Seasonal changes in visual field sensitivity and intraocular pressure in the ocular hypertension treatment study.
Longitudinal testing plays a key role in glaucoma management. Variability between visits hampers the ability to monitor progression. It has previously been shown that average intraocular pressure (IOP) exhibits seasonal fluctuations. This study examines whether visual field sensitivity also exhibits seasonal fluctuations and seeks to determine whether such fluctuations are correlated to seasonal IOP effects. Comparative case series. A total of 33 873 visits by 1636 participants enrolled in the Ocular Hypertension Treatment Study. Participants were split into 6 geographic zones according to the prevailing climate in their location. At each visit, standard automated perimetry was conducted on each eye, and IOP was measured. Mixed effects regression models were formed to look for sinusoidal periodic effects on the change in perimetric mean deviation since the last visit (ΔMD) and on IOP, both overall and within each zone. When all the data were included, a significant seasonal effect on ΔMD was found with magnitude 0.06 dB, peaking in February (P < 0.001). Five of the 6 geographic zones exhibited significant seasonal effects on ΔMD, peaking between January and April, with magnitudes ranging from 0.04 dB (P = 0.049) to 0.21 dB (P < 0.001). Zones with greater climactic variation showed larger seasonal effects on ΔMD. All 6 zones exhibited a seasonal effect on IOP, peaking in January or February, with magnitudes ranging from 0.14 to 0.39 mmHg (P ≤ 0.02 in all cases). However, there was no evidence of a significant association between the magnitudes or dates of peaks of the 2 seasonal effects. The mean deviation was significantly higher in winter than in summer. There is no evidence of an association with seasonal IOP fluctuations. The cause of the seasonal effect on visual field sensitivity is unknown. These findings may help shed light on the glaucomatous disease process and aid efforts to reduce test-retest variability.


Worksite fitness and exercise programs: a review of methodology and health impact.
To examine the methodology of worksite fitness and exercise programs and to assess their effect on health-related fitness, cardiac risk factors, life satisfaction and well-being, and illness and injury. The 52 studies reviewed cover English-language literature for the period from 1972 to 1994, as identified by a search of the Cumulative Index Medicus, Medline, the Canadian Sport Documentation Centre's "Sport Discus," computerized bibliography, and my own files. Reports were divided into five controlled experimental studies, 14 quasi-experimental studies with matched controls (one reported in abstract), and 33 other interventions of varied quality. Methodologic problems include difficulty in allowing for Hawthorne effects, substantial sample attrition, and poor definition of the intervention (exercise or broad-based health promotion). Findings are analyzed by specific fitness and health outcomes. Program participants show small but favorable changes in body mass, skinfolds, aerobic power, muscle strength and flexibility, overall risk-taking behavior, systemic blood pressure, serum cholesterol, and cigarette smoking. Claims of improved mood state are based heavily on uncontrolled studies. Quasi-experimental studies suggest reduced rates of illness and injury among participants, but seasonal and year-to-year differences in health weaken possible conclusions. Participation in worksite fitness programs can enhance health-related fitness and reduce risk-taking behavior, but population effect is limited by low participation rates.


Clinical Significance of Lateral Pedicle Screw Malposition in Lumbar Spine Fusion.
Retrospective cohort study. Our objective was to determine whether lateral pedicle screw breach affects fusion rates and patient-reported outcomes in lumbar fusion surgery. Although lateral pedicle screw malposition is considered relatively benign, few studies have focused specifically on clinical outcomes or fusion rates associated with lateral screw malposition. Twelve-month postoperative computed tomography scans were reviewed for lateral breach, severity of breach, and fusion status. Patients with lateral breach were compared with patients with no breach. Outcome measures included Numerical Pain Rating Scale for back and leg pain, Oswestry Disability Index, and SF-36 physical function (SF-36 PF). Multivariable linear and logistic regression and were adjusted for age, procedure, level, and/or baseline pain score. Forty-five patients (31%) demonstrated 1 or more lateral breaches as compared with 99 patients without breach. After adjusting for baseline scores and fusion level, patients with 2 or more screw breaches experienced SF-36 PF score improvements that were 3.43 points less ( P =0.016) than patients with no lateral breach. After adjusting for baseline Numerical Pain Rating Scale, there was also a significant decrease in the odds of achieving minimally clinical important difference in back pain relief in these patients. There was no observed effect of lateral breach on the odds of successful fusion. The current study did not observe an association between laterally malpositioned pedicle screws and nonunion. However, results are consistent with a negative effect on SF-36 PF scores and self-reported back pain at 12 months.


The pharmacoeconomics of routine postoperative troponin surveillance to prevent and treat myocardial infarction after non-cardiac surgery.
A postoperative troponin leak that was previously considered clinically insignificant has been independently associated with 30-day mortality in unselected surgical patients ≥45 years of age following non-cardiac surgery. To determine whether routine troponin surveillance following non-cardiac surgery and initiation of aspirin and statin therapy in troponin-positive patients is cost-effective. Pharmacoeconomic analysis to determine the cost-effectiveness of routine postoperative surveillance for patients aged ≥45 years undergoing non-cardiac surgery. We compared the total expected cost of hospital care of patients who received routine troponin surveillance and subsequent introduction of statin and aspirin therapy for 30 days in troponin-positive patients with the cost of hospital care of patients who did not receive troponin surveillance. We estimated a 25% relative risk reduction following statin and aspirin therapy for postoperative vascular mortality and non-fatal myocardial infarction. Routine troponin surveillance with initiation of aspirin and statin therapy was cost-effective, with an incremental cost of -R16,724 per event avoided. Routine postoperative troponin surveillance in non-cardiac surgical patients ≥45 years of age requiring a postoperative night in hospital is potentially cost-effective.


Women and Ischemic Heart Disease: Recognition, Diagnosis and Management.
Cardiovascular disease is one of the most frequent causes of death in both males and females throughout the world. However, women exhibit a greater symptom burden, more functional disability, and a higher prevalence of nonobstructive coronary artery disease (CAD) compared to men when evaluated for signs and symptoms of myocardial ischemia. This paradoxical sex difference appears to be linked to a sex-specific pathophysiology of myocardial ischemia including coronary microvascular dysfunction, a component of the 'Yentl Syndrome'. Accordingly, the term ischemic heart disease (IHD) is more appropriate for a discussion specific to women rather than CAD or coronary heart disease. Following the National Heart, Lung, and Blood Institute Heart Truth/American Heart Association, Women's Ischemia Syndrome Evaluation and guideline campaigns, the cardiovascular mortality in women has been decreased, although significant gender gaps in clinical outcomes still exist. Women less likely undergo testing, yet guidelines indicate that symptomatic women at intermediate to high IHD risk should have further test (e.g. exercise treadmill test or stress imaging) for myocardial ischemia and prognosis. Further, women have suboptimal use of evidence-based guideline therapies compared with men with and without obstructive CAD. Anti-anginal and anti-atherosclerotic strategies are effective for symptom and ischemia management in women with evidence of ischemia and nonobstructive CAD, although more female-specific study is needed. IHD guidelines are not "cardiac catheterization" based but related to evidence of "myocardial ischemia and angina". A simplified approach to IHD management with ABCs (aspirin, angiotensin-converting enzyme inhibitors/angiotensin-renin blockers, beta blockers, cholesterol management and statin) should be used and can help to increases adherence to guidelines.


A mechanistic study on the inhibition of α-chymotrypsin by a macrocyclic peptidomimetic aldehyde.
Here we describe an NMR and X-ray crystallography-based characterisation of the mechanism by which a new class of macrocyclic peptidomimetic aldehyde inhibits α-chymotrypsin. In particular, a (13)C-labelled analogue of the inhibitor was prepared and used in NMR experiments to confirm formation of a hemiacetal intermediate on binding with α-chymotrypsin. Analysis of an X-ray crystallographic structure in complex with α-chymotrypsin reveals that the backbone adopts a stable β-strand conformation as per its design. Binding is further stabilised by interaction with the oxyanion hole near the S1 subsite and multiple hydrogen bonds.


Impact of fluoride, milk and water rinsing on surface rehardening of acid softened enamel. An in situ study.
To evaluate the impact of fluoride, milk and water rinsing on surface rehardening of acid softened enamel in situ. Ten subjects performed six tests of4 hours each. In each test, three softened enamel samples were attached to intraoral appliances. For softening, samples were immersed extraorally in an acidic beverage for 120 seconds. Subsequently, specimens were worn intraorally for 5 minutes (Tests 1-3) or 30 minutes (Tests 4-6). Thereafter, the volunteers rinsed with a 250 ppm SnF2/Olaflur solution (Tests 1 and 4), milk (Tests 2 and 5) or non-carbonated mineral water (Tests 3 and 6) for 60 seconds. At each test, one sample was covered with tape during intraoral rinsing and thus, served as control. After rinsing, both test and the control samples were exposed to the oral cavity for up to 4 hours after demineralization. Surface microhardness (SMH) of the specimens was assessed at baseline, immediately after softening and 4 hours after softening. For each subject, the secretion rate of resting and stimulated saliva, buffering capacity and pH-value as well as calcium and phosphate concentration of saliva were measured. Statistical analysis was performed by ANCOVA followed by stratified analyses with Bonferroni correction. Baseline Knoop Hardness (mean +/- S.D.) amounted to 403.1 +/- 39.4. Immediately after softening, mean SMH was reduced to 214.4 +/- 24.1 KHN. Rinsing with 250 ppm fluoride, milk or water after 5 minutes or 30 minutes intraoral exposure of softened samples had a significant effect on rehardening. The increase of SMH (DeltaKHN) was highest after rinsing with fluoride (5 minutes: 95.0 +/- 18.3; 30 minutes: 94.2 +/- 24.3) followed by milk (5 minutes: 77.1 +/- 14.1; 30 minutes: 80.3 +/- 18.7) and water (5 minutes: 49.0 +/- 9.9; 30 minutes: 47.0 +/- 14.1), but did not achieve baseline values. It is concluded that a single rinse with a 250 ppm SnF2/Olaflur solution, milk or water increases rehardening of previously acid softened enamel.


Directed random walks on hierarchical trees with continuous branching: a renormalization group approach.
We investigate the directed random walk on hierarchic trees. Two cases are investigated: random variables on deterministic trees with a continuous branching, and random variables on the trees constructed through the random branching process. We derive renormalization group (partial differential) equations for the branching models with binomial, Poisson, and compound Poisson distributions of random variables on the links of a tree. These renormalization group equations are a new class of reaction-diffusion equations in one dimension.


Occult large epidural hemorrhage in a newborn infant after in-hospital fall.
Management of newborn infants fell in-hospital is especially challenging given the limited signs and symptoms of intracranial hemorrhage in this age group. We present a case of a four day old well appearing newborn infant found to have a severe epidural hemorrhage requiring emergent surgical drainage. Development of imaging protocols for newborn infants suffering in-hospital falls need to consider the potential consequences of missing actionable intracranial hemorrhage when relying on clinical observation as a management strategy.


Tn5-induced mutations affecting virulence factors of Bordetella pertussis.
Transposon Tn5 was used to isolate mutants of Bordetella pertussis. Strains with Tn5 insertions were screened for loss of virulence-associated factors, including filamentous hemagglutinin, hemolysin, and pertussis toxin. Several mutants deficient for hemolysin production were obtained. All produced dermonecrotic toxin, pertussis toxin, and filamentous hemagglutinin, but were found to vary with respect to adenylate cyclase production. One hemolysin mutant had no detectable adenylate cyclase activity; others had 0.6% or 16% wild-type activity, whereas a fourth seemed to be unaffected in terms of adenylate cyclase activity. Mutants deficient in the ability to hemagglutinate sheep erythrocytes were also isolated. These mutants either failed to synthesize or produced reduced amounts of three protein species of 200,000, 130,000, and 100,000 daltons, all of which reacted with antiserum to filamentous hemagglutinin. Pertussis toxin mutants were identified by screening culture supernatants for failure to induce a clustered growth pattern in Chinese hamster ovary cells, and identification was confirmed by the standard histamine-sensitizing assay in mice. These mutants will be useful to determine the relative contribution of each virulence factor to pathogenicity as well as to determine the identity of the antigens important in protective immunity.


Deficiency of the integrin beta 4 subunit in junctional epidermolysis bullosa with pyloric atresia: consequences for hemidesmosome formation and adhesion properties.
Junctional epidermolysis bullosa (JEB) comprises a group of inherited autosomal recessive blistering disorders characterized by dermo-epidermal separation through the lamina lucida of the basement membrane. We identified a patient with JEB associated with pyloric atresia (PA), in whom the integrin beta 4 subunit was completely absent. At the ultrastructural level, the hemidesmosomes were reduced in number, appeared rudimentary and lacked a subbasal dense plate and frequently an inner attachment plaque. However, keratin filaments were still anchored to the cytoplasmic plaque of the hemidesmosome. Immunofluorescence analysis showed that the beta 4 subunit was absent in the skin of the PA-JEB patient, whereas the alpha 6 subunit appeared to be normally distributed along the basement membrane zone, as were the other hemidesmosomal components BP230, BP180 and HD1. Furthermore, the alpha 3 and beta 1 subunits were not only detected at the lateral membranes of basal cells in PA-JEB skin, as in normal skin, but also along the basement membrane zone. The few hemidesmosome-like structures found in cultured keratinocytes from the PA-JEB patient contained the hemidesmosomal components BP230, BP180 and HD1, but not the integrin alpha 6 subunit. Like alpha 3, this subunit was colocalized with vinculin in focal contacts at the ends of actin stress fibers. Immunoprecipitation analysis revealed that alpha 6 was associated with beta 1 on PA-JEB keratinocytes, whereas normal human keratinocytes (NHKs) exclusively express alpha 6 beta 4 on their cell surface. The initial adhesion of PA-JEB and normal keratinocytes to laminin-1 and laminin-5, both ligands for alpha 6 beta 1 and alpha 6 beta 4, was similar. In migration assays, the PA-JEB keratinocytes were more motile on laminin-5 than normal keratinocytes. Our observations indicate that the integrin alpha 6 beta 4 plays a crucial role in the proper assembly of hemidesmosomes and in the stabilization of the dermal-epidermal junction. The fragility of the skin and the blistering in this patient appear to have been due to the deficiency of the integrin beta 4 subunit, which results in the formation of too few and structurally abnormal hemidesmosomes.


Assessment of root surfaces of apicected teeth: a scanning electron microscopy evaluation.
The aim of this study was to determine the apical surface characteristics and presence of dental cracks in single-rooted premolars, resected 3.0 mm from the root apex, using the Er: YAG laser, tungsten carbide bur, and diamond-coated tip, by scanning electron microscopy (SEM). Thirty single-rooted premolar teeth were collected. The instrumented and obturated teeth were divided into three groups according to the root resection method (2.94 μm, 100 mj, 20-Hz Er: YAG laser, plain tapered fissure tungsten carbide bur at a low speed of 40,000 rpm, or a diamond-coated SG6D tip coupled to the handpiece of a conventional ultrasound device). The specimens were prepared for SEM and analyzed by the Kruskal-Wallis and Mann-Whitney statistical tests. The SEM images showed that tungsten carbide burs produced significantly smoother resected root surfaces than the diamond-coated tip. There was no statistically significant difference between the Er: YAG and tungsten carbide bur groups. The analysis of scores obtained for the cut quality by the Kruskal-Wallis test revealed no significant differences among the groups. In our study, five teeth had no cracks after the apical resection. The mean number of cracks per tooth was 3.5 ± 1.780 (Er: YAG laser group), 2.5 ± 1.716 (tungsten carbide bur group), and 4.5 ± 2.593 (diamond-coated tip group). Under the tested conditions smoother surfaces were observed in the groups treated with the tungsten carbide bur and Er: YAG laser when compared with the diamond-coated tips.


Feeding behavior and trophic interaction of three shark species in the Galapagos Marine Reserve.
There is great concern about the future of sharks in Ecuador because of the lack of biological knowledge of most species that inhabit the region. This paper analyzes the feeding behavior of the pelagic thresher shark (Alopias pelagicus), the blue shark (Prionace glauca) and the silky shark (Carcharhinus falciformis) through the use of stable isotopes of carbon and nitrogen (δ13C and δ15N), with the aim of determining the degree of interaction between these species in the Galapagos Marine Reserve. No interspecific differences were found in use of oceanic vs. inshore feeding areas (δ13C: Kruskal-Wallis test, p = 0.09). The position in the hierarchy of the food web where A. pelagicus feeds differed from that of the other species (δ15N: Kruskal-Wallis test, p = 0.01). There were no significant differences in δ13C and δ15N values between males and females of the three species (Student's t-test, p > 0.05), which suggests that both sexes have a similar feeding behavior. A specialist strategy was observed in P. glauca (trophic niche breadth TNB = 0.69), while the other species were found to be generalist (A. pelagicus TNB = 1.50 and C. falciformis TNB = 1.09). The estimated trophic level (TL) varied between the three species. C. falciformis occupied the highest trophic level (TL = 4.4), making it a quaternary predator in the region. The results of this study coincide with the identified behavior in these predators in other areas of the tropical Pacific (Colombia and Mexico), and suggest a pelagic foraging strategy with differential consumption of prey between the three species. These ecological aspects can provide timely information when implementing in conservation measures for these shark species in the Tropical Pacific and Galapagos Marine Reserve.


Controlling Processing, Morphology, and Mechanical Performance in Blends of Polylactide and Thermotropic Polyesters.
Thermoplastic composites based on thermotropic liquid crystalline polymer (LCP) materials are interesting candidates for reinforced composite application due to their promising mechanical performance and potential for recyclability. In combination with a societal push toward the more sustainable use of materials, these properties warrant new interest in this class of composites. Though numerous studies have been performed in the past, a coherent set of design rules for LCP design for the generation of injection-molded reinforced thermoplastic composites is not yet available, likely due to the complex interplay between LCP and matrix components. In this study, we report on the processing of poly(l-lactide) with two different LCPs, at relatively low processing temperatures. The study focuses on critical parameters for the morphological development and mechanical performance of LCP-reinforced composites. The influence of blend composition and the processing conditions, on the mechanical response of the composites, is investigated using rheology, wide-angle X-ray diffraction, mechanical analysis, and microscopy techniques. The study conclusively demonstrates that both the matrix viscosity and viscosity ratio between the dispersed and matrix phase, determine the deformation and breakup of the dispersed LCP droplets during extrusion. In addition, the thermal dependence of the viscosity ratio appears to be a critical parameter for the composite performance after injection molding. For example, during injection molding, stretching and molecular orientation of the LCP phase into highly oriented fibrils are prevented when the viscosity ratio increases rapidly upon cooling. In contrast, melt drawing proves to be a more effective processing route as the extensional flow field stabilizes elongated droplets, independent of the viscosity ratio. Overall, these findings provide valuable insights in the morphological development of LCP-reinforced blends, highlighting the importance of the development of viscoelastic properties as a function of temperature, and provide guidelines for the design of new LCP polymers and their thermoplastic composites.


The cartilage matrisome in adolescent idiopathic scoliosis.
The human spinal column is a dynamic, segmented, bony, and cartilaginous structure that protects the neurologic system and simultaneously provides balance and flexibility. Children with developmental disorders that affect the patterning or shape of the spine can be at risk of neurologic and other physiologic dysfunctions. The most common developmental disorder of the spine is scoliosis, a lateral deformity in the shape of the spinal column. Scoliosis may be part of the clinical spectrum that is observed in many developmental disorders, but typically presents as an isolated symptom in otherwise healthy adolescent children. Adolescent idiopathic scoliosis (AIS) has defied understanding in part due to its genetic complexity. Breakthroughs have come from recent genome-wide association studies (GWAS) and next generation sequencing (NGS) of human AIS cohorts, as well as investigations of animal models. These studies have identified genetic associations with determinants of cartilage biogenesis and development of the intervertebral disc (IVD). Current evidence suggests that a fraction of AIS cases may arise from variation in factors involved in the structural integrity and homeostasis of the cartilaginous extracellular matrix (ECM). Here, we review the development of the spine and spinal cartilages, the composition of the cartilage ECM, the so-called "matrisome" and its functions, and the players involved in the genetic architecture of AIS. We also propose a molecular model by which the cartilage matrisome of the IVD contributes to AIS susceptibility.


Dietary restraint violations influence reward responses in nucleus accumbens and amygdala.
Numerous studies have demonstrated that consuming high-calorie food leads to subsequent overeating by chronic dieters. The present study investigates the neural correlates of such self-regulatory failures using fMRI. Chronic dieters (n = 50) and non-dieters (n = 50) consumed either a 15-oz glass of cold water or a 15-oz milkshake and were subsequently imaged while viewing pictures of animals, environmental scenes, people, and appetizing food items. Results revealed a functional dissociation in nucleus accumbens and amygdala activity that paralleled well-established behavioral patterns of eating observed in dieters and non-dieters. Whereas non-dieters showed the greatest nucleus accumbens activity in response to food items after water consumption, dieters showed the greatest activity after consuming the milkshake. Activity in the left amygdala demonstrated the reverse interaction. Considered together with previously reported behavioral findings, the present results offer a suggested neural substrate for diet failure.


Imaging appearance of dextranomer/hyaluronic acid copolymer implant injections for treatment of velopharyngeal insufficiency.
Dextranomer/hyaluronic acid copolymer implants are used in treating velopharyngeal insufficiency. These posterior nasopharyngeal implants can be mistaken for pathologic conditions such as retropharyngeal abscess on imaging. We studied the imaging appearance of dextranomer/hyaluronic acid copolymer implants in patients treated for velopharyngeal insufficiency. A consecutive series of patients with velopharyngeal insufficiency treated with dextranomer/hyaluronic acid copolymer were included in this study. Data on patient characteristics and volume of dextranomer/hyaluronic acid copolymer injected were obtained. Postoperative imaging characteristics on plain radiography, CT, and MR imaging were assessed. The imaging appearance of postoperative complications was determined. Sixteen patients were included in this study. Seven patients underwent postoperative plain radiographs, 5 patients underwent CT, and 9 patients underwent MR imaging. Plain radiographs demonstrated soft-tissue swelling in the retropharyngeal space, which resolved at 1 month. On CT, dextranomer/hyaluronic acid copolymer implants appeared as bilateral nasopharyngeal soft-tissue masses isoattenuated to hypoattenuated relative to muscle in 80% (4/5) of patients. On MR imaging, dextranomer/hyaluronic acid copolymer implants appeared as bilateral nasopharyngeal soft-tissue masses that were isointense to muscle on T1 (8/9, 88.9%) and hyperintense to muscle on T2 (8/9, 88.9%) and demonstrated no restricted diffusion (4/4, 100.0%) or peripheral enhancement (7/7, 100.0%). The normal postoperative findings of posterior nasopharyngeal dextranomer/hyaluronic acid copolymer injection on MR imaging is characterized by the presence of bilateral nasopharyngeal soft-tissue masses that are isointense to muscle on T1 and hyperintense on T2, with no restricted diffusion or peripheral enhancement. Velopharyngeal dextranomer/hyaluronic acid copolymer implants are iso- to hypoattenuated to muscle on CT and are not visible radiographically once associated implantation-related swelling has resolved.


AccR is a master regulator involved in carbon catabolite repression of the anaerobic catabolism of aromatic compounds in Azoarcus sp. CIB.
Here we characterized the first known transcriptional regulator that accounts for carbon catabolite repression (CCR) control of the anaerobic catabolism of aromatic compounds in bacteria. The AccR response regulator of Azoarcus sp. CIB controls succinate-responsive CCR of the central pathways for the anaerobic catabolism of aromatics by this strain. Phosphorylation of AccR to AccR-P triggers a monomer-to-dimer transition as well as the ability to bind to the target promoter and causes repression both in vivo and in vitro. Substitution of the Asp(60) phosphorylation target residue of the N-terminal receiver motif of AccR to a phosphomimic Glu residue generates a constitutively active derivative that behaves as a superrepressor of the target genes. AccR-P binds in vitro to a conserved inverted repeat (ATGCA-N6-TGCAT) present at two different locations within the PN promoter of the bzd genes for anaerobic benzoate degradation. Because the DNA binding-proficient C-terminal domain of AccR is monomeric, we propose an activation mechanism in which phosphorylation of Asp(60) of AccR alleviates interdomain repression mediated by the N-terminal domain. The presence of AccR-like proteins encoded in the genomes of other β-proteobacteria of the Azoarcus/Thauera group further suggests that AccR constitutes a master regulator that controls anaerobic CCR in these bacteria.


Health hazards of methylammonium lead iodide based perovskites: cytotoxicity studies.
New technologies launch novel materials; besides their performances in products, their health hazards must be tested. This applies to the lead halide perovskite CH3NH3PbI3 as well, which offers fulgurate applications in photovoltaic devices. We report the effects of CH3NH3PbI3 photovoltaic perovskites in human lung adenocarcinoma epithelial cells (A549), human dopaminergic neuroblastoma cells (SH-SY5Y) and murine primary hippocampal neurons by using multiple assays and electron microscopy studies. In cell culture media the major part of the dissolved CH3NH3PbI3 has a strong cell-type dependent effect. Hippocampal primary neurons and neuroblastoma cells suffer a massive apoptotic cell death, whereas exposure to lung epithelial cells dramatically alters the kinetics of proliferation, metabolic activity and cellular morphology without inducing noticeable cell death. Our findings underscore the critical importance of conducting further studies to investigate the effect of short and long-term exposure to CH3NH3PbI3 on health and environment.


Test-Retest Reliability of Kinematic Assessments for Upper Limb Robotic Rehabilitation.
Robot-measured kinematic variables are increasingly used in neurorehabilitation to characterize motor recovery following stroke. However, few studies have evaluated the reliability of these kinematic variables. This study aimed at evaluating the test-retest reliability of typically-used robot-measured kinematic variables in healthy subjects (HS) and patients with stroke (SP). Sixty-one participants (40 HS, 21 SP) carried out a planar robot-pointing task on two consecutive days. Nine robot-measured kinematic variables were computed: movement time (T), mean velocity (mV), maximal velocity (MV), smoothness error (SE), number of velocity peaks (nP), mean arrest period ratio (MAPR), normalized path length (NPL), root mean square error (RMS) from a straight line and the orthogonal projection of the last point of movement (LP). Intraclass Correlation Coefficients (ICC), percentage of the Standard Error of Measurement (SEM measured as a percentage of the mean value of the variable (%SEM)) and percentage of the Minimum Detectable Difference (MDD measured as a percentage of the mean value of the variable (%MDD)) were used to analyze the test-retest reliability of the kinematic variables. ICC scores for all kinematic variables were above 0.75 in both groups. %SEM values were below 10% except for MAPR (13.4%) in HS and nP, MAPR and RMS in SP (13.0%, 11.7% and 15.2% respectively). %MDD values were higher for RMS in SP (42.1%) and MAPR in HS (37.1%) and lower for LP (1.6% in HS and 8.1% in SP). The nine robot-measured kinematic variables all demonstrated good reliability, with high ICC values (>0.75) and an acceptable level of measurement error (%SEM< 16%). However, 3/9 robot-measured kinematic variables, did not appear to be sufficiently sensitive to change (%MDD>30%) to be considered useful in patients with stroke.


Glucose metabolism determines resistance of cancer cells to bioenergetic crisis after cytochrome-c release.
Many anticancer drugs activate caspases via the mitochondrial apoptosis pathway. Activation of this pathway triggers a concomitant bioenergetic crisis caused by the release of cytochrome-c (cyt-c). Cancer cells are able to evade these processes by altering metabolic and caspase activation pathways. In this study, we provide the first integrated system study of mitochondrial bioenergetics and apoptosis signalling and examine the role of mitochondrial cyt-c release in these events. In accordance with single-cell experiments, our model showed that loss of cyt-c decreased mitochondrial respiration by 95% and depolarised mitochondrial membrane potential ΔΨ(m) from -142 to -88 mV, with active caspase-3 potentiating this decrease. ATP synthase was reversed under such conditions, consuming ATP and stabilising ΔΨ(m). However, the direction and level of ATP synthase activity showed significant heterogeneity in individual cancer cells, which the model explained by variations in (i) accessible cyt-c after release and (ii) the cell's glycolytic capacity. Our results provide a quantitative and mechanistic explanation for the protective role of enhanced glucose utilisation for cancer cells to avert the otherwise lethal bioenergetic crisis associated with apoptosis initiation.


Impairment of Social Function in Young Females With Recent-Onset Anorexia Nervosa and Recovered Individuals.
A subgroup of individuals with anorexia nervosa (AN) displays social difficulties; however, it is not clear if individuals with comorbid autism spectrum disorders account for these difficulties. We compared social function using the Autism Diagnostic Observation Schedule in 43 young females with first-episode AN who did not have comorbid autism spectrum disorder, 28 individuals recovered from adolescent-onset AN, and 41 healthy comparison individuals (age range 14-22 years). We measured adaptive behavior with the Vineland-II parent questionnaire, and aspects of social cognition with psychological tests, such as the Reading-the-Mind-in-the-Eyes test, Profile of Nonverbal Sensitivity short version, The Awareness of Social Inference Test, Animated Triangles, and the CANTAB Affective Go/No-go task. Participants with first-episode AN and those recovered from AN displayed difficulties in social function, which were not associated with body mass index or other state factors of the disorder in those with first-episode AN. Mood problems and anxiety were not associated with these difficulties. Parents rated participants with first-episode AN lower than recovered and control participants on the Socialization Domain of Vineland-II. Finally, only participants recovered from AN demonstrated deficits in specific domains of social cognition: perceiving nonverbal bodily gesture and vocal prosody. Young females with first-episode AN and those recovered from AN displayed impairments in social function, which may represent more stable traits of the disorder. Only participants recovered from AN demonstrated deficits in social cognition.


The effects of estrogen deficiency and bisphosphonate treatment on tissue mineralisation and stiffness in an ovine model of osteoporosis.
While much research has been dedicated to understanding osteoporosis, the nature of mineral distribution and the mechanical property variation in diseased bone is poorly understood. The current study aimed to determine the effect of estrogen deficiency and bisphosphonate therapy on bone tissue properties using an ovine model of osteoporosis. Skeletally mature animals (4+ years) were divided into an ovariectomy group (ovx, n=20) and a non treatment control group (control, n=20). A zoledronic acid treated group was also included in which animals were estrogen deficient for 20 months prior to receiving treatment (Zol, n=4). Half of the control and ovx groups were euthanized 12 or 31 months post-operatively and all Zol animals were euthanised at 31 months. Individual trabeculae were removed from the proximal femur and were analysed at specific locations across the width of the trabeculae. The mineral content was measured using quantitative backscatter electron imaging and the modulus was measured using nanoindentation. The spatial distribution of tissue modulus and mineral content in bone from ovariectomised animals was similar to control. However, ovariectomy significantly reduced the overall mineral content and tissue modulus relative to the control group after 12 months. Interestingly, significant differences were not maintained 31 months post-OVX. Treatment with zoledronic acid increased the mineral content and tissue modulus relative to both the ovariectomised and control groups. Zoledronic acid was also found to alter the mineral and modulus gradients normally associated with healthy bone tissue. The current study provides evidence that both estrogen deficiency and zoledronic acid therapy significantly alter mineral content and the mechanical properties of trabecular tissue.


Rationale for the Combination of Dendritic Cell-Based Vaccination Approaches With Chemotherapy Agents.
Owing to their central role in the initiation and regulation of antitumor immunity, dendritic cells (DCs) have been widely tested for use in cancer immunotherapy. Despite several encouraging clinical applications, existing DC-based immunotherapy efforts have yielded inconsistent results. Recent work has identified strategies that may allow for more potent DC-based vaccines, such as the combination with antitumor agents that have the potential to synergistically enhance DC functions. Selected cytotoxic agents may stimulate DCs either by directly promoting their maturation or through the induction of immunogenic tumor cell death. Moreover, they may support DC-induced adaptive immune responses by disrupting tumor-induced immunosuppressive mechanisms via selective depletion or inhibition of regulatory subsets, such as myeloid-derived suppressor cells and/or regulatory T cells (Tregs). Here, we summarize our current knowledge on the capacity of anticancer chemotherapeutics to modulate DC phenotype and functions and the results of ongoing clinical trials evaluating the use of DC-based immunotherapy in combination with chemotherapy in cancer patients.


Empowering village doctors and enhancing rural healthcare using cloud computing in a rural area of mainland China.
China's healthcare system often struggles to meet the needs of its 900 million people living in rural areas due to major challenges in preventive medicine and management of chronic diseases. Here we address some of these challenges by equipping village doctors (ViDs) with Health Information Technology and developing an electronic health record (EHR) system which collects individual patient information electronically to aid with implementation of chronic disease management programs. An EHR system based on a cloud-computing architecture was developed and deployed in Xilingol county of Inner Mongolia using various computing resources (hardware and software) to deliver services over the health network using Internet when available. The system supports the work at all levels of the healthcare system, including the work of ViDs in rural areas. An analysis done on 291,087 EHRs created from November 2008 to June 2011 evaluated the impact the EHR system has on preventive medicine and chronic disease management programs in rural China. From 2008 to 2011 health records were created for 291,087 (26.25%) from 1,108,951 total Xilingol residents with 10,240 cases of hypertension and 1152 cases of diabetes diagnosed and registered. Furthermore, 2945 hypertensive and 305 diabetic patients enrolled in follow-up. Implementing the EHR system revealed a high rate of cholecystectomies leading to investigations and findings of drinking water contaminated with metals. Measures were taken to inform the population and clean drinking water was supplied. The cloud-based EHR approach improved the care provision for ViDs in rural China and increased the efficiency of the healthcare system to monitor the health status of the population and to manage preventive care efforts. It also helped discover contaminated water in one of the project areas revealing further benefits if the system is expanded and improved.


The effects of exposure to scenarios about dementia on stigma and attitudes toward dementia care in a Chinese community.
This study investigated whether brief exposure to information has any effect on stigmatizing attitudes towards older people with dementia, and how people responded to this medical diagnosis. 494 adults were randomly assigned to three groups differentiated by experimental conditions. Group A (control) responded to questions on stigma directly. Group B (symptom) read two vignettes that described the symptoms of two fictitious individuals with dementia, before answering questions on stigma. Group C (label) read the same vignettes which ended with a statement that the person was recently diagnosed with dementia by a physician. Data were analyzed with ANOVA, together with other pre-existing between-subjects factors. Brief exposure to information about dementia led to a statistically significant reduction in stigma (Groups B, C < A), regardless of whether the diagnostic label of "dementia" was included or not. Moreover, lower stigma was reported by persons who knew a relative or friend with dementia, who were younger and more educated, and who thought dementia was treatable. As stigmatizing attitudes toward dementia are still a hindrance to early help-seeking in Asian communities, the findings suggest that community education may play a useful role in alleviating this barrier to early detection and intervention.


Stage transition and laryngeal closure in poststroke patients with dysphagia.
Timely hyolaryngeal excursion and laryngeal closure are essential for safe transfer of the bolus during the pharyngeal swallow. The temporal measures stage transition duration (STD) and laryngeal closure duration (LCD) represent these physiological events. The purpose of this investigation was to determine whether small changes in bolus consistency and volume affect these temporal measures in poststroke patients who aspirate, poststroke patients who do not aspirate, and nonneurologically impaired control subjects. STD and LCD were obtained by frame-by-frame analysis of the videofluoroscopic examinations of 5 and 10 ml thin and nectar thick liquids. Using a three-way analysis of variance, STD was significantly different between the control group and the two poststroke groups; however there was no difference between the two stroke groups. There was no difference among the three groups on LCD. Bolus consistency and bolus volume had no effect. Clinical implications of these findings are discussed.


Autoregulation of root nodule formation: signals of both symbiotic partners studied in a split-root system of Vicia sativa subsp. nigra.
Inhibition of root nodule formation on leguminous plants by already induced or existing root nodules is called autoregulation of root nodule formation (AUT). Optimal conditions for AUT were determined using a split-root technique newly developed for Vicia sativa subsp. nigra. Infection of a root A with nodulating Rhizobium leguminosarum bv. viciae bacteria systemically inhibited nodulation of a spatially separated root B inoculated 2 days later with the same bacteria. This treatment gives complete AUT (total absence of nodules on root B). Only partial AUT of root B was obtained by incubation of root A with mitogenic nodulation (Nod) factors or with a noninfective strain producing normal mitogenic Nod factors. Nonmitogenic Nod factors did not evoke AUT. We identified two systemic plant signals induced by Rhizobium bacteria. Signal 1 (at weak buffering) was correlated with sink formation in root A and induced acidification of B-root medium. This signal is induced by treatment of root A with (i) nodulating rhizobia, (ii) mitogenic Nod factors, (iii) nonmitogenic Nod factors, or (iv) the cytokinin zeatin. Signal 2 (at strong buffering) could only be evoked by treatment with nodulating rhizobia or with mitogenic Nod factors. Most probably, this signal represents the specific AUT signal. Induction of complete AUT appears to require actively dividing nodule cells in nodule primordia, nodule meristems, or both of root A.


Cognitive-behaviour therapy and schizophrenia.
People who experience debilitating psychotic symptoms that affect their everyday life are often, but not always, given a diagnosis of schizophrenia. Although the first line of treatment is medication, many people experience a suboptimal response and after the acute symptoms resolve they can continue to experience both hallucinations and delusions. These are generally termed residual symptoms and are the phenomena that cognitive-behavioural therapy for psychosis (CBTp) was originally devised to target. The success of CBTp in randomised controlled trials from the early 90s and evidence of cost-effectiveness has meant that many healthcare services across the world include CBTp in their treatment armamentaria. For instance, in the UK the National Institute for Health and Care Excellence guidance says that all individuals who have a diagnosis of schizophrenia should be given the option of a course of CBTp. Recently, however, the treatment effects have been re-examined, the targets widened and the premise that CBTp should be solely an adjunct to medication has been questioned. This article will describe and probe some of these changes and reflect on the development of psychological treatments for psychosis.


Activation function-1 domain of androgen receptor contributes to the interaction between subnuclear splicing factor compartment and nuclear receptor compartment. Identification of the p102 U5 small nuclear ribonucleoprotein particle-binding protein as a coactivator for the receptor.
In the androgen receptor (AR), most of its transactivation activity is mediated via the activation function-1 (AF-1). By employing yeast two-hybrid assay, we isolated a cDNA sequence encoding a protein binding to AR-AF-1. This protein, named ANT-1 (AR N-terminal domain transactivating protein-1), enhanced the ligand-independent autonomous AF-1 transactivation function of AR or glucocorticoid receptor but did not enhance that of estrogen receptor alpha. In contrast, the ANT-1 did not enhance any ligand-dependent AF-2 activities. Furthermore, the ligand-independent interaction between AR-AF-1 and ANT-1 was confirmed in vivo and in vitro. The ANT-1 sequence was identical to that of a protein that binds to U5 small nuclear ribonucleoprotein particle, a human homologue of yeast splicing factor Prp6p, involved in spliceosome. ANT-1 was compartmentalized into 20-40 coarse splicing factor compartment speckles against the background of the diffuse reticular distribution. AR colocalized with ANT-1 only in the diffusely distributed area, whereas the ANT-1 speckles were spatially distinct from but surrounded by the AR compartments. The active gene transcription has been shown to couple simultaneously with pre-mRNA processing at the periphery of the splicing factor compartment. The molecular interaction between two spatially distinct subnuclear compartments mediated by ANT-1 may therefore recruit AR into the transcription-splicing-coupling machinery.


Family Perceptions of End-of-Life Care in long-term care facilities.
The study examined the utility of the Family Perception of Care Scale (FPCS), which consists of four subscales: resident care, family support, communication, and rooming. This instrument was developed for the purposes of this study. Overall, family members were satisfied with end-of-life care. Satisfaction did not have a statistically significant relationship to family and resident characteristics. Survey questions with the highest number of low satisfaction ratings included staffing levels, updating families and involving them in care planning, and decision making. Family members considered pain control an important priority, followed by comfort care that included caring for a family member with dignity and sensitivity. Family members also valued it when staff were able to inform them that the death of their family member was near. Place of death was significantly associated with satisfaction, family members being more satisfied with end-of-life care when their family member died in the LTC facility as opposed to in hospital.


Hypersensitivity Pneumonitis A Perspective From Members of the Pulmonary Pathology Society.
- Hypersensitivity pneumonitis (HP) is a lung disease that develops in susceptible individuals after inhalational exposure to an organic antigen or chemical compound. Pathogenesis is attributed to a combination of type III (immune complex-mediated) and type IV (delayed) hypersensitivity reactions to the inciting agent. - To provide an overview of the current status of the medical literature regarding hypersensitivity pneumonitis. - A literature search was performed using PubMed and Google search engines. The terms "hypersensitivity pneumonitis" and "extrinsic allergic alveolitis" were used, with the search starting on January 9, 2017, and concluding March 8, 2017. - As a pathologist, it is important to consider hypersensitivity pneumonitis when examining lung specimens because it is often clinically and pathologically overlooked. Recognizing the often subtle findings and correlating them with the patient's history or suggesting a thorough clinical investigation of potential exposures can be of help in identifying the underlying condition so that the patient can be appropriately managed.


Peyronie's disease intervention trials: methodological challenges and issues.
Peyronie's Disease (PD) has been studied for more than 260 years since Francois de la Peyronie's description in 1743. Based on the current literature, the prevalence of PD seems 3-9% with an average age of onset in the fifth life decade. Much effort has been spent on developing nonsurgical treatment options to cure or at least prevent disease progression. The recent examination of drug trials for erectile dysfunction has led us to assess PD trial methodology more closely. An Iinternet search on PubMed was performed using MeSH words PD, clinical trials, oral, transdermal, intralesional and shock wave therapy focusing on 26 representing studies published over the last 15 years. Mean Outcome Measures. A comprehensive review of the current literature on nonsurgical treatment options for PD was conducted to address methodological issues and challenges in PD trials highlighting trial design, patient population, and symptom and sign assessment. The majority of the reviewed studies are underpowered and the heterogeneity in the methodological approach and patient assessment between the studies is one of the remarkable findings from our review. Studies should use a uniform means of defining the degree and type of penile deformity and a large enough cohort of patients should be studied for adequate study power. An ideally designed PD intervention trial should comprise: (i) a randomized, placebo-controlled design; (ii) with a PD patient set representative of the general PD population; and (iii) a comprehensive symptom and sign assessment before and at the end of treatment which includes an assessment of at least deformity, pain, and sexual function. A number of challenges exist for the design of PD intervention trials and deciphering the data generated from them. The field would benefit greatly from a consensus statement or guidelines development on the design and conduct of such trials.


Bile acid metabolites in serum: intraindividual variation and associations with coronary heart disease, metabolic syndrome and diabetes mellitus.
Bile acids (BAs) regulate glucose and lipid metabolism. In longitudinal and case-control-studies, we investigated the diurnal variation of serum concentrations of the 15 major BAs as well as the biosynthetic precursor 7α-hydroxy-4-cholesten-3-one (C4) and their associations, respectively, with coronary artery disease (CAD), diabetes mellitus type 2 (T2DM), and non-diabetic metabolic syndrome (MetS). In hourly taken blood samples of four healthy probands, the intraindividual 24 h variation of C4, conjugated and unconjugated BAs ranged from 42% to 72%, from 23% to 91%, and from 49% to 90%, respectively. Conjugated BA concentrations mainly increased following food intake. Serum levels of C4 and unconjugated BAs changed with daytime with maxima varying interindividually between 20h00 and 1h00 and between 3h00 and 8h00, respectively. Comparisons of data from 75 CAD patients with 75 CAD-free controls revealed no statistically significant association of CAD with BAs or C4. Comparisons of data from 50 controls free of T2DM or MetS, 50 MetS patients, and 50 T2DM patients revealed significantly increased fasting serum levels of C4 in patients with MetS and T2DM. Multiple regression analysis revealed body mass index (BMI) and plasma levels of triglycerides (TG) as independent determinants of C4 levels. Upon multivariate and principle component analyses the association of C4 with T2DM and/or MetS was not independent of or superior to the canonical MetS components. In conclusion, despite large intra- and interindividual variation, serum levels of C4 are significantly increased in patients with MetS and T2DM but confounded with BMI and TG.


Developmental plasticity of spatial hearing following asymmetric hearing loss: context-dependent cue integration and its clinical implications.
Under normal hearing conditions, comparisons of the sounds reaching each ear are critical for accurate sound localization. Asymmetric hearing loss should therefore degrade spatial hearing and has become an important experimental tool for probing the plasticity of the auditory system, both during development and adulthood. In clinical populations, hearing loss affecting one ear more than the other is commonly associated with otitis media with effusion, a disorder experienced by approximately 80% of children before the age of two. Asymmetric hearing may also arise in other clinical situations, such as after unilateral cochlear implantation. Here, we consider the role played by spatial cue integration in sound localization under normal acoustical conditions. We then review evidence for adaptive changes in spatial hearing following a developmental hearing loss in one ear, and show that adaptation may be achieved either by learning a new relationship between the altered cues and directions in space or by changing the way different cues are integrated in the brain. We next consider developmental plasticity as a source of vulnerability, describing maladaptive effects of asymmetric hearing loss that persist even when normal hearing is provided. We also examine the extent to which the consequences of asymmetric hearing loss depend upon its timing and duration. Although much of the experimental literature has focused on the effects of a stable unilateral hearing loss, some of the most common hearing impairments experienced by children tend to fluctuate over time. We therefore propose that there is a need to bridge this gap by investigating the effects of recurring hearing loss during development, and outline recent steps in this direction. We conclude by arguing that this work points toward a more nuanced view of developmental plasticity, in which plasticity may be selectively expressed in response to specific sensory contexts, and consider the clinical implications of this.


Diffractive and geometric optical systems characterization with the Fresnel Gaussian shape invariant.
Full characterization of optical systems, diffractive and geometric, is possible by using the Fresnel Gaussian Shape Invariant (FGSI) previously reported in the literature. The complex amplitude distribution in the object plane is represented by a linear superposition of complex Gaussians wavelets and then propagated through the optical system by means of the referred Gaussian invariant. This allows ray tracing through the optical system and at the same time allows calculating with high precision the complex wave-amplitude distribution at any plane of observation. This method is similar to conventional ray tracing additionally preserving the undulatory behavior of the field distribution. That is, we are propagating a linear combination of Gaussian shaped wavelets; keeping always track of both, the ray trajectory, and the wave phase of the whole complex optical field. This technique can be applied in a wide spectral range where the Fresnel diffraction integral applies including visible, X-rays, acoustic waves, etc. We describe the technique and we include one-dimensional illustrative examples.


AtCCX3 is an Arabidopsis endomembrane H+ -dependent K+ transporter.
The Arabidopsis (Arabidopsis thaliana) cation calcium exchangers (CCXs) were recently identified as a subfamily of cation transporters; however, no plant CCXs have been functionally characterized. Here, we show that Arabidopsis AtCCX3 (At3g14070) and AtCCX4 (At1g54115) can suppress yeast mutants defective in Na(+), K(+), and Mn(2+) transport. We also report high-capacity uptake of (86)Rb(+) in tonoplast-enriched vesicles from yeast expressing AtCCX3. Cation competition studies showed inhibition of (86)Rb(+) uptake in AtCCX3 cells by excess Na(+), K(+), and Mn(2+). Functional epitope-tagged AtCCX3 fusion proteins were localized to endomembranes in plants and yeast. In Arabidopsis, AtCCX3 is primarily expressed in flowers, while AtCCX4 is expressed throughout the plant. Quantitative polymerase chain reaction showed that expression of AtCCX3 increased in plants treated with NaCl, KCl, and MnCl(2). Insertional mutant lines of AtCCX3 and AtCCX4 displayed no apparent growth defects; however, overexpression of AtCCX3 caused increased Na(+) accumulation and increased (86)Rb(+) transport. Uptake of (86)Rb(+) increased in tonoplast-enriched membranes isolated from Arabidopsis lines expressing CCX3 driven by the cauliflower mosaic virus 35S promoter. Overexpression of AtCCX3 in tobacco (Nicotiana tabacum) produced lesions in the leaves, stunted growth, and resulted in the accumulation of higher levels of numerous cations. In summary, these findings suggest that AtCCX3 is an endomembrane-localized H(+)-dependent K(+) transporter with apparent Na(+) and Mn(2+) transport properties distinct from those of previously characterized plant transporters.


The Association of Brain MRI Characteristics and Postoperative Delirium in Cardiac Surgery Patients.
Delirium is common after cardiac surgery and is associated with adverse consequences, including cognitive decline. Identification of vulnerable older adults might allow for early implementation of delirium-prevention strategies. Brain MRI findings provide insight into structural brain changes that may identify vulnerable patients. The purpose of this study was to examine the association between brain MRI characteristics potentially associated with delirium vulnerability and the development of postoperative delirium in a nested cohort of patients undergoing cardiac surgery. We identified 79 cardiac surgery patients who had brain MRI imaging after cardiac surgery, as part of an ongoing randomized trial evaluating the efficacy of blood pressure management based on cerebral autoregulation monitoring versus standard management for improving neurological outcomes. Cerebral lateral ventricular size, cortical sulcal width, and white matter hyperintensities (WMH) on brain MRI scans were graded on a validated 0 to 9 scale, and categorized into tertiles. New ischemic lesions were characterized as present or absent. Delirium was assessed using a validated chart-review. Neuropsychological testing performed before surgery was used to establish preoperative cognitive baseline. Multivariable logistic regression was used to assess the independent association between MRI characteristics and postoperative delirium. The average age of patients was 70.1 ± 7.8 years old, and 72% were male. Twenty-eight of 79 (35.4%) patients developed postoperative delirium. Patients with delirium had higher unadjusted ventricular size (median 4 vs. 3, P = 0.003), and there was a trend towards higher sulcal sizes and WMH grades. Increasing tertiles of ventricular size (Odds Ratio [OR] 3.59; 95% Confidence Interval [CI] 1.59-8.12; P = 0.002) and sulcal size (OR 2.15; 95%CI 1.13-4.12; P = 0.02) were associated with postoperative delirium, with a trend for tertiles of WMH grade (OR 1.91; 95%CI 0.99-3.68; P = 0.05). In multivariable models adjusted for logistic EuroSCORE, baseline cognitive status, bypass time, and any postoperative complication, each tertile of ventricular size was associated with increased odds of postoperative delirium (OR 3.23 per tertile increase in ventricular size; 95%CI 1.21-8.60; P = 0.02). There were no differences in odds of delirium by tertiles of sulcal grade, tertiles of white matter grade, or presence of new ischemic lesions, in adjusted models. Increased brain ventricular size was independently associated with delirium after cardiac surgery. These results suggest that cerebral atrophy may contribute to increased vulnerability for postoperative delirium. Baseline brain MRIs may be useful in identifying cardiac surgery patients at high risk for postoperative delirium, who might benefit from targeted perioperative approaches to prevent delirium. ClinicalTrials.gov identifier: NCT00981474.


Pilot RCT of a social media parenting intervention for postpartum mothers with depression symptoms.
Objective: This pilot study describes the adaptation of a parenting group intervention for social media, and examines the feasibility, acceptability and initial outcomes of the adapted intervention for mothers with postpartum depression symptoms. Background: Postpartum depression can negatively affect parenting and the parent-infant relationship. Mothers with postpartum depression symptoms experience barriers to access in-person parenting interventions. Methods: A small, randomised controlled trial was conducted with an adapted parenting intervention delivered via social media (Facebook) or in-person for mothers who screened positive for depression in paediatric clinics. Parenting sense of competence, depression symptoms and intervention attendance and satisfaction were assessed. Twenty-four mothers (mean age 26 years; predominantly African American with limited economic resources) participated in the study. Results: Linear regressions showed that the social media group had significantly improved parenting competence and decreased depression severity when compared to the in-person group. Attendance in the social media group was high (83%), but extremely poor in the in-person group (3%). The mothers rated the intervention positively and the majority of the mothers participated by posting comments on the group page on social media. Conclusion: The findings suggest the feasibility and benefit of delivering a parenting intervention through social media for postpartum mothers with high levels of depression symptoms.


Should paroxysmal atrial fibrillation be treated during cardiac surgery?
Randomized controlled trials of permanent atrial fibrillation ablation surgery have shown improved outcomes compared with control patients undergoing concomitant cardiac surgery. Little has been reported regarding patients with paroxysmal atrial fibrillation. We hypothesized that treating paroxysmal atrial fibrillation during cardiac surgery would not adversely affect the perioperative risk and would improve the midterm outcomes. From April 2004 to June 30 2012, 4947 patients (excluding those with transcatheter aortic valve implants, left ventricular assist devices, trauma, transplantation, and isolated atrial fibrillation surgery) underwent cardiac surgery, and 1150 (23%) had preoperative atrial fibrillation. Of these, 552 (48%) had paroxysmal atrial fibrillation. Three groups were compared using propensity score matching: treated (n = 423, 77%), untreated (n = 129, 23%), and no atrial fibrillation (n = 3797). The treated patients had 30-day mortality similar to that of the untreated patients and those without atrial fibrillation. They had fewer perioperative complications (26% vs 46%, P = .001), greater freedom from atrial fibrillation at the last follow-up visit (81% vs 60%, P = .007), and lower mortality (hazard ratio 0.47, P = .007) compared with the untreated patients. Compared with those without atrial fibrillation, the treated patients had fewer perioperative complications (25% vs 48%, P < .001), lower freedom from atrial fibrillation at the last follow-up visit (84% vs 93%, P = .001), and similar mortality. Concomitant surgical ablation of paroxysmal atrial fibrillation was not associated with increased perioperative risk. The treated patients had greater late freedom from atrial fibrillation and midterm survival compared with the untreated patients, and similar midterm survival compared with the patients without atrial fibrillation. These results suggest that paroxysmal atrial fibrillation warrants treatment consideration in select patients undergoing cardiac surgery.


Xylooligosaccharide increases bifidobacteria but not lactobacilli in human gut microbiota.
This study was conducted to determine the tolerance and effects of the prebiotic xylooligosaccharide (XOS) on the composition of human colonic microbiota, pH and short chain fatty acids (SCFA) in order to determine whether significant changes in the microbiota would be achievable without side effects. Healthy adult subjects (n = 32) were recruited in a double-blind, randomized, placebo-controlled study. Subjects received 1.4 g XOS, 2.8 g XOS or placebo in daily doses. The study consisted of a 2 week run-in, an 8 week intervention, and a 2 week washout phase. Stool samples were collected at baseline, after 4 and 8 weeks of intervention and 2 weeks after cessation of intervention. Samples were subjected to culture, pyrosequencing of community DNA, pH and SCFA analyses. Tolerance was evaluated by daily symptom charts. XOS was tolerated without significant gastrointestinal side effects. Bifidobacterium counts increased in both XOS groups compared to the placebo subjects, the 2.8 g per day group showed significantly greater increases than the 1.4 g per day group. Total anaerobic counts and Bacteroides fragilis group counts were significantly higher in the 2.8 g per day XOS group. There were no significant differences in the counts of Lactobacillus, Enterobacteriaceae and Clostridium between the three groups. XOS intervention had no significant effect on stool pH, SCFA or lactic acid. Pyrosequencing showed no notable shifts in bacterial diversity. XOS supplementation may be beneficial to gastrointestinal microbiota and 2.8 g per day may be more effective than 1.4 g per day. The low dose required and lack of gastrointestinal side effects makes the use of XOS as a food supplement feasible.


Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
This article discusses the management of venous thromboembolism (VTE) and thrombophilia, as well as the use of antithrombotic agents, during pregnancy and is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that benefits do, or do not, outweigh risks, burden, and costs. Grade 2 recommendations are weaker and imply that the magnitude of the benefits and risks, burden, and costs are less certain. Support for recommendations may come from high-quality, moderate-quality or low-quality studies; labeled, respectively, A, B, and C. Among the key recommendations in this chapter are the following: for pregnant women, in general, we recommend that vitamin K antagonists should be substituted with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) [Grade 1A], except perhaps in women with mechanical heart valves. For pregnant patients, we suggest LMWH over UFH for the prevention and treatment of VTE (Grade 2C). For pregnant women with acute VTE, we recommend that subcutaneous LMWH or UFH should be continued throughout pregnancy (Grade 1B) and suggest that anticoagulants should be continued for at least 6 weeks postpartum (for a total minimum duration of therapy of 6 months) [Grade 2C]. For pregnant patients with a single prior episode of VTE associated with a transient risk factor that is no longer present and no thrombophilia, we recommend clinical surveillance antepartum and anticoagulant prophylaxis postpartum (Grade 1C). For other pregnant women with a history of a single prior episode of VTE who are not receiving long-term anticoagulant therapy, we recommend one of the following, rather than routine care or full-dose anticoagulation: antepartum prophylactic LMWH/UFH or intermediate-dose LMWH/UFH or clinical surveillance throughout pregnancy plus postpartum anticoagulants (Grade 1C). For such patients with a higher risk thrombophilia, in addition to postpartum prophylaxis, we suggest antepartum prophylactic or intermediate-dose LMWH or prophylactic or intermediate-dose UFH, rather than clinical surveillance (Grade 2C). We suggest that pregnant women with multiple episodes of VTE who are not receiving long-term anticoagulants receive antepartum prophylactic, intermediate-dose, or adjusted-dose LMWH or intermediate or adjusted-dose UFH, followed by postpartum anticoagulants (Grade 2C). For those pregnant women with prior VTE who are receiving long-term anticoagulants, we recommend LMWH or UFH throughout pregnancy (either adjusted-dose LMWH or UFH, 75% of adjusted-dose LMWH, or intermediate-dose LMWH) followed by resumption of long-term anticoagulants postpartum (Grade 1C). We suggest both antepartum and postpartum prophylaxis for pregnant women with no prior history of VTE but antithrombin deficiency (Grade 2C). For all other pregnant women with thrombophilia but no prior VTE, we suggest antepartum clinical surveillance or prophylactic LMWH or UFH, plus postpartum anticoagulants, rather than routine care (Grade 2C). For women with recurrent early pregnancy loss or unexplained late pregnancy loss, we recommend screening for antiphospholipid antibodies (APLAs) [Grade 1A]. For women with these pregnancy complications who test positive for APLAs and have no history of venous or arterial thrombosis, we recommend antepartum administration of prophylactic or intermediate-dose UFH or prophylactic LMWH combined with aspirin (Grade 1B). We recommend that the decision about anticoagulant management during pregnancy for pregnant women with mechanical heart valves include an assessment of additional risk factors for thromboembolism including valve type, position, and history of thromboembolism (Grade 1C). While patient values and preferences are important for all decisions regarding antithrombotic therapy in pregnancy, this is particularly so for women with mechanical heart valves. For these women, we recommend either adjusted-dose bid LMWH throughout pregnancy (Grade 1C), adjusted-dose UFH throughout pregnancy (Grade 1C), or one of these two regimens until the thirteenth week with warfarin substitution until close to delivery before restarting LMWH or UFH) [Grade 1C]. However, if a pregnant woman with a mechanical heart valve is judged to be at very high risk of thromboembolism and there are concerns about the efficacy and safety of LMWH or UFH as dosed above, we suggest vitamin K antagonists throughout pregnancy with replacement by UFH or LMWH close to delivery, after a thorough discussion of the potential risks and benefits of this approach (Grade 2C).


Controlling proton movement: electrocatalytic oxidation of hydrogen by a nickel(II) complex containing proton relays in the second and outer coordination spheres.
A nickel bis(diphosphine) complex containing proton relays in the second and outer coordination spheres, Ni(P(Cy)2N((CH2)2OMe))2, (P(Cy)2N((CH2)2OMe) = 1,5-di(methoxyethyl)-3,7-dicyclohexyl-1,5-diaza-3,7-diphosphacyclooctane), is an electrocatalyst for hydrogen oxidation. The addition of hydrogen to the Ni(II) complex results in rapid formation of three isomers of the doubly protonated Ni(0) complex, [Ni(P(Cy)2N((CH2)2OMe)2H)2](2+). The three isomers show fast interconversion at 40 °C, unique to this complex in this class of catalysts. Under conditions of 1.0 atm H2 using H2O as a base, catalytic oxidation proceeds at a turnover frequency of 5 s(-1) and an overpotential of 720 mV, as determined from the potential at half of the catalytic current. Compared to the previously reported Ni(P(Cy)2N(Bn))2 complex, the new complex operates at a faster rate and at a lower overpotential.


Identification of protein O-glycosylation site and corresponding glycans using liquid chromatography-tandem mass spectrometry via mapping accurate mass and retention time shift.
We reported an improved combinatorial approach for identifying site-specific O-glycosylation using both glycan cleaved and non-cleaved methods. In this approach, a non-reducing β-elimination kit coupled with non-specific enzymes performed efficient digestion, O-glycan cleavage, and partial dephosphorylation without significant side reactions, thus enabling an automatic database search for the cleaved O-glycosylation or serine/threonine (S/T) phosphorylation sites. From the same sample concurrently prepared without β-elimination, the corresponding intact O-glycopeptides were mapped by accurate precursor ion mass using an in-house glycan database majorly composed of GalNAc (mucin-type) core and the retention-time shift (ΔRt). Each glycopeptide assignment was verified by the detection of glycan-specific fragments using collision-induced dissociation (CID) to estimate False Discovery Rate (FDR). Using fetuin as a model, all identified S/T elimination sites were matched to multiple intact glycopeptides with a 31% FDR. This considerably reduced to 0% FDR by ΔRt filtering. This approach was then applied to a protein mixture composed of therapeutic Factor IX and Enbrel(®) mixed with fetuin and kappa-casein. A total of 26 glycosylation sites each of which corresponds to 1-4 glycans were positively mapped and confirmed. The FDR decreased from 33% to 3.3% by ΔRt filtering and exclusion of repeated peptide tags that covered the same glycosylation sites. Moreover, the phosphorylation and O-glycosylation on the same site such as T159 of Factor IX and T170 of kappa-casein were able to be unambiguously differentiated. Thus, our approach is useful for in-depth characterization of site-specific O-glycosylation of a simple mixture such as protein-based therapeutics.


Copper-catalyzed cyanomethylation of allylic alcohols with concomitant 1,2-aryl migration: efficient synthesis of functionalized ketones containing an α-quaternary center.
A copper-catalyzed alkylation of allylic alcohols by alkyl nitriles with concomitant 1,2-aryl migration was developed. Formation of the alkyl nitrile radical was followed by its intermolecular addition to alkenes and the migration of a vicinal aryl group with the concomitant generation of a carbonyl functionality to complete the domino sequence. Mechanistic studies suggested that 1,2-aryl migration proceeded through a radical pathway (neophyl rearrangement). The protocol provided an efficient route to functionalized ketones containing an α-quaternary center.


Patterns of Ichthyobodo necator sensu stricto infections on hatchery-reared Atlantic salmon Salmo salar in Norway.
Infection patterns with ectoparasitic flagellates belonging to the genus Ichthyobodo were studied in an Atlantic salmon Salmo salar (L.) hatchery in western Norway during an 11 mo period, from eyed eggs to smoltification. Since the earlier species designation Ichthyobodo necator (sensu lato, s.l.) has been shown to represent a complex of several species, the epizootiology of different Ichthyobodo spp. is poorly known. Therefore, we employed molecular methods to ascertain the specific identity of the parasites detected in our study. Only I. necator in the recently redefined and restricted sense occurred (I. necator sensu stricto, s.s.). We observed a 2-peak pattern of infection; the first peak occurred among fry in March and the second peak among fingerlings and pre-smolt in August and September. Skin lesions observed on fingerlings and pre-smolt were significantly associated with Ichthyobodo infections. Also, these infections were negatively correlated with both haematocrit values (Hct) and the condition factor (K) of the fish. The patterns of infection on the farmed salmon suggest that I. necator s.s. is an opportunistic parasite of salmon, flourishing in periods when susceptible hosts are present and the environment favours parasite proliferation. Our study is the first to detect and identify I. necator s.s. on wild-caught adult salmonids (brown trout S. trutta L.). Wild salmonids and sticklebacks Gasterosteus aculeatus (L.) caught in the lakes serving as a water supply to the hatchery were found infected with I. necator s.s., hence these are the likely sources of parasites entering the hatchery via the inlet water.


Signal restoration combining Tikhonov regularization and multilevel method with thresholding strategy.
Singular value decomposition (SVD)-based approaches, e.g., truncated SVD and Tikhonov regularization methods, are effective ways to solve problems of small or moderate size. However, SVD, in the sense of computation, is expensive when it is applied in large-sized cases. A multilevel method (MLM) combining SVD-based methods with the thresholding technique for signal restoration is proposed in this paper. Our MLM will transfer large-sized problems to small- or moderate-sized problems in order to make the SVD-based methods available. The linear systems on the coarsest level in the multilevel process will be solved by the Tikhonov regularization method. No presmoothers are implemented in the multilevel process to avoid damaging the parameter choice on the coarsest level. Furthermore, the soft-thresholding denoising technique is employed for the postsmoothers aiming to eliminate the leaving high-frequency information due to the lack of presmoothers. Finally, computational experiments show that our method outperforms other SVD-based methods in signal restoration ability at a shorter CPU-time consumption.


Positive and negative forms of replicability in gene network analysis.
Gene networks have become a central tool in the analysis of genomic data but are widely regarded as hard to interpret. This has motivated a great deal of comparative evaluation and research into best practices. We explore the possibility that this may lead to overfitting in the field as a whole. We construct a model of 'research communities' sampling from real gene network data and machine learning methods to characterize performance trends. Our analysis reveals an important principle limiting the value of replication, namely that targeting it directly causes 'easy' or uninformative replication to dominate analyses. We find that when sampling across network data and algorithms with similar variability, the relationship between replicability and accuracy is positive (Spearman's correlation, rs ∼0.33) but where no such constraint is imposed, the relationship becomes negative for a given gene function (rs ∼ -0.13). We predict factors driving replicability in some prior analyses of gene networks and show that they are unconnected with the correctness of the original result, instead reflecting replicable biases. Without these biases, the original results also vanish replicably. We show these effects can occur quite far upstream in network data and that there is a strong tendency within protein-protein interaction data for highly replicable interactions to be associated with poor quality control. Algorithms, network data and a guide to the code available at: https://github.com/wimverleyen/AggregateGeneFunctionPrediction firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


Sodium- and energy-dependent uptake of myo-inositol by rabbit peripheral nerve. Competitive inhibition by glucose and lack of an insulin effect.
Experimental diabetes consistently reduces the concentration of free myo-inositol in peripheral nerve, which usually exceeds that of plasma by 90-100-fold. This phenomenon has been explicitly linked to the impairment of nerve conduction in the acutely diabetic streptozocin-treated rat. However, the mechanism by which acute experimental diabetes lowers nerve myo-inositol content and presumably alters nerve myo-inositol content and presumably alters nerve myo-inositol metabolism is unknown. Therefore, the effects of insulin and elevated medium glucose concentration of 2-[3H]myo-inositol uptake were studied in a metabolically-defined in vitro peripheral nerve tissue preparation derived from rabbit sciatic nerve, whose free myo-inositol content is reduced by experimental diabetes. The results demonstrate that myo-inositol uptake occurs by at least two distinct transport systems in the normal endoneurial preparation. A sodium- and energy-dependent saturable transport system is responsible for at least 94% of the measured uptake at medium myo-inositol concentrations approximating that present in plasma. This carrier-mediated transport system has a high affinity for myo-inositol (Kt = 63 microM), and is not influenced acutely by physiological concentrations of insulin; it is, however, inhibited by hyperglycemic concentrations of glucose added to the incubation medium in a primarily competitive fashion. Thus, competitive inhibition of peripheral nerve myo-inositol uptake by glucose may constitute a mechanism by which diabetes produces physiologically significant alterations in peripheral nerve myo-inositol metabolism.


Robustifying AdaBoost by adding the naive error rate.
AdaBoost can be derived by sequential minimization of the exponential loss function. It implements the learning process by exponentially reweighting examples according to classification results. However, weights are often too sharply tuned, so that AdaBoost suffers from the nonrobustness and overlearning. Wepropose a new boosting method that is a slight modification of AdaBoost. The loss function is defined by a mixture of the exponential loss and naive error loss functions. As a result, the proposed method incorporates the effect of forgetfulness into AdaBoost. The statistical significance of our method is discussed, and simulations are presented for confirmation.


Insulin use and weight maintenance in well-controlled type 2 diabetes: a prospective cohort study.
Intensification of glycemic control is associated with weight gain, however, less is known about weight change during the maintenance phase of glycemic management. On the basis of current models of energy homeostasis, we hypothesize that insulin use will result in less weight gain than oral antidiabetic agents in patients with well-controlled diabetes. This is a prospective cohort nested within a randomized control trial at an academic clinic, with enrollment from June 2002 to January 2005. A total of 163 patients with type 2 diabetes were enrolled after obtaining glycemic control. Insulin use was assessed by self-report at baseline. Participants were weighed at baseline and five follow-up visits over 24 months. The weight change was compared between insulin users and noninsulin users. The average (s.d.) age was 55 (11), 44% are female and 21% are black. The median duration of diabetes was 5 (0.5-10) years. At baseline, 88 participants (54%) reported insulin use with an average of 69 (6) units/day. Baseline BMI in the insulin users was 35 (6) and 33 (6) in noninsulin patients. Over 24 months, noninsulin patients gained 2.3 additional kilograms compared with insulin users (2.8 kg (6.8) vs. 0.5 kg (6.5), P = 0.065). After adjusting for age, race, sex, baseline weight, intervention status, and change in A1C, insulin users had 2.5 kg less weight gain than noninsulin users (P = 0.033). Less weight gain was observed over 24 months in insulin-treated patients. Whether this effect may be due to central catabolic effects of insulin merits additional confirmatory study and mechanistic investigation.


A Robust Probabilistic Model for Motion Layer Separation in X-ray Fluoroscopy.
Fluoroscopic images are characterized by a transparent projection of 3-D structures from all depths to 2-D. Differently moving structures, for example due to breathing and heartbeat, can be described approximately using independently moving 2-D layers. Separating the fluoroscopic images into the motion layers is desirable to facilitate interpretation and diagnosis. Given the motion of each layer, it is state of the art to compute the layer separation by minimizing a least-squares objective function. However, due to high noise levels and inaccurate motion estimates, the results are not satisfactory in X-ray images. In this work, we propose a probabilistic model for motion layer separation. In this model, we analyze various data terms and regularization terms theoretically and experimentally. We show that a robust penalty function is required in the data term to deal with noise and shortcomings of the image formation model. For the regularization term, we propose to enforce smoothness of the layers using bilateral total variation. On synthetic data, the mean squared error between the estimated layers and the ground truth is improved by 18% compared to the state of the art. In addition, we show qualitative improvements on real X-ray data.


Inhibition of Ca2+/calmodulin-dependent protein kinase II reverses oxaliplatin-induced mechanical allodynia in rats.
Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes severe peripheral neuropathy. We previously reported that oxaliplatin (4 mg/kg, i.p., twice a week) induces mechanical allodynia in the late phase in rats, and that spinal NR2B-containing N-methyl-D-aspartate (NMDA) receptors are involved in the oxaliplatin-induced mechanical allodynia. In the present study, we investigated the involvement of Ca(2+)/calmodulin dependent protein kinase II (CaMKII), which is a major intracellular protein kinase and is activated by NMDA receptor-mediated Ca(2+) influx, in the oxaliplatin-induced mechanical allodynia in rats. An increase of CaMKII phosphorylation was found in the spinal cord (L(4-6)) of oxaliplatin-treated rats. This increased CaMKII phosphorylation was reversed by intrathecal injection of a selective CaMKII inhibitor KN-93 (50 nmol, i.t.) and a selective NR2B antagonist Ro 25-6981 (300 nmol, i.t.). Moreover, acute administration of KN-93 (50 nmol, i.t.) strongly reversed the oxaliplatin-induced mechanical allodynia in von Frey test, while it did not affect the oxaliplatin-induced cold hyperalgesia in acetone test. Similarly, oral administration of trifluoperazine (0.1 and 0.3 mg/kg, p.o.), which is an antipsychotic drug and inhibits calmodulin, reduced both mechanical allodynia and increased CaMKII phosphorylation. On the other hand, trifluoperazine at the effective dose (0.3 mg/kg) had no effect on the paw withdrawal threshold in intact rats. In addition, trifluoperazine at the same dose did not affect the motor coordination in rota-rod test in intact and oxaliplatin-treated rats. These results suggest that CaMKII is involved in the oxaliplatin-induced mechanical allodynia, and trifluoperazine may be useful for the treatment of oxaliplatin-induced peripheral neuropathy in clinical setting.


Cardiac Troponin for Assessment of Myocardial Injury in COVID-19: JACC Review Topic of the Week.
Increases in cardiac troponin indicative of myocardial injury are common in patients with coronavirus disease-2019 (COVID-19) and are associated with adverse outcomes such as arrhythmias and death. These increases are more likely to occur in those with chronic cardiovascular conditions and in those with severe COVID-19 presentations. The increased inflammatory, prothrombotic, and procoagulant responses following severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection increase the risk for acute nonischemic myocardial injury and acute myocardial infarction, particularly type 2 myocardial infarction, because of respiratory failure with hypoxia and hemodynamic instability in critically ill patients. Myocarditis, stress cardiomyopathy, acute heart failure, and direct injury from SARS-CoV-2 are important etiologies, but primary noncardiac conditions, such as pulmonary embolism, critical illness, and sepsis, probably cause more of the myocardial injury. The structured use of serial cardiac troponin has the potential to facilitate risk stratification, help make decisions about when to use imaging, and inform stage categorization and disease phenotyping among hospitalized COVID-19 patients.


Enhanced thermal oxidation stability of reduced graphene oxide by nitrogen doping.
Nitrogen-doped reduced graphene oxide (N-doped RGO) samples with a high level of doping, up to 13 wt. %, have been prepared by annealing graphene oxide under a flow of pure ammonia. The presence of nitrogen within the structure of RGO induces a remarkable increase in the thermal stability against oxidation by air. The thermal stability is closely related with the temperature of synthesis and the nitrogen content. The combustion reaction of nitrogen in different coordination environments (pyridinic, pyrrolic, and graphitic) is analyzed against a graphene fragment (undoped) from a thermodynamic point of view. In agreement with the experimental observations, the combustion of undoped graphene turns out to be more spontaneous than when nitrogen atoms are present.


US public health service clinical practice guideline: treating tobacco use and dependence.
Treating Tobacco Use and Dependence, a Public Health Service-sponsored Clinical Practice Guideline, is a product of the Tobacco Use and Dependence Guideline Panel ("the panel"), consortium representatives, consultants, and staff. These 30 individuals were charged with the responsibility of identifying effective, experimentally validated tobacco dependence treatments and practices. The updated guideline was sponsored by a consortium of seven Federal Government and nonprofit organizations: the Agency for Healthcare Research and Quality (AHRQ), Centers for Disease Control and Prevention (CDC), National Cancer Institute (NCI), National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, Robert Wood Johnson Foundation, and University of Wisconsin Medical School's Center for Tobacco Research and Intervention. This guideline is an updated version of the 1996 Smoking Cessation Clinical Practice Guideline No. 18 that was sponsored by the Agency for Health Care Policy and Research (now the AHRQ), United States Department of Health and Human Services. The original guideline reflected the extant scientific research literature published between 1975 and 1994. The updated guideline was written because new, effective clinical treatments for tobacco dependence have been identified since 1994. The accelerating pace of tobacco research that prompted the update is reflected in the fact that 3,000 articles on tobacco were identified as published between 1975 and 1994, contributing to the original guideline. Another 3,000 were published between 1995 and 1999 and contributed to the updated guideline. These 6,000 articles were screened and reviewed to identify a much smaller group of articles that served as the basis for guideline data analyses and panel opinion. This guideline contains strategies and recommendations designed to assist clinicians, tobacco dependence treatment specialists, and health care administrators, insurers, and purchasers in delivering and supporting effective treatments for tobacco use and dependence. The recommendations were made as a result of a systematic review and analysis of the extant scientific literature, using meta-analysis as the primary analytic technique. The strength of evidence that served as the basis for each recommendation is clearly indicated in the guideline. A draft of the guideline was peer-reviewed prior to publication, and the comments of 70 external reviewers were incorporated into the final document. The key recommendations of the updated guideline, Treating Tobacco Use and Dependence, based on the literature review and expert panel opinion, are as follows: 1. Tobacco dependence is a chronic condition that often requires repeated intervention. However, effective treatments exist that can produce long-term or even permanent abstinence. 2. Because effective tobacco dependence treatments are available, every patient who uses tobacco should be offered at least one of these treatments: Patients willing to try to quit tobacco use should be provided with treatments identified as effective in this guideline. Patients unwilling to try to quit tobacco use should be provided with a brief intervention designed to increase their motivation to quit. 3. It is essential that clinicians and health care delivery systems (including administrators, insurers, and purchasers) institutionalize the consistent identification, documentation, and treatment of every tobacco user seen in a health care setting. 4. Brief tobacco dependence treatment is effective, and every patient who uses tobacco should be offered at least brief treatment. 5. There is a strong dose-response relation between the intensity of tobacco dependence counseling and its effectiveness. Treatments involving person-to-person contact (via individual, group, or proactive telephone counseling) are consistently effective, and their effectiveness increases with treatment intensity (eg, minutes of contact). 6. (ABSTRACT TRUNCATED)


Genome-based identification of cancer genes by proviral tagging in mouse retrovirus-induced T-cell lymphomas.
The identification of tumor-inducing genes is a driving force for elucidating the molecular mechanisms underlying cancer. Many retroviruses induce tumors by insertion of viral DNA adjacent to cellular oncogenes, resulting in altered expression and/or structure of the encoded proteins. The availability of the mouse genome sequence now allows analysis of retroviral common integration sites in murine tumors to be used as a genetic screen for identification of large numbers of candidate cancer genes. By positioning the sequences of inverse PCR-amplified, virus-host junction fragments within the mouse genome, 19 target genes were identified in T-cell lymphomas induced by the retrovirus SL3-3. The candidate cancer genes included transcription factors (Fos, Gfi1, Lef1, Myb, Myc, Runx3, and Sox3), all three D cyclins, Ras signaling pathway components (Rras2/TC21 and Rasgrp1), and Cmkbr7/CCR7. The most frequent target was Rras2. Insertions as far as 57 kb away from the transcribed portion were associated with substantially increased transcription of Rras2, and no coding sequence mutations, including those typically involved in Ras activation, were detected. These studies demonstrate the power of genome-based analysis of retroviral insertion sites for cancer gene discovery, identify several new genes worth examining for a role in human cancer, and implicate the pathways in which those genes act in lymphomagenesis. They also provide strong genetic evidence that overexpression of unmutated Rras2 contributes to tumorigenesis, thus suggesting that it may also do so if it is inappropriately expressed in human tumors.


Herpesvirus saimiri-based gene delivery vectors.
Herpesviruses possess a number of characteristics which make them promising gene delivery vectors. These include their capacity to package large amounts of heterologous DNA and an ability to establish persistent, lifelong infections, where the viral genome remains as a circular non-integrated episome. Herpesvirus saimiri (HVS) is the prototype gamma-2 herpesvirus and is currently being developed as a potential gene delivery vector. In addition to the above properties, HVS-based vectors have the ability to infect a wide range of human cell lines and primary cultures with high efficiencies. Moreover, upon infection the viral genome persists as high copy number, circular, non-integrated episomes which segregate to progeny cells upon division. This allows the HVS-based vector to stably transduce a dividing cell population and provide sustained heterologous gene expression. As such, it offers the characteristics of an artificial chromosome combined with a highly efficient delivery system. This review aims to describe the assessment of HVS-based vectors in both in vitro and in vivo studies, highlighting new developments and possible applications for the treatment of genetic diseases.


Estimating the potential impact of the UK government's sugar reduction programme on child and adult health: modelling study.
To estimate the impact of the UK government's sugar reduction programme on child and adult obesity, adult disease burden, and healthcare costs. Modelling study. Simulated scenario based on National Diet and Nutrition Survey waves 5 and 6, England. 1508 survey respondents were used to model weight change among the population of England aged 4-80 years. Calorie change, weight change, and body mass index change were estimated for children and adults. Impact on non-communicable disease incidence, quality adjusted life years, and healthcare costs were estimated for adults. Changes to disease burden were modelled with the PRIMEtime-CE Model, based on the 2014 population in England aged 18-80. If the sugar reduction programme was achieved in its entirety and resulted in the planned sugar reduction, then the calorie reduction was estimated to be 25 kcal/day (1 kcal=4.18 kJ=0.00418 MJ) for 4-10 year olds (95% confidence interval 23 to 26), 25 kcal/day (24 to 28) for 11-18 year olds, and 19 kcal/day (17 to 20) for adults. The reduction in obesity could represent 5.5% of the baseline obese population of 4-10 year olds, 2.2% of obese 11-18 year olds, and 5.5% of obese 19-80 year olds. A modelled 51 729 quality adjusted life years (95% uncertainty interval 45 768 to 57 242) were saved over 10 years, including 154 550 (132 623 to 174 604) cases of diabetes and relating to a net healthcare saving of £285.8m (€332.5m, $373.5m; £249.7m to £319.8m). The UK government's sugar reduction programme could reduce the burden of obesity and obesity related disease, provided that reductions in sugar levels and portion sizes do not prompt unanticipated changes in eating patterns or product formulation.