Caffeine intake antagonizes salt sensitive hypertension through improvement of renal sodium handling.
High salt intake is a major risk factor for hypertension. Although acute caffeine intake produces moderate diuresis and natriuresis, caffeine increases the blood pressure (BP) through activating sympathetic activity. However, the long-term effects of caffeine on urinary sodium excretion and blood pressure are rarely investigated. Here, we investigated whether chronic caffeine administration antagonizes salt sensitive hypertension by promoting urinary sodium excretion. Dahl salt-sensitive (Dahl-S) rats were fed with high salt diet with or without 0.1% caffeine in drinking water for 15 days. The BP, heart rate and locomotor activity of rats was analyzed and urinary sodium excretion was determined. The renal epithelial Na(+) channel (ENaC) expression and function were measured by in vivo and in vitro experiments. Chronic consumption of caffeine attenuates hypertension induced by high salt without affecting sympathetic nerve activity in Dahl-S rats. The renal α-ENaC expression and ENaC activity of rats decreased after chronic caffeine administration. Caffeine increased phosphorylation of AMPK and decrease α-ENaC expression in cortical collecting duct cells. Inhibiting AMPK abolished the effect of caffeine on α-ENaC. Chronic caffeine intake prevented the development of salt-sensitive hypertension through promoting urinary sodium excretion, which was associated with activation of renal AMPK and inhibition of renal tubular ENaC.


Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus.
Enadenotucirev is an oncolytic group B adenovirus identified by a process of bio-selection for the ability to selectively propagate in and rapidly kill carcinoma cells. It is resistant to inactivation by human blood components, potentially enabling intravenous dosing in patients with metastatic cancer. However, there are no known permissive animal models described for group B adenoviruses that could facilitate a conventional approach to preclinical safety studies. In this manuscript, we describe our tailored preclinical strategy designed to evaluate the key biological properties of enadenotucirev. As enadenotucirev does not replicate in animal cells, a panel of primary human cells was used to evaluate enadenotucirev replication selectivity in vitro, demonstrating that virus genome levels were >100-fold lower in normal cells relative to tumor cells. Acute intravenous tolerability in mice was used to assess virus particle-mediated toxicology and effects on innate immunity. These studies showed that particle toxicity could be ameliorated by dose fractionation, using an initial dose of virus to condition the host such that cytokine responses to subsequent doses were significantly attenuated. This, in turn, supported the initiation of a phase I intravenous clinical trial with a starting dose of 1 × 1010 virus particles given on days 1, 3, and 5.


An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms.
Invasive pancreatic ductal adenocarcinoma is an almost uniformly fatal disease. Several distinct noninvasive precursor lesions can give rise to invasive adenocarcinoma of the pancreas, and the prevention, detection, and treatment of these noninvasive lesions offers the potential to cure early pancreatic cancers. Noninvasive precursors of invasive ductal adenocarcinoma of the pancreas include pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms. Diagnostic criteria, including a distinct ovarian-type stroma, and a consistent nomenclature are well established for mucinous cystic neoplasms. By contrast, consistent nomenclatures and diagnostic criteria have been more difficult to establish for PanINs and IPMNs. Because both PanINs and IPMNs consist of intraductal neoplastic proliferations of columnar, mucin-containing cells with a variable degree of papilla formation, the distinction between these two classes of precursor lesions remains problematic. Thus, considerable ambiguities still exist in the classification of noninvasive neoplasms in the pancreatic ducts. A meeting of international experts on precursor lesions of pancreatic cancer was held at The Johns Hopkins Hospital from August 18 to 19, 2003. The purpose of this meeting was to define an international acceptable set of diagnostic criteria for PanINs and IPMNs and to address a number of ambiguities that exist in the previously reported classification systems for these neoplasms. We present a consensus classification of the precursor lesions in the pancreatic ducts, PanINs and IPMNs.


Evolution in the social brain.
The evolution of unusually large brains in some groups of animals, notably primates, has long been a puzzle. Although early explanations tended to emphasize the brain's role in sensory or technical competence (foraging skills, innovations, and way-finding), the balance of evidence now clearly favors the suggestion that it was the computational demands of living in large, complex societies that selected for large brains. However, recent analyses suggest that it may have been the particular demands of the more intense forms of pairbonding that was the critical factor that triggered this evolutionary development. This may explain why primate sociality seems to be so different from that found in most other birds and mammals: Primate sociality is based on bonded relationships of a kind that are found only in pairbonds in other taxa.


Hydrogen Storage in Pure and Boron-Substituted Nanoporous Carbons-Numerical and Experimental Perspective.
Nanoporous carbons remain the most promising candidates for effective hydrogen storage by physisorption in currently foreseen hydrogen-based scenarios of the world's energy future. An optimal sorbent meeting the current technological requirement has not been developed yet. Here we first review the storage limitations of currently available nanoporous carbons, then we discuss possible ways to improve their storage performance. We focus on two fundamental parameters determining the storage (the surface accessible for adsorption and hydrogen adsorption energy). We define numerically the values nanoporous carbons have to show to satisfy mobile application requirements at pressures lower than 120 bar. Possible necessary modifications of the topology and chemical compositions of carbon nanostructures are proposed and discussed. We indicate that pore wall fragmentation (nano-size graphene scaffolds) is a partial solution only, and chemical modifications of the carbon pore walls are required. The positive effects (and their limits) of the carbon substitutions by B and Be atoms are described. The experimental 'proof of concept' of the proposed strategies is also presented. We show that boron substituted nanoporous carbons prepared by a simple arc-discharge technique show a hydrogen adsorption energy twice as high as their pure carbon analogs. These preliminary results justify the continuation of the joint experimental and numerical research effort in this field.


Medical Devices: Classification and Analysis of Faults Leading to Harms.
Harms from medical devices are important, but have been much less well studied than adverse drug reactions. Information provided to device users is of variable quality. Our aim was to define "medical device fault" and "adverse effect of a medical device"; to establish whether medical device faults arise in design, manufacture, or use; and to consider ways of mitigating the adverse effects of medical devices. We analysed 100 consecutive faults reported by the US Food and Drug Administration (FDA) and 50 faults reported by the UK Medicines and Healthcare products Regulatory Agency (MHRA), and classified faults according to the point at which they occurred. Nearly 70% of reported faults related to devices that entered the body. Over 70% arose at the design stage, a quarter of the faults were associated with manufacture, and less than 5% were primarily caused by faulty use. We defined a medical device fault as an unintended failure in the design, manufacture, or use of a medical device that leads to, or has the potential to lead to, harm to the patient, and an adverse effect of a medical device as an unintended and appreciably harmful effect, caused by a medical device, which demonstrates a hazard of the device and may warrant preventive measures, or a change in the mode of use, or withdrawal of the device. Most faults that generate warnings arise from problems at the design stage, some arise at the manufacturing stage, and a few in usage. Careful assessment of the design of safety-critical devices in the light of previous problems may help to prevent repetition of errors. It would be helpful if, in addition to user manuals, manufacturers were required to produce Summaries of Device Characteristics (SDCs, "labels") that contained a systematically presented set of information about a product.


Spectral multiplexing and coherent-state decomposition in Fourier ptychographic imaging.
Information multiplexing is important for biomedical imaging and chemical sensing. In this paper, we report a microscopy imaging technique, termed state-multiplexed Fourier ptychography (FP), for information multiplexing and coherent-state decomposition. Similar to a typical Fourier ptychographic setting, we use an array of light sources to illuminate the sample from different incident angles and acquire corresponding low-resolution images using a monochromatic camera. In the reported technique, however, multiple light sources are lit up simultaneously for information multiplexing, and the acquired images thus represent incoherent summations of the sample transmission profiles corresponding to different coherent states. We show that, by using the state-multiplexed FP recovery routine, we can decompose the incoherent mixture of the FP acquisitions to recover a high-resolution sample image. We also show that, color-multiplexed imaging can be performed by simultaneously turning on R/G/B LEDs for data acquisition. The reported technique may provide a solution for handling the partially coherent effect of light sources used in Fourier ptychographic imaging platforms. It can also be used to replace spectral filter, gratings or other optical components for spectral multiplexing and demultiplexing. With the availability of cost-effective broadband LEDs, the reported technique may open up exciting opportunities for computational multispectral imaging.


Delay and probability discounting as candidate markers for dementia: an initial investigation.
The present study investigated delay discounting and probability discounting-behavioral economic indices of impulsivity and risk proneness, respectively-in 39 healthy older adults and 25 older adults with mild cognitive impairment (MCI). Relative to the healthy group, it was hypothesized that older adults with MCI would display greater levels of impulsivity, risk proneness, and response inconsistency. The MCI group was found to display a unique delay discounting profile characterized by increasing impulsivity with decreasing reward magnitude, such that cognitively impaired older adults were significantly more impulsive than healthy controls at the small reward magnitude. The two groups exhibited similar levels of probability discounting, though older adults with MCI were significantly less consistent in their risk preferences. The present findings shed light onto decision-making in pre-dementia disease stages and suggest that discounting performance holds potential to complement early diagnostic instruments, likely due to pathophysiological processes in relevant brain regions.


Radio rotation period of jupiter.
The results of observations of Jupiter at 18 megacycles per second indicate that the apparent rotation period drifts cyclically about a constant mean value. The most probable drift period appears to be 11.9 years, Jupiter's orbital period. The mean rotation period during one orbital period is about 0.3 second longer than that of the system III (1957.0) period. This is in close agreement with the rotation period deduced from decimetric observations and probably represents the true rotation period of the magnetic field. The cyclic drift in the rotation period of source A at 18 megacycles per second is explained on the basis of beaming of the escaping radiation at an angle 6 degrees north of the magnetic equator. The apparent rotation period of source A depends on the rate of change of the Jovicentric declination of Earth.


[Body fat and fat mass-fat free mass ratio estimated by bioelectric impedance in the nutritional evaluation of women 35-55 years of age].
Nutritional evaluation during pre-menopause and menopause plays an important role in assessing the changes taking place in a woman's body, a comparison being drawn in this study between the parameters body fat and body fat-muscle ratio (BFMR) estimated by impedancemetry and the body mass index (BMI) for defining nutritional status and body composition. A cross-sectional descriptive study. By random sampling (health card basis), thirty women within the 35-55 age range were selected and then evaluated regarding the relationship between body fat and fat mass (FM)-fat free mass (FFM) ratio (FM/FFM = BFMR) and the BMI, different means of estimating body fat distribution: waist and iliac region circumferences, waist-hip and iliac region-hip ratios and iliac region and sagittal diameters; systolic (SBP) and diastolic blood pressures (DBP) and serum levels of glucose, cholesterol, HDL-cholesterol and triglycerides. The percentage of body fat was highly correlated (p < 0.001) with BMI (r = 0.919), waist (r = 0.866) and iliac region (r = 0.841) circumferences and sagittal (r = 0.783) and iliac region (r = 0.772) diameters, and less highly with glycemia (r = 0.385; p = 0.036) and the SBP (r = 0.497; p = 0.005) and DBP (r = 0.582; p = 0.001). The BFMR showed similar results, no being significantly related to any biochemical parameter. 46.7% of the obese women as per their percentage of body fat (> 33%) had a BMI of under 30. The estimating of the body fat and BFMR parameters among women within the 35-55 age range supplements the nutritional evaluation made by means of the BMI, although in order to define their true figures in this evaluation, the reference values must for the population as a whole must be determined.


A triple modality BSA-coated dendritic nanoplatform for NIR imaging, enhanced tumor penetration and anticancer therapy.
Functional theranostic systems for drug delivery capable of concurrent near-infrared (NIR) fluorescence imaging, active tumor targeting and anticancer therapies are desired for concise cancer diagnosis and treatment. Dendrimers with controllable size and surface functionalities are good candidates for such platforms. However, integration of active targeting ligands and imaging agents separately on the surface or encapsulation of the imaging agents in the inner core of the dendrimers will result in a more complex composition or reduced drug loading efficiency. Herein, we reported a PAMAM-based theranostic system, with a simple integrin-specific imaging ligand prepared from two motifs. One motif is a NIR carbocyanine fluorescent dye (Cyp) for precise in vivo monitoring of the system and identification of tumor or cancer cells, and the other is a novel tumor-penetrating cyclic peptide (CRGDKGPDC, abbreviated iRGD). BSA was non-covalently bonded with Cyp to reduce NIR agent fluorescence-quenching aggregates and enhance imaging signals. The chemotherapy effect of these dendritic systems was achieved by encapsulating paclitaxel into the hydrophobic interior of the dendrimers. In vitro and in vivo targeting and penetrating studies revealed that a significantly high amount of the dendritic systems was endocytosed by HepG2 cells and enhanced accumulation and penetration at tumor sites. Our safety evaluation showed that masking of cationic-end groups of PAMAM to neutral or anionic groups has resulted in decreased or even zero-toxicity. The preliminary antitumor efficacy of the dendritic system was evaluated. In vitro and in vivo studies confirmed that paclitaxel-encapsulated functionalized PAMAM can efficiently kill HepG2 cancer cells. In conclusion, our functionalized theranostic dendritic system could be a promising nanocarrier to effectively deliver drugs to deep tumor regions for anticancer therapy.


Reliability and stability of performances in 400-m swimming and 1500-m running.
To assess the reliability and stability of 400-m swimming and 1500-m running competitions to establish the number of samples needed to obtain a stable pacing profile. Coaches, athletes, and researchers can use these methods to ensure that sufficient data are collected before training and race strategies are constructed or research conclusions are drawn. Lap times were collected from 5 world and European championship finals between 2005 and 2011, resulting in the capture of data from 40 swimmers and 55 runners. A cumulative mean for each lap was calculated, starting with the most recent data, and the number of races needed for this to stabilize to within 1% was reported. Typical error for each lap was calculated for athletes who had competed in more than 1 final. International swimmers demonstrated more reproducible performances than runners in 3 of the 4 laps of the race (P < .01). Variance in runners' lap times significantly decreased by 1.7-2.7% after lap 1, whereas variance in swimmers' lap times tended to increase by 0.1-0.5% after lap 1. To establish a stable profile, at least ten 400-m swimmers and forty-four 1500-m runners must be included. A stable race profile was observed from the analysis of 5 events for 1500-m running and 3 events for 400-m swimming. Researchers and athletes can be more certain about the pacing information collected from 400-m swimming than 1500-m running races, as the swimming data are less variable, despite both events being of similar duration.


Potential Risks and Mitigation Strategies Before the Conduct of a Clinical Trial: An Industry Perspective.
Conduct of clinical trials has undergone substantial changes over the last two decades. Newer markets, evolving guidelines and documentation and high cost involved in conducting the trials have led pharmaceutical companies to prepare a risk mitigation plan. Extensive monitoring of potential risks is an essential element of clinical trials which helps to ensure quality and integrity of a clinical investigation. Every clinical trial has pre (before the trial), conduct and post phase. This article which has been developed as a result of extensive research at ground level by a reputed pharmaceutical company to identify the potential stages of risks that could affect the overall quality and safety of a trial and its outcome during the pre-phase of trial (the stage of the trial where the study design is being planned before initiation of the clinical trial). It includes risks associated with basic study concept, protocol design, Confidential Disclosure Agreement (CDA) and Clinical Trial Authorization (CTA) application signing, vendors of central drug laboratory, site and investigator selection, Clinical Research Coordinator (CRC) meet, Informed Consent Form (ICF), Case Report Form (CRF)/ Status Report Form (SRF) preparation, Ethics Committee (EC) submission, etc. have been highlighted. The risk based mitigation strategy (to develop an effective risk monitoring plan before staring a clinical trial) has also been suggested by authors. A well-tailored and integrated plan, recognition of potential risks and their mitigation strategy can result in the pre exclusion or end to end solution of all the risks associated with pre- phase of clinical trials.


Characterization of genetic aberrations in a single case of metastatic thymic adenocarcinoma.
Thymic adenocarcinoma is an extremely rare subtype of thymic epithelial tumors. Due to its rarity, there is currently no sequencing approach for thymic adenocarcinoma. We performed whole exome and transcriptome sequencing on a case of thymic adenocarcinoma and performed subsequent validation using Sanger sequencing. The case of thymic adenocarcinoma showed aggressive behaviors with systemic bone metastases. We identified a high incidence of genetic aberrations, which included somatic mutations in RNASEL, PEG10, TNFSF15, TP53, TGFB2, and FAT1. Copy number analysis revealed a complex chromosomal rearrangement of chromosome 8, which resulted in gene fusion between MCM4 and SNTB1 and dramatic amplification of MYC and NDRG1. Focal deletion was detected at human leukocyte antigen (HLA) class II alleles, which was previously observed in thymic epithelial tumors. We further investigated fusion transcripts using RNA-seq data and found an intergenic splicing event between the CTBS and GNG5 transcript. Finally, enrichment analysis using all the variants represented the immune system dysfunction in thymic adenocarcinoma. Thymic adenocarcinoma shows highly malignant characteristics with alterations in several cancer-related genes.


Characterization of a new form of inherited hypercholesterolemia: familial recessive hypercholesterolemia.
We previously described a Sardinian family in which the probands had a severe form of hypercholesterolemia, suggestive of familial hypercholesterolemia (FH). However, low density lipoprotein (LDL) receptor activity in fibroblasts from these subjects and LDL binding ability were normal. The characteristics of the pedigree were consistent with an autosomal recessive trait. Sitosterolemia and pseudohomozygous hyperlipidemia were ruled out. A second Sardinian kindred with similar characteristics was identified. Probands showed severe hypercholesterolemia, whereas their parents and grandparents were normolipidemic. FH, familial defective apoprotein (apo) B, sitosterolemia, and cholesteryl ester storage disease were excluded by in vitro studies. We addressed the metabolic basis of this inherited disorder by studying the in vivo metabolism of LDL in 3 probands from these 2 families. 125I-LDL turnover studies disclosed a marked reduction in the fractional catabolic rate (0.19+/-0.01 versus 0.36+/-0.03 pools per day, respectively; P<0.001) and a significant increase in the production rate [20.7+/-4.4 versus 14. 0+/-2.4 mg. kg-1. d-1, respectively; P<0.01] of LDL apoB in the probands compared with normolipidemic controls. We then studied the in vivo biodistribution and tissue uptake of 99mtechnetium-labeled LDL in the probands and compared them with those in normal controls and 1 FH homozygote. The probands showed a significant reduction in hepatic LDL uptake, similar to that observed in the FH homozygote. A reduced uptake of LDL by the kidney and spleen was also observed in all patients. Our findings suggest that this recessive form of hypercholesterolemia is due to a marked reduction of in vivo LDL catabolism. This appears to be caused by a selective reduction in hepatic LDL uptake. We propose that in this new lipid disorder, a recessive defect causes a selective impairment of LDL receptor function in the liver.


Failure rates of class V restorations in the management of root caries in adults - a systematic review.
The aim of this systematic review was to compare cumulative failure rates of different restorative materials in carious class V lesions on the root surfaces of adult patients. The prevalence of root caries is set to increase in the coming years as a result of ageing of the population and a concomitant reduction in levels of edentulousness. Evidence is needed to assist practitioners to select the most appropriate restorative material for use in these lesions. A search of the literature was undertaken using the electronic databases of PubMed, Embase, CENTRAL and OpenSIGLE using keywords relevant to the search question. Two review authors conducted the electronic search independently, and any conflict was resolved by discussion. The references quoted in the full text articles extracted were hand searched for any further eligible studies. Sixty non-duplicate citations were screened. Following review of the titles, abstracts, texts and application of the pre-determined inclusion/exclusion criteria, five studies remained. There is a need for more research in this area as many of the studies identified in this systematic review treated post-radiation, xerostomic patients which are not typical of the general population. Increased adherence to CONSORT guidelines for reporting is also advised to facilitate future systematic review and meta-analysis in this area.


Computational analysis of network activity and spatial reach of sharp wave-ripples.
Network oscillations of different frequencies, durations and amplitudes are hypothesized to coordinate information processing and transfer across brain areas. Among these oscillations, hippocampal sharp wave-ripple complexes (SPW-Rs) are one of the most prominent. SPW-Rs occurring in the hippocampus are suggested to play essential roles in memory consolidation as well as information transfer to the neocortex. To-date, most of the knowledge about SPW-Rs comes from experimental studies averaging responses from neuronal populations monitored by conventional microelectrodes. In this work, we investigate spatiotemporal characteristics of SPW-Rs and how microelectrode size and distance influence SPW-R recordings using a biophysical model of hippocampus. We also explore contributions from neuronal spikes and synaptic potentials to SPW-Rs based on two different types of network activity. Our study suggests that neuronal spikes from pyramidal cells contribute significantly to ripples while high amplitude sharp waves mainly arise from synaptic activity. Our simulations on spatial reach of SPW-Rs show that the amplitudes of sharp waves and ripples exhibit a steep decrease with distance from the network and this effect is more prominent for smaller area electrodes. Furthermore, the amplitude of the signal decreases strongly with increasing electrode surface area as a result of averaging. The relative decrease is more pronounced when the recording electrode is closer to the source of the activity. Through simulations of field potentials across a high-density microelectrode array, we demonstrate the importance of finding the ideal spatial resolution for capturing SPW-Rs with great sensitivity. Our work provides insights on contributions from spikes and synaptic potentials to SPW-Rs and describes the effect of measurement configuration on LFPs to guide experimental studies towards improved SPW-R recordings.


A feasibility study evaluating rhBMP-2/absorbable collagen sponge device for local alveolar ridge preservation or augmentation.
This two-center human clinical trial evaluated recombinant human bone morphogenetic protein-2 delivered in an absorbable collagen sponge (rhBMP-2/ACS) for either alveolar ridge preservation after tooth extraction or augmentation of localized osseous defects. This 24-month study comprised two parts: a 4-month acute safety and bone induction period (Part I) followed by a 20-month, osseointegration, functional restoration, and long-term safety evaluation (Part II). The primary objective of Part I, discussed in this article, was to evaluate the short-term safety and technical feasibility of the rhBMP-2 device implantation. Twelve patients (six preservation and six augmentation) were enrolled in the investigation. Patient safety was monitored by oral examinations, radiographs, and the collection of blood samples to measure serum chemistries, hematology, and potential antibody formation. Technical feasibility was evaluated by collecting information relating to the handling properties of the rhBMP-2/ACS device. The ability of various evaluative tools to measure the bone-inducing activity of the rhBMP-2/ACS device was also assessed. The clinical results suggested that rhBMP-2/ACS was well tolerated locally and systemically, with no serious adverse events. The device was found to be easily handled and adapted to the ridge and extraction socket. Using direct measurements, all sites demonstrated firmness and fullness to palpation at 4 weeks; however, a loss of volume was noted in some treatment areas between 4 and 8 weeks. Augmentation of the alveolar ridge was not observed in the patients as assessed by the evaluation techniques. This trial indicated that the use of rhBMP-2/ACS to preserve alveolar ridge after tooth extraction or augmentation of localized defects is safe and feasible. Bone fill was observed in all alveolar sockets filled with the rhBMP-2 device.


WHO guidance grounded in a comprehensive approach to sexual and reproductive health and human rights: topical pre-exposure prophylaxis.
Two new microbicide products based on topical (vaginal) application of antiretroviral drugs - 1% tenofovir gel and the dapivirine ring - are currently in late-stage clinical testing, and results on their safety and effectiveness are expected to become available in early 2015. WHO guidelines on the use of topical pre-exposure prophylaxis (topical PrEP) are important in order to ensure that these new prevention products are optimally used. Given that these new topical PrEP products are designed to be woman initiated and will likely be delivered in reproductive health settings, it is important to ensure that the guidance be framed in the context of comprehensive sexual and reproductive health and human rights. In addition to the safety and effectiveness data resulting from clinical trials, and the regulatory approval required for new products, the WHO normative guidelines on the use of topical PrEP will be essential for rapid roll-out in countries. Human rights standards and principles provide a framework for the provision of woman-initiated HIV prevention products. These include addressing issues related to the gender inequities which are linked to the provision of HIV-prevention, treatment and care for young girls and women. Effective programming for women and girls must therefore be based on understanding the local, social and community contexts of the AIDS epidemic in the country, and adapting HIV strategies and programmes accordingly. Such a framework therefore is needed not only to ensure optimal uptake of these new products by women and girls but also to address sociocultural barriers to women's and girls' access to these products.


Detecting overlapped functional clusters in resting state fMRI with Connected Iterative Scan: a graph theory based clustering algorithm.
The brain is a complex neural network with interleaving functional connectivity among anatomical regions. However, current functional parcellation algorithms usually emphasize independence or orthogonality between the spatial components, with the interleaving nature underrepresented. This study investigates a method, Connected Iterative Scan (CIS), for identifying functionally overlapped anatomical groups with resting state fMRI. CIS iteratively optimizes a grouping of vertexes in a weighted graph, using a density metric computed based on the input and output weights of a candidate cluster. In this study, CIS is able to detect the overlapped clusters in a simulated dataset. CIS also detects that the default mode network and the task positive network, which were known as two anti-correlated networks, are overlapped at the posterior cingulate cortex and the lateral parietal cortex. CIS also detects the conventional functional clusters in the whole brain neural network (e.g., the visual cluster, the motor cluster, the frontal cluster, etc.), as well as meaningful overlaps, and also revealed the possible existence of an emotional memory functional cluster. CIS was able to identify several hub regions actively participating in many clusters. With the ability to reveal overlapping functional clusters, CIS is potentially useful in revealing the delicate architecture of the brain neural network.


Mammalian spinal biomechanics. I. Static and dynamic mechanical properties of intact intervertebral joints.
Four-point bending was used to apply pure extension and flexion moments to the ligamentous lumbosacral spine and pelvic girdle of monkey (Macaca fascicularis), rabbit (domestic and wild, Oryctolagus cuniculus), badger (Meles meles), wallaby (Wallabia rufogrisea frutica), sheep (Ovis aries), seal (Phoca vitulina) and tiger (Panthera tigris). The absolute ranges of angular change in lumbar-lumbar joints (from X-radiographs) were considerable and similar in monkey and wallaby (greater in flexion) and in rabbit and badger (symmetrical in extension and flexion). Mass-specific bending comparisons showed that monkey and seal joints were the most and least resistant, respectively, to these moments. The patterns of mobility showed no clear scaling effects. Subsequently, additional ligamentous joint complexes (three vertebrae and two intervertebral discs) of monkey, wallaby, tiger, jaguar (Panthera onca) and seal (Halichoerus grypus) were subjected to cyclic extension and flexion moments. Changes in intervertebral angle (y, from X-radiographs) were modelled as functions of applied specific bending moments (x):y=A(1-e-Bx). A and B values represented bending capacities and joint compliances respectively. Homologous monkey and wallaby joints had considerable flexion capacities, with low compliances. Homologous jaguar and tiger joints had limited flexion capacities, but greater compliances. The data suggest that flexion resistance may be controlled by different mechanisms in different species.


Agreement Between the Mini-Cog in the Preoperative Clinic and on the Day of Surgery and Association With Postanesthesia Care Unit Delirium: A Cohort Study of Cognitive Screening in Older Adults.
Cognitive impairment is common in older surgical patients and is associated with postoperative delirium. However, cognitive function is inconsistently assessed preoperatively, leading to missed opportunities to recognize vulnerable patients. We designed a prospective cohort study to assess the agreement of the Mini-Cog screening tool administered in the preoperative clinic (clinic-day test) or immediately before surgery (surgery-day test) and to determine whether a positive screening for cognitive dysfunction in the surgery-day test is associated with postoperative delirium in the postanesthesia care unit (PACU). This was a cohort study of patients aged 65-89 years, scheduled for elective, inpatient surgery under general anesthesia between June 20, 2018 and August 3, 2018. Mini-Cog test scores were obtained during a clinic-day test and surgery-day test. The Short Confusion Assessment Method was performed in the PACU. Agreement between Mini-Cog clinic-day and surgery-day test scores was estimated using an ordinally weighted kappa statistic, κ. Multivariable logistic regression was used to determine whether there was an association between a positive screen for cognitive impairment and PACU delirium. Odds ratio analysis was performed to determine whether the Mini-Cog score was associated with PACU delirium. Of 128 patients meeting eligibility criteria, 80 patients were enrolled. Ten had cognitive impairment based on the Mini-Cog clinic-day test score, while 70 did not. Age, sex, race, education level, subjective memory impairment, and American Society of Anesthesiologists (ASA) physical status were equivalent in the 2 groups. The mean number of days between the clinic-day score and the surgery-day score was 8.4 days (standard deviation [SD] = 6.9). Mini-Cog clinic-day and surgery-day scores had high agreement (κ = 0.78; 95% confidence interval [CI], 0.69-0.87; P < .001), and both scores were highly predictive of PACU delirium. Patients with Mini-Cog surgery-day scores compatible with cognitive impairment (Mini-Cog scores ≤2) had an estimated 12.8 times higher odds of PACU delirium compared to patients with normal cognitive function or Mini-Cog scores >2 (odds ratio [OR] = 12.8; 95% CI, 2.6-63.8, P = .002). Similarly, patients with Mini-Cog clinic-day test scores compatible with cognitive impairment had an estimated 29 times higher odds of PACU delirium compared to patients with normal cognitive function (OR = 29.0; 95% CI, 2.6-63.8, P < .001). These data support the approach of using the Mini-Cog on the day of surgery to screen for cognitive impairment in older patients. Importantly, Mini-Cog surgery-day test scores compatible with cognitive impairment (≤2) were strongly associated with PACU delirium.


Molecular testing for lipomatous tumors: critical analysis and test recommendations based on the analysis of 405 extremity-based tumors.
Ancillary molecular testing has been advocated for diagnostic accuracy in the differentiation of lipomas from atypical lipomatous tumors/well-differentiated liposarcomas (ALT/WDL); however, the implications and specific indications for use are not well-established in the current literature. Herein, we extend previous findings by quantitatively evaluating the impact of molecular testing of lipomatous neoplasms in our routine clinical practice, how it modifies the historical perspective of their clinical course, and the effect of distinct surgical procedures in modulating the risk of local recurrence for these tumors after molecular classification. On the basis of these analyses, we suggest a specific set of basic recommendations for complementary molecular assessment in the diagnosis of lipomatous tumors. Four hundred and five lipomatous neoplasms located in the trunk and extremities were analyzed histologically and for the presence of 12q13-15 amplification on paraffin-embedded tissues by assessing MDM2/CPM amplification. Survival analyses were calculated with Kaplan-Meier and compared with the log-rank. Multivariate analysis was evaluated by the Cox regression method. The 405 tumors were histologically classified as ordinary lipoma (n=324), intramuscular lipoma (n=29), and ALT/WDL (n=52). The level of agreement between the histologic diagnosis and the molecular diagnosis was high (96%) but pathologists showed a tendency to overestimate cytologic atypia and the diagnosis of ALT/WDL (precision, 79%; accuracy, 88%). Molecular assessment led to a major diagnostic reclassification in 18 tumors (4%). Eleven of the tumors histologically classified as ALT/WDL were reclassified as ordinary lipoma (n=5) and intramuscular lipoma (n=6); none of which recurred. Seven ordinary lipomas were reclassified as ALT/WDL, 6 of which were larger than 15 cm and deeply located; 2 recurred locally. After molecular data, the 5-year local recurrence rates for ordinary lipoma, intramuscular lipoma, and ALT/WDL were 1%, 12%, and 44%, respectively. Multivariate analyses after molecular assessment showed tumor type and type of resection to be associated with the risk of local recurrence. Complementary molecular testing refines the histologic classification of lipomatous tumors and better estimates the impact of surgical procedures on the risk of local recurrence. Pathologists tend to overestimate the degree of cytologic atypia and the indiscriminate use of molecular testing should be avoided, especially for extremity-based tumors. Molecular testing should be considered for "relapsing lipomas," tumors with questionable cytologic atypia (even if widely excised), or for large lipomatous tumors (>15 cm) without diagnostic cytologic atypia.


Drug development in solid tumors: personal perspective of Dr. Emil J Freireich's contributions.
The development of chemotherapy for patients with the major cancers progressed from the initial success attained in the treatment of acute leukemias and choriocarcinoma. Many of the principles of therapy were based on the concepts developed in the experimental laboratories and early clinical studies done at the NIH Clinical Center and other centers around the country. The purpose of this review is to describe some of the early advances in cancer therapy and show how many are based on the efforts of Dr. Emil J Freireich. Over his career, Dr. Freireich has published more than 500 papers and worked on more than 70 different drugs and combinations. The principles defined by Dr. Freireich, namely, the use of intermittent intensive chemotherapy to induce complete remissions (CRs), intensification of therapy in remission, and the use of unmaintained remissions to assess cure, have been important in developing curative chemotherapy programs in patients with acute leukemias. These same principles were applied to combination therapy of Hodgkin's disease as the nitrogen mustard, vincristine, procarbazine, and prednisone combination was developed. This led to the high CR and cure rate for this disease. The treatment of metastatic breast cancer does not produce a high proportion of CRs, and cures of metastatic disease are unlikely with chemotherapy alone. But adjuvant chemotherapy after surgery has resulted in a significant reduction in cancer mortality. Many challenges remain in increasing the cure rate for the major solid tumors. New avenues of controlling cell growth and metastases need to be explored. One approach that is exploitable is the use of drugs or nutrients to prevent cancer. Laboratory approaches are now becoming a clinical reality.


Smooth muscle NOS, colocalized with caveolin-1, modulates contraction in mouse small intestine.
Neuronal nitric oxide synthase (nNOS) in myenteric neurons is activated during peristalsis to produce nitric oxide which relaxes intestinal smooth muscle. A putative nNOS is also found in the membrane of intestinal smooth muscle cells in mouse and dog. In this study we studied the possible functions of this nNOS expressed in mouse small intestinal smooth muscle colocalized with caveolin-1(Cav-1). Cav-1 knockout mice lacked nNOS in smooth muscle and provided control tissues. 60 mM KCl was used to increase intracellular [Ca(2+)] through L-type Ca(2+) channel opening and stimulate smooth muscle NOS activity in intestinal tissue segments. An additional contractile response to LNNA (100 microM, NOS inhibitor) was observed in KCl-contracted tissues from control mice and was almost absent in tissues from Cav-1 knockout mice. Disruption of caveolae with 40 mM methyl-beta cyclodextrin in tissues from control mice led to the loss of Cav-1 and nNOS immunoreactivity from smooth muscle as shown by immunohistochemistry and a reduction in the response of these tissues to N-omega-nitro-L-arginine (LNNA). Reconstitution of membrane cholesterol using water soluble cholesterol in the depleted segments restored the immunoreactivity and the response to LNNA added after KCl. Nicardipine (1 microM) blocked the responses to KCl and LNNA confirming the role of L-type Ca(2+) channels. ODQ (1 microM, soluble guanylate cyclase inhibitor) had the same effect as inhibition of NOS following KCl. We conclude that the activation of nNOS, localized in smooth muscle caveolae, by calcium entering through L-type calcium channels triggers nitric oxide production which modulates muscle contraction by a cGMP-dependent mechanism.


The Sparse Laplacian Shrinkage Estimator for High-Dimensional Regression.
We propose a new penalized method for variable selection and estimation that explicitly incorporates the correlation patterns among predictors. This method is based on a combination of the minimax concave penalty and Laplacian quadratic associated with a graph as the penalty function. We call it the sparse Laplacian shrinkage (SLS) method. The SLS uses the minimax concave penalty for encouraging sparsity and Laplacian quadratic penalty for promoting smoothness among coefficients associated with the correlated predictors. The SLS has a generalized grouping property with respect to the graph represented by the Laplacian quadratic. We show that the SLS possesses an oracle property in the sense that it is selection consistent and equal to the oracle Laplacian shrinkage estimator with high probability. This result holds in sparse, high-dimensional settings with p ≫ n under reasonable conditions. We derive a coordinate descent algorithm for computing the SLS estimates. Simulation studies are conducted to evaluate the performance of the SLS method and a real data example is used to illustrate its application.


Troponin Testing and Coronary Syndrome in Geriatric Patients With Nonspecific Complaints: Are We Overtesting?
Elderly patients presenting to the emergency department (ED) with nonspecific complaints (NSCs) often undergo troponin testing to assess for atypical acute coronary syndrome (ACS). However, the rate of ACS and utility of troponin testing in this population is unknown. We sought to determine the rate of ACS and diagnostic yield of troponin testing in elderly patients with NSCs. We retrospectively identified all patients aged ≥ 65 years triaged in the ED with NSCs from January 1, 2017, to June 30, 2017. NSCs were defined a priori and included complaints such as weakness, dizziness, or fatigue. NSCs were verified in ED provider notes by trained abstractors blind to testing results. Exclusions were focal chief complaint in provider notes, fever, and no troponin ordered. ACS was strictly defined and independently adjudicated by two trained physician researchers blind to the study hypothesis. We calculated the proportion of patients with ACS within 30 days and the test characteristics of troponin to diagnose ACS. Screening identified 1,146 encounters, and 552 were excluded for fever or focal chief complaints in the provider notes. Of the remaining 594 patients, troponin was ordered in 412 (69%), comprising the study cohort. The mean (±SD) age was 78.7 (±8.3) years, with 58% female and 75% admitted. Troponin elevation occurred in 81 patients (20%). ACS occurred in 5 of 412 (1.2%). Troponin was 100% sensitive (95% confidence interval [CI] = 48% to 100%) and 81% specific (95% CI = 77% to 85%) for ACS. Of patients with elevated troponin, 93.8% were false positives (no ACS). All patients with troponin elevation were admitted, but only one underwent angiography and no patients received reperfusion therapy. While consideration for ACS is prudent in selected elderly patients with NSCs, ACS was rare and no patients received reperfusion therapy. Given the false-positive rate in our study, our results may not support routine troponin testing for ACS in this population.


Handwriting Without Tears(®): General Education Effectiveness Through a Consultative Approach.
This study explores the effectiveness of the Handwriting Without Tears(®) (HWT) kindergarten printing curriculum in general education through a consultative approach with occupational therapy. One cohort of students was the control (n = 19), whereas two other cohorts were experimental groups learning printing through the HWT curriculum (n = 20 each). The Test of Handwriting Skills-Revised (THS-R) was used to collect end-of-year legibility scores for all cohorts. Both experimental groups individually and both experimental groups combined into one group outperformed the control group on all 10 of the THS-R subtests-scoring significantly higher (p < .05 using analysis of covariance controlling for age and gender) on 6 of the subtests for the former and 7 for the latter-and on overall score. Large treatment effects were found for the standard score for each experimental group (d = 0.81, 1.03, and 1.00). This study supports the consultative role of occupational therapy with teachers in general education for handwriting curriculum implementation and the success of HWT for printing instruction.


Stigma and substance use disorders: an international phenomenon.
To collect and update published information on the stigma associated with substance abuse in nonclinical samples, which has not been recently reviewed. Searching large databases, a total of only 17 articles were published since 1999, with the majority of studies conducted outside the United States. Using major stigma concepts from a sociological framework (stereotyping, devaluation in terms of status loss, discrimination, and negative emotional reactions), the studies reviewed predominantly indicated that the public holds very stigmatized views toward individuals with substance use disorders (SUDs), and that the level of stigma was higher toward individuals with SUDs than toward those with other psychiatric disorders. The prevalence of SUDs is increasing in the US general population, but these disorders remain seriously undertreated. Stigma can reduce willingness of policymakers to allocate resources, reduce willingness of providers in nonspecialty settings to screen for and address substance abuse problems, and may limit willingness of individuals with such problems to seek treatment. All of these factors may help explain why so few individuals with SUDs receive treatment. Public education that reduces stigma and provides information about treatment is needed.


HIV-1, HSV-2 and syphilis among pregnant women in a rural area of Tanzania: prevalence and risk factors.
Evidence suggests that a substantial proportion of new HIV infections in African countries are associated with herpes simplex virus type 2 (HSV-2). Thus, the magnitude of HSV-2 infection in an area may suggest the expected course of the HIV epidemic. We determined prevalence of genital herpes, syphilis and associated factors among pregnant women from a remote rural Tanzanian community that has a low but increasing HIV prevalence. We analysed 1296 sera and responses to a standard structured questionnaire collected from pregnant women aged between 15-49 years, attending six different antenatal clinics within rural Manyara and Singida regions in Tanzania. Linked anonymous testing (with informed consent) of the serum for specific antibodies against HSV-2 was done using a non-commercial peptide- 55 ELISA. Antibodies against syphilis were screened by using rapid plasma reagin (RPR) and reactive samples confirmed by Treponema pallidum haemagglutination assay (TPHA). Previous analysis of the collected sera had shown the prevalence of HIV antibodies to be 2%. In the present study the prevalence of genital herpes and syphilis was 20.7% (95% CI: 18.53-23.00) and 1.6% (95% CI: 1.03-2.51), respectively. The presence of HSV-2 antibodies was associated with polygamy (OR 2.2, 95% CI: 1.62 - 3.01) and the use of contraceptives other than condoms (OR 1.7, 95% CI: 1.21 - 2.41). Syphilis was associated with reporting more than one lifetime sexual partner (OR 5.4, 95% CI: 1.88 - 15.76) and previous spontaneous abortion (OR 4.3, 95% CI: 1.52-12.02). The low prevalence of HIV infection offers a unique opportunity for strengthening HIV prevention in a cost-effective manner. The identification and control of other prevalent curable STIs other than syphilis and specific intervention of HSV-2 in specific populations like pregnant women would be one among approaches towards preventing incident HIV infections.


Cholesterol crystals enhance TLR2- and TLR4-mediated pro-inflammatory cytokine responses of monocytes to the proatherogenic oral bacterium Porphyromonas gingivalis.
Cholesterol deposits and pro-inflammatory cytokines play an essential role in the pathogenesis of atherosclerosis, a predominant cause of cardiovascular disease (CVD). Epidemiological evidence has linked periodontal disease (PD) with atherosclerotic CVD. Accordingly, viable periodontal pathogens, including Porphyromonas gingivalis, have been found in atherosclerotic plaques in humans and mice. We aimed to determine whether cholesterol crystals (CHCs) and oral bacteria synergize in the stimulation of human monocytes. Incubation of human monocytes with CHCs induced secretion of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, and IL-8. Moreover, CHCs markedly enhanced secretion of IL-1β by monocytes stimulated with the toll-like receptor (TLR) 4 agonist Escherichia coli lipopolysaccharide (LPS), and the TLR2 agonist Staphylococcus aureus lipoteichoic acid. Notably, CHCs also enhanced IL-1β secretion induced by P. gingivalis LPS and IL-1β secretion induced by whole P. gingivalis bacteria. This enhancement was abrogated by the NLRP3 inflammasome inhibitors Z-YVAD-FMK and glibenclamide. CHCs had no effect on cytokine production induced by P. gingivalis gingipains. Taken together, our findings support that CHCs, via stimulation of NLRP3 inflammasomes, act in synergy with the periodontal pathogen P. gingivalis to promote monocyte secretion of pro-atherogenic cytokines.


PICK1 is required for the control of synaptic transmission by the metabotropic glutamate receptor 7.
Both postsynaptic density and presynaptic active zone are structural matrix containing scaffolding proteins that are involved in the organization of the synapse. Little is known about the functional role of these proteins in the signaling of presynaptic receptors. Here we show that the interaction of the presynaptic metabotropic glutamate (mGlu) receptor subtype, mGlu7a, with the postsynaptic density-95 disc-large zona occludens 1 (PDZ) domain-containing protein, PICK1, is required for specific inhibition of P/Q-type Ca(2+) channels, in cultured cerebellar granule neurons. Furthermore, we show that activation of the presynaptic mGlu7a receptor inhibits synaptic transmission and this effect also requires the presence of PICK1. These results indicate that the scaffolding protein, PICK1, plays an essential role in the control of synaptic transmission by the mGlu7a receptor complex.


Breast cancer genetic testing: more than a medical management tool.
Knowing whether a harmful hereditary mutation exists in BRCA1 and BRCA2 can enable women to make informed decisions regarding surveillance and surgery options to manage risk. Given the attention in the media about BRCA genetic testing, nurses need to revisit how this knowledge may affect a woman's sense of self and the forces that may influence this decision. This article aims to understand how complex the decision to undergo genetic testing may be for some women by exploring the impact of genetic knowledge on the self, changes to customary definitions for health and illness, and ethical issues and social forces that may influence genetic testing decisions. A review of the literature was undertaken to understand how genetic knowledge may alter meanings attached to the breast and how health is defined, and to identify ethical concerns and social forces that may affect a woman's decision to undergo or decline an offer for genetic testing. An understanding and awareness of the potential benefits and harms of BRCA1 and BRCA2 genetic testing, as well as the social forces that may influence a woman's decision to undergo or decline an offer for genetic testing and the commitment to remain open to the uniqueness of each woman's situation, may enhance the nurse-patient relationship and result in a decision that is ethically in the best interest of the patient.


Characterization and Differentiation of Stem Cells Isolated from Human Newborn Foreskin Tissue.
Circumcision is described as a cultural, medical, and religious process which states surgical removal of the foreskin either partly or fully. Cells isolated from the circumcised tissues are referred as foreskin cells. They have been thought as feeder cell lines for embryonic stem cells. Their fibroblastic properties were also utilized for several experiments. The waste tissues that remain after the circumcision thought to have stem cell properties. Therefore, there have been very few attempts to expose their stem cell properties without turning them into induced pluripotent stem cells. Although stem cell isolation from prepuce and their mesenchymal multilineage differentiation potential have been presented many times in the literature, the current study explored hematopoietical phenotype of newborn foreskin stem cells for the first time. According to the results, human newborn foreskin stem cells (hnFSSCs) were identified by their capability to turn into all three germ layer cell types under in vitro conditions. In addition, these cells have exhibited a stable phenotype and have remained as a monolayer in vitro. hnFSSCs suggested to carry different treatment potentials for bone damages, cartilage problems, nerve damages, lesion formations, and other diseases that are derive from mesodermal, endodermal, and ectodermal origins. Owing to the location of the tissue in the body and differentiation capabilities of hnFSSCs, these cells can be considered as easily obtainable and utilizable even better than the other stem cell sources. In addition, hnFSSCs offers a great potential for tissue engineering approaches due to exhibiting embryonic stem cell-like characteristics, not having any ethical issues, and teratoma induction as in embryonic stem cell applications.


Vascular relaxation of canine visceral arteries after ischemia by means of supraceliac aortic cross-clamping followed by reperfusion.
The supraceliac aortic cross-clamping can be an option to save patients with hipovolemic shock due to abdominal trauma. However, this maneuver is associated with ischemia/reperfusion (I/R) injury strongly related to oxidative stress and reduction of nitric oxide bioavailability. Moreover, several studies demonstrated impairment in relaxation after I/R, but the time course of I/R necessary to induce vascular dysfunction is still controversial. We investigated whether 60 minutes of ischemia followed by 30 minutes of reperfusion do not change the relaxation of visceral arteries nor the plasma and renal levels of malondialdehyde (MDA) and nitrite plus nitrate (NOx). Male mongrel dogs (n = 27) were randomly allocated in one of the three groups: sham (no clamping, n = 9), ischemia (supraceliac aortic cross-clamping for 60 minutes, n = 9), and I/R (60 minutes of ischemia followed by reperfusion for 30 minutes, n = 9). Relaxation of visceral arteries (celiac trunk, renal and superior mesenteric arteries) was studied in organ chambers. MDA and NOx concentrations were determined using a commercially available kit and an ozone-based chemiluminescence assay, respectively. Both acetylcholine and calcium ionophore caused relaxation in endothelium-intact rings and no statistical differences were observed among the three groups. Sodium nitroprusside promoted relaxation in endothelium-denuded rings, and there were no inter-group statistical differences. Both plasma and renal concentrations of MDA and NOx showed no significant difference among the groups. Supraceliac aortic cross-clamping for 60 minutes alone and followed by 30 minutes of reperfusion did not impair relaxation of canine visceral arteries nor evoke biochemical alterations in plasma or renal tissue.


Reducing Anxiety and Stress among Youth in a CBT-Based Equine-Assisted Adaptive Riding Program.
Reining in Anxiety (RiA) is a therapeutic program for youth with mild to moderate anxiety delivered in a therapeutic riding setting by Certified Therapeutic Riding Instructors. RiA was developed after a review of the evidence base for youth anxiety, is manualized, and includes five core CBT components: in vivo exposure, cognitive restructuring, youth psychoeducation, relaxation, and caregiver psychoeducation about anxiety. This study extended findings from a prior RCT that examined (1) the feasibility of collecting saliva samples from horses and children to measure stress (cortisol) and relaxation (oxytocin); (2) whether changes in stress and relaxation occurred both during each lesson and over the course of the 10-week intervention for horses and youth; (3) whether changes in anxiety symptoms, emotional regulation, and self-efficacy found in the first trial were comparable; and (4) if fidelity to the program was reliable. Youth participants (n = 39) ages 6-17 with caregiver-identified mild-to-moderate anxiety participated in a ten-week therapeutic intervention (RiA), which combined adaptive riding and components of CBT. Physiological data and self-report measures were taken at weeks one, four, seven, and ten for the youth and horses. Saliva assays assessed cortisol as a physiological marker of stress and anxiety, and oxytocin as a measure of relaxation. Fidelity data were recorded per session. Anxiety, as measured by caregiver self-reporting, significantly decreased from pre- to post-test, while emotional regulation scores increased. No significant changes in self-efficacy from pre- to post-test were observed. Saliva samples obtained from participants before and after riding sessions showed a consistent decrease in cortisol and a significant increase in oxytocin at two of the four timepoints (Week 1 and Week 7), but no overall pre- to post-test changes. Horse saliva data were collected using a modified bit; there were no significant changes in oxytocin or cortisol, suggesting that the horses did not have an increase in stress from the intervention. RiA may be a promising approach for reducing anxiety and stress among youth, as measured both by self-reported and by physiological measures. Collection of salivary assays for both youth and horses is feasible, and the intervention does not increase stress in the horses. Importantly, RiA can be delivered by adaptive/therapeutic horseback riding instructors in naturalistic (e.g., non-clinic-based) settings. As youth anxiety is a growing public health problem, novel interventions, such as RiA, that can be delivered naturalistically may have the potential to reach more youth and thus improve their quality of life. Further research is needed to examine the comparative value of RiA with other animal-assisted interventions and to assess its cost-effectiveness.


Hiding responses of locusts to approaching objects
Locusts, Locusta migratoria, sitting on a plant stem hide from dark moving or expanding shapes in their environment. The fore- and middle legs perform this avoidance response by making lateral tilting movements, while the hindlegs slide laterally and guide rotation of the posterior body over the stem. During larger turns, the legs take lateral steps when lateral tilting is limited by the joints. Slow hiding movements of less than 300 degrees s-1 of angular velocity are induced by slowly changing (looming) shapes, and interposed stops or slowing of the movement can delay the progress of this hiding manoeuvre. Fast hiding movements with angular velocities between 120 degrees s-1 and 860 degrees s-1 proceed continuously and rapidly in response to rapidly expanding stimuli. Hiding responses to expanding shapes occur only after the expanding image has exceeded a threshold visual angle of 8-9.5 degrees. Hiding response latencies range between 220 ms and 1.2 s for fast hiding and are approximately 1.2 s for most slow hiding responses. Predator-avoidance responses such as freezing, jerking, crouching, walking backwards, dropping or jumping can be used instead of or in conjunction with hiding behaviour. We conclude that the fast hiding behaviour of locusts is a specific goal-directed type of optomotor behaviour requiring positional information from small-field detectors of shape expansion in the interneurone layers of the locust eye.


Responsiveness of the Oswestry Disability Index and the Roland Morris Disability Questionnaire in Italian subjects with sub-acute and chronic low back pain.
An ability to assess longitudinal changes in health status is crucial for the outcome measures used in treatment efficacy trials. The aim of this study was to verify the responsiveness of the Italian versions of the Oswestry Disability Index (ODI) and the Roland Morris Disability Questionnaire (RMDQ) in subjects with subacute or chronic low back pain (LBP). At the beginning and end of an 8 week rehabilitation programme, 179 patients completed a booklet containing the ODI, the RMDQ, a 0-10 numerical rating scale (NRS), and the 36-item Short-Form Health Survey (SF-36). A global perception of change scale was also completed at the end of the programme, and collapsed to produce a dichotomous outcome (i.e. improved vs. not improved). Responsiveness was assessed by means of distribution methods [minimum detectable change (MDC); effect size (ES); standardised response mean (SRM)] and anchor-based methods (ROC curves). The MDC for the ODI and RMDQ was, respectively, 13.67 and 4.87; the ES was 0.53 and 0.68; and the SRM was 0.80 and 0.81. ROC analysis revealed an area under the curve of 0.71 for the ODI and 0.64 for the RMDQ, thus indicating discriminating capacity; the best cut-off point for the dichotomous outcome was 9.5 for the ODI (sensitivity 76% and specificity 63%) and 2.5 for the RMDQ (sensitivity 62% and specificity 55%). These estimates were comparable between the subacute and chronic subjects. Both the ODI and the RMDQ moderately correlated with the SF-36 and NRS (Spearman's and Pearson's correlation coefficients of >0.30). The Italian ODI and RMDQ proved to be sensitive in detecting clinical changes after conservative treatment for subacute and chronic LBP. Our findings are consistent with those published in the literature, thus allowing cross-cultural comparisons and stimulating cross-national studies.


The Handover Toolbox: a knowledge exchange and training platform for improving patient care.
Safe and effective patient handovers remain a global organisational and training challenge. Limited evidence supports available handover training programmes. Customisable training is a promising approach to improve the quality and sustainability of handover training and outcomes. We present a Handover Toolbox designed in the context of the European HANDOVER Project. The Toolbox aims to support physicians, nurses, individuals in health professions training, medical educators and handover experts by providing customised handover training tools for different clinical needs and contexts. The Handover Toolbox uses the Technology Enhanced Learning Design Process (TEL-DP), which encompasses user requirements analysis; writing personas; group concept mapping; analysis of suitable software; plus, minus, interesting rating; and usability testing. TEL-DP is aligned with participatory design approaches and ensures development occurs in close collaboration with, and engagement of, key stakeholders. Application of TEL-DP confirmed that the ideal formats of handover training differs for practicing professionals versus individuals in health profession education programmes. Training experts from different countries differed in their views on the optimal content and delivery of training. Analysis of suitable software identified ready-to-use systems that provide required functionalities and can be further customised to users' needs. Interest rating and usability testing resulted in improved usability, navigation and uptake of the Handover Toolbox. The design of the Handover Toolbox was based on a carefully led stakeholder participatory design using the TEL-DP approach. The Toolbox supports a customisable learning approach that allows trainers to design training that addresses the specific information needs of the various target groups. We offer recommendations regarding the application of the Handover Toolbox to medical educators.


Cannabinoids: a new hope for breast cancer therapy?
Breast cancer is a very common disease that affects approximately 1 in 10 women at some point in their lives. Importantly, breast cancer cannot be considered a single disease as it is characterized by distinct pathological and molecular subtypes that are treated with different therapies and have diverse clinical outcomes. Although some highly successful treatments have been developed, certain breast tumors are resistant to conventional therapies and a considerable number of them relapse. Therefore, new strategies are urgently needed, and the challenge for the future will most likely be the development of individualized therapies that specifically target each patient's tumor. Experimental evidence accumulated during the last decade supports that cannabinoids, the active components of Cannabis sativa and their derivatives, possess anticancer activity. Thus, these compounds exert anti-proliferative, pro-apoptotic, anti-migratory and anti-invasive actions in a wide spectrum of cancer cells in culture. Moreover, tumor growth, angiogenesis and metastasis are hampered by cannabinoids in xenograft-based and genetically-engineered mouse models of cancer. This review summarizes our current knowledge on the anti-tumor potential of cannabinoids in breast cancer, which suggests that cannabinoid-based medicines may be useful for the treatment of most breast tumor subtypes.


Descriptive epidemiology of Paralympic sports injuries.
Paralympic sports have seen an exponential increase in participation since 16 patients took part in the first Stoke Mandeville Games on the opening day of the 1948 London Olympic Games. More than 4,000 athletes took part in the London 2012 Paralympic Games. Few sporting events have seen such rapid evolution. This rapid pace of change also has meant challenges for understanding the injury risks of participation, not only because of the variety of sports, impairment types, the evolution of adapted equipment but also because of the inclusion of additional impairment types and development of new sports over time. Early studies were limited in scope but patterns of injuries are slowly emerging within Winter and Summer Paralympic sports. The IPC's London 2012 study is the largest to date with a prospective cohort study involving 49,910 athlete-days. The results identified large differences across sports and highlighted the need for longitudinal sport specific studies rather than solely games-time studies. This will require collaboration with international sports federations to examine injury patterns and risk factors for injury in this population to appropriately inform injury prevention strategies. Further studies will also need to address the impact of sporting participation, injury, and future health.


Transluminal coronary angioplasty and early restenosis. Fibrocellular occlusion after wall laceration.
Transluminal coronary angioplasty was performed in a 51 year old man with a localised narrowing of the proximal segment of the left anterior descending coronary artery. Initial inflations with a small size balloon catheter were unsuccessful. A second attempt, during the same procedure, using a larger calibre catheter relieved the obstruction but produced a dissection. Angina pectoris reappeared approximately three months later. Another attempt to relieve the obstruction by angioplasty, five months after the initial procedure, induced ST segment elevation before angioplasty, followed by ventricular fibrillation and death. The necropsy showed a split in the pre-existent sclerotic plaque and a dissecting aneurysm of the media. A proliferation of fibrocellular tissue filled the false channel and almost totally occluded the pre-existent arterial lumen. The observation suggests that wall laceration with exposure of smooth muscle cells to blood may have initiated the excessive fibrocellular tissue response. This event may be the underlying pathogenetic mechanism for the occurrence of early restenosis after transluminal coronary angioplasty.


Novel nanoimaging approach: antibodious polymeric nanolabel for intracellular alpha-fetoprotein targeted monitoring.
This study describes preparation and use of novel labeled and antibodious polymeric nanolabels (anti-alpha fetoprotein cross-linked nanolabels) as an immunogenic and semisynthetic nanolabel with potential prognostic and therapeutic roles for hepatoma cancer. Specificity, uptake, and binding efficiencies of the nanolabel have been examined in a human hepatosarcoma cell line HepG2, a human colorectal cell line DLD-1, and a mouse myoblast cell line C2. Labeling of the cells has been performed by treating live and fixed cells with varying concentrations of the nanolabels and then, the cells have been examined under a fluorescence microscope. In addition, all cell lines have also been labeled using FITC-conjugated nanotrastuzumab to compare the results obtained with those of the binding of the FITC-nanoanti-alpha fetoprotein nanolabels. Results show that FITC-conjugated anti-alpha fetoprotein cross-linked nanolabels have been taken up by both live and fixed cells and have efficiently and specifically labeled HepG2 cells at a quite low concentration. Taken all together, the results indicate that the novel targeted nanoimaging tools and technique demonstrated their ability to detect the distribution of the nanolabels as probes in hepatoma cells.


Reconstitution of muscarinic modulation of the KCNQ2/KCNQ3 K(+) channels that underlie the neuronal M current.
Channels from KCNQ2 and KCNQ3 genes have been suggested to underlie the neuronal M-type K(+) current. The M current is modulated by muscarinic agonists via G-proteins and an unidentified diffusible cytoplasmic messenger. Using whole-cell clamp, we studied tsA-201 cells in which cloned KCNQ2/KCNQ3 channels were coexpressed with M(1) muscarinic receptors. Heteromeric KCNQ2/KCNQ3 currents were modulated by the muscarinic agonist oxotremorine-M (oxo-M) in a manner having all of the characteristics of modulation of native M current in sympathetic neurons. Oxo-M also produced obvious intracellular Ca(2+) transients, observed by using indo-1 fluorescence. However, modulation of the current remained strong even when Ca(2+) signals were abolished by the combined use of strong intracellular Ca(2+) buffers, an inhibitor of IP(3) receptors, and thapsigargin to deplete Ca(2+) stores. Muscarinic modulation was not blocked by staurosporine, a broad-spectrum protein kinase inhibitor, arguing against involvement of protein kinases. The modulation was not associated with a shift in the voltage dependence of channel activation. Homomeric KCNQ2 and KCNQ3 channels also expressed well and were modulated individually by oxo-M, suggesting that the motifs for modulation are present on both channel subtypes. Homomeric KCNQ2 and KCNQ3 currents were blocked, respectively, at very low and at high concentrations of tetraethylammonium ion. Finally, when KCNQ2 subunits were overexpressed by intranuclear DNA injection in sympathetic neurons, total M current was fully modulated by the endogenous neuronal muscarinic signaling mechanism. Our data further rule out Ca(2+) as the diffusible messenger. The reconstitution of muscarinic modulation of the M current that uses cloned components should facilitate the elucidation of the muscarinic signaling mechanism.


Tunable plasmonic HfN nanoparticles and arrays.
We present the fabrication of tunable plasmonic hafnium nitride (HfN) nanoparticles. HfN is a metallic refractory material with the potential of supporting plasmon resonances in the visible range, similar to silver and gold, but with the additional benefits of high melting point, chemical stability, and mechanical hardness. However, the preparation of HfN nanoparticles and the experimental demonstration of their plasmonic potential are still in their infancy. Here, high quality HfN thin films were fabricated, for which ellipsometry shows their plasmonic potential. From these thin films, nanorods and nanotriangles were milled using a focused ion beam and the plasmon resonances were identified using cathodoluminescence mapping. As an alternative fabrication strategy, an optimized electron-beam lithography procedure was used to prepare arrays of HfN nanoparticles, which also exhibited clear surface plasmon resonances. These results pave the way to further explore HfN nanoparticles in plasmonically-powered applications where materials robustness is essential.


Biofabrication of human articular cartilage: a path towards the development of a clinical treatment.
Cartilage injuries cause pain and loss of function, and if severe may result in osteoarthritis (OA). 3D bioprinting is now a tangible option for the delivery of bioscaffolds capable of regenerating the deficient cartilage tissue. Our team has developed a handheld device, the Biopen, to allow in situ additive manufacturing during surgery. Given its ability to extrude in a core/shell manner, the Biopen can preserve cell viability during the biofabrication process, and it is currently the only biofabrication tool tested as a surgical instrument in a sheep model using homologous stem cells. As a necessary step toward the development of a clinically relevant protocol, we aimed to demonstrate that our handheld extrusion device can successfully be used for the biofabrication of human cartilage. Therefore, this study is a required step for the development of a surgical treatment in human patients. In this work we specifically used human adipose derived mesenchymal stem cells (hADSCs), harvested from the infra-patellar fat pad of donor patients affected by OA, to also prove that they can be utilized as the source of cells for the future clinical application. With the Biopen, we generated bioscaffolds made of hADSCs laden in gelatin methacrylate, hyaluronic acid methacrylate and cultured in the presence of chondrogenic stimuli for eight weeks in vitro. A comprehensive characterisation including gene and protein expression analyses, immunohistology, confocal microscopy, second harmonic generation, light sheet imaging, atomic force mycroscopy and mechanical unconfined compression demonstrated that our strategy resulted in human hyaline-like cartilage formation. Our in situ biofabrication approach represents an innovation with important implications for customizing cartilage repair in patients with cartilage injuries and OA.


Trauma, comorbidity, and mortality following diagnoses of severe stress and adjustment disorders: a nationwide cohort study.
Longitudinal outcomes following stress or trauma diagnoses are receiving attention, yet population-based studies are few. The aims of the present cohort study were to examine the cumulative incidence of traumatic events and psychiatric diagnoses following diagnoses of severe stress and adjustment disorders categorized using International Classification of Diseases, Tenth Revision, codes and to examine associations of these diagnoses with all-cause mortality and suicide. Data came from a longitudinal cohort of all Danes who received a diagnosis of reaction to severe stress or adjustment disorders (International Classification of Diseases, Tenth Revision, code F43.x) between 1995 and 2011, and they were compared with data from a general-population cohort. Cumulative incidence curves were plotted to examine traumatic experiences and psychiatric diagnoses during the study period. A Cox proportional hazards regression model was used to examine the associations of the disorders with mortality and suicide. Participants with stress diagnoses had a higher incidence of traumatic events and psychiatric diagnoses than did the comparison group. Each disorder was associated with a higher rate of all-cause mortality than that seen in the comparison cohort, and strong associations with suicide were found after adjustment. This study provides a comprehensive assessment of the associations of stress disorders with a variety of outcomes, and we found that stress diagnoses may have long-lasting and potentially severe consequences.


Spinal transection induces widespread proliferation of cells along the length of the spinal cord in a weakly electric fish.
The ability to regenerate spinal cord tissue after tail amputation has been well studied in several species of teleost fish. The present study examined the proliferation and survival of cells following complete spinal cord transection rather than tail amputation in the weakly electric fish Apteronotus leptorhynchus. To quantify cell proliferation along the length of the spinal cord, fish were given a single bromodeoxyuridine (BrdU) injection immediately after spinal transection or sham surgery. Spinal transection significantly increased the density of BrdU⁺ cells along the entire length of the spinal cord at 1 day posttransection (dpt), and most newly generated cells survived up to 14 dpt. To examine longer-term survival of the newly proliferated cells, BrdU was injected for 5 days after the surgery, and fish were sacrificed at 14 or 30 dpt. Spinal transection significantly increased cell proliferation and/or survival, as indicated by an elevated density of BrdU⁺ cells in the spinal cords of spinally transected compared to sham-operated and intact fish. At 14 dpt, BrdU⁺ cells were abundant at all levels of the spinal cord. By 30 dpt, the density of BrdU⁺ cells had decreased at all levels of the spinal cord except at the tip of the tail. Thus, newly generated cells in the caudal-most segment of the spinal cord survived longer than those in more rostral segments. Our findings indicate that spinal cord transection stimulates widespread cellular proliferation; however, there were regional differences in the survival of the newly generated cells.


Attention orienting by gaze and facial expressions across development.
Processing of facial expressions has been shown to potentiate orienting of attention toward the direction signaled by gaze in adults, an important social-cognitive function. However, little is known about how this social attention skill develops. This study is the first to examine the developmental trajectory of the gaze orienting effect (GOE), its modulations by facial expressions, and its links with theory of mind (ToM) abilities. Dynamic emotional stimuli were presented to 222 participants (7-25 years old) with normal trait anxiety using a gaze-cuing paradigm. The GOE was found as early as 7 years of age and decreased linearly until 12-13 years, at which point adult levels were reached. Both fearful and surprised expressions enhanced the GOE compared with neutral expressions. The GOE for fearful faces was also larger than for joyful and angry expressions. These effects did not interact with age and were not driven by intertrial variance. Importantly, the GOE did not correlate with ToM abilities as assessed by the "Reading the Mind in the Eyes" test. The implication of these findings for clinical and typically developing populations is discussed.


Differential effects of malignant mesothelioma cells on THP-1 monocytes and macrophages.
Malignant mesothelioma (MM) is a highly fatal tumor arising from inner body membranes, whose extensive growth is facilitated by its week immunogenicity and by its ability to blunt the immune response which should arise from the huge mass of leukocytes typically infiltrating this tumor. It has been reported that the inflammatory infiltrate found in MM tissues is characterized by a high prevalence of macrophages. Thus, in this work we evaluated the ability of human MM cells to modulate the inflammatory phenotype of human THP-1 monocytes and macrophages, a widely used in vitro model of monocyte/macrophage differentiation. Furthermore, we tested the hypothesis that the exposure to MM cells could alter the differentiation of THP-1 monocytes favoring the development of alternatively activated, tumor-supporting macrophages. Our data prove for the first time that MM cells can polarize monocytes towards an altered inflammatory phenotype and macrophages towards an immunosuppressive phenotype. Moreover, we demonstrate that monocytes cocultivated with MM cells 'keep a memory' of their encounter with the tumor which influences their differentiation to macrophages. On the whole, we provide evidence that MM cells exert distinct, cell-specific effects on monocytes and macrophages. The thorough characterization of such effects may be of a crucial importance for the rational design of new immunotherapeutic protocols.


The effect of diagnostic delays on the drop-out rate and the total delay to diagnosis of tuberculosis.
Numerous patient and healthcare system-related delays contribute to the overall delay experienced by patients from onset of TB symptoms to diagnosis and treatment. Such delays are critical as infected individuals remain untreated in the community, providing more opportunities for transmission of the disease and adversely affecting the epidemic. We present an analysis of the factors that contribute to the overall delay in TB diagnosis and treatment, in a resource-poor setting. Impact on the distribution of diagnostic delay times was assessed for various factors, the sensitivity of the diagnostic method being found to be the most significant. A linear relationship was found between the sensitivity of the test and the predicted mean delay time, with an increase in test sensitivity resulting in a reduced mean delay time and a reduction in the drop-out rate. The results show that in a developing country a number of delay factors, particularly the low sensitivity of the initial sputum smear microscopy test, potentially increase total diagnostic delay times experienced by TB patients significantly. The results reinforce the urgent need for novel diagnostic methods, both for smear positive and negative TB, that are highly sensitive, accessible and point of care, in order to reduce mean delay times.


Host associations and genomic diversity of Borrelia hermsii in an endemic focus of tick-borne relapsing fever in western North America.
An unrecognized focus of tick-borne relapsing fever caused by Borrelia hermsii was identified in 2002 when five people became infected on Wild Horse Island in Flathead Lake, Montana. The terrestrial small mammal community on the island is composed primarily of pine squirrels (Tamiasciurus hudsonicus) and deer mice (Peromyscus maniculatus), neither of which was known as a natural host for the spirochete. Thus a 3-year study was performed to identify small mammals as hosts for B. hermsii. Small mammals were captured alive on two island and three mainland sites, blood samples were collected and examined for spirochetes, and serological tests performed to detect anti-B. hermsii antibodies. Ornithodoros hermsi ticks were collected and fed on laboratory mice to assess infection. Genomic DNA samples from spirochetes isolated from infected mammals and ticks were analyzed by multilocus sequence typing. Eighteen pine squirrels and one deer mouse had detectable spirochetemias when captured, from which 12 isolates of B. hermsii were established. Most pine squirrels were seropositive, and the five species of sciurids combined had a significantly higher prevalence of seropositive animals than did the other six small mammal species captured. The greater diversity of small mammals on the mainland in contrast to the islands demonstrated that other species in addition to pine squirrels were also involved in the maintenance of B. hermsii at Flathead Lake. Ornithodoros hermsi ticks produced an additional 12 isolates of B. hermsii and multilocus sequence typing identified both genomic groups of B. hermsii described previously, and identified a new genomic subdivision. Experimental infections of deer mice with two strains of B. hermsii demonstrated that these animals were susceptible to infection with spirochetes belonging to Genomic Group II but not Genomic Group I. Pine squirrels are the primary hosts for the maintenance of B. hermsii on the islands in Flathead Lake, however serological evidence showed that numerous additional species are also involved on the mainland. Future studies testing the susceptibility of several small mammal species to infection with different genetic types of B. hermsii will help define their role as hosts in this and other endemic foci.


Alternatives to antibiotics-a pipeline portfolio review.
Antibiotics have saved countless lives and enabled the development of modern medicine over the past 70 years. However, it is clear that the success of antibiotics might only have been temporary and we now expect a long-term and perhaps never-ending challenge to find new therapies to combat antibiotic-resistant bacteria. A broader approach to address bacterial infection is needed. In this Review, we discuss alternatives to antibiotics, which we defined as non-compound approaches (products other than classic antibacterial agents) that target bacteria or any approaches that target the host. The most advanced approaches are antibodies, probiotics, and vaccines in phase 2 and phase 3 trials. This first wave of alternatives to antibiotics will probably best serve as adjunctive or preventive therapies, which suggests that conventional antibiotics are still needed. Funding of more than £1·5 billion is needed over 10 years to test and develop these alternatives to antibiotics. Investment needs to be partnered with translational expertise and targeted to support the validation of these approaches in phase 2 trials, which would be a catalyst for active engagement and investment by the pharmaceutical and biotechnology industry. Only a sustained, concerted, and coordinated international effort will provide the solutions needed for the future.


Clever leukemic stem cells branch out.
Individual tumors harbor heterogeneous populations of genetically distinct subclones. Two recent papers in Nature by Notta et al. (2011) and Anderson et al. (2011) reveal genetic heterogeneity in functional leukemic stem cells, which has important implications for how both cancer and normal stem cell populations may adapt to selective pressure.


Transport of stabilized iron nanoparticles in porous media: Effects of surface and solution chemistry and role of adsorption.
Carboxymethyl cellulose (CMC) stabilized zero-valent iron (ZVI) (CMC-ZVI) nanoparticles have been extensively tested for remediation of soil and groundwater. This study investigated effects of iron oxide and aluminum oxide on retention and transport of CMC-ZVI nanoparticles, which have a mean hydrodynamic diameter of 155nm. Column breakthrough experiments showed that the metal oxides coatings on quartz sand greatly enhanced particle retention. A mechanistically sounder transport model was proposed by incorporating a Langmuir-type adsorption rate law into the classic convection-dispersion equation with the adsorption parameters derived from independent experiments. The model allows for a quantitative evaluation of the role of adsorption. While filtration is the primary mechanism for particle retention at lower pore velocities, adsorption becomes more significant at elevated velocities. The presence of 40-80mg-CL-1 of natural organic matter and high ionic strength (up to 200mM CaCl2) had negligible effect on the breakthrough profiles of the nanoparticles. Starch, a neutral polysugar stabilizer, was also tested as a stabilizer. Starch-stabilized ZVI nanoparticles, with a mean hydrodynamic diameter of 303nm, displayed a higher particle retention than CMC-ZVI. The information and modeling approach can facilitate our understanding of fate and transport of stabilized ZVI nanoparticles under various geochemical conditions.


Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis.
There is limited information on test performance for detecting cholangiocarcinoma in primary sclerosing cholangitis (PSC), particularly when used sequentially. This study aimed to characterize diagnostic performance of serum carbohydrate antigen 19-9 (CA 19-9), ultrasonography, computed tomography, magnetic resonance imaging, cholangiography, and biliary cytologic techniques for detecting cholangiocarcinoma in PSC. All consecutive patients with PSC were screened and followed for development of cholangiocarcinoma from 2000 through 2006. Of 230 patients, 23 developed cytopathologically confirmed cholangiocarcinoma with an annual incidence of 1.2%. The optimal cutoff value for serum CA 19-9 was 20 U/mL, which yielded a sensitivity of 78%, specificity of 67%, positive predictive value (PPV) of 23%, and negative predictive value (NPV) of 96%. Serum CA 19-9 combined with either ultrasonography, computed tomography, or magnetic resonance imaging provided a sensitivity of 91%, 100%, and 96%, specificity of 62%, 38%, and 37%, PPV of 23%, 22%, and 24%, and NPV of 98%, 100%, and 98%, respectively, if at least one method was positive. Subsequent cholangiographic examinations in these patients increased specificity to 69% and PPV to 42% while maintaining sensitivity of 91% and NPV of 96%. Following this group, conventional cytology, aneuploidy detection by digital imaging analysis, and aneusomy detection by fluorescence in situ hybridization in brushing samples of biliary strictures had a sensitivity of 50%, 57%, and 86%, specificity of 97%, 94%, and 83%, PPV of 86%, 89%, and 80%, and NPV of 83%, 74%, and 88%, respectively, for detecting cholangiocarcinoma. Tumor serology combined with cross-sectional liver imaging may be useful as a screening strategy and cholangiography with cytologic examination is helpful for the diagnosis of cholangiocarcinoma in patients with PSC.


Cognitive aging in zebrafish.
Age-related impairments in cognitive functions represent a growing clinical and social issue. Genetic and behavioral characterization of animal models can provide critical information on the intrinsic and environmental factors that determine the deterioration or preservation of cognitive abilities throughout life. Behavior of wild-type, mutant and gamma-irradiated zebrafish (Danio rerio) was documented using image-analysis technique. Conditioned responses to spatial, visual and temporal cues were investigated in young, middle-aged and old animals. The results demonstrate that zebrafish aging is associated with changes in cognitive responses to emotionally positive and negative experiences, reduced generalization of adaptive associations, increased stereotypic and reduced exploratory behavior and altered temporal entrainment. Genetic upregulation of cholinergic transmission attenuates cognitive decline in middle-aged achesb55/+ mutants, compared to wild-type siblings. In contrast, the genotoxic stress of gamma-irradiation accelerates the onset of cognitive impairment in young zebrafish. These findings would allow the use of powerful molecular biological resources accumulated in the zebrafish field to address the mechanisms of cognitive senescence, and promote the search for therapeutic strategies which may attenuate age-related cognitive decline.


Public perception of river fish biodiversity in four European countries.
Public support for biodiversity conservation is shaped by people's values and their knowledge, beliefs, and attitudes toward the environment. We conducted the first multinational representative survey of the general public's perceptions of river fish biodiversity in France, Germany, Norway, and Sweden. For the online survey, 1000 respondents per country were randomly selected from large panels following country-specific quotas set on age, gender, and educational level. Questions covered people's level of knowledge, beliefs, values, and attitudes toward river fish, environmental threats, and conservation measures. We found that the public had limited knowledge of freshwater fishes. Two non-native species, rainbow trout (Oncorhynchus mykiss) and brook trout (Salvelinus fontinalis), were widely perceived as native, whereas native Atlantic salmon (Salmo salar) was mostly classified as native in Scandinavia and largely as non-native in central Europe. These results suggest an extinction of experience paralleling the extirpation or decline of salmon stocks in countries such as Germany and France. Respondents thought pollution was the dominant threat to riverine fish biodiversity. In reality, habitat loss, dams, and the spread of non-native fishes are equally important. Despite limited biological knowledge, respondents from all countries held an overwhelmingly proecological worldview, supported conservation stocking, and appreciated native fishes, although only a minority interacted with them directly. Differences among the 4 countries related to several conservation issues. For example, threats to biodiversity stemming from aquaculture were perceived as more prevalent in Norway compared with the other 3 countries. Promoting fish conservation based on charismatic species and use values of fishes may work well in countries with a strong economic and cultural link to the freshwater environment, such as Norway. In countries where people rather abstractly care for nature, focusing conservation messaging on broader ecosystem traits and non-use values of fishes is likely to win more support.


Reducing involuntary memory by interfering consolidation of stressful auditory information: A pilot study.
Intrusive emotional memories were induced by aversive auditory stimuli and modulated with cognitive tasks performed post-encoding (i.e., during consolidation). A between-subjects design was used with four conditions; three consolidation-interference tasks (a visuospatial and two verbal interference tasks) and a no-task control condition. Forty-one participants listened to a soundtrack depicting traumatic scenes (e.g., police brutality, torture and rape). Immediately after listening to the soundtrack, the subjects completed a randomly assigned task for 10 min. Intrusions from the soundtrack were reported in a diary during the following seven-day period. In line with a modality-specific approach to intrusion modulation, auditory intrusions were reduced by verbal tasks compared to both a no-task and a visuospatial interference task.. The study did not control for individual differences in imagery ability which may be a feature in intrusion development. The results provide an increased understanding of how intrusive mental images can be modulated which may have implications for preventive treatment..


Thermophysiological responses and work strain in fishermen on deep-sea fishing vessels.
Fishermen working on deep-sea vessels in the Barents and Norwegian Sea are exposed to low air temperatures, strong winds, high humidity, rain, snow and work at different intensities. Few studies have investigated the effect of environmental work factors on the physiology of this occupational group. The aim of the study was to investigate work strain and thermophysiological responses of fishermen on the trawl and factory decks of deep-sea vessels. Twenty-five professional male fishermen (age 39 ± 13 years) were recruited to the study which was performed on three trawlers in the Norwegian Sea in April, June and August 2014. During a six-hour shift, heart rate (HR), core (Tc) and mean skin (Ts) temperatures were recorded, and questions about subjective thermal sensation and comfort were answered. Short periods of hard (above 86% of HRmax) work raised Tc by 0.8°C to 37.8°C and decreased Ts by 2.3°C to 29.8°C during work on the trawl deck, and subjects reported being warm and sweaty. On the factory deck long periods of fairly light (between 52% and 66% HRmax) work, Tc of 37.4°C and Ts of 30.9°C were measured. Fishermen experience intermittent periods of heavy work on the trawl deck shown with elevated core temperature and HR. Work on the factory deck includes long periods of repetitive work with light to moderate work strain. A better understanding of work strain and environmental challenges during work on Norwegian deep-sea vessels will help identify exposure risks during work in the cold and heat.