Dural arteriovenous malformation of the major venous sinuses: an acquired lesion.
Arteriovenous malformations of the dura are thought to be congenital. However, arteriographic investigations of four patients who, after a head injury, developed dural arteriovenous fistulae with features of congenital malformations suggest that these abnormal communications may also be acquired. Thrombosis or thrombophlebitis in the dural sinus or vein may be the primary event in their formation. The pathogenesis is probably "growth" of the dural arteries normally present in the walls of the sinuses during the organization of an intraluminal thrombus. This may result in a direct communication between artery and vein or sinus, establishing an abnormal shunt. Ultimate fibrosis of the sinus wall and intraluminal thrombus may be the factors responsible for the spontaneous disappearance of such malformations.


Prognostic Value of Noninvasive Cardiovascular Testing in Patients With Stable Chest Pain: Insights From the PROMISE Trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain).
Optimal management of patients with stable chest pain relies on the prognostic information provided by noninvasive cardiovascular testing, but there are limited data from randomized trials comparing anatomic with functional testing. In the PROMISE trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain), patients with stable chest pain and intermediate pretest probability for obstructive coronary artery disease (CAD) were randomly assigned to functional testing (exercise electrocardiography, nuclear stress, or stress echocardiography) or coronary computed tomography angiography (CTA). Site-based diagnostic test reports were classified as normal or mildly, moderately, or severely abnormal. The primary end point was death, myocardial infarction, or unstable angina hospitalizations over a median follow-up of 26.1 months. Both the prevalence of normal test results and incidence rate of events in these patients were significantly lower among 4500 patients randomly assigned to CTA in comparison with 4602 patients randomly assigned to functional testing (33.4% versus 78.0%, and 0.9% versus 2.1%, respectively; both P<0.001). In CTA, 54.0% of events (n=74/137) occurred in patients with nonobstructive CAD (1%-69% stenosis). Prevalence of obstructive CAD and myocardial ischemia was low (11.9% versus 12.7%, respectively), with both findings having similar prognostic value (hazard ratio, 3.74; 95% confidence interval [CI], 2.60-5.39; and 3.47; 95% CI, 2.42-4.99). When test findings were stratified as mildly, moderately, or severely abnormal, hazard ratios for events in comparison with normal tests increased proportionally for CTA (2.94, 7.67, 10.13; all P<0.001) but not for corresponding functional testing categories (0.94 [P=0.87], 2.65 [P=0.001], 3.88 [P<0.001]). The discriminatory ability of CTA in predicting events was significantly better than functional testing (c-index, 0.72; 95% CI, 0.68-0.76 versus 0.64; 95% CI, 0.59-0.69; P=0.04). If 2714 patients with at least an intermediate Framingham Risk Score (>10%) who had a normal functional test were reclassified as being mildly abnormal, the discriminatory capacity improved to 0.69 (95% CI, 0.64-0.74). Coronary CTA, by identifying patients at risk because of nonobstructive CAD, provides better prognostic information than functional testing in contemporary patients who have stable chest pain with a low burden of obstructive CAD, myocardial ischemia, and events. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01174550.


Pre-breeding energetic management in a mixed-strategy breeder.
Integrative biologists have long appreciated that the effective acquisition and management of energy prior to breeding should strongly influence fitness-related reproductive decisions (timing of breeding and reproductive investment). However, because of the difficulty in capturing pre-breeding individuals, and the tendency towards abandonment of reproduction after capture, we know little about the underlying mechanisms of these life-history decisions. Over 10 years, we captured free-living, arctic-breeding common eiders (Somateria mollissima) up to 3 weeks before investment in reproduction. We examined and characterized physiological parameters predicted to influence energetic management by sampling baseline plasma glucocorticoids (i.e., corticosterone), very-low-density lipoprotein (VLDL), and vitellogenin (VTG) for their respective roles in mediating energetic balance, rate of condition gain (physiological fattening rate) and reproductive investment. Baseline corticosterone increased significantly from arrival to the initiation of reproductive investment (period of rapid follicular growth; RFG), and showed a positive relationship with body mass, indicating that this hormone may stimulate foraging behaviour to facilitate both fat deposition and investment in egg production. In support of this, we found that VLDL increased throughout the pre-breeding period, peaking as predicted during RFG. Female eiders exhibited unprecedentedly high levels of VTG well before their theoretical RFG period, a potential strategy for pre-emptively depositing available protein stores into follicles while females are simultaneously fattening. This study provides some of the first data examining the temporal dynamics and interaction of the energetic mechanisms thought to be at the heart of individual variation in reproductive decisions and success in many vertebrate species.


Global taxonomic diversity of living reptiles.
Reptiles are one of the most ecologically and evolutionarily remarkable groups of living organisms, having successfully colonized most of the planet, including the oceans and some of the harshest and more environmentally unstable ecosystems on earth. Here, based on a complete dataset of all the world's diversity of living reptiles, we analyse lineage taxonomic richness both within and among clades, at different levels of the phylogenetic hierarchy. We also analyse the historical tendencies in the descriptions of new reptile species from Linnaeus to March 2012. Although (non-avian) reptiles are the second most species-rich group of amniotes after birds, most of their diversity (96.3%) is concentrated in squamates (59% lizards, 35% snakes, and 2% amphisbaenians). In strong contrast, turtles (3.4%), crocodilians (0.3%), and tuataras (0.01%) are far less diverse. In terms of species discoveries, most turtles and crocodilians were described early, while descriptions of lizards, snakes and amphisbaenians are multimodal with respect to time. Lizard descriptions, in particular, have reached unprecedented levels during the last decade. Finally, despite such remarkably asymmetric distributions of reptile taxonomic diversity among groups, we found that the distributions of lineage richness are consistently right-skewed, with most clades (monophyletic families and genera) containing few lineages (monophyletic genera and species, respectively), while only a few have radiated greatly (notably the families Colubridae and Scincidae, and the lizard genera Anolis and Liolaemus). Therefore, such consistency in the frequency distribution of richness among clades and among phylogenetic levels suggests that the nature of reptile biodiversity is fundamentally fractal (i.e., it is scale invariant). We then compared current reptile diversity with the global reptile diversity and taxonomy known in 1980. Despite substantial differences in the taxonomies (relative to 2012), the patterns of lineage richness remain qualitatively identical, hence reinforcing our conclusions about the fractal nature of reptile biodiversity.


Proteomics of human aqueous humor.
The aqueous humor is a colorless, transparent fluid that fills the anterior chamber of the eye. It plays an important role in maintaining the intraocular pressure and providing nourishment to the lens and cornea. The constitution of the aqueous humor is controlled by the blood-aqueous barrier. Though this ocular fluid has been extensively studied, its role in ocular physiology is still not completely understood. In this study, aqueous humor samples were collected from 250 patients undergoing cataract surgery, subjected to multiple fractionation strategies and analyzed on a Fourier transform LTQ-Orbitrap Velos mass spectrometer. In all, we identified 763 proteins, of which 386 have been identified for the first time in this study. Sorbitol dehydrogenase (SORD), filensin (BFSP1), and phakinin (BFSP2) are some of the proteins that have not been previously reported in the aqueous humor. Gene Ontology analysis revealed 35% of the identified proteins to be extracellular, with a majority of them involved in cell communication and signal transduction. This study comprehensively reports 386 novel proteins that have important potential as biomarker candidates for future research into personalized medicine and diagnostics aimed towards improving visual health.


Inorganic perovskite photocatalysts for solar energy utilization.
The development and utilization of solar energy in environmental remediation and water splitting is being intensively studied worldwide. During the past few decades, tremendous efforts have been devoted to developing non-toxic, low-cost, efficient and stable photocatalysts for water splitting and environmental remediation. To date, several hundreds of photocatalysts mainly based on metal oxides, sulfides and (oxy)nitrides with different structures and compositions have been reported. Among them, perovskite oxides and their derivatives (layered perovskite oxides) comprise a large family of semiconductor photocatalysts because of their structural simplicity and flexibility. This review specifically focuses on the general background of perovskite and its related materials, summarizes the recent development of perovskite photocatalysts and their applications in water splitting and environmental remediation, discusses the theoretical modelling and calculation of perovskite photocatalysts and presents the key challenges and perspectives on the research of perovskite photocatalysts.


CXCR4 positive and angiogenic monocytes in myocardial infarction.
Limited data are available on the role of monocytes in cardiac repair. In the present study, we evaluated the dynamic alterations of monocytes with reparative and angiogenic potential in patients with myocardial infarction(MI). Reparative CXCR4+ monocytes, and CD34+ and KDR+ monocytes with angiogenic potential derived from individual monocyte subsets were quantified by flow cytometry in patients with ST-elevation MI (n=50) and stable coronary artery disease (CAD, n=40). Parameters were measured on days 1, 3, 7 and 30 post MI. Monocyte subsets were defined as CD14++CD16-CCR2+ ('classical', Mon1), CD14++CD16+CCR2+ ('intermediate', Mon2), CD14+CD16++CCR2- ('non-classical', Mon3). Plasma levels of inflammatory cytokines, fibrinolytic factors and microparticles (MPs) were assessed on day 1. CXCR4+ and KDR+ monocytes were increased following MI, being more prominently associated with Mon2 (median[IQR] of CXCR4+ Mon2 60[25-126] per μl in STEMI vs. 27[21-41] per μl in stable CAD). The counts of CXCR4+ Mon2 in STEMI significantly reduced by day 30 of follow-up (27[18-47], p<0.001). Expression of the pro-reparative scavenger receptor CD163 on Mon3 was reduced in acute MI (p=0.008), and on other subsets later during the follow-up with lowest levels at day 3 post-MI (p<0.001 for Mon1, p=0.02 for Mon2). CD204 expression on Mon1 correlated with tissue type plasminogen activator levels (r=0.46, p=0.001). Interleukin(IL)6 levels correlated with counts of Mon2-derived CXCR4+ and KDR+ cells. Interleukin-1β correlated with KDR+ Mon2 counts. IL10 correlated with CXCR4+ Mon2 levels. Low count of CXCR4+ Mon2 and low CD163 expression by Mon2 were associated with higher ejection fraction six-weeks after MI. In conclusion, the Mon2 subset has the most prominent role in the observed changes in reparative monocytes in MI. The association of reparative monocytes with inflammatory/fibrinolytic markers indicates a complex interplay of these cells in the post-MI state.


Genetic control of branching morphogenesis.
The genetic programs that direct formation of the treelike branching structures of two animal organs have begun to be elucidated. In both the developing Drosophila tracheal (respiratory) system and mammalian lung, a fibroblast growth factor (FGF) signaling pathway is reiteratively used to pattern successive rounds of branching. The initial pattern of signaling appears to be established by early, more global embryonic patterning systems. The FGF pathway is then modified at each stage of branching by genetic feedback controls and other signals to give distinct branching outcomes. The reiterative use of a signaling pathway by both insects and mammals suggests a general scheme for patterning branching morphogenesis.


Representation of surface luminance and contrast in primary visual cortex.
In visual perception, object identification requires both the ability to define regions of uniform luminance and zones of luminance contrast. Neural processes underlying contrast detection have been well studied, while those defining luminance remain poorly understood and controversial. Partially because stimuli comprised of uniform luminance are relatively ineffective in driving responses of cortical neurons, little effort has been made to systematically compare responses of individual neurons to both uniform luminance and contrast. Using large static uniform luminance and contrast stimuli, modulated temporally in luminance or contrast, we found a continuum of responses ranging from a few cells modulated only by luminance (luminance-only), to many cells modulated by both luminance and contrast (luminance-contrast), and to many others modulated only by contrast (contrast-only) in primary visual cortex. Moreover, luminance-contrast cells had broader orientation tuning, larger receptive field (RF) and lower spatial frequency Preference, on average, than contrast-only cells. Contrast-only cells had contrast responses more linearly correlated to the spatial structure of their RFs than luminance-contrast cells. Taken together these results suggest that luminance and contrast are represented, to some degree, by independent mechanisms that may be shaped by different classes of subcortical and/or cortical inputs.


Fragmentation reactions using electrospray ionization mass spectrometry: an important tool for the structural elucidation and characterization of synthetic and natural products.
Over the last decade, the number of studies reporting the use of electrospray ionization mass spectrometry (ESI-MS) in combination with collision cells (or other activation methods) to promote fragmentation of synthetic and natural products for structural elucidation purposes has considerably increased. However, the lack of a systematic compilation of the gas-phase fragmentation reactions subjected to ESI-MS/MS conditions still represents a challenge and has led to many misunderstood results in the literature. This review article exploits the most common fragmentation reactions for ions generated by ESI in positive and negative modes using collision cells in an effort to stimulate the use of this technique by non-specialists, undergraduate students and researchers in related areas.


Down-regulation of types I, II and III inositol 1,4,5-trisphosphate receptors is mediated by the ubiquitin/proteasome pathway.
Activation of certain phosphoinositidase-C-linked cell-surface receptors is known to cause an acceleration of the proteolysis of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] receptors and, thus, lead to Ins(1,4,5)P3-receptor down-regulation. In the current study we have sought to determine whether the ubiquitin/proteasome pathway is involved in this adaptive response. The data presented show (i) that activation of phosphoinositidase-C-linked receptors causes Ins(1,4,5)P3-receptor ubiquitination in a range of cell types (AR4-2J cells, INS-1 cells and rat cerebellar granule cells), (ii) that the Ins(1,4,5)P3-receptor down-regulation induced by activation of these receptors is blocked by proteasome inhibitors, (iii) that all known Ins(1,4,5)P3 receptors (types I, II and III) are substrates for ubiquitination, (iv) that ubiquitination occurs while Ins(1,4,5)P3 receptors are membrane-bound, (v) that Ins(1,4, 5)P3-receptor ubiquitination and down-regulation are stimulated only by those agonists that elevate Ins(1,4,5)P3 concentration persistently, and (vi) that a portion of cellular Ins(1,4,5)P3 receptors (those that are not type-I-receptor-associated) can be resistant to ubiquitination and degradation. In total these data indicate that the ubiquitin/proteasome pathway mediates Ins(1,4, 5)P3-receptor down-regulation and suggest that ubiquitination is stimulated by the binding of Ins(1,4,5)P3 to its receptor.


Cognitive health expectancies of cardiovascular risk factors for cognitive decline and dementia.
Cognitive health expectancy estimates the proportion of the lifespan that is lived in good cognitive health at the population level. A number of cardiovascular diseases have been identified to be risk factors for cognitive decline and dementia including diabetes, stroke, heart diseases and hypertension. The aim of this study was to examine how these cardiovascular conditions relate to cognitive health expectancy. Longitudinal data were obtained from the US Health and Retirement Study. Multistate modelling was used to estimate total life expectancy (LE), cognitive impairment free life expectancy (CIFLE) and years spent with cognitive impairment (CILE) across self-reported diabetes, hypertension, heart problems and stroke. Individual and cumulative effects of multiple cardiovascular conditions were examined. The presence of cardiovascular disease was associated with a 5- to 9-year decrease in LE and 4- to 8-year decrease in CIFLE at age 55. The outcomes varied in a hierarchical fashion by cardiovascular condition. Relative to other conditions, individuals with stroke had the shortest LE and CIFLE. Analysis of multiple cardiovascular risk factors revealed that each additional cardiovascular condition was associated with an exponential decrease in LE and CIFLE. Having a cardiovascular condition is associated with a lower CIFLE and higher proportion of life lived with cognitive impairment. However, the outcomes vary depending on the type of cardiovascular condition. Reducing incidence of stroke and minimising exposure to multiple cardiovascular risk factors may be beneficial in helping to improve population estimates of cognitive health expectancy.


Absent Left Main Coronary Artery and Separate Ostia of Left Coronary System in a Patient with Holt-Oram Syndrome and Sinus Node Dysfunction.
Holt-Oram syndrome (HOS) is a rare but significant syndrome consisting of structural heart defects, conduction abnormalities, and upper extremity anomalies. It was first described in the British Heart Journal in 1960 by Mary Holt and Samuel Oram as a report of atrial septal defect, conduction disturbances, and hand malformations occurring in family members. Patients can present with heart blocks or symptoms of underlying congenital heart defects. A 41-year-old man with Holt-Oram syndrome presented with seizure-like activity and was found to have an underlying conduction disturbance. Physical exam showed bilateral atrophic upper extremities with anatomic disfiguration, and weakness of the intrinsic hand muscles. Cardiovascular exam revealed a slow heart rate with irregular rhythm. EKG showed sinus arrest with junctional escape rhythm. Cardiac catheterization revealed coronary anomalies, including absent left main coronary artery and separate ostia of the left anterior ascending and left circumflex coronary artery. Coronary arteries were patent. Following electrophysiology study, sick sinus syndrome and AV block were diagnosed, and the patient received implantation of a permanent pacemaker. This patient presented with a seizure-like episode attributed to hypoxia during asystole from an underlying cardiac conduction defect associated with Holt-Oram syndrome. Arrhythmias and heart blocks are seen in these patients, and conduction defects are highly associated with congenital heart defects. Holt-Oram syndrome rarely presents with coronary artery anomalies. There is no reported case of separate coronary ostia and absent left main coronary artery. Prompt diagnosis is important since anomalies in coronary and upper extremity vasculature might be challenging for invasive procedures.


Magnetic resonance imaging of oxygen microbubbles.
Oxygen loaded microbubbles are being investigated as a means of reducing tumour hypoxia in order to improve response to cancer therapy. To optimise this approach, it is desirable to be able to measure changes in tissue oxygenation in real-time during treatment. In this study, the feasibility of using magnetic resonance imaging (MRI) for this purpose was investigated. Longitudinal relaxation time (T1) measurements were made in simple hydrogel phantoms containing two different concentrations of oxygen microbubbles. T1 was found to be unaffected by the presence of oxygen microbubbles at either concentration. Upon application of ultrasound to destroy the microbubbles, however, a statistically significant reduction in T1 was seen for the higher microbubble concentration. Further work is needed to assess the influence of physiological conditions upon the measurements, but these preliminary results suggest that MRI could provide a method for quantifying the changes in tissue oxygenation produced by microbubbles during therapy.


An early Phase II randomised controlled trial testing the effect on persecutory delusions of using CBT to reduce negative cognitions about the self: the potential benefits of enhancing self confidence.
Research has shown that paranoia may directly build on negative ideas about the self. Feeling inferior can lead to ideas of vulnerability. The clinical prediction is that decreasing negative self cognitions will reduce paranoia. Thirty patients with persistent persecutory delusions were randomised to receive brief CBT in addition to standard care or to standard care (ISRCTN06118265). The six session intervention was designed to decrease negative, and increase positive, self cognitions. Assessments at baseline, 8 weeks (posttreatment) and 12 weeks were carried out by a rater blind to allocation. The primary outcomes were posttreatment scores for negative self beliefs and paranoia. Secondary outcomes were psychological well-being, positive beliefs about the self, persecutory delusions, social comparison, self-esteem, anxiety, and depression. Trial recruitment and retention were feasible and the intervention highly acceptable to the patients. All patients provided follow-up data. Posttreatment there was a small reduction in negative self beliefs (Cohen's d=0.24) and a moderate reduction in paranoia (d=0.59), but these were not statistically significant. There were statistically significant improvements in psychological well-being (d=1.16), positive beliefs about the self (d=1.00), negative social comparison (d=0.88), self-esteem (d=0.62), and depression (d=0.68). No improvements were maintained. No adverse events were associated with the intervention. The intervention produced short-term gains consistent with the prediction that improving cognitions about the self will reduce persecutory delusions. The improvement in psychological well-being is important in its own right. We recommend that the different elements of the intervention are tested separately and that the treatment is lengthened.


Bone quality and strength are greater in growing male rats fed fructose compared with glucose.
Optimization of peak bone mass during adolescence is important for osteoporosis prevention. Studies in rodents and humans have demonstrated the harmful effects of sugar intake on bone health. With the high levels of sucrose in the diets of adolescents, it is necessary to understand the influence of glucose and fructose on growing bones. This study compared the effects of dietary glucose and fructose on bone formation, microarchitecture, and strength. Because of the different metabolic effects of glucose and fructose, we hypothesized that their individual effects on bone would be different. Eighteen male Sprague-Dawley rats (age, 60 days) were randomly assigned to high-fructose (n = 9; 40% fructose, 10% glucose) or high-glucose diet (n = 9; 50% glucose) for 12 weeks. Bone measurements included histology and histomorphometry of trabecular bone in the distal femur and a 3-point bending test of the whole tibia. Whole liver mass and postprandial serum glucose, insulin, and triglycerides were used to assess differences in energy metabolism between the diets. There were no differences in food intake, body weight, or visceral adiposity between groups, but fructose consumption led to heavier livers (P = .001) and elevated serum triglycerides (P = .00). The distal femurs of fructose-fed rats had greater bone volume (bone volume/total volume; P = .03), lower bone surface (bone surface/bone volume; P = .02), and thicker trabeculae (trabecular thickness; P = .01). The tibias of the fructose-fed rats also withstood a greater maximum flexure load (P = .032). These results indicate that consumption of the high-fructose diet resulted in stronger bones with enhanced microarchitecture than consumption of the high-glucose diet.


Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis.
The liver provides for long-term energy needs of the body by converting excess carbohydrate into fat for storage. Insulin is one factor that promotes hepatic lipogenesis, but there is increasing evidence that glucose also contributes to the coordinated regulation of carbohydrate and fat metabolism in liver by mechanisms that are independent of insulin. In this study, we show that the transcription factor, carbohydrate response element-binding protein (ChREBP), is required both for basal and carbohydrate-induced expression of several liver enzymes essential for coordinated control of glucose metabolism, fatty acid, and the synthesis of fatty acids and triglycerides in vivo.


New atypical antipsychotics for schizophrenia: iloperidone.
The optimal treatment of schizophrenia poses a challenge to develop more effective treatments and safer drugs, to overcome poor compliance, discontinuation and frequent switching with available antipsychotics. Iloperidone is a new dopamine type 2/serotonin type 2A (D(2)/5-HT(2A)) antagonist structurally related to risperidone, expected to give better efficacy with less extrapyramidal symptoms than D(2) receptor antagonist antipsychotics. In double-blind phase III trials iloperidone reduced the symptoms of schizophrenia at oral doses from 12 to 24 mg. It was more effective than placebo in reducing positive and negative syndrome total score and Brief Psychiatric Rating scale scores; it was as effective as haloperidol and risperidone in post-hoc analysis. Its long-term efficacy was equivalent to that of haloperidol. The most common adverse events were dizziness, dry mouth, dyspepsia and somnolence, with few extrapyramidal symptoms and metabolic changes in short- and long-term studies in adults. Akathisia was rare, but prolongation of the corrected QT (QTc) interval was comparable to haloperidol and ziprasidone, which is of particular concern. Further comparative studies are needed to clarify the benefit/risk profile of iloperidone and its role in the treatment of schizophrenia.


Neuronal vacuolation in raccoons (Procyon lotor).
Microscopic vacuolar changes in neuronal perikaryon are described in two free-ranging raccoons (Procyon lotor) from different geographic locations in the United States. Both animals were negative for rabies and scrapie-associated antigens. Microscopically, lesions were not seen in the neuropil. Neuronal vacuolations have previously been documented in brains of normal animals and in diseases such as rabies and prion-associated encephalopathies. Although experimental transmission of a spongiform mink encephalopathy has been documented in raccoons, a naturally occurring spongiform encephalopathy has not been described in this species. The presence of neuronal vacuolations in the raccoons is novel and requires further investigation to elucidate the mechanism of this phenomenon.


FoxM1 inhibition sensitizes resistant glioblastoma cells to temozolomide by downregulating the expression of DNA-repair gene Rad51.
Recurrent glioblastoma multiforme (GBM) is characterized by resistance to radiotherapy and chemotherapy and a poor clinical prognosis. In this study, we investigated the role of the oncogenic transcription factor FoxM1 in GBM cells' resistance to alkylator temozolomide (TMZ) and its potential molecular mechanism. FoxM1 expression levels were measured by immunohistochemical analysis in 38 pairs of primary and recurrent GBM tumor samples. Expression levels were also measured in primary recurrent GBM cell lines, and their responses to TMZ were characterized. In a mechanistic study, an siRNA array was used to identify downstream genes, and a chromatin immunoprecipitation assay was used to confirm transcriptional regulation. Recurrent tumors that were TMZ resistant expressed higher levels of FoxM1 than did primary tumors. Recurrent GBM cell lines expressed higher levels of FoxM1 and the DNA damage repair gene Rad51 and were resistant to TMZ. TMZ treatment led to increased FoxM1 and Rad51 expression. FoxM1 knockdown inhibited Rad51 expression and sensitized recurrent GBM cells to TMZ cytotoxicity. FoxM1 directly regulated Rad51 expression through 2 FoxM1-specific binding sites in its promoter. Rad51 reexpression partially rescued TMZ resistance in FoxM1-knockdown recurrent GBM cells. A direct correlation between FoxM1 expression and Rad51 expression was evident in recurrent GBM tumor samples. Targeting the FoxM1-Rad51 axis may be an effective method to reverse TMZ resistance in recurrent GBM.


MiR expression profiles of paired primary colorectal cancer and metastases by next-generation sequencing.
MicroRNAs (miRs) have been recognized as promising biomarkers. It is unknown to what extent tumor-derived miRs are differentially expressed between primary colorectal cancers (pCRCs) and metastatic lesions, and to what extent the expression profiles of tumor tissue differ from the surrounding normal tissue. Next-generation sequencing (NGS) of 220 fresh-frozen samples, including paired primary and metastatic tumor tissue and non-tumorous tissue from 38 patients, revealed expression of 2245 known unique mature miRs and 515 novel candidate miRs. Unsupervised clustering of miR expression profiles of pCRC tissue with paired metastases did not separate the two entities, whereas unsupervised clustering of miR expression profiles of pCRC with normal colorectal mucosa demonstrated complete separation of the tumor samples from their paired normal mucosa. Two hundred and twenty-two miRs differentiated both pCRC and metastases from normal tissue samples (false discovery rate (FDR) <0.05). The highest expressed tumor-specific miRs were miR-21 and miR-92a, both previously described to be involved in CRC with potential as circulating biomarker for early detection. Only eight miRs, 0.5% of the analysed miR transcriptome, were differentially expressed between pCRC and the corresponding metastases (FDR <0.1), consisting of five known miRs (miR-320b, miR-320d, miR-3117, miR-1246 and miR-663b) and three novel candidate miRs (chr 1-2552-5p, chr 8-20656-5p and chr 10-25333-3p). These results indicate that previously unrecognized candidate miRs expressed in advanced CRC were identified using NGS. In addition, miR expression profiles of pCRC and metastatic lesions are highly comparable and may be of similar predictive value for prognosis or response to treatment in patients with advanced CRC.


Molecular cloning of a feline leukemia virus that induces fatal immunodeficiency disease in cats.
A replication-defective variant of feline leukemia virus was molecularly cloned directly from infected tissue and found to induce a rapid and fatal immunodeficiency syndrome in cats. Studies with cloned viruses also showed that subtle mutational changes would convert a minimally pathogenic virus into one that would induce an acute form of immunodeficiency. The data suggest that acutely pathogenic viruses may be selected against by current methods for isolation of the human and simian immunodeficiency viruses.


Guidelines for topical PUVA: a report of a workshop of the British photodermatology group.
Psoralen photochemotherapy [psoralen ultraviolet A (PUVA)] plays an important part in dermatological therapeutics, being an effective and generally safe treatment for psoriasis and other dermatoses. In order to maintain optimal efficacy and safety, guidelines concerning best practice should be available to operators and supervisors. The British Photodermatology Group (BPG) have previously published recommendations on PUVA, including UVA dosimetry and calibration, patient pretreatment assessment, indications and contraindications, and the management of adverse reactions.1 While most current knowledge relates to oral PUVA, the use of topical PUVA regimens is also popular and presents a number of questions peculiar to this modality, including the choice of psoralen, formulation, method of application, optimal timing of treatment, UVA regimens and relative benefits or risks as compared with oral PUVA. Bath PUVA, i.e. generalized immersion, is the most frequently used modality of topical treatment, practised by about 100 centres in the U.K., while other topical preparations tend to be used for localized diseases such as those affecting the hands and feet. This paper is the product of a recent workshop of the BPG and includes guidelines for bath, local immersion and other topical PUVA. These recommendations are based, where possible, on the results of controlled studies, or otherwise on the consensus view on current practice.


Supramolecular structure of self-assembled monolayers of ferrocenyl terminated n-alkanethiolates on gold surfaces.
It is important to understand the structure of redox-active self-assembled monolayers (SAMs) down to the atomic scale, since these SAMS are widely used as model systems in studies of mechanisms of charge transport or to realize electronic functionality in molecular electronic devices. We studied the supramolecular structure of SAMs of n-alkanethiolates with ferrocenyl (Fc) end groups (S(CH2)nFc, n = 3 or 4) on Au(111) by scanning tunneling microscopy (STM). In this system, the tilt angle of the Fc units with respect to the surface normal (α) depends on the value of n because the Au-S-C bond angle is fixed. The ordered domains of the SAMs were imaged by STM after annealing at 70 °C at ultrahigh vacuum conditions. High resolution electron energy loss spectroscopy (HREELS) and cyclic voltammetry show that this annealing step only removed physisorbed material and did not affect the structure of the SAM. The STM images revealed the presence of row defects at intervals of 4 nm, that is, six molecules. We determined by near edge X-ray absorption fine structure spectroscopy (NEXAFS) that the Fc units of the SAMs of SC3Fc are more parallel to the Au(111) plane with a tilt angle α = 60.2° than the Fc units of SC4Fc SAMs (α = 45.4°). These tilt angles are remarkably close to the tilt angles measured by X-ray diffraction data of bulk crystals (bc-plane). Based on our data, we conclude that the molecules are standing up and the SAMs pack into lattices that are distorted from their bulk crystal structures (because of the build-up stain due to the differences in size between the Fc units and thiolate anchoring groups).


Bilateral orchiectomy with or without flutamide for metastatic prostate cancer.
Combined androgen blockade for the treatment of metastatic prostate cancer consists of an antiandrogen drug plus castration. In a previous trial, we found that adding the antiandrogen flutamide to leuprolide acetate (a synthetic gonadotropin-releasing hormone that results in medical ablation of testicular function) significantly improved survival as compared with that achieved with placebo plus leuprolide acetate. In the current trial, we compared flutamide plus bilateral orchiectomy with placebo plus orchiectomy. We randomly assigned patients who had never received antiandrogen therapy and who had distant metastases from adenocarcinoma of the prostate to treatment with bilateral orchiectomy and either flutamide or placebo. Patients were stratified according to the extent of disease and according to performance status. Of the 1387 patients who were enrolled in the trial, 700 were randomly assigned to the flutamide group and 687 to the placebo group. Overall, the incidence of toxic effects was minimal; the only notable differences between the groups were the greater rates of diarrhea and anemia with flutamide. There was no significant difference between the two groups in overall survival (P=0.14). The estimated risk of death (hazard ratio) for flutamide as compared with placebo was 0.91 (90 percent confidence interval, 0.81 to 1.01). Flutamide was not associated with enhanced benefit in patients with minimal disease. The addition of flutamide to bilateral orchiectomy does not result in a clinically meaningful improvement in survival among patients with metastatic prostate cancer.


LAG-3, a novel lymphocyte activation gene closely related to CD4.
We have identified a novel human gene of the Ig superfamily, designated LAG-3. Expression of this gene is undetectable in resting PBL, while it is found (a 2-kb message) in activated T and NK cells. The LAG-3 gene includes eight exons; the corresponding cDNA encodes a 498-amino acid membrane protein with four extracellular IgSF domains. The first one belongs to the V-SET; it is particular since it includes an extra loop in the middle of the domain and an unusual intrachain disulphide bridge. The three other domains belong to the C2-SET. Strong internal homologies are found in the LAG-3 molecule between domains 1 and 3, as well as between domains 2 and 4. It is therefore likely that LAG-3 has evolved by duplication of a pre-existing gene encoding a two IgSF-domain structure. The compared analysis of LAG-3 and CD4, with respect to both their peptidic sequence as well as their exon/intron organization, indicated that the two molecules are closely related. This point is strengthened by the finding that both genes are located on the distal part of the short arm of chromosome 12.


Hyalinizing trabecular tumor of the thyroid: diagnosis of a rare tumor using ultrasonography, cytology, and intraoperative frozen sections.
The goal of this study was to evaluate the clinicopathological and imaging features of thyroid nodules surgically diagnosed as hyaline trabecular tumor (HTT), and to assess the role of cytology and frozen sections (FS) in the diagnosis of HTT. This study included 21 thyroid nodules in 21 patients treated from August 2005 to March 2015 (mean age, 53.3 years) who were either diagnosed as HTT or had HTT suggested as a possible diagnosis based on cytology, FS, or the final pathology report. Patients' medical records were retrospectively reviewed for cytopathologic results and outcomes during the course of follow-up. Sonograms were reviewed and categorized. Twelve nodules from 12 patients were surgically confirmed as HTT. Ultrasonography (US)-guided fine needle aspiration (FNA) was performed on 11 nodules, of which six (54.5%) were papillary thyroid carcinoma (PTC) or suspicious for PTC and three (27.3%) were HTT or suspicious for HTT. Intraoperative FS suggested the possibility of HTT in seven nodules, of which four (57.1%) were confirmed as HTT. US-FNA suggested the diagnosis of HTT in 10 nodules, of which three (30.0%) were confirmed as HTT. Common US features of the 12 pathologically confirmed cases of HTT were hypoechogenicity or marked hypoechogenicity (83.4%), absence of calcifications (91.7%), parallel shape (100.0%), presence of vascularity (75.0%), and probable benignity (58.3%). HTT should be included in the differential diagnosis of solid tumors with hypoechogenicity or marked hypoechogenicity and otherwise benign US features that have been diagnosed as PTC through cytology.


Black and Hairy Nightshade, the First Weedy Hosts of Potato virus A in the United States.
Potato virus A (PVA; genus Potyvirus, family Potyviridae) occurs wherever potatoes are grown and may reduce tuber yields as much as 40%. Its host range consists of six experimental hosts (Lycopersicon pimpinellifolium (Jusl.) P. Mill., Nicandra physalodes (L.) Gaertn., Nicotiana tabacum L., Solanum demissum Lindl., S. demissum × S. tuberosum, and Nicotiana debneyi Domin.) and two natural hosts (S. tuberosum L. and S. betaceae (Cav.) Sendt.) (1). N. physalodes and Nicotiana tabacum sometimes grow in nature in the eastern and southern United States (2) but have not been reported to be PVA sources in nature. PVA is known to survive winter in temperate climates only in tubers used for potato propagation and potato volunteers. We detected PVA in all six Black Nightshade (S. nigrum L.) and all six Hairy Nightshade (S. sarrachoides Sendt.) weeds expressing mild mosaic symptoms and growing in PVA-infected potato fields near Prosser, WA in September of 2002. PVA was not detected in any of the 24 Cutleaf Nightshade (S. trifolium) plants selected from the same fields. The virus was detected using double antibody sandwich enzyme-linked immunosorbent assay with a test kit obtained from Agdia, Inc. (Elkhart, IN) and by reverse transcription-polymerase chain reaction using primers designated 3 (gta-ctg-aac-tgg-aaa-agt-act) and 4 (ccc-tga-cag-ttg-aaa-cat-aag) (3). One positive control for these assays was a PVA virus isolate from the "Shultz Collection" provided by Robert Goth (USDA, ARS, Beltsville, MD) in 1986. The Agdia, Inc. test kit also provided a positive control. We also transmitted PVA from one of the Black Nightshade and one of the Hairy Nightshade weeds to greenhouse-produced Nicotiana megalosiphon Van Heurck & Mull. Agr., Nicotiana tabacum cv. Samsum NN, S. tuberosum cv. Russet Burbank, S. sarrachoides, and S. nigrum plants by Myzus persicae Sulzer in a stylet-borne manner. The virus was transmitted from the greenhouse test plants back to S. sarrachoides and S. nigrum plants where it produced mild mosaic symptoms identical to virus from the original sources. PVA was not transmitted from weedy sources to Datura tatula L., Physalis floridana Rydb., or S. trifolium. M. persicae readily colonized S. sarrachoides, S. nigrum, and S. trifolium in the field and greenhouse. Since black and hairy nightshade are frequently found in potato fields (4) and our findings show these weeds to be hosts of PVA, their role in the epidemiology of this disease should be more fully evaluated. References: (1) A. Brunt. Potyviruses. Pages 77-86 in: Virus and Virus-Like Diseases of Potatoes and Production of Seed Potatoes. G. Loebenstein et al., eds. Kluwer Academic Publishers, Boston, 2001 (2) A. Ogg and B. S. Rogers. Rev. Weed Sci. 4:25, 1989. (3) M. Rajamaki et al. Virology 88:311, 1998. (4) USDA, NTPD, National Plant Data Center, Version 3.5 On-line Publication, 2004.


Almond ingestion at mealtime reduces postprandial glycemia and chronic ingestion reduces hemoglobin A(1c) in individuals with well-controlled type 2 diabetes mellitus.
Cohort studies are equivocal regarding a relationship between regular nut consumption and reduced risk of type 2 diabetes mellitus. Although acute trials show reductions in postprandial glycemia in healthy individuals ingesting 60 to 90 g almonds, trials have not been conducted using a single serving of almonds (28 g) in individuals with type 2 diabetes mellitus. This randomized crossover trial examined the impact of one serving of almonds at mealtime on postprandial glycemia, insulinemia, and plasma glucagon-like peptide-1 in healthy individuals and individuals with type 2 diabetes mellitus. On 2 occasions separated by at least 1 week, 19 adults (including 7 adults with type 2 diabetes mellitus) consumed a standardized evening meal and fasted overnight before ingesting the test meal (bagel, juice, and butter) with or without almonds. A small pilot study (6-7 subjects per group) was also conducted to observe whether chronic almond ingestion (1 serving 5 d/wk for 12 weeks) lowered hemoglobin A(1c) in individuals with type 2 diabetes mellitus. A standard serving of almonds reduced postprandial glycemia significantly in participants with diabetes (-30%, P = .043) but did not influence glycemia in participants without diabetes (-7%, P = .638). Insulinemia and glucagon-like peptide-1 at 30 minutes postmeal were not impacted by almond ingestion for either group. In the pilot study, regular almond ingestion for 12 weeks reduced hemoglobin A(1c) by 4% (P = .045 for interaction) but did not influence fasting glucose concentrations. These data show that modest almond consumption favorably improves both short-term and long-term markers of glucose control in individuals with uncomplicated type 2 diabetes mellitus.


Enhanced solubilization and desorption of organochlorine pesticides (OCPs) from soil by oil-swollen micelles formed with a nonionic surfactant.
The effect of oil-swollen micelles formed with nonionic surfactant polyoxyethylene sorbitan monooleate (Tween 80), cosurfactant 1-pentanol, and linseed oil on the solubilization and desorption of organochlorine pesticides (OCPs) including DDT and γ-HCH from both loam soil and clay soil were investigated. Results showed that the solubilizing capacities of oil-swollen micelles were dependent on the critical micelle concentration (CMC) of Tween 80. Once the concentrations of oil-swollen micelles exceeded the CMC of Tween 80, the oil-swollen micelles exhibited much higher solubilizing capacity than empty Tween 80 micelles for the two OCPs. Desorption tests revealed that oil-swollen micelles could successfully enhance desorption of OCPs from both loam soil and clay soil. However, compared with the efficiencies achieved by empty Tween 80 micelles, oil-swollen micelles exhibited their superiority to desorb OCPs only in loam soil-water system while was less effective in clay soil-water system. Distribution of Tween 80, 1-pentanol and linseed oil in soil-water system revealed that the difference in the sorption behavior of linseed oil onto the two soils is responsible for the different effects of oil-swollen micelles on the desorption of OCPs in loam soil and clay soil systems. Therefore, oil-swollen micelles formed with nonionic surfactant Tween 80 are better candidates over empty micelle counterparts to desorb OCPs from soil with relatively lower sorption capacity for oil fraction, which may consequently enhance the availability of OCPs in soil environment during remediation processes of contaminated soil.


Selective Nonnuclear Estrogen Receptor Activation Decreases Stroke Severity and Promotes Functional Recovery in Female Mice.
Estrogens provide neuroprotection in animal models of stroke, but uterotrophic effects and cancer risk limit translation. Classic estrogen receptors (ERs) serve as transcription factors, whereas nonnuclear ERs govern numerous cell processes and exert beneficial cardiometabolic effects without uterine or breast cancer growth in mice. Here, we determined how nonnuclear ER stimulation with pathway-preferential estrogen (PaPE)-1 affects stroke outcome in mice. Ovariectomized female mice received vehicle, estradiol (E2), or PaPE-1 before and after transient middle cerebral artery occlusion (tMCAo). Lesion severity was assessed with MRI, and poststroke motor function was evaluated through 2 weeks after tMCAo. Circulating, spleen, and brain leukocyte subpopulations were quantified 3 days after tMCAo by flow cytometry, and neurogenesis and angiogenesis were evaluated histologically 2 weeks after tMCAo. Compared with vehicle, E2 and PaPE-1 reduced infarct volumes at 3 days after tMCAo, though only PaPE-1 reduced leukocyte infiltration into the ischemic brain. Unlike E2, PaPE-1 had no uterotrophic effect. Both interventions had negligible effect on long-term poststroke neuronal or vascular plasticity. All mice displayed a decline in motor performance at 2 days after tMCAo, and vehicle-treated mice did not improve thereafter. In contrast, E2 and PaPE-1 treatment afforded functional recovery at 6 days after tMCAo and beyond. Thus, the selective activation of nonnuclear ER by PaPE-1 decreased stroke severity and improved functional recovery in mice without undesirable uterotrophic effects. The beneficial effects of PaPE-1 are also associated with attenuated neuroinflammation in the brain. PaPE-1 and similar molecules may warrant consideration as efficacious ER modulators providing neuroprotection without detrimental effects on the uterus or cancer risk.


Plant natriuretic peptides are apoplastic and paracrine stress response molecules.
Higher plants contain biologically active proteins that are recognized by antibodies against human atrial natriuretic peptide (ANP). We identified and isolated two Arabidopsis thaliana immunoreactive plant natriuretic peptide (PNP)-encoding genes, AtPNP-A and AtPNP-B, which are distantly related members of the expansin superfamily and have a role in the regulation of homeostasis in abiotic and biotic stresses, and have shown that AtPNP-A modulates the effects of ABA on stomata. Arabidopsis PNP (PNP-A) is mainly expressed in leaf mesophyll cells, and in protoplast assays we demonstrate that it is secreted using AtPNP-A:green fluorescent protein (GFP) reporter constructs and flow cytometry. Transient reporter assays provide evidence that AtPNP-A expression is enhanced by heat, osmotica and salt, and that AtPNP-A itself can enhance its own expression, thereby generating a response signature diagnostic for paracrine action and potentially also autocrine effects. Expression of native AtPNP-A is enhanced by osmotica and transiently by salt. Although AtPNP-A expression is induced by salt and osmotica, ABA does not significantly modulate AtPNP-A levels nor does recombinant AtPNP-A affect reporter expression of the ABA-responsive RD29A gene. Together, these results provide experimental evidence that AtPNP-A is stress responsive, secreted into the apoplastic space and can enhance its own expression. Furthermore, our findings support the idea that AtPNP-A, together with ABA, is an important component in complex plant stress responses and that, much like in animals, peptide signaling molecules can create diverse and modular signals essential for growth, development and defense under rapidly changing environmental conditions.


Meta-analysis of genome-wide association studies of aggressive and chronic periodontitis identifies two novel risk loci.
Periodontitis is one of the most common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. It is classified into the widespread moderate form chronic periodontitis (CP) and the rare early-onset and severe phenotype aggressive periodontitis (AgP). These different disease manifestations are thought to share risk alleles and predisposing environmental factors. To obtain novel insights into the shared genetic etiology and the underlying molecular mechanisms of both forms, we performed a two step-wise meta-analysis approach using genome-wide association studies of both phenotypes. Genotypes from imputed genome-wide association studies (GWAS) of AgP and CP comprising 5,095 cases and 9,908 controls of North-West European genetic background were included. Two loci were associated with periodontitis at a genome-wide significance level. They located within the pseudogene MTND1P5 on chromosome 8 (rs16870060-G, P = 3.69 × 10-9, OR = 1.36, 95% CI = [1.23-1.51]) and intronic of the long intergenic non-coding RNA LOC107984137 on chromosome 16, downstream of the gene SHISA9 (rs729876-T, P = 9.77 × 10-9, OR = 1.24, 95% CI = [1.15-1.34]). This study identified novel risk loci of periodontitis, adding to the genetic basis of AgP and CP.


Rats quit nicotine for a sweet reward following an extensive history of nicotine use.
Drug use may be exacerbated in environments which lack alternative means of engaging in rewarding behaviour. When alternative rewards are available, drug use may decrease-an effect that can be harnessed for therapeutic benefit. This idea is particularly well-supported by recent preclinical evidence demonstrating that a majority of rats will readily choose a potent non-drug reward over cocaine or heroin. Here we examine whether the same holds true for nicotine, a drug considered to have one of the highest addiction liabilities amongst drugs of abuse. Rats were trained to nose-poke separately for saccharin or nicotine on alternate days. Using a discrete-trial, forced-choice procedure, rats were then allowed to choose between nicotine and saccharin. This was followed by choice testing after a decrease in saccharin concentration (0.2-0%), omission of the fluid reward, an increase in nicotine concentration and following an extended nicotine self-administration history. All rats demonstrated a clear and immediate preference for saccharin at all times. This was despite variations in reward concentrations, or after an extensive nicotine history. Notably, rats preferred to nose-poke for water over nicotine and would omit responses when no fluid was delivered, rather than resume responding for nicotine. Overall, this study confirms and extends to nicotine previous research on other drugs of abuse, including cocaine and heroin. The ease with which rats quit nicotine in the present study contrasts with the well-known difficulty of humans to quit tobacco smoking. Possible factors that could explain this apparent discrepancy are discussed.


Epidemiology of U.K. Military Burns 2008-2013.
After sustaining burn injuries overseas, U.K. Armed Forces personnel are evacuated to the Royal Centre for Defence Medicine. The objective was to review the etiology of U.K. Military burns managed at the center between 2008 and 2013. Analysis will aid provision planning and assist in the prevention of burn injuries for future tours. The International Burn Injury Database database of all U.K. Armed Forces burn injured patients evacuated to the Queen Elizabeth University Hospital Birmingham between 2008 and 2013 were reviewed retrospectively. Analysis included patient demographics, injury mechanism, burn severity, management, and mortality. There were 65 military personnel with burn injuries requiring repatriation to the United Kingdom. Percentage of 78.5 were sustained in Afghanistan. The mean age was 25 (18-46) years. Percentage of 70.8 were considered noncombat burn injuries. Of the noncombat burns, the mechanism of injury most commonly involved burning waste and misuse of fuels and scalds. The mean TBSA for all patients was 6% (0.05-51%). Areas most commonly affected included arms, legs, and face. The length of hospital stay for combat vs noncombat burn injury patients was 10 vs 7 days. There were no fatalities. In conclusion, substantially fewer military personnel sustained combat burns between 2008 and 2013 than in preceding study period (19 vs 79). The number of accidental noncombat burns remained constant. The decrease in combat burns may reflect a relative decrease in military intensity and effective protective equipment and safety measures. Further education may allow for an additional decrease in preventable burn injuries.


Probing the reaction mechanism of IspH protein by x-ray structure analysis.
Isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) represent the two central intermediates in the biosynthesis of isoprenoids. The recently discovered deoxyxylulose 5-phosphate pathway generates a mixture of IPP and DMAPP in its final step by reductive dehydroxylation of 1-hydroxy-2-methyl-2-butenyl 4-diphosphate. This conversion is catalyzed by IspH protein comprising a central iron-sulfur cluster as electron transfer cofactor in the active site. The five crystal structures of IspH in complex with substrate, converted substrate, products and PP(i) reported in this article provide unique insights into the mechanism of this enzyme. While IspH protein crystallizes with substrate bound to a [4Fe-4S] cluster, crystals of IspH in complex with IPP, DMAPP or inorganic pyrophosphate feature [3Fe-4S] clusters. The IspH:substrate complex reveals a hairpin conformation of the ligand with the C(1) hydroxyl group coordinated to the unique site in a [4Fe-4S] cluster of aconitase type. The resulting alkoxide complex is coupled to a hydrogen-bonding network, which serves as proton reservoir via a Thr167 proton relay. Prolonged x-ray irradiation leads to cleavage of the C(1)-O bond (initiated by reducing photo electrons). The data suggest a reaction mechanism involving a combination of Lewis-acid activation and proton coupled electron transfer. The resulting allyl radical intermediate can acquire a second electron via the iron-sulfur cluster. The reaction may be terminated by the transfer of a proton from the beta-phosphate of the substrate to C(1) (affording DMAPP) or C(3) (affording IPP).


Profile measurement taken with liquid-crystal gratings.
Profile measurement taken with liquid-crystal gratings and a phase-shifting technique is proposed, and its effectiveness is verified by experiment. The surface profile is obtained by measurement of the phase distributions of the sinusoidal gratings deformed by an object's surface. The liquid-crystal grating gives an accurate phase shift, an arbitrary projection pitch, and a constant surface brightness compared with conventional gratings such as a laser interference fringe grating and a Ronchi grating. Therefore a flexible measuring system may be developed with it. Two gratings with different pitches are used to measure an object with large steps. A two-color projection system can be used to produce such gratings simultaneously. Locally varying reflectivity on a surface can also be compensated by adjustment of the color component of the projected grating with a liquid-crystal grating. Thus the contrast in the projected grating can be made uniform, and a good profile measurement can be accomplished.


Amygdala and emotionality in Parkinson's disease: An integrative review of the neuropsychological evidence.
Parkinson's disease (PD) is often accompanied by significant changes in emotionality, such as apathy, anhedonia, anxiety and depression. The present review summarizes the empirical evidence, including amygdala changes and psychological changes in emotionality in people suffering from PD. Seventeen empirical full-text articles including research on both amygdala and emotionality in PD were reviewed. The changes in amygdala volumes as well as changes in binding potentials, functional connectivity, regional homogeneity and regional cerebral blood flow were found to have various impacts on emotionality in people with PD. The integration of the results showed that some effects of amygdala changes on emotionality were lateralized. Some of the reviewed studies indicated that the volume loss in the left amygdala was found to be related to increased anxiety, whereas bilateral volume loss in amygdala was linked to increased depressivity. The reviewed results also support a hypothesis of bradylimbic affective disturbance in patients with PD. The disturbed activation of amygdala accompanying the evaluation of negative facial expressions implies that the evaluation of the content of affective stimuli in terms of their affective meanings is disturbed in PD patients. Impaired evaluation of affective attributes given by amygdala-based translational deficits is likely to be related to problems in translating the results of cognitive appraisal into somatomotor, arousal and other changes. This mechanism is suggested to be responsible for apathy as well as for other changes in emotionality accompanying PD.


Sex-specific effects of sex steroids on alveolar epithelial Na+ transport.
Alveolar fluid clearance mediates perinatal lung transition to air breathing in newborn infants, which is accomplished by epithelial Na+ channels (ENaC) and Na-K-ATPase. Male sex represents a major risk factor for developing respiratory distress, especially in preterm infants. We previously showed that male sex is associated with reduced epithelial Na+ transport, possibly contributing to the sexual dimorphism in newborn respiratory distress. This study aimed to determine sex-specific effects of sex steroids on epithelial Na+ transport. The effects of testosterone, 5α-dihydrotestosterone (DHT), estradiol, and progesterone on Na+ transport and Na+ channel expression were determined in fetal distal lung epithelial (FDLE) cells of male and female rat fetuses by Ussing chamber and mRNA expression analyses. DHT showed a minor effect only in male FDLE cells by decreasing epithelial Na+ transport. However, flutamide, an androgen receptor antagonist, did not abolish the gender imbalance, and testosterone lacked any effect on Na+ transport in male and female FDLE cells. In contrast, estradiol and progesterone increased Na+ transport and Na+ channel expression especially in females, and prevented the inhibiting effect of DHT in males. Estrogen receptor inhibition decreased Na+ channel expression and eliminated the sex differences. In conclusion, female sex steroids stimulate Na+ transport especially in females and prevent the inhibitory effect of DHT in males. The ineffectiveness of testosterone suggests that Na+ transport is largely unaffected by androgens. Thus, the higher responsiveness of female cells to female sex steroids explains the higher Na+ transport activity, possibly leading to a functional advantage in females.


[Characteristics of acupoint selection of acupuncture-moxibustion for vertigo in history: a data mining research].
The data mining technique is adopted to analyze characteristics and rules of acupoint and meridian selection of acupuncture-moxibustion for treatment of vertigo at different time periods in the ancient. The data is collected from literature regarding acupuncture-moxibustion from the pre-Qin period to the end of Qing Dynasty, so as to establish a clinical literature database of ancient acupuncture-moxibustion for treatment of vertigo. Data mining method is applied to analyze the commonly used meridians, acupoints and special acupoints in different dynasties, also possible rules are explored. Totally 82 pieces of prescription of acupuncture-moxibustion for treatment of vertigo are included. In the history the leading selection of acupoitns are Fengchi (GB 20), Hegu (LI 4), Shangxing (GV 23) and Jiexi (ST 41) while that of meridians are mainly three yang meridians of foot and the Governor Vessel, especially the acupoints on the Bladder Meridian of foot yangming had the highest utilization rate, accounting for 23.04%. The acupoint selection is characterized by special acupoint, accounting for 80.6%, among which the crossing points are the most common choice. Distal-proximal acupoints combination is the most frequent method. The results indicate that the ancient acupuncture-moxibustion for treatment of vertigo focused on acupoints in the yang meridians, and the specific acupoints play an essential role in prescription; also the principle of syndrome differentiation and selecting acupoints along the meridians could be seen.


Recent trends in cystic fibrosis-related diabetes.
To provide an updated literature review highlighting important aspects of cystic fibrosis-related diabetes (CFRD) including epidemiology, pathogenesis, complications, screening, and management. Although CFRD continues to be associated with increased rates of mortality in the cystic fibrosis (CF) population, this has improved over the past several years, and the previous sex difference is no longer present. Recent studies support that CFRD is primarily caused by insulin deficiency due to loss of beta cells, which may occur via a number of mechanisms including oxidative stress. Aggressive screening programs with oral-glucose tolerance testing and early treatment with insulin for patients with CFRD with or without fasting hyperglycemia have led to improvements in nutritional states and lung function. Oral agents do not appear to be effective in CFRD. CFRD is the most common comorbidity in the CF population and is associated with microvascular complications and protein catabolism leading to worse health outcomes. Recognition of glycemic abnormalities through aggressive screening has led to improvements in nutritional status, pulmonary function, and mortality rates.


Ibandronate in osteoporosis: preclinical data and rationale for intermittent dosing.
Ibandronate is a highly potent, nitrogen-containing bisphosphonate. Unlike most other bisphosphonates, it is under clinical development for both oral and intravenous (i.v.) administration. Ibandronate can be used in convenient intermittent regimens that may optimize therapeutic outcome with enhanced compliance by patients. The preclinical pharmacokinetics (PK) and pharmacology of ibandronate have been extensively explored in a large preclinical development program involving various recommended animal models of human osteoporosis. These experimental studies of ibandronate indicate that the preclinical pharmacology and PK profile of ibandronate are broadly similar to those of other nitrogen-containing bisphosphonates. The efficacy of intermittent administration of subcutaneous (s.c.) and i.v. ibandronate has been demonstrated in four animal models (rat, dog, minipig, and monkey). Thus in rats, dogs, and monkeys with estrogen depletion, and in minipigs with glucocorticoid-induced bone loss, ibandronate administered s.c. or i.v. with extended intervals between doses reduces bone turnover, increases bone mineral density, and maintains bone quality in a dose-dependent manner. Furthermore, studies in rats and dogs comparing continuous and intermittent treatment schedules indicate similar efficacy when the same cumulative dose is applied over the duration of the study. These studies with ibandronate illustrate the concept that the total cumulative dose of bisphosphonate administered determines the response, independent of whether the dose is given daily or less frequently in a given time period. The efficacy of intermittent regimens has also been verified in models of secondary osteoporosis due to secondary hyperparathyroidism or immobilization (both in rats), or due to glucocorticoids in minipigs. Important factors for determining efficacy and the magnitude of response are the doses given, the length of the interval between doses, and the underlying bone turnover rate. The mechanisms underlying the remarkable efficacy of intermittent bisphosphonate dosing are not fully understood and further research is needed. Importantly, ibandronate is the only bisphosphonate so far proven to reduce the risk of vertebral fractures significantly with a between-dose interval >2 months, in a prospective clinical trial. Collectively, the preclinical studies on ibandronate have provided a sound basis for the design of the convenient regimens currently being examined in clinical trials.


Theoretical effects of transmembrane electroneutral exchange on membrane potential.
Transmembrane electroneutral transport mechanisms [e.g., Na/H exchange, Cl/HCO3 exchange, (K + Cl) cotransport] have recently been identified in a wide variety of cell types. If these exchanges sum to give a net electroneutral Na/K exchange, they may hyperpolarize the membrane potential beyond the value calculated from the Mullins-Noda equation, provided the cell maintains steady state intracellular ionic concentrations. In extreme circumstances, the membrane potential could hyperpolarize beyond the potassium reversal potential. This effect is mediated by the electrogenic Na/K pump. If either Na or K exchanges electroneutrally against a third ion (e.g., Na/Ca exchange), then the exchange may depolarize the membrane potential.


Conformational changes occurring upon reduction and NO binding in nitrite reductase from Pseudomonas aeruginosa.
Nitrite reductase (NiR) from Pseudomonas aeruginosa (EC 188.8.131.52) (NiR-Pa) is a soluble enzyme catalyzing the reduction of nitrite (NO2-) to nitric oxide (NO). The enzyme is a 120 kDa homodimer, in which each monomer carries one c and one d1 heme. The oxidized and reduced forms of NiR from Paracoccus denitrificans GB17 (previously called Thiosphaera pantotropha) (NiR-Pd) have been described [Fülop, V., et al. (1995) Cell 81, 369-377; Williams, P. A., et al. (1997) Nature 389, 406-412], and we recently reported on the structure of oxidized NiR-Pa at 2.15 A [Nurizzo, D., et al. (1997) Structure 5, 1157-1171]. Although the domains carrying the d1 heme are almost identical in both NiR-Pa and NiR-Pd oxidized and reduced structures, the c heme domains show a different pattern of c heme coordination, depending on the species and the redox state. The sixth d1 heme ligand in oxidized NiR-Pd was found to be Tyr25, whereas in NiR-Pa, the homologuous Tyr10 does not interact directly with Fe3+, but via a hydroxide ion. Furthermore, upon reduction, the axial ligand of the c heme of NiR-Pd changes from His17 to Met108. Finally, in the oxidized NiR-Pa structure, the N-terminal stretch of residues (1-29) of one monomer interacts with the other monomer (domain swapping), which does not occur in NiR-Pd. Here the structure of reduced NiR-Pa is described both in the unbound form and with the physiological product, NO, bound at the d1 heme active site. Although both structures are similar to that of reduced NiR-Pd, significant differences with respect to oxidized NiR-Pd were observed in two regions: (i) a loop in the c heme domain (residues 56-62) is shifted 6 A away and (ii) the hydroxide ion, which is the sixth coordination ligand of the heme, is removed upon reduction and NO binding and the Tyr10 side chain rotates away from the position adopted in the oxidized form. The conformational changes observed in NiR-Pa as the result of reduction are less extensive than those occurring in NiR-Pd. Starting with oxidized structures that differ in many respects, the two enzymes converge, yielding reduced conformations which are very similar to each other, which indicates that the conformational changes involved in catalysis are considerably diverse.


"Freshwater killer whales": beaching behavior of an alien fish to hunt land birds.
The behavioral strategies developed by predators to capture and kill their prey are fascinating, notably for predators that forage for prey at, or beyond, the boundaries of their ecosystem. We report here the occurrence of a beaching behavior used by an alien and large-bodied freshwater predatory fish (Silurus glanis) to capture birds on land (i.e. pigeons, Columbia livia). Among a total of 45 beaching behaviors observed and filmed, 28% were successful in bird capture. Stable isotope analyses (δ(13)C and δ(15)N) of predators and their putative prey revealed a highly variable dietary contribution of land birds among individuals. Since this extreme behavior has not been reported in the native range of the species, our results suggest that some individuals in introduced predator populations may adapt their behavior to forage on novel prey in new environments, leading to behavioral and trophic specialization to actively cross the water-land interface.


Liver fat content is associated with increased carotid atherosclerosis in a Chinese middle-aged and elderly population: the Shanghai Changfeng study.
Nonalcoholic fatty liver disease is closely associated with metabolic syndrome and cardiovascular disease (CVD). We investigated whether the liver fat content (LFC) is independently associated with carotid artery intima-media thickness (CIMT) and evaluated the contribution of the LFC to the increased CIMT. We conducted a community-based study among 1809 participants (682 males and 1127 females) from the Changfeng Study who were at least 45 years old. A standard interview, anthropometrics and laboratory parameters were performed for each participant. The CIMT was determined by ultrasonography. A large CIMT value was defined as 75th percentile of the maximum CIMT. A standardised ultrasonographic hepatic-renal ratio was used to assess the LFC. The median LFC value was 6% (interquartile range, 3-14%), and 34% of the subjects had hepatic steatosis based on the criteria for diagnosis of steatosis by quantitative ultrasound. The maximum CIMT, average CIMT and plaque score were strongly associated with the LFC (β = 0.319, 0.324 and 1.361, respectively; all P < 0.05) after adjustment for age, gender, smoking history, low-density lipoprotein cholesterol and metabolic syndrome. The multiple logistic regression analysis showed that a 1 SD increase in the LFC, the OR for having a large CIMT was 1.350 (95% CI 1.180-1.545; P < 0.001) after adjustment for all potential confounders. These results suggest that the LFC is independently associated with carotid atherosclerosis in the Chinese population, and that the risk of atherosclerosis is proportional to the degree of hepatic steatosis.


Comparative study of acute and mid-term complications with leadless and transvenous cardiac pacemakers.
Leadless cardiac pacemakers (LCPs) aim to mitigate lead- and pocket-related complications seen with transvenous pacemakers (TVPs). The purpose of this study was to compare complications between the LCP cohort from the LEADLESS Pacemaker IDE Study (Leadless II) trial and a propensity score-matched real-world TVP cohort. The multicenter LEADLESS II trial evaluated the safety and efficacy of the Nanostim LCP (Abbott, Abbott Park, IL) using structured follow-up, with serious adverse device effects independently adjudicated. TVP data were obtained from Truven Health MarketScan claims databases for patients implanted with single-chamber TVPs between April 1, 2010 and March 31, 2014 and more than 1 year of preimplant enrollment data. Comorbidities and complications were identified via International Classification of Diseases, Ninth Revision and Current Procedural Terminology codes. Short-term (≤1 months) and mid-term (>1-18 months) complications were compared between the LCP cohort and a propensity score-matched subset of the TVP cohort. Among 718 patients with LCPs (mean age 75.6 ± 11.9 years; 62% men) and 1436 patients with TVPs (mean age 76.1 ± 12.3 years; 63% men), patients with LCPs experienced fewer complications (hazard ratio 0.44; 95% confidence interval 0.32-0.60; P < .001), including short-term (5.8% vs 9.4%; P = .01) and mid-term (0.56% vs 4.9%; P < .001) events. In the short-term time frame, patients with LCPs had more pericardial effusions (1.53% vs 0.35%; P = .005); similar rates of vascular events (1.11% vs 0.42%; P = .085), dislodgments (0.97% vs 1.39%; P = .54), and generator complications (0.70% vs 0.28%; P = .17); and no thoracic trauma compared to patients with TVPs (rate of thoracic trauma 3.27%). In short- and mid-term time frames, TVP events absent from the LCP group included lead-related, pocket-related, and infectious complications. Patients with LCPs experienced fewer overall short- and mid-term complications, including infectious and lead- and pocket-related events, but more pericardial effusions, which were uncommon but serious.


Structural functionality of skeletal muscle mitochondria and its correlation with metabolic diseases.
The skeletal muscle is one of the largest organs in the mammalian body. Its remarkable ability to swiftly shift its substrate selection allows other organs like the brain to choose their preferred substrate first. Healthy skeletal muscle has a high level of metabolic flexibility, which is reduced in several metabolic diseases, including obesity and Type 2 diabetes (T2D). Skeletal muscle health is highly dependent on optimally functioning mitochondria that exist in a highly integrated network with the sarcoplasmic reticulum and sarcolemma. The three major mitochondrial processes: biogenesis, dynamics, and mitophagy, taken together, determine the quality of the mitochondrial network in the muscle. Since muscle health is primarily dependent on mitochondrial status, the mitochondrial processes are very tightly regulated in the skeletal muscle via transcription factors like peroxisome proliferator-activated receptor-γ coactivator-1α, peroxisome proliferator-activated receptors, estrogen-related receptors, nuclear respiratory factor, and Transcription factor A, mitochondrial. Physiological stimuli that enhance muscle energy expenditure, like cold and exercise, also promote a healthy mitochondrial phenotype and muscle health. In contrast, conditions like metabolic disorders, muscle dystrophies, and aging impair the mitochondrial phenotype, which is associated with poor muscle health. Further, exercise training is known to improve muscle health in aged individuals or during the early stages of metabolic disorders. This might suggest that conditions enhancing mitochondrial health can promote muscle health. Therefore, in this review, we take a critical overview of current knowledge about skeletal muscle mitochondria and the regulation of their quality. Also, we have discussed the molecular derailments that happen during various pathophysiological conditions and whether it is an effect or a cause.


Data interpretation for spectral sensors with correlated bands.
New classes of spectral sensors are emerging that have significant overlap in the band spectral response functions. While conventional sensors such as the Multispectral Thermal Images (MTI) or Landsat may have responses with a few percent overlap between adjacent bands, some of the emerging sensors can have more than 50% correlation among all spectral bands. The traditional geometrical models used to describe spectral data fail when such high levels of correlation exist. In this paper we present a generalized geometrical model that relies on functional analysis. We define a sensor space and a scene space that can be used to characterize the suitability of a sensor for a particular spectral sensing task. We demonstrate that classifiers based on first-order distance and angle metrics fail for sensors with highly correlated bands unless appropriate preprocessing is carried out. We further show that second-order statistical classifiers are largely immune to many of the problems introduced by the correlated band responses.


Supported Intervention Versus Intervention Alone for Management of Fecal Incontinence in Patients With Inflammatory Bowel Disease: A Multicenter Mixed-Methods Randomized Controlled Trial.
The aims of this study were to test a noninvasive self-management intervention supported by specialist nurses versus intervention alone in patients with inflammatory bowel disease (IBD) experiencing fecal incontinence and to conduct a qualitative evaluation of the trial. Multicenter, parallel-group, open-label, mixed-methods randomized controlled trial (RCT). The sample comprised patients from a preceding case-finding study who reported fecal incontinence and met study requirements; the RCT was delivered via IBD outpatient clinics in 6 hospitals (5 in major UK cities, 1 rural) between September 2015 and August 2017. Sixteen participants and 11 staff members were interviewed for qualitative evaluation. Adults with IBD completed the study activities over a 3-month period following randomization. Each participant received either four 30-minute structured sessions with an IBD clinical nurse specialist and a self-management booklet or the booklet alone. Low retention numbers precluded statistical analysis; individual face-to-face or telephone interviews, recorded digitally and transcribed professionally, were conducted to evaluate the RCT. Transcripts were analyzed thematically using an inductive method. Sixty-seven participants (36%) of the targeted 186 participants were recruited. The groups comprised 32 participants (17% of targeted participants) allocated to the nurse + booklet intervention and 35 (18.8% of targeted participants) allocated to the booklet alone. Less than one-third (n = 21, 31.3%) completed the study. Given the low recruitment and high attrition, statistical analysis of quantitative data was considered futile. Participant interviews were conducted concerning study participation and 4 themes emerged that described experiences of patients and staff. These data provided insights into reasons for low recruitment and high attrition, as well as challenges of delivering resource-heavy studies in busy health service environments. Alternative approaches to trials of nurse-led interventions in hospital settings are needed as many interfering factors may prevent successful completion.


Improving conservation of Florida manatees (Trichechus manatus latirostris): conceptualization and contributions toward a regional warm-water network management strategy for sustainable winter habitat.
We used southwestern Florida as a case study to lay the groundwork for an intended and organized decision-making process for managing warm-water habitat needed by endangered manatees to survive winters in Florida. Scientists and managers have prioritized (a) projecting how the network of warm-water sites will change over the next 50 years as warmed industrial discharges may expire and as flows of natural springs are reduced through redirection of water for human uses, and (b) mitigating such changes to prevent undue consequences to manatees. Given the complexities introduced by manatee ecology; agency organizational structure; shifting public demands; fluctuating resource availability; and managing within interacting cultural, social, political, and environmental contexts, it was clear that a structured decision process was needed. To help promote such a process, we collected information relevant to future decisions including maps of known and suspected warm-water sites and prototyped a characterization of sites and networks. We propose steps that would lead to models that might serve as core tools in manatee/warm-water decision-making, and we summarized topics relevant for informed decision-making (e.g., manatee spatial cognition, risk of cold-stress morbidity and mortality, and human dimensions). A major impetus behind this effort is to ensure proactively that robust modeling tools are available well in advance of the anticipated need for a critical management decision.


Probing charges on solid-liquid interfaces with the resistive-pulse technique.
Our manuscript addresses the issue of probing an effective surface charge that any surface can acquire at the solid/liquid interface. Even if a particle is predicted to be neutral based on its chemical structure, the particle can carry finite surface charges when placed in a solution. We present tools to probe the presence of surface charge densities of meso-particles, characterized with zeta potentials below 10 mV. The tools are based on the resistive-pulse technique, which uses single pores to probe properties of individual objects including molecules, particles, and cells. The presented experiments were performed with particles 280 and 400 nm in diameter and single pores with opening diameter tuned between ∼ 200 nm and one micron. Surface charge properties were probed in two modes: (i) the passage of the particles through pores of diameters larger than the particles, as well as (ii) an approach curve of a particle to a pore that is smaller than the particle diameter. The curve in the latter mode has a biphasic character starting with a low-amplitude current decrease, followed by a current enhancement reaching an amplitude of ∼10% of the baseline current. The current increase was long-lasting and stable, and shown to strongly depend on the particle surface charge density. The results are explained via voltage-modulation of ionic concentrations in the pore.


Influence of CT contrast agents on dose calculations in a 3D treatment planning system.
In treatment planning for conformal radiotherapy, it is possible to attain high accuracy in contouring the outline of the target volume and organs at risk by giving contrast agents (CAs) during the CT scan. In order to calculate the dose from the CT scans, Hounsfield units (HUs) are converted into the parameters of a standard set of tissues with given atomic composition and density. Due to the high atomic number of contrast media, high HU values are obtained during CT scanning. The Helax treatment planning system, for instance, erroneously takes them for high density tissue. This misinterpretation results in high absorption of high-energy photon beams and thus affects the dose calculation significantly. A typical bolus diameter of 3 cm and HU values of 1,400 cause an overdose of up to 7.4% and 5.4% for 6 MV and 25 MV photon beams, respectively. However, since the CA concentration and its expansion are rather low the effect on dose calculation in treatment planning is negligible.


Hydrogen-bonding alcohol-water interactions in binary ethanol, 1-propanol, and 2-propanol+methane structure II clathrate hydrates.
The small alcohols ethanol, 1-propanol, and 2-propanol are miscible in water, form strong hydrogen bonds with water molecules, and are usually known as inhibitors for clathrate hydrate formation. However, in the presence of methane or other help gases, clathrate hydrates of these substances have been synthesized. In this work, molecular dynamics simulations are used to characterize guest-host hydrogen bonding, microscopic structures, and guest dynamics of binary structure II clathrate hydrates of methane (small cages) with ethanol, 1-propanol, and 2-propanol in the temperature range of 100-250 K to gain insight into the stability of these materials. We observe that these alcohols form structures with dynamic long-lived ( approximately 10 ps) guest-host hydrogen bonds in the hydrate phases while maintaining the general cage structure of the sII clathrate hydrate form. The hydroxyl groups of ethanol, 1-propanol, and 2-propanol act as both proton acceptors and proton donors and there is a considerable probability of simultaneous hydrogen bonding between O and H hydroxyl atoms with different cage water molecules. The presence of the nonpolar methane molecule and the hydrophobic moieties of the alcohols stabilize the hydrate phase, despite the strong and prevalent alcohol-water hydrogen bonding. The effect of the alcohol molecules on the structural properties of the hydrate and the effect of guest-host hydrogen bonding on the guest dynamics are studied.


Strength and fatigability of the dominant and nondominant hip abductors.
Contralateral muscular imbalances have been suggested to increase the risk of lower extremity injury. Previous groups have assessed strength of the quadriceps and hamstring muscle groups; however, no previous authors have compared bilateral hip-abductor muscular performance. To examine the strength and fatigability of the hip abductors in the dominant and nondominant legs. Single-group, repeated-measures design. Musculoskeletal laboratory. Forty-two healthy subjects (23 males, 19 females; age = 24.3 +/- 2.7 years, height = 173.4 +/- 9.8 cm, mass = 73.7 +/- 11.6 kg). Subjects performed three 5-second maximal voluntary isometric contraction (MVIC) trials of the hip abductors with the dominant and nondominant legs. Following the maximal strength trials, subjects performed a submaximal (50% of MVIC) 30-second fatigue trial with each leg. Peak torque (PT) was recorded from each MVIC trial. Surface electromyography was used to record muscle activity during the fatigue trials. Power spectral analysis was used to determine the median frequency of each 0.512-second portion of the fatigue trials. Median frequencies were plotted against time, and linear regression was used to determine the median frequency slope (MF(slope)). Data were analyzed using 2-tailed, paired t tests. Hip-abduction PT of the dominant leg (81.0 +/- 23.7 Nm) was significantly larger than that of the nondominant leg (76.1 +/- 9.9 Nm, P = 0.02). There was no difference in MF(slope) between the dominant (-0.37 +/- 0.29) and nondominant limbs (-0.35 +/- 0.34, P = 0.84). The PT and MF(slope) were not significantly correlated (r = -0.07, P = 0.53). Hip-abduction strength differences exist between the dominant and nondominant legs. Measures of strength and fatigability were poorly related; therefore, clinicians may opt to assess hip strength and fatigability independent of each another.


Temporal coding: assembly formation through constructive interference.
Temporal coding is studied for an oscillatory neural network model with synchronization and acceleration. The latter mechanism refers to increasing (decreasing) the phase velocity of each unit for stronger (weaker) or more coherent (decoherent) input from the other units. It has been demonstrated that acceleration generates the desynchronization that is needed for self-organized segmentation of two overlapping patterns. In this letter, we continue the discussion of this remarkable feature, giving also an example with several overlapping patterns. Due to acceleration, Hebbian memory implies a frequency spectrum for pure pattern states, defined as coherent patterns with decoherent overlapping patterns. With reference to this frequency spectrum and related frequency bands, the process of pattern retrieval, corresponding to the formation of temporal coding assemblies, is described as resulting from constructive interference (with frequency differences due to acceleration) and phase locking (due to synchronization).


Vapochromic features of new luminogens based on julolidine-containing styrene copolymers.
We report on vapochromic films suitable for detecting volatile organic compounds (VOCs), based on new polystyrene copolymers containing julolidine fluorescent molecular rotors (JCAEM). Poly(styrene-co-hydroxyethylmethacrylate) copolymers functionalized with cyanovinyl-julolidine moieties of different compositions were prepared, (P(STY-co-JCAEM)(m) with m = 0.06-0.61). The sensing performance of the spin-coated copolymer films demonstrated significant vapochromism when exposed to VOCs characterized by high vapour pressure and a favourable interaction with the polymer matrix, such as Et2O and CH2Cl2. It is worth mentioning that the fluorescence decrease rate was 7 times faster than that of previously investigated julolidine-based fluorescent molecular rotors dispersed in PS films. This phenomenon was attributed to the better control of the JCAEM moiety distribution in the polymer matrix conferred by the covalent approach, combined with a minimal film thickness of 4 microns. These factors, in concert, strongly accelerate the deactivation pathways of the JCAEM units in the presence of VOCs which interact well. Overall, the present results support the use of julolidine-enriched styrene copolymers as effective chromogenic materials suitable for the fast detection of VOCs.


Inhibition of human vascular smooth muscle cell migration and proliferation by beta-cyclodextrin tetradecasulfate.
Smooth muscle cell migration and proliferation are important regulatory processes in the development of intimal thickening after vascular injury. beta-cyclodextrin tetradecasulfate, an orally active synthetic heparin mimic, is effective in inhibiting rabbit aortic smooth muscle cell proliferation in vitro and in limiting restenosis in an experimental angioplasty restenosis model in rabbits (Hermann et al., 1993). However, its effects on migration are unknown, as are its effects on human vascular smooth muscle cell biology in general. Using a Transwell assay system, we demonstrated a dose dependent inhibition of human vascular smooth muscle cell random migration for beta-cyclodextrin tetradecasulfate with half maximal inhibition between 100-500 micrograms/ml and 85 +/- 1% inhibition at 10(3) micrograms/ml (P < .001, n = 4). At this latter concentration, inhibition of migration was also demonstrable using a linear under-agarose assay, where the mean velocity for beta-cyclodextrin tetradecasulfate-treated cells (8 +/- 2 microns/h, +/- S.E.) was significantly less than for control cells (21 +/- 4, P < .01), but equaled that of control cells 48 h after drug withdrawal (21 +/- 1, P = NS). Single cell analysis over 17 h using time lapse video microscopy revealed significant inhibition of total migration pathway distance for beta-cyclodextrin tetradecasulfate-treated smooth muscle cells compared with control smooth muscle cells (0.40 +/- 0.03 mm vs. 0.73 +/- 0.03, P < .01). We also demonstrated a dose-dependent inhibition of serum-induced proliferation by beta-cyclodextrin tetradecasulfate in both cultured human umbilical vein and coronary artery smooth muscle cells. To assess whether beta-cyclodextrin tetradecasulfate had any direct cellular toxicity, we measured the release of intracellular LDH at 6 or 24 h. At 10(3) micrograms/ml or less, there was no increase in LDH release compared with untreated cultures. Thus, beta-cyclodextrin tetradecasulfate may be an effective agent in inhibiting intimal thickening after vascular injury by limiting both smooth muscle cell migration and proliferation.


Comparison of Agar Media for Detection and Quantification of Shiga Toxin-Producing Escherichia coli in Cattle Feces.
The isolation and quantification of non-O157 Shiga toxin-producing Escherichia coli (STEC) from cattle feces are challenging. The primary objective of this study was to evaluate the performance of selected agar media in an attempt to identify an optimal medium for the detection and quantification of non-O157 STEC in cattle feces. Comparison studies were performed using CHROMagar STEC, Possé differential agar (Possé), Possé modified by the reduction or addition of antimicrobials, STEC heart infusion washed blood agar with mitomycin C (SHIBAM), and SHIBAM modified by the addition of antimicrobials. Fourteen STEC strains, two each belonging to serogroups O26, O45, O103, O111, O121, O145, and O157, were used to test detection in inoculated fecal suspensions at concentrations of 10(2) or 10(3) CFU/g. One STEC strain from each of these seven serogroups was used to estimate the concentration of recovered STEC in feces inoculated at 10(3), 10(4), or 10(5) CFU/g. Significantly more suspensions (P < 0.05) were positive for STEC when plated on Possé containing reduced concentrations of novobiocin and potassium tellurite compared with SHIBAM, but not SHIBAM modified by containing these same antimicrobials at the same concentrations. Numerically, more suspensions were positive for STEC by using this same form of modified Possé compared with Possé, but this difference was not statistically significant. More suspensions were positive for STEC cultured on CHROMagar STEC compared with those on Possé (P < 0.05) and on modified Possé (P = 0.05). Most inoculated fecal suspensions below 10(4) CFU/g of feces were underestimated or not quantifiable for the concentration of STEC by using CHROMagar STEC or modified Possé. These results suggest that CHROMagar STEC performs better than Possé or SHIBAM for detection of STEC in bovine feces, but adjustments in the concentrations of novobiocin and potassium tellurite in the latter two media result in significant improvements in their performance.


Epidemiological impact of a syphilis vaccine: a simulation study.
Despite the availability of inexpensive antimicrobial treatment, syphilis remains prevalent worldwide, affecting millions of individuals. Furthermore, syphilis infection is suspected of increasing both susceptibility to, and tendency to transmit, HIV. Development of a syphilis vaccine would be a potentially promising step towards control, but the value of dedicating resources to vaccine development should be evaluated in the context of the anticipated benefits. Here, we use a detailed mathematical model to explore the potential impact of rolling out a hypothetical syphilis vaccine on morbidity from both syphilis and HIV and compare it to the impact of expanded 'screen and treat' programmes using existing treatments. Our results suggest that an efficacious vaccine has the potential to sharply reduce syphilis prevalence under a wide range of scenarios, while expanded treatment interventions are likely to be substantially less effective. Our modelled interventions in our simulated study populations are expected to have little effect on HIV, and in some scenarios lead to small increases in HIV incidence, suggesting that interventions against syphilis should be accompanied with interventions against other sexually transmitted infections to prevent the possibility that lower morbidity or lower perceived risk from syphilis could lead to increases in other sexually transmitted diseases.


Increased stability and DNA site discrimination of "single chain" variants of the dimeric beta-barrel DNA binding domain of the human papillomavirus E2 transcriptional regulator.
Human papillomavirus infects millions of people worldwide and is a causal agent of cervical cancer in women. The HPV E2 protein controls the expression of all viral genes through binding of its dimeric C-terminal domain (E2C) to its target DNA site. We engineered monomeric versions of the HPV16 E2C, in order to probe the link of the dimeric beta-barrel fold to stability, dimerization, and DNA binding. Two single-chain variants, with 6 and 12 residue linkers (scE2C-6 and scE2C-12), were purified and characterized. Spectroscopy and crystallography show that the native structure is unperturbed in scE2C-12. The single chain variants are stabilized with respect to E2C, with effective concentrations of 0.6 to 6 mM. The early folding events of the E2C dimer and scE2C-12 are very similar and include formation of a compact species in the submillisecond time scale and a non-native monomeric intermediate with a half-life of 25 ms. However, monomerization changes the unfolding mechanism of the linked species from two-state to three-state, with a high-energy intermediate. Binding to the specific target site is up to 5-fold tighter in the single chain variants. Nonspecific DNA binding is up to 7-fold weaker in the single chain variants, leading to an overall 10-fold increased site discrimination capacity, the largest described so far for linked DNA binding domains. Titration calorimetric binding analysis, however, shows almost identical behavior for dimer and single-chain species, suggesting very subtle changes behind the increased specificity. Global analysis of the mechanisms probed suggests that the dynamics of the E2C domain, rather than the structure, are responsible for the differential properties. Thus, the plastic and dimeric nature of the domain did not evolve for a maximum affinity, specificity, and stability of the quaternary structure, likely because of regulatory reasons and for roles other than DNA binding played by partly folded dimeric or monomeric conformers.