Risk factors and the incidence of coronary artery disease in young middle-aged Japanese men: results from a 10-year cohort study.
The objective of this study was to elucidate the relationship between risk factors and the coronary artery disease (CAD) in young middle-aged Japanese men. A cohort study of 2,764 young middle-aged Japanese men aged 3544 (mean+/-SD: 42.3+/-2.5) years based on a 10-year followup to identify the risk factors for the occurrence of CAD was conducted. There were 35 cases of CAD during the follow up; 25 myocardial infarctions and 10 angina pectoris. The Cox Proportional hazard model was used to identify the independent risk factors for CAD. Adjustment was made for variables including age, body mass index, smoking habit, systolic blood pressure, total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), fasting plasma glucose (FPG), and triglyceride. TC, low HDLC, and FPG were identified as significant independent risk factors for CAD. Adjusted hazard ratio (HR) of a high level of TC> or = 220 (mg/dl) for CAD was 5.46 (95% confidence interval (CI): 1.9617.51) and that of a high level of HDLC<50(mg/dl) was 9.01 (95%CI: 1.1372.17), and a high level of FPG> or = 110 (mg/dl) was 2.94 (95%CI: 1.228.23). Considering the combination of these risk factors, adjusted HR for CAD of the subjects who had 2 risk factors was 8.37 (95%CI: 2.2131.65). Using the database of young middle-aged Japanese men, TC, low HDLC, and FPG were found to be important risk factors for CAD, and the combination of these risk factors was associated with CAD.


Nonenzymatic glycosylation of HDL and impaired HDL-receptor-mediated cholesterol efflux.
Previous studies have shown that nonenzymatic glycosylation of high-density lipoprotein (HDL) inhibits high-affinity binding to cultured cells and the candidate HDL-receptor protein. Because binding of HDL to its receptor is required for HDL-receptor-mediated cholesterol efflux from cells, we hypothesized that glycosylated HDL3 would have reduced ability to remove cholesterol from cells. HDL3 was glycosylated in vitro to achieve up to 40-50% reductions in free-lysine residues. Glycosylated HDL3 had a slightly greater ability than control HDL3 to sequester cholesterol directly from the plasma membrane, as predicted by changes in lipid composition. This process is independent of HDL-receptor binding and should not be influenced by reduced binding of HDL3. In contrast, efflux of intracellular cholesterol from cells, which is HDL-receptor dependent, was reduced 25-40%. The ability of glycosylated HDL3 to diminish cholesterol esterification was significantly reduced, indicating reduced net cholesterol efflux. Steady-state efflux of LDL-derived cholesterol was also markedly reduced. These findings suggest that nonenzymatically glycosylated HDL is functionally abnormal and might contribute to the accelerated development of atherosclerosis in patients with diabetes mellitus.


Risk assessment of engineered nanomaterials and nanotechnologies--a review.
With the increasing utilization of engineered nanomaterials (ENM), the potential exposure of workers to ENM is likely to increase significantly. Very little is known though, of the risks posed by ENM to human health, in particular concerning those characteristics that are technologically attractive: small size, high surface to mass ratio, and surface reactivity. ENM risk assessment is hampered by a lack of exposure as well as toxicity data specific to the multitude of ENM being developed. An economical approach to this problem urgently calls for intelligent testing strategies to capture essential features of ENM, thereby allowing over-arching ENM risk assessment. The data gaps of ENM risk assessment include (1) ENM aerosol standards and agreement on ENM key metrics; (2) dependable exposure scenarios, affordable monitoring technologies, exposure data and models; and (3) biomedical data on ENM translocation and toxicity, and associated testing strategies (which must be linked to the exposure scenarios). The special features of ENM do not, however, create a need to amend the current overall approach to the risk assessment of chemicals.


Lower serum calcium is independently associated with CKD progression.
Disturbances in calcium metabolism are common in individuals with chronic kidney disease (CKD), but whether they are associated with subsequent kidney function decline is less clear. In a CKD 3-5 cohort of 15,755 adult citizens of Stockholm with creatinine tests taken during 2006-2011 and concurrent calcium testing at cohort entry, we investigated the association between baseline serum calcium and the subsequent change in estimated glomerular filtration rate (eGFR, by CKD-EPI) decline using linear mixed models. Mean (SD) baseline corrected serum calcium was 9.6 (0.5) mg/dL. Mean (95%-confidence interval [CI]) eGFR decline was -0.82 (-0.90; -0.74) mL/min/1.73 m2/year. In advanced CKD stages, higher baseline serum calcium was associated with less rapid kidney function decline. The adjusted change (95%-CI) in eGFR decline associated with each mg/dL increase in baseline serum calcium was -0.10 (-0.28; 0.26), 0.39 (0.07; 0.71), 0.34 (-0.02; 0.70) and 0.68 (0.36; 1.00) mL/min/1.73 m2/year for individuals in CKD stage 3a, 3b, 4, and 5, respectively. In a subgroup of patients using vitamin D supplements, the association between baseline serum calcium and CKD progression was eliminated, especially in CKD stage 3b and 4. To conclude, in individuals with CKD stage 3b to 5, lower baseline corrected serum calcium, rather than higher baseline serum calcium, associated with a more rapid CKD progression. Lower serum corrected calcium seems to be indicative for vitamin D deficiency.


Energy Expenditure Equation Choice: Effects on Cycling Efficiency and its Reliability.
There are several published equations to calculate energy expenditure (EE) from gas exchanges. The authors assessed whether using different EE equations would affect gross efficiency (GE) estimates and their reliability. Eleven male and 3 female cyclists (age 33 [10] y; height: 178 [11] cm; body mass: 76.0 [15.1] kg; maximal oxygen uptake: 51.4 [5.1] mL·kg-1·min-1; peak power output: 4.69 [0.45] W·kg-1) completed 5 visits to the laboratory on separate occasions. In the first visit, participants completed a maximal ramp test to characterize their physiological profile. In visits 2 to 5, participants performed 4 identical submaximal exercise trials to assess GE and its reliability. Each trial included three 7-minute bouts at 60%, 70%, and 80% of the gas exchange threshold. EE was calculated with 4 equations by Péronnet and Massicotte, Lusk, Brouwer, and Garby and Astrup. All 4 EE equations produced GE estimates that differed from each other (all P < .001). Reliability parameters were only affected when the typical error was expressed in absolute GE units, suggesting a negligible effect-related to the magnitude of GE produced by each EE equation. The mean coefficient of variation for GE across different exercise intensities and calculation methods was 4.2%. Although changing the EE equation does not affect GE reliability, exercise scientists and coaches should be aware that different EE equations produce different GE estimates. Researchers are advised to share their raw data to allow for GE recalculation, enabling comparison between previous and future studies.


Evidence of a unique and common genetic etiology between the CAR and the remaining part of the diurnal cycle: A study of 14 year-old twins.
By and large, studies have reported moderate contributions of genetic factors to cortisol secreted in the early morning and even smaller estimates later in the day. In contrast, the cortisol awakening response (CAR) has shown much stronger heritability estimates, which prompted the hypothesis that the etiology of cortisol secretion may vary according to the time of day. A direct test of this possibility has, however, not yet been performed. To describe the specific and common etiology of the CAR, awakening level and cortisol change from morning to evening in an age-homogenous sample of twin adolescents. A total of 592 participants of the Québec Newborn Twin Study, a population-based 1995-1998 cohort of families with twins in Canada, have collected saliva at awakening, 30 min later, at the end of afternoon and in the evening over four collection days. Multivariate Cholesky models showed both specific and common sources of variance between the CAR, awakening and cortisol diurnal change. The CAR had the strongest heritability estimates, which, for the most part, did not overlap with the other indicators. Conversely, similar magnitudes of genetic and environmental contributions were detected at awakening and for diurnal change, which partially overlapped. Our study unraveled differences between the latent etiologies of the CAR and the rest of the diurnal cycle, which may contribute to identify regulatory genes and environments and detangle how these indicators each relate to physical and mental health.


Initial Correction Predicts the Need for Secondary Achilles Tendon Procedures in Patients With Idiopathic Clubfoot Treated With Ponseti Casting.
The Ponseti method is the most common method to treat idiopathic clubfoot in North America. Despite initial correction, recurrence is common with this method. The factors predictive of recurrence are not well defined in the literature. A retrospective chart review was done of procedures performed at our institution from 2005 to 2010 in children undergoing general anesthesia for primary percutaneous Achilles tenotomy for the treatment of idiopathic clubfoot using the Ponseti casting method (101 patients, 148 feet). All patients were followed up for at least 2 years postoperatively (2 to 7.5 y, average 3.5 y). The patients were divided into 2 groups: group N with no repeat procedures on Achilles tendon and group R with a secondary procedure to address the residual equinus deformity. We looked at postoperative equinus correction through the use of postoperative measurements on digital images using a goniometer. The amount of postoperative dorsiflexion at the initial procedure was compared between the 2 groups using the paired t test. The feet were then divided into 3 groups on the basis of the amount of initial correction, and the rates of future surgical procedures were compared among these groups. A total of 101 patients (148 feet) were evaluated. Seventy-two patients (106 feet) did not have any future procedures to address equinus deformity (group N). Twenty-nine patients (42 feet) underwent future procedure (group R) to correct the residual equinus. The N and R groups differed in amount of postoperative dorsiflexion (14.0 vs. 5.1; P<0.01). Patients in whom at least 10 degrees of dorsiflexion was achieved after the initial tenotomy had only a 12% rate of future procedures. Patients with neutral or less than neutral dorsiflexion had 64% chance of future procedures to address the residual equinus. Residual equinus deformity after Achilles tenotomy in clubfeet treated by the Ponseti method is associated with a high rate of future surgical procedures. Correction of this deformity before bracing could potentially decrease the rate of future surgery. Level III—Retrospective.


Documenting, modelling and exploiting P300 amplitude changes due to variable target delays in Donchin's speller.
The P300 is an endogenous event-related potential (ERP) that is naturally elicited by rare and significant external stimuli. P300s are used increasingly frequently in brain-computer interfaces (BCIs) because the users of ERP-based BCIs need no special training. However, P300 waves are hard to detect and, therefore, multiple target stimulus presentations are needed before an interface can make a reliable decision. While significant improvements have been made in the detection of P300s, no particular attention has been paid to the variability in shape and timing of P300 waves in BCIs. In this paper we start filling this gap by documenting, modelling and exploiting a modulation in the amplitude of P300s related to the number of non-targets preceding a target in a Donchin speller. The basic idea in our approach is to use an appropriately weighted average of the responses produced by a classifier during multiple stimulus presentations, instead of the traditional plain average. This makes it possible to weigh more heavily events that are likely to be more informative, thereby increasing the accuracy of classification. The optimal weights are determined through a mathematical model that precisely estimates the accuracy of our speller as well as the expected performance improvement w.r.t. the traditional approach. Tests with two independent datasets show that our approach provides a marked statistically significant improvement in accuracy over the top-performing algorithm presented in the literature to date. The method and the theoretical models we propose are general and can easily be used in other P300-based BCIs with minimal changes.


A single-center study of treatment outcomes of pediatric basal ganglia germinoma in Taiwan.
A basal ganglia (BG) germinoma is a rare tumor, and the optimal treatment remains unknown. We evaluated the clinical outcomes of treatment of BG germinoma in pediatric patients in Taiwan. We retrospectively reviewed the medical records of 34 children with BG germinoma who were treated with radiotherapy (RT) at Taipei Veterans General Hospital between 1989 and 2016. The median follow-up time is 8.3 years (1.8-25.2 years). Survival was analyzed using the Kaplan-Meier estimate. Univariate Cox proportional-hazards models were used to identify the potential risk factors. Only four patients (11.8%) experienced recurrence and all successfully underwent salvage therapy. One patient (2.97%) died due to suspected radiotherapy (RT)-related sarcoma in the scalp. The 2-, 3-, and 5-year DFS rates were 91.2%, 88.2%, and 79.4%, respectively; the 2-, 3-, and 5-year OS rates were 97.1%, 94.1%, and 82.4%, respectively. Focal RT showed low DFS in the Kaplan-Meier survival curves (P = .028) compared with non-focal RT (whole ventricle, whole brain, or cranial spinal area). In the univariate Cox proportional-hazards model, there was a significant difference in DFS between focal and non-focal RT (P = .03). There is no difference in DFS and OS between BG germinoma patients and non-BG germinoma patients. We found an excellent DFS and OS in pediatric patients with BG germinoma treated with RT. Whole ventricle irradiation is recommended for good tumor control and low treatment-related toxicity. BG germinoma patients showed similar treatment results as germinoma patients in other common sites.


Indigenous enteric eosinophils control DCs to initiate a primary Th2 immune response in vivo.
Eosinophils natively inhabit the small intestine, but a functional role for them there has remained elusive. Here, we show that eosinophil-deficient mice were protected from induction of Th2-mediated peanut food allergy and anaphylaxis, and Th2 priming was restored by reconstitution with il4(+/+) or il4(-/-) eosinophils. Eosinophils controlled CD103(+) dendritic cell (DC) activation and migration from the intestine to draining lymph nodes, events necessary for Th2 priming. Eosinophil activation in vitro and in vivo led to degranulation of eosinophil peroxidase, a granule protein whose enzymatic activity promoted DC activation in mice and humans in vitro, and intestinal and extraintestinal mouse DC activation and mobilization to lymph nodes in vivo. Further, eosinophil peroxidase enhanced responses to ovalbumin seen after immunization. Thus, eosinophils can be critical contributors to the intestinal immune system, and granule-mediated shaping of DC responses can promote both intestinal and extraintestinal adaptive immunity.


Association of white matter hyperintensity volume with decreased cognitive functioning: the Framingham Heart Study.
To examine the relationship between white matter hyperintensity (WMH) volume on magnetic resonance images and cognitive tests in a large, population-based sample. Quantitative magnetic resonance imaging and neuropsychological evaluations were performed in 1820 dementia- and stroke-free participants from the Framingham Offspring Cohort. The WMH volume relative to total cranial volume was computed; WMH volumes more than 1 SD above the age-predicted mean were defined as large. Adjusting for age, sex, education, height, and Framingham Stroke Risk Profile, we examined the relationship between WMH and 3 cognitive factors derived from a neuropsychological test battery (verbal memory, visuospatial memory and organization, and visual scanning and motor speed) and 3 individual measures of new learning, abstract reasoning, and naming. Compared with those with no or little WMH volume, participants with large WMH volume performed worse on the cognitive factors of visuospatial memory and organization (P = .04) and visual scanning and motor speed (P = .01), as well as on new learning (P = .04), but not on verbal memory (P = .52). In this younger community-based population of nondemented individuals, those with large WMH volume, as compared with those with less or no WMH volumes, performed significantly worse in cognitive domains generally associated with frontal lobe systems and, to a lesser extent, the medial temporal area. Further study will clarify whether large WMH volume and associated cognitive impairment lead to future risk of stroke or dementia.


Capillary plexuses are vulnerable to neutrophil extracellular traps.
Capillary plexuses are commonly regarded as reliable networks for blood flow and robust oxygen delivery to hypoxia sensitive tissues. They have high levels of redundancy to assure adequate blood supply when one or more of the capillaries in the network are blocked by a clot. However, despite having extensive capillary plexuses, many vital organs are often subject to secondary organ injury in patients with severe inflammation. Recent studies have suggested that neutrophils play a role in this pathology, even though their precise contribution remains elusive. Here we investigate the effect of chromatin fibres released from overly-activated neutrophils (neutrophil extracellular traps, NETs) on the flow of blood through microfluidic networks of channels replicating geometrical features of capillary plexuses. In an in vitro setting, we show that NETs can decouple the traffic of red blood cells from that of plasma in microfluidic networks. The effect is astonishingly disproportionate, with NETs from less than 200 neutrophils resulting in more than half of a 0.6 mm(2) microfluidic network to become void of red blood cell traffic. Importantly, the NETs are able to perturb the blood flow in capillary networks despite the presence of anti-coagulants. If verified to occur in vivo, this finding could represent a novel mechanism for tissue hypoxia and secondary organ injury during severe inflammation in patients already receiving antithrombotic and anticoagulant therapies.


Fibrinogen depletion attenuates Staphyloccocus aureus infection by preventing density-dependent virulence gene up-regulation.
Staphylococcus aureus undergoes a density-dependent conversion in phenotype from tissue-adhering to tissue-damaging and phagocyte-evading that is mediated in part by the quorum-sensing operon, agr, and its effector, RNAIII. Contributions of host factors to this mechanism for regulating virulence have not been studied. We hypothesized that fibrinogen, as a component of the inflammatory response, could create spatially constrained microenvironments around bacteria that increase density independently of bacterial numbers and thus potentiate quorum-sensing-dependent virulence gene expression. Here we show that transient fibrinogen depletion significantly reduces the bacterial burden and the consequential morbidity and mortality during experimental infection with wild-type S. aureus, but not with bacteria that lack expression of the quorum-sensing operon, agr. In addition, it inhibits in vivo activation of the promoter for the agr effector, RNAIII, and downstream targets of RNAIII, including alpha hemolysin and capsule production. Moreover, both in vitro and in vivo, the mechanism for promoting this phenotypic switch in virulence involves clumping of the bacteria, demonstrating that S. aureus responds to fibrinogen-mediated bacterial clumping by enhancing density-dependent virulence gene expression. These data demonstrate that down-modulation of specific inflammatory components of the host that augment bacterial quorum sensing can be a strategy for enhancing host defense against infection.


Effect of word and syllable frequency on activation during lexical decision and reading aloud.
This functional MRI (fMRI) study investigated the effect of lexical and syllable frequency on visual word processing during lexical decision and reading aloud. Previous research has shown a dissociation of syllable and word frequency effects in Spanish using behavioral and electrophysiological measures, suggesting that sublexical (syllabic) representations are computed and mediate the firing of lexical candidates. Here, we characterize the neuroanatomical basis of these lexical and sublexical manipulations and their dependence on task. During lexical decision, words with low vs. high lexical frequency increased activation in left frontal, anterior cingulate, supplemental motor area (SMA), and pre-SMA regions; while words with high vs. low syllable frequency increased activation in a left anterior inferior temporal region. In contrast, when the words were read aloud those with low vs. high syllable frequency increased activation in the left anterior insula, with no other significant effects. On the basis of the neuroanatomy, we propose that the contrasting effects of syllable frequency during lexical decision and reading aloud reflect two different cognitive processes in visual word processing. Specifically, words with high-frequency syllables may increase lexical competition in the inferior temporal lobe while facilitating articulatory planning in the left anterior insula.


Endoscopic vidian neurectomy: the value of preoperative computed tomographic guidance.
To explore the vidian nerve anatomy by endoscopy and paranasal sinus computed tomography (CT) to elucidate the appropriate surgical approach based on preoperative CT images. Retrospective analysis. Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China. Sixty-seven patients underwent 106 endoscopic vidian neurectomies between January 9, 2006, and June 30, 2009. Paranasal sinus CT had been performed in all patients 2 weeks before surgery. Preoperative surgical planning was based on CT images, which were compared with intraoperative endoscopic findings. Two endoscopic approaches were used for vidian nerve transection, and the success rates were recorded for each. The transsphenoidal approach was successful on 42 sides (39.6%), while the transnasal approach was successful on 91 sides (85.8%). Success rates for the transsphenoidal approach were 0.0%, 72.1% (31 of 43 sides), and 84.6% (11 of 13 sides) for canal corpus types 1, 2, and 3, respectively. Success rates for the transsphenoidal approach were 50.0% (28 of 56 sides), 51.9% (14 of 27 sides), 0.0%, and 0.0% for canal floor relationship types 1, 2, 3, and 4, respectively. The transsphenoidal approach was successful only in patients without an embedded canal and with a canal floor relationship type 1 or type 2. Presence of the septum and continuation of the canal bony structure also influenced the choice of surgical approach. The vidian nerve can be precisely identified and microinvasively transected using endoscopy. Preoperative CT images delineate the vidian canal and enhance preoperative surgical planning.


Polymeric carbon nitride nanomesh as an efficient and durable metal-free catalyst for oxidative desulfurization.
We report the first use of polymeric carbon nitride (CN) for the catalytic selective oxidation of H2S. The as-prepared CN with unique ultrathin "nanomeshes" structure exhibits excellent H2S conversion and high S selectivity. In particular, the CN nanomesh also displays better durability in the desulfurization reaction than traditional catalysts, such as carbon- and iron-based materials.


Cooperation and the evolution of intelligence.
The high levels of intelligence seen in humans, other primates, certain cetaceans and birds remain a major puzzle for evolutionary biologists, anthropologists and psychologists. It has long been held that social interactions provide the selection pressures necessary for the evolution of advanced cognitive abilities (the 'social intelligence hypothesis'), and in recent years decision-making in the context of cooperative social interactions has been conjectured to be of particular importance. Here we use an artificial neural network model to show that selection for efficient decision-making in cooperative dilemmas can give rise to selection pressures for greater cognitive abilities, and that intelligent strategies can themselves select for greater intelligence, leading to a Machiavellian arms race. Our results provide mechanistic support for the social intelligence hypothesis, highlight the potential importance of cooperative behaviour in the evolution of intelligence and may help us to explain the distribution of cooperation with intelligence across taxa.


Emerging pharmacological therapies in schizophrenia: what's new, what's different, what's next?
There are several new and emerging medication interventions for both the acute and maintenance treatment phases of schizophrenia. Recently approved are 2 new dopamine receptor partial agonists, brexpiprazole and cariprazine, as well as 2 new long-acting injectable antipsychotic formulations, aripiprazole lauroxil and 3-month paliperidone palmitate. Although differences in efficacy compared to other available choices are not expected, the new oral options offer different tolerability profiles that may be attractive for individual patients who have had difficulties with older medications. The new long-acting injectable options provide additional flexibility in terms of increasing the time interval between injections. In Phase III of clinical development is a novel antipsychotic, lumateperone (ITI-007), that appears to have little in the way of significant adverse effects. Deutetrabenazine and valbenazine are agents in Phase III for the treatment of tardive dyskinesia, a condition that can be found among persons receiving chronic antipsychotic therapy. On the horizon are additional injectable formulations of familiar antipsychotics, aripiprazole and risperidone, that may be more convenient than what is presently available.


One week of magnesium supplementation lowers IL-6, muscle soreness and increases post-exercise blood glucose in response to downhill running.
Magnesium supplementation modulates glucose metabolism and inflammation, which could influence exercise performance and recovery. This study investigated the effect of magnesium intake on physiological responses and performance during eccentric exercise and recovery. Nine male recreational runners completed a counterbalanced, double-blind, placebo-controlled, cross-over study, registered at ClinicalTrial.gov. Participants consumed low magnesium diets and were supplemented with 500 mg/day of magnesium (SUP) or placebo (CON) for 7 days prior to a 10 km downhill (- 10%) running time trial (TT), separated by a 2-week washout period. At baseline and 24 h post-TT, maximal muscle force was measured. Interleukin-6 (IL-6), soluble interleukin-6 receptor (sIL-6R) and creatine kinase (CK) were measured at rest, 0 h, 1 h and 24 h post-TT. Muscle soreness was measured at the previous times plus 48 h and 72 h post. Glucose and lactate were measured during the TT. The main effect of condition was detected for IL-6 (SUP: 1.36 ± 0.66 vs CON: 2.06 ± 1.14 pg/ml) (P < 0.05, η2 = 0.54), sIL-6R (SUP: 27,615 ± 8446 vs CON: 24,368 ± 7806 pg/ml) (P < 0.05, η2 = 0.41) and muscle soreness (P < 0.01, η2 = 0.67). Recovery of blood glucose and muscle soreness were enhanced in SUP post-TT. There were no differences in glucose and lactate during the TT, or post measures of CK and maximal muscle force. Magnesium supplementation reduced the IL-6 response, enhanced recovery of blood glucose, and muscle soreness after strenuous exercise, but did not improve performance or functional measures of recovery.


Physiological correlates of beat-to-beat, ambulatory, and day-to-day home blood pressure variability after transient ischemic attack or minor stroke.
Visit-to-visit and day-to-day variability in systolic blood pressure (SBP) are associated with an increased risk of stroke, more strongly than variability on 24-hour ambulatory BP monitoring, but underlying physiological mechanisms are unclear. We related potentially relevant physiological characteristics to beat-to-beat, ambulatory, and day-to-day BP variability to identify underlying mechanisms and potential therapeutic targets. BP variability (coefficient of variation [CV]) on 1-month home BP monitoring (3 sitting readings, 3× daily), on 24-hour ambulatory BP monitoring, and on 5-minute beat-to-beat monitoring was related to BP reactivity (to mental arithmetic), arterial aging (aortic stiffness: carotid-femoral pulse wave velocity; aortic pulsatility), heart rate variability (CV of normal-to-normal R-R interval), and orthostatic responses. In 223 patients within 6 weeks of a transient ischemic attack or minor stroke, beat-to-beat and home SBP-CVs were associated with response to arithmetic (beat-to-beat odds ratio per SD=1.64; P<0.0001 and home BP monitoring, 1.41; P=0.025), aortic stiffness (1.84; P<0.0001 and 1.31; P=0.04), aortic pulsatility (1.98; P<0.0001 and 1.61; P<0.0001), and heart rate variability-CV of normal-to-normal R-R interval (1.34; P=0.03 and 1.35; P=0.03), independently of age, sex, and aortic BP. Orthostatic BP changes were associated only with SBP-CV on home BP monitoring (0.62; P=0.002). In contrast, no physiological measures were associated with within-day BP variability on awake ambulatory BP monitoring except response to mental arithmetic (1.40; P=0.01). Beat-to-beat and day-to-day SBP variability, but not variability on ambulatory BP monitoring, had similar physiological correlates, suggesting common underlying mechanisms and identifying potentially treatable targets that may be responsible for the relationship between SBP variability and stroke risk.


The structure of a mixed GluR2 ligand-binding core dimer in complex with (S)-glutamate and the antagonist (S)-NS1209.
Ionotropic glutamate receptors (iGluRs) mediate fast synaptic transmission between cells of the central nervous system and are involved in various aspects of normal brain function. iGluRs are implicated in several brain disorders, e.g. in the high-frequency discharge of impulses during an epileptic seizure. (RS)-NS1209 functions as a competitive antagonist at 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionate receptors, and shows robust preclinical anticonvulsant and neuroprotective effects. This study explores 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionate receptor binding and selectivity of this novel class of antagonists. We present here the first X-ray structure of a mixed GluR2 ligand-binding core dimer, with the high-affinity antagonist (S)-8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6,7,8,9,-tetrahydro-1H-pyrrolo[3,2-h]-isoquinoline-2,3-dione-3-O-(4-hydroxybutyrate-2-yl)oxime [(S)-NS1209] in one protomer and the endogenous ligand (S)-glutamate in the other. (S)-NS1209 stabilises an even more open conformation of the D1 and D2 domains of the ligand-binding core than that of the apo structure due to steric hindrance. This is the first time ligand-induced hyperextension of the binding domains has been observed. (S)-NS1209 adopts a novel binding mode, including hydrogen bonding to Tyr450 and Gly451 of D1. Parts of (S)-NS1209 occupy new areas of the GluR2 ligand-binding cleft, and bind near residues that are not conserved among receptor subtypes. The affinities of (RS)-NS1209 at the GluR2 ligand-binding core as well as at GluR1-6 and mutated GluR1 and GluR3 receptors have been measured. Two distinct binding affinities were observed at the GluR3 and GluR4 receptors. In a functional in vitro assay, no difference in potency was observed between GluR2(Q)(o) and GluR3(o) receptors. The thermodynamics of binding of the antagonists (S)-NS1209, DNQX and (S)-ATPO to the GluR2 ligand-binding core have been determined by displacement isothermal titration calorimetry. The displacement of (S)-glutamate by all antagonists was shown to be driven by enthalpy.


Effect of low-dose perindopril/indapamide on albuminuria in diabetes: preterax in albuminuria regression: PREMIER.
Microalbuminuria in diabetes is a risk factor for early death and an indicator for aggressive blood pressure (BP) lowering. We compared a combination of 2 mg perindopril/0.625 mg indapamide with enalapril monotherapy on albumin excretion rate (AER) in patients with type 2 diabetes, albuminuria, and hypertension in a 12-month, randomized, double-blind, parallel-group international multicenter study. Four hundred eighty-one patients with type 2 diabetes and hypertension (systolic BP > or =140 mm Hg, <180 mm Hg, diastolic BP <110 mm Hg) were randomly assigned (age 59+/-9 years, 77% previously treated for hypertension). Results from 457 patients (intention-to-treat analysis) were available. After a 4-week placebo period, patients with albuminuria >20 and <500 microg/min were randomly assigned to a combination of 2 mg perindopril/0.625 mg indapamide or to 10 mg daily enalapril. After week 12, doses were adjusted on the basis of BP to a maximum of 8 mg perindopril/2.5 mg indapamide or 40 mg enalapril. The main outcome measures were overnight AER and supine BP. Both treatments reduced BP. Perindopril/indapamide treatment resulted in a statistically significant higher fall in both BP (-3.0 [95% CI -5.6, -0.4], P=0.012; systolic BP -1.5 [95% CI -3.0, -0.1] diastolic BP P=0.019) and AER -42% (95% CI -50%, -33%) versus -27% (95% CI -37%, -16%) with enalapril. The greater AER reduction remained significant after adjustment for mean BP. Adverse events were similar in the 2 groups. Thus, first-line treatment with low-dose combination perindopril/indapamide induces a greater decrease in albuminuria than enalapril, partially independent of BP reduction. A BP-independent effect of the combination may increase renal protection.


Does community health care require different competencies from physicians and nurses?
Recently competency approach in Health Professionals' Education (HPE) has become quite popular and for an effective competency based HPE, it is important to design the curriculum around the health care needs of the population to be served and on the expected roles of the health care providers. Unfortunately, in community settings roles of health providers tend to be described less clearly, particularly at the Primary Health Care (PHC) level where a multidisciplinary and appropriately prepared health team is generally lacking. Moreover, to tailor the education on community needs there is no substantial evidence on what specific requirements the providers must be prepared for. This study has explored specific tasks of physicians and nurses employed to work in primary or secondary health care units in a context where there is a structural scarcity of community health care providers. In-depth Interviews of 11 physicians and 06 nurses working in community settings of Pakistan were conducted along with review of their job descriptions. At all levels of health settings, physicians' were mostly engaged with diagnosing and prescribing medical illness of patients coming to health center and nurses depending on their employer were either providing preventive health care activities, assisting physicians or occupied in day to day management of health center. Geographical location or level of health facility did not have major effect on the roles being expected or performed, however the factors that determined the roles performed by health providers were employer expectations, preparation of health providers for providing community based care, role clarity and availability of resources including health team at health facilities. Exploration of specific tasks of physicians and nurses working in community settings provide a useful framework to map competencies, and can help educators revisit the curricula and instructional designs accordingly. Furthermore, in community settings there are many synergies between the roles of physicians and nurses which could be simulated as learning activities; at the same time these two groups of health providers offer distinct sets of services, which must be harnessed to build effective, non-hierarchal, collaborative health teams.


A Multiple-Imputation "Forward Bridging" Approach to Address Changes in the Classification of Asian Race/Ethnicity on the US Death Certificate.
The incomparability of old and new classification systems for describing the same data can be seen as a missing-data problem, and, under certain assumptions, multiple imputation may be used to "bridge" 2 classification systems. One example of such a change is the introduction of detailed Asian-American race/ethnicity classifications on the 2003 version of the US national death certificate, which was adopted for use by 38 states between 2003 and 2011. Using county- and decedent-level data from 3 different national sources for pre- and postadoption years, we fitted within-state multiple-imputation models to impute ethnicities for decedents classified as "other Asian" during preadoption years. We present mortality rates derived using 3 different methods of calculation: 1) including all states but ignoring the gradual adoption of the new death certificate over time, 2) including only the 7 states with complete reporting of all ethnicities, and 3) including all states and applying multiple imputation. Estimates from our imputation model were consistently in the middle of the other 2 estimates, and trend results demonstrated that the year-by-year estimates of the imputation model were more similar to those of the 7-state model. This work demonstrates how multiple imputation can provide a "forward bridging" approach to make more accurate estimates over time in newly categorized populations.


Blood levels of glutamate oxaloacetate transaminase are more strongly associated with good outcome in acute ischaemic stroke than glutamate pyruvate transaminase levels.
Ischaemic stroke is associated with an excessive release of glutamate in brain. GOT (glutamate-oxaloacetate transaminase) and GPT (glutamate-pyruvate transaminase) are two enzymes that are able to metabolize blood glutamate facilitating the lowering of extracellular levels of brain glutamate. Our aim was to study the association between blood levels of both enzymes and stroke outcome in patients with acute ischaemic stroke. We prospectively studied 365 patients with first ischaemic stroke<12 h. Glutamate, GOT and GPT levels were determined in blood samples obtained at admission. We considered functional outcome at 3 months [good outcome: mRS (modified Rankin Scale)≤2; poor outcome mRS >2], END (early neurological deterioration) in the first 72 h [increment ≥4 points in NIHSS (National Institutes of Health Stroke Scale)] and infarct volume [CT (computed tomography) at 36-72 h] as end points. We have found an inverse correlation between GOT and GPT levels and blood glutamate levels. Patients with poor outcome showed lower levels of GOT (11.9±8.2 compared with 22.7±10.2 m-units/ml, P<0.0001) and GPT (19.5±14.3 compared with 24.7±20.3 m-units/ml; P=0.004). A negative correlation has been found between GOT (Pearson coefficient=-0.477, P<0.0001) and GPT (Pearson coefficient=-0.116; P=0.027) levels and infarct volume. Patients with END showed higher levels of blood glutamate (381.7±97.9 compared with 237.6±114.0 μmol/l, P<0.0001) and lower levels of GOT (10.8±6.7 compared with 18.1±10.8 m-units/ml; P<0.0001). This clinical study shows an association between high blood GOT and GPT levels and good outcome in ischaemic stroke patients, this association being stronger for GOT than GPT levels.


Economical multiple-site intradermal immunisation with human diploid-cell-strain vaccine is effective for post-exposure rabies prophylaxis.
An economical post-exposure regimen of Mérieux human diploid-cell-strain vaccine (HDCSV) was compared with Semple vaccine (SV), the most widely used vaccine in Asia. 155 patients bitten by animals proved to be rabid received either conventional courses of SV (34 severe and 43 mild cases) or HDCSV, 0.1 ml intradermally, at eight sites on day 0, at four sites on day 7, and at one site on days 28 and 91 (36 severe and 42 mild cases). All severely bitten patients were given equine anti-rabies serum (EARS), 80 IU/kg on day 0. There were no deaths from rabies in either group. Follow-up was 97.5% at 1 year and 93% at 2 years. 88% of patients given HDCSV alone had detectable neutralising antibody on day 7 in contrast to 2% given SV alone. Antibody persisted until 1 year in all sera tested from HDCSV patients in contrast to only 48% of SV sera. The high dose of EARS resulted in pronounced suppression of response to HDCSV. There were no serious systemic side-effects but local side-effects were significantly more common in the SV group. The multiple-site intradermal HDCSV regimen was at least as effective as SV. The amount of HDCSV used was 30% of the conventional dose.


Posterior hypothalamus-sparing surgery improves outcome after childhood craniopharyngioma.
Quality of life (QoL) is frequently impaired in childhood-onset craniopharyngioma (CP) by hypothalamic syndrome. The debate, whether pretreatment hypothalamic involvement (HI) has apriori prognostic impact or surgical hypothalamic lesions (HL) determine outcome, is controversial. Survival and outcome of CPs recruited between 2007 and 2014 in KRANIOPHARYNGEOM 2007 were analyzed with regard to reference-confirmed presurgical HI and surgical HL. Radiological findings, BMI and QoL were assessed at diagnosis and during follow-up. QoL was assessed using Pediatric Quality of Life (PEDQOL) questionnaire. One hundred sixty-nine CPs were included presenting with no HI (n = 11), anterior (n = 49) and anterior + posterior (a + p) HI (n = 109) prior to surgery. The latter 109 were analyzed for postoperative HL (no lesion: n = 23, anterior HL: n = 29, a + pHL: n = 57). Progression-free survival (PFS) was higher after complete resection. The highest PFS was observed in CP with a + pHL, especially when compared between non-irradiated subgroups (P = 0.006). Overall survival (OS) rates were 1.0 in all subgroups. CP with a + pHL developed higher BMI (P ≤ 0.001) during follow-up compared between subgroups. 55/109 pts with a + pHI completed PEDQOL at diagnosis (48/109 at 3 years follow-up). QoL was worse for a + pHL patients in terms of physical, social and emotional functionality when compared with the anterior HL and no HL subgroup. BMI development and QoL during follow-up were similar for patients with anterior HL and without HL. Posterior hypothalamus-sparing surgical strategies are associated with higher QoL, decreased development of obesity and lower PFS in CP.


Activation of the DNA-dependent protein kinase by drug-induced and radiation-induced DNA strand breaks.
The DNA-dependent protein kinase (DNA-PK) is a DNA-end activated protein kinase that is required for efficient repair of DNA double-strand breaks (DSBs) and for normal resistance to ionizing radiation. DNA-PK is composed of a DNA-binding subunit, Ku, and a catalytic subunit, DNA-PKcs (PRKDC). We have previously shown that PRKDC is activated when the enzyme interacts with the terminal nucleotides of a DSB. These nucleotides are often damaged when DSBs are introduced by anticancer agents and could therefore prevent recognition by DNA-PK. To determine whether DNA-PK could recognize DNA strand breaks generated by agents used in the treatment of cancer, we damaged plasmid DNA with anticancer drugs and ionizing radiation. The DNA breaks were tested for the ability to activate purified DNA-PK. The data indicate that DSBs produced by bleomycin, calicheamicin and two types of ionizing radiation ((137)Cs gamma rays and N(7+) ions: high and low linear energy transfer, respectively) activate DNA-PK to levels matching the kinase activation obtained with simple restriction endonuclease-induced DSBs. In contrast, the protein-linked DSBs produced by etoposide and topoisomerase II failed to bind and activate DNA-PK. Our findings indicate that DNA-PK recognizes DSBs regardless of chemical complexity but cannot recognize the protein-linked DSBs produced by etoposide and topoisomerase II.


Effect of tranexamic acid in traumatic brain injury: a nested randomised, placebo controlled trial (CRASH-2 Intracranial Bleeding Study).
To assess the effect of tranexamic acid (which reduces bleeding in surgical patients and reduces mortality due to bleeding in trauma patients) on intracranial haemorrhage in patients with traumatic brain injury. A nested, randomised, placebo controlled trial. All investigators were masked to treatment allocation. All analyses were by intention to treat. Patients 270 adult trauma patients with, or at risk of, significant extracranial bleeding within 8 hours of injury, who also had traumatic brain injury. Patients randomly allocated to tranexamic acid (loading dose 1 g over 10 minutes, then infusion of 1 g over 8 hours) or matching placebo. Intracranial haemorrhage growth (measured by computed tomography) between hospital admission and then 24-48 hours later, with adjustment for Glasgow coma score, age, time from injury to the scans, and initial haemorrhage volume. Of the 133 patients allocated to tranexamic acid and 137 allocated to placebo, 123 (92%) and 126 (92%) respectively provided information on the primary outcome. All patients provided information on clinical outcomes. The mean total haemorrhage growth was 5.9 ml (SD 26.8) and 8.1 mL (SD 29.2) in the tranexamic acid and placebo groups respectively (adjusted difference -3.8 mL (95% confidence interval -11.5 to 3.9)). New focal cerebral ischaemic lesions occurred in 6 (5%) patients in the tranexamic acid group versus 12 (9%) in the placebo group (adjusted odds ratio 0.51 (95% confidence interval 0.18 to 1.44)). There were 14 (11%) deaths in the tranexamic acid group and 24 (18%) in the placebo group (adjusted odds ratio 0.47 (0.21 to 1.04)). This trial shows that neither moderate benefits nor moderate harmful effects of tranexamic acid in patients with traumatic brain injury can be excluded. However, the analysis provides grounds for further clinical trials evaluating the effect of tranexamic acid in this population. Trial registration ISRCTN86750102.


Occurrence of G gamma Hb F in Greek HPFH: analysis of heterozygotes and compound heterozygotes with beta thalassaemia.
Haemoglobin F has been isolated from the red cells of individuals with the Greek form of hereditary persistence of fetal haemoglobin (HPFH), and the glycine/alanine composition of the gamma CB3 peptides determined. In contrast to previous reports we have shown that the Hb F of the Greek HPFH heterozygotes contains significant amounts of G gamma chains and circumstantial evidence indicates that these are the products of the same chromosome that carries the Greek HPFH determinant. Hence this chromosome must be directing the synthesis of G gamma, A gamma and (probably) beta and delta chains, thus implying that the Greek form of HPFH does not result from a deletion involving the globin chain structural genes. Analysis of the levels and structure of Hb F from the Greek HPFH heterozygotes and from separated cell populations from the Greek HPFH/beta thalassaemia compound heterozygotes indicate that the Greek HPFH determinant, while allowing an overall increase in gamma chain synthesis, is not the sole factor determining the absolute amount of Hb F production on a cellular basis.


Infants born to mothers with severe acute respiratory syndrome.
Severe acute respiratory syndrome (SARS) is a newly discovered infectious disease caused by a novel coronavirus. During the community outbreak in Hong Kong, 5 liveborn infants were born to pregnant women with SARS. A systematic search for perinatal transmission of the SARS-associated coronavirus, including serial reverse transcriptase-polymerase chain reaction assays, viral cultures, and paired serologic titers, failed to detect the virus in any of the infants. In addition, none of the infants developed clinical, radiologic, hematologic, or biochemical evidence suggestive of SARS. One preterm infant developed jejunal perforation and another developed necrotizing enterocolitis with ileal perforation shortly after birth. This case series is the first report to describe the clinical course of the first cohort of liveborn infants born to pregnant women with SARS.


Photophysical and photobiological properties of a sulfonated chlorin photosensitiser TPCS(2a) for photochemical internalisation (PCI).
This study investigated the photophysical and photobiological properties of a new amphiphilic chlorin photosensitiser, disulfonated tetraphenylchlorin (TPCS(2a)), for photochemical internalisation (PCI). The absorption and fluorescence spectra of TPCS(2a) were examined in a range of solvents together with fluorescence lifetime measurements. The fluorescence lifetime of TPCS(2a) was found to be 8.5 ns in methanol, whereas non-exponential decays were observed in distilled water due to sensitiser dimerisation. The singlet oxygen quantum yield of TPCS(2a) was determined as 0.62 in deuterated methanol by direct observation of singlet oxygen phosphorescence. In a human oral squamous carcinoma (HN5) cell line, intracellular co-localisation of TPCS(2a) and Alexa488-labelled saporin, a macromolecular toxin, was observed corresponding predominantly to a lysosomal distribution. Intracellular fluorescence redistribution of TPCS(2a) and Alexa488-saporin was observed after 405 nm irradiation. Using two-photon confocal microscopy at 840 nm, and fluorescence lifetime imaging (FLIM), the lifetime was measured as 6 ns in HN5 cells. PCI using TPCS(2a) was shown to be very effective, and a synergistic increase in saporin toxicity was achieved in HN5 cells where viability was significantly reduced after light exposure compared to saporin (25 nM) treatment alone. The results demonstrate the favourable photophysical and photobiological properties of TPCS(2a) for PCI, which induces the relocalisation of a macromolecular anti-cancer toxin inside cells and significantly enhances cell death.


Differential poisoning of human and Aspergillus nidulans DNA topoisomerase I by bi- and terbenzimidazoles.
DNA topoisomerase I has been partially purified from Aspergillus nidulans. The purified enzyme is most likely the major nuclear DNA topoisomerase I on the basis of the following findings. (1) Purified DNA topoisomerase I can relax both positively and negatively supercoiled DNA. (2) Neither an energy cofactor nor Mg(II) is required for the relaxation or the cleavage reaction of the enzyme. On the basis of a phosphate-transfer experiment, the Aspergillus topoisomerase I was shown to have a molecular mass (Mr) of 105 kDa. The differential sensitivity of the human and Aspergillus topoisomerase I was compared using a number of known human DNA topoisomerase I poisons. Like human DNA topoisomerase I, Aspergillus topoisomerase I is highly sensitive to the poisoning activity of camptothecin and a number of bi- and terbenzimidazoles. However, unlike human topoisomerase I, Aspergillus topoisomerase I is completely resistant to monobenzimidazoles, protoberberines (e.g. coralyne), and nitidine. Cytotoxicity studies using yeast expressing human and yeast topoisomerase I cDNAs have also demonstrated a similar differential sensitivity of yeast topoisomerase I to these human topoisomerase I poisons. These results together suggest that the nuclear fungal topoisomerase I may be sufficiently different from its human counterpart to serve as a molecular target for the development of antifungal drugs.


Pathogenicity of Candida albicans auxotrophic mutants in experimental infections.
Auxotrophic and prototrophic control strain pairs of Candida albicans constructed by molecular biology methodologies were evaluated for pathogenicity in a systemic mouse model. Mutants that were auxotrophic for adenine, uracil, and heme each showed a lowered level of pathogenicity relative to control strains. It can be concluded from these experiments that decreased pathogenicity in each case is due to the auxotrophic mutation, because mutant and control strains were constructed so as to differ at a single locus. These observations suggest that new therapeutic agents for Candida infections might be designed based upon the inhibition of biosynthetic pathways that, in some cases, might be absent from the host.


Enriching semantic knowledge bases for opinion mining in big data applications.
This paper presents a novel method for contextualizing and enriching large semantic knowledge bases for opinion mining with a focus on Web intelligence platforms and other high-throughput big data applications. The method is not only applicable to traditional sentiment lexicons, but also to more comprehensive, multi-dimensional affective resources such as SenticNet. It comprises the following steps: (i) identify ambiguous sentiment terms, (ii) provide context information extracted from a domain-specific training corpus, and (iii) ground this contextual information to structured background knowledge sources such as ConceptNet and WordNet. A quantitative evaluation shows a significant improvement when using an enriched version of SenticNet for polarity classification. Crowdsourced gold standard data in conjunction with a qualitative evaluation sheds light on the strengths and weaknesses of the concept grounding, and on the quality of the enrichment process.


Identification and brief treatment of alcohol problems with medical patients: an international perspective.
This article summarizes the proceedings of a symposium at the 2002 RSA meeting in San Francisco, California. The chair was Peter Monti and co-chair was Nancy Barnett. The aim of the symposium was to bring together researchers from the United States, Sweden, and Mexico to present current findings on the development and implementation of screening and intervention research in Emergency Departments (ED). Cheryl Cherpitel presented findings on the performance of the Rapid Alcohol Problems Screen (RAPS4), a 4-item instrument used for screening for alcohol dependence and harmful drinking in the ED. Dr. Cherpitel also presented for her collaborator, Guilherme Borges, their research on the performance of a number of screening measures including the RAPS among Mexicans and Mexican-Americans with alcohol-related disorders in the ED. Preben Bendtsen described the implementation of an alcohol screening and intervention procedure delivered by ordinary ED staff in Sweden. Nancy Barnett presented data on characteristics related to readiness to change alcohol use in a sample of young adults who were treated in an ED for injury or intoxication.


15N NMR spectroscopic and theoretical GIAO-DFT studies for the unambiguous characterization of disubstituted 1,2,3-triazoles.
The 1,2,3-triazole ring has recently attracted a renewed interest as a structural scaffold with many applications in different fields. However, very often, the unambiguous assignment of the correct structure is not an easy task, and the development of robust characterization methodologies is needed. Herein, the three possible isomeric forms of disubstituted 1,2,3-triazole (1,4- or 1,5- or 2,4-disubstituted derivatives) have been characterized and distinguished by routine (1)H/(15)N gHMBC experiments at (15)N natural abundance. The calculated (GIAO-B3LYP/6-311++G**) (15)N NMR chemical shifts showed good agreement with the experimental values, further supporting their unambiguous structural characterization.


A Phylogenetic Codon Substitution Model for Antibody Lineages.
Phylogenetic methods have shown promise in understanding the development of broadly neutralizing antibody lineages (bNAbs). However, the mutational process that generates these lineages, somatic hypermutation, is biased by hotspot motifs which violates important assumptions in most phylogenetic substitution models. Here, we develop a modified GY94-type substitution model that partially accounts for this context dependency while preserving independence of sites during calculation. This model shows a substantially better fit to three well-characterized bNAb lineages than the standard GY94 model. We also demonstrate how our model can be used to test hypotheses concerning the roles of different hotspot and coldspot motifs in the evolution of B-cell lineages. Further, we explore the consequences of the idea that the number of hotspot motifs, and perhaps the mutation rate in general, is expected to decay over time in individual bNAb lineages.


Application of laser spectroscopy for measurement of exhaled ethane in patients with lung cancer.
There is increasing interest in ethane (C(2)H(6)) in exhaled breath as a non-invasive marker of oxidative stress (OS) and thereby a potential indicator of disease. However, the lack of real-time measurement techniques has limited progress in the field. Here we report on a novel Tunable Diode Laser Spectrometer (TDLS) applied to the analysis of exhaled ethane in patients with lung cancer. The patient group (n=52) comprised randomly selected patients presenting at a respiratory clinic. Of these, a sub-group (n=12) was subsequently diagnosed with lung cancer. An age-matched group (n=12) corresponding to the lung cancer group was taken from a larger control group of healthy adults (n=58). The concentration of ethane in a single exhaled breath sample collected from all subjects was later measured using the TDLS. This technique is capable of real-time analysis of samples with accuracy 0.1 parts per billion (ppb), over 10 times less than typical ambient levels in the northern hemisphere. After correcting for ambient background, ethane in the control group (26% smokers) ranged from 0 to 10.54 ppb (median of 1.9 ppb) while ethane in the lung cancer patients (42% smokers) ranged from 0 to 7.6 ppb (median of 0.7 ppb). Ethane among the non-lung cancer patients presenting for investigation of respiratory disease ranged from 0 to 25 ppb (median 1.45 ppb). We conclude that, while the TDLS proved effective for accurate and rapid sample analysis, there was no significant difference in exhaled ethane among any of the subject groups. Comments are made on the suitability of the technique for monitoring applications.


Examining social capital in relation to sleep duration, insomnia, and daytime sleepiness.
Sleep, which plays an important role in health and well-being, is socially patterned such that certain demographic groups have worse sleep health than others. One possible mechanism driving sleep disparities is social capital. The current study examines the association between social capital and self-reported sleep variables (eg, duration, insomnia symptoms, and daytime sleepiness) among a sample of 1007 participants from the Sleep Health and Activity, Diet and Environment Study (SHADES). Logistic regressions were used to estimate whether the sleep variables were associated with social capital measures. All models control for age, sex, race/ethnicity (Non-Hispanic White, Black/African-American, Hispanic/Latino, Asian, and multicultural/other), income, and education (less than high school, high school graduate, some college, and college graduate). Lower likelihood of membership in groups was seen for long sleepers (>9hrs, p-value<0.05) and beliefs that neighbors rarely/never help each other was more likely among short sleepers (5-6hrs, p-value<0.05), relative to 7-8 h sleepers. A decreased sense of belonging was seen among short sleepers (5-6hrs, p-value<0.05). Decreased likelihood of trust was reported by those with moderate-severe insomnia (p-value<0.05). Similarly, neighborhood improvement efforts were less likely among individuals with moderate-to-severe insomnia (p-value<0.05). Results of our study show that short and long sleep duration, as well as insomnia, were inversely related to measures of social capital, such as group memberships and a sense of neighborhood belonging. Future research may explore the directionality of the relationship between social capital and sleep and perhaps consider future interventions to improve low social capital and/or poor sleep in community samples.


Sleep disturbance in women who undergo surgical menopause compared with women who experience natural menopause.
Women who undergo surgical menopause (SM) experience a relatively more acute and precipitous drop of estrogen compared with women who experience natural menopause (NM). Few studies, however, have compared sleep quality in women who experience natural versus SM. Participants were 526 postmenopausal women (mean age 60.2 ± 7.64). All participants completed self-report questionnaires about insomnia symptoms, sleep-interfering behaviors, depression, sleep quality, and gynecological history. Analysis of covariance was conducted to compare women who experienced NM versus SM on sleep variables. Logistic regression analysis was used to determine whether NM or SM groups predicted insomnia status. Regression-based moderation analysis was conducted to explore the moderating effect of type of menopause on the relationship between sleep-interfering behaviors and insomnia symptoms. Among the sample, 81.6% (n = 429) reported going through NM and 18.4% (n = 97) reported going through SM. The SM group was significantly younger by 7.2 years (P < 0.001). Women in the SM group reported significantly worse sleep quality (P = 0.007), especially for sleep duration (P = 0.001) and habitual sleep efficiency (P = 0.010) compared with women in the NM group. Regression analysis indicated that individuals in the SM group were 2.131 (95% CI 1.055-4.303) times more likely to have insomnia compared with the NM group (P = 0.027). In addition, women in the SM group who displayed more sleep-interfering behaviors also had a higher severity of insomnia symptoms compared with women who experience NM (ß = 0.26, P = 0.03). Menopause can be both physically and psychologically challenging, but women who undergo SM experience worse sleep quality compared with women who experience NM, and may benefit from behavioral interventions.


Getting patients to their lipid targets: a practical approach to implementing therapeutic lifestyle changes.
Improving clinical outcomes in patients at high risk for coronary heart disease (CHD) requires a multimodal approach, especially in patients with the metabolic risk factors that constitute the metabolic syndrome, which is associated with an elevated risk of CHD at all levels of low-density lipoprotein cholesterol (LDL-C). Achieving optimal clinical outcomes requires a comprehensive and aggressive therapeutic plan that includes pharmacotherapy and lifestyle changes. Effective pharmacotherapy for components of the metabolic syndrome (eg, hypertension, elevated LDL-C levels, prothrombotic state) is important in improving clinical outcomes, as is pharmacotherapy for glycemic control in patients with diabetes. Therapeutic lifestyle changes recommended for treatment of metabolic syndrome include smoking cessation, exercise programs, nutritional counseling, and weight control. Patient questionnaires are an effective way to help tailor recommendations to individual patients and thereby increase compliance. Clinicians can also help motivate patients by offering practical tips for modifying diet and eating habits and explaining all the benefits of exercise. These combined approaches can be used to help more patients achieve their lipid goals, and new pharmacologic therapies currently under investigation may further expand available treatment options.


Long-term depression at parallel fiber to Golgi cell synapses.
Golgi cells (GoCs) are the primary inhibitory interneurons of the granular layer of the cerebellum. Their inhibition of granule cells is central to operate the relay of excitatory inputs to the cerebellar cortex. Parallel fibers (PFs) establish synapses to the GoCs in the molecular layer; these synapses contain AMPA, N-methyl-D-aspartate (NMDA), and mostly group II metabotropic glutamate receptors. Long-term changes in the efficacy of synaptic transmission at the PF-GoC synapse have not been described previously. We used whole cell patch-clamp recordings of GoCs in acute rat cerebellar slices to study synaptic plasticity. We report that high-frequency burst stimulation of PFs, using a current-clamp or voltage-clamp induction protocol, gave rise to long-term depression (LTD) at the PF-GoC synapse. This form of LTD was not associated with persistent changes of paired-pulse ratio, suggesting a postsynaptic origin. Furthermore, LTD induction was not dependent on activation of NMDA receptors. PF-GoC LTD does require activation of specifically group II metabotropic glutamate receptors and of protein kinase A.


[Family Health Support Centers: challenges and opportunities from the perspective of primary care professionals in the city of São Paulo, Brazil].
Family Health Support Centers (NASF) were created in Brazil to increase the case-resolution capacity of primary healthcare. Prior to their implementation in the West Side of the city of São Paulo, Brazil, a series of workshops were held for primary healthcare professionals to prepare a proposal for such centers. Hermeneutic analysis was used to study the transcribed material. The thematic categories were: role, constitution, and functioning of the NASF, relationship with family health teams, and interdisciplinarity. The participants' expected the NASF to be an empowering device for comprehensiveness of care, intervening in an existing culture of unnecessary referrals while fostering linkage with other levels of care. The participants also expected the NASF to contribute to the discussion on health professionals' training and stimulating reflection with policymakers on health indicators based exclusively on the number of consultations. These indicators fail to reflect the impact on the services' activities and the quality of care offered to the population in the coverage area.


Serum IgG subclass antibodies to a variety of food antigens in patients with coeliac disease.
Levels of serum IgA, IgG, and IgG subclass antibodies to a variety of dietary antigens were determined by enzyme linked immunosorbent assays in 14 adults with untreated coeliac disease and in 10 disease controls selected because of raised total IgG activities. The untreated coeliacs showed somewhat higher total IgG activity (p approximately 0.05) and significantly raised IgA and IgG1 + IgG3 activities to gliadin but reduced IgG4 activity (p less than 0.02) compared with the controls. High IgA and IgG1 + IgG3 activities were positively correlated (r = 0.67, p less than 0.01), and so were IgG and IgG4 activities (r = 0.64, p less than 0.02). Conversely, a high IgG2 response to gliadin appeared related to a low IgA response (r = 0.55, p less than 0.05). The IgG2 response was most prominent to oat flour antigens, followed by IgG1; and the main response to soy antigens resided in IgG1, followed by IgG2 in both disease groups. There was no difference in antibody activities to oat and soy between the two groups, and raised activity to bovine serum albumin was seldom encountered. The IgA activity to alpha-lactalbumin and ovalbumin tended to be increased in the coeliacs compared with the controls. The IgG4 subclass dominated the IgG response to beta-lactoglobulin and ovalbumin and was often raised to alpha-lactalbumin, especially in the disease controls. The IgG subclass pattern to casein parallelled that to gliadin with dominance of the IgG1- and IgG3-subclass activities, especially in the coeliacs. The phlogistic potential of a response in these two subclasses might be relevant to the pathogenesis of coeliac disease and could contribute to a raised IgA gliadin response by increasing mucosal permeability. IgA activity seemed to be highest against antigens usually involved in IgE mediated food allergy.


Strategy for surveying the proteome using affinity proteomics and mass spectrometry.
Antibody-based microarrays is a rapidly evolving technology that has gone from the first proof-of-concept studies to more demanding proteome profiling applications, during the last years. Miniaturized microarrays can be printed with large number of antibodies harbouring predetermined specificities, capable of targeting high- as well as low-abundant analytes in complex, nonfractionated proteomes. Consequently, the resolution of such proteome profiling efforts correlate directly to the number of antibodies included, which today is a key limiting factor. To overcome this bottleneck and to be able to perform in-depth global proteome surveys, we propose to interface affinity proteomics with MS-based read-out, as outlined in this technical perspective. Briefly, we have defined a range of peptide motifs, each motif being present in 5-100 different proteins. In this manner, 100 antibodies, binding 100 different motifs commonly distributed among different proteins, would potentially target a protein cluster of 10(4) individual molecules, i.e. around 50% of the nonredundant human proteome. Notably, these motif-specific antibodies would be directly applicable to any proteome in a specie independent manner and not biased towards abundant proteins or certain protein classes. The biological sample is digested, exposed to these immobilized antibodies, whereby motif-containing peptides are specifically captured, enriched and subsequently detected and identified using MS.


Utilisation of postnatal care among rural women in Nepal.
Postnatal care is uncommon in Nepal, and where it is available the quality is often poor. Adequate utilisation of postnatal care can help reduce mortality and morbidity among mothers and their babies. Therefore, our study assessed the utilisation of postnatal care at a rural community level. A descriptive, cross-sectional study was carried out in two neighbouring villages in early 2006. A total of 150 women who had delivered in the previous 24 months were asked to participate in the study using a semi-structured questionnaire. The proportion of women who had received postnatal care after delivery was low (34%). Less than one in five women (19%) received care within 48 hours of giving birth. Women in one village had less access to postnatal care than women in the neighbouring one. Lack of awareness was the main barrier to the utilisation of postnatal care. The woman's own occupation and ethnicity, the number of pregnancies and children and the husband's socio-economic status, occupation and education were significantly associated with the utilisation of postnatal care. Multivariate analysis showed that wealth as reflected in occupation and having attended antenatal are important factors associated with the uptake of postnatal care. In addition, women experiencing health problems appear strongly motivated to seek postnatal care. The postnatal care has a low uptake and is often regarded as inadequate in Nepal. This is an important message to both service providers and health-policy makers. Therefore, there is an urgent need to assess the actual quality of postnatal care provided. Also there appears to be a need for awareness-raising programmes highlighting the availability of current postnatal care where this is of sufficient quality.


Microneedle-mediated immunization of an adenovirus-based malaria vaccine enhances antigen-specific antibody immunity and reduces anti-vector responses compared to the intradermal route.
Substantial effort has been placed in developing efficacious recombinant attenuated adenovirus-based vaccines. However induction of immunity to the vector is a significant obstacle to its repeated use. Here we demonstrate that skin-based delivery of an adenovirus-based malaria vaccine, HAdV5-PyMSP1₄₂, to mice using silicon microneedles induces equivalent or enhanced antibody responses to the encoded antigen, however it results in decreased anti-vector responses, compared to intradermal delivery. Microneedle-mediated vaccine priming and resultant induction of low anti-vector antibody titres permitted repeated use of the same adenovirus vaccine vector. This resulted in significantly increased antigen-specific antibody responses in these mice compared to ID-treated mice. Boosting with a heterologous vaccine; MVA-PyMSP1₄₂ also resulted in significantly greater antibody responses in mice primed with HAdV5-PyMSP1₄₂ using MN compared to the ID route. The highest protection against blood-stage malaria challenge was observed when a heterologous route of immunization (MN/ID) was used. Therefore, microneedle-mediated immunization has potential to both overcome some of the logistic obstacles surrounding needle-and-syringe-based immunization as well as to facilitate the repeated use of the same adenovirus vaccine thereby potentially reducing manufacturing costs of multiple vaccines. This could have important benefits in the clinical ease of use of adenovirus-based immunization strategies.


[Assessment of comorbidity in autism spectrum disorders].
It is often difficult to determine whether there is psychiatric comorbidity in addition to an autism spectrum disorder (ASD) or whether the observed behavior is described adequately by the ASD diagnosis. To show when the possibility of comorbidity needs to be seriously considered in children and adults with ASD. We will focus on the most common comorbid disorders in children and adults with ASD, namely anxiety, depression and ADHD. Discussion of the literature and clinical experiences. In order to diagnose ASD and comorbidities it is important to record a detailed developmental history. This can also serve as a baseline for the client's behaviour. Changes in the pattern of behaviour with respect to the baseline can often be indicative of the presence of a comorbid disorder. Since ASD is a life long disorder and comorbidity needing treatment or interventions can be present during various phases of life, the diagnostic procedure needs to continue even after ASD has been diagnosed.


Pillars and Pitfalls of the New Pharmacovigilance Legislation: Consequences for the Identification of Adverse Drug Reactions Deriving From Abuse, Misuse, Overdose, Occupational Exposure, and Medication Errors.
Rationale: The aim of this study is to investigate if following the implementation of the Regulation EU/1235/2010 and the Directive 2010/84/EU there was an increase of individual case safety reports (ICSRs) deriving from a medication error, abuse, misuse, overdose, or occupational exposure. Other objectives are the identification of drugs mostly involved in such cases, to establish if the codification of aforementioned conditions is performed correctly and, whenever codification errors exist, to identify predictors of codification errors. Finally, we estimated the magnitude of these errors on signal detection activities. Methods: ICSRs sent through Campania Region (Italy) spontaneous reporting system from July 2nd 2012 to December 31th 2017 were used as data source. A multivariable logistic regression model was used to identify predictors of codification errors. Four measures of disproportionality were used to investigate the magnitude of codification errors on a known safety signal or rather the association between benzodiazepines derivatives and abuse. Results: In all, 358 (1.4%) out of 25610 ICSRs reported "non-normal use" of drugs, mainly as cases of abuse. Drugs mostly involved in abuse were "Benzodiazepines derivatives" (171/358; 47.8%). For medication errors instead, "Other antiseptics and disinfectants" (9/358; 2.5%). At the first quality control, 125 (34.9%) out of 358 ICSRs did not have a codification of "non-normal use" or codifications were performed wrongly. Codification errors included misclassification of abuse as overdose (10/125; 8.0%) and misclassification of medication error as overdose (7/125; 5.6%) or abuse (7/125; 5.6%). Compared to pharmaceutical companies, patients/citizens (as reporters) had a 24.88 higher odd (Reporting Odds Ratio 24.88, 95%CI 1.82-449.95; p-value: 0.02) of performing un-classification or misclassification of aforementioned codifications. Codification errors were associated with the underestimation of measure of disproportionality' estimates in the identification of the safety signal "Benzodiazepine derivatives /abuse". Conclusion: In conclusion, this study found that in Campania Region (southern Italy) there was an exponential increase of ICSR reporting "non-normal use," mainly as cases of abuse, with an improvable proportion of cases misclassified/unclassified. Moreover, this study found that ICSRs sent by patients/citizens were associated with an increased odd of un-classification or misclassification that had a relevant impact on signal detection activities.


Chaos and language.
Human language is a complex communication system with unlimited expressibility. Children spontaneously develop a native language by exposure to linguistic data from their speech community. Over historical time, languages change dramatically and unpredictably by accumulation of small changes and by interaction with other languages. We have previously developed a mathematical model for the acquisition and evolution of language in heterogeneous populations of speakers. This model is based on game dynamical equations with learning. Here, we show that simple examples of such equations can display complex limit cycles and chaos. Hence, language dynamical equations mimic complicated and unpredictable changes of languages over time. In terms of evolutionary game theory, we note that imperfect learning can induce chaotic switching among strict Nash equilibria.


Apple intake is inversely associated with all-cause and disease-specific mortality in elderly women.
Higher fruit intake is associated with lower risk of all-cause and disease-specific mortality. However, data on individual fruits are limited, and the generalisability of these findings to the elderly remains uncertain. The objective of this study was to examine the association of apple intake with all-cause and disease-specific mortality over 15 years in a cohort of women aged over 70 years. Secondary analyses explored relationships of other fruits with mortality outcomes. Usual fruit intake was assessed in 1456 women using a FFQ. Incidence of all-cause and disease-specific mortality over 15 years was determined through the Western Australian Hospital Morbidity Data system. Cox regression was used to determine the hazard ratios (HR) for mortality. During 15 years of follow-up, 607 (41·7%) women died from any cause. In the multivariable-adjusted analysis, the HR for all-cause mortality was 0·89 (95% CI 0·81, 0·97) per sd (53 g/d) increase in apple intake, HR 0·80 (95% CI 0·65, 0·98) for consumption of 5-100 g/d and HR 0·65 (95% CI 0·48, 0·89) for consumption of >100 g/d (an apple a day), compared with apple intake of <5 g/d (P for trend=0·03). Our analysis also found that higher apple intake was associated with lower risk for cancer mortality, and that higher total fruit and banana intakes were associated lower risk of CVD mortality (P<0·05). Our results support the view that regular apple consumption may contribute to lower risk of mortality.


Excepftonally strong near-bottom flows on the continental rise of nova scotia.
Recent current velocity measurements across the lower continental rise of Nova Scotia show a deep equatorwardflow with speeds (maximum, 73 centimeters per second) among the highest recorded for the deep sea. Silicate measurements indicate that this flow usually consists of southern-source (Antarctic) bottom water. These measurements confirm the existence of a second and deeper western boundary flow that was earlier inferredfrom geological observations.


The balancing act of the liver: tissue regeneration versus fibrosis.
Epithelial cell loss alters a tissue's optimal function and awakens evolutionarily adapted healing mechanisms to reestablish homeostasis. Although adult mammalian organs have a limited regeneration potential, the liver stands out as one remarkable exception. Following injury, the liver mounts a dynamic multicellular response wherein stromal cells are activated in situ and/or recruited from the bloodstream, the extracellular matrix (ECM) is remodeled, and epithelial cells expand to replenish their lost numbers. Chronic damage makes this response persistent instead of transient, tipping the system into an abnormal steady state known as fibrosis, in which ECM accumulates excessively and tissue function degenerates. Here we explore the cellular and molecular switches that balance hepatic regeneration and fibrosis, with a focus on uncovering avenues of disease modeling and therapeutic intervention.


On the Perception of Newcomers: Toward an Evolved Psychology of Intergenerational Coalitions.
Human coalitions frequently persist through multiple, overlapping membership generations, requiring new members to cooperate and coordinate with veteran members. Does the mind contain psychological adaptations for interacting within these intergenerational coalitions? In this paper, we examine whether the mind spontaneously treats newcomers as a motivationally privileged category. Newcomers-though capable of benefiting coalitions-may also impose considerable costs (e.g., they may free ride on other members, they may be poor at completing group tasks). In three experiments we show (1) that the mind categorizes coalition members by tenure, including newcomers; (2) that tenure categorization persists in the presence of orthogonal and salient social dimensions; and (3) that newcomers elicit a pattern of impressions consistent with their probable ancestral costs. These results provide preliminary evidence for a specialized component of human coalitional psychology: an evolved concept of newcomer.


Parasympathetic withdrawal increases heart rate after 2 weeks at 3454 m altitude.
Heart rate is increased in chronic hypoxia and we tested whether this is the result of increased sympathetic nervous activity, reduced parasympathetic nervous activity, or a non-autonomic mechanism. In seven lowlanders, heart rate was measured at sea level and after 2 weeks at high altitude after individual and combined pharmacological inhibition of sympathetic and/or parasympathetic control of the heart. Inhibition of parasympathetic control of the heart alone or in combination with inhibition of sympathetic control abolished the high altitude-induced increase in heart rate. Inhibition of sympathetic control of the heart alone did not prevent the high altitude-induced increase in heart rate. These results indicate that a reduced parasympathetic nervous activity is the main mechanism underlying the elevated heart rate in chronic hypoxia. Chronic hypoxia increases resting heart rate (HR), but the underlying mechanism remains incompletely understood. We investigated the relative contributions of the sympathetic and parasympathetic nervous systems, along with potential non-autonomic mechanisms, by individual and combined pharmacological inhibition of muscarinic and/or β-adrenergic receptors. In seven healthy lowlanders, resting HR was determined at sea level (SL) and after 15-18 days of exposure to 3454 m high altitude (HA) without drug intervention (control, CONT) as well as after intravenous administration of either propranolol (PROP), or glycopyrrolate (GLYC), or PROP and GLYC in combination (PROP+GLYC). Circulating noradrenaline concentration increased from 0.9 ± 0.4 nmol l-1 at SL to 2.7 ± 1.5 nmol l-1 at HA (P = 0.03). The effect of HA on HR depended on the type of autonomic inhibition (P = 0.006). Specifically, HR was increased at HA from 64 ± 10 to 74 ± 12 beats min-1 during the CONT treatment (P = 0.007) and from 52 ± 4 to 59 ± 5 beats min-1 during the PROP treatment (P < 0.001). In contrast, HR was similar between SL and HA during the GLYC treatment (110 ± 7 and 112 ± 5 beats min-1 , P = 0.28) and PROP+GLYC treatment (83 ± 5 and 85 ± 5 beats min-1 , P = 0.25). Our results identify a reduction in cardiac parasympathetic activity as the primary mechanism underlying the elevated HR associated with 2 weeks of exposure to hypoxia. Unexpectedly, the sympathoactivation at HA that was evidenced by increased circulating noradrenaline concentration had little effect on HR, potentially reflecting down-regulation of cardiac β-adrenergic receptor function in chronic hypoxia. These effects of chronic hypoxia on autonomic control of the heart may concern not only HA dwellers, but also patients with disorders that are associated with hypoxaemia.


Information Retrieval and Text Mining Technologies for Chemistry.
Efficient access to chemical information contained in scientific literature, patents, technical reports, or the web is a pressing need shared by researchers and patent attorneys from different chemical disciplines. Retrieval of important chemical information in most cases starts with finding relevant documents for a particular chemical compound or family. Targeted retrieval of chemical documents is closely connected to the automatic recognition of chemical entities in the text, which commonly involves the extraction of the entire list of chemicals mentioned in a document, including any associated information. In this Review, we provide a comprehensive and in-depth description of fundamental concepts, technical implementations, and current technologies for meeting these information demands. A strong focus is placed on community challenges addressing systems performance, more particularly CHEMDNER and CHEMDNER patents tasks of BioCreative IV and V, respectively. Considering the growing interest in the construction of automatically annotated chemical knowledge bases that integrate chemical information and biological data, cheminformatics approaches for mapping the extracted chemical names into chemical structures and their subsequent annotation together with text mining applications for linking chemistry with biological information are also presented. Finally, future trends and current challenges are highlighted as a roadmap proposal for research in this emerging field.


Changing patterns of cancer incidence in the early- and late-HAART periods: the Swiss HIV Cohort Study.
The advent of highly active antiretroviral therapy (HAART) in 1996 led to a decrease in the incidence of Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma (NHL), but not of other cancers, among people with HIV or AIDS (PWHA). It also led to marked increases in their life expectancy. We conducted a record-linkage study between the Swiss HIV Cohort Study and nine Swiss cantonal cancer registries. In total, 9429 PWHA provided 20,615, 17,690, and 15,410 person-years in the pre-, early-, and late-HAART periods, respectively. Standardised incidence ratios in PWHA vs the general population, as well as age-standardised, and age-specific incidence rates were computed for different periods. Incidence of KS and NHL decreased by several fold between the pre- and early-HAART periods, and additionally declined from the early- to the late-HAART period. Incidence of cancers of the anus, liver, non-melanomatous skin, and Hodgkin's lymphoma increased in the early- compared with the pre-HAART period, but not during the late-HAART period. The incidence of all non-AIDS-defining cancers (NADCs) combined was similar in all periods, and approximately double that in the general population. Increases in the incidence of selected NADCs after the introduction of HAART were largely accounted for by the ageing of PWHA.


In situ study of the thermal stability of supported Pt nanoparticles and their stabilization via atomic layer deposition overcoating.
Downscaling of supported Pt structures to the nanoscale is motivated by the augmentation of the catalytic activity and selectivity, which depend on the particle size, shape and coverage. Harsh thermal and chemical conditions generally required for catalytic applications entail an undesirable particle coarsening, and consequently limit the catalyst lifetime. Herein we report an in situ synchrotron study on the stability of supported Pt nanoparticles and their stabilization using atomic layer deposition (ALD) as the stabilizing methodology against particle coarsening. Pt nanoparticles were thermally annealed up to 850 °C in an oxidizing environment while recording in situ synchrotron grazing incidence small angle X-ray scattering (GISAXS) 2D patterns, thereby obtaining continuous information about the particle radius evolution. Al2O3 overcoat as a protective capping layer against coarsening via ALD was investigated. In situ data proved that only 1 cycle of Al2O3 ALD caused an augmentation of the onset temperature for particle coarsening. Moreover, the results showed a dependence of the required overcoat thickness on the initial particle size and distribution, being more efficient (i.e. requiring lower thicknesses) when isolated particles are present on the sample surface. The Pt surface accessibility, which is decisive in catalytic applications, was analyzed using the low energy ion scattering (LEIS) technique, revealing a larger Pt surface accessibility for a sample with Al2O3 overcoat than for a sample without a protective layer after a long-term isothermal annealing.


Removal of dental amalgam decreases anti-TPO and anti-Tg autoantibodies in patients with autoimmune thyroiditis.
The impact of dental amalgam removal on the levels of anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies was studied in patients with autoimmune thyroiditis (AT) with and without mercury allergy. Thirty-nine patients with AT were tested by an optimized lymphocyte proliferation test MELISA for allergy (hypersensitivity) to inorganic mercury. Patients were divided into two groups: Group I (n = 12) with no hypersensitivity to mercury and Group II (n = 27) with hypersensitivity to mercury. Amalgam fillings were removed from the oral cavities of 15 patients with hypersensitivity to mercury (Group IIA) and left in place in the remaining 12 patients (Group IIB). The laboratory markers of AT, anti-TPO and anti-Tg autoantibodies, were determined in all groups at the beginning of the study and six months later. Compared to levels at the beginning of the study, only patients with mercury hypersensitivity who underwent amalgam replacement (Group IIA) showed a significant decrease in the levels of both anti-Tg (p=0.001) and anti-TPO (p=0.0007) autoantibodies. The levels of autoantibodies in patients with or without mercury hypersensitivity (Group I and Group IIB) who did not replace amalgam did not change. Removal of mercury-containing dental amalgam in patients with mercury hypersensitivity may contribute to successful treatment of autoimmune thyroiditis.


Persistent pulmonary hypertension of the newborn.
Failure of the normal circulatory adaptation to extrauterine life results in persistent pulmonary hypertension of the newborn (PPHN). Although this condition is most often secondary to parenchymal lung disease or lung hypoplasia, it may also be idiopathic. PPHN is characterized by elevated pulmonary vascular resistance with resultant right-to-left shunting of blood and hypoxemia. Although the preliminary diagnosis of PPHN is often based on differential cyanosis and labile hypoxemia, the diagnosis is confirmed by echocardiography. Management strategies include optimal lung recruitment and use of surfactant in patients with parenchymal lung disease, maintaining optimal oxygenation and stable blood pressures, avoidance of respiratory and metabolic acidosis and alkalosis, and pulmonary vasodilator therapy. Extracorporeal membrane oxygenation is considered when medical management fails. Although mortality associated with PPHN has decreased significantly with improvements in medical care, there remains the potential risk for neurodevelopmental disability which warrants close follow-up of affected infants after discharge.


Coccidioidomycosis in liver transplant recipients in an endemic area.
Coccidioidomycosis is an infection caused by Coccidioides species, which are endemic for the Southwestern United States and parts of Central America and South America. Most infected individuals are asymptomatic or have mild-to-moderate respiratory illness. Coccidioidomycosis is more severe in patients with depressed cellular immunity, such as organ transplant recipients. We retrospectively reviewed charts of 391 liver transplant recipients (mean follow-up, 38.7 months; range, 2-105 months). Before transplantation, 12 patients had a history of coccidioidomycosis and 13 patients had asymptomatic seropositivity. Of these 25 patients, 23 had no active coccidioidomycosis posttransplantation and 2 had reactivated infection. One of 5 patients with indeterminate serology before transplantation died of disseminated coccidioidomycosis shortly after transplantation. De novo coccidioidomycosis developed in 12 patients (3%) who had no evidence of coccidioidomycosis pretransplantation. Of 15 total episodes of posttransplantation coccidioidomycosis, 10 (66%) occurred during the first year. Dissemination was noted in 33% of active coccidioidomycosis after transplantation; two patients (13%) died of coccidioidomycosis. Because most coccidioidal infections occurred in the first posttransplantation year despite targeted antifungal prophylaxis, we recommend a new strategy of universal antifungal prophylaxis for 6-12 months for liver transplant recipients who reside in the endemic area.


Effects of Rag1 on the preference and performance of soybean defoliators.
The Rag1 gene confers antibiotic resistance to soybean aphid, Aphis glycines Matsumura (Hemiptera: Aphididae), and in 2010, varieties expressing Rag1 were released for commercial use in the United States. We do not know how Rag1 varieties will influence the broader community of defoliating insects that inhabit soybean fields. In 2010 and 2011, the preference and performance of pest insects that defoliate soybeans [Glycines max (L.) Merr] were tested using Rag1 and aphid-susceptible varieties. Three coleopterans and four lepidopterans were used: northern corn rootworm, Diabrotica barberi Smith & Lawrence (Coleoptera: Chrysomelidae); southern corn rootworm, Diabrotica undecimpunctata howardi Barber (Coleoptera: Chrysomelidae); bean leaf beetle, Ceratoma trsifurcata Förster (Coleoptera: Chrysomelidae); fall armyworm, Spodoptera frugiperda (J. E. Smith) (Lepidoptera: Noctuidae); corn earworm, Helicoverpa zea (Boddie) (Lepidoptera: Noctuidae); soybean looper, Chrysodeix includens (Walker) (Lepidoptera: Noctuidae); and velvet-bean caterpillar, Anticarsia gemmatalis Hübner (Lepidoptera: Noctuidae). The preference of insects was evaluated in choice and no-choice tests using Rag1 and susceptible soybeans. Lepidopterans also were evaluated on Rag1 leaves using four nutritional indices: relative growth rate, approximate digestibility, and efficiency of conversion of ingested material. In the majority of preference tests, no effect of Rag1 was detected, and in cases where preferences were found, there was no consistent pattern of preference for Rag1 vs. susceptible leaf tissue. Helicoverpa zea demonstrated a preference for resistant leaf tissue, but this was dependent on the genetic background of the variety. Evaluations of nutritional indices indicated that three species of Lepidoptera, S. frugiperda, H. zea, and A. gemmatalis, displayed reduced conversion efficiency for Rag1 soybeans, suggesting effects of antibiosis.


Frequency and Complexity of De Novo Structural Mutation in Autism.
Genetic studies of autism spectrum disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variants (SVs) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping, and de novo assembly to genome sequencing of 235 subjects (71 affected individuals, 26 healthy siblings, and their parents), we compiled an atlas of 29,719 SV loci (5,213/genome), comprising 11 different classes. We found a high diversity of de novo mutations, the majority of which were undetectable by previous methods. In addition, we observed complex mutation clusters where combinations of de novo SVs, nucleotide substitutions, and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%) and propose that genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs, but not an elevated rate of genome rearrangement.


Retrieval and classification of dental research articles.
Successful retrieval of a corpus of literature on a broad topic can be difficult. This study demonstrates a method to retrieve the dental and craniofacial research literature. We explored MeSH manually for dental or craniofacial indexing terms. MEDLINE was searched using these terms, and a random sample of references was extracted from the resulting set. Sixteen dental research experts categorized these articles, reading only the title and abstract, as either: (1) dental research, (2) dental non-research, (3) non-dental, or (4) not sure. Identify Patient Sets (IPS), a probabilistic text classifier, created models, based on the presence or absence of words or UMLS phrases, that distinguished dental research articles from all others. These models were applied to a test set with different inputs for each article: (1) title and abstract only, (2) MeSH terms only, or (3) both. By title and abstract only, IPS correctly classified 64% of all dental research articles present in the test set. The percentage of correctly classified dental research articles in this retrieved set was 71%. MeSH term inclusion decreased performance. Computer programs that use text input to categorize articles may aid in retrieval of a broad corpus of literature better than indexing terms or key words alone.