Infra-slow brain dynamics as a marker for cognitive function and decline.
Functional magnetic resonance imaging (fMRI) enables measuring human brain activity, in vivo. Yet, the fMRI hemodynamic response unfolds over very slow timescales (<0.1-1 Hz), orders of magnitude slower than millisecond timescales of neural spiking. It is unclear, therefore, if slow dynamics as measured with fMRI are relevant for cognitive function. We investigated this question with a novel application of Gaussian Process Factor Analysis (GPFA) and machine learning to fMRI data. We analyzed slowly sampled (1.4 Hz) fMRI data from 1000 healthy human participants (Human Connectome Project database), and applied GPFA to reduce dimensionality and extract smooth latent dynamics. GPFA dimensions with slow (<1 Hz) characteristic timescales identified, with high accuracy (>95%), the specific task that each subject was performing inside the fMRI scanner. Moreover, functional connectivity between slow GPFA latents accurately predicted inter-individual differences in behavioral scores across a range of cognitive tasks. Finally, infra-slow (<0.1 Hz) latent dynamics predicted CDR (Clinical Dementia Rating) scores of individual patients, and identified patients with mild cognitive impairment (MCI) who would progress to develop Alzheimer's dementia (AD). Slow and infra-slow brain dynamics may be relevant for understanding the neural basis of cognitive function, in health and disease.


Lifelong training preserves some redox-regulated adaptive responses after an acute exercise stimulus in aged human skeletal muscle.
Several redox-regulated responses to an acute exercise bout fail in aged animal skeletal muscle, including the ability to upregulate the expression of antioxidant defense enzymes and heat shock proteins (HSPs). These findings are generally derived from studies on sedentary rodent models and thus may be related to reduced physical activity and/or intraspecies differences as opposed to aging per se. This study, therefore, aimed to determine the influence of age and training status on the expression of HSPs, antioxidant enzymes, and NO synthase isoenzymes in quiescent and exercised human skeletal muscle. Muscle biopsy samples were obtained from the vastus lateralis before and 3 days after an acute high-intensity-interval exercise bout in young trained, young untrained, old trained, and old untrained subjects. Levels of HSP72, PRX5, and eNOS were significantly higher in quiescent muscle of older compared with younger subjects, irrespective of training status. 3-NT levels were elevated in muscles of the old untrained but not the old trained state, suggesting that lifelong training may reduce age-related macromolecule damage. SOD1, CAT, and HSP27 levels were not significantly different between groups. HSP27 content was upregulated in all groups studied postexercise. HSP72 content was upregulated to a greater extent in muscle of trained compared with untrained subjects postexercise, irrespective of age. In contrast to every other group, old untrained subjects failed to upregulate CAT postexercise. Aging was associated with a failure to upregulate SOD2 and a downregulation of PRX5 in muscle postexercise, irrespective of training status. In conclusion, lifelong training is unable to fully prevent the progression toward a more stressed muscular state as evidenced by increased HSP72, PRX5, and eNOS protein levels in quiescent muscle. Moreover, lifelong training preserves some (e.g., CAT) but not all (e.g., SOD2, HSP72, PRX5) of the adaptive redox-regulated responses after an acute exercise bout. Collectively, these data support many but not all of the findings from previous animal studies and suggest parallel aging effects in humans and mice at rest and after exercise that are not modulated by training status in human skeletal muscle.


Human extrahepatic and intrahepatic cholangiocyte organoids show region-specific differentiation potential and model cystic fibrosis-related bile duct disease.
The development, homeostasis, and repair of intrahepatic and extrahepatic bile ducts are thought to involve distinct mechanisms including proliferation and maturation of cholangiocyte and progenitor cells. This study aimed to characterize human extrahepatic cholangiocyte organoids (ECO) using canonical Wnt-stimulated culture medium previously developed for intrahepatic cholangiocyte organoids (ICO). Paired ECO and ICO were derived from common bile duct and liver tissue, respectively. Characterization showed both organoid types were highly similar, though some differences in size and gene expression were observed. Both ECO and ICO have cholangiocyte fate differentiation capacity. However, unlike ICO, ECO lack the potential for differentiation towards a hepatocyte-like fate. Importantly, ECO derived from a cystic fibrosis patient showed no CFTR channel activity but normal chloride channel and MDR1 transporter activity. In conclusion, this study shows that ECO and ICO have distinct lineage fate and that ECO provide a competent model to study extrahepatic bile duct diseases like cystic fibrosis.


Structure, function, and targets of the transcriptional regulator SvtR from the hyperthermophilic archaeal virus SIRV1.
We have characterized the structure and the function of the 6.6-kDa protein SvtR (formerly called gp08) from the rod-shaped virus SIRV1, which infects the hyperthermophilic archaeon Sulfolobus islandicus that thrives at 85 degrees C in hot acidic springs. The protein forms a dimer in solution. The NMR solution structure of the protein consists of a ribbon-helix-helix (RHH) fold between residues 13 and 56 and a disordered N-terminal region (residues 1-12). The structure is very similar to that of bacterial RHH proteins despite the low sequence similarity. We demonstrated that the protein binds DNA and uses its beta-sheet face for the interaction like bacterial RHH proteins. To detect all the binding sites on the 32.3-kb SIRV1 linear genome, we designed and performed a global genome-wide search of targets based on a simplified electrophoretic mobility shift assay. Four targets were recognized by the protein. The strongest binding was observed with the promoter of the gene coding for a virion structural protein. When assayed in a host reconstituted in vitro transcription system, the protein SvtR (Sulfolobus virus transcription regulator) repressed transcription from the latter promoter, as well as from the promoter of its own gene.


Development and validation of the online social support for smokers scale.
Social networks play an important role in smoking. Provision of social support during cessation is a cornerstone of treatment. Online social networks for cessation are ubiquitous and represent a promising modality for smokers to receive and provide the support necessary for cessation. There are no existing measures specific to online social support for smoking cessation. The objective was to develop a measure of social support to be used in online smoking cessation treatment research. Initial items for the Online Social Support for Smokers Scale (OS4) were based on existing theory and scales delineated in various taxonomies. Preliminary field analysis (N = 73) was conducted on 23 initial items to optimize the scale. Further development was conducted on a refined 15-item scale in the context of a large randomized trial of Internet and telephone cessation treatment with follow-ups at 3, 6, 12, and 18 months. In all, 1326 participants were randomized to an enhanced Internet arm that included a large online social network; psychometric analyses employed 3-month follow-up data from those reporting use of the enhanced Internet intervention at least once (n = 873). Items were subjected to a factor analysis, and the internal consistency reliability of the scale was examined along with construct and criterion validity. Other measures used in the study included demographics, nicotine dependence, partner support for cessation, general social support, social integration, stress, depression, health status, online community use, Internet use behaviors, intervention satisfaction, and 30-day point prevalence abstinence. The final 12-item OS4 scale demonstrated high internal consistency reliability (Cronbach alphas .86-.89) across demographic and smoking strata of interest. The OS4 also demonstrated good construct and criterion validity, with the directionality of the observed associations providing support for most a priori hypotheses. Significant Pearson correlations were observed between the OS4 and the Partner Interaction Questionnaire (PIQ) Positive subscale (ρ = .24, P < .001). As hypothesized, participants with the highest OS4 scores were more likely to have actively participated in the enhanced Internet community and to have high levels of satisfaction with the enhanced Internet intervention. In logistic regression analyses, the OS4 was highly predictive of 30-day point-prevalence abstinence at 6, 12, and 18 months (all P values <.001). The odds of abstinence at 6 months rose by 48% for each standard unit increase in online social support (95% confidence interval [CI] 1.17-1.71), dropping only slightly to 37% at 12 and 18 months (95% CI 1.17-1.59). The OS4 is a brief, reliable, and valid instrument for measuring online social support for smoking cessation. Results should be replicated and extended, but this study suggests the OS4 can be used to advance theory, understand mechanisms, and potentially help to improve the tailoring of Internet-based smoking cessation treatments. It can also inspire development of similar measures for other online health-related intervention research. Clinicaltrials.gov #NCT00282009; http://clinicaltrials.gov/ct2/show/NCT00282009 (Archived by WebCite at http://www.webcitation.org/60XNj3xM6).


Application of the Enzymatic Electrochemical Biosensors for Monitoring Non-Competitive Inhibition of Enzyme Activity by Heavy Metals.
The inhibition effect of the selected heavy metals (Ag+, Cd2+, Cu2+, and Hg2+) on glucose oxidase (GOx) enzyme from Aspergillus niger (EC 18.104.22.168.) was studied using a new amperometric biosensor with an electrochemical transducer based on a glassy carbon electrode (GCE) covered with a thin layer of multi-wall carbon nanotubes (MWCNTs) incorporated with ruthenium(IV) oxide as a redox mediator. Direct adsorption of multi-wall carbon nanotubes (MWCNTs) and subsequent covering with Nafion® layer was used for immobilization of GOx. The analytical figures of merit of the developed glucose (Glc) biosensor are sufficient for determination of Glc in body fluids in clinical analysis. From all tested heavy metals, mercury(II) has the highest inhibition effect. However, it is necessary to remember that cadmium and silver ions also significantly inhibit the catalytic activity of GOx. Therefore, the development of GOx biosensors for selective indirect determination of each heavy metal still represents a challenge in the field of bioelectroanalysis. It can be concluded that amperometric biosensors, differing in the utilized enzyme, could find their application in the toxicity studies of various poisons.


Secondary stability of microthickness hydroxyapatite-coated dental implants installed without primary stability in dogs.
The objective of this study was to evaluate the secondary stability of microthickness hydroxyapatite (HA)-coated implants placed without primary stability in dogs. A total of 48 implants were placed in six dogs. The groups were divided according to the absence or presence of primary stability and healing periods (4 and 8 weeks). Two implants for histological analysis and removal torque test in experimental group were placed without primary stability, showing rotational movement. The other two implants in control group were placed with primary stability. Mechanical test values and histometric measurements were analyzed. The experimental group showed significant increase in a time-dependent manner, while the mean values of the control group were constant in the mechanical tests. The HA layer remained intact, and substantial bone fragments were attached on the surface of the retrieved implant. All implants appeared to be in intimate contact with the host bone and without any inflammation after both 4 and 8 weeks of healing in histology. The HA-coated implants exhibited mechanically and histometrically comparable osseointegration after 4 weeks of healing, regardless of primary stability, and the HA-coating layer demonstrated high resistance to exfoliation.


LH release by Cu and Ni salts and metal-GnRH complexes, in vitro.
The present studies were undertaken to examine the effect of copper and nickel salts and their complexes with GnRH on LH release from the pig anterior pituitary cells in vitro. The potency of Cu-GnRH and Ni-GnRH binding to GnRH receptors with iodinated GnRH as a radioactive tracer was also verified. The incubation of pig pituitary cells with Cu and Ni acetate salts showed no effect of the studied ions on LH release at any concentration used. However, nickel salt at a lower dose (10(-10) and 10(-9) M) tended to decrease LH output. By contrast, the native GnRH as well as its metal complexes significantly stimulated LH release after three hours of treatment and Cu-GnRH was found to be the most effective. The results showed that Cu and Ni complexes with GnRH but not their acetate salts are effective in LH release from pig pituitary cells collected from adult female pigs.


Gaining new insights into nanoporous gold by mining and analysis of published images.
One way of expediting materials development is to decrease the need for new experiments by making greater use of published literature. Here, we use data mining and automated image analysis to gather new insights on nanoporous gold (NPG) without conducting additional experiments or simulations. NPG is a three-dimensional porous network that has found applications in catalysis, sensing, and actuation. We assemble and analyze published images from among thousands of publications on NPG. These images allow us to infer a quantitative description of NPG coarsening as a function of time and temperature, including the coarsening exponent and activation energy. They also demonstrate that relative density and ligament size in NPG are not correlated, indicating that these microstructure features are independently tunable. Our investigation leads us to propose improved reporting guidelines that will enhance the utility of future publications in the field of dealloyed materials.


Bone mineral density in patients with psoriatic arthritis.
Little information is available concerning bone mass in patients with psoriatic arthritis (PsA): the existence of less severe periarticular osteoporosis is considered possible, but there are no data concerning the existence of systemic osteoporosis. We investigated bone mineral density (BMD) in patients with PsA. We studied 186 patients with non-axial PsA and 100 healthy subjects, equally divided into 3 groups: women of child-bearing age, women in menopause, and men. No patient had previously received steroid treatment. In all patients, evaluation was made of disease duration, inflammation indices (erythrocyte sedimentation rate, C-reactive protein), functional indices (Steinbrocker scale), and the Health Assessment Questionnaire (HAQ). BMD was measured by fan-beam x-ray densitometry of the lumbar spine, femur, and total body (evaluating the whole skeleton, as well as the spine, trunk, and upper and lower limbs). Ultrasound densitometry of the heel was also performed. BMD was significantly lower in the arthritic than in the healthy subjects regardless of sex, menopausal status, or age, as expressed in g/cm2 (lumbar spine 1.112 vs 1.326; femoral neck 0.870 vs 1.006; total body 1.125 vs 1.203) or by T and Z scores (lumbar T = -1.36, Z = -0.98; femoral neck T = -1.12, Z = -0.83; total body T = -1.09, Z = -0.65). Ultrasound densitometry of the heel was similarly altered (stiffness 96 vs 77; T -1.78; Z -1.29). Among the PsA patients, demineralization in at least one skeletal region was observed in 67% of premenopausal women (marked in 11%), 100% of postmenopausal women (marked in 47%), and 80% of the men (marked in 29%). In premenopausal women, demineralization did not correlate with the disease variables; in postmenopausal women and the men, it correlated with a decline in the functional indices and the HAQ score. This was confirmed by analysis of the relative risk of osteoporosis expressed in odds ratios (HAQ: 1.6; age: 1.4; years since menopause: 1.7). Demineralization was observed in more than 2/3 of our PsA patients without axial involvement. This demineralization was not related to the indices of inflammation or disease duration, but there is a delayed correlation with HAQ score, as well as age and the number of years since menopause.


Dominant negative ER induces apoptosis in GH(4) pituitary lactotrope cells and inhibits tumor growth in nude mice.
The ER plays an important role in the proliferation and differentiation of lactotrope tumor cells. GH(4) cells were infected with adenoviral vectors (AdL540Q and Ad1-536) to investigate the ability of dominant negative ER mutants to affect the regulation of gene expression and cell growth by endogenous ER. The dominant negative mutants suppressed estradiol stimulation of an estrogen-responsive reporter gene and the PRL promoter in these cells. AdL540Q or Ad1--536 infection also inhibited GH(4) cell growth and induced apoptosis, increasing the expression of the proapoptotic Bax protein and decreasing the expression of antiapoptotic Bcl-2. AdwtER-infected cells also showed decreased Bcl-2 protein. E2-induced activation of p38 MAPK, an enzyme that may participate in apoptosis, was observed in cells infected with AdwtER, AdL540Q, and Ad1--536. Consistent with the apoptotic effects in vitro, infection of GH(4) cells with AdL540Q or Ad1--536 inhibited the ability of the cells to form tumors in nude mice. These results indicate that dominant negative ER mutants induce apoptosis of GH(4) cells and suppress tumor formation and development. The delivery of dominant negative ERs by adenoviral vectors may provide an alternative modality for the targeted therapy of pituitary lactotrope adenomas and other estrogen-responsive tumors.


First Report of Tomato torrado virus Infecting Tomato in Colombia.
Tomato (Solanum lycopersicum L.) plants grown in plastic greenhouses near Villa de Leyva, northeast of Bogota, Colombia showed necrotic spots on the leaves in September 2008. Initial symptoms were necrosis beginning at the base of leaflets that were surrounded by yellow areas. These symptoms resembled those described for Tomato torrado virus (ToTV; family Secoviridae, genus Torradovirus), which was first found in Spain (2). Other (tentative) members of the genus Torradovirus, Tomato marchitez virus (ToMarV), Tomato chocolate spot virus (ToChSV), and Tomato chocolàte virus (ToChV) (3) induce similar symptoms on tomato plants. One sample, coded T418, was stored in the freezer and brought to our lab in 2011. Serological tests (double-antibody sandwich-ELISA) using polyclonal antibodies (Prime Diagnostics, Wageningen, The Netherlands) on leaf extracts showed the absence of Pepino mosaic virus (PepMV), Tobacco mosaic virus (TMV), Tomato spotted wilt virus (TSWV), Cucumber mosaic virus (CMV), Potato virus X (PVX), and Potato virus Y (PVY). Leaf extracts were mechanically inoculated onto the indicator plants Physalis floridana, Nicotiana hesperis '67A', and N. occidentalis 'P1' (six plants in total) and were kept in a greenhouse at 20°C with 16 h of light. Necrotic symptoms appeared 4 to 5 days postinoculation and resembled those described for ToTV (2). Two dip preparations of systemically infected P. floridana and N. occidentalis leaves were examined by electron microscopy, which revealed the presence of spherical virus particles of approximately 30 nm. To confirm the presence of ToTV, total RNA was extracted from the original leaf material and an inoculated P. floridana and N. occidentalis plant using the Qiagen Plant Mini Kit (Qiagen, Hilden, Germany) following manufacturer's instructions. ToTV-specific primer sets ToTV-Dp33F/ToTV-Dp20R (5'-TGCTCAATGTTGGAAACCCC-3'/5'-AGCCCTTCATAGGCTAGCC-3', amplifying a fragment of the RNA1 polyprotein with an expected size of 751 bp) and ToTV-Dp1F/ToTV-Dp2R (5'-ACAAGAGGAGCTTGACGAGG-3'/5'-AAAGGTAGTGTAATGGTCGG-3', amplifying a fragment on the RNA2 movement protein region with an expected size of 568 bp) were used to amplify the indicated regions in a reverse transcription (RT)-PCR using the One-Step Access RT-PCR system (Promega, Madison, WI). Amplicons of the predicted size were obtained in all tested materials. The PCR products were purified with the Qiaquick PCR Purification Kit (Qiagen) and sequenced directly. BLAST analyses of the obtained sequences (GenBank Accession Nos. JQ314230 and JQ314229) confirmed the identity of isolate T418 as ToTV, with 99% identity to isolate PRI-ToTV0301 in both fragments (GenBank Accession Nos. DQ388879 and DQ388880 for RNA1 and RNA 2, respectively). To our knowledge, this is the first report of ToTV in Colombia, and interestingly, since ToTV has been found only in Europe and Australia (1) so far, this is the first report of ToTV on the American continent. References: (1) C. F. Gambley et al. Plant Dis. 94:486, 2010. (2) M. Verbeek et al. Arch. Virol. 152:881, 2007. (3) M. Verbeek et al. Arch. Virol. 155:751, 2010.


PEHO syndrome (progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy): neuroradiologic findings.
To investigate the radiologic characteristics of the clinical progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) symptom complex. This complex is nonspecific, but within this syndrome, a subgroup with a defined neuropathologic phenotype and apparently autosomal recessive inheritance exists. Brain CT or MR studies were performed on 21 patients with the clinical PEHO syndrome. Their previous neuroradiologic studies were re-evaluated. Twelve patients (group A) showed uniform changes with early progressive brain atrophy accentuated infratentorially, and abnormal myelination. The gyral pattern was normal. Brain atrophy of nine patients (group B) differed by being less progressive, supra- rather than infratentorial, and often combined with abnormal gyral formation. Postmortem studies permitted correlation of radiographic and morphologic findings in three cases. Two autopsied group A patients were compatible with the true PEHO syndrome, while one group B patient was incompatible. Group A seems to correspond to the core group of the PEHO syndrome. During a patient's life, a suggestive diagnosis of the true PEHO syndrome is thus feasible, although neuropathologic studies are needed for a conclusive diagnosis.


On Pixel-Wise Explanations for Non-Linear Classifier Decisions by Layer-Wise Relevance Propagation.
Understanding and interpreting classification decisions of automated image classification systems is of high value in many applications, as it allows to verify the reasoning of the system and provides additional information to the human expert. Although machine learning methods are solving very successfully a plethora of tasks, they have in most cases the disadvantage of acting as a black box, not providing any information about what made them arrive at a particular decision. This work proposes a general solution to the problem of understanding classification decisions by pixel-wise decomposition of nonlinear classifiers. We introduce a methodology that allows to visualize the contributions of single pixels to predictions for kernel-based classifiers over Bag of Words features and for multilayered neural networks. These pixel contributions can be visualized as heatmaps and are provided to a human expert who can intuitively not only verify the validity of the classification decision, but also focus further analysis on regions of potential interest. We evaluate our method for classifiers trained on PASCAL VOC 2009 images, synthetic image data containing geometric shapes, the MNIST handwritten digits data set and for the pre-trained ImageNet model available as part of the Caffe open source package.


Cryo-EM structure of the native butyrylcholinesterase tetramer reveals a dimer of dimers stabilized by a superhelical assembly.
The quaternary structures of the cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), are essential for their localization and function. Of practical importance, BChE is a promising therapeutic candidate for intoxication by organophosphate nerve agents and insecticides, and for detoxification of addictive substances. Efficacy of the recombinant enzyme hinges on its having a long circulatory half-life; this, in turn, depends strongly on its ability to tetramerize. Here, we used cryoelectron microscopy (cryo-EM) to determine the structure of the highly glycosylated native BChE tetramer purified from human plasma at 5.7 Å. Our structure reveals that the BChE tetramer is organized as a staggered dimer of dimers. Tetramerization is mediated by assembly of the C-terminal tryptophan amphiphilic tetramerization (WAT) helices from each subunit as a superhelical assembly around a central lamellipodin-derived oligopeptide with a proline-rich attachment domain (PRAD) sequence that adopts a polyproline II helical conformation and runs antiparallel. The catalytic domains within a dimer are asymmetrically linked to the WAT/PRAD. In the resulting arrangement, the tetramerization domain is largely shielded by the catalytic domains, which may contribute to the stability of the human BChE (HuBChE) tetramer. Our cryo-EM structure reveals the basis for assembly of the native tetramers and has implications for the therapeutic applications of HuBChE. This mode of tetramerization is seen only in the cholinesterases but may provide a promising template for designing other proteins with improved circulatory residence times.


Targeting signals and subunit interactions in coated vesicle adaptor complexes.
There are two clathrin-coated vesicle adaptor complexes in the cell, one associated with the plasma membrane and one associated with the TGN. The subunit composition of the plasma membrane adaptor complex is alpha-adaptin, beta-adaptin, AP50, and AP17; while that of the TGN adaptor complex is gamma-adaptin, beta'-adaptin, AP47, and AP19. To search for adaptor targeting signals, we have constructed chimeras between alpha-adaptin and gamma-adaptin within their NH2-terminal domains. We have identified stretches of sequence in the two proteins between amino acids approximately 130 and 330-350 that are essential for targeting. Immunoprecipitation reveals that this region determines whether a construct coassemblies with AP50 and AP17, or with AP47 and AP19. These observations suggest that these other subunits may play an important role in targeting. In contrast, beta- and beta'-adaptins are clearly not involved in this event. Chimeras between the alpha- and gamma-adaptin COOH-terminal domains reveal the presence of a second targeting signal. We have further investigated the interactions between the adaptor subunits using the yeast two-hybrid system. Interactions can be detected between the beta/beta'-adaptins and the alpha/gamma-adaptins, between the beta/beta'-adaptins and the AP50/AP47 subunits, between alpha-adaptin and AP17, and between gamma-adaptin and AP19. These results indicate that the adaptor subunits act in concert to target the complex to the appropriate membrane.


Obesity in Switzerland: do estimates depend on how body mass index has been assessed?
In Switzerland monitoring of obesity in the general population is based on body mass index (BMI) derived from self-reported weight and height. This approach may lead to misclassification of obese subjects and misinterpretation of obesity prevalence and trends. In order to explore this potential bias, we compared studies with measured and self-reported data. We analysed five studies based on measured BMI and five studies based on self-reported BMI, all of which were carried out in Switzerland between 1977 and 2004 and encompassed men and women aged 35-74 years. Obesity was defined as BMI>or=30 kg/m2. The prevalence of obesity was markedly higher (1.6 times) in studies with measured BMI in both sexes: 14.2% vs 8.8% in men and 12.5% vs 7.9% in women. These differences tended to increase with age in both sexes. However, a similar upward trend in the prevalence of obesity was observed with both methods (absolute increase per year in men and women respectively: 0.24% and 0.25% using measured BMI vs 0.17% and 0.20% using self-reported BMI). In Switzerland obesity prevalence in adults has clearly increased in the past three decades. Although the use of self-reported height and weight leads to a valid estimation of this increase, it results in a considerable underestimation of obesity prevalence rates in Switzerland. The type of assessment of height and weight should be taken into consideration when comparing prevalences of obesity between studies or regions or when using these prevalences to assess associated health risks or costs.


Geometry of thermodynamic control.
A deeper understanding of nonequilibrium phenomena is needed to reveal the principles governing natural and synthetic molecular machines. Recent work has shown that when a thermodynamic system is driven from equilibrium then, in the linear response regime, the space of controllable parameters has a Riemannian geometry induced by a generalized friction tensor. We exploit this geometric insight to construct closed-form expressions for minimal-dissipation protocols for a particle diffusing in a one-dimensional harmonic potential, where the spring constant, inverse temperature, and trap location are adjusted simultaneously. These optimal protocols are geodesics on the Riemannian manifold and reveal that this simple model has a surprisingly rich geometry. We test these optimal protocols via a numerical implementation of the Fokker-Planck equation and demonstrate that the friction tensor arises naturally from a first-order expansion in temporal derivatives of the control parameters, without appealing directly to linear response theory.


The identifying and counseling of breastfeeding women by pharmacists.
Concerns about medications influence breastfeeding decisions. Mothers may stop breastfeeding when they take medications. After the distribution of Thomas Hale's Medications and Mother's Milk (MMM) (Hale Publishing, Amarillo, TX, 2006) by the Rhode Island Department of Health (Providence, RI) in November 2006 to Rhode Island pharmacies, we investigated, during the summer of 2007, what strategies and resources pharmacists were using to identify breastfeeding women and guide medication recommendations. Copies of MMM were sent to 47 pharmacies in Rhode Island. Subsequently, one pharmacist at each site completed a confidential, 10-question written survey. The survey response rate was 92%. More than half (58%) of the pharmacists surveyed never asked women if they were breastfeeding. Most (85%) of pharmacists reported feeling somewhat or very comfortable giving advice to breastfeeding women. All but one pharmacist who had received MMM reported using the reference at least monthly. More than half (52%) of the pharmacists reported using the Physician's Desk Reference (Thomson PDR, Montvale, NJ). Pharmacists need a consistent approach to identify breastfeeding women and access to reliable, continuously updated resources to guide their advice about medication use to breastfeeding women. Physicians and pharmacists should collaborate to prevent medication use from being a barrier to breastfeeding.


Magneto-transport in MoS2: phase coherence, spin-orbit scattering, and the hall factor.
We have characterized phase coherence length, spin-orbit scattering length, and the Hall factor in n-type MoS2 2D crystals via weak localization measurements and Hall-effect measurements. Weak localization measurements reveal a phase coherence length of ~50 nm at T = 400 mK for a few-layer MoS2 film, decreasing as T(-1/2) with increased temperatures. Weak localization measurements also allow us, for the first time without optical techniques, to estimate the spin-orbit scattering length to be 430 nm, pointing to the potential of MoS2 for spintronics applications. Via Hall-effect measurements, we observe a low-temperature Hall mobility of 311 cm(2)/(V s) at T = 1 K, which decreases as a power law with a characteristic exponent γ = 1.5 from 10 to 60 K. At room temperature, we observe Hall mobility of 24 cm(2)/(V s). By determining the Hall factor for MoS2 to be 1.35 at T = 1 K and 2.4 at room temperature, we observe drift mobility of 420 and 56 cm(2)/(V s) at T = 1 K and room temperature, respectively.


Human latent inhibition: Problems with the stimulus exposure effect.
Latent inhibition (LI) is a startlingly simple effect in which preexposure of a stimulus without consequence retards subsequent responding to a stimulus-consequence relation. The effect was first demonstrated with Pavlovian conditioning in animals and was later suggested to be a marker of human psychopathology such as schizophrenia. Individual differences in LI has supported the continued use of animal models to understand human mental health. In this review, we ask whether there is sufficient evidence to support the continued application of LI from animal models to human psychopathology because of the weak evidence for LI in humans. There is considerable variability in the methods used to assess LI, sustaining different theoretical accounts of the effects observed, which differ from the accepted accounts of LI as demonstrated in animals. The review shows that although there have been many experiments testing human LI, none provide the necessary experimental controls to support the conclusion that retarded responding is caused simply by preexposure to a stimulus, as has been demonstrated with animal models. Establishing this conflict, we set out a framework for future research.


Dental services and attitudes towards its regular utilization among civil servants in ibadan, Nigeria.
Regular utilization of dental services is key to the attainment of optimal oral health state, an integral component of general health and well being needed for effective productivity by working personnel. This study assessed the rate and pattern of dental service utilization among civil servants and their attitudes towards its regular use. A multi-stage sampling technique was used to select participants from the Federal Secretariat in Ibadan, Nigeria. A structured, standardized, pretested and self-administered questionnaire was utilized to elicit responses on dental services and attitudes towards their regular utilization. Responses to knowledge and attitude questions were scored and categorized. Chi-squared test was used to test associations between variables at 5% level of significance. A total of 400 civil servants participated in the study. Their mean age was 44.0 ±7.3years. Many 291(72.8%) were well informed about dental health care and services, but few 156 (39%) had ever utilized it. Of the utilizers, 32 (20.5%) visited within the previous one year period, while others last visited in more than one year period. Few 17 (10.9%) of the utilizers visited for routine dental checks, 103 (66%) for acute pain relief, while the rest had other dental health care needs. The majority 312 (78.0%) showed positive attitude towards regular dental service utilization and this improved with higher educational attainment, improved level of income, being aware of dental services and having ever utilized it (all p<0.05). Despite the awareness and positive attitude towards regular dental service use, their utilization rate was relatively low, episodic and problem driven. Appropriate oral health promotion strategies to enhance utilization of preventive dental services are strongly recommended for them.


Efficacy of Structured Yoga Intervention for Sleep, Gastrointestinal and Behaviour Problems of ASD Children: An Exploratory Study.
Autism Spectrum Disorder (ASD) is a neuro developmental disorder which appears at early childhood age between 18 and 36 months. Apart from behaviour problems ASD children also suffer from sleep and Gastrointestinal (GI) problems. Major behaviour problems of ASD children are lack of social communication and interaction, less attention span, repetitive and restrictive behaviour, lack of eye to eye contact, aggressive and self-injurious behaviours, sensory integration problems, motor problems, deficiency in academic activities, anxiety and depression etc. Our hypothesis is that structured yoga intervention will brings significant changes in the problems of ASD children. The aim of this study was to find out efficacy of structured yoga intervention for sleep problems, gastrointestinal problems and behaviour problems of ASD children. It was an exploratory study with pre-test and post-test control design. Three sets of questionnaires having 61 questions developed by researchers were used to collect data pre and post yoga intervention. Questionnaires were based on three problematic areas of ASD children as mentioned above and were administered to parents by teachers under the supervision of researcher and clinical psychologists. Experimental group was given yoga intervention for a period of 90 days and control group continued with school curriculum. Both children and parents participated in this intervention. Significant changes were seen post yoga intervention in three areas of problems as mentioned above. Statistical analysis also showed significance value of 0.001 in the result. Structured yoga intervention can be conducted for a large group of ASD children with parent's involvement. Yoga can be used as alternative therapy to reduce the severity of symptoms of ASD children.


Optical absorption enhancement in a hybrid system photonic crystal - thin substrate for photovoltaic applications.
A hybrid approach for light trapping using photonic crystal nanostructures (nanorods, nanopillars or nanoholes) on top of an ultra thin film as a substrate is presented. The combination of a nanopatterned layer with a thin substrate shows an enhanced optical absorption than equivalent films without patterning and can compete in performance with nanostructured systems without a substrate. The designs are tested in four relevant materials: amorphous silicon (a-Si), crystalline silicon (Si), gallium arsenide (GaAs) and indium phosphide (InP). A consistent enhancement is observed for all of the materials when using a thin hybrid system (300 nm) even compared to the non patterned thin film with an anti-reflective coating (ARC). A realistic solar cell structure composed of a hybrid system with a layer of indium tin oxide (ITO) an ARC and a back metal layer is performed, showing an 18% of improvement for the nanostructured device.


Crystallization and crystallographic analysis of the Rhodococcus rhodochrous NCIMB 13064 DhaA mutant DhaA31 and its complex with 1,2,3-trichloropropane.
Haloalkane dehalogenases hydrolyze carbon-halogen bonds in a wide range of halogenated aliphatic compounds. The potential use of haloalkane dehalogenases in bioremediation applications has stimulated intensive investigation of these enzymes and their engineering. The mutant DhaA31 was constructed to degrade the anthropogenic compound 1,2,3-trichloropropane (TCP) using a new strategy. This strategy enhances activity towards TCP by decreasing the accessibility of the active site to water molecules, thereby promoting formation of the activated complex. The structure of DhaA31 will help in understanding the structure-function relationships involved in the improved dehalogenation of TCP. The mutant protein DhaA31 was crystallized by the sitting-drop vapour-diffusion technique and crystals of DhaA31 in complex with TCP were obtained using soaking experiments. Both crystals belonged to the triclinic space group P1. Diffraction data were collected to high resolution: to 1.31 Å for DhaA31 and to 1.26 Å for DhaA31 complexed with TCP.


Remote video auditing in the endoscopy unit for evaluation of duodenoscope reprocessing in a tertiary care center.
BACKGROUND : A significant proportion of duodenoscope-transmitted infections have resulted from errors related to reprocessing. Remote video auditing (RVA) is a tool that can monitor reprocessing compliance but it has not been previously evaluated in a tertiary care setting. The aims of this study were to evaluate: 1) RVA feasibility in a tertiary care setting (defined as the ability to audit every step of duodenoscope reprocessing without delaying the next procedure due to unavailability of duodenoscopes); and 2) the use of RVA as a compliance monitoring tool. METHODS : This was a prospective study at a tertiary care center. A video camera with offsite monitoring was installed in March 2018. Auditors delivered a compliance score after each procedure. The duodenoscope was not used until it passed the audit. Feasibility and compliance data were collected from April 2018 to August 2019 after a 1-month run-in phase. Both per-step compliance and overall 100 % compliance rates were measured. RESULTS : Of 743 duodenoscope reprocessing procedures, 32 666 individual steps were audited and 99.9 % of the steps were fully viewable. The mean time per audit was 38.3 minutes, the mean duodenoscope turnover time was 76.1 minutes, and there were no delays to the next procedure due to unavailability of duodenoscopes. The per-step compliance rate was 99.5 % but the overall 100 % compliance rate was 90.3 %. CONCLUSIONS : The use of RVA in duodenoscope reprocessing was feasible and promoted sustained high-level compliance in a tertiary care center.


The CRISPR system--keeping zebrafish gene targeting fresh.
We are entering a new era in our ability to modify and edit the genomes of model organisms. Zinc finger nucleases (ZFNs) opened the door to the first custom nuclease-targeted genome engineering in the late 1990s. However, ZFNs remained out of reach for most research labs because of the difficulty of production, high costs, and modest efficacy in many applications. Transcription activator-like effector nucleases (TALENs) were built upon a DNA binding system discovered in a group of plant bacterial pathogens and broadened custom nuclease technology, showing significant improvements in both targeting flexibility and efficiency. Perhaps most importantly, TALENs are open source and easy to produce, providing zebrafish laboratories around the world with affordable tools that can be made in-house rapidly, at low cost, and with reliably high activity. Now a new system for targeted genome engineering derived from the CRISPR/Cas system in eubacteria and archaea promises to simplify this process further. Together, these tools will help overcome many of the bottlenecks that have constrained gene targeting in zebrafish, paving the way for advanced genome engineering applications in this model teleost.


Habitat filtering across tree life stages in tropical forest communities.
Tropical tree communities are shaped by local-scale habitat heterogeneity in the form of topographic and edaphic variation, but the life-history stage at which habitat associations develop remains poorly understood. This is due, in part, to the fact that previous studies have not accounted for the widely disparate sample sizes (number of stems) that result when trees are divided into size classes. We demonstrate that the observed habitat structuring of a community is directly related to the number of individuals in the community. We then compare the relative importance of habitat heterogeneity to tree community structure for saplings, juveniles and adult trees within seven large (24-50 ha) tropical forest dynamics plots while controlling for sample size. Changes in habitat structuring through tree life stages were small and inconsistent among life stages and study sites. Where found, these differences were an order of magnitude smaller than the findings of previous studies that did not control for sample size. Moreover, community structure and composition were very similar among tree sub-communities of different life stages. We conclude that the structure of these tropical tree communities is established by the time trees are large enough to be included in the census (1 cm diameter at breast height), which indicates that habitat filtering occurs during earlier life stages.


An 18-electron system containing a superheavy element: theoretical studies of sg@au12.
M@Au12 cage molecules (M = transition element from group 6) are interesting clusters with high-symmetric structure and significant stability. As the heavier homologue of W is (106)Sg, it is interesting to pinpoint whether the Sg@Au12 cluster is also stable. Geometric and electronic structures and bonding of various Sg@Au12 isomers were investigated with density functional theory (PW91, PBE, B3LYP) and wave function theory (MP2, CCSD(T)) approaches. The lowest-energy isomer of Sg@Au12 has icosahedral symmetry with significant Sg(6d)-Au(6s) covalent-metallic interaction and is comparable to the lighter homologues (M = Mo, W), with similar binding energy, although Sg follows (as a rare case) the textbook rule "ns below (n - 1)d". The 12 6s valence electrons from Au12 and the six 7s6d ones from Sg can be viewed as an 18e system below and above the interacting Au 5d band, forming nine delocalized multicenter bond pairs with a high stability of ∼0.8 eV of bond energy per each of the 12 Sg-Au contacts. Different prescriptions (orbital, multipole-deformation, charge-partition, and X-ray-spectroscopy based ones) assign ambiguous atomic charges to the centric and peripheral atoms; atomic core-level energy shifts correspond to some negative charge shift to the gold periphery, more so for Cr@Au12 than for Sg@Au12 or Au@Au12.


Fe/Ni core/shell nanowires and nanorods: a combined first-principles and atomistic simulation study.
In recent years, construction and characterization of core-shell structures have attracted great attention because of their unique functional properties and their integration into technological devices. However, some aspects of their basic physics still remain to be explored. In this study, we report on an extensive hierarchical multiscale modeling methodology applied to Fe-Ni core/shell nanostructures of technological interest. As a first step, supported on a first-principles study, we develop a methodology to compute primordial but unprecedented parameters such as the exchange coupling and the equilibrium bond distances at the interface, namely JFe-Ni = 35.48 meV and d = 2.5 Å. This methodology can be used for computing fundamental parameters in mixed systems by knowing the parameters in the bulk samples, and the so-obtained results can be used in higher size scale simulations. As a proof, the results obtained are used as input parameters for atomistic simulations on Fe-Ni samples made out of a Fe core surrounded by a Ni shell whose external diameter varies finely in the range 60-110 nm. The inner diameter and height are fixed to be 40 and 50 nm, respectively. We address the structural, electronic, static magnetic and hysteresis properties of the Fe-Ni core/shell cylindrical nanostructures in different size ranges. These nanostructures reveal different magnetic properties with novel complex states, which are studied in detail.


Fitness evaluation of two Brazilian Aedes aegypti field populations with distinct levels of resistance to the organophosphate temephos.
In Brazil, decades of dengue vector control using organophosphates and pyrethroids have led to dissemination of resistance. Although these insecticides have been employed for decades against Aedes aegypti in the country, knowledge of the impact of temephos resistance on vector viability is limited. We evaluated several fitness parameters in two Brazilian Ae. aegypti populations, both classified as deltamethrin resistant but with distinct resistant ratios (RR) for temephos. The insecticide-susceptible Rockefeller strain was used as an experimental control. The population presenting the higher temephos resistance level, Aparecida de Goiânia, state of Goiás (RR(95) of 19.2), exhibited deficiency in the following four parameters: blood meal acceptance, amount of ingested blood, number of eggs and frequency of inseminated females. Mosquitoes from Boa Vista, state of Roraima, the population with lower temephos resistance level (RR(95) of 7.4), presented impairment in only two parameters, blood meal acceptance and frequency of inseminated females. These results indicate that the overall fitness handicap was proportional to temephos resistance levels. However, it is unlikely that these disabilities can be attributed solely to temephos resistance, since both populations are also resistant to deltamethrin and harbour the kdr allele, which indicates resistance to pyrethroids. The effects of reduced fitness in resistant populations are discussed.


Anti-inflammatory implications of the microbial transformation of dietary phenolic compounds.
Due to the success of therapeutic anti-inflammatory compounds to inhibit, retard, and reverse the development of colon cancer, the identification of dietary compounds as chemopreventives is being vigorously pursued. However, an important factor often overlooked is the metabolic transformation of the food-derived compounds in the gut that may affect their bioactivity. Commonly consumed dietary phenolics (esterified ferulic acid and its 5-5'-linked dimer), which have the potential to undergo predominant microbial transformations (de-esterification, hydrogenation, demethylation, dehydroxylation, and dimer cleavage), were incubated with human microbiota. The metabolites were identified (high-performance liquid chromatography and nuclear magnetic resonance) and confirmed to be present in fresh fecal samples from 4 human volunteers. The potential anti-inflammatory properties were compared by measuring the ability of the parent compounds and their metabolites to modulate prostanoid production in a cell line in which the inflammatory pathways were stimulated following a cytokine-induced insult. The compounds were readily de-esterified and hydrogenated, but no dimer cleavage occurred. Only the monomer underwent demethylation and selective de-hydroxylation. The resultant metabolites had differing effects on prostanoid production ranging from a slight increase to a significant reduction in magnitude. This suggests that the microbial transformation of dietary compounds will have important inflammatory implications in the chemoprevention of colon cancer.


Efficacy of Solitaire Stent Arterial Embolectomy in Treating Acute Cardiogenic Cerebral Embolism in 17 Patients.
BACKGROUND Thrombolysis with rtPA is the only accepted drug therapy for acute ischemic stroke. Since acute cerebral stroke is so pervasive, newly developed recanalization methods have the potential for wide-ranging impacts on patient health and safety. We explored the efficacy and safety of Solitaire stent arterial embolectomy in the treatment of acute cardiogenic cerebral embolism. MATERIAL AND METHODS Between October 2012 and June 2015, 17 patients underwent Solitaire stent arterial embolectomy, either alone or in combination with rtPA intravenous thrombolysis, to treat acute cardiogenic cerebral embolism. Sheath placement time, vascular recanalization time, number of embolectomy attempts, and IV rtPA dose and time were recorded. Success and safety of the recanalization procedure, as well as clinical outcomes, were assessed. These results were compared to 16 control patients who were treated using only rtPA IV thrombolysis. RESULTS Full recanalization of the occluded arteries was achieved in 15 (88.2%) of the Solitaire stent patients. NIH Stroke Scale scores of embolectomy patients improved by an average of 12.59 ± 8.24 points between admission and discharge, compared to 5.56 ± 5.96 in the control group (P<0.05). Glasgow Coma Score improvement between admission and discharge was also significantly higher in the embolectomy group (P<0.05). There was no significant difference in symptomatic intracerebral hemorrhage, high perfusion encephalopathy, incidence of hernia, or mortality between the 2 groups (P>0.05). CONCLUSIONS Solitaire stent embolectomy is a safe and effective alternative to simple venous thrombolytic therapy, and it can significantly improve short-term neurological function and long-term prognosis in acute cardiogenic cerebral embolism.


Separation of hydrophobic polymer additives by microemulsion electrokinetic chromatography.
Microemulsion electrokinetic chromatography (MEEKC) has been applied to the separation of some phenolic antioxidants [Irganox 1024, Irganox 1035, Irganox 1076, Irganox 1010, Irganox 1330, Irgafos 138, Irganox 168 and 2,6-di-tert.-butyl-4-methylphenol (BHT)]. Due to the extremely hydrophobic nature of these analytes, they could not be separated using standard MEEKC conditions and two alternative approaches were investigated. Using an acidic buffer (phosphate, pH 2.5) to effectively suppress the electroosmotic flow, the addition of 2-propanol to the aqueous phase of the microemulsion buffer to improve partitioning of the analytes, and a negative separation voltage, separation of five of the analytes in under 10 min was possible. The second approach, using a basic buffer (borate, pH 9.2) and a positive separation voltage resulted in complete resolution of all eight analytes. A mixed surfactant system comprising the anionic sodium dodecyl sulfate (SDS) and neutral Brij 35 was used to reduce the overall charge and with it the mobility of the droplets, and hence the separation time. Using an optimised MEEKC buffer consisting of 2.25% (w/w) SDS, 0.75% (w/w) Brij 35, 0.8% (w/w) n-octane, 6.6% (w/w) 1-butanol, 25% (w/w) 2-propanol and 64.6% (w/w) 10 mM borate buffer (pH 9.2) the eight target analytes were baseline separated in under 25 min. For these analytes, MEEKC was found to be superior to micellar electrokinetic chromatography in every respect. Specifically, the solubility of the analytes was better, the selectivity was more favourable, the analysis time was shorter and the separation efficiency was up to 72% higher when using the MEEKC method. Detection limits from 5.4 to 26 microg/ml were obtained and the calibration plot was linear over more than one order of magnitude. The optimised method could be applied to the determination of Irganox 1330 and Irganox 1010 in polypropylene.


LifeWatch observatory data: phytoplankton observations in the Belgian Part of the North Sea.
This paper describes a phytoplankton data series generated through systematic observations in the Belgian Part of the North Sea (BPNS). Phytoplankton samples were collected during multidisciplinary sampling campaigns, visiting nine nearshore stations with monthly frequency and an additional eight offshore stations on a seasonal basis. The data series contain taxon-specific phytoplankton densities determined by analysis with the Flow Cytometer And Microscope (FlowCAM®) and associated image-based classification. The classification is performed by two separate semi-automated classification systems, followed by manual validation by taxonomic experts. To date, 637,819 biological particles have been collected and identified, yielding a large dataset of validated phytoplankton images. The collection and processing of the 2017-2018 dataset are described, along with its data curation, quality control and data storage. In addition, the classification of images using image classification algorithms, based on convolutional neural networks (CNN) from 2019 onwards, is also described. Data are published in a standardised format together with environmental parameters, accompanied by extensive metadata descriptions and finally labelled with digital identifiers for traceability. The data are published under a CC-BY 4.0 licence, allowing the use of the data under the condition of providing the reference to the source.


Supplementary eye field contributions to the execution of saccades to remembered target locations.
Multiple lines of evidence indicate that an anatomically discrete region within the dorsal medial frontal cortex--the supplementary eye field (SEF)--is involved in oculomotor control. To delineate this role further, repetitive transcranial magnetic stimulation (rTMS; 10 Hz, 500 ms) was administered either immediately after the presentation of three-step saccade sequences, or, immediately before response execution of memory-guided saccades. In addition, the effects of changes to visuospatial and temporal order demands were examined by contrasting performance in the presence and the absence of target location information. Results revealed that the SEF supports the processing of spatial information relevant to saccade amplitude. Independently of the time of stimulation, saccade gain was reduced by rTMS applied over the SEF, though only when response execution was performed in the absence of target location information. These results provide evidence of a causal role for the SEF in oculomotor control in the absence of visual feedback.


Quantitative Study of the Macular Microvasculature in Human Donor Eyes.
To precisely quantify the macular microvasculature density using microperfusion and labeling techniques in human donor eyes. Such information may be useful in understanding the role of the macular microvasculature in coping with the metabolic requirements of the neurons in this densely packed region, and provide a reference point for clinical studies using recently developed optical imaging techniques. The macular microvasculature was perfusion-labeled in 18 human donor eyes and optical stacks collected from regions superior, temporal, inferior, and nasal to the foveola using confocal microscopy. The optical slices were separated into the deep macula vascular layer (DL), and the superficial layer (SL) in which all the vessels superficial to the deep macular vessel layer were included. The DL and SL images were analyzed and vessel density measured according to their orientation from the foveola and in foveal and parafoveal regions. Vessel densities were compared across regions and age groups. Both the SL and DL showed an increase in vessel density with increasing eccentricity from the foveal to parafoveal regions. Vessel density was found to rank in the order of inferior > superior > temporal > nasal in both SL and DL layers. The SL vascular density was approximately 31%, whereas DL was approximately 17%. The DL was planar in nature and density not affected by age. Age-related increase in vessel density was observed in the SL. Microperfusion and labeling techniques in combination with confocal microscopy has enabled collection of reliable data on vascular density in the macula region. Regional differences may reflect well-matched vascular supply and neuronal demands. Age-related changes might indicate the importance of stable blood supply for the human macula.


Ocular higher-order wavefront aberrations in the Japanese adult population: the Yamagata Study (Funagata).
To investigate the relationship between age and ocular higher-order wavefront aberrations (HOAs) in an adult Japanese population, in addition to factors associated with HOA variations. In the Yamagata Study (Funagata) cohort, 227 adult Japanese participants (aged 37-86 years) underwent systemic and ophthalmologic examinations in 2012. Ocular, corneal, and internal HOAs were measured in micrometers. From the Zernike coefficients, we calculated the root mean square of the total HOA, coma, and spherical aberration for a pupil diameter of 4 mm. Linear regression analyses were used to determine whether HOAs were associated with age or other factors. Multiple adjusted linear regression analyses demonstrated that all components of logarithmic HOAs increase with age. Ocular, corneal, and internal HOAs increased by 0.012/y (P < 0.001), 0.007/y (P = 0.010), and 0.014/y (P < 0.001), respectively. Ocular coma also significantly increased with age (0.010/y, P = 0.007), but corneal (P = 0.963) and internal (P = 0.476) coma did not. Age-related spherical aberration increased only in the internal component (0.019/y, P = 0.001). In addition to age, ocular and corneal HOAs were mainly affected by corneal indexes. Aging is associated with increases in ocular HOAs, independent of other possible confounding factors. The association of ocular HOAs with corneal parameters indicates that ocular HOAs are mainly generated by the cornea. Internal HOAs, supposedly generated from cataract progression, may be associated with systemic factors, including serum creatinine levels and blood pressure.


Predictors of poor treatment response to additional CBT in real panic disorder patients: The role of DLPF, orbitofrontal cortex, parietal lobule, frontal eye field and amygdala in PD.
Previous functional brain imaging studies have described various and contradictory activation findings in patients with panic disorder (PD). Our study focused on patients with a chronic PD, who were investigated and treated in a conventional manner, which represents the real PD patients in clinical practice. Continuing their medication, patients were included in a six-week cognitive-behavioral therapy (CBT) program in the psychiatry department. At the onset of the study, participants underwent clinical evaluation using standard scales and were examined using fMRI while listening to verbal threat-related stimuli contrasted to neutral words. According to the therapeutic outcome, they were subsequently divided into two groups, responders, and nonresponders and the two groups were mutually compared. In non-responders compared to responders, we found increased pre-treatment activation in dorsolateral prefrontal cortex bilaterally, left orbitofrontal cortex, left frontal eye field, right parietal lobule and left amygdala. In addition, both groups showed negative fMRI BOLD correlation with BAI improvement and positive correlation with CGI improvement across the ROIs. We suggest that DLPFC over-activation may reveal a lack of cognitive control over emotional processing, which makes subsequent CBT less effective. Despite several limitations, we found neuroimaging predictors of poor CBT response, under the conditions of standard clinical practice, in real PD patients.


The evolution of organized neurological surgery in the United States.
In this "nation of associations," organizations are frequently established to serve the common interests of their constituencies. The periodic emergence of associations serving the neurosurgical community is a matter of historical record. However, little attention has been paid to the reasons why these neurosurgical associations have come into being. Because little has been published documenting the developmental phases of these associations, the research for this study has concentrated on the personal correspondence of the founders, as well as on the minutes and the historical records of the organizations themselves. The results demonstrate a definite pattern in the sequence of events that has led to the establishment of five national neurosurgical organizations over the past 75 years. All of them were designed to pursue the same general goals. Yet, each was conceived by its designers to fulfill unmet needs of the surgeons that it was established to represent. It is postulated that the definable pattern of these events provides a sound basis for predicting a reoccurrence of the phenomenon in the future. The conspicuous absence of several prominent academic and research societies from these discussions is not meant to reflect upon the value of these organizations to their respective constituencies. This study is limited to the evolutionary "chain" of organizations devoted to the specialty as a whole, which have, to one extent or another, played a part in the development of policies and activities that have influenced the neurosurgical specialty since its inception. Other national, regional, and special interest societies continue to serve defined elements of the specialty and could be the subject of a similar historical summary.


Dietary flaxseed enhances the inhibitory effect of tamoxifen on the growth of estrogen-dependent human breast cancer (mcf-7) in nude mice.
This study determined the effect of 10% dietary flaxseed (FS) and tamoxifen (TAM), alone and in combination, on the growth of estrogen-dependent human breast cancer (MCF-7) in athymic mice with or without 17beta-estradiol (E2) supplementation. Ovariectomized mice received injection with MCF-7 cells, were implanted with an E2 pellet (1.7 mg), and fed the basal diet (BD). When tumor reached approximately 40 mm2, the E2 implant was removed, and mice were randomized to the following groups and maintained at either low (E2 pellet removed) or high E2 level (new E2 pellet implanted) for 6 weeks: (a) positive control with new E2 pellet, fed BD, (b) negative control with no E2 implant, fed BD, (c) TAM group with TAM pellet (5 mg) implant, fed BD, (d) FS group fed 10% FS, (e) FS+TAM group with TAM implant, fed 10% FS. Tumor growth was monitored weekly. At low E2 level, FS regressed the pretreatment tumor size by 74%. TAM regressed tumor initially but later induced an increase so that the tumor size was finally similar to the pretreatment size. A tumor regression >53% was induced by FS+TAM than by TAM alone. At high E2 level, FS, TAM, and FS+TAM inhibited the tumor growth by 22, 41, and 50%, respectively, compared with the positive control. Decreased tumor size was attributable to reduced tumor cell proliferation and increased apoptosis. FS inhibited the growth of human estrogen-dependent breast cancer and strengthened the tumor-inhibitory effect of TAM at both low and high E2 levels.


Acute kidney injury associated with smoking synthetic cannabinoid.
Synthetic cannabinoids are illegal drugs of abuse known to cause adverse neurologic and sympathomimetic effects. They are an emerging health risk: 11% of high school seniors reported smoking them during the previous 12 months. We describe the epidemiology of a toxicologic syndrome of acute kidney injury associated with synthetic cannabinoids, review the toxicologic and public health investigation of the cluster, and describe clinical implications of the cluster investigation. Case series of nine patients affected by the toxicologic syndrome in Oregon and southwestern Washington during May-October 2012. Cases were defined as acute kidney injury (creatinine > 1.3 mg/dL) among persons aged 13-40 years without known renal disease who reported smoking synthetic cannabinoids. Toxicology laboratories used liquid chromatography and time-of-flight mass spectrometry to test clinical and product specimens for synthetic cannabinoids, their metabolites, and known nephrotoxins. Public health alerts informed clinicians, law enforcement, and the community about the cluster and the need to be alert for toxidromes associated with emerging drugs of abuse. Patients were males aged 15-27 years (median, 18 years), with intense nausea and flank or abdominal pain, and included two sets of siblings. Peak creatinine levels were 2.6-17.7 mg/dL (median, 6.6 mg/dL). All patients were hospitalized; one required dialysis; none died. No alternate causes of acute kidney injury or nephrotoxins were identified. Patients reported easily purchasing synthetic cannabinoids at convenience, tobacco, and adult bookstores. One clinical and 2 product samples contained evidence of a novel synthetic cannabinoid, XLR-11 ([1-(5-fluoropentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone). Whether caused by direct toxicity, genetic predisposition, or an as-yet unidentified nephrotoxin, this association between synthetic cannabinoid exposure and acute kidney injury reinforces the need for vigilance to detect new toxicologic syndromes associated with emerging drugs of abuse. Liquid chromatography and time-of-flight mass spectrometry are useful tools in determining the active ingredients in these evolving products and evaluating them for toxic contaminants.


CD73 Predicts Favorable Prognosis in Patients with Nonmuscle-Invasive Urothelial Bladder Cancer.
CD73 is a membrane associated 5'-ectonucleotidase that has been proposed as prognostic biomarker in various solid tumors. The aim of this study is to evaluate CD73 expression in a cohort of patients with primary bladder cancer in regard to its association with clinicopathological features and disease course. Tissue samples from 174 patients with a primary urothelial carcinoma were immunohistochemically assessed on a tissue microarray. Associations between CD73 expression and retrospectively obtained clinicopathological data were evaluated by contingency analysis. Survival analysis was performed to investigate the predictive value of CD73 within the subgroup of pTa and pT1 tumors in regard to progression-free survival (PFS). High CD73 expression was found in 46 (26.4%) patients and was significantly associated with lower stage, lower grade, less adjacent carcinoma in situ and with lower Ki-67 proliferation index. High CD73 immunoreactivity in the subgroup of pTa and pT1 tumors (n = 158) was significantly associated with longer PFS (HR: 0.228; p = 0.047) in univariable Cox regression analysis. High CD73 immunoreactivity was associated with favorable clinicopathological features. Furthermore, it predicts better outcome in the subgroup of pTa and pT1 tumors and may thus serve as additional tool for the selection of patients with favorable prognosis.


Enhanced inactivation and acceleration of activation of the sodium channel associated with epilepsy in man.
Generalized epilepsy with febrile seizures-plus (GEFS+) is a benign Mendelian syndrome characterized by childhood-onset febrile and afebrile seizures. Three point mutations within two voltage-gated sodium channel genes have been identified so far: in GEFS+ type 1 a mutation in the beta1-subunit gene SCN1B, and in GEFS+ type 2 two mutations within the neuronal alpha-subunit gene SCN1A. Functional expression of the SCN1B and one of the SCN1A mutations revealed defects in fast channel inactivation which are in line with previous findings on myotonia causing mutations in SCN4A, the skeletal muscle sodium channel alpha-subunit gene, all showing an impaired fast inactivation. We now studied the second GEFS+ mutation (T875M in SCN1A), using the highly homologous SCN4A gene (mutation T685M). Unexpectedly, the experiments revealed a pronounced enhancement of both fast and slow inactivation and a defect of channel activation for T685M compared to wild-type channels. Steady-state fast and slow inactivation curves were shifted in the hyperpolarizing direction, entry into slow inactivation was threefold accelerated, recovery from slow inactivation was slowed by threefold and the time course of activation was slightly but significantly accelerated. In contrast to other disease-causing mutations in SCN1A, SCN1B and SCN4A, the only mechanism that could explain hyperexcitability of the cell membrane would be the acceleration of activation. Because the enhancement of slow inactivation was the most obvious alteration in gating found for T685M, this might be the disease-causing mechanism for that mutation. In this case, the occurrence of epileptic seizures could be explained by a decrease of excitability of inhibitory neurons.


Recurrent diabetic ketoacidosis in inner-city minority patients: behavioral, socioeconomic, and psychosocial factors.
To conduct a bedside study to determine the factors driving insulin noncompliance in inner-city patients with recurrent diabetic ketoacidosis (DKA). We analyzed socioeconomic and psychological factors in 164 adult patients with DKA who were admitted to Grady Hospital between July 2007 and August 2010, including demographics, diabetes treatment, education, and mental illness. The Patient Health Questionnaire-9 and the Short Form-36 surveys were used to screen for depression and assess quality of life. The average number of admissions was 4.5 ± 7 per patient. A total of 73 patients presented with first-time DKA, and 91 presented with recurrent DKA; 96% of patients were African American. Insulin discontinuation was the leading precipitating cause in 68% of patients; other causes were new-onset diabetes (10%), infection (15%), medical illness (4%), and undetermined causes (3%). Among those who stopped insulin, 32% gave no reasons for stopping, 27% reported lack of money to buy insulin, 19% felt sick, 15% were away from their supply, and 5% were stretching insulin. Compared with first-time DKA, those with recurrent episodes had longer duration of diabetes (P < 0.001), were a younger age at the onset of diabetes (P = 0.04), and had higher rates of depression (P = 0.04), alcohol (P = 0.047) and drug (P < 0.001) abuse, and homelessness (P = 0.005). There were no differences in quality-of-life scores, major psychiatric illnesses, or employment between groups. Poor adherence to insulin therapy is the leading cause of recurrent DKA in inner-city patients. Several behavioral, socioeconomic, psychosocial, and educational factors contribute to poor compliance. The recognition of such factors and the institution of culturally appropriate interventions and education programs might reduce DKA recurrence in minority populations.


Partitioning of polybrominated diphenyl ethers to dissolved organic matter isolated from Arctic surface waters.
Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame retardant that is distally transported to the Arctic. Little is known about the fate of PBDEs in Arctic surface waters, especially in the presence of dissolved organic matter (DOM). DOM has been shown to interact with hydrophobic organic contaminants and can alter their mobility, bioavailability, and degradation in the environment. In this study, the partitioning of six PBDE congeners between Arctic DOM (isolated via solid phase extraction) and water was measured using the aqueous solubility enhancement method. Measured dissolved organic carbon (DOC)-water partition coefficient (KDOC) values were nearly an order of magnitude lower than previously reported values for the same PBDE congeners in soil or commercial organic matter, ranging from 10(3.97) to 10(5.16) L kg(-1) of organic carbon. Measured results compared favorably with values calculated using polyparameter linear free energy models for Suwannee River fulvic acid. Log KDOC values increased with increasing PBDE hydrophobicity. Slightly lower than expected values were observed for the highest brominated congeners, which we attribute to steric hindrance. This study is the first to comprehensively measure KDOC values for a range of PBDE congeners with DOM isolated from Arctic surface waters.


L-carnitine reduces in human conjunctival epithelial cells hypertonic-induced shrinkage through interacting with TRPV1 channels.
Ocular surface health depends on conjunctival epithelial (HCjE) layer integrity since it protects against pathogenic infiltration and contributes to tissue hydration maintenance. As the same increases in tear film hyperosmolarity described in dry eye disease can increase corneal epithelial transient receptor potential vanilloid type-1 (TRPV1) channel activity, we evaluated its involvement in mediating an osmoprotective effect by L-carnitine against such stress. Using siRNA gene silencing, Ca(2+) imaging, planar patch-clamping and relative cell volume measurements, we determined if the protective effects of this osmolyte stem from its interaction with TRPV1. TRPV1 activation by capsaicin (CAP) and an increase in osmolarity to ≈ 450 mOsM both induced increases in Ca(2+) levels. In contrast, blocking TRPV1 activation with capsazepine (CPZ) fully reversed this response. Similarly, L-carnitine (1 mM) also reduced underlying whole-cell currents. In calcein-AM loaded cells, hypertonic-induced relative cell volume shrinkage was fully blocked during exposure to L-carnitine. On the other hand, in TRPV1 gene-silenced cells, this protective effect by L-carnitine was obviated. The described L-carnitine osmoprotective effect is elicited through suppression of hypertonic-induced TRPV1 activation leading to increases in L-carnitine uptake through a described Na(+)-dependent L-carnitine transporter.


Identification of trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene as a major mutagenic metabolite of 6-nitrochrysene.
Liver 9000 X g supernatant from rats was used to study the metabolism of [6- 14C]nitrochrysene under aerobic conditions. The major ethyl acetate-soluble metabolite (1.06 nmol/mg of protein in 30 min) was identified as 1,2-dihydro-1,2-dihydroxy-6-nitrochrysene, based on its mass, UV, and proton magnetic resonance spectra. Under aerobic conditions, 6-aminochrysene was not detected as a metabolite. However, when incubations were carried out in an atmosphere of 4% O2 in N2, both 1,2-dihydro-1,2-dihydroxy-6-nitrochrysene (0.04 nmol/mg of protein) and 6-aminochrysene (0.05 nmol/mg of protein) were detected. Further metabolism of the 14C-labeled 1,2-dihydro-1,2-dihydroxy-6-nitrochrysene by rat liver 9000 X g supernatant under aerobic conditions gave a major metabolite which was identified tentatively as 1,2-dihydroxy-6-nitrochrysene. The mutagenic activities of 6-nitrochrysene, trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene and 6-aminochrysene were assessed in Salmonella typhimurium strains TA100 and TA98. In the absence of rat liver 9000 X g supernatant, trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene was the more potent mutagen in TA100 but, in TA98, it was less active than was 6-nitrochrysene. In the presence of rat liver 9000 X g supernatant, both trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene and 6-nitrochrysene were more mutagenic in TA100 than in the assays performed without an activating system, and the dihydrodiol metabolite was more mutagenic than was 6-nitrochrysene. In TA98 with activation, trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene, 6-aminochrysene, and 6-nitrochrysene were all mutagenic. The results of this study indicate that trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene is a major proximate mutagen of 6-nitrochrysene in S. typhimurium TA100.


World Workshop on Oral Medicine VI: a systematic review of the treatment of mucous membrane pemphigoid.
To determine the efficacy and safety of interventions for mucous membrane pemphigoid (MMP). We conducted a systematic review from 2003 to 2013 according to the Cochrane Collaboration methodology. Randomized controlled trials (RCTs) or controlled clinical trials and observational studies were included, with diagnosis confirmed by clinical, histopathologic, and immunofluorescence criteria. The primary outcome was lesion remission or healing; several relevant secondary outcomes were also included. In the final analysis, 1 RCT and 32 observational studies were included. The one included RCT with a high risk of bias in multiple domains found limited evidence that pentoxifylline, combined with corticosteroid and cyclophosphamide, was more effective than standard therapy (corticosteroid + cyclophosphamide alone) for ocular MMP. We summarize here the outcomes from 32 observational studies examining 242 patients across 19 unique treatments. Interventions that show promise include rituximab and intravenous immunoglobulin. This systematic review is the most recent since 2003-2009. There is still lack of high-quality research providing evidence-based MMP treatments.


A peer-education intervention to reduce injection risk behaviors for HIV and hepatitis C virus infection in young injection drug users.
To evaluate whether a behavioral intervention, which taught peer education skills, could reduce injection and sexual risk behaviors associated with primary HIV and hepatitis C virus infection (HCV) among young injection drug users (IDU). We conducted a randomized controlled trial involving HIV and HCV antibody-negative IDU, aged 15-30 years, recruited in five United States cities. A six-session, small-group, cognitive behavioral, skills-building intervention in which participants were taught peer education skills (n = 431) was compared with a time-equivalent attention control (n = 423). Baseline visits included interviews for sociodemographic, psychosocial, and behavioral factors during the previous 3 months; HIV and HCV antibody testing; and pre/posttest counselling. Procedures were repeated 3 and 6 months postintervention. The intervention produced a 29% greater decline in overall injection risk 6 months postintervention relative to the control [proportional odds ratio 0.71; 95% confidence limit (CL) 0.52, 0.97], and a 76% decrease compared with baseline. Decreases were also observed for sexual risk behaviors, but they did not differ by trial arm. Overall HCV infection incidence (18.4/100 person-years) did not differ significantly across trial arms (relative risk 1.15; 95% CL 0.72, 1.82). No HIV seroconversions were observed. Interventions providing information, enhancing risk-reduction skills, and motivating behavior change through peer education training can reduce injection risk behaviors, although risk elimination might be necessary to prevent HCV transmission.


Vectorial van Cittert-Zernike theorem based on spatial averaging: experimental demonstrations.
The van Cittert-Zernike theorem is extended to the vectorial regime based on spatial averaging over the observation plane, and experimental demonstrations are presented. The theorem connects complex vectorial source structure to the degree of coherence and polarization of the spatially fluctuating vectorial field in the far field. Experimentation is carried out by making use of the space averages as a replacement of ensemble averages for the Gaussian stochastic field. For quantitative comparison with the theorem, analytical and experimental results are presented for a rectangular aperture with different vectorial source structures.


High major histocompatibility complex class I polymorphism despite bottlenecks in wild and domesticated populations of the zebra finch (Taeniopygia guttata).
Two subspecies of zebra finch, Taeniopygia guttata castanotis and T. g. guttata are native to Australia and the Lesser Sunda Islands, respectively. The Australian subspecies has been domesticated and is now an important model system for research. Both the Lesser Sundan subspecies and domesticated Australian zebra finches have undergone population bottlenecks in their history, and previous analyses using neutral markers have reported reduced neutral genetic diversity in these populations. Here we characterize patterns of variation in the third exon of the highly variable major histocompatibility complex (MHC) class I α chain. As a benchmark for neutral divergence, we also report the first mitochondrial NADH dehydrogenase 2 (ND2) sequences in this important model system. Despite natural and human-mediated population bottlenecks, we find that high MHC class I polymorphism persists across all populations. As expected, we find higher levels of nucleotide diversity in the MHC locus relative to neutral loci, and strong evidence of positive selection acting on important residues forming the peptide-binding region (PBR). Clear population differentiation of MHC allele frequencies is also evident, and this may be due to adaptation to new habitats and associated pathogens and/or genetic drift. Whereas the MHC Class I locus shows broad haplotype sharing across populations, ND2 is the first locus surveyed to date to show reciprocal monophyly of the two subspecies. Despite genetic bottlenecks and genetic drift, all surveyed zebra finch populations have maintained high MHC Class I diversity. The diversity at the MHC Class I locus in the Lesser Sundan subspecies contrasts sharply with the lack of diversity in previously examined neutral loci, and may thus be a result of selection acting to maintain polymorphism. Given uncertainty in historical population demography, however, it is difficult to rule out neutral processes in maintaining the observed diversity. The surveyed populations also differ in MHC Class I allele frequencies, and future studies are needed to assess whether these changes result in functional immune differences.


Surface plasmon effects induced by uncollimated emission of semiconductor microstructures.
We have recently proposed an innovative microstructure for a monolithically integrated surface plasmon resonance (SPR) device comprising a metal coated SiO(2) layer deposited atop a photoluminescence emitting quantum well (QW) wafer. The functioning of such a device is based on the uncollimated and incoherent emission of semiconductors. We discuss the results of our calculations aimed at the description of SPs coupling in QW semiconductor-based SPR architectures designed for biosensing applications. Two SPs modes could be coupled in the 0(th) diffraction order where the injected in-plane wavevectors from the QW structures can always meet SPR conditions. This results in increasing the SPs coupling efficiency up to 100 times higher than in case of indirect SPs injection.


PPARA Polymorphism Influences the Cardiovascular Benefit of Fenofibrate in Type 2 Diabetes: Findings From ACCORD-Lipid.
The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-α), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported white subjects treated with simvastatin and randomized to fenofibrate or placebo in the ACCORD-Lipid trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (hazard ratio 0.49; 95% CI 0.34-0.72), whereas no benefit was observed for other genotypes (P interaction = 3.7 × 10-4). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD (N = 585, P = 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total N = 3059, P = 0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11-a proinflammatory and atherogenic chemokine also known as eotaxin (P for rs6008845-by-fenofibrate interaction = 0.003). The GTEx data set revealed regulatory functions of rs6008845 on PPARA expression in many tissues. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify patients with type 2 diabetes who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia.


The functional role of motor activation in language processing: motor cortical oscillations support lexical-semantic retrieval.
There is increasing experimental evidence that processing action-related language results in the automatic activation of associated regions of the motor and premotor cortex. However, the functional significance of motor activation in language processing is still under debate. In the present EEG study, we set out to investigate if language-induced motor activation primarily reflects the retrieval of lexical-semantic information or post-lexical motor imagery. The processing of action verbs was found accompanied by an early activation of motor-related brain areas, as reflected by a desynchronization in the mu- and beta-frequency bands which was localized to motor and premotor areas. A stronger motor activation was observed for verbs presented in an animal context (e.g. "The deer jumped over the stream") compared to a human context (e.g. "The athlete jumped over the fence") and motor resonance was directly modulated by the cloze probability of the noun-verb pairs. The onset of the motor effects preceded classical measures of semantic integration (i.e. the N400 component) and the strength of motor activation was found inversely related to the size of the N400 effect. These findings support the hypothesis that motor activation in language processing primarily supports the retrieval and integration of lexical-semantic information.


Exaggerated effects of particulate matter air pollution in genetic type II diabetes mellitus.
Prior experimental and epidemiologic data support a link between exposure to fine ambient particulate matter (<2.5 μm in aerodynamic diameter, PM2.5) and development of insulin resistance/Type II diabetes mellitus. This study was designed to investigate whether inhalational exposure of concentrated PM2.5 in a genetically susceptible animal model would result in abnormalities in energy metabolism and exacerbation of peripheral glycemic control. KKay mice, which are susceptible to Type II DM, were assigned to either concentrated ambient PM2.5 or filtered air (FA) for 5-8 weeks via a whole body exposure system. Glucose tolerance, insulin sensitivity, oxygen consumption and heat production were evaluated. At euthanasia, blood, spleen and visceral adipose tissue were collected to measure inflammatory cells using flow cytometry. Standard immnunohistochemical methods, western blotting and quantitative PCR were used to assess targets of interest. PM2.5 exposure influenced energy metabolism including O2 consumption, CO2 production, respiratory exchange ratio and thermogenesis. These changes were accompanied by worsened insulin resistance, visceral adiposity and inflammation in spleen and visceral adipose depots. Plasma adiponectin were decreased in response to PM2.5 exposure while leptin levels increased. PM2.5 exposure resulted in a significant increase in expression of inflammatory genes and decreased UCP1 expression in brown adipose tissue and activated p38 and ERK pathways in the liver of the KKay mice. Concentrated ambient PM2.5 exposure impairs energy metabolism, concomitant with abnormalities in glucose homeostasis, increased inflammation in insulin responsive organs, brown adipose inflammation and results in imbalance in circulating leptin/adiponectin levels in a genetically susceptible diabetic model. These results provide additional insights into the mechanisms surrounding air pollution mediated susceptibility to Type II DM.


Supracondylar fractures: what's new?
In the past 5 to 7 years many advances have been made in the treatment of type III supracondylar fractures of the humerus. Gartland's three-type classification has continued to be used as a valuable tool to determine the aggressiveness of treatment. Use of cast immobilization for type III injuries has been shown to produce inferior results. Percutaneous pin fixation for reduced fractures has been established as the ideal treatment for most type III displaced fractures. Mediolateral or three lateral pin constructs provide the most rigid fixation. It is now apparent that the anterior interosseous nerve is probably the most commonly injured nerve. Recent technology in evaluating the vascular system has shown that the incidence of injuries to the brachial artery is probably higher than originally suspected. However, the management of these arterial injuries in patients who appear to have adequate profusion of the forearm musculature for normal function is still controversial, with recommendations varying from simple observation to aggressive primary arterial repair. Cubitus varus has been found to be due primarily to angulation in the coronal plane. Fortunately the incidence of complications after corrective osteotomies with this deformity has decreased from 50% to less than 15%. Although ipsilateral fractures are usually the result of greater forces of trauma, the incidence of associated neurovascular compromise does not appear to be any greater. Better recognition of flexion-type injuries has shown that the incidence is greater than originally suspected. A large percentage of these completely displaced flexion injuries may require open surgical intervention to obtain adequate reduction.


Using DSM-III criteria to diagnose delirium in elderly general medical patients.
Studies of delirium in general medical populations have used criteria for delirium different from current DSM-III or DSM-IIIR criteria of the American Psychiatric Association, or have used DSM-III or DSM-IIIR criteria without operationalizing the components of these criteria. Therefore this prospective study was conducted to establish an approach to operationalizing DSM-III criteria and to determine the incidence and prevalence of delirium. Two hundred thirty-five consecutive subjects age 70 and over admitted to general medicine underwent daily standardized screening. Patients with low scores on screening tests or clinical evidence suggestive of any psychiatric disorder and controls were seen by a psychiatrist, who determined whether delirium was present by applying explicit operational definitions to each component of the DSM-III criteria for delirium. We conclude that the syndrome of delirium as defined by the American Psychiatric Association is prevalent on admission among elderly on general medical services, but the number of cases developing in the hospital is much less than often stated in the literature.


Organized behavioral responses to lateral hypothalamic electrical stimulation in infant rats.
Brief trains of electrical stimulation (500 msec) were administered to 3-, 6-, 10-, and 15-day-old rat pups through electrodes directed at the medical forebrain bundle (MFB) at the level of the lateral hypothalamus. Stimulation was given at three different frequencies: once per 30 sec, once per 20 sec, and once per 10 sec. Pups 10 days of age and younger became behaviorally activated by stimulation and reliably emitted a series of behavioral responses including mouthing, licking, pawing, gaping, probing, and stretch and lordosis responses. Behavior increased with increasing frequency of stimulation and became more organized with age. Sequences of organized behavior patterns are elicited by MFB stimulation which in their culmination take on the characteristics of motivational responses. Fifteen-day-old pups did not respond to these stimulation parameters. These findings indicate that the components of motivational systems are present and can be elicited at an early age. As development progresses, responses become more organized until stimulation parameters effective in rats 3 to 10 days of age become ineffective in activating behavior in day 15 pups.


Sexual sadism: avoiding its misuse in sexually violent predator evaluations.
The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), Task Force has recently rejected the proposal to include coercive paraphilia as an official diagnosis, reaffirming that rape is a crime and not a mental disorder. We hope this will discourage what has been the inappropriate practice of giving rapists the made-up diagnosis of paraphilia, NOS, nonconsent, to facilitate their psychiatric commitment under sexually violent predator (SVP) statutes. Losing the paraphilia, NOS, option has tempted some SVP evaluators to overdiagnose sexual sadism, which is an official DSM mental disorder. To prevent this improper application and to clarify those rare instances in which this diagnosis might apply, we present a brief review of the research on sexual sadism; an annotation of its definitions that have been included in the DSM since the Third Edition, published in 1980, and in the International Classification of Diseases, Tenth Edition (ICD-10); and a two-step process for making a diagnostic decision. Rape and sexual sadism have in common violence, cruelty, and a callous indifference on the part of the perpetrator to the suffering of the victim, but they differ markedly in motivation. Rapists use violence to enforce the victim's cooperation, to express aggression, or both. In contrast, in sexual sadism, the violence, domination, and infliction of pain and humiliation are a preferred or necessary precondition for sexual arousal. Only a small proportion of rapists qualify for the diagnosis of sexual sadism.


Effect of ret/PTC 1 rearrangement on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model.
microRNAs (miRNAs) are a group of non-coding single stranded RNAs measuring approximately 22 nt in length that have been found to control cell growth, differentiation and apoptosis. miRNAs negatively regulate their target genes and recently have been implicated in tumourigenesis. Furthermore, miRNA expression profiling correlates with various cancers, with these genes thought to act as both tumour suppressors and oncogenes. ret/PTC 1 is an oncogene with constitutive kinase activity implicated in the development of papillary thyroid carcinoma (PTC). This rearrangement leads to aberrant MAPK activation that is implicated in PTC tumourigenesis. The aim of this study was to identify the effect that ret/PTC 1 has on transcription and post-transcriptional regulation in PTC by using DNA microarray and microRNA analysis. DNA microarray analysis revealed a group of genes differentially expressed between normal thyroid cell lines and those harbouring a ret/PTC 1 rearrangement.Furthermore, a unique miRNA expression signature differentiated between PTC cell lines with ret/PTC 1 and a normal thyroid cell line. 21 miRNAs showed significant overexpression and 14 miRNAs showed underexpression in these cell lines when compared to normal thyroid. Several of these up/down regulated miRNAs may be involved in PTC pathogenesis.