Amniotic membrane extract-loaded double-layered wound dressing: evaluation of gel properties and wound healing.
The conservative single-layered wound dressing system is decomposed when mixed in polyvinyl alcohol (PVA) solution, which means it cannot be used with a temperature-sensitive drug. The goal of this investigation was to make an amniotic membrane extract (AME)-loaded double-layered wound dressing with an improved healing result compared to the conservative single-layered wound dressing systems. The double-layered wound dressing was developed with PVA/sodium alginate using a freeze-melting technique; one layer was PVA layer and the other was the drug-loaded sodium alginate layer. Its gel properties were assessed compared to single-layered wound dressings. Moreover, in vivo wound-healing effects and histopathology were calculated compared to commercial products. The double-layered wound dressing gave a similar gel fraction and Young's module as single-layered wound bandages developed with only PVA, and a similar inflammation ability and WVTR as single-layered wound dressings developed with PVA and sodium alginate. Our data indicate that these double-layered wound bandages were just as swellable, but more elastic and stronger than single-layered wound dressings comprised of the same polymers and quantities, possibly giving an acceptable level of moisture and accumulation of exudates in the wound zone. Compared to the commercial product, the double-layered wound dressing comprising 6.7% PVA, 0.5% sodium alginate and 0.01% AME significantly enhanced the wound-healing effect in the wound-healing test. Histological investigations showed that superior full-thickness wound-healing effects compared to the commercial product. Therefore, the double-layered wound dressing would be an outstanding wound-dressing system with improved wound healing and good gel property.


Human health effects of air pollution.
Hazardous chemicals escape to the environment by a number of natural and/or anthropogenic activities and may cause adverse effects on human health and the environment. Increased combustion of fossil fuels in the last century is responsible for the progressive change in the atmospheric composition. Air pollutants, such as carbon monoxide (CO), sulfur dioxide (SO(2)), nitrogen oxides (NOx), volatile organic compounds (VOCs), ozone (O(3)), heavy metals, and respirable particulate matter (PM2.5 and PM10), differ in their chemical composition, reaction properties, emission, time of disintegration and ability to diffuse in long or short distances. Air pollution has both acute and chronic effects on human health, affecting a number of different systems and organs. It ranges from minor upper respiratory irritation to chronic respiratory and heart disease, lung cancer, acute respiratory infections in children and chronic bronchitis in adults, aggravating pre-existing heart and lung disease, or asthmatic attacks. In addition, short- and long-term exposures have also been linked with premature mortality and reduced life expectancy. These effects of air pollutants on human health and their mechanism of action are briefly discussed.


Motor system changes in the aging brain: what is normal and what is not.
Age-related changes in the nervous system may present with physical signs that are not unlike early manifestations of several clinical disorders. Gait disturbances (immobility), balance difficulties (instability), and certain motor control problems (i.e., tremor) are not necessarily signs of a disease state. The clinician needs to be reminded that most physiologic functions decline at a rate of 1% per year, beginning at age 30. Often compounding "natural" decline are the motor problems related to disuse. This is especially true for the inactive individual suffering from depression, cardiac or pulmonary insufficiency, painful joint and muscle conditions, substance abuse and, sometimes, simply social isolation.


Axis Patterning by BMPs: Cnidarian Network Reveals Evolutionary Constraints.
BMP signaling plays a crucial role in the establishment of the dorso-ventral body axis in bilaterally symmetric animals. However, the topologies of the bone morphogenetic protein (BMP) signaling networks vary drastically in different animal groups, raising questions about the evolutionary constraints and evolvability of BMP signaling systems. Using loss-of-function analysis and mathematical modeling, we show that two signaling centers expressing different BMPs and BMP antagonists maintain the secondary axis of the sea anemone Nematostella. We demonstrate that BMP signaling is required for asymmetric Hox gene expression and mesentery formation. Computational analysis reveals that network parameters related to BMP4 and Chordin are constrained both in Nematostella and Xenopus, while those describing the BMP signaling modulators can vary significantly. Notably, only chordin, but not bmp4 expression needs to be spatially restricted for robust signaling gradient formation. Our data provide an explanation of the evolvability of BMP signaling systems in axis formation throughout Eumetazoa.


Spontaneous action potential activity and synaptic currents in the embryonic turtle cerebral cortex.
We used loose-patch and whole-cell recording techniques to study the development of spontaneous action potential activity and spontaneous excitatory and inhibitory synaptic currents in embryonic neurons in the cerebral hemispheres of turtles. Sporadic action potential activity appeared early in development at stage 17, soon after morphologically identifiable pyramidal and nonpyramidal neurons were first observed in the cortex. As the cortical plate matured in midembryonic stages, action potential activity became more regular and fell into one of two distinct patterns, tonic and intermittent high-frequency firing. Spontaneous excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) appeared at developmental stages 18 and 20, respectively, after action potential activity was established. EPSCs and IPSCs exhibited characteristic ionic dependence and pharmacology throughout development. EPSCs reversed in direction at the equilibrium potential for cations and were sensitive to 6-cyano-7-nitroquinoxaline-2,3-dione, an antagonist of the non-NMDA type of glutamate receptor. IPSCs reversed at the equilibrium potential for chloride and were sensitive to bicuculline methiodide, a GABAA receptor antagonist. Spontaneous synaptic currents differed in their time course of development and in waveform parameters. Spontaneous synaptic currents differed in their time course of development and in waveform parameters. Spontaneous EPSCs appeared at stage 18 and increased progressively in frequency, from 0.2 +/- 0.1 Hz at stage 20 to 3.2 +/- 2.0 Hz at stage 26 (hatching), while spontaneous IPSCs appeared at stage 20 and surpassed EPSCs in frequency, increasing to 7.1 +/- 1.6 Hz at stage 26. EPSCs exhibited stable amplitudes during development, with a mean conductance of 126 +/- 20 pS at stage 26, while IPSCs increased in mean amplitude, from 180 +/- 12 pS at stage 18 to 260 +/- 44 pS at stage 26. The rise time to peak conductance of both types of synaptic currents increased with developmental time, for EPSCs increasing from 1.5 +/- 0.5 msec at stage 20 to 2.7 +/- 0.6 msec at stage 26 and for IPSCs increasing from 2.9 +/- 0.2 msec at stage 18 to 6.2 +/- 0.8 msec at stage 26. While the decay time constants increased for EPSCs, from 3.9 +/- 1.2 msec at stage 20 to 8.7 +/- 2.3 msec at stage 26, decay time constants for IPSCs showed a decreasing trend from 24.0 +/- 5.2 msec at stage 18 to 18.4 +/- 5.3 msec at stage 26. The excitatory and inhibitory synaptic currents were sensitive to the sodium channel blocker TTX and were thus dependent, in part, on spontaneous action potential activity.(ABSTRACT TRUNCATED AT 400 WORDS)


Geomorphic controls on elevational gradients of species richness.
Elevational gradients of biodiversity have been widely investigated, and yet a clear interpretation of the biotic and abiotic factors that determine how species richness varies with elevation is still elusive. In mountainous landscapes, habitats at different elevations are characterized by different areal extent and connectivity properties, key drivers of biodiversity, as predicted by metacommunity theory. However, most previous studies directly correlated species richness to elevational gradients of potential drivers, thus neglecting the interplay between such gradients and the environmental matrix. Here, we investigate the role of geomorphology in shaping patterns of species richness. We develop a spatially explicit zero-sum metacommunity model where species have an elevation-dependent fitness and otherwise neutral traits. Results show that ecological dynamics over complex terrains lead to the null expectation of a hump-shaped elevational gradient of species richness, a pattern widely observed empirically. Local species richness is found to be related to the landscape elevational connectivity, as quantified by a newly proposed metric that applies tools of complex network theory to measure the closeness of a site to others with similar habitat. Our theoretical results suggest clear geomorphic controls on elevational gradients of species richness and support the use of the landscape elevational connectivity as a null model for the analysis of the distribution of biodiversity.


Relationship between students' locus of control and satisfaction.
This article describes a study that was undertaken to examine the influence of the 'locus of control' (LOC) on perceived satisfaction of nursing students. LOC is an internal, dynamic capacity of an individual which influences how one deals with everyday outcomes. Rotter (1966) proposes that the degree to which people believe their lives are under their own control is an important variable of personality which varies from person to person. People with an internal orientation believe they have control over what happens to them, whereas people with an external orientation attribute what happens to them to fate, luck, chance or powerful others. Three groups of 50 students in first, second and third years of the nursing diploma course were tested on LOC (Rotter, 1966) and satisfaction (Betz et al, 1970; Pennington et al, 1989) questionnaires. It was anticipated that the students would become more internal on the LOC orientation over time and would therefore perceive greater satisfaction with time on the course. The effects of LOC on satisfaction were analysed using t-tests, analysis of variance and Pearson's product-moment correlation. Results showed that students with internal orientation on LOC perceived greater satisfaction than students with an external orientation. However, no significant differences in LOC were found between the groups. The nursing students tested were found to be more external in their LOC orientation than other student populations have been in the past. The implications of this and the other findings for future research are discussed.


Cloning, Assembly, and Modification of the Primary Human Cytomegalovirus Isolate Toledo by Yeast-Based Transformation-Associated Recombination.
Genetic engineering of cytomegalovirus (CMV) currently relies on generating a bacterial artificial chromosome (BAC) by introducing a bacterial origin of replication into the viral genome using in vivo recombination in virally infected tissue culture cells. However, this process is inefficient, results in adaptive mutations, and involves deletion of viral genes to avoid oversized genomes when inserting the BAC cassette. Moreover, BAC technology does not permit the simultaneous manipulation of multiple genome loci and cannot be used to construct synthetic genomes. To overcome these limitations, we adapted synthetic biology tools to clone CMV genomes in Saccharomyces cerevisiae. Using an early passage of the human CMV isolate Toledo, we first applied transformation-associated recombination (TAR) to clone 16 overlapping fragments covering the entire Toledo genome in Saccharomyces cerevisiae. Then, we assembled these fragments by TAR in a stepwise process until the entire genome was reconstituted in yeast. Since next-generation sequence analysis revealed that the low-passage-number isolate represented a mixture of parental and fibroblast-adapted genomes, we selectively modified individual DNA fragments of fibroblast-adapted Toledo (Toledo-F) and again used TAR assembly to recreate parental Toledo (Toledo-P). Linear, full-length HCMV genomes were transfected into human fibroblasts to recover virus. Unlike Toledo-F, Toledo-P displayed characteristics of primary isolates, including broad cellular tropism in vitro and the ability to establish latency and reactivation in humanized mice. Our novel strategy thus enables de novo cloning of CMV genomes, more-efficient genome-wide engineering, and the generation of viral genomes that are partially or completely derived from synthetic DNA. IMPORTANCE The genomes of large DNA viruses, such as human cytomegalovirus (HCMV), are difficult to manipulate using current genetic tools, and at this time, it is not possible to obtain, molecular clones of CMV without extensive tissue culture. To overcome these limitations, we used synthetic biology tools to capture genomic fragments from viral DNA and assemble full-length genomes in yeast. Using an early passage of the HCMV isolate Toledo containing a mixture of wild-type and tissue culture-adapted virus. we directly cloned the majority sequence and recreated the minority sequence by simultaneous modification of multiple genomic regions. Thus, our novel approach provides a paradigm to not only efficiently engineer HCMV and other large DNA viruses on a genome-wide scale but also facilitates the cloning and genetic manipulation of primary isolates and provides a pathway to generating entirely synthetic genomes.


StarTrek illusion--general object constancy phenomenon?
We report a new powerful type of contrast and size illusion caused by apparent motion in depth, which we called the StarTrek illusion. We found that an optic flow pattern consistent with objects moving in depth strongly modulates their apparent contrast. Disks that appeared to move away from the observer appeared to grow higher in contrast and larger, while their retinal size and contrast remained constant. We explain this illusion of contrast by the term contrast constancy: Normally, objects lose their contrast when viewed from far away, but when this expected loss does not happen, the brain infers that the physical contrast of the object increases as the object moves away. This is perceived as the illusory increase of the object's contrast. The contrast constancy is largely analogous to the well-known size constancy phenomenon. We discovered that the two phenomena are related. By adjusting the size of the disks during the optic flow motion, the illusory contrast increase could be easily canceled or even reversed. On the other hand, the illusory size increase could not be manipulated the same way by contrast modulation. Our results suggest that the brain may use the same scaling factor to account for the size and contrast change with distance and that the estimated object size affects the contrast calculation.


Acute and chronic effects of antidepressants on the G-protein alpha subunit profiles in vitro and in vivo.
Neurochemical studies on the etiopathogenesis of depression are also focusing on the transduction system beyond receptors. Trimeric G-proteins play a crucial role in the transmembrane signalling, signal amplification and intracellular processing. Abnormalities of G-protein levels are observed in subjects with depression, G-protein modulation is considered to play a role in the antidepressant mode of action. We studied acute or chronic administration of antidepressants from different pharmacological groups. We used immunochemical estimation (ELISA) of the main types of G-protein alpha subunits from isolated membranes of C6 glioma cells and rat brain tissue. Significant elevation of G alpha q/11 subunits after chronic administration of sertraline and significant reduction of G alpha s subunit levels following both acute and chronic administrations of sertraline were found. In contrast, no significant effects on G alpha subunit levels following acute desipramine and moclobemide administration were observed in vitro. Chronic moclobemide effect in vivo is causing significant elevation of Galpha s and Galpha i1,2 subunit levels. Results show involvement of antidepressant drugs in the C6 glioma signal transduction cascades modulation in dependence on the antidepressant class. Significant influence in the cAMP system modulation is observed after administration both SSRI and MAOA inhibitors. Astrocytoma cells - C6 glioma cells also can offer a model system of the glia where modulation of cell signalization cascades can influence cell functioning and production of neurotrophic factor molecules relevant to the antidepressant treatment and depression etiopathogenesis.


Extreme Postinjection Flare in Response to Intra-Articular Triamcinolone Acetonide (Kenalog).
As intra-articular corticosteroid injections (CSIs) are a common treatment for osteoarthritis, physicians must well understand their potential side effects. Postinjection flares are an acute side effect of intra-articular CSIs, with symptoms ranging from mild joint effusion to disabling pain. The present case involved a severe postinjection flare that occurred after the patient, a 56-year-old woman with moderate osteoarthritis in the left knee, received 2 mL of 1% lidocaine and 2 mL (40 mg) of triamcinolone acetonide (Kenalog). Two hours after injection, she experienced swelling and intense pain in the knee and was unable to ambulate. The knee was aspirated with a return of 25 mL of "butterscotch"-colored fluid. This case is novel in that its acuity of onset, severity of symptoms, and synovial fluid analysis mimicked septic arthritis, which was ultimately ruled out with negative cultures and confirmation of triamcinolone acetonide crystals in the synovial aspirate, viewed by polarized light microscopy. Thus, the patient's reaction represents an acute crystal-induced inflammatory response. Although reactions to an intra-articular CSI of this severity are rare, it is important for treating physicians to inform patients of this potential side effect.


Bisphosphonates: mode of action and pharmacology.
The profound effects of the bisphosphonates on calcium metabolism were discovered over 30 years ago, and they are now well established as the major drugs used for the treatment of bone diseases associated with excessive resorption. Their principal uses are for Paget disease of bone, myeloma, bone metastases, and osteoporosis in adults, but there has been increasing and successful application in pediatric bone diseases, notably osteogenesis imperfecta. Bisphosphonates are structural analogues of inorganic pyrophosphate but are resistant to enzymatic and chemical breakdown. Bisphosphonates inhibit bone resorption by selective adsorption to mineral surfaces and subsequent internalization by bone-resorbing osteoclasts where they interfere with various biochemical processes. The simpler, non-nitrogen-containing bisphosphonates (eg, clodronate and etidronate) can be metabolically incorporated into nonhydrolysable analogues of adenosine triphosphate (ATP) that may inhibit ATP-dependent intracellular enzymes. In contrast, the more potent, nitrogen-containing bisphosphonates (eg, pamidronate, alendronate, risedronate, ibandronate, and zoledronate) inhibit a key enzyme, farnesyl pyrophosphate synthase, in the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds that are essential for the posttranslational modification of small guanosine triphosphate (GTP)-binding proteins (which are also GTPases) such as Rab, Rho, and Rac. The inhibition of protein prenylation and the disruption of the function of these key regulatory proteins explains the loss of osteoclast activity. The recently elucidated crystal structure of farnesyl diphosphate reveals how bisphosphonates bind to and inhibit at the active site via their critical nitrogen atoms. Although bisphosphonates are now established as an important class of drugs for the treatment of many bone diseases, there is new knowledge about how they work and the subtle but potentially important differences that exist between individual bisphosphonates. Understanding these may help to explain differences in potency, onset and duration of action, and clinical effectiveness.


Spatial buffering of light-evoked potassium increases by retinal Müller (glial) cells.
Activity-dependent variations in extracellular potassium concentration in the central nervous system may be regulated, in part, by potassium spatial buffering currents in glial cells. The role of spatial buffering in the retina was assessed by measuring light-evoked potassium changes in amphibian eyecups. The amplitude of potassium increases in the vitreous humor was reduced to approximately 10 percent by 50 micromolar barium, while potassium increases in the inner plexiform layer were largely unchanged. The decrease in the vitreal potassium response was accurately simulated with a numerical model of potassium current flow through Müller cells, the principal glial cells of the retina. Barium also substantially increased the input resistance of Müller cells and blocked the Müller cell-generated M-wave, indicating that barium blocks the potassium channels of Müller cells. Thus, after a light-evoked potassium increase within the retina, there is a substantial transfer of potassium from the retina to the vitreous humor by potassium current flow through Müller cells.


Comparing response options for the International Outcome Inventory for Hearing Aids (IOI-HA) and for Alternative Interventions (IOI-AI) daily-use items.
This study investigated how clients quantify use of hearing rehabilitation. Comparisons focused on the daily-use item of the International Outcome Inventory for Hearing Aids (IOI-HA), and for Alternative Interventions (IOI-AI). Adults with hearing impairment completed the original versions of the IOI-HA and the IOI-AI daily-use item which has five numerical response options (e.g. 1-4 hours/day) and a modified version with five word response options (e.g. 'Sometimes'). Respondents completed both IOI versions immediately after intervention completion and three months later. In total, 64 people who had obtained hearing aids completed both IOI-HA versions and 27 people who had participated in communication programs completed both IOI-AI versions. Participants reported higher scores on the modified (word) daily-use item than on the original (number) daily-use item. Participants who completed the IOI-AI did so significantly more than participants who completed the IOI-HA. This was true both after intervention completion and three months later. This study showed that comparisons between IOI-HA and IOI-AI daily-use item scores should be made with caution. Word daily-use response options are recommended for the IOI-AI (i.e. Never; Rarely; Sometimes; Often; and Almost always).


The impact of the 21-gene Recurrence Score assay on clinical decision-making in node-positive (up to 3 positive nodes) estrogen receptor-positive breast cancer patients.
Oncotype DX testing is reimbursed in Israel for node-negative and node-positive (N1+; up to 3 positive nodes including micrometastases), estrogen receptor positive (ER+), breast cancer patients. This retrospective study evaluated the impact of Oncotype DX testing on treatment decisions in N1+/ER+ breast cancer patients. To this end, we compared treatments for all N+ patients for whom testing had been ordered with treatments for patients with similar characteristics where the test had not been available. The retrospective analysis included 951 patients (282 Oncotype DX, 669 controls), all of whom received endocrine therapy with or without chemotherapy. In Oncotype DX patients, 7.1, 37.0, and 100 % of those with low, intermediate, and high Recurrence Score results (Oncotype DX summary score) received chemotherapy, respectively (P < 0.0001, all comparisons). Chemotherapy use was lower in Oncotype DX patients versus controls (24.5 vs. 70.1 %). In a multivariate logistic regression analysis in which the probability of receiving chemotherapy was modeled as a function of Oncotype DX testing, age, tumor size, tumor grade, nodal status, and the interactions between Oncotype DX testing and the other covariates, Oncotype DX testing was associated with significantly lower odds of receiving chemotherapy (odds ratio 0.16; 95 % CI 0.11-0.24; P < 0.0001). In summary, our findings suggest that Oncotype DX testing has a significant impact on reducing chemotherapy use in N1+/ER+ breast cancer patients in Israel.


Thermal singularity and droplet motion in one-component fluids on solid substrates with thermal gradients.
Using a continuum model capable of describing the one-component liquid-gas hydrodynamics down to the contact line scale, we carry out numerical simulation and physical analysis for the droplet motion driven by thermal singularity. For liquid droplets in one-component fluids on heated or cooled substrates, the liquid-gas interface is nearly isothermal. Consequently, a thermal singularity occurs at the contact line and the Marangoni effect due to temperature gradient is suppressed. Through evaporation or condensation in the vicinity of the contact line, the thermal singularity makes the contact angle increase with the increasing substrate temperature. This effect on the contact angle can be used to move the droplets on substrates with thermal gradients. Our numerical results for this kind of droplet motion are explained by a simple fluid dynamical model at the droplet length scale. Since the mechanism for droplet motion is based on the change of contact angle, a separation of length scales is exhibited through a comparison between the droplet motion induced by a wettability gradient and that by a thermal gradient. It is shown that the flow field at the droplet length scale is independent of the statics or dynamics at the contact line scale.


The histology of reactive lymph nodes.
For histological evaluation of a lymph node specimen, it is essential to understand the morphology of the reaction patterns in the normal lymph node after challenge with antigen. The four different immunological reaction patterns seen in the lymph node each take place in their own compartment. Thus the follicle (or germinal) center cell reaction takes place in the follicle, the plasma cell reaction takes place in the medullary cords, the specific cellular response takes place in the paracortex, while in the sinuses, a histiocytic reaction may be observed. Often one reaction is followed or accompanied by another. Furthermore, because different antigenic challenges stimulate the four reactions in different ways, lymph node histology is highly variable and dependent on the kind of antigenic stimulation. Each of the four different reactions (and thus each of the four lymph node compartments) is described morphologically and immunohistologically. Markers identify the B-cell (follicle, medullary cords), T-cell (paracortex), or histiocytic (sinuses) nature of the compartments. A number of malignant conditions that can resemble benign lymph node lesions are discussed briefly, and morphologic and marker criteria for differential diagnosis are reviewed. Recognition of the four different reaction patterns with the addition of marker studies should allow a high percentage of accurate diagnoses.


Lateralization and gender differences in the dopaminergic response to unpredictable reward in the human ventral striatum.
Electrophysiological studies have shown that mesostriatal dopamine (DA) neurons increase activity in response to unpredicted rewards. With respect to other functions of the mesostriatal dopaminergic system, dopamine's actions show prominent laterality effects. Whether changes in DA transmission elicited by rewards also are lateralized, however, has not been investigated. Using [¹¹C]raclopride-PET to assess the striatal DA response to unpredictable monetary rewards, we hypothesized that such rewards would induce an asymmetric reduction in [¹¹C]raclopride binding in the ventral striatum, reflecting lateralization of endogenous dopamine release. In 24 healthy volunteers, differences in the regional D₂/₃ receptor binding potential (ΔBP) between an unpredictable reward condition and a sensorimotor control condition were measured using the bolus-plus-constant-infusion [¹¹C]raclopride method. During the reward condition subjects randomly received monetary awards while performing a 'slot-machine' task. The ΔBP between conditions was assessed in striatal regions-of-interest and compared between left and right sides. We found a significant condition × lateralization interaction in the ventral striatum. A significant reduction in binding potential (BP(ND) ) in the reward condition vs. the control condition was found only in the right ventral striatum, and the ΔBP was greater in the right than the left ventral striatum. Unexpectedly, these laterality effects appeared to be partly accounted for by gender differences, as our data showed a significant bilateral BP(ND) reduction in women while in men the reduction reached significance only in the right ventral striatum. These data suggest that DA release in response to unpredictable reward is lateralized in the human ventral striatum, particularly in males.


Time-series models for border inspection data.
We propose a new modeling approach for inspection data that provides a more useful interpretation of the patterns of detections of invasive pests, using cargo inspection as a motivating example. Methods that are currently in use generally classify shipments according to their likelihood of carrying biosecurity risk material, given available historical and contextual data. Ideally, decisions regarding which cargo containers to inspect should be made in real time, and the models used should be able to focus efforts when the risk is higher. In this study, we propose a dynamic approach that treats the data as a time series in order to detect periods of high risk. A regulatory organization will respond differently to evidence of systematic problems than evidence of random problems, so testing for serial correlation is of major interest. We compare three models that account for various degrees of serial dependence within the data. First is the independence model where the prediction of the arrival of a risky shipment is made solely on the basis of contextual information. We also consider a Markov chain that allows dependence between successive observations, and a hidden Markov model that allows further dependence on past data. The predictive performance of the models is then evaluated using ROC and leakage curves. We illustrate this methodology on two sets of real inspection data.


Vibrios and Aeromonas.
There are many similarities in the Vibrionaceae that cause human illness in the United States (see Table 1). Vibrios are characteristically indigenous to marine, estuarine, and brackish environments. They are distributed mainly in Gulf of Mexico coastal water, and these organisms "bloom" when the water is warm. Outbreaks of disease in humans frequently occur in summer, coinciding with multiplication of vibrios in warm water. Sporadic cases and small outbreaks of cholera continue to occur in persons living on or near the Gulf of Mexico, but infection in most persons is unrecognized. In fact, more serious and frequent illnesses result from V. vulnificus wound infections and from gastroenteritis caused by vibrios other than V. cholerae 01. Underlying hepatic or neoplastic disease (especially leukemia) apparently increases the likelihood and severity of illnesses caused by V. vulnificus and Aeromonas. Some Vibrionaceae produce clinical illness by means of enterotoxins identical or similar to cholera toxin. For many others, hemolysins, cytotoxins, and other exotoxins are necessary to produce disease; the importance of these virulence factors often is not known or the importance of these virulence factors often is not known or is of doubtful significance. Also, purported pathogenicity as demonstrated by animal models, such as fluid accumulation in ligated ileal loops, is quite nonspecific and needs to be interpreted cautiously. For Plesiomonas, a mode of pathogenesis has not been discovered. Eating raw shellfish (frequently raw oysters) has been linked epidemiologically to enteric infections with most of these bacteria; foreign travel and exposure to seawater are other frequently observed epidemiologic associations with infection. Foreign travel, particularly to the Yucatan Peninsula of Mexico, has been strongly associated with the acquisition of non-01 V. cholerae and Plesiomonas organisms. Most Vibrionaceae in the United States are susceptible in vitro--and illnesses from them are responsive--to tetracycline, trimethoprim-sulfamethoxazole, and other common antimicrobial agents. However, as for other bacteria that cause diarrhea, the main treatment for uncomplicated disease is the judicious replacement of fluids and electrolytes lost in diarrhea. A loose network of surveilance for these organisms comprises hospital and public health laboratories in Gulf coastal states that plate diarrheal stools on TCBS agar. As recognized pathogens are more assiduously screened for, and as newly identified vibrios are definitely included or excluded as enteric pathogens, the clinical importance of these members of the Vibrionaceae family should become clearer.


Towards Targeted Interventions in Low- and Middle-Income Countries: Risk Profiles of People Who Inject Drugs in Haiphong (Vietnam).
People who inject drugs (PWID) are a dominant risk group afflicted by blood-borne viruses, mental health disorders, and social precariousness. Risk reduction interventions are administered to PWID regardless of their characteristics or specific risks. The objective of this cross-sectional analysis was to empirically identify profiles of PWID regarding their drug use, risk behaviors, and mental health in order to tailor adapted interventions taking into account limited access to comprehensive care in middle-income countries. PWID were recruited using respondent-driven sampling. PWID with urine testing positive for heroin or methamphetamine and manifesting recent skin injection marks were enrolled. Classification of participants was based on drug use, injection, risky sexual behavior, and mental health data. This was subjected to multiple correspondence analysis followed by hierarchical cluster analysis combined with K-means methodology. From October 2016 to January 2017, 1490 participants were recruited of which 1383 were eligible and enrolled. HCV prevalence was 70.5% and HIV prevalence 29.4%. The cluster analysis identified five distinct profiles: profile 1: recent injection practices and high alcohol consumption, profile 2: at-risk injection and sexual behaviors with precarious situations, profile 3: no sexual activity and older age, profile 4: frequent injections with high methamphetamine use, and profile 5: stable partnerships and less frequent injections. Our study has identified profiles of PWID at particularly high risks, and they should thus be targeted for interventions tailored to their specific risks.


Use of hormone replacement therapy and adenocarcinomas and squamous cell carcinomas of the uterine cervix.
Exogenous hormones may influence the development of cervical adenocarcinomas. Incidence rates of adenocarcinomas and use of noncontraceptive hormones have increased since the 1970s, but few studies have investigated this potential relationship. We conducted a multicenter case-control study of 124 women with adenocarcinomas, 139 women with squamous cell carcinomas matched on age, diagnosis date, clinic, and stage of disease (in situ or invasive) to adenocarcinoma cases, and 307 healthy community controls who were also matched on age, ethnicity, and residence to adenocarcinoma cases. Participants completed in-person interviews regarding exogenous hormone use before diagnosis and other risk factors and volunteered cervical samples for human papillomavirus (HPV) testing via a PCR-based method. Odds ratios (ORs) with 95% confidence intervals (CIs) estimated relative risks. Only 13 adenocarcinoma cases (10.5%), 7 squamous carcinoma cases (5%), and 20 controls (6.5%) had used noncontraceptive hormones for menopausal symptoms, irregular periods, or disease prevention; most use was short-term, former use. Ever-use was associated with adenocarcinomas (OR = 2.1, 95% CI 0.95-4.6) but not squamous carcinomas (OR = 0.85, 95% CI 0.34-2.1). No trends were seen with duration of use or ages at first use, but unopposed estrogens were positively associated with adenocarcinomas (OR = 2.7). Unopposed estrogens remained associated with adenocarcinomas (OR = 2.0) when analyses were restricted to the HPV-positive controls. Menopausal status was not associated with adenocarcinomas or squamous carcinomas and did not modify the other associations. Although small numbers warrant tentative conclusions, exogenous estrogens, especially unopposed estrogens, were positively associated with adenocarcinomas. Noncontraceptive hormones were negatively but weakly associated with squamous carcinomas.


Effects of Nd:YAG lasers on root canal walls: a light and scanning electron microscopic study.
This study evaluated amounts of debris, smear layer, and recrystallized dentin on root canal walls treated with an Nd:YAG laser. The presence of carbonized material was also assessed. The root canals of 36 extracted incisors were prepared by stepdown and stepback techniques and divided into 4 groups. One group was not treated further, while 3 others were exposed to the laser beam at an energy density of 159, 239, or 318 J/cm2. The roots were split longitudinally, photographed, and examined using a scanning electron microscope. The amounts of debris, smear layer, and recrystallized dentin were recorded from horizontal bands around the root, 2, 6, and 10 mm from the apices. Mean smear layer scores were similar for all groups at the 3 levels examined, ranging from 2.157 to 2.851 on a scale of 0.0 to 3.0. Mean debris scores were similar for all groups at the 3 levels examined, ranging from 0.774 to 1.408 on a scale of 0.0 to 3.0. Recrystallized dentin was recorded in all 3 irradiated groups at the 2-mm level, but only in the group irradiated with 318 J/cm2 at the 6- and 10-mm levels. Severe carbonization was recorded at the 2-mm level. Use of the Nd:YAG laser did not reduce the mean amounts of debris and smear layer compared to a nonirradiated group. Carbonization was recorded in the apical part of the canal, but this is not obvious when only scanning electron photomicrographs are examined.


The internet-based knowledge acquisition and management method to construct large-scale distributed medical expert systems.
The Internet offers an unprecedented opportunity to construct powerful large-scale medical expert systems (MES). In these systems, a cost-effective medical knowledge acquisition (KA) and management scheme is highly desirable to handle the large quantities of, often conflicting, medical information collected from medical experts in different medical fields and from different geographical regions. In this paper, we demonstrate that a medical KA/management system can be built upon a three-tier distributed client/server architecture. The knowledge in the system is stored/managed in three knowledge bases. The maturity of the medical know-how controls the knowledge flow through these knowledge bases. In addition, to facilitate the knowledge representation and application in these knowledge bases as well as information retrieval across the Internet, an 8-digit numeric coding scheme with a weight value system is proposed. At present, a medical KA and management system based on the proposed method is being tested in clinics. Current results have showed that the method is a viable solution to construct, modify, and expand a distributed MES through the Internet.


An antioxidant potential of hydromethanolic extract of urtica parviflora roxb.
Antioxidant activity of hydromethanolic extract of Urtica parviflora Roxb. (family Urticaceae) was investigated by different in vitro methods, namely, nitric oxide scavenging, DPPH scavenging, and reducing power assay. In the present study, plant extract exhibited dose dependent free radical scavenging and reducing activity. The antioxidant activity of the hydromethanolic extract of Urtica parviflora Roxb. was compared with ascorbic acid as standard. In addition, phytochemical screening of hydromethanolic extract of the plant was undertaken to identify the phytochemicals present in the extract. Phytochemical examination revealed the presence of alkaloids, polysaccharides, saponins, flavonoids, phenolic compounds, glycosides and tannins. It was concluded that the extract contains important phytoconstituents responsible for antioxidant effect. The study indicated that Urtica parviflora could protect the cell injury caused by the reactive oxygen species and might be a valuable source of antioxidant both for medicine and food industry.


Responsiveness and Minimal Important Change of the IKDC of Middle-Aged and Older Patients With a Meniscal Tear.
Responsiveness and the minimal important change (MIC) are important measurement properties to evaluate treatment effects and to interpret clinical trial results. The International Knee Documentation Committee (IKDC) Subjective Knee Form is a reliable and valid instrument for measuring patient-reported knee-specific symptoms, functioning, and sports activities in a population with meniscal tears. However, evidence on responsiveness is of limited methodological quality, and the MIC has not yet been established for patients with symptomatic meniscal tears. To evaluate the responsiveness and determine the MIC of the IKDC for patients with meniscal tears. Cohort study (design); Level of evidence 2. This study was part of the ESCAPE trial: a noninferiority multicenter randomized controlled trial comparing arthroscopic partial meniscectomy with physical therapy. Patients aged 45 to 70 years who were treated for a meniscal tear by arthroscopic partial meniscectomy or physical therapy completed the IKDC and 3 other questionnaires (RAND 36-Item Health Survey, EuroQol-5D-5L, and visual analog scales for pain) at baseline and 6-month follow-up. Responsiveness was evaluated by testing predefined hypotheses about the relation of the change in IKDC with regard to the change in the other self-reported outcomes. An external anchor question was used to distinguish patients reporting improvement versus no change in daily functioning. The MIC was determined by the optimal cutoff point in the receiver operating characteristic curve, which quantifies the IKDC score that best discriminated between patients with and without improvement in daily function. Data from all 298 patients who completed baseline and 6-month follow-up questionnaires were analyzed. Responsiveness of the IKDC was confirmed in 7 of 10 predefined hypotheses about the change in IKDC score with regard to other patient-reported outcome measures. One hypothesis differed in the expected direction, while 2 hypotheses failed to meet the expected magnitude by 0.02 and 0.01 points. An MIC of 10.9 points was calculated for the IKDC of middle-aged and older patients with meniscal tears. This study showed that the IKDC is responsive to change among patients aged 45 to 70 years with meniscal tears, with an MIC of 10.9 points. This strengthens the value of the IKDC in quantifying treatment effects in this population.


Simulations of anion transport through OprP reveal the molecular basis for high affinity and selectivity for phosphate.
The outer membrane protein OprP from Pseudomonas aeruginosa forms a phosphate selective pore. To understand the mechanism of phosphate permeation and selectivity, we used three simulation techniques [equilibrium molecular dynamics simulations, steered molecular dynamics, and calculation of a potential of mean force (PMF)]. The PMF for phosphate reveals a deep free energy well midway along the OprP channel. Two adjacent phosphate-binding sites (W1 and W2), each with a well depth of approximately 8 kT, are identified close to the L3 loop in the most constricted region of the pore. A dissociation constant for phosphate of 6 microM is computed from the PMF, within the range of reported experimental values. The transfer of phosphate between sites W1 and W2 is correlated with changes in conformation of the sidechain of K121, which serves as a "charged brush" to facilitate phosphate passage between the two subsites. OprP also binds chloride, but less strongly than phosphate, as calculated from a Cl(-) PMF. The difference in affinity and hence selectivity is due to the "Lys-cluster" motif, the positive charges of which interact strongly with a partially dehydrated phosphate ion but are shielded from a Cl(-) by the hydration shell of the smaller ion. Our simulations suggest that OprP does not conform to the conventional picture of a channel with relatively flat energy landscape for permeant ions, but rather resembles a membrane-inserted binding protein with a high specificity that allows access to a centrally located binding site from both the extracellular and the periplasmic spaces.


Comparative transcriptome analysis of hepatopancreas reveals the potential mechanism of shrimp resistant to Vibrio parahaemolyticus infection.
Vibrio parahaemolyticus carrying a pathogenic plasmid (VPAHPND) is one of the main causative agents of acute hepatopancreatic necrosis disease (AHPND) in shrimp aquaculture. Knowledge about the mechanism of shrimp resistant to VPAHPND is very helpful for developing efficient strategy for breeding AHPND resistant shrimp. In order to learn the mechanism of shrimp resistant to AHPND, comparative transcriptome was applied to analyze the different expressions of genes in the hepatopancreas of shrimp from different families with different resistance to VPAHPND. Through comparative analysis on the hepatopancreas of shrimp from VPAHPND resistant family and susceptible family, we found that differentially expressed genes (DEGs) were mainly involved in immune and metabolic processes. Most of the immunity-related genes among DEGs were highly expressed in the hepatopancreas of shrimp from resistant family, involved in recognition of pathogen-associated molecular patterns, phagocytosis and elimination of pathogens, maintenance of reactive oxygen species homeostasis and other immune processes etc. However, most metabolic-related genes were highly expressed in the hepatopancreas of shrimp from susceptible family, involved in metabolism of lipid, vitamin, cofactors, glucose, carbohydrate and serine. Interestingly, when we analyzed the expression of above DEGs in the shrimp after VPAHPND infection, we found that the identified immune-related genes remained at high expression levels in the hepatopancreas of shrimp from the VPAHPND resistant family, and most of the identified metabolic-related genes were still at high expression levels in the hepatopancreas of shrimp from the VPAHPND susceptible family. The data suggested that the differential expression of these immune-related and metabolic-related genes in hepatopancreas might contribute to the resistance variations of shrimp to VPAHPND. These results provided valuable information for understanding the resistant mechanism of shrimp to VPAHPND.


The refined crystal structure of Drosophila lebanonensis alcohol dehydrogenase at 1.9 A resolution.
Drosophila alcohol dehydrogenase (DADH; EC 22.214.171.124) is a NAD(H)-dependent oxidoreductase belonging to the short-chain dehydrogenases/reductases (SDR) family. This homodimeric enzyme catalyzes the dehydrogenation of alcohols to their respective ketones or aldehydes in the fruit-fly Drosophila, both for metabolic assimilation and detoxification purposes. The crystal structure of the apo form of DADH, one of the first biochemically characterized member of the SDR family, was solved at 1.9 A resolution by Patterson methods. The initial model was improved by crystallographic refinement accompanied by electron density averaging, R-factor=20.5%, R-free=23.8%.DADH subunits show an alpha/beta single domain structure with a characteristic NAD(H) binding motif (Rossmann fold). The peptide chain of a subunit is folded into a central eight-stranded beta-sheet flanked on each side by three alpha-helices. The dimers have local 2-fold symmetry. Dimer association is dominated by a four-helix bundle motif as well as two C-terminal loops from each subunit, which represent a unique structural feature in SDR enzymes with known structure. Three structural features are characteristic for the active site architecture. (1) A deep cavity which is covered by a flexible loop (33 residues) and the C-terminal tail (11 residues) from the neighboring subunit. The hydrophobic surface of the cavity is likely to increase the specificity of this enzyme towards secondary aliphatic alcohols. (2) The residues of the catalytic triad (Ser138, Tyr151, Lys155) are known to be involved in enzymatic catalysis in the first line. The Tyr151 OH group is involved in an ionic bond with the Lys155 side-chain. Preliminary electrostatic calculations have provided evidence that the active form of Tyr151 is a tyrosinate ion at physiological pH. (3) Three well-ordered water molecules in hydrogen bond distance to side-chains of the catalytic triad may be significant for the proton release steps in DADH catalysis.A ternary structure-based sequence alignment with ten members of the SDR family with known three-dimensional structure has suggested to define a model consisting of four groups of residues, which relates the observed low degree of sequence identity to quite similar folding patterns and nearly identical distributions of residues involved in catalysis.


The adenovirus L4 33-kilodalton protein binds to intragenic sequences of the major late promoter required for late phase-specific stimulation of transcription.
The adenovirus late IVa2 protein is required for maximally efficient transcription from the viral major late (ML) promoter, and hence, the synthesis of the majority of viral late proteins. This protein is a sequence-specific DNA-binding protein that also promotes the assembly of progeny virus particles. Previous studies have established that a IVa2 protein dimer (DEF-B) binds specifically to an intragenic ML promoter sequence necessary for late phase-specific stimulation of ML transcription. However, activation of transcription from the ML promoter correlates with binding of at least one additional infected-cell-specific protein, termed DEF-A, to the promoter. Using an assay for the DNA-binding activity of DEF-A, we identified the unknown protein by using conventional purification methods, purification of FLAG-tagged IVa2-protein-containing complexes, and transient synthesis of viral late proteins. The results of these experiments established that the viral L4 33-kDa protein is the only component of DEF-A: the IVa2 and L4 33-kDa proteins are necessary and sufficient for formation of all previously described complexes in the intragenic control region of the ML promoter. Furthermore, the L4 33-kDa protein binds to the promoter with the specificity characteristic of DEF-A and stimulates transcription from the ML promoter in transient-expression assays.


Cloning of rat interleukin-3 receptor beta-subunit from cultured microglia and its mRNA expression in vivo.
The high-affinity receptors for interleukin-3 (IL-3), GM-CSF, and IL-5 are composed of a ligand binding (alpha-) and a transducing (beta-) subunit. Two distinct transducing subunits (clones AIC2A and AIC2B) have been cloned from mouse, whereas in humans, only one (common) beta-subunit (beta c) has been found. A PCR-based cloning strategy was used to obtain a full-length cDNA sequence from rat microglia including 5'-untranslated regions. Sequence analysis revealed a number of features indicative of the presence of only one beta-subunit in the rat. Most likely, the new rIL-3R beta cDNA is the rat equivalent of human respective murine (AIC2B) beta c subunits. Regulation of rIL-3R beta mRNA expression was investigated in cultured microglia and in vivo. Purified microglia expressed significant amounts of rIL-3R beta mRNA. Addition of lipopolysaccharide (LPS) resulted in a marked upregulation of rIL-3R beta mRNA within approximately 4 hr. No downregulation was observed within 1 week's treatment. No rIL-3R beta mRNA was detectable in normal rat brain. However, 3 hr after a single injection of LPS into the tail vein of a rat, a marked induction of receptor mRNA occurred in a variety of brain regions. Transcriptional rates subsided significantly after 24 hr. rIL-3R beta mRNA was visualized by in situ hybridizations with cRNA antisense probes in ramified cells formerly characterized as microglial cells. rIL-3R beta mRNA was also induced in rat brain after occlusion of middle cerebral artery (MCAO).(ABSTRACT TRUNCATED AT 250 WORDS)


Plasmacytoid dendritic cells move down on the list of suspects: in search of the immune pathogenesis of chronic hepatitis C.
Chronic hepatitis C is a major public health problem. Despite numerous clinical studies in humans and experimental observations made in chimpanzees, hepatitis C pathogenesis remains poorly understood. Here, we review the clinical features of acute and chronic disease, and discuss the role of the immune system in the pathogenesis of disease. Many are aware of the dual role of T cells: responsibility for clearance of the virus during acute phase; and liver injury during chronic phase. Nonetheless, there is an emerging belief that failure to prime HCV-specific T cells is responsible for the failure to spontaneously clear the virus, and possibly, for the lack of response to pegylated-IFNalpha(2a)/ribavirin therapy. We have focused on the latest suspects, plasmacytoid dendritic cells (pDCs), considered to be the professional type I IFNs producing cells. We review the somewhat contradictory data regarding the functional capacity of pDCs in chronic HCV patients and argue that, while lower in relative concentration as compared to healthy individuals, they are not defective in their ability to initiate an innate inflammatory response. Thus, instead of being the culprit, pDCs may in fact represent a novel therapeutic target in order to improve upon existing therapies for treating HCV patients.


Lebetin 2, a Snake Venom-Derived Natriuretic Peptide, Attenuates Acute Myocardial Ischemic Injury through the Modulation of Mitochondrial Permeability Transition Pore at the Time of Reperfusion.
Cardiac ischemia is one of the leading causes of death worldwide. It is now well established that natriuretic peptides can attenuate the development of irreversible ischemic injury during myocardial infarction. Lebetin 2 (L2) is a new discovered peptide isolated from Macrovipera lebetina venom with structural similarity to B-type natriuretic peptide (BNP). Our objectives were to define the acute cardioprotective actions of L2 in isolated Langendorff-perfused rat hearts after regional or global ischemia-reperfusion (IR). We studied infarct size, left ventricular contractile recovery, survival protein kinases and mitochondrial permeability transition pore (mPTP) opening in injured myocardium. L2 dosage was determined by preliminary experiments at its ability to induce cyclic guanosine monophosphate (cGMP) release without changing hemodynamic effects in normoxic hearts. L2 was found to be as effective as BNP in reducing infarct size after the induction of either regional or global IR. Both peptides equally improved contractile recovery after regional IR, but only L2 increased coronary flow and reduced severe contractile dysfunction after global ischemia. Cardioprotection afforded by L2 was abolished after isatin or 5-hydroxydecanote pretreatment suggesting the involvement of natriuretic peptide receptors and mitochondrial KATP (mitoKATP) channels in the L2-induced effects. L2 also increased survival protein expression in the reperfused myocardium as evidenced by phosphorylation of signaling pathways PKCε/ERK/GSK3β and PI3K/Akt/eNOS. IR induced mitochondrial pore opening, but this effect was markedly prevented by L2 treatment. These data show that L2 has strong cardioprotective effect in acute ischemia through stimulation of natriuretic peptide receptors. These beneficial effects are mediated, at least in part, by mitoKATP channel opening and downstream activated survival kinases, thus delaying mPTP opening and improving IR-induced mitochondrial dysfunction.


Potts model for haplotype associations.
Bayesian spatial modeling has become important in disease mapping and has also been suggested as a useful tool in genetic fine mapping. We have implemented the Potts model and applied it to the Genetic Analysis Workshop 14 (GAW14) simulated data. Because the "answers" were known we have analyzed latent phenotype P1-related observed phenotypes affection status (genetically determined) and i (random) in the Danacaa population replicate 2. Analysis of the microsatellite/single-nucleotide polymorphism-based haplotypes at chromosomes 1 and 3 failed to identify multiple clusters of haplotype effects. However, the analysis of separately simulated data with postulated differences in the effects of the two clusters has yielded clear estimated division into the two clusters, demonstrating the correctness of the algorithm. Although we could not clearly identify the disease-related and the non-associated groups of haplotypes, results of both GAW14 and our own simulation encourage us to improve the efficiency and sensitivity of the estimation algorithm and to further compare the proposed method with more traditional methods.


Concurrent Respiratory Motion Correction of Abdominal PET and Dynamic Contrast-Enhanced-MRI Using a Compressed Sensing Approach.
We present an approach for concurrent reconstruction of respiratory motion-compensated abdominal dynamic contrast-enhanced (DCE)-MRI and PET data in an integrated PET/MR scanner. The MR and PET reconstructions share the same motion vector fields derived from radial MR data; the approach is robust to changes in respiratory pattern and does not increase the total acquisition time. Methods: PET and DCE-MRI data of 12 oncologic patients were simultaneously acquired for 6 min on an integrated PET/MR system after administration of 18F-FDG and gadoterate meglumine. Golden-angle radial MR data were continuously acquired simultaneously with PET data and sorted into multiple motion phases on the basis of a respiratory signal derived directly from the radial MR data. The resulting multidimensional dataset was reconstructed using a compressed sensing approach that exploits sparsity among respiratory phases. Motion vector fields obtained using the full 6-min (MC6-min) and only the last 1 min (MC1-min) of data were incorporated into the PET reconstruction to obtain motion-corrected PET images and in an MR iterative reconstruction algorithm to produce a series of motion-corrected DCE-MR images (moco_GRASP). The motion-correction methods (MC6-min and MC1-min) were evaluated by qualitative analysis of the MR images and quantitative analysis of SUVmax and SUVmean, contrast, signal-to-noise ratio (SNR), and lesion volume in the PET images. Results: Motion-corrected MC6-min PET images demonstrated 30%, 23%, 34%, and 18% increases in average SUVmax, SUVmean, contrast, and SNR and an average 40% reduction in lesion volume with respect to the non-motion-corrected PET images. The changes in these figures of merit were smaller but still substantial for the MC1-min protocol: 19%, 10%, 15%, and 9% increases in average SUVmax, SUVmean, contrast, and SNR; and a 28% reduction in lesion volume. Moco_GRASP images were deemed of acceptable or better diagnostic image quality with respect to conventional breath-hold Cartesian volumetric interpolated breath-hold examination acquisitions. Conclusion: We presented a method that allows the simultaneous acquisition of respiratory motion-corrected diagnostic quality DCE-MRI and quantitatively accurate PET data in an integrated PET/MR scanner with negligible prolongation in acquisition time compared with routine PET/DCE-MRI protocols.


Psychosocial workload and stress in the workers' representative.
Using a data set of works councils of trade union IG Metal, this paper investigates psychosocial stress and strain on this specific group in comparison to employees working in administration in general (leadership and non-leadership-role) and a national reference value. For assessing psychosocial work factors on works councils within the sector represented by the trade union IG Metal in Germany, a research by using the German standard version of COPSOQ (Copenhagen Psychosocial Questionnaire) was performed. The instrument includes 87 single items forming 25 aspects of strain and stress. Results from the study group of works councils were compared to those from employees working in administration and to the general population mean (COPSOQ database). Statistical analysis included t-tests, analysis of variance and multiple comparisons of means. To be significant in terms of statistics, p<0.05 (two-tailed) and a minimum deviation of 5 or more points between groups' mean values identify the relevant values. All in all, 309 works councils from a national survey of the German chemical and metalworking industries took part in the study. 113 were full-time works council members (exempted from the duty to perform their regular work), 196 were voluntary members (acting as employee representatives on an honorary basis alongside their normal duties). Comparison between works councils and employees working in administration (leadership roles (N=1810) and non-leadership roles (N=2970)) and for employees in general (N=35.000) showed unfavourable values for works councils for most scales. Significantly higher values indicating higher strain and stress were found for the scales: emotional demands, work-privacy conflict, role conflicts, mobbing, cognitive stress symptoms and burnout. Unfavourable results were obtained for the aspects: quality of leadership, social support, sense of community and general health. Favourable findings were found on the scales: influence at work, quantity of social relations and the partly positive values for quantitative demands and commitment to the workplace. Compared to the reference groups, works council members perceive the psychosocial demands of working life as more exhausting for the majority of aspects. This allows several conclusions. One reason may be the extended tasks employee representatives face, an other may be that the education of most works council members does not seem appropriate to the high demands of their managerial and executive tasks.


Mining Social Entrepreneurship Strategies Using Topic Modeling.
Despite the burgeoning research on social entrepreneurship (SE), SE strategies remain poorly understood. Drawing on extant research on the social activism and social change, empowerment and SE models, we explore, classify and validate the strategies used by 2,334 social entrepreneurs affiliated with the world's largest SE support organization, Ashoka. The results of the topic modeling of the social entrepreneurs' strategy profiles reveal that they employed a total of 39 change-making strategies that vary across resources (material versus symbolic strategies), specificity (general versus specific strategies), and mode of participation (mass versus elite participation strategies); they also vary across fields of practice and time. Finally, we identify six meta-SE strategies-a reduction from the 39 strategies-and identify four new meta-SE strategies (i.e., system reform, physical capital development, evidence-based practices, and prototyping) that have been overlooked in prior SE research. Our findings extend and deepen the research into SE strategies and offer a comprehensive model of SE strategies that advances theory, practice and policy making.


Combined Left Recurrent Laryngeal Nerve and Phrenic Nerve Palsy: A Rare Presentation of Thoracic Aortic Aneurysm.
Hoarseness of voice due to Vocal Cord Palsy (VCP) resulting from aortic aneurysm is a rare entity. Hoarseness due to left Recurrent Laryngeal Nerve (RLN) paralysis caused by identifiable cardiovascular disease has been described as Ortner's syndrome or Cardiovocal syndrome. Very rarely, thoracic aortic aneurysm can cause Phrenic Nerve (PN) palsy causing hemidiaphragm paralysis. But, aortic aneurysm causing both RLN and PN palsy is an extremely rare occasion. Our literature review showed only three cases of combined RLN and PN palsy due to thoracic aortic aneurysm. Here we report a 70-year-old patient having hoarseness of voice for six years for which he was on symptomatic treatment. He presented to us with cough and blood tinged sputum, left sided chest pain, loss of appetite and weakness since two months duration. Based on clinical history and chest radiograph, lung malignancy was suspected. To our surprise, Contrast Enhanced Computed Tomography (CECT) revealed partially thrombosed saccular thoracic aneurysm originating distal to origin of left subclavian artery. He was referred to the cardiothoracic vascular surgeon for surgical treatment, but was reluctant to go for surgery. He is now being followed up by cardiothoracic vascular surgery and cardiology department and his condition has remained the same.


SurgiCal Obesity Treatment Study (SCOTS): protocol for a national prospective cohort study of patients undergoing bariatric surgery in Scotland.
The efficacy of bariatric surgery for large-scale, long-term weight loss is well established. However, many questions remain over the continual benefits and cost-effectiveness of that weight loss for overall health, particularly when accounting for potential complications and adverse events of surgery. Health research institutes in the UK and the USA have called for high-quality longitudinal cohort studies of patients undergoing bariatric surgery, assessing outcomes such as surgical complications, mortality, diabetes remission, microvascular complications, cardiovascular events, mental health, cost and healthcare use. SurgiCal Obesity Treatment Study (SCOTS) is a national, prospective, observational, cohort study of patients undergoing primary bariatric surgical procedures in Scotland. This study aims to recruit 2000 patients and conduct a follow-up for 10 years postbariatric surgery using multiple data collection methods: surgeon-recorded data, electronic health record linkage, and patient-reported outcome measures. Outcomes measured will include: mortality, weight change, diabetes, surgical, cardiovascular, cancer, behavioural, reproductive/urological and nutritional variables. Healthcare utilisation and economic productivity will be collected to inform cost-effectiveness analysis. The study has received a favourable ethical opinion from the West of Scotland Research Ethics committee. All publications arising from this cohort study will be published in open-access peer-reviewed journals. All SCOTS investigators (all members of the research team at every recruiting site) will have the ability to propose research suggestions and potential publications using SCOTS data; a publications committee will approve all requests for use of SCOTS data and propose writing committees and timelines. Lay-person summaries of all research findings will be published simultaneously on the SCOTS website (http://www.scotsurgeystudy.org.uk).


Inhibition of tissue angiotensin converting enzyme. Quantitation by autoradiography.
Inhibition of angiotensin converting enzyme (ACE) in serum and tissues of rats was studied after administration of lisinopril, an ACE inhibitor. Tissue ACE was assessed by quantitative in vitro autoradiography using the ACE inhibitor [125I]351A, as a ligand, and serum ACE was measured by a fluorimetric method. Following oral administration of lisinopril (10 mg/kg), serum ACE activity was acutely reduced but recovered gradually over 24 hours. Four hours after lisinopril administration, ACE activity was markedly inhibited in kidney (11% of control level), adrenal (8%), duodenum (8%), and lung (33%; p less than 0.05). In contrast, ACE in testis was little altered by lisinopril (96%). In brain, ACE activity was markedly reduced 4 hours after lisinopril administration in the circumventricular organs, including the subfornical organ (16-22%) and organum vasculosum of the lamina terminalis (7%; p less than 0.05). In other areas of the brain, including the choroid plexus and caudate putamen, ACE activity was unchanged. Twenty-four hours after administration, ACE activity in peripheral tissues and the circumventricular organs of the brain had only partially recovered toward control levels, as it was still below 50% of control activity levels. These results establish that lisinopril has differential effects on inhibiting ACE in different tissues and suggest that the prolonged tissue ACE inhibition after a single oral dose of lisinopril may reflect targets involved in the hypotensive action of ACE inhibitors.


Sloppy paired acts as the downstream target of wingless in the Drosophila CNS and interaction between sloppy paired and gooseberry inhibits sloppy paired during neurogenesis.
Wingless (Wg) and other Wnt proteins play a crucial role in a number of developmental decisions in a variety of organisms. In the ventral nerve cord of the Drosophila embryo, Wg is non-autonomously required for the formation and specification of a neuronal precursor cell, NB4-2. NB4-2 gives rise to a well-studied neuronal lineage, the RP2/sib lineage. While the various components of the Wg-signaling pathway are also required for generating NB4-2, the target gene(s) of this pathway in the signal-receiving cell is not known. In this paper, we show that sloppy paired 1 and sloppy paired 2 function as the downstream targets of the Wg signaling to generate the NB4-2 cell. Thus, while the loss-of-function mutations in wg and slp have the same NB4-2 formation and specification defects, these defects in wg mutants can be rescued by expressing slp genes from a heterologous promoter. That slp genes function downstream of the Wg signaling is also indicated by the result that expression of slp genes is lost from the neuroectoderm in wg mutants and that ectopic expression of wg induces ectopic expression of slp. Finally, previous results show that Gooseberry (Gsb) prevents Wg from specifying NB4-2 identity to the wg-expressing NB5-3. In this paper, we also show that gsb interacts with slp and prevents Slp from specifying NB4-2 identity. Overexpression of slp overcomes this antagonistic interaction and respecifies NB5-3 as NB4-2. This respecification, however, can be suppressed by a simultaneous overexpression of gsb at high levels. This mechanism appears to be responsible for specifying NB5-3 identity to a row 5 neuroblast and preventing Wg from specifying NB4-2 identity to that cell.


Adaptive evolution of centromere proteins in plants and animals.
Centromeres represent the last frontiers of plant and animal genomics. Although they perform a conserved function in chromosome segregation, centromeres are typically composed of repetitive satellite sequences that are rapidly evolving. The nucleosomes of centromeres are characterized by a special H3-like histone (CenH3), which evolves rapidly and adaptively in Drosophila and Arabidopsis. Most plant, animal and fungal centromeres also bind a large protein, centromere protein C (CENP-C), that is characterized by a single 24 amino-acid motif (CENPC motif). Whereas we find no evidence that mammalian CenH3 (CENP-A) has been evolving adaptively, mammalian CENP-C proteins contain adaptively evolving regions that overlap with regions of DNA-binding activity. In plants we find that CENP-C proteins have complex duplicated regions, with conserved amino and carboxyl termini that are dissimilar in sequence to their counterparts in animals and fungi. Comparisons of Cenpc genes from Arabidopsis species and from grasses revealed multiple regions that are under positive selection, including duplicated exons in some grasses. In contrast to plants and animals, yeast CENP-C (Mif2p) is under negative selection. CENP-Cs in all plant and animal lineages examined have regions that are rapidly and adaptively evolving. To explain these remarkable evolutionary features for a single-copy gene that is needed at every mitosis, we propose that CENP-Cs, like some CenH3s, suppress meiotic drive of centromeres during female meiosis. This process can account for the rapid evolution and the complexity of centromeric DNA in plants and animals as compared to fungi.


A new entity for the negotiation of public procurement prices for patented medicines in Mexico.
As countries expand health insurance coverage, their expenditures on medicines increase. To address this problem, WHO has recommended that every country draw up a list of essential medicines. Although most medicines on the list are generics, in many countries patented medicines represent a substantial portion of pharmaceutical expenditure. To help control expenditure on patented medicines, in 2008 the Mexican Government created the Coordinating Commission for Negotiating the Price of Medicines and other Health Inputs (CCPNM), whose role, as the name suggests, is to enter into price negotiations with drug manufacturers for patented drugs on Mexico's list of essential medicines. Mexico's public expenditure on pharmaceuticals has increased substantially in the past decade owing to government efforts to achieve universal health-care coverage through Seguro Popular, an insurance programme introduced in 2004 that guarantees access to a comprehensive package of health services and medicines. Since 2008, the CCPNM has improved procurement practices in Mexico's public health institutions and has achieved significant price reductions resulting in substantial savings in public pharmaceutical expenditure. The CCPNM has successfully changed the landscape of price negotiation for patented medicines in Mexico. However, it is also facing challenges, including a lack of explicit indicators to assess CCPNM performance; a shortage of permanent staff with sufficient technical expertise; poor coordination among institutions in preparing background materials for the annual negotiation process in a timely manner; insufficient communication among committees and institutions; and a lack of political support to ensure the sustainability of the CCPNM.


Predicting response to BET inhibitors using computational modeling: A BEAT AML project study.
Despite advances in understanding the molecular pathogenesis of acute myeloid leukaemia (AML), overall survival rates remain low. The ability to predict treatment response based on individual cancer genomics using computational modeling will aid in the development of novel therapeutics and personalize care. Here, we used a combination of genomics, computational biology modeling (CBM), ex vivo chemosensitivity assay, and clinical data from 100 randomly selected patients in the Beat AML project to characterize AML sensitivity to a bromodomain (BRD) and extra-terminal (BET) inhibitor. Computational biology modeling was used to generate patient-specific protein network maps of activated and inactivated protein pathways translated from each genomic profile. Digital drug simulations of a BET inhibitor (JQ1) were conducted by quantitatively measuring drug effect using a composite AML disease inhibition score. 93% of predicted disease inhibition scores matched the associated ex vivo IC50 value. Sensitivity and specificity of CBM predictions were 97.67%, and 64.29%, respectively. Genomic predictors of response were identified. Patient samples harbouring chromosomal aberrations del(7q) or -7, +8, or del(5q) and somatic mutations causing ERK pathway dysregulation, responded to JQ1 in both in silico and ex vivo assays. This study shows how a combination of genomics, computational modeling and chemosensitivity testing can identify network signatures associating with treatment response and can inform priority populations for future clinical trials of BET inhibitors.


Pervasive Effects of Aging on Gene Expression in Wild Wolves.
Gene expression levels change as an individual ages and responds to environmental conditions. With the exception of humans, such patterns have principally been studied under controlled conditions, overlooking the array of developmental and environmental influences that organisms encounter under conditions in which natural selection operates. We used high-throughput RNA sequencing (RNA-Seq) of whole blood to assess the relative impacts of social status, age, disease, and sex on gene expression levels in a natural population of gray wolves (Canis lupus). Our findings suggest that age is broadly associated with gene expression levels, whereas other examined factors have minimal effects on gene expression patterns. Further, our results reveal evolutionarily conserved signatures of senescence, such as immunosenescence and metabolic aging, between wolves and humans despite major differences in life history and environment. The effects of aging on gene expression levels in wolves exhibit conservation with humans, but the more rapid expression differences observed in aging wolves is evolutionarily appropriate given the species' high level of extrinsic mortality due to intraspecific aggression. Some expression changes that occur with age can facilitate physical age-related changes that may enhance fitness in older wolves. However, the expression of these ancestral patterns of aging in descendant modern dogs living in highly modified domestic environments may be maladaptive and cause disease. This work provides evolutionary insight into aging patterns observed in domestic dogs and demonstrates the applicability of studying natural populations to investigate the mechanisms of aging.


Effect of directness of exposure and trauma type on Mental Health Literacy of PTSD.
Research has demonstrated that Post-Traumatic Stress Disorder (PTSD) is one of the most widely recognized mental disorders, but recognition is affected by trauma type. The current study investigated the effect of direct versus indirect exposure to traumatic event and trauma types on Mental Health Literacy (MHL) of PTSD. Two hundred and thirty-three participants were asked to identify the mental health problem after presentation of an unlabeled vignette describing a character experiencing PTSD symptoms. The six vignettes described the same symptoms but differed in directness (direct/indirect exposure) and trauma type (rape, military combat or man-made disaster). It was hypothesized that (1) recognition rate would be higher in direct than indirect conditions, and (2) higher in military combat, followed by man-made disaster, and lowest in rape condition. Overall, correct recognition of PTSD was 42.5%. Recognition in direct exposure vignettes was significantly higher than indirect, supporting the first hypothesis. The second hypothesis was only partly supported. While PTSD recognition in rape vignettes was significantly lower than the other two scenarios, no difference was found between combat and man-made disaster trauma types. Our findings implied under-recognition of PTSD, with lack of awareness of different causes of PTSD and of PTSD from indirect trauma exposure. The latter finding is important in the light of DSM-V revisions to diagnostic criteria for PTSD.


Investigations of temperature and pH variations on metal trophic transfer in turbot (Scophthalmus maximus).
Studying dietary metal transfer kinetics is essential to gain a better understanding in global metal accumulation rates and its impacts in marine fish. While there exists a solid understanding on the influence of various biotic factors on this transfer, metal assimilation in fish might be also affected by abiotic factors, as has been observed in marine invertebrates. The present study therefore aims to understand the potential effects of two climate-related master variables, temperature and pH, on the assimilation efficiency (AE) of essential (Co and Zn) and non-essential (Ag) metals in the turbot Scophthalmus maximus using radiotracer tools. Juvenile turbots were acclimated for 8 weeks at two temperatures (17 and 20 °C) and pH (7.5 and 8.0) regimes, under controlled laboratory conditions, and then fed with radiolabelled shrimp (57Co, 65Zn and 110mAg). Assimilation efficiencies of Co and Ag in juvenile turbot, determined after a 21-day depuration period, were not affected by pre-exposition to the different environmental conditions. In contrast, temperature did significantly influence Zn AE (p < 0.05), while pH variations did not affect the assimilation of any of the metals studied. In fact, temperature is known to affect gut physiology, specifically the membrane properties of anterior intestine cells where Zn is adsorbed and assimilated from the ingested food. These results are relevant to accurately assess the influence of abiotic factors in AEs of metals in fish as they are highly element-dependent and also modulated by metabolic processes.


Analysis of fine-mode aerosol retrieval capabilities by different passive remote sensing instrument designs.
Remote sensing of aerosol optical properties is difficult, but multi-angle, multi-spectral, polarimetric instruments have the potential to retrieve sufficient information about aerosols that they can be used to improve global climate models. However, the complexity of these instruments means that it is difficult to intuitively understand the relationship between instrument design and retrieval success. We apply a Bayesian statistical technique that relates instrument characteristics to the information contained in an observation. Using realistic simulations of fine size mode dominated spherical aerosols, we investigate three instrument designs. Two of these represent instruments currently in orbit: the Multiangle Imaging SpectroRadiometer (MISR) and the POLarization and Directionality of the Earths Reflectances (POLDER). The third is the Aerosol Polarimetry Sensor (APS), which failed to reach orbit during recent launch, but represents a viable design for future instruments. The results show fundamental differences between the three, and offer suggestions for future instrument design and the optimal retrieval strategy for current instruments. Generally, our results agree with previous validation efforts of POLDER and airborne prototypes of APS, but show that the MISR aerosol optical thickness uncertainty characterization is possibly underestimated.


Postconditioning--A new link in nature's armor against myocardial ischemia-reperfusion injury.
Reperfusion injury is a complex process involving several cell types (endothelial cells, neutrophils, and cardiomyocytes), soluble proinflammatory mediators, oxidants, ionic and metabolic dyshomeostasis, and cellular and molecular signals. These participants in the pathobiology of reperfusion injury are not mutually exclusive. Some of these events take place during the very early moments of reperfusion, while others, seemingly triggered in part by the early events, are activated within a later timeframe. Postconditioning is a series of brief mechanical interruptions of reperfusion following a specific prescribed algorithm applied at the very onset of reperfusion. This algorithm lasts only from 1 to 3 minutes depending on species. Although associated with re-occlusion of the coronary artery or re-imposition of hypoxia in cell culture, the reference to ischemia has been dropped. Postconditioning has been observed to reduce infarct size and apoptosis as the "end games" in myocardial therapeutics; salvage of infarct size was similar to that achieved by the gold standard of protection, ischemic preconditioning. The cardioprotection was also associated with a reduction in: endothelial cell activation and dysfunction, tissue superoxide anion generation, neutrophil activation and accumulation in reperfused myocardium, microvascular injury, tissue edema, intracellular and mitochondrial calcium accumulation. Postconditioning sets in motion triggers and signals that are functionally related to reduced cell death. Adenosine has been implicated in the cardioprotection of postconditioning, as has e-NOS, nitric oxide and guanylyl cyclase, opening of K(ATP) channels and closing of the mitochondrial permeability transition pore. Cardioprotection by postconditioning has also been associated with the activation of intracellular survival pathways such as ERK1/2 and PI3 kinase - Akt pathways. Other pathways have yet to be identified. Although many of the pathways involved in postconditioning have also been identified in ischemic preconditioning, some may not be involved in preconditioning (ERK1/2). The timing of action of these pathways and other mediators of protection in postconditioning differs from that of preconditioning. In contrast to preconditioning, which requires a foreknowledge of the ischemic event, postconditioning can be applied at the onset of reperfusion at the point of clinical service, i.e. angioplasty, cardiac surgery, transplantation.


Medicaid prior authorization and opioid medication abuse and overdose.
The US opioid medication epidemic has resulted in serious health consequences for patients. Formulary management tools adopted by payers, specifically prior authorization (PA) policies, may lower the rates of opioid medication abuse and overdose. We compared rates of opioid abuse and overdose among enrollees in plans that varied in their use of PA from "High PA" (ie, required PA for 17 to 74 opioids), with "Low PA" (ie, required PA for 1 opioid), and "No PA" policies for opioid medications. Retrospective cohort study of patients initiating opioid treatment in Pennsylvania Medicaid from 2010 to 2012. Generalized linear models with generalized estimating equations were employed to assess the relationships between the presence of PA policies and opioid medication abuse and overdose, as measured in Medicaid claims data, adjusting for demographics, comorbid health conditions, benzodiazepine/muscle relaxant use, and emergency department use. The study cohort included 297,634 enrollees with a total of 382,828 opioid treatment episodes. Compared with plans with No PA, enrollees in High PA (adjusted rate ratio [ARR], 0.89; 95% confidence interval [CI], 0.85-0.93; P <.001) and Low PA plans (ARR, 0.93; 95% CI, 0.87-1.00; P = .04) had lower rates of abuse. Enrollees in the Low PA plan had a lower rate of overdose than those within plans with No PA (ARR, 0.75; 95% CI, 0.59-0.95; P = .02). High PA plan enrollees were also less likely than No PA enrollees to experience an overdose, but this association was not statistically significant (ARR, 0.88; 95% CI, 0.76-1.02; P = .08). Enrollees within Medicaid plans that utilize PA policies appear to have lower rates of abuse and overdose following initiation of opioid medication treatment.


Towards the identification of ancestrally shared regenerative mechanisms across the Metazoa: A Transcriptomic case study in the Demosponge Halisarca caerulea.
Regeneration is an essential process for all multicellular organisms, allowing them to recover effectively from internal and external injury. This process has been studied extensively in a medical context in vertebrates, with pathways often investigated mechanistically, both to derive increased understanding and as potential drug targets for therapy. Several species from other parts of the metazoan tree of life, including Hydra, planarians and echinoderms, noted for their regenerative capabilities, have previously been targeted for study. Less well-documented for their regenerative abilities are sponges. This is surprising, as they are both one of the earliest-branching extant metazoan phyla on Earth, and are rapidly able to respond to injury. Their sessile lifestyle, lack of an external protective layer, inability to respond to predation and filter-feeding strategy all mean that regeneration is often required. In particular the demosponge genus Halisarca has been noted for its fast cell turnover and ability to quickly adjust its cell kinetic properties to repair damage through regeneration. However, while the rate and structure of regeneration in sponges has begun to be investigated, the molecular mechanisms behind this ability are yet to be catalogued. Here we describe the assembly of a reference transcriptome for Halisarca caerulea, along with additional transcriptomes noting response to injury before, shortly following (2h post-), and 12h after trauma. RNAseq reads were assembled using Trinity, annotated, and samples compared, to allow initial insight into the transcriptomic basis of sponge regenerative processes. These resources are deep, with our reference assembly containing >92.6% of the BUSCO Metazoa set of genes, and well-assembled (N50s of 836, 957, 1688 and 2032 for untreated, 2h, 12h and reference transcriptomes respectively), and therefore represent excellent qualitative resources as a bedrock for future study. The generation of transcriptomic resources from sponges before and following deliberate damage has allowed us to study particular pathways within this species responsible for repairing damage. We note particularly the involvement of the Wnt cascades in this process in this species, and detail the contents of this cascade, along with cell cycle, extracellular matrix and apoptosis-linked genes in this work. This resource represents an initial starting point for the continued development of this knowledge, given H. caerulea's ability to regenerate and position as an outgroup for comparing the process of regeneration across metazoan lineages. With this resource in place, we can begin to infer the regenerative capacity of the common ancestor of all extant animal life, and unravel the elements of regeneration in an often-overlooked clade.


Time to response for clinical and patient-reported outcomes in patients with psoriatic arthritis treated with tofacitinib, adalimumab, or placebo.
This study examined the time to clinically meaningful response in patients with active psoriatic arthritis treated with tofacitinib, adalimumab, or placebo switching to tofacitinib. Data were from two phase 3 studies, OPAL Broaden (12 months) and OPAL Beyond (6 months). Patients received tofacitinib 5 or 10 mg twice daily (BID), adalimumab 40 mg once every 2 weeks (OPAL Broaden only), or placebo switching to tofacitinib 5 or 10 mg BID at month 3. Baseline to initial response time was according to pre-defined clinically meaningful criteria on Health Assessment Questionnaire-Disability Index (HAQ-DI; ≥ 0.35-point improvement), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F; ≥ 4-point improvement), Psoriatic Arthritis Disease Activity Score (PASDAS; post-baseline score ≤ 3.2 and > 1.6-point improvement from baseline), and minimal disease activity (MDA; meeting at least 5 of 7 criteria) composite. In OPAL Broaden, median time to initial HAQ-DI score response was 29, 53, and 30 days in patients treated with tofacitinib 5 mg BID, tofacitinib 10 mg BID, or adalimumab, compared with 162 and 112 days in patients treated with placebo switching to tofacitinib 5 or 10 mg BID at month 3, respectively. Across studies, median time to initial FACIT-F total score response was shorter in patients receiving tofacitinib 5 mg BID (31 days) vs other groups (84-92 days). Median time to initial response was approximately 11 (MDA)/6-9 months (PASDAS) in tofacitinib/adalimumab groups in OPAL Broaden. This analysis demonstrates tofacitinib's efficacy on most patient-reported and clinical endpoints over time and shows a shorter time to initial, clinically meaningful response in patients receiving tofacitinib vs patients switching from placebo to tofacitinib. ClinicalTrials.gov , NCT01877668. Registered June 12, 2013. ClinicalTrials.gov , NCT01882439. Registered June 18, 2013.


Asymptomatic malaria parasitaemia and seizure control in children with nodding syndrome; a cross-sectional study.
Plasmodium falciparum is epileptogenic and in malaria endemic areas, is a leading cause of acute seizures. In these areas, asymptomatic infections are common but considered benign and so, are not treated. The effects of such infections on seizures in patients with epilepsy is unknown. This study examined the relationship between P. falciparum infection and seizure control in children with a unique epilepsy type, the nodding syndrome. This cross-sectional study was nested in an ongoing trial 'Doxycycline for the treatment of nodding syndrome (NCT02850913)'. We hypothesised that, in patients with epilepsy, infection by P. falciparum, including asymptomatic infections, increases the risk of seizures and impairs seizure control. Participants were Ugandan children with nodding syndrome, age ≥8 years, receiving sodium valproate. All had standardised testing including documentation of the number of seizures in the past month, a rapid malaria test and if positive, the peripheral blood parasite density. The primary outcome was the number of seizures in the past month (30 days). A total of 164/240 (68%) had malaria. Asymptomatic infections (without fever) were seen in 160/240 (67%) and symptomatic infections in 4/240 (2.7%). In participants without malaria, the median (IQR) number of seizures in the past month was 2.0 (1.0-4.0) and it was 4.0 (2.0-7.5) in participants with malaria, p=0.017. The number of seizures in asymptomatic persons was 3.0 (IQR 2.0-7.3) and 6.0 (IQR 4.0-10.0) in symptomatic individuals, p=0.024. Additionally, in asymptomatic patients, a positive correlation was observed between the parasite density and number of seizures, r=0.33, p=0.002. In patients with nodding syndrome, both asymptomatic and symptomatic malaria are associated with an increased risk of seizures and poorer seizure control. Similar effects should be examined in other epilepsy disorders. Malaria prevention should be strengthened for these patients and chemotreatment and prevention studies considered to improve seizure control.


Starchy foods and glycemic index.
Different starchy foods produce different glycemic responses when fed individually, and there is some evidence that this also applies in the context of the mixed meal. A major reason appears to relate to the rate at which the foods are digested and the factors influencing this. A similar ranking in terms of glycemic response to specific foods is seen independent of the carbohydrate tolerance status of the groups tested. Potentially clinically useful starchy foods producing relatively flat glycemic responses have been identified. Many of these are considered ethnic or traditional and include legumes; pasta; grains such as barley, parboiled rice, and bulgur (cracked wheat); and whole-grain breads such as pumpernickel. Specific incorporation of these foods into diets has been associated with reductions in low-density lipoprotein cholesterol and triglyceride levels in hyperlipidemia and with improved blood glucose control in insulin-dependent diabetic patients. To facilitate identification of such foods, it has been suggested that the glycemic response should be indexed to a standard (e.g., white bread) to allow comparisons to be made between the glycemic index of foods tested in different groups of subjects. The scope of application of this principle is subject to further investigation. It may be used to expand the range of possibly useful starchy foods for trial in the diets of diabetic patients.


The central role of the temporo-parietal junction and the superior longitudinal fasciculus in supporting multi-item competition: evidence from lesion-symptom mapping of extinction.
The present study examined the relations between the lesions linked to visual and tactile extinction (VE and TE), and those related to visual field defects and spatial neglect. Continuous variations in patients' performance were used to assess the link between behavioural scores and integrity of both grey and white matter (GM and WM). We found both common and distinct neural substrates associated with extinction and neglect. Damage to angular and middle occipital gyri, superior temporal sulcus (STS) and insula were linked to VE. Lesions involving the supramarginal gyrus (SMG), intraparietal sulcus, middle frontal and superior temporal gyri (MFG and STG) were associated exclusively with spatial neglect. Lesions affecting the temporo-parietal junction (TPJ), the middle temporal region, middle frontal area (BA46) as well as the insula and putamen were linked to both spatial neglect and VE. Analysis of the relations between VE and TE highlighted the TPJ as the common site for both modalities. These findings suggest that the TPJ plays a general role in identifying salient events in the sensory environment across multiple modalities. Furthermore, WM analyses pointed to superior longitudinal fasciculus (SLF) as critical for interconnecting components of the visuospatial attention network. We demonstrated that functional disconnections resulting from SLF damage contribute to altered performance on attention tasks measuring not only neglect but also VE and TE. We propose that the SLF supports interactions between functionally specialized regions involved in attentional control across multiple sensory modalities.


The improved Boer goat.
The history, origin and characteristics of the South African Boer breed of goats are reviewed. The development was carried out by a handful of farmers in the Eastern Cape, particularly in the district of Somerset East. The prototype for the breed was selected from several existing breeds of goats in South Africa in order to achieve the present functional characteristics and type. The Boer goat is a hardy breed with great capacity for adaptation and an exceptional ability to withstand and resist diseases. The Boer goat is highly fertile, conception rate is about 90%, kidding rate about 189% and fecundity rate 210%. Weaning weight at 120 days averages 29kg. Boer doe produces enough milk to raise twins easily. Boer goat yields flavoursome, succulent, tender and tasty lean meat of high quality, particularly during the young stage. Boer goat is able to maintain a high level of production up to 10 years of age. Details on breed standards of the Boer goat are presented. Numerous countries had imported Boer goats from South Africa including USA, New Zealand, Australia, Germany, Israel, France and more recently China.