osteoarthritis. ClinicalTrials.gov ( NCT02797392 ). Registered April 29,2016.


Willingness to pay for a cardiovascular prevention program in highly educated adults: a randomized controlled trial.
The aim of this study was to determine adults' Willingness To Pay (WTP) for CardioVascular Disease (CVD) intervention programs of different intensities. Three hundred fourteen participants were randomized to two study conditions: (i) CVD risk assessment/communication; (ii) CVD risk assessment/communication + a behavior change program. The behavior change program was aimed at increasing physical activity, reducing saturated fat intake and smoking cessation. It consisted of a tailored Web site and individual coaching with a self-selected dose. At post-assessment, WTP and perceived autonomy support items were included. The intervention dose was registered throughout the trial and post-hoc intervention dose groups were created. Pearson Chi-Square tests, Student's t-tests, one-way analyses of variance were used to examine WTP-differences between the study conditions and intervention dose groups. Twenty-four months after baseline, 61 and 135 participants of the control and intervention condition, respectively, completed the questionnaires. No WTP difference was found between the study conditions. However, participants that selected a higher intervention dose were willing to pay significantly more for their program (p < .05). In general, people want to pay the same amount of money for a CVD prevention program, irrespective of the inclusion of a behavior change program. However, there seems to be an association between the self-selected dose of the latter program and the WTP.


Enrollment of adolescents aged 16-17 years old in microbicide trials: an evidence-based approach.
This article explores the ethics and feasibility of enrolling adolescent females in microbicide trials using data from 16- to 17-year-old participants of the Phase 3 trial of the candidate vaginal microbicide, Carraguard. Secondary analysis was conducted to compare health, behavioral, and operational outcomes between 16- to 17-year-olds and 18- to 19-year-olds screened for and enrolled in the trial. Analytical approaches included Kaplan-Meier survival analysis, Cox proportional hazards modeling, and generalized estimating equations for nonsurvival end points. Results reveal no significant differences between the two age groups for health (sexually transmitted infection, adverse event), risk behavior, or operational (adherence, follow-up) outcomes. However, data suggest that after 1 year of trial participation, human immunodeficiency virus (HIV) and pregnancy incidence were higher and increased more rapidly for the 16- to 17-year-olds than for 18- to 19-year-olds; this finding is entirely consistent with other incidence data for HIV infection among South African youth and cannot be attributed to study participation without a comparison outside the trial. Data from the Carraguard trial provide no evidence that inclusion of 16- to 17-year-olds in the trial had any detrimental effect on trial participants or on the conduct of research. These data provide an argument motivating the inclusion of sexually active adolescents aged 16-17 years into future trials in order to avoid delaying access to an effective product for adolescents at high risk of HIV acquisition. Careful support for adolescent-inclusive protocols (including appropriate counseling) must be incorporated into study design.


Amygdaloid kindling and cerebrospinal cyclic nucleotides.
The kindling model of experimental epilepsy is characterized by a persistent seizure pattern and long-lasting seizure susceptibility without associated tissue damage. In order to examine the relationship between CSF cyclic nucleotides and epilepsy. CSF cAMP and cGMP were measured before and after kindling, or after electrically induced seizures. Cyclic AMP and cGMP levels in cisternal CSF decreased significantly 1 week after the amygdaloid kindling. This finding suggests decreased levels of brain cAMP and cGMP in this type of epileptogenesis. A slight increase in CSF cyclic nucleotides concentrations was found after triggering both partial and generalized seizures. There was, however, no difference in increase of cAMP and cGMP levels between partial seizure and generalized convulsion, indicating that differences in intensity ictal or postictal events cannot be reflected in the CSF cyclic nucleotide concentrations.


Immunoglobulin-binding proteins in ticks: new target for vaccine development against a blood-feeding parasite.
Humans have a long history of trying to control ticks. At first, attempts focused on modifying the habitat, whereas later efforts relied heavily on the use of chemicals. Current research is directed at finding a vaccine against ticks. A strategy of targeting 'concealed antigens' succeeded with the first commercialised vaccine against the cattle tick Boophilus microplus. However, vaccine development against other tick species appears unsatisfactory to date. Vaccination depends on a specific antibody-mediated immunoreaction that damages the parasite. Immunoglobulin molecules of vertebrate hosts can pass through gut barriers into the haemolymph of ectoparasites while retaining antibody activity. Research on the ixodid tick Rhipicephalus appendiculatus revealed that host immunoglobulin-G in the parasite was excreted via salivation, during feeding. Immunoglobulin-binding proteins in tick haemolymph and salivary glands are thought to be responsible for such excretion. The discovery of an immunoglobulin excretion system in ticks indicates that they have a highly developed mechanism to protect themselves from their host's antibody attack. Such a mechanism questions whether immunization strategies will be effective against ticks, unless they circumvent or disable the ticks' immunoglobulin excretion system.


A Novel Surgical Procedure for Er:YAG Laser-Assisted Periodontal Regenerative Therapy: Case Series.
The objective of this study was to evaluate an Er:YAG laser (ErL) application for periodontal regenerative surgery in angular bone defects at nine sites in six patients. Debridement was thoroughly performed using a combination of curettage with a Gracey-type curette and ErL irradiation at a panel setting of 70 mJ/pulse and 20 Hz with sterile saline spray. After applying an enamel matrix derivative and autogenous bone grafting, ErL was used to form a blood clot coagulation on the grafted bone surface at 50 mJ/pulse and 20 Hz without water spray for approximately 30 seconds. Twelve months after surgery the mean probing depth had improved from 6.2 mm to 2.0 mm, the mean clinical attachment level had reduced from 7.5 mm to 3.4 mm, and bleeding on probing had improved from (+) to (-). Mean intrabony defect depth decreased from 6.0 mm before surgery to 1.0 mm 12 months after surgery. A novel procedure for periodontal regenerative surgery applying ErL irradiation for thorough decontamination during debridement as well as blood coagulation following autogenous bone grafting seems to have achieved favorable and stable healing of periodontal pockets with significant clinical improvement and desirable regeneration of angular bone defects, including one-wall defects.


Gallstones.
Gallstone disease is a worldwide medical problem, but the incidence rates show substantial geographical variation, with the lowest rates reported in African populations. Publications in English language on gallstones which were obtained from reprint requests and PubMed database formed the basis for this paper. Data extracted from these sources included authors, country, year of publication, age and sex of patients, pathogenesis, risk factors for development of gallstones, racial distribution, presenting symptoms, complications and treatment. Gallstones occur worldwide, however it is commonest among North American Indians and Hispanics but low in Asian and African populations. High biliary protein and lipid concentrations are risk factors for the formation of gallstones, while gallbladder sludge is thought to be the usual precursor of gallstones. Biliary calcium concentration plays a part in bilirubin precipitation and gallstone calcification. Treatment of gallstones should be reserved for those with symptomatic disease, while prophylactic cholecystectomy is recommended for specific groups like children, those with sickle cell disease and those undergoing weight-loss surgical treatments. Treatment should be undertaken for a little percentage of patients with gallstones, as majority of those who harbor them never develop symptoms. The group that should undergo cholecystectomy include those with symptomatic gallstones, sickle cell disease patients with gall stones, and patients with morbid obesity who are undergoing laparotomy for other reasons.