The activities of the Escherichia coli MalK protein in maltose transport, regulation, and inducer exclusion can be separated by mutations.
The maltose regulon consists of several genes encoding proteins involved in the uptake and utilization of maltose and maltodextrins. Five proteins make up a periplasmic binding-protein-dependent active transport system. One of these proteins, MalK, contains an ATP-binding site and is thought to couple the hydrolysis of ATP to the accumulation of substrate. Beside its function in transport, MalK has two additional roles: (i) it negatively regulates mal regulon expression and (ii) it serves as the target for regulation of transport activity by enzyme IIIGlc of the phosphotransferase system. To determine whether the three functions of MalK are separable, we have isolated and characterized three classes of malK mutations. The first type (class I) exhibited constitutive mal gene expression but still allowed normal transport of maltose; the second type (class II) lacked the ability to transport maltose but retained the ability to repress the mal genes. Class I mutations were localized in the last third of the gene, at amino acids 267 (Trp to Gly) and 346 (Gly to Ser). Mutations of class II were found at the positions 137 (Gly to Ala), 140 (delta Gln Arg), and 158 (Asp to Asn). These mutations are near or within the region of MalK that exhibits extensive homology to the B site of an ATP-binding fold. In addition, site-directed mutagenesis was used to add or remove one amino acid in the A site of the ATP-binding fold. Plasmids carrying these mutations also behaved as class II mutants. The third class of malK mutations resulted in resistance to the enzyme IIIGlc-mediated inhibitory effects of alpha-methylglucoside. These mutations did not interfere with the regulatory function of MalK. One of these mutations (exchanging a serine at position 282 for leucine) is located in a short stretch of amino acids that exhibits homology to a sequence in the Escherichia coli Lac permease in which alpha-methylglucoside-resistant mutations have been found.


Nutrient Sensor mTORC1 Regulates Insulin Secretion by Modulating β-Cell Autophagy.
The dynamic regulation of autophagy in β-cells by cycles of fasting-feeding and its effects on insulin secretion are unknown. In β-cells, mechanistic target of rapamycin complex 1 (mTORC1) is inhibited while fasting and is rapidly stimulated during refeeding by a single amino acid, leucine, and glucose. Stimulation of mTORC1 by nutrients inhibited the autophagy initiator ULK1 and the transcription factor TFEB, thereby preventing autophagy when β-cells were continuously exposed to nutrients. Inhibition of mTORC1 by Raptor knockout mimicked the effects of fasting and stimulated autophagy while inhibiting insulin secretion, whereas moderate inhibition of autophagy under these conditions rescued insulin secretion. These results show that mTORC1 regulates insulin secretion through modulation of autophagy under different nutritional situations. In the fasting state, autophagy is regulated in an mTORC1-dependent manner, and its stimulation is required to keep insulin levels low, thereby preventing hypoglycemia. Reciprocally, stimulation of mTORC1 by elevated leucine and glucose, which is common in obesity, may promote hyperinsulinemia by inhibiting autophagy.


Nutrient digestibility and endogenous protein losses in the foregut and small intestine of weaned dairy calves fed calf starters with conventional or enzyme-treated soybean meal.
The aims of this experiment were (1) to compare the effects of a soybean meal with an enzymatic treatment (ESBM) to reduce the concentration of antinutritional factors versus a standard soybean meal (SBM) on foregut and small intestine digestion in weaned dairy calves and (2) to estimate the endogenous losses of crude protein (CP) in the small intestine. Our hypothesis was that a diet containing ESBM instead of SBM would improve ruminal and small intestine digestion and absorption of nutrients. A T-cannula was placed in the duodenum, and a second T-cannula was installed in the distal ileum of 12 Holstein calves at approximately 3 wk of age. Calves were weaned on d 42, and on d 50 they were assigned randomly to a quadruplicated 3 × 3 Latin square with 10-d periods. Digesta samples were collected on d 7 and 8 from the ileum and d 9 and 10 from the duodenum. The diets were fed for ad libitum intake and consisted of a calf starter (CS) of 20% CP with SBM as the main source of protein (CTRL), and an isonitrogenous CS with an ESBM instead of SBM (ENZT). A third diet with a low content of CP (10%) and no soy protein was fed to estimate endogenous N losses and digestibilities of test ingredients. Flows and digestibilities of nutrients were compared between CTRL and ENZT and their test ingredients (SBM vs. ESBM, respectively). Duodenal net flows of CP and total AA as well as ruminal microbial protein synthesis per kilogram of digested CP were greater, and flow of nonprotein N and CP true (corrected by endogenous and microbial flows) foregut digestibility were lower with ENZT than CTRL. The apparent small intestine digestibilities of CP and total AA were greater for ESBM than SBM, but there were no differences between the CTRL and ENZT diets. We observed no differences in digestibilities at the duodenum or ileum of starch or NDF, but true small intestine digestibilities of CP and all AA were greater with ENZT than CTRL. Total endogenous protein losses in the small intestine estimated from calves fed the low-CP with no soy protein diet were 37 ± 1.5 g of CP and 29 ± 1.4 g of AA/kg of DMI. These values may be considered the basal endogenous losses as they are similar to values obtained with the regression method, which estimates N losses when dietary N is null. Our results indicated that the inclusion of an ESBM improved the efficiency of ruminal microbial protein synthesis per digested kilogram of organic matter and CP, and increased CP and AA absorption in the small intestine despite a greater proportion of undigested dietary protein entering the duodenum.


Simultaneous determination of 42 organic chemicals in bottled water by combining C18 extraction disk with GC-MS and LC/MS/MS technique.
A method for the determination of 42 hazard residues required by 'Japan Positive List System' in bottled water was described. Hazard compounds in bottled water were extracted with a solid phase extraction step using C18 disks. Determination was carried out by gas chromatography/mass spectrometry (GC/MS) and liquid chromatography-tandem mass spectrometry (LC/MS/MS). The disk extraction has high throughput which is well adapted to isolate and enrich these compounds from large volumes of water. For the water sample spiked at three concentration levels (LOQ, 4 times LOQ and 8 times LOQ), the recoveries of all analytes ranged between 65% and 120% with a relative standard deviation<24% (n=8).


Pulmonary afferent control of breathing as end-expiratory lung volume decreases.
We studied reflex changes in breathing elicited by graded reductions in end-expiratory lung volume (EEVL) and the vagal nerves responsible. The chests of nine dogs anesthetized with alpha-chloralose were opened, and the lungs were ventilated by a phrenic nerve-driven servo-respirator. The immediate effects of a 50% reduction in end-expiratory transpulmonary pressure (EEPtp) from control (EEVL equivalent to functional residual capacity) were to significantly increase both tidal volume (VT) and breathing frequency (f) from 0.402 +/- 0.101 to 0.453 +/- 0.091 liter (mean +/- SD) and 11.8 +/- 5.4 to 15.7 +/- 6.4 breaths/min, respectively (P less than 0.05). Further reductions in EEPtp to 0 cmH2O did not change VT but augmented f to 19.6 +/- 6.6 breaths/min (P less than 0.05). The increase in f as EEVL decreased was due entirely to a reduction in expiratory time. Vagotomy abolished these reflexes. By 90 s after reduction in EEVL, arterial PCO2 fell significantly and VT returned to or below control values. We therefore repeated these experiments in five dogs whose blood gases were controlled by cardiopulmonary bypass. There were no secondary changes in VT and by 90 s breathing pattern could be characterized as rapid and deep. In another eight dogs submitted to the same collapse protocol, we recorded action potentials from all known categories of pulmonary vagal afferents. These studies demonstrated that the changes in breathing pattern induced by a 50% reduction in EEPtp were due to a withdrawal of slowly adapting stretch receptor activity; however, continued increases in f as EEVL was reduced further were due to increases in rapidly adapting stretch receptor activity.(ABSTRACT TRUNCATED AT 250 WORDS)


Plaque volume and occurrence and location of periprocedural myocardial necrosis after percutaneous coronary intervention: insights from delayed-enhancement magnetic resonance imaging, thrombolysis in myocardial infarction myocardial perfusion grade analysis, and intravascular ultrasound.
Myocardial necrosis can occur during percutaneous coronary intervention (PCI) despite optimal adjunctive pharmacology and careful technique. We investigated the mechanisms of procedural infarction using angiographic analysis, intravascular ultrasound, and delayed-enhancement magnetic resonance imaging. Fifty-two patients (64 vessels) who underwent complex PCI were studied. All patients were preloaded with clopidogrel and received glycoprotein IIb/IIIa inhibitors. "Adjacent" myonecrosis was defined as the presence of an area of new gadolinium hyperenhancement close to the stent. "Distal" myonecrosis was defined as situated at least 10 mm downstream from the stent. Fifteen vessels (23%) had evidence of new hyperenhancement after PCI. Of these, 8 (12%) had the distal type, and 7 (11%) had the adjacent type. Intravascular ultrasound showed a significantly greater reduction in plaque volume (91.6+/-51.5 versus 8+/-14 versus 20+/-35 mm3; P < 0.001) in the group with distal hyperenhancement compared with patients without new hyperenhancement or adjacent hyperenhancement. In the entire sample, a significant correlation was seen between changes in plaque volume (rho = 0.58, P < 0.001) after PCI and the mass of new necrosis measured by magnetic resonance imaging. Thrombolysis in Myocardial Infarction perfusion grade assessment of a closed microvasculature after PCI carried an odds ratio of 8.0 (95% confidence interval, 1.4 to 46.1; P = 0.02) for the occurrence of hyperenhancement, whereas side-branch occlusion was associated with an odds ratio of 16.2 (95% confidence interval, 2.6 to 102.5; P = 0.03). However, a closed microvasculature was associated with distal hyperenhancement (P = 0.02), and side-branch occlusion was associated with adjacent hyperenhancement (P < 0.001). These data suggest that distal embolization of plaque material occurs in contemporary PCI of native coronary arteries. Efforts to minimize procedural necrosis may require careful review of side branch anatomy and/or use of distal protection during extensive coronary stenting.


Challenges to the global control of tuberculosis.
Diagnosis and treatment of tuberculosis (TB) will likely navigate a historical turning point in the 2010s with a new management paradigm emerging. However, global control of TB remains a formidable challenge for the decades to come. The estimated case detection rate of TB globally was 66%, and there were 310 000 estimated multidrug-resistant TB (MDR-TB) cases among the 6.2 million TB patients notified in 2011. Although new tools are being introduced for the diagnosis of MDR-TB, there are operational and cost issues related to their use that require urgent attention, so that the poor and vulnerable can benefit. World Health Organization (WHO) estimated that globally, 3.7% of new cases and 20% of previously treated cases have MDR-TB. However, the scale-up of programmatic management of drug-resistant TB is slow, with only 60 000 MDR-TB cases notified to WHO in 2011. The overall proportion of treatment success of MDR-TB notified globally in 2009 was 48%, far below the global target of 75% success rate. Although new tools and drugs have the potential to significantly improve both case detection and treatment outcome, adequate health systems and human resources are needed for rapid uptake and proper implementation to have the impact required to eliminate TB. Hence, the global TB community should broaden its scope, seek intersectoral collaboration and advocate for cost reduction of new tools, while ensuring that the basics of TB control are implemented to reduce the TB burden through the current 'prevention through case management' paradigm.


Super-resolution RESOLFT microscopy of lipid bilayers using a fluorophore-switch dyad.
Dyads consisting of a photochromic switch covalently linked to a fluorescent dye allow the emission from the dye to be controlled by reversible photoisomerization of the switch; one form of the switch quenches fluorescence by accepting energy from the dye. Here we investigate the use of dyads of this type for super-resolution imaging of lipid bilayers. Giant unilamellar vesicles stained with the dyads were imaged with about a two-fold resolution-enhancement compared with conventional confocal microscopy. This was achieved by exciting the fluorophore at 594 nm, using a switch activated by violet and red light (405/640 nm).


Interleukin-17 accelerates allograft rejection by suppressing regulatory T cell expansion.
Interleukin-17 (IL-17), which is predominantly produced by T helper 17 cells distinct from T helper 1 or T helper 2 cells, participates in the pathogenesis of infectious, autoimmune, and allergic disorders. However, the precise role in allograft rejection remains uncertain. In the present study, we investigated the role of IL-17 in acute allograft rejection using IL-17-deficient mice. Donor hearts from FVB mice were heterotopically transplanted into either C57BL/6J-IL-17-deficient (IL-17(-/-)) or -wild-type mice. Allograft survival was significantly prolonged in IL-17(-/-) recipient mice due to reduced local inflammation accompanied by decreased inflammatory cell recruitment and cytokine/chemokine expression. IL-17(-/-) recipient mice exhibited decreased IL-6 production and reciprocally enhanced regulatory T cell expansion, suggesting a contribution of regulatory T cells to prolonged allograft survival. Indeed, allografts transplanted into anti-CD25 mAb-treated IL-17(-/-) recipient mice (regulatory T cell-depleted) developed acute rejection similar to wild-type recipient mice. Surprisingly, we found that gamma delta T cells rather than CD4(+) and CD8(+) T cells were key IL-17 producers in the allografts. In support, equivalent allograft rejection was observed in Rag-2(-/-) recipient mice engrafted with either wild-type or IL-17(-/-) CD4(+) and CD8(+) T cells. Finally, hearts transplanted into gamma delta T cell-deficient mice resulted in decreased allograft rejection compared with wild-type controls. During heart transplantation, (1) IL-17 is crucial for acceleration of acute rejection; (2) IL-17-deficiency enhances regulatory T cell expansion; and (3) gamma delta T cells rather than CD4(+) and CD8(+) T cells are a potential source of IL-17. IL-17 neutralization may provide a potential target for novel therapeutic treatment for cardiac allograft rejection.


A targeted RNAi screen of the breast cancer genome identifies KIF14 and TLN1 as genes that modulate docetaxel chemosensitivity in triple-negative breast cancer.
To identify biomarkers within the breast cancer genome that may predict chemosensitivity in breast cancer. We conducted an RNA interference (RNAi) screen within the breast cancer genome for genes whose loss-of-function enhanced docetaxel chemosensitivity in an estrogen receptor-negative, progesterone receptor-negative, and Her2-negative (ER-, PR-, and Her2-, respectively) breast cancer cell line, MDA-MB-231. Top candidates were tested for their ability to modulate chemosensitivity in 8 breast cancer cell lines and to show in vivo chemosensitivity in a mouse xenograft model. From ranking chemosensitivity of 328 short hairpin RNA (shRNA) MDA-MB-231 cell lines (targeting 133 genes with known somatic mutations in breast cancer), we focused on the top two genes, kinesin family member 14 (KIF14) and talin 1 (TLN1). KIF14 and TLN1 loss-of-function significantly enhanced chemosensitivity in four triple-negative breast cancer (TNBC) cell lines (MDA-MB-231, HCC38, HCC1937, and Hs478T) but not in three hormone receptor-positive cell lines (MCF7, T47D, and HCC1428) or normal human mammary epithelial cells (HMEC). Decreased expression of KIF14, but not TLN1, also enhanced docetaxel sensitivity in a Her2-amplified breast cancer cell line, SUM190PT. Higher KIF14 and TLN1 expressions are found in TNBCs compared with the other clinical subtypes. Mammary fat pad xenografts of KIF14- and TLN1-deficient MDA-MB-231 cells revealed reduced tumor mass compared with control MDA-MB-231 cells after chemotherapy. KIF14 expression is also prognostic of relapse-free and overall survival in representative breast cancer expression arrays. KIF14 and TLN1 are modulators of response to docetaxel and potential therapeutic targets in TNBC.


Ancient invasions: from endosymbionts to organelles.
The acquisitions of mitochondria and plastids were important events in the evolution of the eukaryotic cell, supplying it with compartmentalized bioenergetic and biosynthetic factories. Ancient invasions by eubacteria through symbiosis more than a billion years ago initiated these processes. Advances in geochemistry, molecular phylogeny, and cell biology have offered insight into complex molecular events that drove the evolution of endosymbionts into contemporary organelles. In losing their autonomy, endosymbionts lost the bulk of their genomes, necessitating the evolution of elaborate mechanisms for organelle biogenesis and metabolite exchange. In the process, symbionts acquired many host-derived properties, lost much of their eubacterial identity, and were transformed into extraordinarily diverse organelles that reveal complex histories that we are only beginning to decipher.


The effect of changes in Medicare reimbursement on the practice of office and hospital-based endoscopic surgery for bladder cancer.
Procedures performed in the office offer potential cost savings. Recent analyses suggest, however, that a fee-for-service system may incentivize subscale operations and, thus, contribute to excessive spending. The authors of this report sought to characterize changes in the practice of office-based and hospital-based endoscopic bladder surgery after 2005 increases in Medicare reimbursement. All office and hospital-based endoscopic surgeries that were performed in a faculty practice from 2002 through 2007 were identified using billing codes for procedures, diagnoses, and procedure locations and then analyzed using the chi-square test and logistic regression. Costs were estimated based on published Medicare reimbursements for office and hospital-based surgeries. In total, 1341 endoscopic bladder surgeries were performed, including 764 in the office and 577 in the hospital. After 2005, the odds ratio (OR) for office surgery occurring among all cystoscopies and for surgery occurring in the office versus the hospital was 2.01 (95% confidence interval [CI], 1.71-2.37) and 2.29 (95% CI, 1.83-2.87), respectively. Among all treated lesions that were associated with a diagnosis of bladder cancer and nonbladder cancer, the OR for a procedure occurring in the office versus the hospital was 1.36 (95% CI, 1.07-1.73) and 1.99 (95% CI, 1.52-2.60), respectively. The likelihood of repeat surgery on the same lesion increased after 2005 (OR, 2.86; 95% CI, 1.46-5.62), and the likelihood of an office surgery leading to a bladder cancer diagnosis at the next visit declined (OR, 0.29; 95% CI, 0.16-0.51). The overall estimated expenditure increased by 50%. After 2005, more bladder lesions were identified and treated in the office. In a single group practice, office treatment of bladder cancer did not fully explain this new practice pattern, suggesting a lowered threshold for office intervention.


The evaluation of developmental toxicity of chemicals exposed occupationally using whole embryo culture.
The purpose of this study was to employ the whole embryo culture (WEC) system to evaluate the developmental toxicity of industrial chemicals. Five chemicals including lead, cadmium, vinyl chloride, 1,2-dichloroethan, and carbon disulphide were tested in our laboratory both in vitro and in vivo (except lead). In vitro studies showed that cadmium and lead were teratogenic in the rat; whilst carbon disulphide, 1,2-dichloroethan and vinyl chloride mainly induced embryo growth retardation. The in vitro effects on development of the five industrial chemicals were similar to the effects in vivo. The in vitro effects were studied by three different exposure routes, direct exposure--chemicals added to the culture medium; indirect exposure--serum prepared from treated rats then used as culture medium, and pre-exposure--embryos treated maternally then explanted into control (untreated) culture medium. Comparing these three different exposure routes suggests that the last exposure route is the most effective when using WEC to evaluate developmental toxicity of industrial chemicals. The effects on embryo development of culturing in sera prepared from subjects occupationally exposed to antineoplastic drugs (ADs) was also tested by the WEC system. Embryos were cultured with human serum that was thought to contain ADs or ADs' metabolic materials (serum taken from nurses routinely handling ADs), to evaluate the effects of ADs on embryo development. Embryos (9.5-day) cultured with serum from 11 female nurses who had been handling ADs for 2-17 years in the oncology department all survived, but showed slight growth retardation. Embryos cultured with serum from 30 healthy and unexposed people served as controls and embryo development in their serum was normal.


Gender- and race-specific metabolic score and cardiovascular disease mortality in adults: A structural equation modeling approach--United States, 1988-2006.
Consider all metabolic syndrome (MetS) components [systolic (SBP) and diastolic (DBP) blood pressures, waist circumference, HDL cholesterol, triglycerides (TG), and fasting glucose] and gender/race differential risk when assessing cardiovascular disease (CVD) risk. We estimated a gender- and race-specific continuous MetS score using structural equation modeling and tested its association with CVD mortality using data from National Health and Nutrition Examination Survey III linked with the National Death Index. Cox proportional hazard regression tested the association adjusted for sociodemographic and behavior characteristics. For men, continuous MetS components associated with CVD mortality were SBP (hazard ratio = 1.50, 95% confidence interval = 1.14-1.96), DBP (1.48, 1.16-1.90), and TG (1.15, 1.12-1.16). In women, SBP (1.44, 1.27-1.63) and DBP (1.24, 1.02-1.51) were associated with CVD mortality. MetS score was not significantly associated with CVD mortality in men; but significant associations were found for all women (1.34, 1.06-1.68), non-Hispanic white women (1.29, 1.01-1.64), non-Hispanic black women (2.03, 1.12-3.69), and Mexican-American women (3.57, 2.21-5.76). Goodness-of-fit and concordance were overall better for models with the MetS score than MetS (yes/no). When assessing CVD mortality risk, MetS score provided additional information than MetS (yes/no).


Integrating two-dimensional paths: do desert ants process distance information in the absence of celestial compass cues?
When performing foraging trips desert ants of the genus Cataglyphis continuously process and update a ;home vector' that enables them to return to their nest on the shortest route. This capacity of path integration requires two types of information: (i) information about the travelling directions, and (ii) odometric information about the distances travelled in a particular direction. We have investigated how these two necessary pieces of information interact within the path integration processor. The specific question is: how do the ants process distance information if there is no simultaneous input from the sky compass available. Ants were trained to forage in a ;Z'-shaped channel system, the three segments of which joined at right angles. Individual animals were transferred from the feeder to a test field where their homing paths could be observed. In the crucial tests the middle segment of the maze was covered by orange Perspex that did not transmit the UV part of the spectrum, and thus precluded the perception of polarization patterns. Changes of the ant's processing of odometric information within this channel segment directly translate into a change in homing direction on the test field. The results indicate that the odometric information about travelling distance is largely ignored for path integration if there is no simultaneous input from the sky-view-based compass. They further show that idiothetic information cannot adequately substitute for the polarization compass to infer travelling directions.


Advantage of using a recombinant activated factor VII in traumatic haemorrhagic shock: The Bordeaux experience.
Several series of patient studies have been published on the use of rFVIIa in traumatic haemorrhagic shock, although to date no international recommendations have been produced. France does not currently recognise traumatic haemorrhagic shock as an appropriate indication for the use of rFVIIa. In this retrospective study, we present our experience in the use of rFVIIa in traumatic haemorrhagic shock. Twenty-seven patients treated with rFVIIa after a traumatic injury between May 2005 and December 2008 were included. Average age was 46 years old. Eighty per cent of patients were polytransfused. Mortality rate was 33%. Adjusted mortality rate, using the Boffard study criteria, was 8.3%. We observed significant differences between the group of patients who died and the group of survivors in pH, PT, Hb, ionised calcaemia, temperature and platelet count. We observed significant differences between the successful rFVIIa group and the failed rFVIIa group in pH, Hb, platelet count and ionised calcaemia. Ten patients had an rFVIIa injection only and 17 patients had an rFVIIa injection combined with a mechanical procedure to stop the bleeding. Two patients presented with thromboembolic complications. We observed a tendency to recommend an rFVIIa injection before radical treatment is applied. It seems to us legitimate to recommend earlier use of rFVIIa in cases of traumatic haemorrhagic shock in the context of haematological damage control combined with the use of an algorithm to predict the risk involved in polytransfusion and a more aggressive transfusion strategy.


The Periplasmic Trehalase Affects Type 1 Fimbria Production and Virulence of Extraintestinal Pathogenic Escherichia coli Strain MT78.
Extraintestinal pathogenic Escherichia coli (ExPEC) is responsible for various infections outside the gastrointestinal tract in humans and other animals. ExPEC strain MT78 is invasive to various nonphagocytic cells and highly virulent in vivo To identify genes required for invasion of nonphagocytic cells by this strain, we applied signature-tagged mutagenesis to generate a library of mutants and tested them for invasion of avian fibroblasts. Mutants showing reduced cellular invasion included those with insertions in the fim operon, encoding type 1 fimbriae. Another attenuated mutant showed a disruption in the treA gene, which encodes a periplasmic trehalase. The substrate of TreA, trehalose, can be metabolized and used as a carbon source or can serve as an osmoprotectant under conditions of osmotic stress in E. coli K-12. We generated and characterized mutant MT78ΔtreA In contrast to the wild type, MT78ΔtreA was able to grow under osmotic stress caused by 0.6 M urea but not in minimal M9 medium with trehalose as the only carbon source. It presented decreased association and invasion of avian fibroblasts, decreased yeast agglutination titer, and impaired type 1 fimbria production. In a murine model of urinary tract infection, MT78ΔtreA was less able to colonize the bladder. All phenotypes were rescued in the complemented mutant. Our results show that the treA gene is needed for optimal production of type 1 fimbriae in ExPEC strain MT78 and that loss of treA significantly reduces its cell invasion capacity and colonization of the bladder in a murine model of urinary tract infection.


Conflict processing in kindergarten children: New evidence from distribution analyses reveals the dynamics of incorrect response activation and suppression.
The development of cognitive control is known to follow a long and protracted development. However, whether the interference effect in conflict tasks in children would entail the same core processes as in adults, namely an automatic activation of incorrect response and its subsequent suppression, remains an open question. We applied distributional analyses to reaction times and accuracy of 5- and 6-year-old children performing three conflict tasks (flanker, Simon, and Stroop) in a within-participants design. This revealed both strong commonalities and differences between children and adults. As in adults, fast responses were more error prone than slow ones on incompatible trials, indicating a fast "automatic" activation of the incorrect response. In addition, the strength of this activation differed across tasks, following a pattern similar to that of adults. Moreover, modeling the data with a drift diffusion model adapted for conflict tasks allowed one to better assess the origin of the typical slowing down observed in children. Besides showing that advanced distribution analyses can be successfully applied to children, the current results support the notion that interference effects in 5- and 6-year-olds are driven by mechanisms very similar to the ones at play in adults but with different time courses.


General regression methods for respondent-driven sampling data.
Respondent-driven sampling is a variant of link-tracing sampling techniques that aim to recruit hard-to-reach populations by leveraging individuals' social relationships. As such, a respondent-driven sample has a graphical component which represents a partially observed network of unknown structure. Moreover, it is common to observe homophily, or the tendency to form connections with individuals who share similar traits. Currently, there is a lack of principled guidance on multivariate modelling strategies for respondent-driven sampling to address peer effects driven by homophily and the dependence between observations within the network. In this work, we propose a methodology for general regression techniques using respondent-driven sampling data. This is used to study the socio-demographic predictors of HIV treatment optimism (about the value of antiretroviral therapy) among gay, bisexual and other men who have sex with men, recruited into a respondent-driven sampling study in Montreal, Canada.


Site-specific growth and density control of carbon nanotubes by direct deposition of catalytic nanoparticles generated by spark discharge.
Catalytic iron nanoparticles generated by spark discharge were used to site-selectively grow carbon nanotubes (CNTs) and control their density. The generated aerosol nanoparticles were deposited on a cooled substrate by thermophoresis. The shadow mask on top of the cooled substrate enabled patterning of the catalytic nanoparticles and, thereby, patterning of CNTs synthesized by chemical vapor deposition. The density of CNTs could be controlled by varying the catalytic nanoparticle deposition time. It was also demonstrated that the density could be adjusted by changing the gap between the shadow mask and the substrate, taking advantage of the blurring effect of the deposited nanoparticles, for an identical deposition time. As all the processing steps for the patterned growth and density control of CNTs can be performed under dry conditions, we also demonstrated the integration of CNTs on fully processed, movable silicon microelectromechanical system (MEMS) structures.


Optical Coherence Tomography for Retinal Surgery: Perioperative Analysis to Real-Time Four-Dimensional Image-Guided Surgery.
Magnification of the surgical field using the operating microscope facilitated profound innovations in retinal surgery in the 1970s, such as pars plana vitrectomy. Although surgical instrumentation and illumination techniques are continually developing, the operating microscope for vitreoretinal procedures has remained essentially unchanged and currently limits the surgeon's depth perception and assessment of subtle microanatomy. Optical coherence tomography (OCT) has revolutionized clinical management of retinal pathology, and its introduction into the operating suite may have a similar impact on surgical visualization and treatment. In this article, we review the evolution of OCT for retinal surgery, from perioperative analysis to live volumetric (four-dimensional, 4D) image-guided surgery. We begin by briefly addressing the benefits and limitations of the operating microscope, the progression of OCT technology, and OCT applications in clinical/perioperative retinal imaging. Next, we review intraoperative OCT (iOCT) applications using handheld probes during surgical pauses, two-dimensional (2D) microscope-integrated OCT (MIOCT) of live surgery, and volumetric MIOCT of live surgery. The iOCT discussion focuses on technological advancements, applications during human retinal surgery, translational difficulties and limitations, and future directions.


Spodoptera frugiperda Smith (Lepidoptera: Noctuidae) in Cameroon: Case study on its distribution, damage, pesticide use, genetic differentiation and host plants.
Maize farmers in sub-Saharan Africa recently experienced unusual damage in their farms, attributed to the fall armyworm (FAW) Spodoptera frugiperda (J. E. Smith). This pest was first recorded in Africa in 2016, but detailed information on its distribution and damage and farmer's response in invaded areas are largely lacking. In this study, we determined FAW distribution, genetic diversity, host plants, crop damage, and farmers' responses. S. frugiperda was recorded in the 10 regions of Cameroon. Average percentage of infested plants and damage severity (on a scale of 1 to 5) were lowest-20.7 ± 7.4% and 2.1 ± 0.1 respectively-in the Sahelian regions and greatest-69.0 ± 4.3% and 3.1 ± 0.1 respectively-in the Western Highlands. Altitude did not influence FAW incidence and severity and its larvae infrequently co-occurred with maize stemborers on the same plants, suggesting possible direct and/or indirect competition between the two groups of maize pests. In response to this new threat to maize production, farmers have opted for the application of synthetic pesticides. Although our experiments were not designed to determine pesticide efficacy, as parameters such as time since application were not considered, our observations suggest lack of a drastic effect on S. frugiperda infestations on maize. There were two haplotypes of FAW co-occurring in Cameroon corresponding to the rice and corn strains and separated by 1.7% sequence divergence, which does not support the existence of cryptic species. S. frugiperda larvae were also recorded on Sorghum bicolor (L.) Moench (10.6%), Solanum tuberosum L. (2.8%), Ipomoea batatas (L.) Lam. (1.9%), Saccharum officinarum L (0.8%), Phaseolus vulgaris L. (0.4%) and Gossypium hirsutum L. (1.9%). This study show that two strains are present in all agroecological zones in Cameroon, and probably in neighboring countries of central Africa sharing the same agroecologies. Management options should therefore consider the use of specific natural enemies and an informed decision of intervention based on strain capture and damage threshold, to avoid pesticide resistance that may arise from inadequate use of chemicals. Further studies should also be undertaken to assess the response of the two S. frugiperda strains to biopesticides and botanical insecticides.


Polarization gating in ultrafast-optics imaging of skeletal muscle tissues.
By comparing the results of polarization-dependent, time-resolved intensity profiles of photons transmitted through diluted milk, chicken breast tissue, and chopped chicken breast tissue, we found that the inherent anisotropic optical property of skeletal muscle tissue resulted in coherent coupling between two mutually perpendicular polarization directions. This coupling process led to difficulty in using the conventional polarization gating method for imaging unless the anisotropy characteristics were well understood. However, imaging based on polarization gating in diluted milk and chopped chicken breast tissue, which had an isotropic random-scattering nature, was quite effective.


The mediterranean dietary pattern and breast cancer risk in Greek-Cypriot women: a case-control study.
Diet has long been suspected to impact on breast cancer risk. In this study we evaluated whether the degree of adherence to a Mediterranean diet pattern modifies breast cancer risk amongst Greek-Cypriot women. Subjects included 935 cases and 817 controls, all participating in the MASTOS case-control study in Cyprus. The study was approved by the Cyprus National Bioethics Committee. Information on dietary intakes was collected using an interviewer administered 32-item Food Frequency Questionnaire. Information on demographic, anthropometric, lifestyle, and other confounding factors was also collected. Adherence to the Mediterranean Diet pattern was assessed using two a-priory defined diet scores. In addition, dietary patterns specific to our population were derived using Principal Component Analysis (PCA). Logistic regression models were used to assess the association between the dietary patters and breast cancer risk. There was no association with breast cancer risk for either score, however, higher consumptions of vegetables, fish and olive oil, were independently associated with decreased risk. In addition, the PCA derived component which included vegetables, fruit, fish and legumes was shown to significantly reduce risk of breast cancer (ORs across quartiles of increasing levels of consumption: 0.89 95%CI: 0.65-1.22, 0.64 95%CI: 0.47-0.88, 0.67 95%CI: 0.49-0.92, P trend < 0.0001), even after adjustment for relevant confounders. Our results suggest that adherence to a diet pattern rich in vegetables, fish, legumes and olive oil may favorably influence the risk of breast cancer. This study is the first investigation of dietary effects on breast cancer risk in Cyprus, a country whose population has traditionally adhered to the Mediterranean diet.


Mitotic p21Cip1/CDKN1A is regulated by cyclin-dependent kinase 1 phosphorylation.
The multifunctional protein p21Cip1/CDKN1A (p21) is an important and universal Cdk-interacting protein. Recently, we have reported that p21 is involved in the regulation of the mitotic kinase Cdk1/cyclin B1 and critical for successful mitosis and cytokinesis. In the present work we show that S130 of p21 is phosphorylated by Cdk1/cyclin B1 during mitosis, which reduces p21's stability and binding affinity to Cdk1/cyclin B1. Interfering with this phosphorylation results in extended mitotic duration and defective chromosome segregation, indicating that this regulation ensures proper mitotic progression. Given that p53, the major transcriptional activator of p21, is the most frequently mutated gene in human cancer and that deregulated Cdk1 associates with the development of different types of cancer, this work provides new insight into the understanding of how deregulated p21 contributes to chromosomal instability and oncogenesis.


Genetic variation and coronary atherosclerosis in patients with systemic lupus erythematosus.
Coronary artery disease is the major cause of mortality in patients with systemic lupus erythematosus (SLE). Increased cardiovascular risk in SLE is not explained by traditional risk factors. We examined the hypothesis that genetic variation contributes to the presence of coronary atherosclerosis in patients with SLE. The genotypes of single-nucleotide polymorphisms (SNP) in 152 candidate genes linked with autoimmune or cardiovascular risk were determined in 125 patients with SLE. Coronary artery calcium (CAC), a measure of coronary atherosclerosis, was detected in 32 patients (26%) by electron-beam computed tomography. Polymorphism in 20 of the candidate genes (ADAM33, ADIPOQ, CCL5, CCR7, CDKN2B, CSF1, IL4, IL12A, IL23R, INS, IRF5, MIF, MS4A1, PTGS1, PTPN22, RETN, SELE, TNFSF4, TNFRSF11B, and VCAM1) were nominally associated with the presence of CAC (p-values = 0.001-0.047 after adjustment for age, sex and race). Some of these are known susceptibility genes for SLE and others have been implicated in cardiovascular disease in other populations. No association withstood false discovery rate adjustment. Replication studies in additional cohorts of patients with SLE may be informative.


Interactive and automated application of virtual microscopy.
Virtual microscopy can be applied in an interactive and an automated manner. Interactive application is performed in close association to conventional microscopy. It includes image standardization suitable to the performance of an individual pathologist such as image colorization, white color balance, or individual adjusted brightness. The steering commands have to include selection of wanted magnification, easy navigation, notification, and simple measurements (distances, areas). The display of the histological image should be adjusted to the physical limits of the human eye, which are determined by a view angle of approximately 35 seconds. A more sophisticated performance should include acoustic commands that replace the corresponding visual commands. Automated virtual microscopy includes so-called microscopy assistants which can be defined similar to the developed assistants in computer based editing systems (Microsoft Word, etc.). These include an automated image standardization and correction algorithms that excludes images of poor quality (for example uni-colored or out-of-focus images), an automated selection of the most appropriate field of view, an automated selection of the best magnification, and finally proposals of the most probable diagnosis. A quality control of the final diagnosis, and feedback to the laboratory determine the proposed system. The already developed tools of such a system are described in detail, as well as the results of first trials. In order to enhance the speed of such a system, and to allow further user-independent development a distributed implementation probably based upon Grid technology seems to be appropriate. The advantages of such a system as well as the present pathology environment and its expectations will be discussed in detail.


Protective role of Ginkgo biloba against hepatotoxicity and nephrotoxicity in uranium-treated mice.
The aim of the present study was to investigate the protective role of Ginkgo biloba leaf extract against uranium (U)-induced toxicity in Swiss albino mice. The mice were randomly divided into six groups, each consisting of six animals: Group I (control) received tap water alone, Group II received U at a dose of 5 mg/kg of body weight, Group III received G. biloba at a dose of 50 mg/kg of body weight, Group IV received G. biloba at a dose of 150 mg/kg of body weight, Group V received G. biloba (50 mg/kg of body weight) and U (5 mg/kg of body weight), and Group VI received G. biloba (150 mg/kg of body weight) and U (5 mg/kg of body weight) by oral gavage for 5 days. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and creatinine levels were determined to assess liver and kidney function, respectively. Also, liver and kidney samples were taken for the determination of tissue malondialdehyde (MDA) and reduced glutathione (GSH) levels, and histopathological changes in liver and kidneys were investigated. The results indicated that there was a significant increase (P < .05) in selected serum parameters. Serum AST, ALT, BUN, and creatinine levels significantly increased in mice treated with U alone when compared to the other groups. Moreover, U-induced oxidative damage caused a significant decrease in GSH levels and a significant increase in MDA levels of liver and kidney tissues. Treatment with G. biloba produced amelioration in biochemical indices of hepatotoxicity and nephrotoxicity according to Group II. Each dose of G. biloba provided significant protection against U-induced toxicity, and its strongest effect was observed at a dose of 150 mg/kg of body weight. In vivo results showed that G. biloba extract is a potent protector against U-induced toxicity, and its protective role is dose-dependent.


Clinical EFT as an evidence-based practice for the treatment of psychological and physiological conditions: A systematic review.
Since the turn of the century, Emotional Freedom Techniques (EFT) has come into widespread use in medical and psychological treatment settings. It is also used as self-help by tens of millions of people each year. Clinical EFT, the manualized form of the method, has been validated as an "evidence-based" practice using criteria published by the American Psychological Association (APA) Division 12 Task Force on Empirically Validated Therapies. Its three essential ingredients are exposure, cognitive framing, and acupressure. In 2013 we published a paper defining Clinical EFT and reviewing published research. It has been viewed or downloaded over 36,000 times, indicating widespread interest in this treatment modality. Here we update our findings based on subsequently published literature and propose directions for future research. We performed a systematic review of the literature to identify randomized controlled trials (RCTs) and meta-analyses. Retrieval of 4,167 results resulted in the identification of 56 RCTs (n = 2,013), 41 of which were published subsequent to our earlier review, as well as eight meta-analyses. RCTs have found EFT treatment to be effective for (a) psychological conditions such as anxiety, depression, phobias, and posttraumatic stress disorder (PTSD); (b) physiological issues such as pain, insomnia, and autoimmune conditions; (c) professional and sports performance; and (d) biological markers of stress. Meta-analyses evaluating the effect of EFT treatment have found it to be "moderate" to "large." Successful independent replication studies have been carried out for anxiety, depression, PTSD, phobias, sports performance, and cortisol levels. We outline the next steps in EFT research. These include determining its impact on cancer, heart disease, diabetes, and cognitive impairment; analysis of the large-scale datasets made possible by mobile apps; and delivery through channels such as virtual practitioner sessions, artificial intelligence agents, online courses, apps, virtual reality platforms, and standardized group therapy. Subsequent research has confirmed the conclusions of earlier studies. These find Clinical EFT to be efficacious for a range of psychological and physiological conditions. Comparatively few treatment sessions are required, treatment is effective whether delivered in person or virtually, and symptom improvements persist over time. Treatment is associated with measurable biological effects in the dimensions of gene expression, brain synchrony, hormonal synthesis, and a wide range of biomarkers. Clinical EFT is a stable and mature method with an extensive evidence base. Its use in primary care settings as a safe, rapid, reliable, and effective treatment for both psychological and medical diagnoses continues to grow.


Cord blood is the optimal graft source for the treatment of pediatric patients with lysosomal storage diseases: clinical outcomes and future directions.
Initially used as an alternative hematopoietic stem cell source for patients without a human leukocyte antigen-matched bone marrow or peripheral blood stem cell donor, unrelated cord blood (UCB) is now the preferred donor source when hematopoietic stem cell transplantation (HSCT) is used to treat patients with lysosomal storage disorders (LSD). Without transplantation, these patients have serious progressive multi-system deterioration and premature death. UCB transplantation favorably alters the natural history of these diseases and prolongs survival. It primarily works through cellular enzyme replacement by healthy engrafted donor cells providing a continuous endogenous supply of enzyme throughout the body and, thorough engraftment of donor-derived microgial cells, in the central nervous system. HSCT in LSD, the majority performed in patients with mucopolysaccharidoses and leukodystrophies, is associated with remarkably high rates of engraftment and survival. Importantly, recipients of UCB, as compared with other donor sources, more often achieve full-donor chimerism and normalization of enzyme levels, which has been associated with superior long-term clinical prognosis. Additionally, UCB units are readily available, reducing time to transplantation and thereby providing access to transplant at young ages, another highly important predictor for long-term neuro-developmental function. For these reasons, UCB grafts are nowadays considered to be the optimal graft source for HSCT in patients with LSD.


Steroids mediate resistance to the bactericidal effect of phosphatidylcholines against Helicobacter pylori.
Helicobacter pylori assimilates various steroids as membrane lipid components, but it can also survive in the absence of steroids. It thus remains to be clarified as to why the organism relies on steroid physiologically. In this study, we have found that phosphatidylcholine carrying a linoleic acid molecule or arachidonic acid molecule has the potential to kill steroid-free H. pylori. The bactericidal action of phosphatidylcholines against H. pylori was due to the lytic activity of the phosphatidylcholines themselves and not due to the lytic activity of the unsaturated fatty acids or lyso-phosphatidylcholine resulting from the hydrolysis of the phosphatidylcholines. In contrast to the steroid-free H. pylori, the organism that absorbed and glucosylated free cholesterol was unaffected by the bactericidal action of the phosphatidylcholines. Similarly, H. pylori that absorbed estrone without glucosylating it also resisted the bactericidal action of the phosphatidylcholines. The steroids absorbed by H. pylori existed in both the outer and inner membranes, while the glucosyl-steroids produced via the steroid absorption were localized in the outer membrane rather than in the inner membrane. These results indicate that H. pylori absorbs the steroids to reinforce the membrane lipid barrier and thereby expresses resistance to the bacteriolytic action of hydrophobic compounds such as phosphatidylcholine.


Short repeats in the heme oxygenase 1 gene promoter is associated with increased levels of inflammation, ferritin and higher risk of type-2 diabetes mellitus.
We evaluated the relationship between the HO1 genotype, ferritin levels and the risk of type-2 diabetes and inflammation. Eight hundred thirty-five individuals were evaluated and classified according to their nutritional status and the presence of type-2 diabetes: 153 overweight (OW); 62 obese (OB); 55 type-2 diabetes mellitus (DM); 202 OWDM; 239 OBDM and 124 controls (C). We studied biochemical (glycemia, insulin, lipid profile, liver enzyme, creatinine, hsCRP), hematological (hemoglobin, free erythrocyte protoporphyrin, transferrin receptor and serum Fe and ferritin) and oxidative stress (SOD, GHS and TBARS) parameters. We determined heme oxygenase activity and the (GT)n polymorphism in its gene promoter. Individuals with diabetes, independent of nutritional status, showed high levels of ferritin and HO activity compared to control subjects. Allelic frequency was not different between the groups (Chi(2), NS) however, genotypes were different (Chi(2), P<0.001). The SS (short-short) genotype was higher in all DM individuals compared to controls and MM was higher in controls. SM (short-medium) genotype was an independent risk factor for DM in logistic regression analysis. We observed high risk for type-2 diabetes mellitus in the presence of SM genotype and high levels of ferritin (OR adjusted: 2.7; 1.9-3.6; p<0.001; compared to control group). It was also significantly related to inflammation. The SM genotype in HO1 gene promoter and ferritin levels were associated with higher risk for type-2 diabetes and for having a higher marker of inflammation, which is the main risk factor for the development of chronic diseases.


Omega-3 fatty acids and cancers: a systematic update review of epidemiological studies.
Experimental models showed consistently a modulation of carcinogenesis by omega 3 polyunsaturated fatty acids (ω3 PUFA). Fish intake is often described as part of a beneficial dietary pattern. However, observational epidemiological studies on the relationship between ω3 PUFA reported conflicting results. The objective of this systematic review is to determine whether there exists any progress in the evaluation of the causal relationship between dietary ω3 PUFA and cancers since the previous FAO/OMS expert consultation and whether it is possible to propose preventive and/or adjuvant therapeutic recommendations. Prospective and case-control observational studies published since 2007 and meeting validity criteria were considered together with RCT. Experimental studies are mentioned to provide for biological plausibility. When evaluating the level of evidence, a portfolio approach was used, weighted by a hierarchy giving higher importance to prospective studies followed by RCT if any. There is a probable level of evidence that ALA per se is neither a risk factor nor a beneficial factor with regards to cancers. Observational studies on colorectal, prostate and breast cancers only provided limited evidence suggesting a possible role of LC-ω3PUFA in cancer prevention because insufficient homogeneity of the observations. Explanation for heterogeneity might be the inherent difficulties associated with epidemiology (confounding and dietary pattern context, measurement error, level of intake, genetic polymorphism). The role of LC-ω3PUFA as adjuvant, might be considered of possible use, in view of the latest RCT on lung cancers even if RCT on other cancers still need to be undertaken.


Intraindividual cognitive variability before and after sports-related concussion.
Inconsistent performance is associated with cognitive dysfunction in a number of clinical populations. However, intraindividual cognitive variability in healthy individuals is poorly understood. Inconsistency poses a challenge to clinicians when interpreting change over time. This study examined intraindividual cognitive variability within a sample of college athletes tested at baseline and postconcussion. Athletes (n = 71) and control participants (n = 42) were tested with a comprehensive neuropsychological battery at baseline and postconcussion (athletes) or one month later (controls). A subset of indices with high internal consistency was used to calculate overall performance and performance variability. A k-means cluster analysis of baseline and postconcussion performance variability examined heterogeneity within the sample. In the athlete sample, performance variability was significantly greater than zero, and was negatively correlated with overall performance at both time points (p < .001). Wechsler Test of Adult Reading Full Scale IQ estimate was significantly correlated with overall performance (p < .01), but not with performance variability. Cluster analysis revealed low-variability (n = 46) and high-variability (n = 25) cluster groups. Whereas the low-variability cluster group exhibited a pattern of performance similar to that of control participants, membership in the high-variability cluster group was associated with postconcussion cognitive dysfunction. These findings suggest that normative cognitive performance in college athletes is characterized by significant intraindividual variation across tests. Cross-test intraindividual variability may impart clinically meaningful information, as higher levels of variability were related to poorer overall performance and postconcussion cognitive dysfunction.


Epigenetic population differentiation in field- and common garden-grown Scabiosa columbaria plants.
Populations often differ in phenotype and these differences can be caused by adaptation by natural selection, random neutral processes, and environmental responses. The most straightforward way to divide mechanisms that influence phenotypic variation is heritable variation and environmental-induced variation (e.g., plasticity). While genetic variation is responsible for most heritable phenotypic variation, part of this is also caused by nongenetic inheritance. Epigenetic processes may be one of the underlying mechanisms of plasticity and nongenetic inheritance and can therefore possibly contribute to heritable differences through drift and selection. Epigenetic variation may be influenced directly by the environment, and part of this variation can be transmitted to next generations. Field screenings combined with common garden experiments will add valuable insights into epigenetic differentiation, epigenetic memory and can help to reveal part of the relative importance of epigenetics in explaining trait variation. We explored both genetic and epigenetic diversity, structure and differentiation in the field and a common garden for five British and five French Scabiosa columbaria populations. Genetic and epigenetic variation was subsequently correlated with trait variation. Populations showed significant epigenetic differentiation between populations and countries in the field, but also when grown in a common garden. By comparing the epigenetic variation between field and common garden-grown plants, we showed that a considerable part of the epigenetic memory differed from the field-grown plants and was presumably environmentally induced. The memory component can consist of heritable variation in methylation that is not sensitive to environments and possibly genetically based, or environmentally induced variation that is heritable, or a combination of both. Additionally, random epimutations might be responsible for some differences as well. By comparing epigenetic variation in both the field and common environment, our study provides useful insight into the environmental and genetic components of epigenetic variation.


Joint Kinetics and Kinematics During Common Lower Limb Rehabilitation Exercises.
Unilateral body-weight exercises are commonly used to strengthen the lower limbs during rehabilitation after injury, but data comparing the loading of the limbs during these tasks are limited. To compare joint kinetics and kinematics during 3 commonly used rehabilitation exercises. Descriptive laboratory study. Laboratory. A total of 9 men (age = 22.1 ± 1.3 years, height = 1.76 ± 0.08 m, mass = 80.1 ± 12.2 kg) participated. Participants performed the single-legged squat, forward lunge, and reverse lunge with kinetic data captured via 2 force plates and 3-dimensional kinematic data collected using a motion-capture system. Peak ground reaction forces, maximum joint angles, and peak sagittal-joint moments. We observed greater eccentric and concentric peak vertical ground reaction forces during the single-legged squat than during both lunge variations (P ≤ .001). Both lunge variations demonstrated greater knee and hip angles than did the single-legged squat (P < .001), but we observed no differences between lunges (P > .05). Greater dorsiflexion occurred during the single-legged squat than during both lunge variations (P < .05), but we noted no differences between lunge variations (P = .70). Hip-joint moments were greater during the forward lunge than during the reverse lunge (P = .003) and the single-legged squat (P = .011). Knee-joint moments were greater in the single-legged squat than in the reverse lunge (P < .001) but not greater in the single-legged squat than in the forward lunge (P = .41). Ankle-joint moments were greater during the single-legged squat than during the forward lunge (P = .002) and reverse lunge (P < .001). Appropriate loading progressions for the hip should begin with the single-legged squat and progress to the reverse lunge and then the forward lunge. In contrast, loading progressions for the knee and ankle should begin with the reverse lunge and progress to the forward lunge and then the single-legged squat.


Editorial Commentary: Spine Pathology May Compromise the Results of Hip Arthroscopy: Will Hip Arthroscopy Improve Low Back Pain?
Pathology of the lumbar spine and hip commonly occur concurrently. The hip-spine connection has been well documented in the hip arthroplasty literature but until recently has been largely ignored in the setting of hip arthroscopy. Physical examination and diagnostic workup of the lumbosacral junction are warranted to further our understanding of the effects of lumbosacral motion and pathology in patients with concomitant femoroacetabular impingement syndrome. An understanding of this relationship will better allow surgeons to counsel and preoperatively optimize patients undergoing evaluation and treatment of femoroacetabular impingement syndrome. Several studies have reported that patients with a previous lumbar arthrodesis undergoing hip arthroplasty have lower patient-reported outcomes and greater revision rates compared with patients without previous lumbar surgery, and similar to its effect on outcomes after hip arthroplasty, lumbar spine disease can compromise outcomes after hip arthroscopy. On the other side of the coin, hip arthroplasty has been shown to improve low back pain in patients with concomitant hip osteoarthritis. Can the arthroscopic treatment of nonarthritic hip pathology offer a similar result? We won't know unless we look.


Sunitinib resistance in renal cell carcinoma.
Of the many targeted therapies introduced since 2006, sunitinib has carved its way to become the most commonly used first-line therapy for the treatment of metastatic renal cell carcinoma (RCC). Despite significant improvements in progression-free survival, 30% of the patients are intrinsically resistant to sunitinib and the remaining 70% who respond initially will eventually become resistant in 6-15 months. While the molecular mechanisms of acquired resistance to sunitinib have been unravelling at a rapid rate, the mechanisms of intrinsic resistance remain elusive. Combination therapy, sunitinib rechallenge and sequential therapy have been investigated as means to overcome resistance to sunitinib. Of these, sequential therapy appears to be the most promising strategy. This mini review summarises our emerging understanding of the molecular mechanisms, and the strategies employed to overcome sunitinib resistance.


An experimental study of a virtual reality counselling paradigm using embodied self-dialogue.
When faced with a personal problem people typically give better advice to others than to themselves. A previous study showed how it is possible to enact internal dialogue in virtual reality (VR) through participants alternately occupying two different virtual bodies - one representing themselves and the other Sigmund Freud. They could maintain a self-conversation by explaining their problem to the virtual Freud and then from the embodied perspective of Freud see and hear the explanation by their virtual doppelganger, and then give some advice. Alternating between the two bodies they could maintain a self-dialogue, as if between two different people. Here we show that the process of alternating between their own and the Freud body is important for successful psychological outcomes. An experiment was carried out with 58 people, 29 in the body swapping Self-Conversation condition and 29 in a condition where they only spoke to a Scripted Freud character. The results showed that the Self-Conversation method results in a greater perception of change and help compared to the Scripted. We compare this method with the distancing paradigm where participants imagine resolving a problem from a first or third person perspective. We consider the method as a possible strategy for self-counselling.


A phase I study of TNP-470 administered to patients with advanced squamous cell cancer of the cervix.
A Phase I study of the novel angiogenesis inhibitor TNP-470 was performed. Patients with inoperable recurring or metastatic squamous cell cancer of the cervix with evaluable disease, no coagulopathy, and adequate renal, hepatic, and hematological function were eligible. One course of treatment consisted of an i.v. infusion of TNP-470 over 60 min every other day for 28 days, followed by a 14-day rest period. The starting dose was 9.3 mg/m2. Eighteen evaluable patients were treated, with a median age of 48 years (range 27-55) and performance status Zubrod 1 (range 0-2). Grade 3 neurotoxicities consisting of weakness, nystagmus, diplopia, and ataxia were encountered in two patients receiving the 71.2 mg/m2 dose. An intermediate dose level of 60 mg/m2 was evaluated and found to be well tolerated by three patients. Only one patient experienced grade 3 nausea on the 60 mg/m2 dose level. No myelosuppression, retinal hemorrhage, weight loss, or significant alopecia were observed. One patient had a complete response, which continues for 26 months, and three patients with initially progressive disease stage had stable disease for 5, 7.7, and 19+ months. Other Phase I studies, including over 200 patients, were performed concurrently with this study. Based on this experience, the dose of TNP-470 recommended for further studies is 60 mg/m2 as a 60-min i.v. infusion every Monday, Wednesday, and Friday. Neurotoxicity was dose limiting, but appears to be reversible. Otherwise, the treatment was well tolerated. The drug may be active in squamous cell cancer of the cervix. Further studies of TNP-470 in squamous cell cancer of the cervix are warranted.


M1 macrophages act as LTβR-independent lymphoid tissue inducer cells during atherosclerosis-related lymphoid neogenesis.
The goal of this study was to characterize the role of inflammatory macrophages in the induction of the vascular smooth muscle cell (VSMC)-mediated formation of aortic tertiary lymphoid organs (TLOs). Mouse bone marrow-derived M1 macrophages acted as lymphoid tissue inducer cells. Indeed, they expressed high levels of tumour necrosis factor (TNF)-α and membrane-bound lymphotoxin (LT)-α, two inducing cytokines that triggered expression of the chemokines CCL19, CCL20, and CXCL16, as did M1 supernatant. The blockade of LTβR signalling with LTβR-Ig had no effect, whereas that of TNFR1/2 signalling reduced chemokine expression by VSMCs in both wild-type (WT) and LTβR KO mice, demonstrating that LTβR signalling is dispensable for the M1-inducing effect. This effect was corroborated by the development of TLOs observed in LTβR KO->apolipoprotein E knockout (ApoE KO) aortic segments after orthotopic transplantation. Furthermore, treatment of ApoE KO mice with anti-TNF-α antibody decreased the number and incidence of aortic TLOs. Finally, lymphoid nodules composed of T and B cells formed in in vivo-implanted scaffolds seeded with VSMCs previously stimulated ex vivo by M1-conditioned medium. These results are the first to identify M1 macrophages as inducer cells that trigger the expression of chemokines by VSMCs independently of LTβR signalling. We propose that the dialogue between macrophages and VSMCs-established across the vascular wall-contributes to the formation of aortic TLOs.


High-grade transformation of adenoid cystic carcinoma delineated with a fibrous rim: a case report.
High-grade transformation or dedifferentiation in carcinoma is progression of a low-grade malignant neoplasm to a high-grade carcinoma or poorly differentiated adenocarcinoma. This is rarely observed in adenoid cystic carcinoma of the salivary glands. A 39 year-old woman presented with a painless mass at the left submandibulary region that had been growing slowly for 5 years. Submandibulary mass resection revealed a mass with peripheral adenoid cystic carcinoma and a central high-grade tumor delineated with a fibrous rim, raising the possibility of a hybrid or composite carcinoma, requiring differential diagnosis depending upon morphology and immunohistochemistry findings. The final histopathological diagnosis was high-grade transformation of adenoid cystic carcinoma. After surgical therapy, the patient was irradiated to the neck and submandibulary region. No sign of tumor recurrence has been evident for 36 months. This present case seems to be another rare case with high-grade transformation of adenoid cystic carcinoma and the fibrous rim may be a histopathological feature of such cases, which should be kept in mind.


Suppression of growth and invasive behavior of human prostate cancer cells by ProstaCaid™: mechanism of activity.
Since the use of dietary supplements as alternative treatments or adjuvant therapies in cancer treatment is growing, a scientific verification of their biological activity and the detailed mechanisms of their action are necessary for the acceptance of dietary supplements in conventional cancer treatments. In the present study we have evaluated the anti-cancer effects of dietary supplement ProstaCaid™ (PC) which contains mycelium from medicinal mushrooms (Ganoderma lucidum, Coriolus versicolor, Phellinus linteus), saw palmetto berry, pomegranate, pumpkin seed, green tea [40% epigallocatechin-3-gallate (EGCG)], Japanese knotweed (50% resveratrol), extracts of turmeric root (BCM-95®), grape skin, pygeum bark, sarsaparilla root, Scutellaria barbata, eleuthero root, Job's tears, astragalus root, skullcap, dandelion, coptis root, broccoli, and stinging nettle, with purified vitamin C, vitamin D3, selenium, quercetin, citrus bioflavonoid complex, β sitosterolzinc, lycopene, α lipoic acid, boron, berberine and 3.3'-diinodolymethane (DIM). We show that PC treatment resulted in the inhibition of cell proliferation of the highly invasive human hormone refractory (independent) PC-3 prostate cancer cells in a dose- and time-dependent manner with IC50 56.0, 45.6 and 39.0 µg/ml for 24, 48 and 72 h, respectively. DNA-microarray analysis demonstrated that PC inhibits proliferation through the modulation of expression of CCND1, CDK4, CDKN1A, E2F1, MAPK6 and PCNA genes. In addition, PC also suppresses metastatic behavior of PC-3 by the inhibition of cell adhesion, cell migration and cell invasion, which was associated with the down-regulation of expression of CAV1, IGF2, NR2F1, and PLAU genes and suppressed secretion of the urokinase plasminogen activator (uPA) from PC-3 cells. In conclusion, the dietary supplement PC is a promising natural complex with the potency to inhibit invasive human prostate cancer.


The local enhancement of radiation dose from photons of MeV energies obtained by introducing materials of high atomic number into the treatment region.
With the advent of therapeutic radiation treatment machines with photon end point energies of several MeV, a new channel is available to transfer the photon energy to biological material, namely, pair production. This process has a photon threshold energy of 1.02 MeV. The probability of pair production, which depends on the square of the atomic number (Z) of the interacting material, increases markedly as the photon energy is further increased. As the goal of treatment planning in radiation therapy is to locally maximize the absorbed dose in abnormal cells and minimize the dose in surrounding normal cells, in this study the authors measured the dose enhancement which could be expected if a high-Z material such as gold was present adjacent to tumor sites during irradiation. The authors used photon beams produced by electron accelerators with energies ranging from 6 to 25 MV. They chose either gold or lead foils as high-Z materials, the measurements being repeated using the same geometry but replacing the high-Z materials with a low-Z material (aluminum). The comparison of the experimental results using low- and high-Z materials verified the theoretical prediction of the expected dose enhancement. The effect of finite range of the electron-positron pairs was also studied by varying the spacing between two foils placed parallel or orthogonal to the incident photon beam. Using an 18 MV photon beam, the authors observed a maximum dose enhancement of 44%. They intend therefore to proceed from these phantom studies to animal measurements.


VEGF-A induces angiogenesis by perturbing the cathepsin-cysteine protease inhibitor balance in venules, causing basement membrane degradation and mother vessel formation.
Tumors initiate angiogenesis primarily by secreting vascular endothelial growth factor (VEGF-A(164)). The first new vessels to form are greatly enlarged, pericyte-poor sinusoids, called mother vessels (MV), that originate from preexisting venules. We postulated that the venular enlargement necessary to form MV would require a selective degradation of their basement membranes, rigid structures that resist vascular expansion. To identify the specific proteases responsible for MV formation, we induced angiogenesis in mouse tissues with an adenoviral vector expressing VEGF-A(164) (Ad-VEGF-A(164)) or with VEGF-A-secreting TA3/St mammary tumors. We found that MV formation resulted from greatly increased activity of cathepsins (B>S>L) in venules transitioning into MV, as well as from a reciprocal decrease in the expression of several cysteine protease inhibitors (CPI), stefin A and cystatins B and C, by these same venules. Using a fluorescence probe that selectively binds cellular sites of cathepsin protease activity in vivo, we showed that increased cathepsin activity was localized exclusively to perivenular cells, not to venule endothelial cells. CPI strikingly inhibited angiogenesis in the Matrigel assay, and Ad-VEGF-A(164)-induced angiogenesis was reduced by approximately 50% in cathepsin B-null mice. Thus, VEGF-A, whether expressed by interstitial cells infected with an adenoviral vector or by tumor cells, upsets the normal cathepsin-CPI balance in nearby venules, leading to degradation of their basement membranes, an important first step in angiogenesis.


Ovarian follicle development requires Smad3.
Smad3 is an important mediator of the TGF beta signaling pathway. Interestingly, Smad3-deficient (Smad3-/-) mice have reduced fertility compared with wild-type (WT) mice. To better understand the molecular mechanisms underlying the reduced fertility in Smad3-/- animals, this work tested the hypothesis that Smad3 deficiency interferes with three critical aspects of folliculogenesis: growth, atresia, and differentiation. Growth was assessed by comparing the size of follicles, expression of proliferating cell nuclear antigen, and expression of cell cycle genes in Smad3-/- and WT mice. Atresia was assessed by comparing the incidence of atresia and expression of bcl-2 genes involved in cell death and cell survival in Smad3-/- and WT mice. Differentiation was assessed by comparing the expression of FSH receptor (FSHR), estrogen receptor (ER) alpha, ER beta, and inhibin alpha-, beta(A)-, and beta(B)-subunits in Smad3-/- and WT mice. Because growth, atresia, and differentiation are regulated by hormones, estradiol, FSH, and LH levels were compared in Smad3-/- and WT mice. Moreover, because alterations in folliculogenesis can affect the ability of mice to ovulate, the number of corpora lutea and ovulated eggs in response to gonadotropin treatments were compared in Smad3-/- and WT animals. The results indicate that Smad3 deficiency slows follicle growth, which is characterized by small follicle diameters, low levels of proliferating cell nuclear antigen, and low expression of cell cycle genes (cyclin-dependent kinase 4 and cyclin D2). Smad3 deficiency also causes atretic follicles, degenerated oocytes, and low expression of bcl-2. Furthermore, Smad3 deficiency affects follicular differentiation as evidenced by decreased expression of ER beta, increased expression of ER alpha, and decreased expression of inhibin alpha-subunits. Smad3 deficiency causes low estradiol and high FSH levels. Finally, Smad3-/- ovaries have no corpora lutea, and they do not ovulate after ovulatory induction with exogenous gonadotropins. Collectively, these data provide the first evidence that reduced fertility in Smad3-/- mice is due to impaired folliculogenesis, associated with altered expression of genes that control cell cycle progression, cell survival, and cell differentiation. The findings that Smad3-/- follicles have impaired growth, increased atresia, and altered differentiation in the presence of high FSH levels, normal expression of FSHR, and lower expression of cyclin D2, suggest a possible interaction between Smad3 and FSH signaling downstream of FSHR in the mouse ovary.


Mutagenicity and antimutagenicity of (-)-hinokinin a trypanosomicidal compound measured by Salmonella microsome and comet assays.
The dibenzylbutyrolactone lignan (-)-hinokinin (HK) was derived by partial synthesis from (-)-cubebin, isolated from the dry seeds of the pepper, Piper cubeba. Considering the good trypanosomicidal activity of HK and recalling that natural products are promising starting points for the discovery of novel potentially therapeutic agents, the aim of the present study was to investigate the (anti) mutagenic∕ genotoxic activities of HK. The mutagenic∕ genotoxic activities were evaluated by the Ames test on Salmonella typhimurium strains TA98, TA97a, TA100 and TA102, and the comet assay, so as to assess the safe use of HK in the treatment of Chagas' disease. The antimutagenic ∕antigenotoxic potential of HK were also tested against the mutagenicity of a variety of direct and indirect acting mutagens, such as 4- nitro-o-phenylenediamine (NOPD), sodium azide (SA), mitomycin C (MMC), benzo[a]pyrene (B[a]P), aflatoxin B1 (AFB1), 2-aminoanthracene (2-AA) and 2-aminofluorene (2-AF), by the Ames test, and doxorubicin (DXR) by the comet assay. The mutagenicity∕genotoxicity tests showed that HK did not induce any increase in the number of revertants or extent of DNA damage, demonstrating the absence of mutagenic and genotoxic activities. On the other hand, the results on the antimutagenic potential of HK showed a strong inhibitory effect against some direct and indirect-acting mutagens. Regarding the use of HK as an antichagasic drug, the absence of mutagenic effects in animal cell and bacterial systems is encouraging. In addition, HK may be a new potential antigenotoxic ∕ antimutagenic agent from natural sources. However, the protective activity of HK is not general and varies with the type of DNA damage-inducing agent used.


Women who report having sex with women: British national probability data on prevalence, sexual behaviors, and health outcomes.
We estimated the prevalence of same-sex experience among women and compared women reporting sex with women and men and women reporting sex exclusively with women with women reporting sex exclusively with men, in terms of sociodemographics and sexual, reproductive, and general health risk behaviors and outcomes. We used a British probability survey (n=6399 women, aged 16 to 44 years) conducted from 1999 to 2001 with face-to-face interviewing and computer-assisted self-interviewing. We found that 4.9% of the women reported same-sex partner(s) ever; 2.8% reported sex with women in the past 5 years (n=178); 85.0% of these women also reported male partner(s) in this time. Compared with women who reported sex exclusively with men, women who reported sex with women and men reported significantly greater male partner numbers, unsafe sex, smoking, alcohol consumption, and intravenous drug use and had an increased likelihood of induced abortion and sexually transmitted infection diagnoses (age-adjusted odds ratios=3.07 and 4.41, respectively). For women, a history of sex with women may be a marker for increased risk of adverse sexual, reproductive, and general health outcomes compared with women who reported sex exclusively with men. A nonjudgmental review of female patients' sexual history should help practitioners discuss risks that women may face.


Chronic oral ascorbic acid therapy worsens skeletal muscle metabolism in patients with chronic heart failure.
Chronic heart failure (CHF) is associated with abnormalities of skeletal muscle metabolism. This may be due to impaired oxygen delivery as a result of endothelial dysfunction. We postulated that ascorbic acid would improve oxygen delivery to exercising muscle and improve skeletal muscle metabolism. We studied skeletal muscle metabolism using (31)P magnetic resonance spectroscopy in 39 CHF patients. Endothelial function was assessed by changes in pulse wave velocity. Subjects were randomised to receive 4 g ascorbic acid daily for 4 weeks in a placebo-controlled double-blind study. Ascorbic acid significantly increased phosphocreatine utilization during exercise. In addition, glycolytic ATP synthesis increased in the ascorbic acid group (change in rate of ATP synthesis at 1 min -0.21+/-0.76 with placebo, 2.06+/-0.60 following ascorbic acid; p<0.05). Phosphocreatine and ADP recovery after exercise were not changed. The fall in pulse wave velocity during reactive hyperaemia was increased by ascorbic acid from -6.3+/-2.6% to -12.1+/-2.0% (p<0.05). These findings suggest that ascorbic acid increased both phosphocreatine utilization and glycolytic ATP synthesis during exercise in patients with CHF implying worsened skeletal muscle metabolism despite improvements in endothelial function.


Presurgical brain mapping of the language network in pediatric patients with epilepsy using resting-state fMRI.
Epilepsy affects neural processing and often causes intra- or interhemispheric language reorganization, rendering localization solely based on anatomical landmarks (e.g., Broca's area) unreliable. Preoperative brain mapping is necessary to weigh the risk of resection with the risk of postoperative deficit. However, the use of conventional mapping methods (e.g., somatosensory stimulation, task-based functional MRI [fMRI]) in pediatric patients is technically difficult due to low compliance and their unique neurophysiology. Resting-state fMRI (rs-fMRI), a "task-free" technique based on the neural activity of the brain at rest, has the potential to overcome these limitations. The authors hypothesized that language networks can be identified from rs-fMRI by applying functional connectivity analyses. Cases in which both task-based fMRI and rs-fMRI were acquired as part of the preoperative clinical protocol for epilepsy surgery were reviewed. Task-based fMRI consisted of 2 language tasks and 1 motor task. Resting-state fMRI data were acquired while the patients watched an animated movie and were analyzed using independent component analysis (i.e., data-driven method). The authors extracted language networks from rs-fMRI data by performing a similarity analysis with functionally defined language network templates via a template-matching procedure. The Dice coefficient was used to quantify the overlap. Thirteen children underwent conventional task-based fMRI (e.g., verb generation, object naming), rs-fMRI, and structural imaging at 1.5T. The language components with the highest overlap with the language templates were identified for each patient. Language lateralization results from task-based fMRI and rs-fMRI mapping were comparable, with good concordance in most cases. Resting-state fMRI-derived language maps indicated that language was on the left in 4 patients (31%), on the right in 5 patients (38%), and bilateral in 4 patients (31%). In some cases, rs-fMRI indicated a more extensive language representation. Resting-state fMRI-derived language network data were identified at the patient level using a template-matching method. More than half of the patients in this study presented with atypical language lateralization, emphasizing the need for mapping. Overall, these data suggest that this technique may be used to preoperatively identify language networks in pediatric patients. It may also optimize presurgical planning of electrode placement and thereby guide the surgeon's approach to the epileptogenic zone.


[Glycopeptide heteroresistance and tolerance in hospital grampositive isolates: "invisible" phenomena to the clinician with clinical implications?].
This article reviews the concepts of heteroresistance and tolerance to glycopeptides in gram-positive bacteria isolated from hospitalised patients. Heteroresistance (resistant subpopulations among the total bacterial population of the strain, that can be selected by the treatment) and tolerance (capability of survival, but not growth, in the presence of usually lethal antibiotic concentrations) have in common several characteristics: 1) the absence of its determination in laboratory daily practice, 2) they implied a decrease in antimicrobial activity not reflected in MIC values (thus being "invisible" to clinicians in daily routine laboratory reports), 3) the decrease in antimicrobial activity may have clinical implications and 4) they affect a wide spectrum of gram positive bacteria in the hospital (Staphylococcus aureus, coagulase-negative staphylococci, enterococci and different estreptococcal species). The decrease produced in the bactericidal activity (that is critical for the treatment of bacteremias, endocarditis, meningitis and infections in immunocompromised patients) has clinical implications such aspersistance of bacteremia, refractory bacteremia, relapse of infections and increased length of stay. Two strategies are possible to overcome tolerance and heteroresistance: addition of antibiotics to obtain bactericidal activity by synergism (key factor for which it should be taken intoaccount antagonic combinations or high resistance to aminoglycosides when choosing the antibiotic regimen), or the use of bactericidal compounds to which grampositive bacteria show susceptibility and absence of heteroresistance and tolerance (in contrast to glycopeptides), as is the case of lipopeptide daptomycin.


The Efficacy of Intraoperative Frozen Section Analysis During Breast-Conserving Surgery for Patients with Ductal Carcinoma In Situ.
Recently, the incidence of ductal carcinoma in situ (DCIS), a noninvasive breast malignancy, has increased. This has resulted in an increase in the incidence of breast-conserving surgery (BCS). Numerous studies have suggested that intraoperative frozen section analysis (IFSA) could reduce the rate of additional excisions required to obtain adequate resection margins. However, DCIS is a known risk factor for positive margin status during BCS. Furthermore, some authors have concluded that IFSA may not be reliable for the detection of DCIS. The aim of this study was to evaluate the safety and efficacy of IFSA in patients with DCIS. The operative and pathological reports of patients with DCIS, who underwent BCS at our institute between 2006 and 2015, were retrospectively reviewed. The results of IFSA and the pathological findings of final reanalyzed frozen tissue specimens were analyzed. In total, 25 patients were included in our analysis. None of the patients required additional operations. The correct diagnosis rate for IFSA was 89.6%, with a sensitivity and specificity of 60.0% and 95.8%, respectively. IFSA could be beneficial for determining safety resection margins in patients with DCIS.


Rapid serial processing of natural scenes: color modulates detection but neither recognition nor the attentional blink.
The exact function of color vision for natural-scene perception has remained puzzling. In rapid serial visual presentation (RSVP) tasks, categorically defined targets (e.g., animals) are detected typically slightly better for color than for grayscale stimuli. Here we test the effect of color on animal detection, recognition, and the attentional blink. We present color and grayscale RSVP sequences with up to two target images (animals) embedded. In some conditions, we modify either the hue or the intensity of each pixel. We confirm a benefit of color over grayscale images for animal detection over a range of stimulus onset asynchronies (SOAs), with improved hit rates from 50 to 120 ms and overall improved performance from 90 to 120 ms. For stimuli in which the hue is inverted, performance is similar to grayscale for small SOAs and indistinguishable from original color only for large SOAs. For subordinate category discrimination, color provides no additional benefit. Color and grayscale sequences show an attentional blink, but differences between color and grayscale are fully explained by single-target differences, ruling out the possibility that the color benefit is purely attentional.


Amino-polyvinyl alcohol coated superparamagnetic iron oxide nanoparticles are suitable for monitoring of human mesenchymal stromal cells in vivo.
Mesenchymal stromal cells (MSCs) are promising candidates in regenerative cell-therapies. However, optimizing their number and route of delivery remains a critical issue, which can be addressed by monitoring the MSCs' bio-distribution in vivo using super-paramagnetic iron-oxide nanoparticles (SPIONs). In this study, amino-polyvinyl alcohol coated (A-PVA) SPIONs are introduced for cell-labeling and visualization by magnetic resonance imaging (MRI) of human MSCs. Size and surface charge of A-PVA-SPIONs differ depending on their solvent. Under MSC-labeling conditions, A-PVA-SPIONs have a hydrodynamic diameter of 42 ± 2 nm and a negative Zeta potential of 25 ± 5 mV, which enable efficient internalization by MSCs without the need to use transfection agents. Transmission X-ray microscopy localizes A-PVA-SPIONs in intracellular vesicles and as cytosolic single particles. After identifying non-interfering cell-assays and determining the delivered and cellular dose, in addition to the administered dose, A-PVA-SPIONs are found to be non-toxic to MSCs and non-destructive towards their multi-lineage differentiation potential. Surprisingly, MSC migration is increased. In MRI, A-PVA-SPION-labeled MSCs are successfully visualized in vitro and in vivo. In conclusion, A-PVA-SPIONs have no unfavorable influences on MSCs, although it becomes evident how sensitive their functional behavior is towards SPION-labeling. And A-PVA-SPIONs allow MSC-monitoring in vivo.


High doses of carbamazepine for refractory partial epilepsy.
Forty-eight patients with partial seizures were analysed during treatment with 1200 mg/d or more of carbamazepine (CBZ). Thirty-three were on monotherapy and fifteen on polytherapy. The other drugs were kept unchanged in the patients on polytherapy. The dose of CBZ was increased if no control was observed and the patient had no side effects. The doses used ranged between 1200 and 1900 mg/day (1200 mg/day, n = 18; 1300 mg/day, n = 1; 1400 mg/day, n = 7; 1600 mg/day, n = 9; 1700 mg/day, n = 4; 1800 mg/day, n = 8; 1900 mg/day, n = 1). Anticonvulsant plasma levels were taken to confirm patient compliance. The average plasma level was 9.6 ug/mL. The period of follow up varied from 3 to 96 months (M = 25.6). Seizure's control was observed in 7 (14.48%) patients taking 1200 mg/day and in 2 (4.16%) patients taking 1400 mg/day of CBZ. Thirty-nine patients did not show any control (81.21%). Ten patients (20.81%) had signs of intoxication. When patients have no improvement with 1400 mg/day, it is difficult to obtain any control despite the use of higher doses of CBZ, which frequently expose the patient to significant side effects.


Effective Refractive Index and Lipid Content of Extracellular Vesicles Revealed Using Optical Waveguide Scattering and Fluorescence Microscopy.
Extracellular vesicles (EVs) are generating a growing interest because of the key roles they play in various biological processes and because of their potential use as biomarkers in clinical diagnostics and as efficient carriers in drug-delivery and gene-therapy applications. Their full exploitation, however, depends critically on the possibility to classify them into different subpopulations, a task that in turn relies on efficient means to identify their unique biomolecular and physical signatures. Because of the large heterogeneity of EV samples, such information remains rather elusive, and there is accordingly a need for new and complementary characterization schemes that can help expand the library of distinct EV features. In this work, we used surface-sensitive waveguide scattering microscopy with single EV resolution to characterize two subsets of similarly sized EVs that were preseparated based on their difference in buoyant density. Unexpectedly, the scattering intensity distribution revealed that the scattering intensity of the high-density (HD) population was on an average a factor of three lower than that of the low-density (LD) population. By further labeling the EV samples with a self-inserting lipid-membrane dye, the scattering and fluorescence intensities from EVs could be simultaneously measured and correlated at the single-particle level. The labeled HD sample exhibited not only lower fluorescence and scattering intensities but also lower effective refractive index ( n ≈ 1.35) compared with the LD EVs ( n ≈ 1.38), indicating that both the lipid and protein contents were indeed lower in the HD EVs. Although separation in density gradients of similarly sized EVs is usually linked to differences in biomolecular content, we suggest based on these observations that the separation rather reflects the ability of the solute of the gradient to penetrate the lipid membrane enclosing the EVs, that is, the two gradient bands are more likely because of the differences in membrane permeability than to differences in biomolecular content of the EVs.


An objective measure for the assessment and management of fluid shifts in acute major burns.
Major burns are life threatening. Fluid resuscitation is required for survival to maintain intravascular volumes and prevent hypovolemic shock. Bioimpedance spectroscopy (BIS) has been recognised as a potential method of monitoring fluid shifts after burn and in other disease states. The aims of this study were to examine the reliability of BIS across different dressing conditions and electrode positions, establish the influence of Acticoat™ on BIS variable measures and determine the validity of whole-body BIS to assess net fluid shift in the presence of moderate to major burns. An observational longitudinal cohort study was conducted from December 2014 to February 2016. Patients with over 15% total body surface area (TBSA) burns and injury less than 48 h were enrolled in the study. BIS triplicate measures were collected in an open wound and with an ActicoatTM dressing (at 5 half hour intervals). Standard and alternate electrode placements were utilised for the reliability analysis and standard placement only for determining the validity of BIS in moderate to major burns. The ImpediMde SFB7 was used to collect whole-body and segmental BIS measures. Stata statistical software, release 14 was utilised to analyse all results. Descriptive analyses were performed and were reported using the means and standard deviations (SD). BIS-repeated measures established BIS raw resistance (R), and predicted volume variables were reliable in any condition (intra-class correlation coefficient (ICC) 0.996-0.999, 95% confidence intervals (CI) 0.996-0.999) without a systematic difference. Acticoat™ dressings significantly influenced all BIS-predicted volumes (p ≤ 0.01) as determined by multilevel mixed effects (MLME) linear regression analysis. Validity of BIS was demonstrated by resistance variables significantly decreasing with increasing net ionic fluid shift and increased TBSA (severity of injury) and calculated fluid volumes increasing with increasing net fluid shift and TBSA. BIS resistance also decreased with time as oedema reduced. For clinical use, a calculator was developed to adjust BIS variables when an Acticoat™ dressing is in situ, thus facilitating BIS variable change estimates in real time, with dressings intact. BIS may be used clinically to monitor fluid volume change in major acute burns.


Prevalence of suicidal behaviors and associated factors among Peruvian adolescent students: an analysis of a 2010 survey.
Adolescence is one of the stages in life most affected by suicide. In Peru, 22% of suicides occur in people 10 to 19 years old. However, mental health overall and factors associated with suicidal behaviors have not been well studied. To determine the prevalence of suicidal behaviors (ideation and ideation plus suicidal planning) and associated factors in Peruvian adolescent students. A cross-sectional study analyzing data from the Global School-based Student Health Survey for Peru in 2010 was conducted to measure the prevalence of suicidal behaviors (ideation and ideation plus suicidal planning) and associated factors in Peruvian adolescent students. Of the 2521 students evaluated, 19.9% (95% CI: 17.8 to 22.2) presented suicidal ideation and 12.7% (95% CI: 11.1 to 14.5) presented suicidal planning in the last 12 months. Females had a higher prevalence of both ideation (27.5%, 95% CI: 24.9 to 30.4) and ideation plus suicidal planning (18.5%, 95% CI: 16.4 to 20.7). Multivariate analysis found that being female, having little parental support, having felt loneliness, having suffered from physical aggression, having been bullied, and alcohol consumption, were associated with ideation and ideation plus suicidal planning in adolescent students. Ideation and ideation plus suicidal planning is a problem in the Peruvian adolescent population and is associated with several factors. Strategies are needed to identify and register suicide in adolescents in Peru and to develop prevention programs.