Dystrophia Helsinglandica--corneal morphology, topography and sensitivity in a hereditary corneal disease with recurrent erosive episodes.
The aim of this study was to describe the morphology, corneal topography and sensitivity in individuals with Dystrophia Helsinglandica. This autosomal dominant corneal disease is characterized by recurrent corneal erosive episodes and progressive subepithelial fibrosis not significantly affecting visual acuity. The corneas of nine affected and nine unaffected individuals were examined using slit-lamp biomicroscopy, in vivo confocal microscopy (IVCM) and videokeratography. Corneal mechanical sensitivity was also measured using a non-contact esthesiometer. Slit-lamp biomicroscopy revealed that the affected individuals represented different stages of corneal changes, from a nearly normal cornea to subepithelial fibrosis of the central cornea. Corneal changes in affected individuals did not significantly decrease the best spectacle-corrected visual acuity. In vivo confocal microscopy detected morphological changes in the epithelium and stroma. Subepithelial opacity formation including altered keratocytes could be found in the anterior stroma in all affected eyes. With the exception of two eyes (one affected and one unaffected), all videokeratographies showed irregular astigmatism. Corneal sensitivity was significantly lower in affected individuals (p = 0.01). Age and corneal sensitivity showed no correlation. The main morphological findings in affected individuals were discrete and progressive subepithelial fibrosis, in the in vivo confocal microscope corresponding to optically dense extracellular matrix and activated keratocytes. Subbasal nerve morphology was changed in the affected family members who also showed a decreased corneal sensitivity. The findings are per se not specific to the disease. The changes probably reflect a healing response to erosive events on the corneal surface influenced by the genotype.


An endogenous circadian rhythm in sleep inertia results in greatest cognitive impairment upon awakening during the biological night.
Sleep inertia is the impaired cognitive performance immediately upon awakening, which decays over tens of minutes. This phenomenon has relevance to people who need to make important decisions soon after awakening, such as on-call emergency workers. Such awakenings can occur at varied times of day or night, so the objective of the study was to determine whether or not the magnitude of sleep inertia varies according to the phase of the endogenous circadian cycle. Twelve adults (mean, 24 years; 7 men) with no medical disorders other than mild asthma were studied. Following 2 baseline days and nights, subjects underwent a forced desynchrony protocol composed of seven 28-h sleep/wake cycles, while maintaining a sleep/wakefulness ratio of 1:2 throughout. Subjects were awakened by a standardized auditory stimulus 3 times each sleep period for sleep inertia assessments. The magnitude of sleep inertia was quantified as the change in cognitive performance (number of correct additions in a 2-min serial addition test) across the first 20 min of wakefulness. Circadian phase was estimated from core body temperature (fitted temperature minimum assigned 0 degrees ). Data were segregated according to: (1) circadian phase (60 degrees bins); (2) sleep stage; and (3) 3rd of the night after which awakenings occurred (i.e., tertiary 1, 2, or 3). To control for any effect of sleep stage, the circadian rhythm of sleep inertia was initially assessed following awakenings from Stage 2 (62% of awakening occurred from this stage; n = 110). This revealed a significant circadian rhythm in the sleep inertia of cognitive performance (p = 0.007), which was 3.6 times larger during the biological night (circadian bin 300 degrees , approximately 2300-0300 h in these subjects) than during the biological day (bin 180 degrees , approximately 1500-1900 h). The circadian rhythm in sleep inertia was still present when awakenings from all sleep stages were included (p = 0.004), and this rhythm could not be explained by changes in underlying sleep drive prior to awakening (changes in sleep efficiency across circadian phase or across the tertiaries), or by the proportion of the varied sleep stages prior to awakenings. This robust endogenous circadian rhythm in sleep inertia may have important implications for people who need to be alert soon after awakening.


Patterns in trouble sleeping among women at mid-life: results from a British prospective cohort study.
Although trouble sleeping is a common problem among women at mid-life, patterns in trouble sleeping relating to social and health-related risk factors are unclear. This analysis describes the dynamics of trouble sleeping among women at mid-life. The National Survey of Health and Development is a nationally representative study of births in 1946 in England, Scotland, and Wales followed up through mid-life. Multistate life table analysis utilised 893 women interviewed annually between ages 48 to 54 years. Women spent an average of 2.6 years with trouble sleeping, and the average length of a continuous episode of trouble sleeping was 2.4 years. Among women who reported at least one episode, the average number of episodes was 1.5. Health-related risk factors at age 43 of number of physical conditions, anxiety and depression symptoms, use of prescription medication, and current or past trouble sleeping were related to increased total and per episode duration of trouble sleeping over the 7-year study interval and increased duration per episode. Differences associated with these risk factors ranged from 1.2 to 1.8 years for duration over the study interval and 0.5 to 0.8 years per episode. There was no association between average number of episodes per woman reporting at least one episode and these health-related risk factors at age 43. This study provides support for association between increased duration of trouble sleeping, in total and per episode, and health risk factors at age 43, suggesting a long-term relationship between risk factors and sleep.


Three-dimensional modeling of removal torque and fracture progression around implants.
In the present study, a model for simulations of removal torque experiments was developed using finite element method. The interfacial retention and fracturing of the surrounding material caused by the surface features during torque was analyzed. It was hypothesized that the progression of removal torque and the phases identified in the torque response plot represents sequential fractures at the interface. The 3-dimensional finite element model fairly accurately predicts the torque required to break the fixation of acid-etched implants, and also provides insight to how sequential fractures progress downwards along the implant side.


Behaviroal, pharmacological, and molecular characterization of an amphibian cannabinoid receptor.
Investigation of cannabinoid pharmacology in a vertebrate with a phylogenetic history distinct from that of mammals may allow better understanding of the physiological significance of cannabinoid neurochemistry. Taricha granulosa, the roughskin newt, was used here to characterize an amphibian cannabinoid receptor. Behavioral experiments demonstrated that the cannabinoid agonist levonantradol inhibits both newt spontaneous locomotor activity and courtship clasping behavior. Inhibition of clasping was dose-dependent and potent (IC(50) = 1.2 microgram per animal). Radioligand binding studies using [(3)H]CP-55940 allowed identification of a specific binding site (K(D) = 6.5 nM, B(max) = 1,853 fmol/mg of protein) in brain membranes. Rank order of affinity of several ligands was consistent with that reported for mammalian species (K(D), nM) : CP-55940 (3.8) > levonantradol (13.0) > WIN55212-2 (25.7) >> anandamide (1,665) approximately anandamide 100 microM phenylmethylsulfonyl fluoride (2,398). The cDNA encoding the newt CB1 cannabinoid receptor was cloned, and the corresponding mRNA of 5.9 kb was found to be highly expressed in brain. A nonclonal Chinese hamster ovary cell line stably expressing the newt CB1 cannabinoid receptor was prepared that allowed demonstration of cannabinoid-mediated inhibition of adenylate cyclase (EC 22.214.171.124) activity. This inhibition was dose-dependent and occurred at concentrations consistent with affinities determined through radioligand binding experiments. The behavioral, pharmacological, and molecular cloning results demonstrate that a CB1 cannabinoid receptor is expressed in the CNS of the roughskin newt. This amphibian CB1 is very similar in density, ligand binding affinity, ligand binding specificity, and amino acid sequence to mammalian CB1. The high degree of evolutionary conservation of cannabinoid signaling systems implies an important physiological role in vertebrate brain function.


Silver nanowire interactions with primary human alveolar type-II epithelial cell secretions: contrasting bioreactivity with human alveolar type-I and type-II epithelial cells.
Inhaled nanoparticles have a high deposition rate in the alveolar units of the deep lung. The alveolar epithelium is composed of type-I and type-II epithelial cells (ATI and ATII respectively) and is bathed in pulmonary surfactant. The effect of native human ATII cell secretions on nanoparticle toxicity is not known. We investigated the cellular uptake and toxicity of silver nanowires (AgNWs; 70 nm diameter, 1.5 μm length) with human ATI-like cells (TT1), in the absence or presence of Curosurf® (a natural porcine pulmonary surfactant with a low amount of protein) or harvested primary human ATII cell secretions (HAS; containing both the complete lipid as well as the full protein complement of human pulmonary surfactant i.e. SP-A, SP-B, SP-C and SP-D). We hypothesised that Curosurf® or HAS would confer improved protection for TT1 cells, limiting the toxicity of AgNWs. In agreement with our hypothesis, HAS reduced the inflammatory and reactive oxygen species (ROS)-generating potential of AgNWs with exposed TT1 cells. For example, IL-8 release and ROS generation was reduced by 38% and 29%, respectively, resulting in similar levels to that of the non-treated controls. However in contrast to our hypothesis, Curosurf® had no effect. We found a significant reduction in AgNW uptake by TT1 cells in the presence of HAS but not Curosurf. Furthermore, we show that the SP-A and SP-D are likely to be involved in this process as they were found to be specifically bound to the AgNWs. While ATI cells appear to be protected by HAS, evidence suggested that ATII cells, despite no uptake, were vulnerable to AgNW exposure (indicated by increased IL-8 release and ROS generation and decreased intracellular SP-A levels one day post-exposure). This study provides unique findings that may be important for the study of lung epithelial-endothelial translocation of nanoparticles in general and associated toxicity within the alveolar unit.


Cognitive Training Reorganizes Network Modularity in Traumatic Brain Injury.
Background. Graph-theoretic approaches are increasingly popular for identifying the patterns of disrupted neural systems after traumatic brain injury (TBI). However, the patterns of neuroplasticity in brain organization after cognitive training in TBI are less well understood. Objective. We identified the patterns of training-induced neuroplasticity of the whole-brain network in TBI, using resting-state functional connectivity and graph theory. Methods. A total of 64 civilians and veterans with TBI were randomized into either a strategy-based cognitive training group (n = 33) or a knowledge-based training group (active control group; n = 31) for 8 weeks. The participants experienced mild to severe TBI without focal damage and persistent cognitive dysfunctions. A subset of participants complained of subclinical but residual psychiatric symptoms. We acquired their resting-state functional magnetic resonance imaging before training, immediately posttraining, and 3 months posttraining. From participants' resting-state networks, we obtained the modularity, participation coefficient, within-module connectivity, global efficiency, and local efficiency over multiple network densities. We next performed longitudinal analyses on those measures corrected for multiple comparisons across network densities using false discovery rate (FDR). Results. Relative to the knowledge-based training group, the strategy-based cognitive training group had reduced modularity and increased participation coefficient, global efficiency, and local efficiency over time (Pnodal < .05; qFDR < 0.05). Brain behavior analysis revealed that the participation coefficient and global efficiency within the strategy-based cognitive training group correlated with trail-making scores in the context of training (Pnodal < .05; qFDR < 0.05). Conclusions. Cognitive training reorganized modular networks in TBI over the whole brain. Graph-theoretic approaches may be useful in identifying a potential brain-based marker of training efficacy in TBI.


Colony dimorphism in bradyrhizobium strains.
Ten isolates of Bradyrhizobium spp. which form two colony types were studied; the isolates originated from a range of legume species. The two colony types differed in the amount of gum formed or size or both, depending on the strain. Whole 7-day-old colonies of each type were subcultured to determine the proportion of cells which had changed to the other type. An iterative computerized procedure was used to determine the rate of switching per generation between the two types and to predict proportions reached at equilibrium for each strain. The predicted proportions of the wetter (more gummy) or larger colony type at equilibrium differed significantly between strains, ranging from 0.9999 (strain CIAT 2383) to 0.0216 (strain CIAT 2469), because some strains switched faster from dry to wet (or small to large) and others switched faster from wet to dry (or large to small). Predicted equilibrium was reached after about 140 generations in strain USDA 76. In all but one strain (CIAT 3030) the growth rate of the wetter colony type was greater than or similar to that of the drier type. The mean difference in generation time between the two colony types was 0.37 h. Doubling times calculated for either colony type after 7 days of growth on the agar surface ranged from 6.0 to 7.3 h. The formation of two persistent colony types by one strain (clonal or colony dimorphism) may be a common phenomenon among Bradyrhizobium strains.


Allergic reactions associated with metal alloys in porcelain-fused-to-metal fixed prosthodontic devices-A systematic review.
To systematically review the allergic reactions associated with metal alloys in porcelain-fused-to-metal (PFM) fixed prosthetic devices. After reviewing the titles and abstracts of the articles as well as removing duplicates, 22 articles were considered relevant. PubMed, Web of Science, ScienceDirect, and Google Scholar from 1970 to 2012 were evaluated, and randomized studies, review articles, case reports, cross-sectional surveys, and abstracts were included. Conference papers and posters were excluded. Although reported, allergic reactions to metallic alloys in the context of PFM devices are not well documented. Allergic reactions to high noble and noble metal alloy cores of palladium and gold and to base metal alloys nickel and cobalt in the context of PFM fixed partial dentures (FPDs) are reported. Each type of metal is associated with a different rate of allergic reactions, which may be attributed to the extent of corrosion of the alloy, population exposure, and the biologic environment. Because few studies document allergic reactions to metals that comprise PFM crowns and partial dentures, further research in this field is necessary to determine the frequency and type of reactions elicited. Though allergic reactions to metal alloys used in dentistry are well documented, only few articles focus on the correlation between FPDs and metal allergies. Thus, this paper surveys case reports of hypersensitivity reactions linked to FPDs and reviews the current literature on allergic reactions to the metallic elements comprising those devices.


Decision making for pancreatic resection in patients with intraductal papillary mucinous neoplasms.
To identify a practical approach for preoperative decision-making in patients with intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. Between March 1999 and November 2006, the clinical characteristics, pathological data and computed tomography/magnetic resonance imaging (CT/MRI) of 54 IPMNs cases were retrieved and analyzed. The relationships between the above data and decision-making for pancreatic resection were analyzed using SPSS 13.0 software. Univariate analysis of risk factors for malignant or invasive IPMNs was performed with regard to the following variables: carcinoembryonic antigen, carbohydrate antigen 19-9 (CA19-9) and the characteristics from CT/MRI images. Receiver operating characteristic (ROC) curve analysis for pancreatic resection was performed using significant factors from the univariate analysis. CT/MRI images, including main and mixed duct IPMNs, tumor size > 30 mm or a solid component appearance in the lesion, and preoperative serum CA19-9 > 37 U/mL had good predictive value for determining pancreatic resection (P < 0.05), but with limitations. Combining the above factors (CT/MRI images and CA19-9) improved the accuracy and sensitivity for determining pancreatic resection in IPMNs. Using ROC analysis, the area under the curve reached 0.893 (P < 0.01, 95%CI: 0.763-1.023), with a sensitivity, specificity, positive predictive value and negative predictive value of 95.2%, 83.3%, 95.2% and 83.3%, respectively. Combining preoperative CT/MRI images and CA19-9 level may provide useful information for surgical decision-making in IPMNs.


CCL20 Displays Antimicrobial Activity Against Cryptosporidium parvum, but Its Expression Is Reduced During Infection in the Intestine of Neonatal Mice.
CCL20 is a chemokine with antimicrobial activity. We investigated its expression and role during neonatal cryptosporidiosis, a worldwide protozoan enteric disease leading to severe diarrhea. Surprisingly, during infection by Cryptosporidium parvum, CCL20 production by the intestine of neonatal mice is reduced by a mechanism independent both of the enteric flora and of interferon γ, a key cytokine for the resolution of this infection. However, oral administration of recombinant CCL20 to neonatal mice significantly reduced the parasite load by a mechanism that was independent of immune cell recruitment and occurred instead by direct cytolytic activity on free stages of the parasite. MiR21 functionally targets CCL20 and is upregulated during the infection, thus contributing to the downregulation of the chemokine. Our findings demonstrate for the first time the direct antiparasitic activity of CCL20 against an enteric protozoan and its downregulation during C. parvum infection, which is detrimental to parasite clearance.


Different Polycomb group complexes regulate common target genes in Arabidopsis.
Polycomb group (PcG) proteins convey epigenetic inheritance of repressed transcriptional states. Although the mechanism of the action of PcG is not completely understood, methylation of histone H3 lysine 27 (H3K27) is important in establishing PcG-mediated transcriptional repression. We show that the plant PcG target gene PHERES1 is regulated by histone trimethylation on H3K27 residues mediated by at least two different PcG complexes in plants, containing the SET domain proteins MEDEA or CURLY LEAF/SWINGER. Furthermore, we identify FUSCA3 as a potential PcG target gene and show that FUSCA3 is regulated by MEDEA and CURLY LEAF/SWINGER. We propose that different PcG complexes regulate a common set of target genes during the different stages of plant development.


Sleep during transcendental meditation.
Five experienced practitioners of transcendental meditation spent appreciable parts of meditation sesions in sleep stages 2, 3, and 4. Time spent in each sleep stage varied both between sessions for a given subject and between subjects. In addition, we compare electroencephalogram records made during meditation with those made during naps taken at the same time of day. The range of states observed during meditation does not support the view that meditation produces a single, unique state of consciousness.


The validity of Iran's national university entrance examination (Konkoor) for predicting medical students' academic performance.
In Iran, admission to medical school is based solely on the results of the highly competitive, nationwide Konkoor examination. This paper examines the predictive validity of Konkoor scores, alone and in combination with high school grade point averages (hsGPAs), for the academic performance of public medical school students in Iran. This study followed the cohort of 2003 matriculants at public medical schools in Iran from entrance through internship. The predictor variables were Konkoor total and subsection scores and hsGPAs. The outcome variables were (1) Comprehensive Basic Sciences Exam (CBSE) scores; (2) Comprehensive Pre-Internship Exam (CPIE) scores; and (3) medical school grade point averages (msGPAs) for the courses taken before internship. Pearson correlation and regression analyses were used to assess the relationships between the selection criteria and academic performance. There were 2126 matriculants (1374 women and 752 men) in 2003. Among the outcome variables, the CBSE had the strongest association with the Konkoor total score (r = 0.473), followed by msGPA (r = 0.339) and the CPIE (r = 0.326). While adding hsGPAs to the Konkoor total score almost doubled the power to predict msGPAs (R2 = 0.225), it did not have a substantial effect on CBSE or CPIE prediction. The Konkoor alone, and even in combination with hsGPA, is a relatively poor predictor of medical students' academic performance, and its predictive validity declines over the academic years of medical school. Care should be taken to develop comprehensive admissions criteria, covering both cognitive and non-cognitive factors, to identify the best applicants to become "good doctors" in the future. The findings of this study can be helpful for policy makers in the medical education field.


Nephritogenic anti-DNA antibodies regulate gene expression in MRL/lpr mouse glomerular mesangial cells.
Lupus-associated IgG anti-double-stranded DNA antibodies are thought to be pathogenic in the kidney due to cross-reaction with glomerular antigens, leading subsequently to immune complex formation in situ and complement activation. We undertook this study to determine if pathogenic anti-DNA antibodies may also contribute to renal damage by directly influencing mesangial gene expression. Complementary DNA microarray gene profiling was performed in primary mesangial cells (derived from lupus-prone MRL/lpr mice) treated with pathogenic, noncomplexed anti-DNA antibodies. Significant gene up-regulation induced by anti-DNA antibodies as determined by microarray analysis was further investigated by real-time polymerase chain reaction and methods to detect the relevant proteins. Induction of proinflammatory genes by pathogenic antibodies was confirmed by comparing gene expression in glomeruli of old versus young MRL/lpr mice, and by antibody injection in vivo. Pathogenic, but not nonpathogenic, antibodies significantly induced a number of transcripts, including CXCL1/KC, LCN2, iNOS, CX3CL1/fractalkine, SERPINA3G, and IkappaBalpha ("marker genes"). Blocking of Fcgamma receptors or using Fcgamma chain-knockout mesangial cells had no effect on the gene regulation effect of the pathogenic antibody R4A, indicating a non-Fc-dependent mechanism. The glomerular expression of these marker genes increased over time with the development of glomerular antibody deposition and active nephritis in MRL/lpr mice. Moreover, injection of R4A into SCID mice in vivo significantly up-regulated glomerular marker gene expression. These findings indicate that the renal pathogenicity of anti-DNA antibodies may be attributed in part to their ability to directly modulate gene expression in kidney mesangial cells through both Fc-dependent and non-Fc-dependent mechanisms.


Indications of future performance of native and non-native adult oysters under acidification and warming.
Globally, non-native species (NNS) have been introduced and now often entirely replace native species in captive aquaculture; in part, a result of a perceived greater resilience of NSS to climate change and disease. Here, the effects of ocean acidification and warming on metabolic rate, feeding rate, and somatic growth was assessed using two co-occurring species of oysters - the introduced Pacific oyster Magallana gigas (formerly Crassostrea gigas), and native flat oyster Ostrea edulis. Biological responses to increased temperature and pCO2 combinations were tested, the effects differing between species. Metabolic rates and energetic demands of both species were increased by warming but not by elevated pCO2. While acidification and warming did not affect the clearance rate of O. edulis, M. gigas displayed a 40% decrease at 750 ppm pCO2. Similarly, the condition index of O. edulis was unaffected, but that of M. gigas was negatively impacted by warming, likely due to increased energetic demands that were not compensated for by increased feeding. These findings suggest differing stress from anthropogenic CO2 emissions between species and contrary to expectations, this was higher in introduced M. gigas than in the native O. edulis. If these laboratory findings hold true for populations in the wild, then continued CO2 emissions can be expected to adversely affect the functioning and structure of M. gigas populations with significant ecological and economic repercussions, especially for aquaculture. Our findings strengthen arguments in favour of investment in O. edulis restoration in UK waters.


Evidence for multiple, developmentally regulated isoforms of Ptprq on hair cells of the inner ear.
Ptprq is a receptor-like inositol lipid phosphatase associated with the shaft connectors of hair bundles. Three lines of evidence suggest Ptprq is a chondroitin sulfate proteoglycan: (1) chondroitinase ABC treatment causes a loss of the ruthenium-red reactive, electron-dense particles associated with shaft connectors, (2) chondroitinase ABC causes an increase in the electrophoretic mobility of Ptprq, and (3) hair bundles in the developing inner ear of wild-type mice, but not those of Ptprq(-/-) mice, react with monoclonal antibody (mAb) 473-HD, an IgM that recognizes the dermatan-sulfate-dependent epitope DSD1. Two lines of evidence indicate that there may be multiple isoforms of Ptprq expressed in hair bundles. First, although Ptprq is expressed throughout the lifetime of most hair cells, hair bundles in the mouse and chick inner ear only express the DSD1 epitope transiently during development. Second, mAb H10, a novel mAb that recognizes an epitope common to several avian inner-ear proteins including Ptprq, only stains mature hair bundles in the extrastriolar regions of the vestibular maculae. MAb H10 does not stain mature hair bundles in the striolar regions of the maculae or in the basilar papilla, nor does it stain immature hair bundles in any organ. Three distinct, developmentally regulated isoforms of Ptprq may therefore be expressed on hair bundles of the chick inner ear. Hair bundles in the mature chick ear that do not express the H10 epitope have longer shaft connectors than those that do, indicating the presence or absence of the H10 epitope on Ptprq may modulate the spacing of stereocilia.


Clonal anergy is induced in vitro by T cell receptor occupancy in the absence of proliferation.
Murine Th1 clones that receive signals through their TCR in the absence of APC-derived co-stimulatory signals do not produce IL-2 and instead become anergic, i.e., they are subsequently unable to produce IL-2 in response to Ag and normal APC. The critical cellular event required to prevent the induction of this anergic state appears to be T cell proliferation. Anergy was induced when T cell clones were stimulated under conditions where both TCR occupancy and costimulatory signals were provided but where proliferation in response to the IL-2 produced was prevented. Once induced, anergy could be reversed if the T cells were allowed to undergo multiple rounds of cell division. These results show that anergy is induced as a consequence of TCR occupancy in the absence of cell division; this can be achieved either by limiting IL-2 production because of deficient provision of co-stimulatory signals or by preventing response to IL-2.


Genotoxicity Expert Panel review: weight of evidence evaluation of the genotoxicity of glyphosate, glyphosate-based formulations, and aminomethylphosphonic acid.
In 2015, the International Agency for Research on Cancer (IARC) published a monograph concluding there was strong evidence for genotoxicity of glyphosate and glyphosate formulations and moderate evidence for genotoxicity of the metabolite aminomethylphosphonic acid (AMPA). These conclusions contradicted earlier extensive reviews supporting the lack of genotoxicity of glyphosate and glyphosate formulations. The IARC Monograph concluded there was strong evidence of induction of oxidative stress by glyphosate, glyphosate formulations, and AMPA. The Expert Panel reviewed the genotoxicity and oxidative stress data considered in the IARC Monograph, together with other available data not considered by IARC. The Expert Panel defined and used a weight of evidence (WoE) approach that included ranking of studies and endpoints by the strength of their linkage to events associated with carcinogenic mechanisms. Importantly, the Expert Panel concluded that there was sufficient information available from a very large number of regulatory genotoxicity studies that should have been considered by IARC. The WoE approach, the inclusion of all relevant regulatory studies, and some differences in interpretation of individual studies led to significantly different conclusions by the Expert Panel compared with the IARC Monograph. The Expert Panel concluded that glyphosate, glyphosate formulations, and AMPA do not pose a genotoxic hazard and the data do not support the IARC Monograph genotoxicity evaluation. With respect to carcinogenicity classification and mechanism, the Expert Panel concluded that evidence relating to an oxidative stress mechanism of carcinogenicity was largely unconvincing and that the data profiles were not consistent with the characteristics of genotoxic carcinogens.


Viral immediate-early proteins abrogate the modification by SUMO-1 of PML and Sp100 proteins, correlating with nuclear body disruption.
PML nuclear bodies (NBs) are subnuclear structures whose integrity is compromised in certain human diseases, including leukemia and neurodegenerative disorders. Infection by a number of DNA viruses similarly triggers the reorganization of these structures, suggesting an important role for the NBs in the viral infection process. While expression of the adenovirus E4 ORF3 protein leads to only a moderate redistribution of PML to filamentous structures, the herpes simplex virus (HSV) ICP0 protein and the cytomegalovirus (CMV) IE1 protein both induce a complete disruption of the NB structure. Recently, we and others have shown that the NB proteins PML and Sp100 are posttranslationally modified by covalent linkage with the ubiquitin-related SUMO-1 protein and that this modification may promote the assembly of these structures. Here we show that the HSV ICP0 and CMV IE1 proteins specifically abrogate the SUMO-1 modification of PML and Sp100, whereas the adenovirus E4 ORF3 protein does not affect this process. The potential of ICP0 and IE1 to alter SUMO-1 modification is directly linked to their capacity to disassemble NBs, thus strengthening the role for SUMO-1 conjugation in maintenance of the structural integrity of the NBs. This observation supports a model in which ICP0 and IE1 disrupt the NBs either by preventing the formation or by degrading of the SUMO-1-modified PML and Sp100 protein species. Finally, we show that the IE1 protein itself is a substrate for SUMO-1 modification, thus representing the first viral protein found to undergo this new type of posttranslational modification.


(R)- and (S)-ketamine induce differential fMRI responses in conscious rats.
(R,S)-ketamine exerts robust antidepressant effects in patients with depression when given at sub-anesthetic doses. Each of the enantiomers in this racemic mixture, (R)-ketamine and (S)-ketamine, have been reported to exert antidepressant effects individually. However, the neuropharmacological effects of these enantiomers and the mechanisms underlying their antidepressive actions have not yet been fully elucidated. Therefore, we investigated the effect of (R,S)-, (R)-, and (S)-ketamine on brain activity by functional MRI (fMRI) in conscious rats and compared these with that of N-methyl-D-aspartate receptor (NMDAR) antagonist MK-801 (n = 5~7). We also assessed their pharmacokinetic profiles (n = 4) and their behavioral effects (n = 7~9). This pharmacological MRI study revealed a significant positive response to (S)-ketamine specifically in the cortex, nucleus accumbens and striatum. In contrast, negative fMRI responses were observed in various brain regions after (R)-ketamine administration. (R,S)-ketamine, evoked significant positive fMRI responses specifically in the cortex, nucleus accumbens and striatum, and this fMRI response pattern was comparable with that of (S)-ketamine. MK-801-induced similar fMRI response pattern to (S)-ketamine. The fMRI responses to (S)-ketamine and MK-801 showed differential temporal profiles, which corresponded with brain concentration profiles. (S)-ketamine and MK-801 significantly increased locomotor activity, while (R)-ketamine produced no noticeable change. (R,S)-ketamine tended to increase locomotor activity. Our novel fMRI findings show that (R)-ketamine and (S)-ketamine induce completely different fMRI response patterns on rat, and that the response produced by the latter is similar to that elicited by an NMDAR antagonist. Our findings provide insight into the antidepressant mechanism of (R,S)-ketamine.


Fast wavefront adaptive holography in Nd:YVO4 for ultrasound optical tomography imaging.
Several approaches exist to perform acousto-optic imaging of multiple-scattering media such as biological samples. Up to now, most of the coherent detection methods use holographic setup based on photorefractive crystals such as BSO or SPS. One of the issue of these techniques is the moderate response time compared to the speckle decorrelation time in biological sample. We introduce a new approach for the holographic detection based on two-wave mixing in a Nd:YVO4 gain medium enabling us to perform a fast wavefront adaption (50 μs) of the speckle field from a multiple-scattering sample.


Risk factors for stent graft thrombosis after transjugular intrahepatic portosystemic shunt creation.
To identify risk factors of stent graft thrombosis after transjugular intrahepatic portosystemic shunt (TIPS) creation. Patients who underwent TIPS creation between June 2003 and January 2016 and with follow-up assessing stent graft patency were included (n=174). Baseline comorbidities, liver function, procedural details and follow-up liver function tests were analyzed in association with hazards of thrombosis on follow-up. Competing risk cox regression models were used considering liver transplant after TIPS creation as the competing risk variable. One-, 2- and 5-year primary patency rates were 94.1%, 91.7% and 78.2%, respectively. Patient age [sub-hazard ratio (sHR): 1.13; P=0.001], body mass index (BMI) <30 (sHR: 33.08; P=0.008) and a higher post-TIPS portosystemic pressure gradient (sHR: 1.14; P=0.023) were significantly associated with TIPS thrombosis in multivariate analysis. A higher rate of TIPS thrombosis was observed in those for whom the procedure was clinically unsuccessful (P=0.014). A significant increase in incidence of thrombosis was noted with increasing tertiles of post-TIPS portosystemic gradients (P value for trend=0.017). Older age, lower BMI and higher post-TIPS portosystemic gradients were associated with higher hazards of shunt thrombosis after TIPS creation using stent grafts. Higher rates of shunt thrombosis were seen in patients for whom TIPS creation was clinically unsuccessful. The association between TIPS thrombosis and higher post-TIPS portosystemic gradients may indicate impaired flow through the shunt, a finding which may be technical or anatomic in nature and should be assessed before procedure completion.


Merkel Cells Activate Sensory Neural Pathways through Adrenergic Synapses.
Epithelial-neuronal signaling is essential for sensory encoding in touch, itch, and nociception; however, little is known about the release mechanisms and neurotransmitter receptors through which skin cells govern neuronal excitability. Merkel cells are mechanosensory epidermal cells that have long been proposed to activate neuronal afferents through chemical synaptic transmission. We employed a set of classical criteria for chemical neurotransmission as a framework to test this hypothesis. RNA sequencing of adult mouse Merkel cells demonstrated that they express presynaptic molecules and biosynthetic machinery for adrenergic transmission. Moreover, live-cell imaging directly demonstrated that Merkel cells mediate activity- and VMAT-dependent release of fluorescent catecholamine neurotransmitter analogs. Touch-evoked firing in Merkel-cell afferents was inhibited either by pre-synaptic silencing of SNARE-mediated vesicle release from Merkel cells or by neuronal deletion of β2-adrenergic receptors. Together, these results identify both pre- and postsynaptic mechanisms through which Merkel cells excite mechanosensory afferents to encode gentle touch. VIDEO ABSTRACT.


Nicotine reduction revisited: science and future directions.
Regulation of nicotine levels in cigarettes and other tobacco products is now possible with the passage of the Family Smoking Prevention and Tobacco Control Act (FSPTCA) in 2009, giving the US Food and Drug Administration (FDA) authority to regulate tobacco products, and with Articles 9-11 of the WHO Framework Convention on Tobacco Control. Both regulatory approaches allow establishing product standards for tobacco constituents, including nicotine. The FSPTCA does not allow nicotine levels to be decreased to zero, although the FDA has the authority to reduce nicotine yields to very low, presumably non-addicting levels. The proposal to reduce levels of nicotine to a level that is non-addicting was originally suggested in 1994. Reduction of nicotine in tobacco products could potentially have a profound impact on reducing tobacco-related morbidity and mortality. To examine this issue, two meetings were convened in the US with non-tobacco-industry scientists of varied disciplines, tobacco control policymakers and representatives of government agencies. This article provides an overview of the current science in the area of reduced nicotine content cigarettes and key conclusions and recommendations for research and policy that emerged from the deliberations of the meeting members.


Circulating Vitamin K Is Inversely Associated with Incident Cardiovascular Disease Risk among Those Treated for Hypertension in the Health, Aging, and Body Composition Study (Health ABC).
Background: A role for vitamin K in coronary artery calcification (CAC), a subclinical manifestation of cardiovascular disease (CVD), has been proposed because vitamin K-dependent proteins, including the calcification inhibitor matrix Gla protein (MGP), are present in vascular tissue. Observational studies found that low circulating phylloquinone (vitamin K-1) was associated with increased CAC progression, especially in persons treated for hypertension. It is unknown whether hypertension treatment modifies this putative role of vitamin K in clinical CVD risk.Objective: We determined the association between vitamin K status and incident clinical CVD in older adults in the Health ABC (Health, Aging, and Body Composition Study) and whether the association differed by hypertension treatment status.Methods: Plasma phylloquinone was measured in 1061 participants free of CVD (70-79 y of age, 58% women, 39% black). Plasma uncarboxylated MGP [(dp)ucMGP] was measured in a subset of 635 participants. Multivariate Cox models estimated the HR for incident CVD over 12.1 follow-up years. Effect modification by hypertension was tested with the use of interaction terms.Results: Neither low plasma phylloquinone (<0.2 nmol/L) nor elevated (dp)ucMGP (≥574 pmol/L) was significantly associated with incident CVD [respective HRs (95% CIs): 1.27 (0.75, 2.13) and 1.02 (0.72, 1.45)]. In participants treated for hypertension (n = 489; 135 events), low plasma phylloquinone was associated with higher CVD risk overall (HR: 2.94; 95% CI: 1.41, 6.13). In those with untreated hypertension (n = 153; 48 events) and without hypertension (n = 418; 92 events), low plasma phylloquinone was not associated with incident CVD. The association between high (dp)ucMGP did not differ by hypertension treatment status (P-interaction = 0.72).Conclusions: Vitamin K status was not significantly associated with CVD risk overall, but low plasma phylloquinone was associated with a higher CVD risk in older adults treated for hypertension. Additional evidence from larger clinical studies is needed to clarify the importance of vitamin K to CVD in persons treated for hypertension, a segment of the population at high risk of clinical CVD events.


The anticoagulant effect of Apis mellifera phospholipase A2 is inhibited by CORM-2 via a carbon monoxide-independent mechanism.
Bee venom phospholipase A2 (PLA2) has potential for significant morbidity. Ruthenium (Ru)-based carbon monoxide releasing molecules (CORM) inhibit snake venoms that are anticoagulant and contain PLA2. In addition to modulating heme-bearing proteins with carbon monoxide, these CORM generate reactive Ru species that form adducts with histamine residues resulting in changes in protein function. This study sought to identify anticoagulant properties of bee venom PLA2 via catalysis of plasma phospholipids required for thrombin generation. Another goal was to determine if Ru-based CORM inhibit bee venom PLA2 via carbon monoxide release or via potential binding of reactive Ru species to a key histidine residue in the catalytic site of the enzyme. Anticoagulant activity of bee venom PLA2 was assessed via thrombelastography with normal plasma. Bee venom PLA2 was then exposed to different CORM and a metheme forming agent and anticoagulant activity was reassessed. Using Ru, boron and manganese-based CORM and a metheme forming agent, it was demonstrated that it was unlikely that carbon monoxide interaction with a heme group attached to PLA2 was responsible for inhibition of anticoagulant activity by Ru-based CORM. Exposure of PLA2 to a Ru-based CORM in the presence of histidine-rich human albumin resulted in loss of inhibition of PLA2. Ru-based CORM likely inhibit bee venom PLA2 anticoagulant activity via formation of reactive Ru species that bind to histidine residues of the enzyme.


Transient IGF-I gene expression during the maturation of functionally related central projection neurons.
Insulin-like growth factor I (IGF-I) is a monomeric peptide with significant homology to proinsulin. IGF-I has a number of potent effects on cultured neural tissue, including the stimulation of mitosis in sympathetic neuroblasts; the promotion of neurite outgrowth in cortical, sensory, and sympathetic neurons; and the induction of oligodendrocyte differentiation. In order to determine the sites in which IGF-I may play a role in neural development in vivo, the pattern of IGF-I gene expression in the developing rat brain has been analyzed by means of in situ hybridization histochemistry. Transient IGF-I gene expression is seen during the maturation of specific groups of functionally related sensory and cerebellar projection neurons. IGF-I mRNA is abundant within developing cerebellar Purkinje cells and in the major cerebellar relay centers, including the inferior olive, medial vestibular and lateral reticular nuclei of the brainstem, and the deep cerebellar and red nuclei. Similarly, IGF-I mRNA is localized in the synaptic stations of the developing olfactory, auditory, visual, and somatosensory systems. For example, in the auditory system, IGF-I mRNA is abundant in the cochlear nucleus, superior olive, lateral lemniscus, medial geniculate body, and inferior colliculus. In each system, IGF-I gene expression is found predominantly in long-axon projection neurons, appearing during a relatively late stage in their development, at a time of maturation of dendrites and synapse formation. The specific timing and selective localization of neuronal IGF-I gene expression described in this study suggest that IGF-I may have a role in the shaping of system-specific synaptic connections or myelinization.


Canadian Society for Exercise Physiology position stand: Benefit and risk for promoting childhood physical activity.
Current guidelines recommend children accumulate 60 min of daily physical activity; however, highly publicized sudden-death events among young athletes raise questions regarding activity safety. An expert group convened (June 2012) to consider the safety of promoting increased physical activity for children, and recommended the publication of an evidence-based statement of current knowledge regarding the benefits and risks of physical activity for children. Recommendations for encouraging physical activity while maximizing the opportunity to identify children who have been prescribed a physical activity restriction include (1) professionals and (or) researchers that encourage children to change the type of physical activity or to increase the frequency, intensity, or duration of their activity should inquire whether a child has primary healthcare provider-prescribed activity limitations before the child's activity participation changes; (2) physical activity researchers should prioritize the development of evidence regarding the benefits and risks of childhood physical activity and inactivity, particularly data on the risks of sedentary lifestyles and physical activity-associated injury risks that accounts for the amount of activity performed, and the effectiveness of current risk-management strategies and screening approaches; (3) professionals and researchers should prioritize the dissemination of information regarding the benefits of physical activity and the risks of sedentary behaviour in children; and (4) parents and professionals should encourage all children to accumulate at least 60 min of physical activity daily. The recommendations are established as a minimum acceptable standard that is applicable to all physical activity opportunities organized for children, whether those opportunities occur in a community, school, or research setting.


Emotion self-regulation, psychophysiological coherence, and test anxiety: results from an experiment using electrophysiological measures.
This study investigated the effects of a novel, classroom-based emotion self-regulation program (TestEdge) on measures of test anxiety, socioemotional function, test performance, and heart rate variability (HRV) in high school students. The program teaches students how to self-generate a specific psychophysiological state--psychophysiological coherence--which has been shown to improve nervous system function, emotional stability, and cognitive performance. Implemented as part of a larger study investigating the population of tenth grade students in two California high schools (N = 980), the research reported here was conducted as a controlled pre- and post-intervention laboratory experiment, using electrophysiological measures, on a random stratified sample of students from the intervention and control schools (N = 136). The Stroop color-word conflict test was used as the experiment's stimulus to simulate the stress of taking a high-stakes test, while continuous HRV recordings were gathered. The post-intervention electrophysiological results showed a pattern of improvement across all HRV measures, indicating that students who received the intervention program had learned how to better manage their emotions and to self-activate the psychophysiological coherence state under stressful conditions. Moreover, students with high test anxiety exhibited increased HRV and heart rhythm coherence even during a resting baseline condition (without conscious use of the program's techniques), suggesting that they had internalized the benefits of the intervention. Consistent with these results, students exhibited reduced test anxiety and reduced negative affect after the intervention. Finally, there is suggestive evidence from a matched-pairs analysis that reduced test anxiety and increased psychophysiological coherence appear to be directly associated with improved test performance--a finding consistent with evidence from the larger study.


The inhibition of pyruvate and Ls(+)-isocitrate oxidation by succinate oxidation in rat liver mitochondria.
1. The effects of succinate oxidation on pyruvate and also isocitrate oxidation by rat liver mitochondria were studied. 2. Succinate oxidation was without effect on pyruvate and isocitrate oxidation when respiration was maximally activated with ADP. 3. When respiration was partially inhibited by atractylate, succinate oxidation severely inhibited the oxidation of pyruvate and isocitrate. 4. This inhibitory effect of succinate was associated with a two- to three-fold increase in the reduction of mitochondrial NAD(+) but no change in the reduction of cytochrome b. 5. It is concluded that, in the partially energy-controlled state, respiration is more severely inhibited at the first phosphorylating site than at the other two. 6. The effects of succinate oxidation are compared with those of palmitoylcarnitine oxidation. It is concluded that a rapid flow of electrons directly into the respiratory chain at the level of cytochrome b is in itself inadequate to inhibit the oxidation of intramitochondrial NADH. 7. The effects of succinate oxidation on pyruvate oxidation were similar in rat heart and liver mitochondria.


Multisource drug policies in Latin America: survey of 10 countries.
Essential drug lists and generic drug policies have been promoted as strategies to improve access to pharmaceuticals and control their rapidly escalating costs. This article reports the results of a preliminary survey conducted in 10 Latin American countries. The study aimed to document the experiences of different countries in defining and implementing generic drug policies, determine the cost of registering different types of pharmaceutical products and the time needed to register them, and uncover the incentives governments have developed to promote the use of multisource drugs. The survey instrument was administered in person in Chile, Ecuador and Peru and by email in Argentina, Brazil, Bolivia, Colombia, Costa Rica, Nicaragua and Uruguay. There was a total of 22 respondents. Survey responses indicated that countries use the terms generic and bioequivalence differently. We suggest there is a need to harmonize definitions and technical concepts.


Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study.
Longitudinal studies have linked the systemic inflammatory markers interleukin 6 (IL-6) and C-reactive protein (CRP) with the risk of developing heart disease and diabetes mellitus, which are common comorbidities for depression and psychosis. Recent meta-analyses of cross-sectional studies have reported increased serum levels of these inflammatory markers in depression, first-episode psychosis, and acute psychotic relapse; however, the direction of the association has been unclear. To test the hypothesis that higher serum levels of IL-6 and CRP in childhood would increase future risks for depression and psychosis. The Avon Longitudinal Study of Parents and Children (ALSPAC)is a prospective general population birth cohort study based in Avon County, England. We have studied a subsample of approximately 4500 individuals from the cohort with data on childhood IL-6 and CRP levels and later psychiatric assessments. Levels of IL-6 and CRP were measured in nonfasting blood samples obtained in participants at age 9 years. Participants were assessed at age 18 years. Depression was measured using the Clinical Interview Schedule-Revised (CIS-R) and Mood and Feelings Questionnaire (MFQ), thus allowing internal replication; psychotic experiences (PEs) and psychotic disorder were measured by a semistructured interview. After adjusting for sex, age, body mass index, ethnicity, social class, past psychological and behavioral problems, and maternal postpartum depression, participants in the top third of IL-6 values compared with the bottom third at age 9 years were more likely to be depressed (CIS-R) at age 18 years (adjusted odds ratio [OR], 1.55; 95% CI, 1.13-2.14). Results using the MFQ were similar. Risks of PEs and of psychotic disorder at age 18 years were also increased with higher IL-6 levels at baseline (adjusted OR, 1.81; 95% CI, 1.01-3.28; and adjusted OR, 2.40; 95% CI, 0.88-6.22, respectively). Higher IL-6 levels in childhood were associated with subsequent risks of depression and PEs in a dose-dependent manner. Higher levels of the systemic inflammatory marker IL-6 in childhood are associated with an increased risk of developing depression and psychosis in young adulthood. Inflammatory pathways may provide important new intervention and prevention targets for these disorders. Inflammation might explain the high comorbidity between heart disease, diabetes mellitus, depression, and schizophrenia.


Distribution and assessment of marine debris in the deep Tyrrhenian Sea (NW Mediterranean Sea, Italy).
Marine debris is a recognized global ecological concern. Little is known about the extent of the problem in the Mediterranean Sea regarding litter distribution and its influence on deep rocky habitats. A quantitative assessment of debris present in the deep seafloor (30-300 m depth) was carried out in 26 areas off the coast of three Italian regions in the Tyrrhenian Sea, using a Remotely Operated Vehicle (ROV). The dominant type of debris (89%) was represented by fishing gears, mainly lines, while plastic objects were recorded only occasionally. Abundant quantities of gears were found on rocky banks in Sicily and Campania (0.09-0.12 debris m(-2)), proving intense fishing activity. Fifty-four percent of the recorded debris directly impacted benthic organisms, primarily gorgonians, followed by black corals and sponges. This work provides a first insight on the impact of marine debris in Mediterranean deep ecosystems and a valuable baseline for future comparisons.


Pulmonary hypertension in interstitial lung disease.
To examine recent advances in the understanding of the prevalence, pathophysiology, natural history, diagnosis, and treatment of pulmonary hypertension associated with interstitial lung disease. Significant progress has recently been made in understanding the etiology of various causes of pulmonary hypertension, including those associated with interstitial lung disease, and new data regarding the various pathophysiologic mechanisms of pulmonary hypertension in interstitial lung disease have been published. Therapeutic agents that were initially studied in patients with idiopathic pulmonary arterial hypertension are now being applied to interstitial lung disease-related pulmonary hypertension. Short-term hemodynamic benefits and disease-related quality of life outcomes that are associated with these advanced therapies are now better understood, but data regarding long-term outcomes and the efficacy of combination therapies remain lacking for interstitial lung disease-related pulmonary hypertension. Lung transplantation outcomes in the treatment of pulmonary hypertension associated with interstitial lung disease have been further defined. Pulmonary hypertension associated with interstitial lung disease is now frequently recognized and is associated with substantial morbidity and mortality. Various new pharmacotherapies as well as lung transplantation are increasing the treatment options for these disorders, although timing of advanced therapies and long-term benefits and toxicities remain uncertain.


Steering attosecond electron wave packets with light.
Photoelectrons excited by extreme ultraviolet or x-ray photons in the presence of a strong laser field generally suffer a spread of their energies due to the absorption and emission of laser photons. We demonstrate that if the emitted electron wave packet is temporally confined to a small fraction of the oscillation period of the interacting light wave, its energy spectrum can be up- or downshifted by many times the laser photon energy without substantial broadening. The light wave can accelerate or decelerate the electron's drift velocity, i.e., steer the electron wave packet like a classical particle. This capability strictly relies on a sub-femtosecond duration of the ionizing x-ray pulse and on its timing to the phase of the light wave with a similar accuracy, offering a simple and potentially single-shot diagnostic tool for attosecond pump-probe spectroscopy.


The temporal dynamics of evolutionary diversification in Ipomoea.
Molecular phylogenies are used as a basis for making inferences about macroevolutionary history. However, a robust phylogeny does not contain the information that is necessary to make many of these inferences. Complex methodologies that incorporate important assumptions about the nature of evolutionary history are therefore required. Here, we explore the implications of these assumptions for making inferences about the macroevolutionary history of Ipomoea - a large pantropical genus of flowering plants that contains the sweet potato (Ipomoea batatas), a crop of global economic importance. We focus on assumptions that underlie inferences of divergence times, and diversification parameters (speciation rates, extinction rates, and net diversification rates). These are among the most fundamental variables in macroevolutionary research. We use a series of novel approaches to explore the implications of these assumptions for inferring the age of Ipomoea, the ages of major clades within Ipomoea, whether there are significant differences in diversification parameters among clades within Ipomoea, and whether the storage root of I. batatas evolved in pre-human times. We show that inferring an age estimate for Ipomoea and major clades within Ipomoea is highly problematic. Inferred divergence times are sensitive to uncertain fossil calibrations and differing assumptions about among-branch-substitution-rate-variation. Despite this uncertainty, we are able to make robust inferences about patterns of variation in diversification parameters within Ipomoea, and that the storage root of I. batatas evolved in pre-human times. Taken together, this study presents novel and generalizable insights into the implications of methodological assumptions for making inferences about macroevolutionary history. Further, by presenting novel findings relating to the temporal dynamics of evolution in Ipomoea, as well as more specifically to I. batatas, this study makes a valuable contribution to our understanding of tropical plant evolution, and the evolutionary context in which economically important crops evolve.


How Many Kinds of Birds Are There and Why Does It Matter?
Estimates of global species diversity have varied widely, primarily based on variation in the numbers derived from different inventory methods of arthropods and other small invertebrates. Within vertebrates, current diversity metrics for fishes, amphibians, and reptiles are known to be poor estimators, whereas those for birds and mammals are often assumed to be relatively well established. We show that avian evolutionary diversity is significantly underestimated due to a taxonomic tradition not found in most other taxonomic groups. Using a sample of 200 species taken from a list of 9159 biological species determined primarily by morphological criteria, we applied a diagnostic, evolutionary species concept to a morphological and distributional data set that resulted in an estimate of 18,043 species of birds worldwide, with a 95% confidence interval of 15,845 to 20,470. In a second, independent analysis, we examined intraspecific genetic data from 437 traditional avian species, finding an average of 2.4 evolutionary units per species, which can be considered proxies for phylogenetic species. Comparing recent lists of species to that used in this study (based primarily on morphology) revealed that taxonomic changes in the past 25 years have led to an increase of only 9%, well below what our results predict. Therefore, our molecular and morphological results suggest that the current taxonomy of birds understimates avian species diversity by at least a factor of two. We suggest that a revised taxonomy that better captures avian species diversity will enhance the quantification and analysis of global patterns of diversity and distribution, as well as provide a more appropriate framework for understanding the evolutionary history of birds.


The mid-domain effect and species richness patterns:what have we learned so far?
If species' ranges are randomly shuffled within a bounded geographical domain free of environmental gradients, ranges overlap increasingly toward the center of the domain, creating a "mid-domain" peak of species richness. This "mid-domain effect" (MDE) has been controversial both in concept and in application. Empirical studies assess the degree to which the evolutionary, ecological, and historical processes that undeniably act on individual species and clades produce geographical patterns that resemble those produced by MDE models. MDE models that resample empirical range size frequency distributions (RSFDs) balance the risk of underestimating and overestimating the role of MDE, whereas theoretical RSFDs are generally biased toward underestimating MDE. We discuss the inclusion of nonendemic species in MDE models, rationales for setting domain limits, and the validity of one- and two-dimensional MDE models. MDE models, though null models, are not null hypotheses to be simplistically rejected or accepted. They are a means of estimating the expected effect of geometric constraints within the context of multiple causality. We call for assessment of MDE on an equal statistical footing with other candidate explanations for richness gradients. Although some critics have categorically dismissed MDE, an overview of the 21 MDE studies published to date reveals a substantial signature of MDE in natural patterns and justifies continued work.


Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves.
1. Permanent therapy with oral anticoagulants offers the most consistent protection in patients with mechanical heart valves. 2. Antiplatelet agents alone do not consistently protect patients with mechanical prosthetic heart valves, including patients in sinus rhythm with St. Jude Medical valves in the aortic position. 3. Levels of oral anticoagulants that prolong the INR to 2.0 to 3.0 appear satisfactory for patients with St. Jude Medical bileaflet and Medtronic-Hall tilting disk mechanical valves in the aortic position, provided they are in sinus rhythm and the left atrium is not enlarged. Presumably, this is also true for the CarboMedics bileaflet valve, based on the observation of no clinically important difference in the rate of systemic embolism with this valve and the St. Jude Medical bileaflet valve. 4. Levels of oral anticoagulants that prolong the INR to 2.5 to 3.5 are satisfactory for tilting disk valves and bileaflet prosthetic valves in the mitral position. 5. Experience in patients with caged ball valves who had prothrombin time ratios reported in terms of the INR is sparse, because few such valves have been inserted in recent years. The number of surviving patients with caged ball valves continues to decrease. It has been suggested that the most advantageous level of the INR in patients with caged ball or caged disk valves should be as high as 4.0 to 4.9. However, others have shown a high rate of major hemorrhage with an INR that is even somewhat lower, 3.0-4.5. The problem is self-limited, however, because few such valves are being inserted. 6. In patients with mechanical heart valves, aspirin, in addition to oral anticoagulants, has been shown to diminish the frequency of thromboemboli. The risk of bleeding is somewhat increased if the INR is 2.0 to 3.0 or 2.5 to 3.5. However, if the INR is 3.0 to 4.5, the risk of bleeding becomes excessive with aspirin. There are no investigations in which aspirin 80 mg/d in combination with oral anticoagulants was evaluated. 7. Data are insufficient to recommend dipyridamole over low doses of aspirin in combination with warfarin. Whether dipyridamole plus aspirin is more effective than aspirin alone when used with warfarin is undetermined. 8. Patients with bioprosthetic valves in the mitral position as well as patients with bioprosthetic valves in the aortic position may be at risk for thromboemboli during the first 3 months after operation. 9. Among patients with bioprosthetic valves in the mitral position, oral anticoagulants at an INR of 2.0 to 2.3 were as effective as an INR of 2.5 to 4.0 and were associated with fewer bleeding complications during the first 3 months after operation.10. Aspirin may reduce the long-term frequency of thromboembolism in patients with bioprosthetic valves.


Phenolic metabolites and substantial microbiome changes in pig feces by ingesting grape seed proanthocyanidins.
Proanthocyanidin (PAC) consumption has been linked to better colonic health, but PACs are poorly absorbed, making them a target for colonic metabolism. The resulting metabolites are low molecular weight and could potentially be absorbed. To understand the effects of dietary PACs it would be important to resolve the metabolic issue and link these changes to microbial population changes in a suitable model for human digestion. Here, six crossbred female pigs were fed a diet containing 1% (w/w) of MegaNatural® Gold grape seed extract (GSE) daily for 6 days. Fecal samples were analyzed by normal phase LC coupled to fluorescence detection and LC-MS/ToF. DNA was extracted from pig fecal samples and the V3/V4 region of the 16S rRNA gene was sequenced using an Illumina MiSeq. Intact parent PACs (dimer-pentamer) were observed in the feces on days 3 and 6 at similar high levels (∼400 mg kg(-1) total) during ingestion of GSE but were absent 48 h post-feeding. The major phenolic metabolites were 4-hydroxyphenylvaleric acid and 3-hydroxybenzoic acid which increased by ∼30 and 3 mg kg(-1) respectively. The GSE diet also caused an ecological shift in the microbiome, dramatically increasing Lachnospiraceae, Clostridales, Lactobacillus and Ruminococcacceae. The relationship between dietary PACs and colon health may be attributable to the altered bacterial populations or phenolic compounds in the colon.


Genetically null mice reveal a central role for epidermal growth factor receptor in the differentiation of the hair follicle and normal hair development.
Mice harboring a targeted disruption of the epidermal growth factor receptor (EGFR) allele exhibit a severely disorganized hair follicle phenotype, fuzzy coat, and systemic disease resulting in death before 3 weeks. This skin phenotype was reproduced in whole skin grafts and in grafts of EGFR null hair follicle buds onto nude mice, providing a model to evaluate the natural evolution of skin lacking the EGFR. Hair follicles in grafts of null skin did not progress from anagen to telogen and scanning electron micrografts revealed wavy, flattened hair fibers with cuticular abnormalities. Many of the EGFR null hair follicles in the grafted skin were consumed by an inflammatory reaction resulting in complete hair loss in 67% of the grafts by 10 weeks. Localization of follicular differentiation markers including keratin 6, transglutaminase, and the hair keratins mHa2 and hacl-1 revealed a pattern of premature differentiation within the null hair follicles. In intact EGFR null mice, proliferation in the interfollicular epidermis, but not hair follicles, was greatly decreased in the absence of EGFR. In contrast, grafting of EGFR null skin resulted in a hyperplastic response in the epidermis that did not resolve even after 10 weeks, although the wound-induced hyperplasia in EGFR wild-type grafts had resolved within 3 to 4 weeks. Thus, epithelial expression of the EGFR has complex functions in the skin. It is important in delaying follicular differentiation, may serve to protect the hair follicle from immunological reactions, and modifies both normal and wound-induced epidermal proliferation but seems dispensable for follicular proliferation.


Ambiguity, ambivalence, and apprehensions of taking HIV-1 pre-exposure prophylaxis among male couples in San Francisco: a mixed methods study.
We conducted a mixed-methods study to examine serodiscordant and seroconcordant (HIV-positive/HIV-positive) male couples' PrEP awareness, concerns regarding health care providers offering PrEP to the community, and correlates of PrEP uptake by the HIV-negative member of the couple. Qualitative sub-study included one-on-one interviews to gain a deeper understanding of participants' awareness of and experiences with PrEP and concerns regarding health care providers offering PrEP to men who have sex with men (MSM). Quantitative analyses consisted of a cross-sectional study in which participants were asked about the likelihood of PrEP uptake by the HIV-negative member of the couple and level of agreement with health care providers offering PrEP to anyone requesting it. We used multivariable regression to examine associations between PrEP questions and covariates of interest and employed an inductive approach to identify key qualitative themes. Among 328 men (164 couples), 62% had heard about PrEP, but approximately one-quarter were mistaking it with post-exposure prophylaxis. The majority of participants had low endorsement of PrEP uptake and 40% were uncertain if health care providers should offer PrEP to anyone requesting it. Qualitative interviews with 32 men suggest that this uncertainty likely stems from concerns regarding increased risk compensation. Likelihood of future PrEP uptake by the HIV-negative member of the couple was positively associated with unprotected insertive anal intercourse but negatively correlated with unprotected receptive anal intercourse. Findings suggest that those at greatest risk may not be receptive of PrEP. Those who engage in moderate risk express more interest in PrEP; however, many voice concerns of increased risk behavior in tandem with PrEP use. Results indicate a need for further education of MSM communities and the need to determine appropriate populations in which PrEP can have the highest impact.


Medullary carcinoma of the thyroid gland and the MEN 2 syndromes.
Medullary thyroid carcinoma (MTC) is an uncommon neoplasm in children that usually is associated with the multiple endocrine neoplasia (MEN) syndrome types 2A and 2B and with familial medullary thyroid carcinoma (FMTC). Recently, germline mutations in the RET proto-oncogene have been found in patients with these syndromes. Thus, with direct DNA testing, kindred members with MEN 2A, MEN 2B, or FMTC can be identified before clinical of biochemical evidence of MTC develops. It has been hypothesized that prophylactic thyroidectomy early in childhood, based on a positive genetic test, produces a better clinical outcome than thyroidectomy at the time MTC is diagnosed either clinically or biochemically. In the present report, the Washington University experience with MTC in children with MEN 2A and 2B is reviewed. Sixteen patients with MEN 2A who had thyroidectomy based on the biochemical diagnosis of MTC are compared with 14 children with MEN 2A who underwent prophylactic thyroidectomy based on direct genetic testing. In addition, the clinical results of 11 patients with MEN 2B treated for MTC are reviewed. After 3 years of follow-up there has been no biochemical or clinical evidence of MTC among the 14 children who had prophylactic thyroidectomy. Among the 16 children with MEN 2A who had thyroidectomy because of elevated basal of stimulated calcitonin levels, four (25%) have persistent of recurrent MTC after a mean follow-up period of 7.6 years. Of the 11 patients with MEN 2B who underwent thyroidectomy during childhood, one has died and seven (70%) of the remaining patients have recurrent MTC after a mean follow-up period of 11 years. The authors conclude that a significant number of children with MEN 2A or MEN 2B, who have clinical of biochemical evidence of MTC before thyroidectomy, have persistent or recurrent disease after long-term clinical follow-up. The diagnosis by direct DNA testing in patients with these syndromes allows prophylactic thyroidectomy before the development of extensive local or metastatic MTC.


Mobile therapy: case study evaluations of a cell phone application for emotional self-awareness.
Emotional awareness and self-regulation are important skills for improving mental health and reducing the risk of cardiovascular disease. Cognitive behavioral therapy can teach these skills but is not widely available. This exploratory study examined the potential of mobile phone technologies to broaden access to cognitive behavioral therapy techniques and to provide in-the-moment support. We developed a mobile phone application with touch screen scales for mood reporting and therapeutic exercises for cognitive reappraisal (ie, examination of maladaptive interpretations) and physical relaxation. The application was deployed in a one-month field study with eight individuals who had reported significant stress during an employee health assessment. Participants were prompted via their mobile phones to report their moods several times a day on a Mood Map-a translation of the circumplex model of emotion-and a series of single-dimension mood scales. Using the prototype, participants could also activate mobile therapies as needed. During weekly open-ended interviews, participants discussed their use of the device and responded to longitudinal views of their data. Analyses included a thematic review of interview narratives, assessment of mood changes over the course of the study and the diurnal cycle, and interrogation of this mobile data based on stressful incidents reported in interviews. Five case studies illustrate participants' use of the mobile phone application to increase self-awareness and to cope with stress. One example is a participant who had been coping with longstanding marital conflict. After reflecting on his mood data, particularly a drop in energy each evening, the participant began practicing relaxation therapies on the phone before entering his house, applying cognitive reappraisal techniques to cope with stressful family interactions, and talking more openly with his wife. His mean anger, anxiety and sadness ratings all were lower in the second half of the field study than in the first (P </= .01 for all three scales). Similar changes were observed among other participants as they used the application to negotiate bureaucratic frustrations, work tensions and personal relationships. Participants appeared to understand the mood scales developed for this experience sampling application and responded to them in a way that was generally consistent with self-reflection in weekly interviews. Interview accounts of mood changes, associated with diurnal cycles, personal improvement over the course of the study, and stressful episodes, could be seen in the experience sampling data. Discrepancies between interview and experience-sampling data highlighted the ways that individuals responded to the two forms of inquiry and how they calibrated mood ratings over the course of the study. Participants quickly grasped the Mood Mapping and therapeutic concepts, and applied them creatively in order to help themselves and empathize with others. Applications developed for mobile phones hold promise for delivering state-of-the-art psychotherapies in a nonstigmatizing fashion to many people who otherwise would not have access to therapy.


Macrophage Blockade Using CSF1R Inhibitors Reverses the Vascular Leakage Underlying Malignant Ascites in Late-Stage Epithelial Ovarian Cancer.
Malignant ascites is a common complication in the late stages of epithelial ovarian cancer (EOC) that greatly diminishes the quality of life of patients. Malignant ascites is a known consequence of vascular dysfunction, but current approved treatments are not effective in preventing fluid accumulation. In this study, we investigated an alternative strategy of targeting macrophage functions to reverse the vascular pathology of malignant ascites using fluid from human patients and an immunocompetent murine model (ID8) of EOC that mirrors human disease by developing progressive vascular disorganization and leakiness culminating in massive ascites. We demonstrate that the macrophage content in ascites fluid from human patients and the ID8 model directly correlates with vascular permeability. To further substantiate macrophages' role in the pathogenesis of malignant ascites, we blocked macrophage function in ID8 mice using a colony-stimulating factor 1 receptor kinase inhibitor (GW2580). Administration of GW2580 in the late stages of disease resulted in reduced infiltration of protumorigenic (M2) macrophages and dramatically decreased ascites volume. Moreover, the disorganized peritoneal vasculature became normalized and sera from GW2580-treated ascites protected against endothelial permeability. Therefore, our findings suggest that macrophage-targeted treatment may be a promising strategy toward a safe and effective means to control malignant ascites of EOC.


Pulmonary function changes in ozone-interaction of concentration and ventilation.
A total of 28 healthy young subjects have been exposed for 2 h to ozone (0.37-0.75 ppm) under conditions of either rest or intermittent light exercise (sufficient to increase the respiratory minute volume by a factor of 2.5). All pulmonary function tests (vital capacity, forced expiratory volume, maximum expiratory flow-volume curve, slope of phase III of alveolar nitrogen plateau) showed a significant deterioration relative to parallel control experiments. Responses were related to the dose of ozone as calculated from the product of concentration, exposure time, and respiratory minute volume during exposure, changes at 1 h averaging approximately one-half those seen at 2 h.


Mechanistic impact of outdoor air pollution on asthma and allergic diseases.
Over the past decades, asthma and allergic diseases, such as allergic rhinitis and eczema, have become increasingly common, but the reason for this increased prevalence is still unclear. It has become apparent that genetic variation alone is not sufficient to account for the observed changes; rather, the changing environment, together with alterations in lifestyle and eating habits, are likely to have driven the increase in prevalence, and in some cases, severity of disease. This is particularly highlighted by recent awareness of, and concern about, the exposure to ubiquitous environmental pollutants, including chemicals with oxidant-generating capacities, and their impact on the human respiratory and immune systems. Indeed, several epidemiological studies have identified a variety of risk factors, including ambient pollutant gases and airborne particles, for the prevalence and the exacerbation of allergic diseases. However, the responsible pollutants remain unclear and the causal relationship has not been established. Recent studies of cellular and animal models have suggested several plausible mechanisms, with the most consistent observation being the direct effects of particle components on the generation of reactive oxygen species (ROS) and the resultant oxidative stress and inflammatory responses. This review attempts to highlight the experimental findings, with particular emphasis on several major mechanistic events initiated by exposure to particulate matters (PMs) in the exposure-disease relationship.


The continuum-of-addiction: cigarette smoking in relation to price among Americans aged 15-29.
We studied the relationship between current cigarette smoking and price among 34145 respondents, aged 15-29 years, to the 1992-1993 Tobacco Use Supplements to the Current Population Survey. The price elasticity of current smoking varied inversely with age: -0.831 (S.E. 0.402) for ages 15-17; -0.524 (S.E. 0.256) for ages 18-20; -0.370 (S.E. 0.188) for ages 21-23; -0.202 (S.E. 0.175) for ages 24-26; and -0.095 (S.E. 0.157) for ages 27-29. In response to higher prices, older youth were more likely to reduce the number of cigarettes smoked per day than to quit entirely. Among 15-17-year-olds, smoking cigarettes 'some days' was more sensitive to price than smoking 'every day'. Cigarette smoking was inversely related to the prices of premium brands, but not discount brands.


An ileal Crohn's disease gene signature based on whole human genome expression profiles of disease unaffected ileal mucosal biopsies.
Previous genome-wide expression studies have highlighted distinct gene expression patterns in inflammatory bowel disease (IBD) compared to control samples, but the interpretation of these studies has been limited by sample heterogeneity with respect to disease phenotype, disease activity, and anatomic sites. To further improve molecular classification of inflammatory bowel disease phenotypes we focused on a single anatomic site, the disease unaffected proximal ileal margin of resected ileum, and three phenotypes that were unlikely to overlap: ileal Crohn's disease (ileal CD), ulcerative colitis (UC), and control patients without IBD. Whole human genome (Agilent) expression profiling was conducted on two independent sets of disease-unaffected ileal samples collected from the proximal margin of resected ileum. Set 1 (47 ileal CD, 27 UC, and 25 Control non-IBD patients) was used as the training set and Set 2 was subsequently collected as an independent test set (10 ileal CD, 10 UC, and 10 control non-IBD patients). We compared the 17 gene signatures selected by four different feature-selection methods to distinguish ileal CD phenotype with non-CD phenotype. The four methods yielded different but overlapping solutions that were highly discriminating. All four of these methods selected FOLH1 as a common feature. This gene is an established biomarker for prostate cancer, but has not previously been associated with Crohn's disease. Immunohistochemical staining confirmed increased expression of FOLH1 in the ileal epithelium. These results provide evidence for convergent molecular abnormalities in the macroscopically disease unaffected proximal margin of resected ileum from ileal CD subjects.


Intraoperative real-time near-infrared optical imaging for the identification of metastatic brain tumors via microscope and exoscope.
As chemotherapy and radiotherapy have developed, the role of a neurosurgeon in the treatment of metastatic brain tumors is gradually changing. Real-time intraoperative visualization of brain tumors by near-infrared spectroscopy (NIRS) is feasible. The authors aimed to perform real-time intraoperative visualization of the metastatic tumor in brain surgery using second-window indocyanine green (SWIG) with microscope and exoscope systems. Ten patients with intraparenchymal brain metastatic tumors were administered 5 mg/kg indocyanine green (ICG) 1 day before the surgery. In some patients, a microscope was used to help identify the metastases, whereas in the others, an exoscope was used. NIRS with the exoscope and microscope revealed the tumor location from the brain surface and the tumor itself in all 10 patients. The NIR signal could be detected though the normal brain parenchyma up to 20 mm. While the mean signal-to-background ratio (SBR) from the brain surface was 1.82 ± 1.30, it was 3.35 ± 1.76 from the tumor. The SBR of the tumor (p = 0.030) and the ratio of Gd-enhanced T1 tumor signal to normal brain (T1BR) (p = 0.0040) were significantly correlated with the tumor diameter. The SBR of the tumor was also correlated with the T1BR (p = 0.0020). The tumor was completely removed in 9 of the 10 patients, as confirmed by postoperative Gd-enhanced MRI. This was concomitant with the absence of NIR fluorescence at the end of surgery. SWIG reveals the metastatic tumor location from the brain surface with both the microscope and exoscope systems. The Gd-enhanced T1 tumor signal may predict the NIR signal of the metastatic tumor, thus facilitating tumor resection.


Nationwide online social networking for cardiovascular care in Korea using Facebook.
To examine the use of online social networking for cardiovascular care using Facebook. All posts and comments in a Facebook group between June 2011 and May 2012 were reviewed, and a survey was conducted. A total of 298 members participated. Of the 277 wall posts, 26.7% were question posts requesting rapid replies, and 50.5% were interesting cases shared with other members. The median response time for the question posts was 16 min (IQR 8-47), which tended to decrease as more members joined the group. Many members (37.4%) accessed the group more than once a day, and more than half (64%) monitored the group posts in real time with automatic notifications of new posts. Most members expressed confidence in the content posted. Facebook enables online social networking between physicians in near-real time and appears to be a useful tool for physicians to share clinical experience and request assistance in decision-making.


Influence of Aloe vera on collagen characteristics in healing dermal wounds in rats.
Wound healing is a fundamental response to tissue injury that results in restoration of tissue integrity. This end is achieved mainly by the synthesis of the connective tissue matrix. Collagen is the major protein of the extracellular matrix, and is the component which ultimately contributes to wound strength. In this work, we report the influence of Aloe vera on the collagen content and its characteristics in a healing wound. It was observed that Aloe vera increased the collagen content of the granulation tissue as well as its degree of crosslinking as seen by increased aldehyde content and decreased acid solubility. The type I/type III collagen ratio of treated groups were lower than that of the untreated controls, indicating enhanced levels of type III collagen. Wounds were treated either by topical application or oral administration of Aloe vera to rats and both treatments were found to result in similar effects.


A companding approach for nonuniform quantization of digital holograms of three-dimensional objects.
We apply two novel nonuniform quantization techniques to digital holograms of three-dimensional real-world objects. Our companding approach, combines the efficiency of uniform quantization with the improved performance of nonuniform quantization. We show that the performance of companding techniques can be comparable with k-means clustering and a competitive neural network, while only requiring a single-pass processing step. The quantized holographic pixels are coded using lossless techniques for the calculation of compression ratio.


Effective surgical adjuvant therapy for high-risk rectal carcinoma.
Radiation therapy as an adjunct to surgery for rectal cancer has been shown to reduce local recurrence but has not improved survival. In a previous study, combined radiation and chemotherapy improved survival significantly as compared with surgery alone, but not as compared with adjuvant radiation, which many regard as standard therapy. We designed a combination regimen to optimize the contribution of chemotherapy, decrease recurrence, and improve survival as compared with adjuvant radiation alone. Two hundred four patients with rectal carcinoma that was either deeply invasive or metastatic to regional lymph nodes were randomly assigned to postoperative radiation alone (4500 to 5040 cGy) or to radiation plus fluorouracil, which was both preceded and followed by a cycle of systemic therapy with fluorouracil plus semustine (methyl-CCNU). After a median follow-up of more than seven years, the combined therapy had reduced the recurrence of rectal cancer by 34 percent (P = 0.0016; 95 percent confidence interval, 12 to 50 percent). Initial local recurrence was reduced by 46 percent (P = 0.036; 95 percent confidence interval, 2 to 70 percent), and distant metastasis by 37 percent (P = 0.011; 95 percent confidence interval, 9 to 57 percent). In addition, combined therapy reduced the rate of cancer-related deaths by 36 percent (P = 0.0071; 95 percent confidence interval, 14 to 53 percent) and the overall death rate by 29 percent (P = 0.025; 95 percent confidence interval, 7 to 45 percent). Its acute toxic effects included nausea, vomiting, diarrhea, leukopenia, and thrombocytopenia. These effects were seldom severe. Severe, delayed treatment-related reactions, usually small-bowel obstruction requiring surgery, occurred in 6.7 percent of all patients receiving radiation, and the frequencies of these complications were comparable in both treatment groups. The combination of postoperative local therapy with radiation plus fluorouracil and systemic therapy with a fluorouracil-based regimen significantly and substantively improves the results of therapy for rectal carcinoma with a poor prognosis, as compared with postoperative radiation alone.


Clinical and doppler ultrasound evaluation of peripheral arterial diseases in Kano, North-western Nigeria.
Doppler ultrasound scan is a non-invasive and cheap tool that complements the roles of computed tomography, magnetic resonance imaging and catheter digital subtraction angiography in the screening, diagnosis and follow up of vascular diseases. In this study, we evaluated and described the findings of the Doppler ultrasound of the peripheral arteries performed at Aminu Kano Teaching Hospital (AKTH), Kano, Nigeria. All the findings of peripheral arterial Doppler ultrasound examinations performed at AKTH during a period of 18 months (from February 2012 to July 2013) were reviewed. All examinations were done using 7.5 MHz linear transducer connected to Mindary Digital Ultrasound Imaging System (Model DC-6; Shenzhen Mindray Biomed Electronics, Shenzhen, China). A 3.5 MHz convex transducer of the same machine was used in obese patients and those with severe subcutaneous oedema. The findings of 50 males and 28 females were reviewed. Their mean age was 55.8 ΁ 17.9 years. Diabetic foot disease, intermittent claudication, gangrene and limb swellings were the most common indications for arterial Doppler examination of the lower limbs, constituting 32.1%, 20.5%, 16.7% and 15.4%, respectively. Significant luminal stenosis, total luminal occlusion and loss of arterial resistance were the most frequent findings, constituting 29%, 26.9% and 7.7%, respectively. Femoro-popliteal and below the knee arteries were commonly involved by these abnormalities. Arrhythmia, increased intimal media thickness and wall calcifications were the common compounding findings while diabetes and hypertension were frequently associated clinical problems of these patients. Doppler ultrasound has a high diagnostic yield in depicting abnormalities in patients with clinical features of peripheral arterial disease.


Spectral anomalies due to temporal correlation in a white-light interferometer.
We present what we believe to be the first experimental demonstration of anomalous spectral behavior such as spectral shifts and spectral switches due to temporal correlation around the intensity minima in a white-light interferometer. Unusual behavior in the number of spectral fringes, measured within the source bandwidth, as a function of path delay between the interfering beams is also reported. Experimental observations match well with the spectra calculated by using the interference law in the spectral domain.


Specific molecular features in the organization and biosynthesis of the cell wall of Aspergillus fumigatus.
The cell wall of Aspergillus fumigatus is composed of a branched beta1,3 glucan covalently bound to chitin, beta1,3, beta1,4 glucans, and galactomannan, that is embedded in an amorphous cement composed of alpha1,3 glucan, galactomannan and polygalactosamin. The mycelial cell wall of A. fumigatus is very different from the yeast Saccharomyces cerevisiae cell wall, and in particular lacks beta1,6 glucans and proteins covalently bound to cell wall polysaccharides. The differences in cell wall composition between the mould A. fumigatus and the yeast S. cerevisiae are also reflected at the genomic level where unique features have been identified in A. fumigatus. A single gene codes for the glucan synthase catalytic subumit; this finding has lead to the development of a RNAi methodology for the disruption of essential genes in A. fumigatus. In contrast to the glucan synthase, multiple genes have been found in the chitin synthase and the alpha glucan synthase families; in spite of homologous sequences, each gene in each family have very different function. Similarly homologous mannosyltransferase genes are found in yeast and moulds but they lead to the synthesis of very different N-mannan structures. This chemo-genomic comparative analysis has also suggested that GPI-anchored proteins do not have a role of linker in the three dimensional organization of the fungal cell wall.


Enhanced West Nile virus surveillance in a dengue-endemic area--Puerto Rico, 2007.
In June of 2007, West Nile virus (WNV) was detected in sentinel chickens and blood donors in Puerto Rico, where dengue virus (DENV) is hyperendemic. Enhanced human surveillance for acute febrile illness (AFI) began in eastern Puerto Rico on July 1, 2007. Healthcare providers submitted specimens from AFI cases for WNV and DENV virology and serology testing. Over 6 months, 385 specimens were received from 282 cases; 115 (41%) specimens were DENV laboratory-positive, 86 (31%) specimens were laboratory-indeterminate, and 32 (11%) specimens were laboratory-negative for WNV and DENV. One WNV infection was detected by anti-WNV immunoglobulin M (IgM) antibody and confirmed by a plaque reduction neutralization test. DENV and WNV infections could not be differentiated in 27 cases (10%). During a period of active WNV transmission, enhanced human surveillance identified one case of symptomatic WNV infection. Improved diagnostic methods are needed to allow differentiation of WNV and DENV in dengue-endemic regions.


Assessment of proprioceptive allodynia after tooth-clenching exercises.
To (A) evaluate test-retest reliability of vibrotactile sensitivity in the masseter muscle and (B) test if (1) the vibration threshold is decreased after experimental tooth clenching, (2) intense vibrations exacerbate pain after tooth clenching, (3) pain and fatigue are increased after tooth clenching, and (4) pressure pain thresholds are decreased after tooth clenching. In part A, 25 healthy female volunteers (mean age: 42 ± 12 years) participated, and 16 healthy females (mean age 32 ± 10 years) participated in three 60-minute sessions, each with 24- and 48-hour follow-ups in part B. Participants were randomly assigned tooth-clenching exercises with clenching levels of 10%, 20%, or 40% of maximal voluntary clenching. A Vibrameter applied to the right masseter muscle measured perceived intensity of vibration and perceived discomfort, which were assessed on 0-50-100 numeric rating scales. An electronic algometer measured pressure pain threshold (PPT). Two 0- to 100-mm visual analog scales measured pain intensity (VASpain) and fatigue (VASfatigue). Measurements were made on the right masseter muscle. Interclass correlation coefficient (ICC) was used to calculate test-retest reliability of VT measurements. Outcome variables were tested with two-way ANOVAs for repeated measures and Dunnett's post-hoc test. Moderate long-term (ICC 0.59) and good short-term (ICC 0.92) reliability was found for VT on the masseter muscle. Clenching level had no main effect on perceived intensity of vibration; time effects (P < .05) were only observed at 40 minutes (Dunnett's test: P < .01). Clenching level and time had no effect on perceived discomfort. Only time effects were significant for PPT (P < .01), with reductions at 50 and 60 minutes compared to baseline (Dunnett's test: P < .05). Clenching level and time had main effects for VASpain and VASfatigue (P < .001). Experimental tooth clenching appears to evoke moderate levels of pain and fatigue and short-lasting hyperalgesia to mechanical stimulation, but not proprioceptive allodynia. The absence of proprioceptive allodynia does not necessarily exclude delayed onset muscle soreness (DOMS) but warrants further studies on the clinical manifestations of DOMS in jaw muscles.