Illustrated identification keys to strongylid parasites (Strongylidae: Nematoda) of horses, zebras and asses (Equidae).
The Equidae (the horse, Equus caballus, the ass, Equus asinus, zebras and their hybrids) are hosts to a great variety of nematode parasites, some of which can cause significant morbidity or mortality if individual hosts are untreated. Worldwide the nematode parasites of horses belong to 7 suborders, 12 families, 29 genera and 83 species. The great majority (19 of 29 genera and 64 of 83 species) are members of the family Strongylidae, which includes the most common and pathogenic nematode parasites of horses. Only the Strongylidae are included in this treatise. The Strongylidae (common name strongylids) of horses--nematodes with a well-developed buccal capsule, a mouth collar with two leaf-crowns, and a strongyloid (common name of superfamily Strongyloidea) copulatory bursa--can be separated into two subfamilies: Strongylinae (common name strongylins), usually large or medium-sized with a globular or funnel-shaped buccal capsule; and Cyathostominae (common name cyathostomins), usually small to medium-sized with a cylindrical buccal capsule. The increased attention to strongylid nematode parasites of horses has resulted in the need for updated diagnostic keys to these parasites using readily recognizable characters and the most recent literature on their systematics. Because the cyathostomins have been historically difficult to identify, and because they have emerged as the most significant nematode pathogens of horses, we provide a brief nomenclatural and taxonomic history and an introduction to the morphology of this group. This treatise is intended to serve as a basic working tool--providing easy identifications to genus and species of adult strongylid nematodes of equids. All strongylid nematodes normally parasitic in horses, the ass (and their hybrids), and zebras are included. The keys are illustrated with line drawings and halftone photomicrographs of each species. A short discussion of the systematics of the genus and species is provided for each genus following the species descriptions. Species diagnoses and a synonymy of each species is provided. Geographic distribution, prevalence, and location in host are also given for each species.


Dairy cow trade-off preference for 2 different lying qualities: Lying surface and lying space.
Lying down is an important behavior for cows, contributing to their health and welfare. With dairy cows being housed for increasingly longer periods, if not year-round, it is important to ensure that dairy cow lying comfort is not compromised when they are housed. The aim of this study was to assess cow preference for 2 different qualities of lying area that appear to be important to cows-surface type and an open lying space-to better understand how to optimize lying comfort for cows when housed. Twenty-four Holstein dairy cows were used during the study, which took place in Scotland from July to November 2018. The study consisted of 6 experimental periods, each lasting a total of 21 d. Cows were tested 4 at a time and individually housed in their own test pen. Each pen had 3 lying surfaces: sand, mattress, and straw (2.4 m × 2.4 m each) with a freestall in the middle of each, which could be removed. Cows were given access to one surface at a time (training period) with a freestall for 2 d, and then given a choice of all 3 surfaces for 2 d. When given the choice with freestalls in position, cows spent, on average, the largest amount of their lying time on straw (46.6 ± 7.8%) followed by mattress (44.3 ± 12.4%). Freestalls were then removed and the training and choice phase was repeated on the following day, with cows, on average, spending the most time lying on straw (64.4 ± 7.2%). Finally, a freestall was refitted onto each cow's most preferred surface and the cows were given a choice between lying on their most preferred surface with a freestall (P1 + freestall) or on their second or third preferred surface without a freestall (P2 + open and P3 + open, respectively) for 3 d. During this final trade-off stage, of the 19 cows for which data were available, 14 cows chose to give up the opportunity to lie down on their most preferred surface to have more space on P2 + open and P3 + open, 3 cows chose to lie down on P1 + freestall, and 2 cows made no clear choice. Overall, cows spent the largest amount of their total lying time on their second most preferred surface as an open lying space (65.7 ± 6.9%) compared with their preferred surface with a freestall (20.5 ± 5.9%) and their third preferred surface as an open lying space (13.8 ± 3.7%). The results indicate that when lying down, these dairy cows value an open lying space more than the lying surface.


Effects of Paeoniae Radix, a traditional Chinese medicine, on the pharmacokinetics of phenytoin.
Phenytoin (PHT), one of the most widely prescribed antiepileptic drugs, has been reported to be associated with numerous drug-drug interactions. However, there are far fewer reports about the pharmacokinetic interactions between PHT and traditional Chinese medicines (TCMs). Paeoniae Radix (PR), one of the well-known TCMs, is used as an adjunct in some epileptic patients. In the present work, we studied the influences of PR on the pharmacokinetics of PHT in rats to identify the possible interactions between PR and PHT. A single dose of PHT (100 mg/kg) alone or in combination with PR extract (300 mg/kg) was administered by gavage to male SD rats. Serial blood samples of PHT were obtained for up to 24 h post-administration and measured by high-performance liquid-chromatography. The free (unbound) plasma concentrations of PHT were determined by fluorescence polarization immunoassay. The plasma concentrations were used to construct pharmacokinetic profiles by plotting drug concentration-time curves. All data were subsequently processed by the computer program WINNONLIN. Statistical comparisons of pharmacokinetic parameters were performed with the unpaired Student t-test. The mean maximum plasma concentration of PHT was attained 2 h after oral administration of PHT alone and 4-6 h after oral administration of PHT in combination with PR. The plasma level of PHT declined with a half-life of 5.38 h after PHT alone and 4.03 h after PHT and PR given together. No statistically significant differences were obtained in most of the pharmacokinetic parameters (Cmax, AUC, t1/2, MRT and CL/F) and protein binding rates of PHT between the two treatments. However, significant differences in Tmax and Vd/F between groups were noted. The significant increase in Tmax indicated that simultaneous oral administration of PR delayed the absorption of PHT. The delayed absorption of PHT might lead to its slow onset of clinical effect. There were no significant differences in Cmax, AUC, t1/2, MRT and CL/F of PHT between the two groups, showing that PR could not significantly affect the extent of absorption, metabolism and elimination of PHT. No significant difference in protein binding rate was found, indicating that PR might not significantly alter the protein binding of PHT. While a significant decrease in Vd/F was noted, the mechanism underlying the apparently decreased Vd/F of PHT influenced by PR needs further study.


Borg scale is valid for ratings of perceived exertion for individuals with Parkinson's disease.
Parkinson's disease is a neurodegenerative disease that has traditionally been treated with anti-parkinsonian medication. There is increasing evidence that exercise is beneficial to those with PD, therefore, it is necessary to validate a measure of exertion that can be implemented across exercise settings that may not have the capability to actively monitor heart rate. The aim of this project was to determine the validity of the Borg RPE scale in individuals with PD undergoing a maximal progressive cycling exercise test. Thirty-eight males and females (58.5 ± 8.1 yrs) with a clinical diagnosis of idiopathic PD, Hoehn and Yahr stage II-III, completed a maximal exercise test. Heart rate was monitored continuously, with RPE being recorded during the last minute of each stage of the test. Correlation analysis was used to evaluate the relationship between RPE and continuous heart rate monitoring. A significant, positive correlation was present between RPE and heart rate and RPE and workload, r = 0.61 and r = 0.77 respectively. A separate mixed effects model regression analyses indicated that RPE was a significant predictor of heart rate (p < 0.001) and workload (p < 0.001). The results of a mixed effect models that RPE scores indicated that RPE values at commonly prescribed workout intensities were not associated with age, gender, or disease severity (p>0.05). Significant, positive correlation between RPE and HR indicates that the Borg category ratio scale may be used in individuals with Parkinson's disease in which formal exercise testing may not be available.


Differential regulations of fibronectin and laminin in Smad2 activation in vascular endothelial cells in response to disturbed flow.
Atherosclerosis occurs in arterial curvatures and branches, where the flow is disturbed with low and oscillatory shear stress (OSS). The remodeling and alterations of extracellular matrices (ECMs) and their composition is the critical step in atherogenesis. In this study, we investigated the effects of different ECM proteins on the regulation of mechanotransduction in vascular endothelial cells (ECs) in response to OSS. Through the experiments ranging from in vitro cell culture studies on effects of OSS on molecular signaling to in vivo examinations on clinical specimens from patients with coronary artery disease (CAD), we elucidated the roles of integrins and different ECMs, i.e., fibronectin (FN) and laminin (LM), in transforming growth factor (TGF)-β receptor (TβR)-mediated Smad2 activation and nuclear factor-κB (NF-κB) signaling in ECs in response to OSS and hence atherogenesis. OSS at 0.5±12 dynes/cm2 induces sustained increases in the association of types I and II TβRs with β1 and β3 integrins in ECs grown on FN, but it only transient increases in ECs grown on LM. OSS induces a sustained activation of Smad2 in ECs on FN, but only a transient activation of Smad2 in ECs on LM. OSS-activation of Smad2 in ECs on FN regulates downstream NF-κB signaling and pro-inflammatory gene expression through the activation of β1 integrin and its association with TβRs. In contrast, OSS induces transient activations of β1 and β3 integrins in ECs on LM, which associate with type I TβR to regulate Smad2 phosphorylation, resulting in transient induction of NF-κB and pro-inflammatory gene expression. In vivo investigations on diseased human coronary arteries from CAD patients revealed that Smad2 is highly activated in ECs of atherosclerotic lesions, which is accompanied by the concomitant increase of FN rather than LM in the EC layer and neointimal region of atherosclerotic lesions. Our findings provide new insights into the mechanisms of how OSS regulates Smad2 signaling and pro-inflammatory genes through the complex signaling networks of integrins, TβRs, and ECMs, thus illustrating the molecular basis of regional pro-inflammatory activation within disturbed flow regions in the arterial tree.


Numerical modeling and verification of a sonobioreactor and its application on two model microorganisms.
Ultrasound has many uses, such as in medical imaging, monitoring of crystallization, characterization of emulsions and suspensions, and disruption of cell membranes in the food industry. It can also affect microbial cells by promoting or slowing their growth and increasing the production of some metabolites. However, the exact mechanism explaining the effect of ultrasound has not been identified yet. Most equipment employed to study the effect of ultrasound on microorganisms has been designed for other applications and then only slightly modified. This results in limited control over ultrasound frequency and input power, or pressure distribution in the reactor. The present study aimed to obtain a well-defined reactor by simulating the pressure distribution of a sonobioreactor. Specifically, we optimized a sonotrode to match the bottle frequency and compared it to measured results to verify the accuracy of the simulation. The measured pressure distribution spectrum presented the same overall trend as the simulated spectrum. However, the peaks were much less intense, likely due to non-linear events such as the collapse of cavitation bubbles. To test the application of the sonobioreactor in biological systems, two biotechnologically interesting microorganisms were assessed: an electroactive bacterium, Geobacter sulfurreducens, and a lignocellulose-degrading fungus, Fusarium oxysporum. Sonication resulted in increased malate production by G. sulfurreducens, but no major effect on growth. In comparison, morphology and growth of F. oxysporum were more sensitive to ultrasound intensity. Despite considerable morphological changes at 4 W input power, the growth rate was not adversely affected; however, at 12 W, growth was nearly halted. The above findings indicate that the novel sonobioreactor provides an effective tool for studying the impact of ultrasound on microorganisms.


The serpentine optical waveguide: engineering the dispersion relations and the stopped light points.
We present a study a new type of optical slow-light structure comprising a serpentine shaped waveguide were the loops are coupled. The dispersion relation, group velocity and GVD are studied analytically using a transfer matrix method and numerically using finite difference time domain simulations. The structure exhibits zero group velocity points at the ends of the Brillouin zone, but also within the zone. The position of mid-zone zero group velocity point can be tuned by modifying the coupling coefficient between adjacent loops. Closed-form analytic expressions for the dispersion relations, group velocity and the mid-zone zero v(g) points are found and presented.


Effects of red clover extracts on breast cancer cell migration and invasion.
Postmenopausal hormone therapy is associated with increased incidence of breast cancer. For this reason alternative therapeutic options to treat menopausal symptoms have been developed. Red clover extracts (RCE) are rich in isoflavones, particularly genistein and daidzein and they have been proved to be effective in reducing vasomotor symptoms in a number of studies. Due to their partial selectivity of action on estrogen receptors (ERs) these compounds have been claimed to be safer on the breast. In this article, we explored the action of RCE on motility and invasion of ER positive breast cancer cells and we partially characterized the signaling mechanisms. The principal isoflavones contained in RCE acted as weak estrogenic compounds when administered alone. However, when provided in association with physiological amounts of estradiol, RCE acted as estrogen antagonist on remodeling of actin cytoskeleton that are requested to enact cell movement and with related modifications of the activity of actin-binding proteins, such as moesin. These results offer novel information on the molecular actions of isoflavones contained in red clover on breast cancer cells, supporting a possible action of these molecules as natural selective estrogen receptor modulators in the presence of physiological amounts of estrogens.


Propolis prevents aluminium-induced genetic and hepatic damages in rat liver.
Aluminium is present in several manufactured foods and medicines and is also used in water purification. Therefore, the present experiment was undertaken to determine the effectiveness of propolis in modulating the aluminium chloride (AlCl(3)) induced genotoxicity and hepatotoxicity in liver of rats. Animals were assigned to 1 of 4 groups: control; 34 mg AlCl(3)/kg bw; 50mg propolis/kg bw; AlCl(3) (34 mg/kg bw) plus propolis (50mg/kg bw), respectively. Rats were orally administered their respective doses daily for 30 days. At the end of the experiment, rats were anesthetized and hepatocytes (HEP) were isolated for counting the number of micronucleated hepatocytes (MNHEPs). In addition, the levels of serum enzymes and histological alterations in liver were investigated. AlCl(3) caused a significant increase in MNHEPs, alkaline phosphatase, transaminases (AST and ALT) and lactate dehydrogenase (LDH). Furthermore, severe pathological damages such as: sinusoidal dilatation, congestion of central vein, lipid accumulation and lymphocyte infiltration were established in liver. On the contrary, treatment with propolis alone did not cause any adverse effect on above parameters. Moreover, simultaneous treatments with propolis significantly modulated the toxic effects of AlCl(3). It can be concluded that propolis has beneficial influences and could be able to antagonize AlCl(3) toxicity.


Transcutaneous Vagus Nerve Stimulation Enhances Post-error Slowing.
People tend to slow down after they commit an error, a phenomenon known as post-error slowing (PES). It has been proposed that slowing after negative feedback or unforeseen errors is linked to the activity of the locus coeruleus-norepinephrine (LC-NE) system, but there is little direct evidence for this hypothesis. Here, we assessed the causal role of the noradrenergic system in modulating PES by applying transcutaneous vagus nerve stimulation (tVNS), a new noninvasive and safe method to stimulate the vagus nerve and to increase NE concentrations in the brain. A single-blind, sham-controlled, between-group design was used to assess the effect of tVNS in healthy young volunteers (n = 40) during two cognitive tasks designed to measure PES. Results showed increased PES during active tVNS, as compared with sham stimulation. This effect was of similar magnitude for the two tasks. These findings provide evidence for an important role of the noradrenergic system in PES.


Haiti, insecurity, and the politics of asylum.
In this article, I seek to show how states of insecurity provoked by ongoing social, economic, and political ruptures in Haiti can disorder individual subjectivity and generate the flight of individuals seeking asylum within and across borders. Nongovernmental actors working in Haiti and with Haitians in the diaspora frequently managed the long-term psychosocial effects of insecurity. Their interventions can range from repressive to compassionate and influence the formation of identity and the embodied experiences of trauma for vulnerable Haitians. The case of a young Haitian refugee who was repatriated to Haiti from the United States in the 1990s demonstrates how insecurity is both an existential state reflecting the disordering of embodied experience, as well as a collective sociopolitical condition the effects of which cannot be managed or contained within national borders. The case is emblematic of the plight of thousands of Haitians affected by the January 12, 2010, earthquake.


Quantifying the number of pregnancies at risk of malaria in 2007: a demographic study.
Comprehensive and contemporary estimates of the number of pregnancies at risk of malaria are not currently available, particularly for endemic areas outside of Africa. We derived global estimates of the number of women who became pregnant in 2007 in areas with Plasmodium falciparum and P. vivax transmission. A recently published map of the global limits of P. falciparum transmission and an updated map of the limits of P. vivax transmission were combined with gridded population data and growth rates to estimate total populations at risk of malaria in 2007. Country-specific demographic data from the United Nations on age, sex, and total fertility rates were used to estimate the number of women of child-bearing age and the annual rate of live births. Subregional estimates of the number of induced abortions and country-specific stillbirths rates were obtained from recently published reviews. The number of miscarriages was estimated from the number of live births and corrected for induced abortion rates. The number of clinically recognised pregnancies at risk was then calculated as the sum of the number of live births, induced abortions, spontaneous miscarriages, and stillbirths among the population at risk in 2007. In 2007, 125.2 million pregnancies occurred in areas with P. falciparum and/or P. vivax transmission resulting in 82.6 million live births. This included 77.4, 30.3, 13.1, and 4.3 million pregnancies in the countries falling under the World Health Organization (WHO) regional offices for South-East-Asia (SEARO) and the Western-Pacific (WPRO) combined, Africa (AFRO), Europe and the Eastern Mediterranean (EURO/EMRO), and the Americas (AMRO), respectively. Of 85.3 million pregnancies in areas with P. falciparum transmission, 54.7 million occurred in areas with stable transmission and 30.6 million in areas with unstable transmission (clinical incidence <1 per 10,000 population/year); 92.9 million occurred in areas with P. vivax transmission, 53.0 million of which occurred in areas in which P. falciparum and P. vivax co-exist and 39.9 million in temperate regions with P. vivax transmission only. In 2007, 54.7 million pregnancies occurred in areas with stable P. falciparum malaria and a further 70.5 million in areas with exceptionally low malaria transmission or with P. vivax only. These represent the first contemporary estimates of the global distribution of the number of pregnancies at risk of P. falciparum and P. vivax malaria and provide a first step towards a more informed estimate of the geographical distribution of infection rates and the corresponding disease burden of malaria in pregnancy.


Library analysis of SCHEMA-guided protein recombination.
The computational algorithm SCHEMA was developed to estimate the disruption caused when amino acid residues that interact in the three-dimensional structure of a protein are inherited from different parents upon recombination. To evaluate how well SCHEMA predicts disruption, we have shuffled the distantly-related beta-lactamases PSE-4 and TEM-1 at 13 sites to create a library of 2(14) (16,384) chimeras and examined which ones retain lactamase function. Sequencing the genes from ampicillin-selected clones revealed that the percentage of functional clones decreased exponentially with increasing calculated disruption (E = the number of residue-residue contacts that are broken upon recombination). We also found that chimeras with low E have a higher probability of maintaining lactamase function than chimeras with the same effective level of mutation but chosen at random from the library. Thus, the simple distance metric used by SCHEMA to identify interactions and compute E allows one to predict which chimera sequences are most likely to retain their function. This approach can be used to evaluate crossover sites for recombination and to create highly mosaic, folded chimeras.


Thermal conductivity and viscosity measurements of ethylene glycol-based Al2O3 nanofluids.
The dispersion and stability of nanofluids obtained by dispersing Al2O3 nanoparticles in ethylene glycol have been analyzed at several concentrations up to 25% in mass fraction. The thermal conductivity and viscosity were experimentally determined at temperatures ranging from 283.15 K to 323.15 K using an apparatus based on the hot-wire method and a rotational viscometer, respectively. It has been found that both thermal conductivity and viscosity increase with the concentration of nanoparticles, whereas when the temperature increases the viscosity diminishes and the thermal conductivity rises. Measured enhancements on thermal conductivity (up to 19%) compare well with literature values when available. New viscosity experimental data yield values more than twice larger than the base fluid. The influence of particle size on viscosity has been also studied, finding large differences that must be taken into account for any practical application. These experimental results were compared with some theoretical models, as those of Maxwell-Hamilton and Crosser for thermal conductivity and Krieger and Dougherty for viscosity.


Safety versus accessibility in maternal and perinatal care.
This article adds to the debate on appropriate staffing in maternity units. My starting point for assessing staffing norms is the staff required to provide a safe maternity unit. A survey in 12 districts showed that their health facilities were not adequately prepared to perform all the essential emergency services required. Lack of staff was often cited as a reason. To test this notion, two norms (World Health Organization (WHO) and Greenfield) giving the minimum staff required for the provision of safe maternity services were applied to the 12 districts. Assuming the appropriate equipment is available and the facility is open 24 hours a day 7 days a week, at a minimum there need to be ten professional nurses with midwifery/advanced midwives to ensure safety for mother and baby in every maternity unit. The norms indicate that the units should do a minimum of 500-1,200 deliveries per year to be cost-effective. All 12 districts had sufficient staff according to the WHO. When the numbers of facilities with maternity units were compared with Council for Scientific and Industrial Research and WHO norms for number of health facilities per population, a large excess of facilities was found. Per district there were sufficient personnel to perform the number of deliveries for that district using the WHO or Greenfield formulas, but per site there were insufficient personnel. In my view there are sufficient personnel to provide safe maternity services, but too many units are performing deliveries, leading to dilution of staff and unsafe services. A realignment of maternity units must be undertaken to provide safe services, even at the expense of accessibility.


The oncofusion protein FUS-ERG targets key hematopoietic regulators and modulates the all-trans retinoic acid signaling pathway in t(16;21) acute myeloid leukemia.
The ETS transcription factor ERG has been implicated as a major regulator of both normal and aberrant hematopoiesis. In acute myeloid leukemias harboring t(16;21), ERG function is deregulated due to a fusion with FUS/TLS resulting in the expression of a FUS-ERG oncofusion protein. How this oncofusion protein deregulates the normal ERG transcription program is unclear. Here, we show that FUS-ERG acts in the context of a heptad of proteins (ERG, FLI1, GATA2, LYL1, LMO2, RUNX1 and TAL1) central to proper expression of genes involved in maintaining a stem cell hematopoietic phenotype. Moreover, in t(16;21) FUS-ERG co-occupies genomic regions bound by the nuclear receptor heterodimer RXR:RARA inhibiting target gene expression and interfering with hematopoietic differentiation. All-trans retinoic acid treatment of t(16;21) cells as well as FUS-ERG knockdown alleviate the myeloid-differentiation block. Together, the results suggest that FUS-ERG acts as a transcriptional repressor of the retinoic acid signaling pathway.


Nuclear Genomic Instability and Aging.
The nuclear genome decays as organisms age. Numerous studies demonstrate that the burden of several classes of DNA lesions is greater in older mammals than in young mammals. More challenging is proving this is a cause rather than a consequence of aging. The DNA damage theory of aging, which argues that genomic instability plays a causal role in aging, has recently gained momentum. Support for this theory stems partly from progeroid syndromes in which inherited defects in DNA repair increase the burden of DNA damage leading to accelerated aging of one or more organs. Additionally, growing evidence shows that DNA damage accrual triggers cellular senescence and metabolic changes that promote a decline in tissue function and increased susceptibility to age-related diseases. Here, we examine multiple lines of evidence correlating nuclear DNA damage with aging. We then consider how, mechanistically, nuclear genotoxic stress could promote aging. We conclude that the evidence, in toto, supports a role for DNA damage as a nidus of aging.


Teaching medical students to recognise their strengths and limitations in leadership, teamwork and communication by military led tutorials.
The General Medical Council has stipulated that greater importance must be placed on undergraduate students developing their ability to lead and work effectively as part of a team. Wales Universities' Officer Training Corps have attempted to meet this requirement through a third year interactive tutorial which aims to encourage students to recognise their strengths and limitations in the six outcomes of leadership, teamwork, accountability, management, feedback and communication. 16 tutorial groups of 10-15 students were each led by one officer who divided the tutorial group into three teams. The teams worked on complex planning exercises with an intrateam constructive feedback discussion to raise students' awareness of their strengths and limitations as individuals during the task, as perceived by others. The student perception was that all six learning outcomes were achieved by the session. 163 students returned feedback questionnaires and learning outcomes 1-4 were felt to have been addressed effectively or very effectively by 90%, 91%, 90% and 86% respondents, respectively. The fifth and sixth outcomes were less well achieved with only 66% and 64% respondents agreeing that the outcomes were achieved effectively or very effectively. Students commended the instructor's demonstration of leadership and the novel teaching method but improvements could be made in reinforcing why these skills are important.


Risk factors for discontinuation of buprenorphine treatment for opioid use disorders in a multi-state sample of Medicaid enrollees.
Recent U.S. trends demonstrate sharp rises in adverse opioid-related health outcomes, including opioid use disorder (OUD), overdose, and death. Yet few affected people receive treatment for OUD and a minority of those who receive treatment are effectively retained in care. The purpose of this study was to examine duration of buprenorphine treatment for OUD following treatment initiation to identify risk factors for early discontinuation. We analyzed insurance claims from the 2013-2015 MarketScan multi-state Medicaid database. The sample included adults 18-64 years old with an OUD diagnosis in the 6 months before initiating buprenorphine treatment, defined as 6 months without a buprenorphine claim prior to the index buprenorphine claim (N = 17,329 individuals). We used Cox proportional hazards regression to estimate risk of discontinuing treatment (>30 days without buprenorphine supply), and logistic regression to estimate the odds of persistent treatment for a minimum of 180 days. Over one-quarter of the sample discontinued buprenorphine in the first month of treatment (N = 4928; 28.4%) and most discontinued before 180 days (N = 11,189; 64.6%). In the proportional hazards model, risk factors for discontinuation included a lower initial buprenorphine dose (≤4 mg; Hazard Ratio [HR] = 1.72, p < .001), male sex (HR = 1.19, p < .001), younger age (HR = 1.34, p < .001), minority race/ethnicity (black HR = 1.31, p < .001; Hispanic HR = 1.24, p = .01; other HR = 1.09, p < .001), capitated insurance (HR = 1.21, p < .001), comorbid substance use disorders (alcohol HR = 1.07, p = .04; non-opioid drugs HR = 1.14, p < .001), hepatitis C (HR = 1.06, p = .01), opioid overdose history (HR = 1.20, p = .001), or any inpatient care (HR = 1.22, p < .001) in the 6-month baseline period. In logistic models, these risk factors were similarly associated with significantly lower odds of treatment retention for at least 180 days. For Medicaid beneficiaries with OUD treated with buprenorphine, there is a need to implement treatment models that more effectively address barriers to treatment retention. These barriers are particularly challenging for minorities, younger individuals, and those with additional substance use disorders.


Variability of quantal synaptic currents in thalamocortical neurons.
Broad amplitude variability and skewed distributions are characteristic features of quantal synaptic currents (minis) at central synapses. The relative contributions of the various underlying sources are still debated. Through computational models of thalamocortical neurons, we separated intra- from extra-synaptic sources. Our simulations indicate that the external factors of local input resistance and dendritic filtering generate equally small amounts of negatively skewed synaptic variability. The ability of these two factors to reduce positive skew increased as their contribution to variability increased, which in control trials for morphological, biophysical, and experimental parameters never exceeded 10% of the range. With these dendritic factors ruled out, we tested multiple release models, which led to distributions with clearly non-physiological multiple peaks. We conclude that intra-synaptic organization is the primary determinant of synaptic variability in thalamocortical neurons and, due to extra-synaptic mechanisms, is more potent than the data suggested. Thalamortical neurons, especially in rodents, constitute a remarkably favorable system for molecular genetic studies of synaptic variability and its functional consequence.


Profiling physical activity motivation based on self-determination theory: a cluster analysis approach.
In order to promote physical activity uptake and maintenance in individuals who do not comply with physical activity guidelines, it is important to increase our understanding of physical activity motivation among this group. The present study aimed to examine motivational profiles in a large sample of adults who do not comply with physical activity guidelines. The sample for this study consisted of 2473 individuals (31.4% male; age 44.6 ± 12.9). In order to generate motivational profiles based on motivational regulation, a cluster analysis was conducted. One-way analyses of variance were then used to compare the clusters in terms of demographics, physical activity level, motivation to be active and subjective experience while being active. Three motivational clusters were derived based on motivational regulation scores: a low motivation cluster, a controlled motivation cluster and an autonomous motivation cluster. These clusters differed significantly from each other with respect to physical activity behavior, motivation to be active and subjective experience while being active. Overall, the autonomous motivation cluster displayed more favorable characteristics compared to the other two clusters. The results of this study provide additional support for the importance of autonomous motivation in the context of physical activity behavior. The three derived clusters may be relevant in the context of physical activity interventions as individuals within the different clusters might benefit most from different intervention approaches. In addition, this study shows that cluster analysis is a useful method for differentiating between motivational profiles in large groups of individuals who do not comply with physical activity guidelines.


Optimization and continuous fabrication of moth-eye nanostructure array on flexible polyethylene terephthalate substrate towards broadband antireflection.
Reflection loss can cause harmful effects on the performance of optoelectronic devices, such as cell phones, notebooks, displays, solar cells, and light-emitting diode (LED) devices. In order to obtain broadband antireflection (AR) properties, many researchers have utilized surface texture techniques to produce AR subwavelength structures on the interfaces. Among the AR subwavelength structures, the moth-eye nanostructure is one of the most promising structures, with the potential for commercialization in the near future. In this research, to obtain broadband AR performance, the optimization of moth-eye nanostructures was first carried out using the finite difference time domain method within the spectral ranges of 400-800 nm, including the optimization of shape, height, pitch, and residual layer thickness. In addition, the continuous production of moth-eye nanostructure array upon a flexible polyethylene terephthalate substrate was demonstrated by using the roll-to-roll ultraviolet nanoimprint lithography (R2R UV-NIL) process and anodic aluminum oxide mold, which provided a solution for the cost-effective fabrication of moth-eye nanostructure array. The AR performance of moth-eye nanostructure array obtained by the R2R UV-NIL process was also investigated experimentally, and good consistence was shown with the simulated results. This research can provide a beneficial direction for the optimization and cost-effective production of the moth-eye nanostructure array.


Altered cerebrovascular reactivity velocity in mild cognitive impairment and Alzheimer's disease.
Interindividual variation in neurovascular reserve and its relationship with cognitive performance is not well understood in imaging in neurodegeneration. We assessed the neurovascular reserve in amnestic mild cognitive impairment (aMCI) and Alzheimer's dementia (AD). Twenty-eight healthy controls (HC), 15 aMCI, and 20 AD patients underwent blood oxygen level-dependent imaging for 9 minutes, breathing alternatively air and 7% carbon dioxide mixture. The data were parcellated into 88 anatomic regions, and carbon dioxide regressors accounting for different washin and washout velocities were fitted to regional average blood oxygen level-dependent signals. Velocity of cerebrovascular reactivity (CVR) was analyzed and correlated with cognitive scores. aMCI and AD patients had significantly slower response than HC (mean time to reach 90% of peak: HC 33 seconds, aMCI and AD 59 seconds). CVR velocity correlated with Mini Mental State Examination in 35 of 88 brain regions (p = 0.019, corrected for multiple comparisons), including 10 regions of the default-mode network, an effect modulated by age. This easily applicable protocol yielded a practical assessment of CVR in cognitive decline.


Blood sampling in infants (reducing pain and morbidity).
Preterm or ill neonates may undergo 1 to 21 heel punctures or venepunctures a day. These punctures are likely to be painful. Heel punctures comprise 61% to 87% and venepunctures comprise 8% to 13% of the invasive procedures performed on ill infants. Analgesics are rarely given specifically for blood sampling procedures, but 5% to 19% of infants receive analgesia for other indications. We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions to reduce pain-related distress and morbidity during venepuncture in preterm or term babies aged under 12 months in a neonatal unit? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 20 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: oral sweet solutions; pacifiers; and topical anaesthetics (lidocaine-prilocaine cream, tetracaine).


Molecular taxonomy and phylogenetic affinities of two groundwater amphipods, Crangonyx islandicus and Crymostygius thingvallensis, endemic to Iceland.
The amphipod superfamily Crangonyctoidea is distributed exclusively in freshwater habitats worldwide and is characteristic of subterranean habitats. Two members of the family, Crangonyx islandicus and Crymostygius thingvallensis, are endemic to Iceland and were recently discovered in groundwater underneath lava fields. Crangonyx islandicus belongs to a well-known genus with representatives both in North America and in Eurasia. Crymostygius thingvallensis defines a new family, Crymostygidae. Considering the incongruences observed recently between molecular and morphological taxonomy within subterranean species, we aim to assess the taxonomical status of the two species using molecular data. Additionally, the study contributes to the phylogenetic relationships among several crangonyctoidean species and specifically among species from four genera of the family Crangonyctidae. Given the available data we consider how the two Icelandic species could have colonized Iceland, by comparing geographical origin of the species with the phylogeny. Regions of two nuclear (18S and 28S rRNA) and two mitochondrial genes (16S rRNA and COI) for 20 different species of three families of the Crangonyctoidea were sequenced. Four different methods were used to align the RNA gene sequences and phylogenetic trees were constructed using bayesian and maximum likelihood analysis. The Crangonyctidae monophyly is supported. Crangonyx islandicus appeared more closely related to species from the Nearctic region. Crymostygius thingvallensis is clearly divergent from the other species of Crangonyctoidea. Crangonyx and Synurella genera are clearly polyphyletic and showed a geographical association, being split into a Nearctic and a Palearctic group. This research confirms that the studied species of Crangonyctidae share a common ancestor, which was probably widespread in the Northern hemisphere well before the break up of Laurasia. The Icelandic species are of particular interest since Iceland emerged after the separation of Eurasia and North America, is geographically isolated and has repeatedly been covered by glaciers during the Ice Age. The close relation between Crangonyx islandicus and North American species supports the hypothesis of the Trans-Atlantic land bridge between Greenland and Iceland which might have persisted until 6 million years ago. The status of the family Crymostygidae is supported, whereas Crangonyx islandicus might represent a new genus. As commonly observed in subterranean animals, molecular and morphological taxonomy led to different conclusions, probably due to convergent evolution of morphological traits. Our molecular analysis suggests that the family Crangonyctidae needs taxonomic revisions.


Calponin is expressed by subpopulations of connective tissue cells but not olfactory ensheathing cells in the neonatal olfactory mucosa.
Debate has been ongoing on the relative merits of olfactory ensheathing cells (OECs) and Schwann cells as candidates for transplant-mediate repair of CNS lesions. Both glial cells exhibit similar molecular and cellular properties and to date there has been no antigenic marker identified that can clearly distinguish the two cell types. This inability to distinguish between the two cells types prevents confirmation of a controversial statement that cultures of OECs are contaminated with Schwann cells. Recently, proteomic analysis of foetal OECs and adult Schwann cells identified an actin-binding protein, calponin, as a specific marker for OECs. However, at the same time a recent report suggested that adult OECs do not express calponin. It was not clear if this discrepancy was due to methodology, as cells had to be treated with proteinase K to maximize calponin staining or developmental differences with only foetal/neonatal OECs expressing calponin. For this reason we have examined calponin expression in the peripheral olfactory system of embryonic and neonatal rats in vivo and from cells in vitro to assess if calponin is expressed in a developmental manner. In this study we show that: i) proteinase K pretreatment had no effect on calponin staining in both OECs and Schwann cells. ii) calponin immunoreactivity was not expressed by embryonic or neonatal OECs in vitro and in vivo although connective tissue from the olfactory mucosa was strongly positive in neonatal rats but not embryonic rats, iii) calponin expression in the olfactory mucosa was heterogeneous, defining subpopulations of connective tissue cells iv) using functional confrontation assays between OECs or Schwann cells with astrocytes, calponin was expressed heterogeneously by astrocytes. It is concluded that calponin is heterogeneously expressed by neonatal mucosal connective tissue but not expressed by neonatal OECs, embryonic OECs, and neonatal Schwann cells. Furthermore, we propose that calponin is not a specific marker for OECs generated from any developmental age.


Efficacy of the Mindfulness Meditation Mobile App "Calm" to Reduce Stress Among College Students: Randomized Controlled Trial.
College students experience high levels of stress. Mindfulness meditation delivered via a mobile app may be an appealing, efficacious way to reduce stress in college students. We aimed to test the initial efficacy and sustained effects of an 8-week mindfulness meditation mobile app-Calm-compared to a wait-list control on stress, mindfulness, and self-compassion in college students with elevated stress. We also explored the intervention's effect on health behaviors (ie, sleep disturbance, alcohol consumption [binge drinking], physical activity, and healthy eating [fruit and vegetable consumption]) and the feasibility and acceptability of the app. This study was a randomized, wait-list, control trial with assessments at baseline, postintervention (8 weeks), and at follow-up (12 weeks). Participants were eligible if they were current full-time undergraduate students and (1) at least 18 years of age, (2) scored ≥14 points on the Perceived Stress Scale, (3) owned a smartphone, (4) were willing to download the Calm app, (5) were willing to be randomized, and (7) were able to read and understand English. Participants were asked to meditate using Calm at least 10 minutes per day. A P value ≤.05 was considered statistically significant. A total of 88 participants were included in the analysis. The mean age (SD) was 20.41 (2.31) years for the intervention group and 21.85 (6.3) years for the control group. There were significant differences in all outcomes (stress, mindfulness, and self-compassion) between the intervention and control groups after adjustment for covariates postintervention (all P<.04). These effects persisted at follow-up (all P<.03), except for the nonreacting subscale of mindfulness (P=.08). There was a significant interaction between group and time factors in perceived stress (P=.002), mindfulness (P<.001), and self-compassion (P<.001). Bonferroni posthoc tests showed significant within-group mean differences for perceived stress in the intervention group (P<.001), while there were no significant within-group mean differences in the control group (all P>.19). Similar results were found for mindfulness and self-compassion. Effect sizes ranged from moderate (0.59) to large (1.24) across all outcomes. A significant group×time interaction in models of sleep disturbance was found, but no significant effects were found for other health behaviors. The majority of students in the intervention group reported that Calm was helpful to reduce stress and stated they would use Calm in the future. The majority were satisfied using Calm and likely to recommend it to other college students. The intervention group participated in meditation for an average of 38 minutes/week during the intervention and 20 minutes/week during follow-up. Calm is an effective modality to deliver mindfulness meditation in order to reduce stress and improve mindfulness and self-compassion in stressed college students. Our findings provide important information that can be applied to the design of future studies or mental health resources in university programs. ClinicalTrials.gov NCT03891810; https://clinicaltrials.gov/ct2/show/NCT03891810.


Complication of etanercept treatment for rheumatoid arthritis--purulent pericarditis caused by a commensal organism.
The patient presented with increasing fatigue and dyspnoea. The patient had medical history of rheumatoid arthritis for which she had been taking methotrexate for the past 15 years and etanercept for the past 6 years. Initial diagnosis was cardiac failure but further investigation by echocardiogram revealed a large pericardial effusion. Empirical piperacillin-tazobactam was started due to moderately raised inflammatory markers. Four hundred millilitre of frank pus was aspirated from the pericardial sac and antimicrobial treatment was changed to meropenem. Gram positive cocci were seen in the initial Gram stain, but conventional cultures remained negative. However, 16S ribosomal RNA gene sequencing of the pus sample detected the presence of Parvimonas micra genome. Reaccumulation of the effusion required further drainage where again P micra was detected by 16S ribosomal RNA gene sequencing. Two weeks of meropenem was completed followed by treatment with benzylpenicillin and metronidazole.


Scattering due to randomly distributed charge particles in photorefractive crystals.
Scattering due to noisy gratings produced by randomly distributed charge particles in photorefractive crystals is considered. The scattering cross section is analyzed in terms of the fluctuation of the refractive index introduced by the random space-charge field through the Pockels effect. We also consider the noise in photorefractive gratings due to such scattering. A signal-to-noise ratio of 1 leads to a minimum modulation depth for an index grating.


ZBTB24 is a transcriptional regulator that coordinates with DNMT3B to control DNA methylation.
The interplay between transcription factors and epigenetic writers like the DNA methyltransferases (DNMTs), and the role of this interplay in gene expression, is being increasingly appreciated. ZBTB24, a poorly characterized zinc-finger protein, or the de novo methyltransferase DNMT3B, when mutated, cause Immunodeficiency, Centromere Instability, and Facial anomalies (ICF) syndrome, suggesting an underlying mechanistic link. Chromatin immunoprecipitation coupled with loss-of-function approaches in model systems revealed common loci bound by ZBTB24 and DNMT3B, where they function to regulate gene body methylation. Genes coordinately regulated by ZBTB24 and DNMT3B are enriched for molecular mechanisms essential for cellular homeostasis, highlighting the importance of the ZBTB24-DNMT3B interplay in maintaining epigenetic patterns required for normal cellular function. We identify a ZBTB24 DNA binding motif, which is contained within the promoters of most of its transcriptional targets, including CDCA7, AXIN2, and OSTC. Direct binding of ZBTB24 at the promoters of these genes targets them for transcriptional activation. ZBTB24 binding at the promoters of RNF169 and CAMKMT, however, targets them for transcriptional repression. The involvement of ZBTB24 targets in diverse cellular programs, including the VDR/RXR and interferon regulatory pathways, suggest that ZBTB24's role as a transcriptional regulator is not restricted to immune cells.


Fall downs should not fall out: Blunt cerebrovascular injury in geriatric patients after low-energy trauma is common.
There are limited data examining the impact of screening for blunt cerebrovascular injury (BCVI) in the geriatric population sustaining falls. We hypothesize that BCVI screening in this cohort would rarely identify injuries that would change management. A retrospective study (2012-2016) identified patients 65 years or older with Abbreviated Injury Scores for the head and neck region or face region of 1 or greater after falls of 5 ft or less. Patients who met the expanded Denver criteria for BCVI screening were included for analysis. Outcomes were change in management (defined as the initiation of medical, surgical or endovascular therapy for BCVI), stroke attributable to BCVI, in-hospital mortality and acute kidney injury. Univariate analysis was performed where appropriate. A p value less than 0.05 was considered significant. Of 997 patients, 257 (26%) met criteria for BCVI screening after exclusions. The BCVI screening occurred in 100 (39%), using computed tomographic angiography for screening in 85% of patients. Patients who were not screened (n = 157) were more likely to be on preinjury antithrombotic drugs and to have worse renal function compared with the screened group. There were 23 (23%) BCVIs diagnosed in the screened group while one (0.7%) in the nonscreened group had a delayed diagnosis of BCVI. Of the 24 patients with BCVI, 15 (63%) had a change in management, consisting of the initiation of antiplatelet therapy. Comparing the screened to the nonscreened groups, 14% versus 0.7% (p < 0.0001) had a change in management. The screened group had a higher 30-day stroke rate (7% vs. 1%, p = 0.03) but there were no differences in the stroke rate attributable to BCVI (1% vs. 0.7%, p = 0.99), mortality (6% vs. 8%, p = 0.31) or acute kidney injury (5% vs. 6%, p = 0.40). In geriatric patients with low-energy falls meeting criteria for BCVI screening, BCVIs were commonly diagnosed when screened, and the majority of those with BCVI had a change in management. These findings support BCVI screening in this geriatric cohort. Therapeutic/care management, level IV.


Economic burden of neural tube defects and impact of prevention with folic acid: a literature review.
Neural tube defects (NTDs) are the second most common group of serious birth defects. Although folic acid has been shown to reduce effectively the risk of NTDs and measures have been taken to increase the awareness, knowledge, and consumption of folic acid, the full potential of folic acid to reduce the risk of NTDs has not been realized in most countries. To understand the economic burden of NTDs and the economic impact of preventing NTDs with folic acid, a systematic review was performed on relevant studies. A total of 14 cost of illness studies and 10 economic evaluations on prevention of NTDs with folic acid were identified. Consistent findings were reported across all of the cost of illness studies. The lifetime direct medical cost for patients with NTDs is significant, with the majority of cost being for inpatient care, for treatment at initial diagnosis in childhood, and for comorbidities in adult life. The lifetime indirect cost for patients with spina bifida is even greater due to increased morbidity and premature mortality. Caregiver time costs are also significant. The results from the economic evaluations demonstrate that folic acid fortification in food and preconception folic acid consumption are cost-effective ways to reduce the incidence and prevalence of NTDs. This review highlights the significant cost burden that NTDs pose to healthcare systems, various healthcare payers, and society and concludes that the benefits of prevention of NTDs with folic acid far outweigh the cost. Further intervention with folic acid is justified in countries where the full potential of folic acid to reduce the risk of NTDs has not been realized.


THE TOXIC EFFECTS OF FORMALDEHYDE AND FORMALIN.
THE RESULTS OF THIS INVESTIGATION MAY BE SUMMARIZED AS FOLLOWS: 1. The inhalation of formaldehyde gas in even small quantities is followed by bronchitis and pneumonia. Pneumonia is due to the inhalation of the gas and not to secondary infection. 2. Formalin belongs to that rare group of poisons which are capable of producing death suddenly when swallowed. 3. The introduction of formalin into the stomach is followed by the production of a gastritis which varies greatly in character. The duodenum and upper jejunum may also be involved in the inflammatory process. 4. Intraperitoneal injections of formalin cause peritonitis of a fibrino-haemorrhagic character. A definite reaction is obtained when very dilute formalin (1-1000) is employed. In the peritoneal cavity formalin exercises a destructive action upon all organs (pancreas, liver, peritoneal fat, Fallopian tubes, etc.) with which it comes in contact and causes inflammation in these organs. 5. The lethal dose of formalin when injected intraperitoneally into guinea pigs is approximately 2 cc. of 1-1000 formalin for each 100 grm. of body weight. 6. The injection of formalin into the lungs is followed by pneumonia and bronchitis. 7. The inflammation which follows subcutaneous injections of formalin is characterized by intense exudation. 8. The injection of formalin into the muscles produces myositis. 9. The injection of formalin into the anterior chamber of the eye causes the accumulation of an exudate containing leucocytes and fibrin. When formalin is dropped into the conjunctival sac iritis follows and may be severe enough to destroy the eye. 10. Formalin in whatever way introduced into the body is absorbed, and is then capable of producing lesions in the parenchymatous organs. 11. Changes in the liver after absorption of formalin consist of mild or severe grade of cloudy swelling accompanied by vacuolation of the protoplasm, changes in the nuclei and leucocytic infiltration. Focal necrosis may result. Similar changes follow the inhalation of formaldehyde. 12. The injection of formalin or the inhalation of the vapors of formaldehyde produces cloudy swelling of the parenchyma of the kidney. Focal necrosis may result. 13. Pneumonia and bronchitis are found in all animals after the injection of formalin. 14. The leucocytic infiltration which follows the introduction of formalin into an organ has these general characteristics: The eosinophiles are the first leucocytes to appear; these are followed by the other polynuclear leucocytes; last appear the large and small mononuclear leucocytes. Similar phenomena occur in the trachea, bronchi and lungs of animals subjected to formaldehyde inhalations. 15. Formalin is, directly or indirectly, chemiotactic for leucocytes. The tissues which are not infiltrated with leucocytes after the injection of formalin are those which have been so injured by the chemical that an inflammatory reaction is impossible. 16. Animals subjected to chronic poisoning with formalin administered by intraperitoneal injection develop fibrinous peritonitis, associated with marked eosinophilia. The changes in the kidneys and liver consist of cloudy swelling, fatty degeneration, focal necrosis and leucocytic infiltration.


Identifying tobacco retailers in the absence of a licensing system: lessons from Australia.
To estimate the proportion of retailers that sell tobacco in the absence of appropriate local government oversight, and to describe the characteristics by which they differ from those that can expect to receive such oversight. A database of listed tobacco retailers was obtained from a regional Victorian local government. Potential unlisted tobacco retailers were added using online searches, and attempts to visit all retailers were undertaken. GPS coordinates and sales type information of retailers that sold tobacco were recorded and attached to neighbourhood-level data on socioeconomic disadvantage and smoking prevalence using ArcMap. Logistic regression analyses, χ2 tests and t-tests were undertaken to explore differences in numbers of listed and unlisted retailers by business and neighbourhood-level characteristics. Of 125 confirmed tobacco retailers, 43.2% were trading potentially without government oversight. Significant differences were found between listed and unlisted retailers by primary business type (p<0.001), and sales type (p<0.001) but not by the other characteristics. The database of tobacco retailers was inaccurate in two ways: (1) a number of listed retailers no longer operated or sold tobacco, and (2) 43.2% of businesses confirmed as selling tobacco were missing. As no form of licensing system exists in Victoria, it is difficult to identify the number of retailers operating, or to determine how many receive formal regulatory oversight. A positive licensing system is recommended to regulate the sale of tobacco and to generate a comprehensive database of retailers, similar to that which exists for food registration, gaming and liquor-licensed premises.


A multi-centre survey among informal carers who manage medication for older care recipients: problems experienced and development of services.
The UK Government has highlighted the need to develop appropriate information and support services for informal carers. Previous research that has investigated informal caring has found that managing medication is one aspect of the caring role that presents its own problems; however, these have not been subject to detailed examination. The objective of the present paper was to report the number and type of problems experienced by informal carers when managing medication for older care recipients, and to relate these to measures of coping and health. This was a cross-sectional survey undertaken in one district in each of four randomly selected health authority areas in England. Structured interviews, comprising closed and open questions, with 184 informal carers and 93 associated older care recipients were conducted in participants' own homes. Data were gathered on the number and type of medication-related problems experienced in relation to the informal caring role, and the impact of these from carers' perspectives in terms of coping and health. Sixty-seven per cent of carers reported problems with at least one medication-related activity. Problems were associated with all types of medication-related activities, and experienced by carers providing different levels of care for older people. Four themes were identified from carers' accounts which illustrated a diversity of practical problems and anxieties: maintaining continuous supplies of medication in the home; assisting with administration; making clinical judgements; and communicating with care recipients and health professionals. Carers reporting greater numbers of medication-related problems were more likely to experience higher levels of carer strain (P < 0.001) and poorer mental health status (P < 0.001). The findings of the present study provide insights to inform the development of primary care services to support informal carers in the management of medication for older people.


Quantitative proteomics: TGFβ₂ signaling in trabecular meshwork cells.
Transforming growth factor beta 2 (TGFβ₂) is often elevated in the aqueous humor (AH) and trabecular meshwork (TM) of patients with primary open-angle glaucoma (POAG) and appears to contribute to POAG pathogenesis. To better understand TGFβ₂ signaling in the eye, TGFβ₂-induced proteomic changes were identified in cells cultured from the TM, a tissue involved in intraocular pressure (IOP) elevation in glaucoma. Primary cultures of human TM cells from four donors were treated with or without TGFβ₂ (5 ng/mL) for 48 hours; then cellular protein was analyzed by liquid chromatography-mass spectrometry iTRAQ (isobaric tags for relative and absolute quantitation) technology. A total of 853 proteins were quantified. TGFβ₂ treatment significantly altered the abundance of 47 proteins, 40 of which have not previously been associated with TGFβ₂ signaling in the eye. More than half the 30 elevated proteins support growing evidence that TGFβ₂ induces extracellular matrix remodeling and abnormal cytoskeletal interactions in the TM. The levels of 17 proteins were reduced, including four cytoskeletal and six regulatory proteins. Both elevated and decreased regulatory proteins implicate TGFβ₂-altered processes involving transcription, translation, and the glutamate/glutamine cycle. Altered levels of eight mitochondrial proteins support TGFβ₂-induced mitochondrial dysfunction in the TM that in POAG could contribute to oxidative damage in the AH outflow pathway, TM senescence, and elevated IOP. The results expand the repertoire of proteins known to participate in TGFβ₂ signaling, provide new molecular insight into POAG, and establish a quantitative proteomics database for the TM that includes candidate glaucoma biomarkers for future validation studies.


Physiological Challenges to Fishes in a Warmer and Acidified Future.
With the projected levels of global warming and ocean acidification, fishes have to face warmer waters with CO2 levels that are the highest in over 30 million years. The resultant rise in body temperature means that metabolic rates of fish will increase, and some may become energetically compromised. No less worrying, and maybe more surprising, is that rising CO2 concentrations appear to trigger pH regulatory mechanisms that disrupts neural ion gradients, leading to altered neurotransmitter function and maladaptive behavioral changes. We point out the many outstanding questions, including the ultimate one: Will fish be able to adapt to these challenges?


Manisyl-substituted polypyridine coordination compounds: Metallo-supramolecular networks of interdigitated double helices assembled via CH...pi and pi-pi interactions.
A series of ML(2) coordination compounds of manisyl-substituted 2-pyridin-2-yl-1,10-phenanthrolines (pherpys) and 2,2':6',2''-terpyridines (terpys) with Fe(ii), Co(ii), Ni(ii), Cu(ii), Zn(ii), Ru(ii), and Os(ii), were synthesized. The pyridyl-phenanthroline-metal complexes form isomorphous crystals (space group Pcca), except for the zinc complex, which is isostructural but not isomorphous (space group P2(1)/c). Traces of the Ru complex induce the Zn complex to crystallize in the Pcca modification. Terpyridine complexes are isostructural but divided into two subgroups (Pnna and C2/c). Within the crystal lattice, the dications arrange into two-dimensional sheets of interdigitated left- and right-handed double helices via CHpi and pi-pi interactions of the pendant manisyl functionalities. All of the complexes exhibit weak ligand charge transfer (LCT) emission in solution at room temperature and the osmium complexes possess an emissive metal to ligand charge transfer (MLCT) state.


Minimal effects of waterborne exposure to single-walled carbon nanotubes on behaviour and physiology of juvenile rainbow trout (Oncorhynchus mykiss).
Fish behaviours are often considered to be sensitive endpoints of waterborne contaminants, but little attention has been given to engineered nanomaterials. The present study aimed to determine the locomotor and social behaviours of rainbow trout (Oncorhynchus mykiss) during waterborne exposure to single-walled carbon nanotubes (SWCNTs), and to ascertain the physiological basis for any observed effects. Dispersed stock suspensions of SWCNTs were prepared by stirring in sodium dodecyl sulphate (SDS), an anionic surfactant, on an equal w/w basis. Trout were exposed to control (no SWCNT or SDS), 0.25 mg L(-1) SDS (dispersant control), or 0.25 mg L(-1) of SWCNT for 10 days. Video tracking analysis of spontaneous locomotion of individual fish revealed no significant effects of SWCNT on mean velocity when active, total distance moved, or the distribution of swimming speeds. Hepatic glycogen levels were also unaffected. Fish exposed to SWCNTs retained competitive fitness when compelled to compete in energetically costly aggressive interactions with fish from both control groups. Assessment of the respiratory physiology of the fish revealed no significant changes in ventilation rate or gill injuries. Haematocrit and haemoglobin concentrations in the blood were unaffected by SWCNT exposure; and the absence of changes in the red and white pulp of the spleen excluded a compensatory haematopoietic response to protect the circulation. Despite some minor histological changes in the kidneys of fish exposed to SWCNT compared to controls, plasma ion concentrations and tissue electrolytes were largely unaffected. Direct neurotoxicity of SWCNT was unlikely with the brains showing mostly normal histology, and with no effects on acetylcholinesterase or Na(+)/K(+)-ATPase activities in whole brain homogenates. The minimal effects of waterborne exposure to SWCNT observed in this study are in contrast to our previous report of SWCNT toxicity in trout, suggesting that details of the dispersion method and co-exposure concentration of the dispersing agent may alter toxicity.


Rationale and design of the TRANSFACT project phase I: a study to assess the effect of the two different dietary sources of trans fatty acids on cardiovascular risk factors in humans.
Detrimental effects of consumption of industrial trans fatty acids (TFA) from partially hydrogenated vegetable oils (PHVO) on cardiovascular disease (CVD) risk factors are well documented. However, very little information is available on the effect of natural sources of TFA coming from milk fat, dairy products and ruminant meat. In fact, due to the naturally low level of TFA in milk fat, it is almost impossible to conduct a clinical trial with a limited number of subjects (<200). To compare the effects of industrial and natural dietary sources of TFA, two specific test fats have been designed and produced. A substantial amount of milk fat (130 kg) enriched in TFA has been produced by modification of the cow's diet and selection of cows with the highest TFA content. The level obtained was approximately 4- to 7-fold higher than typically present in milk fat (approximately 20 instead of 3-6 g/100 g of total fatty acids). The control fat is composed of PHVO balanced in saturated fatty acids (lauric, myristic and palmitic). Both experimental fats contain about 20-22% of monounsaturated TFA and the volunteers' daily experimental fat intake (54 g), will represent about 12.0 g/day of TFA or 5.4% of the daily energy (based on 2000 kcal/day). These two test fats have been incorporated into food items and will be provided to 46 healthy subjects under a randomised, double blind, controlled, cross-over design. The primary outcome is high-density lipoprotein cholesterol (HDL-C), which is an independent risk factor for CVD. Other parameters such as low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), and HDL-C level and subclasses will be also to be evaluated. We have shown that it is technically feasible to perform a clinical trial on the comparative effects of natural and industrial sources of TFA isomers on CVD risk factors. Results are expected by mid-2006.


The case for an inclusive scholarly communication infrastructure for social sciences and humanities.
This article presents a vision for a scholarly communication research infrastructure for social sciences and humanities (SSH). The COVID-19 pandemic has highlighted the pressing need to access research outputs without the traditional economic and temporal barriers. This article explores the current scholarly communication landscape, assessing the reasons for the slower uptake of open access in SSH research. The authors discuss such frontiers as commercial interests, sources of academic prestige and discipline-specific genres. This article defines and discusses the key areas in which a research infrastructure can play a vital role in making open scholarly communication a reality in SSH: (1) providing a federated and easy access to scattered SSH outputs; (2) supporting publication and dissemination of discipline-specific genres (e.g. monographs, critical editions); (3) providing help with evaluation and quality assurance practices in SSH; (4) enabling scholarly work in national languages, which is significant for local communities; (5) being governed by researchers and for researchers as a crucial factor for productive, useful and accessible services; (6) lastly, considering the needs of other stakeholders involved in scholarly communication, such as publishers, libraries, media, non-profit organisations, and companies. They conclude that a scholarly-driven, inclusive, dedicated infrastructure for the European Research Area is needed in order to advance open science in SSH and to address the issues tackled by SSH researchers at a structural and systemic level.


The 5' noncoding region of grapevine chrome mosaic nepovirus RNA-2 triggers a necrotic response on three Nicotiana spp.
The 5' noncoding region (NCR) of grapevine chrome mosaic nepovirus (GCMV) was cloned in a viral vector derived from potato virus X (PVX). The recombinant virus obtained was inoculated to Nicotiana benthamiana, N. clevelandii, and N. tabacum plants. Infected plants developed necrotic symptoms in place of the vein clearing and mosaic typically observed after inoculation with PVX. Northern (RNA) blot analysis showed that the replication of PVX was not specifically altered by the presence of the GCMV 5' NCR. Inoculation of recombinant PVX harboring deleted forms of the GCMV 5' NCR showed that the three stem-loop structures at the 3' end of the 5' NCR (nucleotides 153 to 206) are dispensable for the induction of necrosis. Further deletion analysis indicated that neither the 5'-most 70 nucleotides of the 5' NCR nor the downstream region (nucleotides 71 to 217) alone is able to induce the necrotic symptoms. In the presence of both the sequence encoding the GCMV coat protein and the GCMV 3' NCR, the GCMV 5' NCR failed to induce necrosis in the PVX background. The mechanisms by which the expression of the 5' NCR might modify PVX symptoms are discussed.


Cardiac and peripheral circulatory responses to angiotension and vasopressin in dogs.
To determine the cardiac and peripheral circulatory responses to changes in afterload with angiotension and vasopressin, we increased mean aortic pressure 25% and 50% above control in splenectomized and ganglion-blocked dogs. We compared these responses to similar mechanical increases in aortic pressure produced by partial balloon occlusion of the descending aorta. With 25% or 50% increases in aortic pressure, angiotensin, vasopressin, and balloon inflation produced no changes in heart rate, right atrial, and mean pulmonary artery pressures. At 25% increase in aortic pressure, cardiac output was maintained with angiotensin and balloon occlusion but decreased with vasopressin. At 50% increase in aortic pressure, cardiac output was maintained with only balloon occlusion and decreased with both angiotensin and vasopressin. Whenever cardiac output fell, central blood volume did not increase as after-load increased. These changes in preload can be explained by alterations in the venous circulation. Vasopressin did not alter venous compliance or unstressed vascular volume but increased resistance to venous return. Angiotensin also increased resistance to venous return but decreased venous compliance and did not change unstressed vascular volume. Balloon occlusion had no effects on these parameters. We conclude that: (a) angiotensin caused significant venoconstriction resulting in maintenance of cardiac output at 25% but not 50% increase in aortic pressure; (b) vasopressin increased the resistance to venous return without venoconstriction; this resulted in a fall in cardiac output even with a 25% increase in aortic pressure; and (c) the effects of the agents on the venous circulation were independent of the mechanical effects of a pressure increase in the arterial circulation.


Changes in triglyceride levels and risk for coronary heart disease in young men.
Current triglyceride levels might be only a weak predictor of risk for coronary heart disease (CHD). To assess the association between changes over time in fasting triglyceride levels and CHD risk in young adults. Follow-up study over 5.5 years after 2 measurements of fasting triglycerides 5 years apart. The Staff Periodic Examination Center of the Israel Defense Forces, Zrifin, Israel. 13,953 apparently healthy, untreated, young men (age 26 to 45 years) with triglyceride levels less than 3.39 mmol/L (<300 mg/dL). Two triglyceride measurements (at enrollment [time 1] and 5 years later [time 2]), lifestyle variables, and incident cases of angiography-proven CHD. Within 5.5 years, 158 new cases of CHD were identified. The multivariate model was adjusted for age; family history; fasting glucose; high-density lipoprotein cholesterol; blood pressure; body mass index; and changes between time 1 and time 2 in body mass index, physical activity, smoking status, and habit of eating breakfast. Investigators categorized triglyceride levels according to low, intermediate, and high tertiles (as measured at time 1 and time 2 [expressed as tertile at time 1/tertile at time 2]). The risk for CHD in men with high-tertile triglyceride levels at time 1 changed depending on the tertile at time 2 (hazard ratios, 8.23 [95% CI, 2.50 to 27.13] for high/high, 6.84 [CI, 1.95 to 23.98] for high/intermediate, and 4.90 [CI, 1.01 to 24.55] for high/low, compared with the stable low/low group). The risk for CHD in men with low-tertile levels at time 1 also changed depending on the tertile at time 2 (hazard ratios, 3.81 [CI, 0.96 to 15.31] for low/intermediate and 6.76 [CI, 1.34 to 33.92] for low/high, compared with the stable low/low group). Participants were healthy and had a low incidence rate of CHD. The study was observational. Two triglyceride measurements obtained 5 years apart may assist in assessing CHD risk in young men. A decrease in initially elevated triglyceride levels is associated with a decrease in CHD risk compared with stable high triglyceride levels. However, this risk remains higher than in those with persistently low triglyceride levels.


X-ray structure of the ternary MTX.NADPH complex of the anthrax dihydrofolate reductase: a pharmacophore for dual-site inhibitor design.
For reasons of bioterrorism and drug resistance, it is imperative to identify and develop new molecular points of intervention against anthrax. Dihydrofolate reductase (DHFR) is a highly conserved enzyme and an established target in a number of species for a variety of chemotherapeutic programs. Recently, the crystal structure of Bacillus anthracis DHFR (baDHFR) in complex with methotrexate (MTX) was determined and, based on the structure, proposals were made for drug design strategies directed against the substrate-binding site. However, little is gleaned about the binding site for NADPH, the cofactor responsible for hydride transfer in the catalytic mechanism. In the present study, X-ray crystallography at 100 K was used to determine the structure of baDHFR in complex with MTX and NADPH. Although the NADPH binding mode is nearly identical to that seen in other DHFR ternary complex structures, the adenine moiety adopts an off-plane tilt of nearly 90 degrees and this orientation is stabilized by hydrogen bonds to functionally conserved Arg residues. A comparison of the binding site, focusing on this region, between baDHFR and the human enzyme is discussed, with an aim at designing species-selective therapeutics. Indeed, the ternary model, refined to 2.3 A resolution, provides an accurate template for testing the feasibility of identifying dual-site inhibitors, compounds that target both the substrate and cofactor-binding site. With the ternary model in hand, using in silico methods, several compounds were identified which could potentially form key bonding contacts in the substrate and cofactor-binding sites. Ultimately, two structurally distinct compounds were verified that inhibit baDHFR at low microM concentrations. The apparent Kd for one of these, (2-(3-(2-(hydroxyimino)-2-(pyridine-4-yl)-6,7-dimethylquinoxalin-2-yl)-1-(pyridine-4-yl)ethanone oxime), was measured by fluorescence spectroscopy to be 5.3 microM.


Phylo-VISTA: interactive visualization of multiple DNA sequence alignments.
The power of multi-sequence comparison for biological discovery is well established. The need for new capabilities to visualize and compare cross-species alignment data is intensified by the growing number of genomic sequence datasets being generated for an ever-increasing number of organisms. To be efficient these visualization algorithms must support the ability to accommodate consistently a wide range of evolutionary distances in a comparison framework based upon phylogenetic relationships. We have developed Phylo-VISTA, an interactive tool for analyzing multiple alignments by visualizing a similarity measure for multiple DNA sequences. The complexity of visual presentation is effectively organized using a framework based upon interspecies phylogenetic relationships. The phylogenetic organization supports rapid, user-guided interspecies comparison. To aid in navigation through large sequence datasets, Phylo-VISTA leverages concepts from VISTA that provide a user with the ability to select and view data at varying resolutions. The combination of multiresolution data visualization and analysis, combined with the phylogenetic framework for interspecies comparison, produces a highly flexible and powerful tool for visual data analysis of multiple sequence alignments. Phylo-VISTA is available at http://www-gsd.lbl.gov/phylovista. It requires an Internet browser with Java Plug-in 1.4.2 and it is integrated into the global alignment program LAGAN at http://lagan.stanford.edu


Alcohol consumption among older adults with symptoms of cognitive decline consulting specialist health care.
To explore alcohol consumption among older Norwegian adults with symptoms of cognitive decline, assess the agreement between the reports of older adults and their next of kin regarding a person's alcohol consumption, and explore clinical and sociodemographic variables associated with agreement. Alcohol consumption was measured among 3608 older adults consulting specialist health care for symptoms of cognitive decline. Agreement between the participant and their next of kin regarding the participant's alcohol consumption was assessed with a weighted kappa (κ). A logistic regression analysis for hierarchical data was used to explore variables associated with agreement. Both the participants and their next of kin reported that more than 20% of the participants consumed alcohol 1-3 times a week, and that approximately 10% consumed alcohol four or more times a week. The agreement between the participant's and their next of kin's report regarding the participant's alcohol consumption was high (κ = .852), and variables associated with agreement were no cognitive decline, not drinking alcohol during the last year or ever as reported by the participant, and low agitation scores on a psychiatric assessment. This paper found alcohol consumption among older adults with symptoms of cognitive decline that was above the national average in Norway. This is also the first paper to demonstrate that a next of kin can be a reliable source of information regarding older adults' alcohol consumption. Health personnel should consider these findings when performing medical assessments or developing interventions for older adults.


Threonine 79 is a hinge residue that governs the fidelity of DNA polymerase beta by helping to position the DNA within the active site.
DNA polymerase beta (pol beta) is an ideal system for studying the role of its different amino acid residues in the fidelity of DNA synthesis. In this study, the T79S variant of pol beta was identified using an in vivo genetic screen. T79S is located in the N-terminal 8-kDa domain of pol beta and has no contact with either the DNA template or the incoming dNTP substrate. The T79S protein produced 8-fold more multiple mutations in the herpes simplex virus type 1-thymidine kinase assay than wild-type pol beta. Surprisingly, T79S is a misincorporation mutator only when using a 3'-recessed primer-template. In the presence of a single nucleotide-gapped DNA substrate, T79S displays an antimutator phenotype when catalyzing DNA synthesis opposite template C and has similar fidelity as wild type opposite templates A, G, or T. Threonine 79 is located directly between two helix-hairpin-helix motifs located within the 8-kDa and thumb domains of pol beta. As the pol beta enzyme closes into its active form, the helix-hairpin-helix motifs appear to assist in the production and stabilization of a 90 degrees bend of the DNA. The function of the bent DNA is to present the templating base to the incoming nucleotide substrate. We propose that Thr-79 is part of a hydrogen bonding network within the helix-hairpin-helix motifs that is important for positioning the DNA within the active site. We suggest that alteration of Thr-79 to Ser disrupts this hydrogen bonding network and results in an enzyme that is unable to bend the DNA into the proper geometry for accurate DNA synthesis.


Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group.
The aim of this work is to produce recommendations on the management of allogeneic stem cell transplantation (allo-SCT) in primary myelofibrosis (PMF). A comprehensive systematic review of articles released from 1999 to 2015 (January) was used as a source of scientific evidence. Recommendations were produced using a Delphi process involving a panel of 23 experts appointed by the European LeukemiaNet and European Blood and Marrow Transplantation Group. Key questions included patient selection, donor selection, pre-transplant management, conditioning regimen, post-transplant management, prevention and management of relapse after transplant. Patients with intermediate-2- or high-risk disease and age <70 years should be considered as candidates for allo-SCT. Patients with intermediate-1-risk disease and age <65 years should be considered as candidates if they present with either refractory, transfusion-dependent anemia, or a percentage of blasts in peripheral blood (PB) >2%, or adverse cytogenetics. Pre-transplant splenectomy should be decided on a case by case basis. Patients with intermediate-2- or high-risk disease lacking an human leukocyte antigen (HLA)-matched sibling or unrelated donor, should be enrolled in a protocol using HLA non-identical donors. PB was considered the most appropriate source of hematopoietic stem cells for HLA-matched sibling and unrelated donor transplants. The optimal intensity of the conditioning regimen still needs to be defined. Strategies such as discontinuation of immune-suppressive drugs, donor lymphocyte infusion or both were deemed appropriate to avoid clinical relapse. In conclusion, we provided consensus-based recommendations aimed to optimize allo-SCT in PMF. Unmet clinical needs were highlighted.


Mechanism of injury of virus-infected cells by antiviral antibody and complement: participation of IgG, F(ab')2, and the alternative complement pathway.
Antibody-mediated C-dependent lysis of cell lines infected with herpes simplex type 1 virus, influenza A degrees virus, measles virus, and mumps virus occurred by the alternative C pathway with the participation of IgG antibodies. Lysis occurred only with immune human sera, Mg++ EGTA immune sera, and immune sera depleted of C4 or treated with Fab anti-C4. Lysis did not occur with nonimmune sera, Mg++ EDTA immune sera, and immune sera heated 50 degrees C for 25 min, depleted of factor B or treated with Fab antifactor B. Lysis was restored to heated and factor B immunodepleted immune sera by addition of factor B, but not by addition of an excess of C2. Further studies showed that lysis of HeLa cells infected with measles virus was induced by both immune IgG and F(ab')2 but not Fab' in the presence of a nonantibody-containing human C source. Lysis of measles virus-infected cells was also indpendent of movement of viral antigens on the surface of the infected cells, as inhibition of viral antigen capping by cytochalasin B or sodium azide was not associated with abrogation of immune lysis.


Autoimmune channelopathies.
Autoimmune disorders of the neuromuscular junction remain a paradigm for our understanding of autoimmunity. Since the role of autoantibodies to acetylcholine receptors in the pathogenesis of myasthenia gravis was first recognized in the 1970s, a range of antibody-mediated disorders of the neuromuscular junction have been described, each associated with an autoantibody to a specific ligand-gated receptor, voltage-gated ion channel or related protein. In addition, antibodies to a ganglionic form of acetylcholine receptor have been detected in autoimmune forms of autonomic neuropathy. In the past few years, a role for antibodies in disorders of the CNS has begun to emerge, challenging our previous concepts regarding the blood-brain barrier and the role of the humoral immune system in CNS pathology. Although it has not yet been definitively shown that these CNS conditions are antibody-mediated, the detection of the specific antibody supports a trial of immunosuppressive therapy to which many patients appear to respond. In this article, we review the roles of antibodies to receptors and ion channels in the peripheral and central nervous systems, concentrating on the recently defined autonomic and CNS conditions and on the role of antibody measurement in diagnosis and management.


Caloric restriction increases learning consolidation and facilitates synaptic plasticity through mechanisms dependent on NR2B subunits of the NMDA receptor.
One of the main focal points of aging research is the search for treatments that will prevent or ameliorate the learning and memory deficiencies associated with aging. Here we have examined the effects of maintaining mature mice on a long-term intermittent fasting diet (L-IFD). We found that L-IFD enhances learning and consolidation processes. We also assessed the long-term changes in synaptic efficiency in these animals. L-IFD mice showed an increase in low-theta-band oscillations, paired-pulse facilitation, and facilitation of long-term synaptic plasticity in the hippocampus with respect to mice fed ad libitum. In addition, we found an increase in the expression of the NMDA receptor subunit NR2B in some brain areas of L-IFD mice. Specific antagonism of this subunit in the hippocampus reversed the beneficial effects of L-IFD. These data provide a molecular and cellular mechanism by which L-IFD may enhance cognition, ameliorating some aging-associated cognitive deficits.


Health effects of passive smoking. 9. Parental smoking and spirometric indices in children.
A systematic quantitative review was conducted of the evidence relating parental smoking to spirometric indices in children. An electronic search of the Embase and Medline databases was completed in April 1997 and identified 692 articles from which we included four studies in neonates, 42 cross-sectional studies in school aged children (22 were included in a meta-analysis), and six longitudinal studies of lung function development. In a pooled analyses of 21 surveys of school aged children the percentage reduction in forced expiratory volume in one second (FEV1) in children exposed to parental smoking compared with those not exposed was 1.4% (95% CI 1.0 to 1.9). Effects were greater on mid expiratory flow rates (5.0% reduction, 95% CI 3.3 to 6.6) and end expiratory flow rates (4.3% reduction, 95% CI 3.1 to 5.5). Adjustment for potential confounding variables had little effect on the estimates. A number of studies reported clear evidence of exposure response. Where exposure was explicitly identified it was usually maternal smoking. Two studies in neonates have reported effects of prenatal exposure to maternal smoking. Of five cross sectional studies that compared effects of perinatal exposure (retrospectively assessed) with current exposure to maternal smoking in later childhood, the three largest concluded that the major effect was in utero or neonatal exposure. Longitudinal studies suggest a small effect of current exposure on growth in lung function, but with some heterogeneity between studies. Maternal smoking is associated with small but statistically significant deficits in FEV1 and other spirometric indices in school aged children. This is almost certainly a causal relationship. Much of the effect may be due to maternal smoking during pregnancy.


The Effect of Meditation on Comprehension of Statements About One-Self and Others: A Pilot ERP and Behavioral Study.
The main goal of this study was to examine the effect of long-term meditation practice on behavioral indicators and ERP peak characteristics during an error-recognition task, where participants were presented with emotionally negative (evoking anxiety or aggression) written sentences describing self-related or non-self-related emotional state and personality traits. In total, 200 sentences written in Russian with varying emotional coloring were presented during the task, with half of the sentences containing a grammatical error that the participants were asked to identify. The EEG was recorded in age-matched control individuals (n = 17) and two groups of Samatha meditators with relatively short- (3-5 years' experience, n = 18) and long-term (10-30 years' experience, n = 18) practice experience. Task performance time (TPT) and accuracy of error detection (AED) were chosen as behavioral values. Amplitude, time latency and cortical distribution of P300 and P600 peaks of ERP were used as a value of speech-related brain activity. All statistical effects of meditation were estimated, controlling for age and sex. No behavioral differences between two groups of meditators were found. General TPT was shorter for both groups of meditators compared to the control group. Non-meditators reacted significantly slower to sentences about aggression than to sentences about anxiety or non-emotional sentences, whereas no significance was found between meditator groups. Non-meditators had better AED for the sentences about one-self than for the sentences about other people, whereas the meditators did not show any significant difference. The amplitude of P300 peak in frontal and left temporal scalp regions was higher for long-term meditators in comparison with both intermediate and control groups. The latency of P300 and P600 in left frontal and temporal regions positively correlated with TPT, whereas the amplitude of P300 in these regions had a negative correlation with TPT. We demonstrate that long-term meditation practice increases the ability of an individual to process negative emotional stimuli. The differences in behavioral reactions after onset of negative information that was self-related and non-self-related, which is typical for non-meditators, disappeared due to the influence of meditation. ERP results could be interpreted as a value of increase in voluntary control over emotional state during meditational practice.


Novel hepatocyte growth factor (HGF) binding domains on fibronectin and vitronectin coordinate a distinct and amplified Met-integrin induced signalling pathway in endothelial cells.
The growth of new blood vessels in adult life requires the initiation of endothelial cell migration and proliferation from pre-existing vessels in addition to the recruitment and differentiation of circulating endothelial progenitor cells. Signals emanating from growth factors and the extracellular matrix are important in regulating these processes. Here we report that fibronectin (FN) and vitronectin (VN) modulate the responses of endothelial cells to HGF (Scatter Factor), an important pro-angiogenic mediator. Novel binding sites for HGF were identified on both FN and VN that generate molecular complexes with enhanced biological activity and these were identified in the supernatants of degranulated platelet suspensions implicating their release and formation in vivo. In the absence of co-stimulation with an ECM glycoprotein, HGF could not promote endothelial cell migration but retained the capacity to induce a proliferative response utilising the Map kinase pathway. Through promoting Met-Integrin association, HGF-FN and HGF-VN complexes coordinated and enhanced endothelial cell migration through activation of the PI-3 kinase pathway involving a Ras-dependent mechanism whereas a Ras-independent and attenuated migratory response was promoted by co-stimulation of cells with HGF and a non-binding partner ECM glycoprotein such as collagen-1. These studies identify a novel mechanism and pathway of HGF signalling in endothelial cells involving cooperation between Met and integrins in a Ras dependent manner. These findings have implications for the regulation of neovascularization in both health and disease.


The learning curve for interpretation of oesophageal high-resolution manometry: a prospective interventional cohort study.
High-resolution manometry has become the preferred choice of oesophagologists for oesophageal motor assessment, but the learning curve among trainees remains unclear. To determine the learning curve of high-resolution manometry interpretation. A prospective interventional cohort study was performed on 18 gastroenterology trainees, naïve to high-resolution manometry (median age 32 ± 4.0 years, 44.4% female). An intake questionnaire and a 1-h standardised didactic session were performed at baseline. Multiple 1-h interpretation sessions were then conducted periodically over 15 months where 10 studies were discussed; 5 additional test studies were provided for interpretation, and results were compared to gold standard interpretation by the senior author. Hypothetical management decisions based on trainee interpretation were separately queried. Accuracy was compared across test interpretations and sessions to determine the learning curve, with a goal of 90% accuracy. Baseline accuracy was low for abnormal body motor patterns (53.3%), but higher for achalasia/outflow obstruction (65.9%). Recognition of achalasia reached 90% accuracy after six sessions (P = 0.01), while overall accurate management decisions reached this threshold by the 4th session (P < 0.001). Based on our data, the threshold of 90% accuracy for recognition of any abnormal from normal pattern was reached after 30 studies (3rd session) but fluctuated. Diagnosis of oesophageal body motor patterns remained suboptimal; accuracy of advisability of fundoplication improved, but did not reach 90%. High-resolution manometry has a steep learning curve among trainees. Achalasia recognition is achieved early, but diagnosis of other abnormal motor patterns and management decisions require further supervised training.