The effect of MK-467, a peripheral α2-adrenoceptor antagonist, on dexmedetomidine-induced sedation and bradycardia after intravenous administration in conscious cats.
To determine a dose of MK-467, a peripheral α2-adrenoceptor antagonist, which, when administered intravenously (IV) concomitantly with 25 μg kg-1 of dexmedetomidine, will prevent bradycardia without altering sedation in cats. Prospective, randomized, controlled, blinded, experimental, crossover study. Eight healthy, adult, purpose-bred cats. Cats were administered seven IV treatments were administered at least 2 weeks apart, consisting of dexmedetomidine 12.5 μg kg-1 (D12.5) and 25 μg kg-1 (D25), MK-467 300 μg kg-1 (M300), and D25 combined with 75, 150, 300 and 600 μg kg-1 of MK-467 (D25M 75, D25M150, D25M300 and D25M600, respectively). Heart rates (HR) were recorded via telemetry and sedation assessed with a simple descriptive score and a visual analogue scale prior to treatments and at intervals until 8 hours thereafter. Data from one cat were excluded because it developed renal failure. Heart rate decreased significantly from baseline after all treatments except M300 and D25M600. The lowest HR for each treatment with dexmedetomidine were 99 ± 21 (D25), 103 ± 22 (D12.5), 114 ± 10 (D25M75), 117 ± 17 (D25M150), 121 ± 12 (D25M300) and 139 ± 15 (D25M600) beats minute-1. Sedation increased with all treatments that included dexmedetomidine, whereas M300 did not induce any central effects. In comparison with D25, the combination of MK-467 with dexmedetomidine reduced the duration of detectable sedation. MK-467 dose-dependently attenuated the bradycardia associated with dexmedetomidine, and shortened the sedative effect without altering its quality. MK-467 may be useful in attenuating reductions in HR in conscious cats administered dexmedetomidine.


Transmigration characteristics of breast cancer and melanoma cells through the brain endothelium: Role of Rac and PI3K.
Brain metastases are common and devastating complications of both breast cancer and melanoma. Although mammary carcinoma brain metastases are more frequent than those originating from melanoma, this latter has the highest tropism to the brain. Using static and dynamic in vitro approaches, here we show that melanoma cells have increased adhesion to the brain endothelium in comparison to breast cancer cells. Moreover, melanoma cells can transmigrate more rapidly and in a higher number through brain endothelial monolayers than breast cancer cells. In addition, melanoma cells have increased ability to impair tight junctions of cerebral endothelial cells. We also show that inhibition of Rac or PI3K impedes adhesion of breast cancer cells and melanoma cells to the brain endothelium. In addition, inhibition of Rac or PI3K inhibits the late phase of transmigration of breast cancer cells and the early phase of transmigration of melanoma cells. On the other hand, the Rac inhibitor EHT1864 impairs the junctional integrity of the brain endothelium, while the PI3K inhibitor LY294002 has no damaging effect on interendothelial junctions. We suggest that targeting the PI3K/Akt pathway may represent a novel opportunity in preventing the formation of brain metastases of melanoma and breast cancer.


Learning only when necessary: better memories of correlated patterns in networks with bounded synapses.
Learning in a neuronal network is often thought of as a linear superposition of synaptic modifications induced by individual stimuli. However, since biological synapses are naturally bounded, a linear superposition would cause fast forgetting of previously acquired memories. Here we show that this forgetting can be avoided by introducing additional constraints on the synaptic and neural dynamics. We consider Hebbian plasticity of excitatory synapses. A synapse is modified only if the postsynaptic response does not match the desired output. With this learning rule, the original memory performances with unbounded weights are regained, provided that (1) there is some global inhibition, (2) the learning rate is small, and (3) the neurons can discriminate small differences in the total synaptic input (e.g., by making the neuronal threshold small compared to the total postsynaptic input). We prove in the form of a generalized perceptron convergence theorem that under these constraints, a neuron learns to classify any linearly separable set of patterns, including a wide class of highly correlated random patterns. During the learning process, excitation becomes roughly balanced by inhibition, and the neuron classifies the patterns on the basis of small differences around this balance. The fact that synapses saturate has the additional benefit that nonlinearly separable patterns, such as similar patterns with contradicting outputs, eventually generate a subthreshold response, and therefore silence neurons that cannot provide any information.


High-resolution multiband polarization epithelial tissue imaging method by sparse representation and fusion.
Multiband polarization epithelial tissue imaging is an effective tool to measure tissue's birefringence and structure for quantitative pathology analysis. To discriminate the pathology accurately, high-resolution multiband polarization images are essential. But it is difficult to acquire high-resolution polarization images because of the limitations of imaging systems. The polarization image calculation process can be regarded as image fusion with fixed rules, and multiband polarization images are intrinsically sparse. In this paper, we propose a novel high-resolution multiband polarization image calculation method by utilizing the sparse representation and image fusion method. The multiband images are first represented in the sparse domain and we further introduce total-variation-regularization terms into the sparse representation framework. Then, polarization parameter images are calculated by simultaneous fusion and reconstruction. Higher quality multiband polarization images can be obtained through additional regularization constraint in the fusion process. Extensive experiments validate that the proposed method achieves much better results than many state-of-the-art algorithms in terms of both peak signal-to-noise-ratio and visual perception.


Different durations of corticosteroid therapy for exacerbations of chronic obstructive pulmonary disease.
Current guidelines recommend that patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) should be treated with systemic corticosteroid for seven to 14 days. Intermittent systemic corticosteroid use is cumulatively associated with adverse effects such as osteoporosis, hyperglycaemia and muscle weakness. Shorter treatment could reduce adverse effects. To compare the efficacy of short-duration (seven or fewer days) and conventional longer-duration (longer than seven days) systemic corticosteroid treatment of adults with acute exacerbations of COPD. Searches were carried out using the Cochrane Airways Group Specialised Register of Trials, MEDLINE and CENTRAL (Cochrane Central Register of Controlled Trials) and ongoing trials registers up to March 2017. Randomised controlled trials comparing different durations of systemic corticosteroid defined as short (i.e. seven or fewer days) or longer (i.e. longer than seven days). Other interventions-bronchodilators and antibiotics-were standardised. Studies with participants requiring assisted ventilation were excluded. We used standard methodological procedures as expected by The Cochrane Collaboration. Eight studies with 582 participants met the inclusion criteria, of which five studies conducted in hospitals with 519 participants (range 28 to 296) contributed to the meta-analysis. Mean ages of study participants were 65 to 73 years, the proportion of male participants varied (58% to 84%) and COPD was classified as severe or very severe. Corticosteroid treatment was given at equivalent daily doses for three to seven days for short-duration treatment and for 10 to 15 days for longer-duration treatment. Five studies administered oral prednisolone (30 mg in four, tapered in one), and two studies provided intravenous corticosteroid treatment. Studies contributing to the meta-analysis were at low risk of selection, performance, detection and attrition bias. In four studies we did not find a difference in risk of treatment failure between short-duration and longer-duration systemic corticosteroid treatment (n = 457; odds ratio (OR) 0.72, 95% confidence interval (CI) 0.36 to 1.46)), which was equivalent to 22 fewer per 1000 for short-duration treatment (95% CI 51 fewer to 34 more). No difference in risk of relapse (a new event) was observed between short-duration and longer-duration systemic corticosteroid treatment (n = 457; OR 1.04, 95% CI 0.70 to 1.56), which was equivalent to nine fewer per 1000 for short-duration treatment (95% CI 68 fewer to 100 more). Time to the next COPD exacerbation did not differ in one large study that was powered to detect non-inferiority and compared five days versus 14 days of systemic corticosteroid treatment (n = 311; hazard ratio 0.95, 95% CI 0.66 to 1.37). In five studies no difference in the likelihood of an adverse event was found between short-duration and longer-duration systemic corticosteroid treatment (n = 503; OR 0.89, 95% CI 0.46 to 1.69, or nine fewer per 1000 (95% CI 44 fewer to 51 more)). Length of hospital stay (n = 421; mean difference (MD) -0.61 days, 95% CI -1.51 to 0.28) and lung function at the end of treatment (n = 185; MD FEV1 -0.04 L; 95% CI -0.19 to 0.10) did not differ between short-duration and longer-duration treatment. Information from a new large study has increased our confidence that five days of oral corticosteroids is likely to be sufficient for treatment of adults with acute exacerbations of COPD, and this review suggests that the likelihood is low that shorter courses of systemic corticosteroids (of around five days) lead to worse outcomes than are seen with longer (10 to 14 days) courses. We graded most available evidence as moderate in quality because of imprecision; further research may have an important impact on our confidence in the estimates of effect or may change the estimates. The studies in this review did not include people with mild or moderate COPD; further studies comparing short-duration systemic corticosteroid versus conventional longer-duration systemic corticosteroid for treatment of adults with acute exacerbations of COPD are required.


Melatonin Absence Leads to Long-Term Leptin Resistance and Overweight in Rats.
Melatonin (Mel), a molecule that conveys photoperiodic information to the organisms, is also involved in the regulation of energy homeostasis. Mechanisms of action of Mel in the energy balance remain unclear; herein we investigated how Mel regulates energy intake and expenditure to promote a proper energy balance. Male Wistar rats were assigned to control, control + Mel, pinealectomized (PINX) and PINX + Mel groups. To restore a 24-h rhythm, Mel (1 mg/kg) was added to the drinking water exclusively during the dark phase for 13 weeks. After this treatment period, rats were subjected to a 24-h fasting test, an acute leptin responsiveness test and cold challenge. Mel treatment reduced food intake, body weight, and adiposity. When challenged to 24-h fasting, Mel-treated rats also showed reduced hyperphagia when the food was replaced. Remarkably, PINX rats exhibited leptin resistance; this was likely related to the capacity of leptin to affect body weight, food intake, and hypothalamic signal-transducer and activator of transcription 3 phosphorylation, all of which were reduced. Mel treatment restored leptin sensitivity in PINX rats. An increased hypothalamic expression of agouti-related peptide (Agrp), neuropeptide Y, and Orexin was observed in the PINX group while Mel treatment reduced the expression of Agrp and Orexin. In addition, PINX rats presented lower UCP1 protein levels in the brown adipose tissue and required higher tail vasoconstriction to get a proper thermogenic response to cold challenge. Our findings reveal a previously unrecognized interaction of Mel and leptin in the hypothalamus to regulate the energy balance. These findings may help to explain the high incidence of metabolic diseases in individuals exposed to light at night.


Control chart methods for monitoring surgical performance: a case study from gastro-oesophageal surgery.
Graphical methods are becoming increasingly used to monitor adverse outcomes from surgical interventions. However, uptake of such methods has largely been in the area of cardiothoracic surgery or in transplants with relatively little impact made in surgical oncology. A number of the more commonly used graphical methods including the Cumulative Mortality plot, Variable Life-Adjusted Display, Cumulative Sum (CUSUM) and funnel plots will be described. Accounting for heterogeneity in case-mix will be discussed and how ignoring case-mix can have considerable consequences. All methods will be illustrated using data from the Scottish Audit of Gastro-Oesophageal Cancer services (SAGOCS) data set.


SU-F-BRCD-02: Activity Assay of a Y-90 Microsphere Sample Using a Coincidence Detection System.
This work takes advantage of a newly-determined, low-uncertainty branching ratio of the internal pair production component of Y-90 decay to spectroscopically assay the activity of a Y-90 microsphere sample with a coincidence detection system (CDS). The CDS pairs a HPGe detector with a large NaI detector. The system is able to electronically filter the bremsstrahlung continuum from the photon spectrum by gating the energy signal from the HPGe with the coincidence signal. This reduces the uncertainty in the spectra measurement compared to measurements with a single HPGe detector. A series of pulsers were used to correct for counting losses. A geometric characterization was completed to find the optimal source position for measurements. An efficiency calibration of the CDS was completed using a Na-22 standard source. To validate the measurement accuracy of the CDS, the activity of a Y-90 standard activity solution from the NIST SRM program was determined and compared to the value given by NIST. The CDS was then used to determine the activity of a Y-90 microsphere sample. This value was compared to the 3.0 GBq value given by the manufacturer. The activity determined with the CDS was within 2.6% from the given activity of the NIST SRM source, which is within the expanded uncertainty associated with the CDS measurement. The activity of the Y-90 microsphere sample was determined to be 3.72 GBq +/- 1.9%. This is 19% higher than the manufacturer-stated activity of 3 GBq. This is outside the manufacturer-stated uncertainty of +/-10%. The ability of CDS to determine the activity of a Y-90 source has been validated with comparison to a NIST Y-90 standard activity solution. The use of the CDS has been extended to determine the activity of a Y-90 microsphere sample.


The Association between the Risk of Premenstrual Syndrome and Vitamin D, Calcium, and Magnesium Status among University Students: A Case Control Study.
Premenstrual syndrome (PMS) is one of major health problems in childbearing age women. Herein, we compared the nutritional status of vitamin D, calcium (Ca) and magnesium (Mg) in young students affected by PMS with those of normal participants. This study was conducted on 62 students aged 20‒25 yr in the city of Abadan (31 PMS cases and 31 controls). All participants completed four or more criteria according to the Utah PMS Calendar 3. Age, height, body mass index (BMI), serum Ca, Mg and vitamin D levels and a 24-hour food recall questionnaire were recorded. Vitamin D serum levels were lower than the normal range in the two groups. The odds ratios (CI 95%) of having PMS based on serum Ca and Mg concentrations were 0.81(0.67 - 0.89) and 0.86 (0.72 - 0.93), respectively. Based on serum levels, 855 of all participants showed vitamin D deficiency and more than one-third of the PMS cases were Mg deficient (P<0.05). In addition, there were signifi-cant differences in dietary intake of Ca and Mg, and potassium but not vitamin D in the two groups. Dietary intakes of Ca and Mg were quite below the recommendation in all participants. Vitamin D, Ca and Mg nutritional status are compromised in PMS subjects. Because PMS is a prevalent health problem among young women, it merits more attention regarding improvement of their health and nutritional status.


The fertility of ram sperm held for 24h at 5 degrees C prior to cryopreservation.
Diluted ram sperm can be held for 24h at 5 degrees C prior to cryopreservation without impacting cryosurvival rates, however, the effects this storage has on subsequent fertility are unknown. These studies were conducted to evaluate the fertility of semen held for 24h (to mimic shipping semen to a cryopreservation center), prior to freezing. Semen from Suffolk rams (n=3 in experiment 1 and n=6 in experiment 2) with initial motility of greater than 70%, were diluted to 200 x 10(6)sperm/mL, in one step, with a Tris-egg yolk-glycerol diluent. In experiment 1, diluted samples were cooled to 5 degrees C over 2h, and then divided. Sperm in one fraction were loaded into 0.5mL straws, frozen (T0) and stored in liquid nitrogen until thawing. Sperm in the second fraction were held at 5 degrees C for 24h (T24) before being frozen. In experiment 2 ejaculates were collected and divided into two fractions. Sperm in one fraction were treated with cholesterol-loaded cyclodextrin (CLC) and sperm in the other served as control. Both fractions were diluted, cooled, and cryopreserved as described in experiment 1. Stage of the estrous cycle was synchronized in ewes (n=196) using controlled internal drug releasing devices (CIDR) for 12d and at CIDR removal each ewe was administered PMSG (500IU in experiment 1 and 350IU in experiment 2) immediately before insemination. Ewes were stratified by age and randomly assigned to one of the semen treatments; experiment 1: Fresh (F), T0, or T24; experiment 2: F, T24, or CLC, and inseminated laparoscopically 56h after CIDR removal. Differences in fertility were detected between experiments, but not for treatments within experiments. Differences in fertility were also observed due to ewe age, with the 3-year-old ewes having the greatest fertility (50.7%) and 6-year-old ewes having the least fertility (9.6%; P<0.05). Differences in the prolificacy rates due to semen treatment were also observed but differences due to ewe age were not detected. Therefore, sperm can be held at 5 degrees C for 24h prior to cryopreservation without altering sperm fertility.


Increased folate catabolism in mice with ascitic tumours.
Folate deficiency is reported in association with certain malignant tumours, and it has been suggested that this arises from increased folate turnover and catabolism in such circumstances. Using an experimental animal model to determine the rate of catabolism of [3H]pteroylglutamate (folic acid) by the quantitative estimation of the two urinary catabolites p-[3H]aminobenzoylglutamate and [3H]acetamidobenzoylglutamate, we have measured the rate of folate catabolism in mice with ascitic tumours. There was a significant increase in the rate of catabolism in the mice with tumours compared with controls over a 10 day period. This was associated with the accumulation of ascitic fluid and an increase in the number of tumour cells in the treated animals. The increase in catabolism appeared to be due to increased cell turnover of the tumour rather than an increase in cell mass, as the increase in mass of the tumour was negligible.


Peptide-Stabilized Emulsions and Gels from an Arginine-Rich Surfactant-like Peptide with Antimicrobial Activity.
The preparation of hydrogels and stable emulsions is important in the formulation of many functional nanostructured soft materials. We investigate the multifunctional self-assembly and bioactivity properties of a novel surfactant-like peptide (SLP) that shows antimicrobial activity, is able to form hydrogels without pH adjustment, and is able to stabilize oil-in-water emulsions. Furthermore, we demonstrate on-demand de-emulsification in response to the protease enzyme elastase. We show that SLP (Ala)9-Arg (A9R) forms β-sheet fibers above a critical aggregation concentration and that water-in-oil emulsions are stabilized by a coating of β-sheet fibers around the emulsion droplets. Furthermore, we demonstrate enzyme-responsive de-emulsification, which has potential in the development of responsive release systems. The peptide shows selective antimicrobial activity against Gram-negative pathogens including Pseudomonas aeruginosa, which causes serious infections. Our results highlight the utility of SLPs in the stabilization of oil/water emulsions and the potential for these to be used to formulate antimicrobial peptide emulsions which are additionally responsive to protease. The peptide A9R has pronounced antibacterial activity against clinically challenging pathogens, and its ability to form β-sheet fibers plays a key role in its diverse structural properties, ranging from hydrogel formation to emulsion stabilization.


A single-stranded DNA binding protein from Drosophila melanogaster: characterization of the heterotrimeric protein and its interaction with single-stranded DNA.
We describe the purification to near homogeneity of a single-stranded DNA binding protein from 0-18-h embryos of Drosophila melanogaster. Drosophila SSB (D-SSB) is a heterotrimer with subunits of molecular weight of 70,000, 30,000, and 8000. It has a Stokes radius of 48.6 +/- 2 A and s20,w = 5.0 +/- 0.2 S. The interaction of D-SSB with ssDNA was examined by the quenching of intrinsic protein fluorescence. The binding site size was determined to be n = 22 +/- 4 nucleotides with a maximum quenching Qm = 35 +/- 3%. Equilibrium titrations indicate that D-SSB binds with low cooperativity, omega = 10-300, and high apparent affinity, K omega = (0.7-5) x 10(7) M-1, at 225 mM NaCl. Sedimentation of D-SSB bound to small oligonucleotides demonstrates that D-SSB does not require protein association for binding. D-SSB stimulates the extent and processivity of DNA synthesis of its cognate DNA polymerase alpha. On the basis of these properties, we conclude that D-SSB is the Drosophila cognate of the human and yeast SSB/RP-A proteins.


Modeling pollutant release from a surface source during rainfall runoff.
Though runoff from manure spread fields is recognized as an important mode of nonpoint-source pollution, there are no models that mechanistically describe transport from a field-spread manure-type source. A mechanistic, physically based model for pollutant release from a surface source, such as field-spread manure, was hypothesized, laboratory tested, and field-applied. The primary objective of this study was to demonstrate the potential applicability of a mechanistic model to pollutant release from surface sources. The laboratory investigation used stable sources and a conservative "pollutant" (KCl) so that the dynamic effects of source dissolution and chemical transformations could be ignored and transport processes isolated. The field investigation used runoff and soluble reactive phosphorus (SP) data collected from a dairy-manure-spread field in the Cannonsville watershed in the Catskills region of New York State. The model predictions corroborated well with observations of runoff and pollutant delivery in both the laboratory and the field. "Pollutant" release from surface sources was generally predicted within 11% of laboratory KCl measurements and field SP observations. Laboratory flume runoff predictions with 15 and 26% errors for 25 and 15 mm h(-1) simulated rainfall intensity experiments, respectively, represented root mean square errors of less than 0.2 mLs(-1). A 26% error was calculated for overland flow predictions in the field, which translated into approximately a 39 mLs(-1) error. Results suggest that the hypothesized model satisfactorily represents the primary mechanisms in pollutant release from surface sources.


Intervention in a family of Boolean networks.
Intervention in a gene regulatory network is used to avoid undesirable states, such as those associated with a disease. Several types of intervention have been studied in the framework of a probabilistic Boolean network (PBN), which is a collection of Boolean networks in which the gene state vector transitions according to the rules of one of the constituent networks and where network choice is governed by a selection distribution. The theory of automatic control has been applied to find optimal strategies for manipulating external control variables that affect the transition probabilities to desirably affect dynamic evolution over a finite time horizon. In this paper we treat a case in which we lack the governing probability structure for Boolean network selection, so we simply have a family of Boolean networks, but where these networks possess a common attractor structure. This corresponds to the situation in which network construction is treated as an ill-posed inverse problem in which there are many Boolean networks created from the data under the constraint that they all possess attractor structures matching the data states, which are assumed to arise from sampling the steady state of the real biological network. Given a family of Boolean networks possessing a common attractor structure composed of singleton attractors, a control algorithm is derived by minimizing a composite finite-horizon cost function that is a weighted average over all the individual networks, the idea being that we desire a control policy that on average suits the networks because these are viewed as equivalent relative to the data. The weighting for each network at any time point is taken to be proportional to the instantaneous estimated probability of that network being the underlying network governing the state transition. The results are applied to a family of Boolean networks derived from gene-expression data collected in a study of metastatic melanoma, the intent being to devise a control strategy that reduces the WNT5A gene's action in affecting biological regulation. The software is available on request. The supplementary Information is available at http://ee.tamu.edu/~edward/tree


SHP-2 activates signaling of the nuclear factor of activated T cells to promote skeletal muscle growth.
The formation of multinucleated myofibers is essential for the growth of skeletal muscle. The nuclear factor of activated T cells (NFAT) promotes skeletal muscle growth. How NFAT responds to changes in extracellular cues to regulate skeletal muscle growth remains to be fully defined. In this study, we demonstrate that mice containing a skeletal muscle-specific deletion of the tyrosine phosphatase SHP-2 (muscle creatine kinase [MCK]-SHP-2 null) exhibited a reduction in both myofiber size and type I slow myofiber number. We found that interleukin-4, an NFAT-regulated cytokine known to stimulate myofiber growth, was reduced in its expression in skeletal muscles of MCK-SHP-2-null mice. When SHP-2 was deleted during the differentiation of primary myoblasts, NFAT transcriptional activity and myotube multinucleation were impaired. Finally, SHP-2 coupled myotube multinucleation to an integrin-dependent pathway and activated NFAT by stimulating c-Src. Thus, SHP-2 transduces extracellular matrix stimuli to intracellular signaling pathways to promote skeletal muscle growth.


Population mobility and spread of HIV across the Indo-Nepal border.
The article reviews information on the epidemiology of HIV/AIDS and behavioural networking to examine the role of population mobility in spreading HIV across the Indo-Nepal border. Documents were collected through a systematic search of electronic databases and web-based information resources, and the review focuses on studies about types of the virus, prevalence of HIV, and sexual and injecting networking. HIV-1 (subtype C) and HIV-2 were identified in Nepal. The prevalence of HIV was higher among male labour migrants and female sex workers (FSWs) who returned from India, especially from Mumbai, than in similar non-migrant groups. In the early 2000s, about 6-10% of Mumbai returnee men, compared to up to 4% of India returnee men and up to 3% of non-migrant men in the far-west Nepal, were identified with HIV. Likewise, when the prevalence of HIV among sex workers in Kathmandu was found to be 17% in 1999-2000, up to 44% of India returnee and 73% of Mumbai returnee FSWs were identified with the virus. These data are, however, based on small samples with questionable representativeness of the target populations and need to be interpreted cautiously. They also generate a biased impression that HIV was coming into Nepal from India. Recently, the possibility of a two-way flow of HIV across the Indo-Nepal border through injecting and sexual networking have been indicated by serological and behavioural data from a south-eastern cluster of Nepal and a north-eastern district of India. Although similar behavioural networks exist along other segments of the border, serological data are unavailable to assess whether and how extensively this phenomenon has caused the spread of HIV. Collaborative research and interventions covering both sides of the border are desirable to fully understand and address the prospect of HIV epidemics associated with cross-border population mixing.


Structural insights into RNA polymerases of negative-sense RNA viruses.
RNA viruses include many important human and animal pathogens, such as the influenza viruses, respiratory syncytial virus, Ebola virus, measles virus and rabies virus. The genomes of these viruses consist of single or multiple RNA segments that assemble with oligomeric viral nucleoprotein into ribonucleoprotein complexes. Replication and transcription of the viral genome is performed by ~250-450 kDa viral RNA-dependent RNA polymerases that also contain capping or cap-snatching activity. In this Review, we compare recent high-resolution X-ray and cryoelectron microscopy structures of RNA polymerases of negative-sense RNA viruses with segmented and non-segmented genomes, including orthomyxoviruses, peribunyaviruses, phenuiviruses, arenaviruses, rhabdoviruses, pneumoviruses and paramyxoviruses. In addition, we discuss how structural insights into these enzymes contribute to our understanding of the molecular mechanisms of viral transcription and replication, and how we can use these insights to identify targets for antiviral drug design.


Associations of circulating insulin-like growth factor-I with intake of dietary proteins and other macronutrients.
Circulating insulin-like growth factor-I (IGF-I) is associated with the risk of several cancers. Dietary protein intake, particularly dairy protein, may increase circulating IGF-I; however, associations with different protein sources, other macronutrients, and fibre are inconclusive. To investigate the associations between intake of protein, macronutrients and their sources, fibre, and alcohol with serum IGF-I concentrations. A total of 11,815 participants from UK Biobank who completed ≥4 24-h dietary assessments and had serum IGF-I concentrations measured at baseline were included. Multivariable linear regression was used to assess the cross-sectional associations of macronutrient and fibre intake with circulating IGF-I concentrations. Circulating IGF-I concentrations were positively associated with intake of total protein (per 2.5% higher energy intake: 0.56 nmol/L (95% confidence interval: 0.47, 0.66)), milk protein: 1.20 nmol/L (0.90, 1.51), and yogurt protein: 1.33 nmol/L (0.79, 1.86), but not with cheese protein: -0.07 nmol/L (-0.40, 0.25). IGF-I concentrations were also positively associated with intake of fibre (per 5 g/day higher intake: 0.46 nmol/L (0.35, 0.57)) and starch from wholegrains (Q5 vs. Q1: 1.08 nmol/L (0.77, 1.39)), and inversely associated with alcohol consumption (>40 g/day vs <1 g/day: -1.36 nmol/L (-1.00, -1.71)). These results show differing associations with IGF-I concentrations depending on the source of dairy protein, with positive associations with milk and yogurt protein intake but no association with cheese protein. The positive association of fibre and starch from wholegrains with IGF-I warrants further investigation.


Frequent alteration of p16(INK4a)/p14(ARF) and p53 pathways in the round cell component of myxoid/round cell liposarcoma: p53 gene alterations and reduced p14(ARF) expression both correlate with poor prognosis.
In myxoid/round cell liposarcoma (MLS/RCLS), the presence of a round cell (RC) component has been reported to correlate with a worse prognosis for the patients. However, little is known about the molecular genetic differences between conventional myxoid (MX) components and RC components in this tumour. The aim of this study was to investigate the possible implications of molecular alterations of G1 to S-phase check-point genes, especially in the RC component. We evaluated the immunohistochemical expression of p53, MDM2, p14 and p16 protein and assessed proliferative activities using MIB-1 in 29 RC components and 81 MX components from 90 cases. Mutation of the p53 gene, amplification of the MDM2 gene, homozygous deletion, methylation status and mutation of the p16(INK4a)/p14(ARF) genes were also investigated, using concordant paraffin-embedded and frozen material. The data were analysed together with clinicopathological factors to assess their prognostic implications in MLS/RCLS. Immunohistochemically, the over-expression of p53 protein (p = 0.01366) and the reduced expression of p14 (p < 0.0001) and p16 (p < 0.0001) proteins were significantly more frequently observed in RC components than in MX components. Reduced expression of p14 protein correlated significantly with hypermethylation of the p14(ARF) gene promoter (p = 0.0176) and over-expression of p53 protein (p = 0.00837). By univariate analysis, reduced expression of p14 and p53 missense mutation were found to reduce the rate of survival significantly (p < 0.05). Multivariate analysis, including clinicopathological factors, revealed that tumour site (p = 0.0251), the presence of an RC component (p = 0.0113), high MIB-1 labelling index (p = 0.0005) and p53 missense mutation (p = 0.0036) were adverse prognostic factors. In MLS/RCLS, reduction of p14 protein expression and p53 mutation were related to poor prognosis. Accordingly, the p14(ARF)/p53 pathway may contribute to the presence of an RC component and malignant progression in this tumour.


Randomized comparison of Burch urethropexy procedures concomitant with gynecologic operations.
We compared the success of laparoscopic Burch colposuspension with the laparotomic Burch colposuspension for the treatment of genuine stress incontinence (GSI) concomitant with gynecologic operations. Fifty-two women with symptoms of GSI, also requiring additional gynecologic operations, were randomly assigned to undergo laparoscopic (n = 26) or laparotomic (n = 26) Burch colposuspension. For all patients complete histories were taken and physical examination, urinalysis, urine culture, multi-channel urodynamics with cystometry, uroflowmetry, and measurement of Valsalva leak-point pressure were performed. Variables analyzed included: age, surgical time, length of catheterization, number of days in hospital, and complications. Both groups were similar in age, parity and menopausal status. Valsalva leak-point pressure significantly increased in the laparoscopy group after the operation. There were no statistical differences in other urodynamics in both groups. The mean operating time in the laparoscopy group was longer than in the laparotomy group. The laparoscopy group required a significantly shorter hospitalization and catheterization than the laparotomy group. The success and complication rates did not differ significantly for both groups. The laparoscopic approach for the treatment of GSI in patients requiring additional gynecologic procedures is associated with a shorter duration of hospital stay compared with the abdominal approach.


Sexual violence and eclampsia: analysis of data from Demographic and Health Surveys from seven low- and middle-income countries.
Scientific literature has provided clear evidence of the profound impact of sexual violence on women's health, such as somatic disorders and mental adverse outcomes. However, consequences related to obstetric complications are not yet completely clarified. This study aimed to assess the association of lifetime exposure to intimate partner sexual violence with eclampsia. We considered all the seven Demographic and Health Surveys (DHS) that included data on sexual violence and on signs and symptoms suggestive of eclampsia for women of reproductive age (15-49 years). We computed unadjusted and adjusted odds ratios (OR) to evaluate the risk of suggestive eclampsia by ever subjected to sexual violence. A sensitivity analysis was conducted restricting the study population to women who had their last live birth over the 12 months before the interview. Self-reported experience of sexual violence ranged from 3.7% in Mali to 9.2% in India while prevalence of women reporting signs and symptoms compatible with eclampsia ranged from 14.3% in Afghanistan to 0.7% in the Philippines. Reported sexual violence was associated with a 2-fold increased odd of signs and symptoms suggestive of eclampsia in the pooled analysis. The sensitivity analysis confirmed the strength of the association between sexual violence and eclampsia in Afghanistan and in India. Women and girls in low-and-middle-income countries are at high risk of sexual violence, which may represent a risk factor for hypertensive obstetric complication. Accurate counseling by health care providers during antenatal care consultations may represent an important opportunity to prevent adverse outcomes during pregnancy.


Assessing spirituality: is there a beneficial role in the management of COPD?
Here,we report on the role of spirituality assessment in the management of chronic obstructive pulmonary disease (COPD). Although a positive effect of addressing spirituality in health care has been proved in a number of chronic diseases, its potential in COPD has received less attention. Although limited, available evidence suggests that spirituality may play an important role in improving quality of life of patients with COPD. The fruitful results in other long-term conditions may lay the foundation for further research on addressing spirituality in COPD. This should focus where the burden of COPD is greatest, including low-resource settings globally. Implementation research should include exploration of an acceptable consultation process to identify patients who would welcome spiritual discussions; how to integrate spiritual approaches into health care professional curricula so that they are aware of its importance and have the confidence to raise it with patients and how to integrate spiritual approaches into holistic COPD care.


Correlating Genotype and Phenotype in the Asexual Yeast Candida orthopsilosis Implicates ZCF29 in Sensitivity to Caffeine.
Candida orthopsilosis is diploid asexual yeast that causes human disease. Most C. orthopsilosis isolates arose from at least four separate hybridizations between related, but not identical, parents. Here, we used population genomics data to correlate genotypic and phenotypic variation in 28 C. orthopsilosis isolates. We used cosine similarity scores to identify 65 variants with potential high-impact (deleterious effects) that correlated with specific phenotypes. Of these, 19 were Single Nucleotide Polymorphisms (SNPs) that changed stop or start codons, or splice sites. One variant resulted in a premature stop codon in both alleles of the gene ZCF29 in C. orthopsilosis isolate 185, which correlated with sensitivity to nystatin and caffeine. We used CRISPR-Cas9 editing to introduce this polymorphism into two resistant C. orthopsilosis isolates. Introducing the stop codon resulted in sensitivity to caffeine and to ketoconazole, but not to nystatin. Our analysis shows that it is possible to associate genomic variants with phenotype in asexual Candida species, but that only a small amount of genomic variation can be easily explored.


Race-ethnic differences of sleep symptoms in an elderly multi-ethnic cohort: the Northern Manhattan Study.
Sleep disorders are associated with stroke and may vary among elderly Hispanics, Blacks and Whites. We evaluated differences in sleep symptoms by race-ethnicity in an elderly population-based urban community sample. Snoring, daytime sleepiness and reported sleep duration were ascertained by standardized interviews as a part of the Northern Manhattan Study, a prospective cohort study of vascular risk factors and stroke risk in a multi-ethnic urban population. Sleep symptoms were compared amongst race-ethnic groups using logistic regression models. A total of 1,964 stroke-free participants completed sleep questionnaires. The mean age was 75 ± 9 years, with 37% men, with 60% Hispanics, 21% Blacks and 19% Whites. In models adjusted for demographic and vascular risk factors, Hispanics had increased odds of frequent snoring (odds ratio, OR: 3.6, 95% confidence interval, CI: 2.3-5.8) and daytime sleepiness (OR: 2.8, 95% CI: 1.7-4.5) compared to White participants. Hispanics were more likely to report long sleep (≥ 9 h of sleep, OR: 1.8, 95% CI: 1.1-3.1). There was no difference in sleep symptoms between Black and White participants. In this cross-sectional analysis among an elderly community cohort, snoring, sleepiness and long sleep duration were more common in Hispanics. Sleep symptoms may be surrogate markers for an underlying sleep disorder which may be associated with an elevated risk of stroke and may be modified by clinical intervention.


Sequence similarity network reveals common ancestry of multidomain proteins.
We address the problem of homology identification in complex multidomain families with varied domain architectures. The challenge is to distinguish sequence pairs that share common ancestry from pairs that share an inserted domain but are otherwise unrelated. This distinction is essential for accuracy in gene annotation, function prediction, and comparative genomics. There are two major obstacles to multidomain homology identification: lack of a formal definition and lack of curated benchmarks for evaluating the performance of new methods. We offer preliminary solutions to both problems: 1) an extension of the traditional model of homology to include domain insertions; and 2) a manually curated benchmark of well-studied families in mouse and human. We further present Neighborhood Correlation, a novel method that exploits the local structure of the sequence similarity network to identify homologs with great accuracy based on the observation that gene duplication and domain shuffling leave distinct patterns in the sequence similarity network. In a rigorous, empirical comparison using our curated data, Neighborhood Correlation outperforms sequence similarity, alignment length, and domain architecture comparison. Neighborhood Correlation is well suited for automated, genome-scale analyses. It is easy to compute, does not require explicit knowledge of domain architecture, and classifies both single and multidomain homologs with high accuracy. Homolog predictions obtained with our method, as well as our manually curated benchmark and a web-based visualization tool for exploratory analysis of the network neighborhood structure, are available at http://www.neighborhoodcorrelation.org. Our work represents a departure from the prevailing view that the concept of homology cannot be applied to genes that have undergone domain shuffling. In contrast to current approaches that either focus on the homology of individual domains or consider only families with identical domain architectures, we show that homology can be rationally defined for multidomain families with diverse architectures by considering the genomic context of the genes that encode them. Our study demonstrates the utility of mining network structure for evolutionary information, suggesting this is a fertile approach for investigating evolutionary processes in the post-genomic era.


Metabolomic Dynamic Analysis of Hypoxia in MDA-MB-231 and the Comparison with Inferred Metabolites from Transcriptomics Data.
Hypoxia affects the tumor microenvironment and is considered important to metastasis progression and therapy resistance. Thus far, the majority of global analyses of tumor hypoxia responses have been limited to just a single omics level. Combining multiple omics data can broaden our understanding of tumor hypoxia. Here, we investigate the temporal change of the metabolite composition with gene expression data from literature to provide a more comprehensive insight into the system level in response to hypoxia. Nuclear magnetic resonance spectroscopy was used to perform metabolomic profiling on the MDA-MB-231 breast cancer cell line under hypoxic conditions. Multivariate statistical analysis revealed that the metabolic difference between hypoxia and normoxia was similar over 24 h, but became distinct over 48 h. Time dependent microarray data from the same cell line in the literature displayed different gene expressions under hypoxic and normoxic conditions mostly at 12 h or earlier. The direct metabolomic profiles show a large overlap with theoretical metabolic profiles deduced from previous transcriptomic studies. Consistent pathways are glycolysis/gluconeogenesis, pyruvate, purine and arginine and proline metabolism. Ten metabolic pathways revealed by metabolomics were not covered by the downstream of the known transcriptomic profiles, suggesting new metabolic phenotypes. These results confirm previous transcriptomics understanding and expand the knowledge from existing models on correlation and co-regulation between transcriptomic and metabolomics profiles, which demonstrates the power of integrated omics analysis.


Efficient exploration of reactive potential energy surfaces using Car-Parrinello molecular dynamics.
The possibility of observing chemical reactions in ab initio molecular dynamics runs is severely hindered by the short simulation time accessible. We propose a new method for accelerating the reaction process, based on the ideas of the extended Lagrangian and coarse-grained non-Markovian metadynamics. We demonstrate that by this method it is possible to simulate reactions involving complex atomic rearrangements and very large energy barriers in runs of a few picoseconds.


Complex history of admixture between modern humans and Neandertals.
Recent analyses have found that a substantial amount of the Neandertal genome persists in the genomes of contemporary non-African individuals. East Asians have, on average, higher levels of Neandertal ancestry than do Europeans, which might be due to differences in the efficiency of purifying selection, an additional pulse of introgression into East Asians, or other unexplored scenarios. To better define the scope of plausible models of archaic admixture between Neandertals and anatomically modern humans, we analyzed patterns of introgressed sequence in whole-genome data of 379 Europeans and 286 East Asians. We found that inferences of demographic history restricted to neutrally evolving genomic regions allowed a simple one-pulse model to be robustly rejected, suggesting that differences in selection cannot explain the differences in Neandertal ancestry. We show that two additional demographic models, involving either a second pulse of Neandertal gene flow into the ancestors of East Asians or a dilution of Neandertal lineages in Europeans by admixture with an unknown ancestral population, are consistent with the data. Thus, the history of admixture between modern humans and Neandertals is most likely more complex than previously thought.


Validation of an automated latex particle-enhanced immunoturbidimetric von Willebrand factor activity assay.
Laboratory diagnosis of von Willebrand disease (VWD) requires accurate measurement of plasma von Willebrand factor (VWF) activity. To evaluate laboratory characteristics, diagnostic accuracy and testing utilities of an automated latex particle-enhanced immunoturbidimetric VWF assay (VWF:Lx) based on a monoclonal antibody recognizing the VWF-platelet glycoprotein (GP) Ib binding domain. Laboratory characteristics including lower detection limit, linearity, precision, sample stability, and method comparison between VWF:Lx and VWF ristocetin cofactor activity by platelet aggregometry (VWF:RCo) were examined. To assess VWF:Lx diagnostic accuracy, 492 patient plasma samples, including 40 previously characterized VWD patient samples, were tested for VWF antigen (VWF:Ag) and VWF:RCo by either aggregometry or flow cytometry, and VWF:Lx with supplemental VWF multimer analysis when indicated. Based on results of VWF:Ag, VWF:RCo and VWF multimer analysis, and available clinical information, samples were categorized as: normal; VWD types 1, 2A/B, 2M, or severe 1 vs. 2M; or acquired VWF abnormalities (AVWA) due to subtle loss of highest molecular weight multimers. VWF:Lx had excellent laboratory characteristics and linear correlation with VWF:RCo (R(2) = 0.93). VWF:Lx accurately classified virtually all normal and VWD patient samples. Compared with VWF:RCo, VWF:Lx had superior sensitivity and specificity for distinguishing severe type 1 vs. 2M VWD and identifying AVWA. A proposed screening panel comprising VWF:Ag and VWF:Lx had 100% and 83% sensitivity for detecting VWD and AVWA, respectively. VWF:Lx has excellent laboratory characteristics and diagnostic accuracy compared with VWF:RCo, and can be used as part of an initial VWD screening panel and as a supplementary test.


Estimation of chronic personal exposure to airborne polycyclic aromatic hydrocarbons.
Polycyclic aromatic hydrocarbons (PAH) exposure from solid fuel burning represents an important public health issue for the majority of the global population. Yet, understanding of individual-level exposures remains limited. To develop regionally adaptable chronic personal exposure model to pro-carcinogenic PAH (c-PAH) for the population in Kraków, Poland. We checked the assumption of spatial uniformity in eight c-PAH using the coefficients of divergence (COD), a marker of absolute concentration differences. Upon successful validation, we developed personal exposure models for eight pro-carcinogenic PAH by integrating individual-level data with area-level meteorological or pollutant data. We checked the resulting model for accuracy and precision against home outdoor monitoring data. During winter, COD of 0.1 for Kraków suggest overall spatial uniformity in the ambient concentration of the eight c-PAH. The three models that we developed were associated with index of agreement approximately equal to 0.9, root mean square error < 2.6 ng/m(3), and 90th percentile of absolute difference ≤ 4 ng/m(3) for the predicted and the observed concentrations for eight pro-carcinogenic PAH. Inexpensive and logistically feasible information could be used to estimate chronic personal exposure to PAH profiles, in lieu of costly and labor-intensive personal air monitoring at wide scale. At the same time, thorough validation through direct personal monitoring and assumption checking are critical for successful model development.


Role of zinc interstitials and oxygen vacancies of ZnO in photocatalysis: a bottom-up approach to control defect density.
Oxygen vacancies (V(O)s) in ZnO are well-known to enhance photocatalytic activity (PCA) despite various other intrinsic crystal defects. In this study, we aim to elucidate the effect of zinc interstitials (Zn(i)) and V(O)s on PCA, which has applied as well as fundamental interest. To achieve this, the major hurdle of fabricating ZnO with controlled defect density requires to be overcome, where it is acknowledged that defect level control in ZnO is significantly difficult. In the present context, we fabricated nanostructures and thoroughly characterized their morphological (SEM, TEM), structural (XRD, TEM), chemical (XPS) and optical (photoluminescence, PL) properties. To fabricate the nanostructures, we adopted atomic layer deposition (ALD), which is a powerful bottom-up approach. However, to control defects, we chose polysulfone electrospun nanofibers as a substrate on which the non-uniform adsorption of ALD precursors is inevitable because of the differences in the hydrophilic nature of the functional groups. For the first 100 cycles, Zn(i)s were predominant in ZnO quantum dots (QDs), while the presence of V(O)s was negligible. As the ALD cycle number increased, V(O)s were introduced, whereas the density of Zn(i) remained unchanged. We employed PL spectra to identify and quantify the density of each defect for all the samples. PCA was performed on all the samples, and the percent change in the decay constant for each sample was juxtaposed with the relative densities of Zn(i)s and V(O)s. A logical comparison of the relative defect densities of Zn(i)s and V(O)s suggested that the former are less efficient than the latter because of the differences in the intrinsic nature and the physical accessibility of the defects. Other reasons for the efficiency differences were elaborated.


Probabilistic inference under time pressure leads to a cortical-to-subcortical shift in decision evidence integration.
Real-life decision-making often involves combining multiple probabilistic sources of information under finite time and cognitive resources. To mitigate these pressures, people "satisfice", foregoing a full evaluation of all available evidence to focus on a subset of cues that allow for fast and "good-enough" decisions. Although this form of decision-making likely mediates many of our everyday choices, very little is known about the way in which the neural encoding of cue information changes when we satisfice under time pressure. Here, we combined human functional magnetic resonance imaging (fMRI) with a probabilistic classification task to characterize neural substrates of multi-cue decision-making under low (1500 ms) and high (500 ms) time pressure. Using variational Bayesian inference, we analyzed participants' choices to track and quantify cue usage under each experimental condition, which was then applied to model the fMRI data. Under low time pressure, participants performed near-optimally, appropriately integrating all available cues to guide choices. Both cortical (prefrontal and parietal cortex) and subcortical (hippocampal and striatal) regions encoded individual cue weights, and activity linearly tracked trial-by-trial variations in the amount of evidence and decision uncertainty. Under increased time pressure, participants adaptively shifted to using a satisficing strategy by discounting the least informative cue in their decision process. This strategic change in decision-making was associated with an increased involvement of the dopaminergic midbrain, striatum, thalamus, and cerebellum in representing and integrating cue values. We conclude that satisficing the probabilistic inference process under time pressure leads to a cortical-to-subcortical shift in the neural drivers of decisions.


Genetic architecture of delayed senescence, biomass, and grain yield under drought stress in cowpea.
The stay-green phenomenon is a key plant trait with wide usage in managing crop production under limited water conditions. This trait enhances delayed senescence, biomass, and grain yield under drought stress. In this study we sought to identify QTLs in cowpea (Vigna unguiculata) consistent across experiments conducted in Burkina Faso, Nigeria, Senegal, and the United States of America under limited water conditions. A panel of 383 diverse cowpea accessions and a recombinant inbred line population (RIL) were SNP genotyped using an Illumina 1536 GoldenGate assay. Phenotypic data from thirteen experiments conducted across the four countries were used to identify SNP-trait associations based on linkage disequilibrium association mapping, with bi-parental QTL mapping as a complementary strategy. We identified seven loci, five of which exhibited evidence suggesting pleiotropic effects (stay-green) between delayed senescence, biomass, and grain yield. Further, we provide evidence suggesting the existence of positive pleiotropy in cowpea based on positively correlated mean phenotypic values (0.34< r <0.87) and allele effects (0.07< r <0.86) for delayed senescence and grain yield across three African environments. Three of the five putative stay-green QTLs, Dro-1, 3, and 7 were identified in both RILs and diverse germplasm with resolutions of 3.2 cM or less for each of the three loci, suggesting that these may be valuable targets for marker-assisted breeding in cowpea. Also, the co-location of early vegetative delayed senescence with biomass and grain yield QTLs suggests the possibility of using delayed senescence at the seedling stage as a rapid screening tool for post-flowering drought tolerance in cowpea breeding. BLAST analysis using EST sequences harboring SNPs with the highest associations provided a genomic context for loci identified in this study in closely related common bean (Phaseolus vulgaris) and soybean (Glycine max) reference genomes.


Renal interstitial fibrosis is reduced in angiotensin II type 1a receptor-deficient mice.
Unilateral ureteral obstruction (UUO) results in tubulointerstitial fibrosis of the affected kidney by stimulating the renin-angiotensin system. This study established a UUO model in angiotensin type 1a receptor (AT1a) deficient (mutant) mice to elucidate the role of angiotensin II through AT1a on the fibrosis of the obstructed kidney (OBK). The relative volume of the tubulointerstitium was measured by an image analyzer; deposition of collagen types III and IV and monocyte/macrophage infiltration were histologically examined using specific antibodies. Also determined were the mRNA levels of transforming growth factor-beta by Northern blot analysis. Nuclear factor-kappaB activity was assessed by gel shift assay. UUO in wild mice resulted in a marked expansion of relative volume of the tubulointerstitium, together with increased deposition of collagen types III and IV and number of infiltrated monocytes/macrophages in the interstitium, relative to sham-operated mice. In comparison, these changes were significantly lower in mutant mice with UUO. The mRNA level of transforming growth factor-beta was significantly higher in the OBK of wild mice with UUO compared with sham-operated mice. In contrast, the increase in mRNA level in the OBK of mutant mice was significantly less than in wild mice. Finally, UUO resulted in activation of nuclear factor-kappaB in wild mice but was inhibited in the OBK of mutant mice. The results provide direct evidence that angiotensin II acting via the AT1a plays a pivotal role in the development of tubulointerstitial fibrosis in UUO.


An examination of the variation in maternal placentae across the genus Poeciliopsis (Poeciliidae).
Placentae show considerable diversity in a number of nonmammalian, viviparous organisms, including amphibians, reptilian sauropsids, teleost fish, and chondrichthyes. However, the evolutionary processes driving the evolution of placenta are still debated. In teleost fishes, the genus Poeciliopsis (Poeciliidae) offers a rare opportunity for studying placental evolution: extensive placentation has evolved three independent times within the last 750,000 years and there is substantial interspecific variation in the degree of embryonic, maternal nutrient provisioning and development of the placenta. In poeciliids, the placenta is composed of a hypertrophied maternal follicular epithelium apposed to a highly vascularized embryonic pericardial sac. To better understand placental evolution, we have undertaken a comprehensive comparative study of the maternal follicle in eight closely related Poeciliopsis species that span the range in postfertilization, embryonic, maternal nutrient provisioning (from lecithotrophs, to moderate matrotrophs, to extensive matrotrophs). Using light and scanning electron microscopy, we found that the species that provide extensive postfertilization maternal nutrient provisioning (extensive matrotrophs) have thicker follicles and more extensive folding of the follicular epithelium compared to the lecithotrophs and moderate matrotrophs. Follicle sections and histology revealed that epithelial folds of the extensive matrotrophs are comprised primarily of cuboidal and columnar cells and are richly supplied with capillaries. Among the extensive matrotrophs, enhancements of follicle traits corresponded with increases in the level of maternal nutrient provisioning. Hypertrophied maternal follicles with richly vascularized folds can serve to increase the surface area and, thus, facilitate the transfer of substances between the mother and developing embryo. Finally, we found egg envelopes in the lecithotrophs and moderate matrotrophs, but not in the extensive matrotrophs. Morphological studies, like this one, can provide a better understanding of the natural variation in the structure and functioning of maternal and offspring traits associated with matrotrophy and, thus, insights into the processes driving placental evolution. J. Morphol. 276:707-720, 2015. © 2015 Wiley Periodicals, Inc.


Transient charge-masking effect of applied voltage on electrospinning of pure chitosan nanofibers from aqueous solutions.
The processing of a polyelectrolyte (whose functionality is derived from its ionized functional groups) into a nanofiber may improve its functionality and yield multiple functionalities. However, the electrospinning of nanofibers from polyelectrolytes is imperfect because polyelectrolytes differ considerably from neutral polymers in their rheological properties. In our study, we attempt to solve this problem by applying a voltage of opposite polarity to charges on a polyelectrolyte. The application of this 'countervoltage' can temporarily mask or screen a specific rheological property of the polyelectrolyte, making it behave as a neutral polymer. This approach can significantly contribute to the development of new functional nanofiber materials.


LvNotch signaling mediates secondary mesenchyme specification in the sea urchin embryo.
Cell-cell interactions are thought to regulate the differential specification of secondary mesenchyme cells (SMCs) and endoderm in the sea urchin embryo. The molecular bases of these interactions, however, are unknown. We have previously shown that the sea urchin homologue of the LIN-12/Notch receptor, LvNotch, displays dynamic patterns of expression within both the presumptive SMCs and endoderm during the blastula stage, the time at which these two cell types are thought to be differentially specified (Sherwood, D. R. and McClay, D. R. (1997) Development 124, 3363-3374). The LIN-12/Notch signaling pathway has been shown to mediate the segregation of numerous cell types in both invertebrate and vertebrate embryos. To directly examine whether LvNotch signaling has a role in the differential specification of SMCs and endoderm, we have overexpressed activated and dominant negative forms of LvNotch during early sea urchin development. We show that activation of LvNotch signaling increases SMC specification, while loss or reduction of LvNotch signaling eliminates or significantly decreases SMC specification. Furthermore, results from a mosaic analysis of LvNotch function as well as endogenous LvNotch expression strongly suggest that LvNotch signaling acts autonomously within the presumptive SMCs to mediate SMC specification. Finally, we demonstrate that the expansion of SMCs seen with activation of LvNotch signaling comes at the expense of presumptive endoderm cells, while loss of SMC specification results in the endoderm expanding into territory where SMCs usually arise. Taken together, these results offer compelling evidence that LvNotch signaling directly specifies the SMC fate, and that this signaling is critical for the differential specification of SMCs and endoderm in the sea urchin embryo.


Hybrid electromagnetic and image-based tracking of endoscopes with guaranteed smooth output.
Flexible fiber-optic bronchoscopy is a widespread medical procedure for the diagnosis and treatment of lung diseases. Navigation systems are needed to track the flexible endoscope within the bronchial tree. Electromagnetic (EM) tracking is currently the only technology used clinically for this purpose. The registration between EM tracking and patient anatomy may become inaccurate due to breathing motion, so the addition of image-based tracking has been proposed as a hybrid EM-image-based system. When EM tracking is used as an initialization for image registration, small changes in the initialization may lead to different local minima and noise is amplified by hybrid tracking. The tracking output is modeled as continuous and uses splines for interpolation, thus smoothness is greatly improved. The bronchoscope pose relative to computed tomography data is interpolated using Catmull-Rom splines for position and spherical linear interpolation (SLERP) for orientation. The hybrid method was evaluated using ground truth poses manually selected by experts, where mean inter-expert agreement was determined as 1.26 mm. Using four dynamic phantom data sets, the accuracy was 4.91 mm, which is equivalent to previous methods. Compared to state-of-art methods, inter-frame smoothness was improved from 2.77-3.72 to 1.24 mm. Hybrid image and electromagnetic endoscope guidance provides a more realistic and physically plausible solution with significantly less jitter. This quantitative result is confirmed by visual comparison of real and virtual video, where the virtual video output is much more consistent and robust, with fewer occasions of tracking loss or unexpected movement compared with previous methods.


Electrical detection of amine ligation to a metalloporphyrin via a hybrid SOI-MOSFET.
A close-packed monolayer of zinc 5,10,15,20-tetrakis(3-carboxyphenyl)porphyrin has been prepared and deposited on the thin native oxide covering the surface of an SOI-MOSFET (silicon-on-insulator metal-oxide-semiconductor field effect transistor) using Langmuir-Blodgett techniques. When the device is exposed to amine vapors in a nitrogen atmosphere, the amine coordinates to the zinc atom. The resulting change in electron distribution within the porphyrin leads to a large change in the drain current of the transistor, biased via a back gate. This change is sensitive to both the amount of amine present and the base strength of the amine. Only very small changes in drain current were observed with a monolayer of free base porphyrin or palmitic acid. After exposure to high pyridine concentrations, the device response saturates, but partially recovers after overnight exposure to flowing nitrogen gas. Interestingly, the device response is instantaneously reset by exposure to visible light, suggesting that photode-ligation occurs. An electrical model for the hybrid device that describes its response to ligand binding in terms of a change in the work function of the porphyrin monolayer has been developed. A transistor response to a few hundred attomoles of bound pyridine can be readily detected. This extreme sensitivity, coupled with the ability to reset the device using light, suggests that such systems might be useful as sensors.


Occupational exposure to pesticides and endotoxin and Parkinson disease in the Netherlands.
Previous research has indicated that occupational exposure to pesticides and possibly airborne endotoxin may increase the risk of developing Parkinson disease (PD). We studied the associations of PD with occupational exposure to pesticides, specifically to the functional subclasses insecticides, herbicides and fungicides, and to airborne endotoxin. In addition we evaluated specific pesticides (active ingredients) previously associated with PD. We used data from a hospital-based case-control study, including 444 patients with PD and 876 age and sex matched controls. Exposures to pesticides from application and re-entry work were estimated with the ALOHA+job-exposure matrix and with an exposure algorithm based on self-reported information on pesticide use. To assess exposure to specific active ingredients a crop-exposure matrix was developed. Endotoxin exposure was estimated with the DOM job-exposure matrix. The results showed almost no significant associations. However, ORs were elevated in the higher exposure categories for pesticides in general, insecticides, herbicides and fungicides, and below unity for endotoxin exposure. The analyses on specific active ingredients showed a significant association of PD risk with the fungicide benomyl. This study did not provide evidence for a relation between pesticide exposure and PD. However, the consistently elevated ORs in the higher exposure categories suggest that a positive association may exist. The possible association with the active ingredient benomyl requires follow-up in other studies. This study did not provide support for a possible association between endotoxin exposure and PD.


Annual rhythms of temporal niche partitioning in the Sparidae family are correlated to different environmental variables.
The seasonal timing of recurring biological processes is essential for organisms living in temperate regions. While ample knowledge of these processes exists for terrestrial environments, seasonal timing in the marine environment is relatively understudied. Here, we characterized the annual rhythm of habitat use in six fish species belonging to the Sparidae family, highlighting the main environmental variables that correlate to such rhythms. The study was conducted at a coastal artificial reef through a cabled observatory system, which allowed gathering underwater time-lapse images every 30 minutes consecutively over 3 years. Rhythms of fish counts had a significant annual periodicity in four out of the six studied species. Species-specific temporal patterns were found, demonstrating a clear annual temporal niche partitioning within the studied family. Temperature was the most important environmental variable correlated with fish counts in the proximity of the artificial reef, while daily photoperiod and salinity were not important. In a scenario of human-induced rapid environmental change, tracking phenological shifts may provide key indications about the effects of climate change at both species and ecosystem level. Our study reinforces the efficacy of underwater cabled video-observatories as a reliable tool for long-term monitoring of phenological events.


Randomized clinical trial comparing abluminal biodegradable polymer sirolimus-eluting stents with durable polymer sirolimus-eluting stents: Nine months angiographic and 5-year clinical outcomes.
The biodegradable polymer drug-eluting stents (DES) were developed to improve vascular healing. However, further data and longer-term follow-up are needed to confirm safety and efficacy of these stents. This randomized clinical trial aimed to compare safety and efficacy of 2 sirolimus-eluting stents (SES): Cordimax-a novel abluminal biodegradable polymer SES and Cypher Select-a durable polymer SES, at 9 months angiographic and 5-year clinical follow-up. We randomized 402 patients with coronary artery disease to percutaneous coronary intervention with Cordimax (n = 202) or Cypher select (n = 200). Angiographic follow-up was performed at 9 months after the index procedure and clinical follow-up annually up to 5 years. The primary endpoint was angiographic in-stent late luminal loss (LLL). Secondary endpoints included angiographic restenosis rate, target vessel revascularization (TVR), and major adverse cardiac events (MACEs; defined as cardiac death, myocardial infarction, or TVR) at 5-year follow-up. Cordimax was noninferior to Cypher select for in-stent LLL (0.25 ± 0.47 vs 0.18 ± 0.49 mm; P = 0.587) and in-stent mean diameter stenosis (22.19 ± 12.21% vs 19.89 ± 10.79%; P = 0.064) at 9 months angiographic follow-up. The MACE rates were not different at 1 year (5.9% vs 4.0%, P = 0.376); however, MACE rates from 2 to 5 years were lower in the Cordimax group (6.8% vs 13.1%; P = 0.039). Abluminal biodegradable polymer SES is noninferior to durable polymer SES at 9-month angiographic and 1-year clinical follow-up. However, MACE rates from 2 to 5 years were less in the abluminal biodegradable polymer group.


Malignant mammary tumor in female dogs: environmental contaminants.
Mammary tumors of female dogs have greatly increased in recent years, thus demanding rapid diagnosis and effective treatment in order to determine the animal survival. There is considerable scientific interest in the possible role of environmental contaminants in the etiology of mammary tumors, specifically in relation to synthetic chemical substances released into the environment to which living beings are either directly or indirectly exposed. In this study, the presence of pyrethroid insecticide was observed in adjacent adipose tissue of canine mammary tumor. High Precision Liquid Chromatography - HPLC was adapted to detect and identify environmental contaminants in adipose tissue adjacent to malignant mammary tumor in nine female dogs, without predilection for breed or age. After surgery, masses were carefully examined for malignant neoplastic lesions. Five grams of adipose tissue adjacent to the tumor were collected to detect of environmental contaminants. The identified pyrethroids were allethrin, cyhalothrin, cypermethrin, deltamethrin and tetramethrin, with a contamination level of 33.3%. Histopathology demonstrated six female dogs (66.7%) as having complex carcinoma and three (33.3%) with simple carcinoma. From these tumors, seven (77.8%) presented aggressiveness degree III and two (22.2%) degree I. Five tumors were positive for estrogen receptors in immunohistochemical analysis. The contamination level was observed in more aggressive tumors. This was the first report in which the level of environmental contaminants could be detected in adipose tissue of female dogs with malignant mammary tumor, by HPLC. Results suggest the possible involvement of pyrethroid in the canine mammary tumor carcinogenesis. Hence, the dog may be used as a sentinel animal for human breast cancer, since human beings share the same environment and basically have the same eating habits.


Electronic and magnetic properties of Ti(2)O(3), Cr(2)O(3), and Fe(2)O(3) calculated by the screened exchange hybrid density functional.
The electronic and magnetic properties of the transition metal sesqui-oxides Cr(2)O(3), Ti(2)O(3), and Fe(2)O(3) have been calculated using the screened exchange (sX) hybrid density functional. This functional is found to give a band structure, bandgap, and magnetic moment in better agreement with experiment than the local density approximation (LDA) or the LDA+U methods. Ti(2)O(3) is found to be a spin-paired insulator with a bandgap of 0.22 eV in the Ti d orbitals. Cr(2)O(3) in its anti-ferromagnetic phase is an intermediate charge transfer Mott-Hubbard insulator with an indirect bandgap of 3.31 eV. Fe(2)O(3), with anti-ferromagnetic order, is found to be a wide bandgap charge transfer semiconductor with a 2.41 eV gap. Interestingly sX outperforms the HSE functional for the bandgaps of these oxides.


Quantitative risk assessment of COVID-19 aerosol transmission indoors: a mechanistic stochastic web application.
An increasing body of literature suggests that aerosol inhalation plays a primary role in COVID-19 transmission, particularly in indoor settings. Mechanistic stochastic models can help public health professionals, engineers, and space planners understand the risk of aerosol transmission of COVID-19 to mitigate it. We developed such model and a user-friendly web application to meet the need of accessible risk assessment tools during the COVID-19 pandemic. We built our model based on the Wells-Riley model of respiratory disease transmission, using quanta emission rates obtained from COVID-19 outbreak investigations. In this report, three modelled scenarios were evaluated and compared to epidemiological studies looking at similar settings: classrooms, weddings, and heavy exercise sessions. We found that the risk of long-range aerosol transmission increased 309-332% when people were not wearing masks, and 424-488% when the room was poorly ventilated in addition to no masks being worn across the scenarios. Also, the risk of transmission could be reduced by ∼40-60% with ventilation rates of 5 ACH for 1-4 h exposure events, and ∼70% with ventilation rates of 10 ACH for 4 h exposure events. Relative humidity reduced the risk of infection (inducing viral inactivation) by a maximum of ∼40% in a 4 h exposure event at 70% RH compared to a dryer indoor environment with 25% RH. Our web application has been used by more than 1000 people in 52 countries as of September 1st, 2021. Future work is needed to obtain SARS-CoV-2 dose-response functions for more accurate risk estimates.


Bioethics: a balancing of concerns in context.
Ethics is a philosophical approach which is increasingly being used to identify acceptable behaviour in a health context. Bioethics has emerged as a term for ethics in health and medical contexts. Bioethics is about the application of reasoning to a health context. It relies on the people in each context to reflect on ethics concerns, and to make acceptable decisions on how to behave. This paper canvasses current concerns in bioethics, and demonstrates the essential features of context, and players in the context, in ethical discussion.


Synthetic efficiency in enzyme mechanisms involving carbocations: aristolochene synthase.
An intramolecular proton-transfer mechanism has been proposed for the carbocationic cyclization of farnesyl pyrophosphate (FPP) to (+)-aristolochene catalyzed by aristolochene synthase. This novel mechanism, which is based on results obtained by high-level ab initio molecular orbital and density functional theory calculations, differs from the previous proposal in the key step of carbocation propagation prior to the formation of the bicyclic carbon skeleton. Previously, germacrene A was proposed to be generated as an intermediate by deprotonation of germacryl cation followed by reprotonation of the C6-C7 double bond to yield eudesmane cation. In the mechanism proposed here the direct intramolecular proton transfer has a computed barrier of about 22 kcal/mol, which is further lowered to 16-20 kcal/mol by aristolochene synthase. An alternative pathway is also possible through a proton shuttle via a pyrophosphate-bound water molecule. The mechanism proposed here is consistent with the observation that germacrene A is not a substrate of aristolochene synthase. Furthermore, the modeled substrate-enzyme complex suggests that Trp 334 and Phe 178 play key roles in positioning the substrate in the reactive orientation in the binding pocket. This is consistent with experimental findings that mutations of either residue lead to pronounced generation of aborted cyclization products.


Epidemiology of hydrocele and spermatocele; incidence, treatment and complications.
Objectives: To estimate the incidence of men seeking specialized care and receiving treatment for hydro or spermatocele complaints. Also, to determine the risk of complications of treatment. Materials and methods: The total number of men living in Sweden each year from 2005 to 2014 was used to calculate incidence and age distribution of adult (≥18 years) men seeking specialized healthcare with either hydro or spermatocele. This was done by using nationwide registries, mandatory by law. They contain information on primary or discharge diagnosis, procedure codes and antibiotic prescriptions. Also, complication rates comparing aspiration (with or without sclerotherapy) and conventional surgery were analysed. Results: The incidence of men with either hydro or spermatocele diagnosis in specialized healthcare was ∼100/100,000 men. The treatment incidence was 17/100,000 men. Orchiectomy was used as primary treatment in 2.4% of cases. The risk of experiencing a complication was clinically and statistically significantly increased with conventional surgery as compared with aspiration, 17.5% (1607/9174) vs 4.6% (181/3920), corresponding to relative risk of 3.79 (95% CI = 3.27-4.40). Hematoma and infections were the most common complications. Conclusion: Hydro and spermatoceles are common, affecting elderly men. Aspiration seems advantageous with respect to complications and can be recommended due to the benign course of the disease. The indication for conventional surgery might be questioned such as the use of orchiectomy as primary treatment.


Growth of B-lymphocyte colonies in vitro.
In semisolid agar cultures containing mercaptoethanol, cells from the spleen, lymph nodes, marrow, peritoneal cavity, thoracic duct, and blood of normal mice generated clusters and colonies of up to 3,000 cells. Colony numbers and growth were markedly enhanced by the addition of sheep red cells. The frequency of colony-forming cells in the spleen or lymph nodes was 0.5-2.0%, and cluster forming cells were approximately five times more numerous. The mononuclear cells comprising these colonies had the electronmicroscopic morphology of immature lymphoid and plasma cells. The majority of the cells possessed Fc receptors, 61-69% reacted with anti-mu-serum and 4-11% with anti-gamma2-serum. Analysis of single cells from individual colonies indicated a higher frequency of the cells with membrane immunoglobulin and a clonal pattern of anti-mu or anti-gamma-reactivity. The clonal nature of colonies was supported by an analysis of NIP-binding cells in colonies grown from CBA spleen cells enriched for NIP-binding cells. Mass-harvested colony cells synthesized immunoglobulin in short-term liquid cultures. It is concluded that the colonies are clones of functionally active B-lymphoid cells.


Fully automated reduction of ocular artifacts in high-dimensional neural data.
The reduction of artifacts in neural data is a key element in improving analysis of brain recordings and the development of effective brain-computer interfaces. This complex problem becomes even more difficult as the number of channels in the neural recording is increased. Here, new techniques based on wavelet thresholding and independent component analysis (ICA) are developed for use in high-dimensional neural data. The wavelet technique uses a discrete wavelet transform with a Haar basis function to localize artifacts in both time and frequency before removing them with thresholding. Wavelet decomposition level is automatically selected based on the smoothness of artifactual wavelet approximation coefficients. The ICA method separates the signal into independent components, detects artifactual components by measuring the offset between the mean and median of each component, and then removing the correct number of components based on the aforementioned offset and the power of the reconstructed signal. A quantitative method for evaluating these techniques is also presented. Through this evaluation, the novel adaptation of wavelet thresholding is shown to produce superior reduction of ocular artifacts when compared to regression, principal component analysis, and ICA.


Simulation-based training for nurses in sterile techniques during central vein catheterization.
The effectiveness of simulation-based training of critical care nurses in sterile techniques has not been determined. To evaluate the effectiveness of simulation-based training of critical care nurses to use sterile techniques during central vein catheterization and the effect of such training on infection rates. A prospective controlled study with 12-month observational follow-up to assess the rate of catheter-related bloodstream infections in a 23-bed medical, surgical, neurological critical care unit. Forty-six critical care nurses completed assessment and training in sterile technique skills in the simulation laboratory. Performance scores at baseline were poor: median scores in each category ranging from 0 to 2 out of a maximum score of 4 and a median total score of 7 out of a maximum score of 24. After simulation-based training, nurses' median scores in each ST category and their total scores improved significantly, with the median total score increasing to 23 (P < .01; median difference, 15; 95% CI, 14-16). After completion of the simulation-based training intervention, the mean infection rate in the unit was reduced by 85% from 2.61 to 0.4 infections per 1000 catheter-days (P = .02). The incidence rate-ratio derived from the Poisson regression (0.15; 95% CI, 0.03-0.78) indicates an 85% reduction in the incidence of catheter-related bloodstream infections in the unit after the intervention. Simulation-based training of critical care nurses in sterile technique is an important component in the strategy to reduce the occurrence of such infections and promote patient safety.


Comparison of the metabolic effects of recombinant human insulin-like growth factor-I and insulin. Dose-response relationships in healthy young and middle-aged adults.
The actions of recombinant human insulin-like growth factor-I (rhIGF-I) and insulin were compared in 21 healthy young (24 +/- 1 yr) and 14 healthy middle-aged (48 +/- 2 yr) subjects during 3-h paired euglycemic clamp studies using one of three doses (rhIGF-I 0.2, 0.4, and 0.8 micrograms/kg.min and insulin 0.2, 0.4, and 0.8 mU/kg.min, doses chosen to produce equivalent increases in glucose uptake). In younger subjects, rhIGF-I infusions suppressed insulin by 19-33%, C-peptide by 47-59% and glucagon by 33-47% (all, P < 0.02). The suppression of C-peptide was less pronounced with insulin than with rhIGF-I (P < 0.007). The metabolic responses to rhIGF-I and insulin were remarkably similar: not only did both hormones increase glucose uptake and oxidation in a nearly identical fashion, but they also produced similar suppression of glucose production, free fatty acid levels, and fat oxidation rates. In contrast, rhIGF-I had a more pronounced amino acid-lowering effect than did insulin (P < 0.004). In middle-aged subjects, basal IGF-I levels were 44% lower (P < 0.0001) whereas basal insulin and C-peptide were 20-25% higher than in younger subjects. Age did not alter the response to rhIGF-I. However, insulin-induced stimulation of glucose uptake was blunted in older subjects (P = 0.05). Our data suggest that absolute IGF-I and relative insulin deficiency contribute to adverse metabolic changes seen in middle age.


Aqueous two-phase system formation kinetics for elastin-like polypeptides of varying chain length.
The kinetics of aqueous two-phase system (ATPS) formation for elastin-like polypeptides (ELP) with defined chemical composition and chain length was investigated by dark field microscopy in an on-chip format with a linear temperature gradient. Scattering intensities from peptide solutions in the presence and absence of sodium dodecyl sulfate (SDS) were recorded as a function of temperature and time, simultaneously. It was found that the formation of the ATPS for three ELPs of different molecular weights (36 075, 59 422, and 129 856 Da) in the absence of SDS followed a coalescence mechanism, and the rate constant and activation energy were independent of chain length. With the introduction of SDS into the ELP solutions, the rate constants were attenuated more strongly with increasing chain length. Moreover, the coalescence process in the presence of SDS showed non-Arrhenius kinetics as a function of temperature. For the two shorter ELPs, ATPS formation occurred via coalescence at all SDS concentrations and temperatures investigated. On the other hand, the coalescence process was greatly suppressed for the longest ELP at elevated temperatures and higher SDS concentrations. Under these circumstances, ATPS formation was forced to proceed via a mixed Ostwald ripening and coalescence mechanism.


Efficacy of Different Types of Mobilization Techniques in Patients With Primary Adhesive Capsulitis of the Shoulder: A Systematic Review.
To systematically review the literature for efficacy of isolated articular mobilization techniques in patients with primary adhesive capsulitis (AC) of the shoulder. PubMed and Web of Science were searched for relevant studies published before November 2014. Additional references were identified by manual screening of the reference lists. All English language randomized controlled trials evaluating the efficacy of mobilization techniques on range of motion (ROM) and pain in adult patients with primary AC of the shoulder were included in this systematic review. Twelve randomized controlled trials involving 810 patients were included. Two reviewers independently screened the articles, scored methodologic quality, and extracted data for analysis. The review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. All studies were assessed in duplicate for risk of bias using the Physiotherapy Evidence Database Scale for randomized controlled trials. The efficacy of 7 different types of mobilization techniques was evaluated. Angular mobilization (n=2), Cyriax approach (n=1), and Maitland technique (n=6) showed improvement in pain score and ROM. With respect to translational mobilizations (n=1), posterior glides are preferred to restore external rotation. Spine mobilizations combined with glenohumeral stretching and both angular and translational mobilization (n=1) had a superior effect on active ROM compared with sham ultrasound. High-intensity mobilization (n=1) showed less improvement in the Constant Murley Score than a neglect group. Finally, positive long-term effects of the Mulligan technique (n=1) were found on both pain and ROM. Overall, mobilization techniques have beneficial effects in patients with primary AC of the shoulder. Because of preliminary evidence for many mobilization techniques, the Maitland technique and combined mobilizations seem recommended at the moment.


Using diaries to collect data in resource-poor settings: questions on design and implementation.
Diaries, as a tool for data collection, have been around for some time. Lessons shared to date come from disparate settings and there remains a degree of ambiguity regarding the value of diaries, particularly in resource-poor settings where populations are often illiterate and highly mobile. We recently designed a pictorial diary for the collection of data on household consumption and expenditure in Tanzania and The Gambia. A random sample of 361 diary keepers in The Gambia and 308 in Tanzania maintained diaries for a period of 12 months. The aim of this paper is to share some of the lessons learnt in developing and applying this instrument. It is structured around a series of questions about diaries that we found relatively few answers to when we first embarked on this study. These questions include: how should a diary be designed? How long should a diary be maintained? When should entries be recorded? Who should keep the diary? The motive behind this paper is simple: to provide future researchers who are contemplating using diaries in resource-poor settings with some practical information that may guide them through this process.


An artificial life view of the Collatz problem.
This letter presents a new, artificial-life-based view of the Collatz problem, a well-known mathematical problem about the behavior of a series of positive integers generated by a simple arithmetical rule. The Collatz conjecture asserts that this series always falls into a 4 → 2 → 1 cycle regardless of its initial values. No formal proof has been given yet. In this letter, the behavior of the series is considered an ecological process of artificial organisms (1s in bit strings). The Collatz conjecture is then reinterpreted as the competition between population growth and extinction. This new interpretation has made it possible to analytically calculate the growth and extinction speeds of bit strings. The results indicate that the extinction is always faster than the growth, providing an ecological explanation for the conjecture. Future research directions are also suggested.


Naturalism and the social model of disability: allied or antithetical?
The question of how disability should be defined is fraught with political, ethical and philosophical complexities. The social model of disability, which posits that disability is socially and politically constructed and is characterised by systemic barriers, has enjoyed broad acceptance that is exemplified by the slow but steady progress in securing civil rights for persons with disabilities. Yet, there remains a palpable tension between disability studies scholars and activists and bioethicists. While philosophers and bioethicists should heed the theories developed from the standpoint of persons with disabilities, disability activists should acknowledge the possibility that philosophical theories about the basic reality of disease, illness, health, function and impairment offer a more steady foundation for social or political critiques of disability. I argue that naturalistic theories of function and dysfunction provide a valuable starting point to clarify questions about the broader concept of disability. A naturalist theory of function may serve as the core of the concept of disability and provide disability scholars and bioethicists alike a stronger set of arguments in analysing real or potential instances of disability.


Genetic dissection of the amyloid precursor protein in developmental function and amyloid pathogenesis.
Proteolytic processing of the amyloid precursor protein (APP) generates large soluble APP derivatives, β-amyloid (Aβ) peptides, and APP intracellular domain. Expression of the extracellular sequences of APP or its Caenorhabditis elegans counterpart has been shown to be sufficient in partially rescuing the CNS phenotypes of the APP-deficient mice and the lethality of the apl-1 null C. elegans, respectively, leaving open the question as what is the role of the highly conserved APP intracellular domain? To address this question, we created an APP knock-in allele in which the mouse Aβ sequence was replaced by the human Aβ. A frameshift mutation was introduced that replaced the last 39 residues of the APP sequence. We demonstrate that the C-terminal mutation does not overtly affect APP processing and amyloid pathology. In contrast, crossing the mutant allele with APP-like protein 2 (APLP2)-null mice results in similar neuromuscular synapse defects and early postnatal lethality as compared with mice doubly deficient in APP and APLP2, demonstrating an indispensable role of the APP C-terminal domain in these development activities. Our results establish an essential function of the conserved APP intracellular domain in developmental regulation, and this activity can be genetically uncoupled from APP processing and Aβ pathogenesis.


Acute ethanol ingestion increases platelet reactivity: is there a relationship to stroke?
The effects of ethanol ingestion on ADP-induced platelet aggregation and associated thromboxane formation were studied in the platelet-rich plasma of 10 healthy male volunteers, each serving as his own control. Ethanol caused a transient decrease in threshold concentration of ADP to produce irreversible aggregation. Over a wide range of ADP total platelet aggregation was increased. In the presence of irreversible aggregation, formation of thromboxane B2 rose from 303 +/- 56 to 950 +/- 212 fmol per 10(7) platelets (p less than 0.01). The effects lasted as long as ethanol was present in blood, did not significantly correlate to blood ethanol levels and exhibited great individual variation. It remains to be proved, whether these observations could contribute to the increased risk of ischemic brain infarction associated with acute ethanol ingestion.


Detecting frontotemporal dysfunction in ALS: utility of the ALS Cognitive Behavioral Screen (ALS-CBS).
Up to half of patients with ALS develop cognitive impairment during the course of the illness. Despite this, there is no simple tool for screening patients in the clinical setting. This study examines the sensitivity, specificity and accuracy of the ALS Cognitive Behavioral Screen (ALS-CBS). We administered the measure to 112 ALS patients, including 31 who also underwent comprehensive neuropsychological testing. Screen results were validated by determining the accuracy against the full battery. Optimal cut-off scores for predicting the correct diagnosis were determined, and mean scores were compared between patients, controls and different diagnostic groups. The results demonstrated that mean cognitive scores differed between ALS and normal controls (p < 0.0001). The cognitive section differentiated ALS-FTD from other ALS patients with 100% accuracy. Cognitively normal ALS patients could be distinguished from those with any cognitive deficit with 71% specificity and 85% sensitivity. A separate behavioral score was significantly lower in the ALS cohort compared to controls (p < 0.0001) and predicted ALS-FTD with 80% sensitivity and 88% specificity. In conclusion, the ALS-CBS can aid in detecting cognitive and behavioral impairment in a clinical setting, although it does not replace formal diagnostic assessment. Further validation with larger sample sizes will clarify its clinical utility.


Inflammatory myopathy in a patient with Aicardi-Goutières syndrome.
Aicardi-Goutières syndrome (AGS) is an inflammatory disorder belonging to the recently characterized group of type I interferonopathies. The most consistently affected tissues in AGS are the central nervous system and skin, but various organ systems and tissues have been reported to be affected, pointing to the systemic nature of the disease. Here we describe a patient with AGS due to a homozygous p.Arg114His mutation in the TREX1 gene. The histologically proven inflammatory myopathy in our patient expands the range of clinical features of AGS. Histological signs of muscle biopsies in the proband, and in two other AGS patients described earlier, are similar to those seen in various autoimmune myositises and could be ascribed to inapproapriate IFN I activation. In view of signs of possible mitochondrial damage in AGS, we propose that mitochondrial DNA could be a trigger of autoimmune responses in AGS.