Prevalence of chromosomal alterations in first-trimester spontaneous pregnancy loss.
Pregnancy loss is often caused by chromosomal abnormalities of the conceptus. The prevalence of these abnormalities and the allocation of (ab)normal cells in embryonic and placental lineages during intrauterine development remain elusive. In this study, we analyzed 1,745 spontaneous pregnancy losses and found that roughly half (50.4%) of the products of conception (POCs) were karyotypically abnormal, with maternal and paternal age independently contributing to the increased genomic aberration rate. We applied genome haplarithmisis to a subset of 94 pregnancy losses with normal parental and POC karyotypes. Genotyping of parental DNA as well as POC extra-embryonic mesoderm and chorionic villi DNA, representing embryonic and trophoblastic tissues, enabled characterization of the genomic landscape of both lineages. Of these pregnancy losses, 35.1% had chromosomal aberrations not previously detected by karyotyping, increasing the rate of aberrations of pregnancy losses to 67.8% by extrapolation. In contrast to viable pregnancies where mosaic chromosomal abnormalities are often restricted to chorionic villi, such as confined placental mosaicism, we found a higher degree of mosaic chromosomal imbalances in extra-embryonic mesoderm rather than chorionic villi. Our results stress the importance of scrutinizing the full allelic architecture of genomic abnormalities in pregnancy loss to improve clinical management and basic research of this devastating condition.


Estimating elasticity in heterogeneous phantoms using Digital Image Elasto-Tomography.
Results from the application of a Digital Image Elasto-Tomography (DIET) system to elasticity distribution estimation in heterogeneous phantoms are presented. Two simple phantoms comprising distinct hard and soft regions were created from silicone, with harmonic surface motion data captured using a steady-state stereo imaging setup. A two-parameter approach to estimating stiffness distribution was used, applying both corroborative and contradictive methods to the inverse problem. The contradictive approach proved more robust in the presence of error in a priori stiffness assumption. These contrast based methods have the ability to reduce the number of parameters required for shape-based stiffness reconstructions, and present a novel approach to inclusion imaging in elastography.


Long-term Risk of Parkinson Disease Following Influenza and Other Infections.
Influenza has been associated with the risk of developing Parkinson disease, but the association is controversial. To examine whether prior influenza and other infections are associated with Parkinson disease more than 10 years after infection. This case-control study used data from 1977 to 2016 from the Danish National Patient Registry. All individuals with Parkinson disease, excluding those with drug-induced parkinsonism, were included and matched to 5 population controls on sex, age, and date of Parkinson diagnosis. Data were analyzed from December 2019 to September 2021. Infections were ascertained between 1977 and 2016 and categorized by time from infection to Parkinson disease diagnosis. To increase specificity of influenza diagnoses, influenza exposure was restricted to months of peak influenza activity. Parkinson disease diagnoses were identified between January 1, 2000, and December 31, 2016. Crude and adjusted odds ratios (ORs) and 95% CIs were calculated by conditional logistic regression overall and stratified by time between infection and Parkinson disease (5 years or less, more than 5 to 10 years, more than 10 years). Of 61 626 included individuals, 23 826 (38.7%) were female, and 53 202 (86.3%) were older than 60 years. A total of 10 271 individuals with Parkinson disease and 51 355 controls were identified. Influenza diagnosed at any time during a calendar year was associated with Parkinson disease more than 10 years later (OR, 1.73; 95% CI, 1.11-2.71). When influenza exposure was restricted to months of highest influenza activity, an elevated OR with a wider confidence interval was found (OR, 1.52; 95% CI, 0.80-2.89). There was no evidence of an association with any type of infection more than 10 years prior to Parkinson disease (OR, 1.04; 95% CI, 0.98-1.10). Several specific infections yielded increased odds of Parkinson disease within 5 years of infection, but results were null when exposure occurred more than 10 years prior. In this case-control study, influenza was associated with diagnoses of Parkinson disease more than 10 years after infection. These observational data suggest a link between influenza and Parkinson disease but do not demonstrate causality. While other infections were associated with Parkinson disease diagnoses soon after infection, null associations after more than 10 years suggest these shorter-term associations are not causal.


A retrospective evaluation of a community-based physical activity health promotion program.
The Community Health Intervention Programmes (CHIPs) is a physical activity-based health promotion program operating in disadvantaged communities in the Western Cape, South Africa with primary school learners, adults and senior adults. Program growth, anecdotal evidence and experience of those involved suggest the program has been positively received by communities. The aim of this study was to conduct a qualitative, retrospective process evaluation concerning both factors associated with successful implementation of the programs, and implementation challenges. 'Success' was defined in consultation with CHIPs staff and stakeholders. Data were gathered through naturalistic observation, structured interviews and focus groups (n = 104), and open-ended questionnaires (n = 81). The sample included CHIPs staff and stakeholders, program members and leaders. Factors contributing to the program's success include: focus on combining social development and exercise science, community development model, scientifically sound program content, appropriate activities, intrapersonal and interpersonal factors, program leadership, encouraging staff, and various contextual factors.' The findings confirm that CHIPs presents a model of sustainable implementation of physical activity in disadvantaged communities, and that it positively impacts the quality of life, perceptions of the role of physical activity in health, and personal responsibility for health of those involved in its programs.


Elective Induction at 39 Weeks of Gestation and the Implications of a Large, Multicenter, Randomized Controlled Trial.
On August 8, 2018, Grobman et al published the findings from the ARRIVE (A Randomized Trial of Induction Versus Expectant Management) trial, a large randomized controlled trial of elective induction of labor in nulliparous women at 39 weeks of gestation compared with expectant management. Conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network, the trial found there was no difference between the two groups in the primary outcome, a composite of neonatal morbidity. Also, there was a reduction in rates of cesarean delivery and hypertensive disorders of pregnancy in the elective induction group. The topic of elective induction has been of interest to clinicians for decades, and research has yielded inconsistent results in the past. This trial offers the best evidence thus far to address this complex issue. Our objective is to briefly review the history and literature regarding elective induction of labor, discuss the recently published ARRIVE trial, and consider its implications on clinical practice and health policy.


Reclaiming food security in the Mohawk community of Kahnawà:ke through Haudenosaunee responsibilities.
Indigenous Peoples are reclaiming their food security, nutrition, and well-being by revitalizing food systems, livelihoods, knowledge-systems, and governance. Our food security research is guided by sustainable self-determination that focuses on restoring Indigenous cultural responsibilities and relationships to land, each other, and the natural world (Corntassel, 2008). Our Kanien'kehá:ka (Mohawk) research team from Kahnawà:ke, in Quebec, Canada, examines food insecurity experiences in our community to explore ways of upholding our Haudenosaunee responsibilities and enhancing local food security. We collaboratively designed the study and interviewed Kahnawakehró:non (people from the Kahnawake community) with traditional knowledge, extensive community experience, and interests in food and culture. Interviews were audio-recorded, transcribed, and analysed by the team. Analysis characterized food insecurity experiences and conditions that challenge and enable food security with attention to traditional food systems, relationships to land, and gender-related responsibilities. Findings show that communal responsibilities generate resilient strategies that provide for all in times of crisis, and long-term food insecurity is managed through social programs, organized charities, and family support. Enhancing food security involves healing and protecting a limited land-base for food production, integrating food production with community priorities for education, training, health, economic development, and scientific innovation. Nurturing spiritual connections with tionhnhéhkwen (life sustaining foods), the natural world, and each other calls for accelerated teaching and practicing our original instructions. Challenges in developing food security leadership, balancing capitalism and subsistence economies, and strengthening social relationships are rooted in the historical colonial and current settler-colonial context that disrupts all aspects of Kanien'kehá:ka society.


Resolution-enhanced subpixel phase retrieval method.
Phase retrieval is a wavefront sensing method that uses a series of intensity images to reconstruct the wavefront. The resolution of phase retrieval testing is limited mainly by the resolution of intensity images captured by CCD cameras. A subpixel phase retrieval method is presented to retrieve the wave field at subpixel resolution by using the information of a sequence of low-resolution images captured along the propagation direction. In this method, the sampling interval for the wave field under test is smaller than the CCD pixel size in phase reconstruction. The wave field is recovered at subpixel resolution by utilizing the energy conservation relationship between CCD pixels and their subpixels by the subpixel phase retrieval (SPR) algorithm. Numerical experiments have shown that more than a fourfold resolution enhancement can be achieved. The method has also been studied in some experiments under noisy and off-axis conditions. A mirror surface testing experiment was conducted to demonstrate the performance of SPR in the real world. The results of these experiments have shown the effectiveness and robustness of this method. SPR allows low-resolution images to be used to retrieve high-resolution wave fields and will be useful in testing wave fields from large objects.


Effects of lipid heterogeneity on model human brain lipid membranes.
Cell membranes naturally contain a heterogeneous lipid distribution. However, homogeneous bilayers are commonly preferred and utilised in computer simulations due to their relative simplicity, and the availability of lipid force field parameters. Recently, experimental lipidomics data for the human brain cell membranes under healthy and Alzheimer's disease (AD) conditions were investigated, since disruption to the lipid composition has been implicated in neurodegenerative disorders, including AD [R. B. Chan et al., J. Biol. Chem., 2012, 287, 2678-2688]. In order to observe the effects of lipid complexity on the various bilayer properties, molecular dynamics simulations were used to study four membranes with increasing heterogeneity: a pure POPC membrane, a POPC and cholesterol membrane in a 1 : 1 ratio (POPC-CHOL), and to our knowledge, the first realistic models of a healthy brain membrane and an Alzheimer's diseased brain membrane. Numerous structural, interfacial, and dynamical properties, including the area per lipid, interdigitation, dipole potential, and lateral diffusion of the two simple models, POPC and POPC-CHOL, were analysed and compared to those of the complex brain models consisting of 27 lipid components. As the membranes gain heterogeneity, a number of alterations were found in the structural and dynamical properties, and more significant differences were observed in the lateral diffusion. Additionally, we observed snorkeling behaviour of the lipid tails that may play a role in the permeation of small molecules across biological membranes. In this work, atomistic description of realistic brain membrane models is provided, which can add insight towards the permeability and transport pathways of small molecules across these membrane barriers.


Self and team prioritisation effects in perceptual matching: Evidence for a shared representation.
Previous research has demonstrated that in-group favouritism occurs not only in higher-level judgments such as reward allocation, but also in low-level perceptual and attentional tasks. Recently, Moradi, Sui, Hewstone, and Humphreys (2015) found a novel effect of in-group bias on a simple perceptual matching task in which football fans responded more efficiently to stimuli newly associated with their own football team than stimuli associated with rival or neutral teams. This result is consistent with a robust self-bias effect in which individuals show a large performance advantage in responding to stimuli associated with the self over stimuli associated with a close friend or a stranger (Sui, He, & Humphreys, 2012). The present research utilised a perceptual matching paradigm to investigate the relations between self and in-group prioritisation amongst a sample of college rowers. Across two experiments, we demonstrated a reliable performance advantage for self and team stimuli. We also found a relationship between the self and team advantage in RT, and demonstrated an overlap in the perception of self- and team-associated shapes that was stronger in participants who reported a greater sense of group identity with their team. Further, we found no relation between the team bias and positive valence implicitly associated with the team, showing that the team bias effects are unlikely to be driven by emotional significance. The results are consistent with an overlap between self and in-group representation, which may provide evidence for a common process driving both self and in-group perceptual advantage effects.


Integrin alpha subunit ratios, cytoplasmic domains, and growth factor synergy regulate muscle proliferation and differentiation.
The role of integrins in muscle differentiation was addressed by ectopic expression of integrin alpha subunits in primary quail skeletal muscle, a culture system particularly amenable to efficient transfection and expression of exogenous genes. Ectopic expression of either the human alpha5 subunit or the chicken alpha6 subunit produced contrasting phenotypes. The alpha5-transfected myoblasts remain in the proliferative phase and are differentiation inhibited even in confluent cultures. In contrast, myoblasts that overexpress the alpha6 subunit exhibit inhibited proliferation and substantial differentiation. Antisense suppression of endogenous quail alpha6 expression inhibits myoblast differentiation resulting in sustained proliferation. These effects of ectopic alpha subunit expression are mediated, to a large extent, by the cytoplasmic domains. Ectopic expression of chimeric alpha subunits, alpha5ex/6cyto and alpha6ex/5cyto, produced phenotypes opposite to those observed with ectopic alpha5 or alpha6 expression. Myoblasts that express alpha5ex/6cyto show decreased proliferation while differentiation is partially restored. In contrast, the alpha6ex/5cyto transfectants remain in the proliferative phase unless allowed to become confluent for at least 24 h. Furthermore, expression of human alpha5 subunit cytoplasmic domain truncations, before and after the conserved GFFKR motif, shows that this sequence is important in alpha5 regulation of differentiation. Ectopic alpha5 and alpha6 expression also results in contrasting responses to the mitogenic effects of serum growth factors. Myoblasts expressing the human alpha5 subunit differentiate only in the absence of serum while differentiation of untransfected and alpha6-transfected myoblasts is insensitive to serum concentration. Addition of individual, exogenous growth factors to alpha5-transfected myoblasts results in unique responses that differ from their effects on untransfected cells. Both bFGF or TGFbeta inhibit the serum-free differentiation of alpha5-transfected myoblasts, but differ in that bFGF stimulates proliferation whereas TGF-beta inhibits it. Insulin or TGF-alpha promote proliferation and differentiation of alpha5-transfected myoblasts; however, insulin alters myotube morphology. TGF-alpha or PDGF-BB enhance muscle alpha-actinin organization into myofibrils, which is impaired in differentiated alpha5 cultures. With the exception of TGF-alpha, these growth factor effects are not apparent in untransfected myoblasts. Finally, myoblast survival under serum-free conditions is enhanced by ectopic alpha5 expression only in the presence of bFGF and insulin while TGF-alpha and TGF-beta promote survival of untransfected myoblasts. Our observations demonstrate (1) a specificity for integrin alpha subunits in regulating myoblast proliferation and differentiation; (2) that the ratio of integrin expression can affect the decision to proliferate or differentiate; (3) a role for the alpha subunit cytoplasmic domain in mediating proliferative and differentiative signals; and (4) the regulation of proliferation, differentiation, cytoskeletal assembly, and cell survival depend critically on the expression levels of different integrins and the growth factor environment in which the cells reside.


Inhibition of aldose reductase prevents colon cancer metastasis.
Colon cancer is the third most common cause of cancer and is the second leading cause of cancer deaths in the USA. Although inhibition of aldose reductase (AR) is known to prevent human colon cancer cell growth in nude mice xenografts, the role of AR in the regulation of cancer metastasis is not known. We now demonstrate the mechanisms by which AR regulates colon cancer metastasis in vitro and in vivo. Inhibition of AR prevented the epidermal growth factor (EGF) or fibroblast growth factor (FGF)-induced migration and invasion of human colon cancer (HT29; KM20) cells by >70% and also inhibited (>80%) the adhesion of the cancer cells to endothelial cells. Treatment of endothelial cells with AR inhibitors significantly (∼85%) downregulated the EGF or FGF-induced expression of Inter-Cellular Adhesion Molecule-1, Vascular cell adhesion molecule-1 and vascular endothelial-cadherin. Furthermore, liver metastasis of green fluorescent protein-labeled KM20 cells injected into the spleen of athymic nude mice was significantly (>65%) prevented by AR inhibitor, fidarestat or ARsiRNA delivered systemically into the mice. Similar results were observed with HT29 cells. AR inhibition or ablation also prevented (70-90%) the increase in the levels of matrix metalloproteinase-2, cyclin D1, CD31, CD34 and the activation of nuclear factor-kappa-binding protein in metastatic liver. Thus, our results indicate that AR regulates cancer cell adhesion, invasion and migration events which initiate metastasis and therefore, AR inhibition could be a novel therapeutic approach for the prevention of colon cancer metastasis.


Prevalence and incidence of type 1 diabetes in the world: a systematic review and meta-analysis.
Background: Diabetes is referred to a group of diseases characterized by high glucose levels in blood. It is caused by a deficiency in the production or function of insulin or both, which can occur because of different reasons, resulting in protein and lipid metabolic disorders. The aim of this study was to systematically review the prevalence and incidence of type 1 diabetes in the world. Methods: A systematic search of resources was conducted to investigate the prevalence and incidence of type 1 diabetes in the world. The databases of Medline (via PubMed and Ovid),ProQuest, Scopus, and Web of Science from January 1980 to September 2019 were searched to locate English articles. The located articles were screened in multiple levels of title, abstract,and full-text and final studies that met the inclusion criteria were retrieved and included in the study. Results: From 1202 located articles, 193 studies were included in this systematic review. The results of meta-analysis showed that the incidence of type 1 diabetes was 15 per 100,000 people and the prevalence was 9.5% (95% CI: 0.07 to 0.12) in the world, which was statistically significant. Conclusion: According to the results, the incidence and prevalence of type 1 diabetes are increasing in the world. As a result, insulin will be difficult to access and afford, especially in underdeveloped and developing countries.


Career preferences of medical students: influence of a new four-week attachment in general practice.
It is not clear why medical students choose one specialty over another. Experiences at medical school are extremely strong determinants of attitudes to the medical specialties, and attitude is the most important factor in determining choice. This study sought to describe the factors influencing career choices of final year medical students, the effect of a new four-week attachment in general practice on career choices, and changes in career choices towards or away from general practice between the final year and the end of the preregistration house officer year. Career preferences, and influences on them, were assessed by questionnaires administered to 206 medical students undergoing their final clinical attachment at the University of Glasgow immediately before and immediately after a four-week attachment in general practice. These were followed up by a postal questionnaire at the end of the preregistration house officer year. One hundred and thirty-one students returned all three questionnaires. Before the attachment, students born outside the UK, and those who had a previous or intercalated degree were significantly less likely to put general practice as a career preference; female students were more likely to put it as their first career choice. After the attachment, the number stating that it was 'likely' or 'very likely' that they would choose general practice as a career increased from 60 to 72--mainly through male students changing their preference--but after the preregistration house officer year it had fallen back to 56. Seventeen of the preregistration house officers were planning to complete posts which would qualify for GP training. Reasons for changing preference towards general practice were mainly to do with a dislike of and disillusionment with hospital medicine and with the perceived lifestyle advantages of general practice. Reasons for changing preference away from general practice were mainly to do with positive feelings about hospital medicine and a dislike of the management aspects of general practice. The general practice attachment influenced students, especially males, towards a career in general practice, but this effect was transient. This cohort of doctors should be followed up in order to discover their ultimate career choices.


Addition of a carbon fiber brush improves anaerobic digestion compared to external voltage application.
Two methods were examined to improve methane production efficiency in anaerobic digestion (AD) based on adding a large amount of surface area using a single electrically conductive carbon brush, or by adding electrodes as done in microbial electrolysis cells (MECs) to form a hybrid AD-MEC. To examine the impact of surface area relative to electrodes, AD reactors were fitted with a single large brush without electrodes (FB), half a large brush with two electrodes with an applied voltage (0.8 V) and operated in closed circuit (HB-CC) or open circuit (HB-OC) mode, or only two electrodes with a closed circuit and no large brush (NB-CC) (equivalent to an MEC). The three configurations with a half or full brush all had improved performance as shown by 57-82% higher methane generation rate parameters in the Gompertz model compared to NB-CC. The retained biomass was much higher in the reactors with large brush, which likely contributed to the rapid consumption of volatile fatty acids (VFAs) and therefore improved AD performance. A different microbial community structure was formed in the large-size brushes compared to the electrodes. Methanothrix was predominant in the biofilm of large-size carbon brush, while Geobacter (anode) and Methanobacterium (cathode) were highly abundant in the electrode biofilms. These results demonstrate that adding a high surface area carbon fiber brush will be a more effective method of improving AD performance than using MEC electrodes with an applied voltage.


High Sensitivity Method to Estimate Distribution of Hyaluronan Molecular Sizes in Small Biological Samples Using Gas-Phase Electrophoretic Mobility Molecular Analysis.
Hyaluronan is a negatively charged polydisperse polysaccharide where both its size and tissue concentration play an important role in many physiological and pathological processes. The various functions of hyaluronan depend on its molecular size. Up to now, it has been difficult to study the role of hyaluronan in diseases with pathological changes in the extracellular matrix where availability is low or tissue samples are small. Difficulty to obtain large enough biopsies from human diseased tissue or tissue from animal models has also restricted the study of hyaluronan. In this paper, we demonstrate that gas-phase electrophoretic molecular mobility analyzer (GEMMA) can be used to estimate the distribution of hyaluronan molecular sizes in biological samples with a limited amount of hyaluronan. The low detection level of the GEMMA method allows for estimation of hyaluronan molecular sizes from different parts of small organs. Hence, the GEMMA method opens opportunity to attain a profile over the distribution of hyaluronan molecular sizes and estimate changes caused by disease or experimental conditions that has not been possible to obtain before.


Faculty development for teaching online: educational and technological issues.
The purpose of this article is to describe the process of creating a faculty development program for online instruction. Both educational and technological issues are discussed. Factors that will facilitate and barriers that will impede the implementation of online courses are included. Many faculty concerns regarding online courses relate to the issues of quality and student learning. Faculty development activities are directed to ensure that courses are developed using sound educational theory and principles. Online courses are first about student learning; using the technology is second. Thus, faculty development programs must be two-pronged, involving instructional design and technology. It is an ongoing process that must be focused on continual training and development.


Density matrix renormalization group pair-density functional theory (DMRG-PDFT): singlet-triplet gaps in polyacenes and polyacetylenes.
The density matrix renormalization group (DMRG) is a powerful method to treat static correlation. Here we present an inexpensive way to calculate correlation energy starting from a DMRG wave function using pair-density functional theory (PDFT). We applied this new approach, called DMRG-PDFT, to study singlet-triplet gaps in polyacenes and polyacetylenes that require active spaces larger than the feasibility limit of the conventional complete active-space self-consistent field (CASSCF) method. The results match reasonably well with the most reliable literature values and have only a moderate dependence on the compression of the initial DMRG wave function. Furthermore, DMRG-PDFT is significantly less expensive than other commonly applied ways of adding additional correlation to DMRG, such as DMRG followed by multireference perturbation theory or multireference configuration interaction.


The molecular basis for the difference in immune hemolysis activity of the Chido and Rodgers isotypes of human complement component C4.
Human C4 displays a structural polymorphism which is consistent with there being two closely linked genetic loci coding for this protein. These give rise to two C4 isotypes, designated C4A and C4B, which can be distinguished by charge and apparent m.w. differences in their respective alpha-chains and by the presence or absence of the Chido/Rodgers blood group antigens. Previous qualitative studies of C4 immune hemolysis activity in whole plasma had suggested that the C4B isotype was functionally more active. By using purified C4A and C4B isolated from individual donors known serologically to possess only one of the C4 isotypes, we examined the molecular basis for the differences in their respective hemolytic activities. It was found that the C4B:C4A hemolytic activity ratio was approximately 4:1. This fourfold difference could not be accounted for by a commensurate difference in the cleavage rate of the two isotypes by C1s by differences in the kinetics of assembly or intrinsic decay of the respective C3 convertase enzymes, or by differences in the rate of isotypic C4b cleavage by factor I in the presence of C4bp . However, the fourfold greater deposition efficiency of nascent C4b of the C4B isotype onto the surface of C1-bearing sheep erythrocytes quantitatively accounted for the observed difference in immune hemolysis function. It was further found that the thioester bond of nascent C4b of the C4A isotype preferentially transacylates onto amino group nucleophiles, whereas in the C4B isotype, acylation of hydroxyl groups is strongly preferred. Thus, the difference in immune hemolysis activity between the two C4 isotypes does not necessarily indicate an impairment of function in C4A; it may merely be a reflection of the relative abundance at the surface of a C1-bearing target of hydroxyl and amino groups capable of being acyl acceptors for nascent C4b. Finally, we also present evidence showing that the apparent m.w. difference between the alpha-chains of the C4A and C4B isotypes is not due to differences in protein glycosylation.


Membrane transport by murine lymphocytes. I. A rapid sampling technique as applied to the adenosine and thymidine systems.
We have developed a rapid sampling technique for animal cells in suspension for the purpose of measuring membrane transport in lymphocytes. The method involves rapid centrifugation of cells through a layer of silicone oil into perchloric acid after incubation periods as short as 4 s. Using this method we have described the uptake of thymidine and the uptake and transport systems of adenosine by murine bulk nonadherent spleen cells. The two uptake systems are markedly different. Adenosine was shown to be taken up by classical carrier-mediated diffusion, while thymidine was not. In addition we have explored the metabolism of the two nucleosides under the conditions we employed for measuring transport or uptake; Both nucleosides are phosphorylated extensively. We also investigated the uptake and metabolism of thymidine over a 2-h interval the standard time used to measure DNA synthesis in lymphocytes. Unless cells were separated from medium by centrifugation through oil before TCA addition, the TCA precipitable counts exceeded the total radioactive uptake. Hence the standard method for measuring thymidine utilization yields estimates under these conditions which can be as much as 100% too high.


[Animal models of human diseases].
The development of efficient ways to predict, prevent, diagnose and treat human diseases is of great interest to human society and is a focus of life science research. It is widely believed that all human diseases may be attributed to the interaction between genetic and environmental risk factors, and this interaction influences the genesis, course, drug response and outcome of the diseases. The most effective approach for research into human diseases is the clinical study, but this can be hampered by disease heterogeneity, marked individual differences and the difficulty in tracking the history and course of a disease. Additionally, no study should be performed on humans without preclinical assessments in non-human animals. The best strategy for research into human diseases is to use animal models that mimic the genesis, course, drug response and outcomes of human disease and where the etiology, genetic background and environmental factors can be strictly controlled, unfeasible in clinical studies of humans. However, there are many problems associated with the study of animal models for human disease, some of which are based on misunderstanding. For this special issue of Zoological Research we discuss these problems and misunderstandings.


An Embodied Account of Early Executive-Function Development.
The importance of executive functioning for later life outcomes, along with its potential to be positively affected by intervention programs, motivates the need to find early markers of executive functioning. In this study, 18-month-olds performed three executive-function tasks-involving simple inhibition, working memory, and more complex inhibition-and a motion-capture task assessing prospective motor control during reaching. We demonstrated that prospective motor control, as measured by the peak velocity of the first movement unit, is related to infants' performance on simple-inhibition and working memory tasks. The current study provides evidence that motor control and executive functioning are intertwined early in life, which suggests an embodied perspective on executive-functioning development. We argue that executive functions and prospective motor control develop from a common source and a single motive: to control action. This is the first demonstration that low-level movement planning is related to higher-order executive control early in life.


The genetic history of Ice Age Europe.
Modern humans arrived in Europe ~45,000 years ago, but little is known about their genetic composition before the start of farming ~8,500 years ago. Here we analyse genome-wide data from 51 Eurasians from ~45,000-7,000 years ago. Over this time, the proportion of Neanderthal DNA decreased from 3-6% to around 2%, consistent with natural selection against Neanderthal variants in modern humans. Whereas there is no evidence of the earliest modern humans in Europe contributing to the genetic composition of present-day Europeans, all individuals between ~37,000 and ~14,000 years ago descended from a single founder population which forms part of the ancestry of present-day Europeans. An ~35,000-year-old individual from northwest Europe represents an early branch of this founder population which was then displaced across a broad region, before reappearing in southwest Europe at the height of the last Ice Age ~19,000 years ago. During the major warming period after ~14,000 years ago, a genetic component related to present-day Near Easterners became widespread in Europe. These results document how population turnover and migration have been recurring themes of European prehistory.


Effects of Tityus serrulatus scorpion toxin gamma on voltage-gated Na+ channels.
The effects of Brazilian scorpion Tityus serrulatus toxin gamma (TiTx gamma) were studied on voltage-gated Na+ channels from human heart (hHl) and rat skeletal muscle (rSkM1). The Na+ channels were expressed in Xenopus laevis oocytes, and Na+ currents were recorded using two-microelectrode voltage-clamp techniques. In control experiments, the threshold of activation of hH1 is more negative than that of rSkM1 by approximately 20 mV. The toxin induces a shift of the voltage dependence of activation toward more negative potential values and reduces the amplitude of the current when administered to rSkM1. In contrast, TiTx gamma has little discernible effect on the current-voltage curve for hH1 at 100 nmol/L. Chimeric channels formed from these two isoforms were constructed to localize the binding site of TiTx gamma on rSkM1. TiTx gamma shifts the activation of a chimera (SSHH) in which domains 1 (D1) and 2 (D2) derive from rSkM1 and domain 3(D3) and 4 (D4) derive from hH1. This finding suggests that the toxin acts on the activation of rSkM1 by binding either to D1 and/or D2. TiTx gamma shifted the activation of another chimera with D2-D3-D4 from rSkM1 (HSSS) toward more hyperpolarizing potentials and had no effect on the activation of other chimeras with only D1-D3-D4 from rSkM1 (SHSS) or only D3 from rSkM1 (HHSH). Finally, a chimera in which D2 is from rSkM1 and all others domains are from hH1 (HSHH) provides further compelling support for our hypothesis. TiTx gamma shifts the activation of this chimera toward more negative potential values. Thus, TiTx gamma action on chimeras segregates with the source of D2: when D2 is from rSkM1, the toxin affects activation. We infer that D2 plays an important role in the activation process of voltage-gated Na+ channels.


Glutathione S-transferase genes and the risk of recurrent miscarriage in Italian women.
To investigate the role of glutathione S-transferases (GSTs) in the pathogenesis of recurrent miscarriage (RM). Genetic association study. University of Rome, Tor Vergata and San Giovanni Calibita, Fatebenefratelli Hospital. One hundred twenty-one women with RM and 113 women without pregnancy complications. Genomic DNA extracted from buccal cells and screening of positive/null genotypes of GSTM1 and GSTT1 genes and single nucleotide polymorphisms of GSTA1, GSTO2, and GSTP1 genes. Occurrence of GST polymorphisms. Women with at least one GSTA1*-69T allele are more frequent in the RM group than in the control group: 67% vs. 48%, respectively. Significant outcomes were obtained considering different genetic models: codominant, dominant, and log-additive. In addition, the combined analysis suggests that GSTA1 and GSTM1 variants have a significant interaction in RM risk. Our study highlighted a significant association between the GSTA1 gene and an increased risk of RM. In particular, the -69T allele in the GSTA1 gene may be considered as a predisposing factor of RM.


FeoC from Klebsiella pneumoniae contains a [4Fe-4S] cluster.
Iron is essential for pathogen survival, virulence, and colonization. Feo is suggested to function as the ferrous iron (Fe(2+)) transporter. The enterobacterial Feo system is composed of 3 proteins: FeoB is the indispensable component and is a large membrane protein likely to function as a permease; FeoA is a small Src homology 3 (SH3) domain protein that interacts with FeoB; FeoC is a winged-helix protein containing 4 conserved Cys residues in a sequence suitable for harboring a putative iron-sulfur (Fe-S) cluster. The presence of an iron-sulfur cluster on FeoC has never been shown experimentally. We report that under anaerobic conditions, the recombinant Klebsiella pneumoniae FeoC (KpFeoC) exhibited hyperfine-shifted nuclear magnetic resonance (NMR) and a UV-visible (UV-Vis) absorbance spectrum characteristic of a paramagnetic center. The electron paramagnetic resonance (EPR) and extended X-ray absorption fine structure (EXAFS) results were consistent only with the [4Fe-4S] clusters. Substituting the cysteinyl sulfur with oxygen resulted in significantly reduced cluster stability, establishing the roles of these cysteines as the ligands for the Fe-S cluster. When exposed to oxygen, the [4Fe-4S] cluster degraded to [3Fe-4S] and eventually disappeared. We propose that KpFeoC may regulate the function of the Feo transporter through the oxygen- or iron-sensitive coordination of the Fe-S cluster.


Effects of Ving Tsun Chinese Martial Art Training on Upper Extremity Muscle Strength and Eye-Hand Coordination in Community-Dwelling Middle-Aged and Older Adults: A Pilot Study.
Objectives. To evaluate the effects of Ving Tsun (VT) martial art training on the upper extremity muscle strength and eye-hand coordination of middle-aged and older adults. Methods. This study used a nonequivalent pretest-posttest control group design. Forty-two community-dwelling healthy adults participated in the study; 24 (mean age ± SD = 68.5 ± 6.7 years) underwent VT training for 4 weeks (a supervised VT session twice a week, plus daily home practice), and 18 (mean age ± SD = 72.0 ± 6.7 years) received no VT training and acted as controls. Shoulder and elbow isometric muscle strength and eye-hand coordination were evaluated using the Lafayette Manual Muscle Test System and a computerized finger-pointing test, respectively. Results. Elbow extensor peak force increased by 13.9% (P = 0.007) in the VT group and the time to reach peak force decreased (9.9%) differentially in the VT group compared to the control group (P = 0.033). For the eye-hand coordination assessment outcomes, reaction time increased by 2.9% in the VT group and decreased by 5.3% in the control group (P = 0.002). Conclusions. Four weeks of VT training could improve elbow extensor isometric peak force and the time to reach peak force but not eye-hand coordination in community-dwelling middle-aged and older adults.


Patent ductus venosus and dioxin resistance in mice harboring a hypomorphic Arnt allele.
The Ah receptor nuclear translocator (ARNT) is the dimeric partner of hypoxia-inducible factors and thus plays a pivotal role in cellular adaptation to low oxygen environments. ARNT is also a dimeric partner for the Ah receptor (AHR), and this complex is essential in regulating the adaptive metabolic response to polycyclic aromatic hydrocarbons. Because of the essential role of ARNT in hypoxia-driven developmental events, it has been difficult to study the physiological significance of AHR.ARNT heterodimers in vivo. To address this issue, we developed a hypomorphic Arnt allele that displayed normal development and allowed the examination of the role of ARNT in AHR biology. In this regard, the AHR is also known to mediate two additional biological processes: the toxicological response to compounds such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) and the developmental closure of a fetal vascular structure known as the ductus venosus. Although the mechanism of the adaptive pathway has been well described, the mechanism of AHR-mediated signal transduction in the toxic and developmental pathways is not well understood. Liver perfusion studies demonstrated that ARNT hypomorphs have a patent ductus venosus, identical to that observed in the Ahr null mice. Parallel dioxin toxicity studies demonstrated that the ARNT hypomorphs exhibited resistance to the end points of dioxin exposure. Moreover, we observed that toxicity could be segregated from the classical adaptive responses such as P4501A induction. Taken in sum, these experiments demonstrate that ARNT is an essential component of AHR developmental signaling and shed light on the mechanism of dioxin toxicity.


Monoaminergic dysregulation in glutathione-deficient mice: possible relevance to schizophrenia?
Several lines of research have implicated glutathione (GSH) in schizophrenia. For instance, GSH deficiency has been reported in the prefrontal cortex of schizophrenics in vivo. Further, in rats postnatal GSH-deficiency combined with hyperdopaminergia led to cognitive impairments in the adult. In the present report we studied the effects of 2-day GSH-deficiency with L-buthionine-(S,R)-sulfoximine on monoaminergic function in mice. The effect of GSH-deficiency per se and when combined with the amphetamine and phencyclidine (PCP) models of schizophrenia was investigated. GSH-deficiency significantly altered tissue levels of dopamine (DA), 5-hydroxytryptamine (5-HT) and their respective metabolites homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in a region-specific fashion. The effects of GSH-deficiency on tissue monoamines were distinct from and, generally, did not interact with the effects of amphetamine (5 mg/kg; i.p.) on tissue monoamines. Microdialysis studies showed that extracellular DA-release after amphetamine (5 mg/kg, i.p.) was two-fold increased in the nucleus accumbens of GSH-deficient mice as compared with control mice. Basal DA was unaltered. Further, extracellular levels of HVA in the frontal cortex and hippocampus and 5-HIAA in the nucleus accumbens were elevated by GSH-deficiency per se. Spontaneous locomotor activity in the open field was unchanged in GSH-deficient mice. In contrast, GSH-deficiency modulated the locomotor responses to mid-range doses of amphetamine (1.5 and 5 mg/kg, i.p.). Further, GSH-deficient mice displayed an increased locomotor response to low (2 and 3 mg/kg, i.p.) doses of phencyclidine (PCP). In conclusion, the data presented here show that even short-term GSH-deficiency has consequences for DA and 5-HT function. This was confirmed on both neurochemical and behavioral levels. How GSH and the monoamines interact needs further scrutiny. Moreover, the open field findings suggest reduced or altered N-methyl-d-aspartate (NMDA) receptor function in GSH-deficient mice. Thus, GSH-deficiency can lead to disturbances in DA, 5-HT and NMDA function, a finding that may have relevance for schizophrenia.


BAHD1 haploinsufficiency results in anxiety-like phenotypes in male mice.
BAHD1 is a heterochomatinization factor recently described as a component of a multiprotein complex associated with histone deacetylases HDAC1/2. The physiological and patho-physiological functions of BAHD1 are not yet well characterized. Here, we examined the consequences of BAHD1 deficiency in the brains of male mice. While Bahd1 knockout mice had no detectable defects in brain anatomy, RNA sequencing profiling revealed about 2500 deregulated genes in Bahd1-/- brains compared to Bahd1+/+ brains. A majority of these genes were involved in nervous system development and function, behavior, metabolism and immunity. Exploration of the Allen Brain Atlas and Dropviz databases, assessing gene expression in the brain, revealed that expression of the Bahd1 gene was limited to a few territories and cell subtypes, particularly in the hippocampal formation, the isocortex and the olfactory regions. The effect of partial BAHD1 deficiency on behavior was then evaluated on Bahd1 heterozygous male mice, which have no lethal or metabolic phenotypes. Bahd1+/- mice showed anxiety-like behavior and reduced prepulse inhibition (PPI) of the startle response. Altogether, these results suggest that BAHD1 plays a role in chromatin-dependent gene regulation in a subset of brain cells and support recent evidence linking genetic alteration of BAHD1 to psychiatric disorders in a human patient.


Involvement of periostin in regression of hyaloidvascular system during ocular development.
A timely regression of the hyaloid vascular system (HVS) is required for the normal ocular development. Although macrophages have a critical role in this process, the exact mechanism remains undetermined. Periostin is a matricellular protein involved in tissue and vascular remodeling. The purpose of our study was to determine whether periostin is involved in the HVS regression. We used wild type (WT) and periostin knockout (KO) mice. Indocyanine green angiography and immunohistochemistry with isolectin B4 were used to evaluate the HVS regression. TUNEL-labeling was used to quantify the number of apoptotic hyaloid vascular endothelial cells. F4/80 and Iba-1 staining was performed to determine the number and location of macrophages in the vitreous. The location of periostin also was investigated by immunohistochemistry. To determine the functional role of periostin, the degree of adhesion of human monocytes to fibronectin was measured by an adhesion assay. The HVS regression and peak in the number of TUNEL-positive apoptotic endothelial cells were delayed in periostin KO mice. The number of F4/80 positive cells in the vitreous was higher in periostin KO mice. Only a small number of Iba-1-positive cells near the hyaloid vessels was co-stained with periostin, and peripheral blood monocytes were not stained with periostin. Adhesion assay showed that periostin increased the degree of attachment of monocytes to fibronectin. These results suggest that periostin, which is secreted by the intraocular macrophages, enhances the HVS regression by intensifying the adhesion of macrophages to hyaloid vessels.


A potent and selective inhibitor of cyclic AMP phosphodiesterase with potential cardiotonic and antithrombotic properties.
Some biochemical and pharmacological properties of a novel, potent inhibitor of cyclic AMP phosphodiesterase, N-cyclohexyl-N-methyl-4-(7-oxy-1,2,3,5-tetrahydroimidazo[2,1-b] quinazolin-2-one) butyramide (RS-82856), were investigated. RS-82856 selectively inhibits the high affinity form of cyclic AMP phosphodiesterase (type IV) isolated from human platelets (Ki = 0.5 nM) with only weak effects on both the nonspecific and cyclic GMP-sensitive phosphodiesterases. The inhibitor reduces both maximum velocity and substrate affinity of the type IV enzyme. This mixed pattern of partial competitive and noncompetitive inhibition was also obtained with one of the two high affinity forms of phosphodiesterase found in dog heart (Ki = 0.75 nM). Of several human and dog tissues examined, RS-82856 exhibits marked selectively for the platelet high affinity enzyme. It also has significant inhibitory effects on cardiac membrane-bound phosphodiesterase. RS-82856 inhibits the aggregation of human platelets in response to adenosine 5'-diphosphate (IC50 = 0.11 microM) in vitro and is active ex vivo for at least 2 hr following oral administration (10 mg/kg) to rhesus monkeys. Administration of RS-82856 to instrumented, anesthetized dogs by either intravenous or intraduodenal routes increases cardiac contractile force and reduces afterload. These data suggest that RS-82856 may be useful as an agent to increase cardiac output in the treatment of congestive heart failure.


Evaluation of the labrum on postoperative magnetic resonance images: a predictor of acetabular development in developmental dysplasia of the hip.
Residual acetabular dysplasia of the hip after open reduction can complicate the treatment of developmental dysplasia of the hip (DDH) due to the potential need for corrective surgery. This retrospective study aimed to determine the predictive factors for acetabular development using postoperative radiographs and magnetic resonance imaging (MRI). We retrospectively investigated 74 hips of patients with DDH who underwent open reduction after reaching walking age and were followed up radiologically until skeletal maturity. We evaluated the cartilaginous acetabulum and labrum using a new method that measures the cartilaginous and labral landmarks on coronal and axial MR T2*-weighted images in patients aged 5 years. The mean age at the time of surgery was 22 months and that at the final survey was 20 years. Severin classification was determined at the final follow-up. Groups with good (53 hips) and poor (21 hips) outcomes were compared using the postoperative radiographic and MRI parameters recorded at 5 years of age. Factors predicting acetabular development were identified using univariate and multiple logistic analyses. There were no significant differences in the bony-acetabular index (AI) and centre-edge (CE) angle between the good and poor outcome groups. However, the poor outcome group had significantly larger cartilaginous- and labral-AIs but significantly smaller cartilaginous- and labral-CE angles than the good outcome group (both p < 0.05). Multiple logistic regression analysis showed that labral-AI and labral-CE angle were predictors of acetabular development after open reduction for DDH, and their optimal cut-offs were 4° (77% sensitivity, 76% specificity) and 37° (68% sensitivity, 85% specificity), respectively. Normal cartilaginous acetabulum development occurs in childhood, and evaluation using only radiographs is difficult. However, labral-AI ⩾4° and labral-CE angle <37° on MRI at 5 years of age offer useful indications for corrective surgery in patients with DDH.


Multiplex PCR for identification of six clinically relevant streptococci.
The aim of this study was to develop a multiplex PCR (mPCR) for simultaneous detection (single reaction) of six clinically relevant streptococcal species: Streptococcus pneumoniae, Streptococcus suis, Streptococcus gallolyticus subsp. gallolyticus, S. gallolyticus subsp. pasteurianus, Streptococcus intermedius and Streptococcus anginosus/constellatus. mPCR with primers specific for S. pneumoniae (lytA), S. suis (recN), S. gallolyticus subsp. gallolyticus (tanB), S. gallolyticus subsp. pasteurianus (SGPB0680 cell wall surface protein), S. intermedius (ily) and S. anginosus/constellatus (moaC) was employed with 37 reference bacterial strains and 442 clinical streptococcal isolates collected from seven tertiary hospitals in north-east Thailand. Results from this mPCR were compared to those obtained with the API 20 Strep and conventional biochemical tests. The six clinically relevant streptococcal species gave the expected amplification products of 229, 362, 531, 723, 819 and 978 bp for S. pneumoniae, S. gallolyticus subsp. gallolyticus, S. gallolyticus subsp. pasteurianus, S. suis, S. intermedius and S. anginosus/S. constellatus, respectively. Non-specific reactions were not observed with the other bacterial species tested. For the 442 clinical streptococci, this mPCR assay confirmed the identity of the species in accordance with results obtained with the API 20 Strep and conventional biochemical tests. This mPCR can be applied to the rapid identification of pure cultures of these six streptococci. The test was shown to be rapid, simple and reliable for the identification of these streptococci at the species level. This assay should be useful for laboratory identification and surveillance of human infections by these bacterial species.


Sweetened beverage intake and risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes.
Sweetened beverage intake is associated with increased risk of type 2 diabetes, but its association with autoimmune diabetes is unclear. We aimed to investigate sweetened beverage intake and risk of latent autoimmune diabetes in adults (LADA); autoimmune diabetes with features of type 2 diabetes. Data from a Swedish population-based study was used, including incident cases of LADA (n = 357) and type 2 diabetes (n = 1136) and randomly selected controls (n = 1371). Diabetes classification was based on onset age (≥35), glutamic acid decarboxylase autoantibodies (GADA) and C-peptide. Sweetened beverage intake information was derived from a validated food frequency questionnaire. ORs adjusted for age, sex, family history of diabetes, education, lifestyle, diet, energy intake and BMI were estimated using logistic regression. Daily intake of >2 servings of sweetened beverages (consumed by 6% of participants) was associated with increased risk of LADA (OR: 1.99, 95% CI: 1.11-3.56), and for each 200 mL daily serving, OR was 1.15 (95% CI: 1.02-1.29). Findings were similar for sugar-sweetened (OR: 1.18, 95% CI: 1.00-1.39) and artificially sweetened beverages (OR: 1.12, 95% CI: 0.95-1.32). Similarly, each daily serving increment in total sweetened beverage conferred 20% higher type 2 diabetes risk (95% CI: 1.07-1.34). In type 2 diabetes patients, high consumers displayed higher HOMA-IR levels (4.5 vs 3.5, P = 0.0002), but lower HOMA-B levels (55 vs 70, P = 0.0378) than non-consumers. Similar tendencies were seen in LADA. High intake of sweetened beverages was associated with increased risk of LADA. The observed relationship resembled that with type 2 diabetes, suggesting common pathways possibly involving insulin resistance.


Telehealth exercise-based cardiac rehabilitation: a systematic review and meta-analysis.
Despite proven effectiveness, participation in traditional supervised exercise-based cardiac rehabilitation (exCR) remains low. Telehealth interventions that use information and communication technologies to enable remote exCR programme delivery can overcome common access barriers while preserving clinical supervision and individualised exercise prescription. This meta-analysis aimed to determine the benefits of telehealth exCR on exercise capacity and other modifiable cardiovascular risk factors compared with traditional exCR and usual care, among patients with coronary heart disease (CHD). CINAHL, The Cochrane Library, Embase, MEDLINE, PubMed and PsycINFO were searched from inception through 31 May 2015 for randomised controlled trials comparing telehealth exCR with centre-based exCR or usual care among patients with CHD. Outcomes included maximal aerobic exercise capacity, modifiable cardiovascular risk factors and exercise adherence. 11 trials (n=1189) met eligibility criteria and were included in the review. Physical activity level was higher following telehealth exCR than after usual care. Compared with centre-based exCR, telehealth exCR was more effective for enhancing physical activity level, exercise adherence, diastolic blood pressure and low-density lipoprotein cholesterol. Telehealth and centre-based exCR were comparably effective for improving maximal aerobic exercise capacity and other modifiable cardiovascular risk factors. Telehealth exCR appears to be at least as effective as centre-based exCR for improving modifiable cardiovascular risk factors and functional capacity, and could enhance exCR utilisation by providing additional options for patients who cannot attend centre-based exCR. Telehealth exCR must now capitalise on technological advances to provide more comprehensive, responsive and interactive interventions.


The co-occurrence of nicotine and other substance use and addiction among youth and adults in the United States: implications for research, practice, and policy.
The increasing popularity of non-cigarette nicotine products, especially among youth, highlights the need for greater attention to their potential risks, including nicotine addiction and other substance use and addiction. To examine the extent to which nicotine product use co-occurs with other substance use and addiction among youth and adults, describe the demographic groups and types of nicotine products associated with an increased risk of such co-occurrence, and discuss implications for research, prevention, clinical practice, and policy. Analyzing 2014 data from two nationally representative US surveys, the National Survey on Drug Use and Health (NSDUH) and the Monitoring the Future (MTF) study, we examined the co-occurrence between nicotine product use and alcohol and other drug use and addiction. Individuals of all ages who reported using nicotine products of any kind were significantly more likely than nonusers to report alcohol, marijuana, other drug, and poly-substance use and to meet diagnostic criteria for a substance-use disorder. Users of multiple nicotine products generally were the most likely to engage in alcohol and other drug use and to be addicted to these other substances. The substantial co-occurrence of all forms of nicotine use and other substance use and addiction underscores the need to control the growing use of non-cigarette nicotine products among youth and to incorporate all forms of nicotine product use into substance use and addiction research, prevention, clinical practice, and policy efforts.


Selective glycoprotein detection through covalent templating and allosteric click-imprinting.
Many glycoproteins are intimately linked to the onset and progression of numerous heritable or acquired diseases of humans, including cancer. Indeed the recognition of specific glycoproteins remains a significant challenge in analytical method and diagnostic development. Herein, a hierarchical bottom-up route exploiting reversible covalent interactions with boronic acids and so-called click chemistry for the fabrication of glycoprotein selective surfaces that surmount current antibody constraints is described. The self-assembled and imprinted surfaces, containing specific glycoprotein molecular recognition nanocavities, confer high binding affinities, nanomolar sensitivity, exceptional glycoprotein specificity and selectivity with as high as 30 fold selectivity for prostate specific antigen (PSA) over other glycoproteins. This synthetic, robust and highly selective recognition platform can be used in complex biological media and be recycled multiple times with no performance decrement.


ERS/ATS workshop report on respiratory health effects of household air pollution.
Exposure to household air pollution (HAP) from solid fuel combustion affects almost half of the world population. Adverse respiratory outcomes such as respiratory infections, impaired lung growth and chronic obstructive pulmonary disease have been linked to HAP exposure. Solid fuel smoke is a heterogeneous mixture of various gases and particulates. Cell culture and animal studies with controlled exposure conditions and genetic homogeneity provide important insights into HAP mechanisms. Impaired bacterial phagocytosis in exposed human alveolar macrophages possibly mediates several HAP-related health effects. Lung pathological findings in HAP-exposed individuals demonstrate greater small airways fibrosis and less emphysema compared with cigarette smokers. Field studies using questionnaires, air pollution monitoring and/or biomarkers are needed to better establish human risks. Some, but not all, studies suggest that improving cookstove efficiency or venting emissions may be associated with reduced respiratory symptoms, lung function decline in women and severe pneumonia in children. Current studies focus on fuel switching, stove technology replacements or upgrades and air filter devices. Several governments have initiated major programmes to accelerate the upgrade from solid fuels to clean fuels, particularly liquid petroleum gas, which provides research opportunities for the respiratory health community.


Oxygen plasmas: a sharp chisel and handy trowel for nanofabrication.
Although extremely chemically reactive, oxygen plasmas feature certain properties that make them attractive not only for material removal via etching and sputtering, but also for driving and sustaining nucleation and growth of various nanostructures in plasma bulk and on plasma-exposed surfaces. In this minireview, a number of representative examples is used to demonstrate key mechanisms and unique capabilities of oxygen plasmas and how these can be used in present-day nano-fabrication. In addition to modification and functionalisation processes typical for oxygen plasmas, their ability to catalyse the growth of complex nanoarchitectures is emphasized. Two types of technologies based on oxygen plasmas, namely surface treatment without a change in the size and shape of surface features, as well as direct growth of oxide structures, are used to better illustrate the capabilities of oxygen plasmas as a powerful process environment. Future applications and possible challenges for the use of oxygen plasmas in nanofabrication are discussed.


Cumulative risk assessment of phthalates exposure for recurrent pregnancy loss in reproductive-aged women population using multiple hazard indices approaches.
Phthalates, which are commonly used in flexible plastics and consumer products, have been reported to be toxic to reproductive and developmental function in mammals. Past studies have focused on the toxic effects on male reproduction, with only a few studies conducted on the risks that cumulative exposure to phthalates have on the female reproductive system. We recruited 260 patients with recurrent pregnancy loss (RPL) of unknown etiology and 203 controls from the clinics of Obstetrics and Gynecology at a medical center in southern Taiwan from 2013 to 2020. The daily intake of phthalates was estimated from urine samples using the back-calculation method, after which the cumulative risk was determined using multiple hazard indices, including a dose-addition model, a receptor effect model, and a hazard index approach. The patients with RPL had a significantly higher cumulative exposure to phthalates (p < 0.05) than did the controls with a hazard index above one. After adjusted logistic regression analysis, we found that the risk of RPL was strongly related to the higher quartiles of DEHP, the DEHPTEQ for the antiandrogenic effect and adverse effects of the female reproductive system and the ERα binding effect (p < 0.05). Our work suggests that more attentions should be paid to the adverse effects induced by phthalates on female reproduction, especially the effects caused by the cumulative exposure to phthalates in women of reproductive age.


The role of macrolides in childhood non-cystic fibrosis-related bronchiectasis.
Non-cystic fibrosis-related bronchiectasis is a chronic inflammatory lung disease, which is regarded as an "orphan" lung disease, with little research devoted to the study of this condition. Bronchiectasis results in impaired quality of life and mortality if left untreated. The tools available in the armamentarium for the management of bronchiectasis entail antibiotic therapy traditionally used to treat exacerbations, stratagems to improve mucociliary clearance, and avoidance of toxins. Macrolides have been known for the last two decades to have not only anti-bacterial effects but immunomodulatory properties as well. In cystic fibrosis, the use of macrolides is well documented in subjects colonized with Pseudomonas aeruginosa, to improve quality of life and lung function. There is currently emerging evidence to suggest the benefit of macrolides in subjects not colonized with Pseudomonas aeruginosa. This beneficial effect has been less explored in the context of bronchiectasis from other causes. The purpose of this paper is to review the current literature on the use of macrolides in non-cystic fibrosis related bronchiectasis in paediatrics.


Precocious development of self-awareness in dolphins.
Mirror-self recognition (MSR) is a behavioral indicator of self-awareness in young children and only a few other species, including the great apes, dolphins, elephants and magpies. The emergence of self-awareness in children typically occurs during the second year and has been correlated with sensorimotor development and growing social and self-awareness. Comparative studies of MSR in chimpanzees report that the onset of this ability occurs between 2 years 4 months and 3 years 9 months of age. Studies of wild and captive bottlenose dolphins (Tursiops truncatus) have reported precocious sensorimotor and social awareness during the first weeks of life, but no comparative MSR research has been conducted with this species. We exposed two young bottlenose dolphins to an underwater mirror and analyzed video recordings of their behavioral responses over a 3-year period. Here we report that both dolphins exhibited MSR, indicated by self-directed behavior at the mirror, at ages earlier than generally reported for children and at ages much earlier than reported for chimpanzees. The early onset of MSR in young dolphins occurs in parallel with their advanced sensorimotor development, complex and reciprocal social interactions, and growing social awareness. Both dolphins passed subsequent mark tests at ages comparable with children. Thus, our findings indicate that dolphins exhibit self-awareness at a mirror at a younger age than previously reported for children or other species tested.


An env gene derived from a primary human immunodeficiency virus type 1 isolate confers high in vivo replicative capacity to a chimeric simian/human immunodeficiency virus in rhesus monkeys.
To explore the roles played by specific human immunodeficiency virus type 1 (HIV-1) genes in determining the in vivo replicative capacity of AIDS viruses, we have examined the replication kinetics and virus-specific immune responses in rhesus monkeys following infection with two chimeric simian/human immunodeficiency viruses (SHIVs). These viruses were composed of simian immunodeficiency virus SIVmac239 expressing HIV-1 env and the associated auxiliary HIV-1 genes tat, vpu, and rep. Virus replication was assessed during primary infection of rhesus monkeys by measuring plasma SIVmac p27 levels and by quantifying virus replication in lymph nodes using in situ hybridization. SHIV-HXBc2, which expresses the HIV-1 env of a T-cell-tropic, laboratory-adapted strain of HIV-1 (HXBc2), replicated well in rhesus monkey peripheral blood leukocytes (PBL) in vitro but replicated only to low levels when inoculated in rhesus monkeys. In contrast, SHIV-89.6 was constructed with the HIV-1 env gene of a T-cell- and macrophage-tropic clone of a patient isolate of HIV-1 (89.6). This virus replicated to a lower level in monkey PBL in vitro but replicated to a higher degree in monkeys during primary infection. Moreover, monkeys infected with SHIV-89.6 developed an inversion in the PBL CD4/CD8 ratio coincident with the clearance of primary viremia. The differences in the in vivo consequences of infection by these two SHIVs could not be explained by differences in the immune responses elicited by these viruses, since infected animals had comparable type-specific neutralizing antibody titers, proliferative responses to recombinant HIV-1 gp120, and virus-specific cytolytic effector T-cell responses. With the demonstration that a chimeric SHIV can replicate to high levels during primary infection in rhesus monkeys, this model can now be used to define genetic determinants of HIV-1 pathogenicity.


Clonal selection drives genetic divergence of metastatic medulloblastoma.
Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord. Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour. Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies.


Non-invasive imaging reveals conditions that impact distribution and persistence of cells after in vivo administration.
Cell-based regenerative medicine therapies are now frequently tested in clinical trials. In many conditions, cell therapies are administered systemically, but there is little understanding of their fate, and adverse events are often under-reported. Currently, it is only possible to assess safety and fate of cell therapies in preclinical studies, specifically by monitoring animals longitudinally using multi-modal imaging approaches. Here, using a suite of in vivo imaging modalities to explore the fate of a range of human and murine cells, we investigate how route of administration, cell type and host immune status affect the fate of administered cells. We applied a unique imaging platform combining bioluminescence, optoacoustic and magnetic resonance imaging modalities to assess the safety of different human and murine cell types by following their biodistribution and persistence in mice following administration into the venous or arterial system. Longitudinal imaging analyses (i) suggested that the intra-arterial route may be more hazardous than intravenous administration for certain cell types, (ii) revealed that the potential of a mouse mesenchymal stem/stromal cell (MSC) line to form tumours depended on administration route and mouse strain and (iii) indicated that clinically tested human umbilical cord (hUC)-derived MSCs can transiently and unexpectedly proliferate when administered intravenously to mice. In order to perform an adequate safety assessment of potential cell-based therapies, a thorough understanding of cell biodistribution and fate post administration is required. The non-invasive imaging platform used here can expose not only the general organ distribution of these therapies, but also a detailed view of their presence within different organs and, importantly, tumourigenic potential. Our observation that the hUC-MSCs but not the human bone marrow (hBM)-derived MSCs persisted for a period in some animals suggests that therapies with these cells should proceed with caution.


A population-based twin study of alcoholism in women.
To clarify the role of genetic factors in the etiology of alcoholism in women. Personal structured psychiatric interviews conducted by researchers "blinded" to the status of the co-twin in an epidemiologic sample of 1030 female-female twin pairs of known zygosity from the population-based Virginia Twin Registry. Three definitions of lifetime prevalence of alcoholism based on Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised criteria: (1) alcoholism with tolerance or dependence; (2) alcoholism with or without tolerance-dependence; and (3) alcoholism with or without tolerance-dependence or problem drinking. Using narrow, intermediate, or broad definitions, the probandwise concordance for alcoholism was consistently higher in monozygotic than in dizygotic twin pairs. Multifactorial threshold models suggested that the heritability of liability to alcoholism in women is in the range of 50% to 60%. The results support the hypothesis that genetic factors play a major role in the etiology of alcoholism in women. Women should be well represented in the efforts currently under way to elucidate the molecular basis of the genetic susceptibility to alcoholism.


Structural insights into the recognition of nucleoside reverse transcriptase inhibitors by HIV-1 reverse transcriptase: First crystal structures with reverse transcriptase and the active triphosphate forms of lamivudine and emtricitabine.
The retrovirus HIV-1 has been a major health issue since its discovery in the early 80s. In 2017, over 37 million people were infected with HIV-1, of which 1.8 million were new infections that year. Currently, the most successful treatment regimen is the highly active antiretroviral therapy (HAART), which consists of a combination of three to four of the current 26 FDA-approved HIV-1 drugs. Half of these drugs target the reverse transcriptase (RT) enzyme that is essential for viral replication. One class of RT inhibitors is nucleoside reverse transcriptase inhibitors (NRTIs), a crucial component of the HAART. Once incorporated into DNA, NRTIs function as a chain terminator to stop viral DNA replication. Unfortunately, treatment with NRTIs is sometimes linked to toxicity caused by off-target side effects. NRTIs may also target the replicative human mitochondrial DNA polymerase (Pol γ), causing long-term severe drug toxicity. The goal of this work is to understand the discrimination mechanism of different NRTI analogues by RT. Crystal structures and kinetic experiments are essential for the rational design of new molecules that are able to bind selectively to RT and not Pol γ. Structural comparison of NRTI-binding modes with both RT and Pol γ enzymes highlights key amino acids that are responsible for the difference in affinity of these drugs to their targets. Therefore, the long-term goal of this research is to develop safer, next generation therapeutics that can overcome off-target toxicity.


The performance of dialysis care: routinization and adaptation on the floor.
Previous studies of communication in dialysis centers primarily focused on communication between nurses and patients. In this study, ethnographic methods were used to explore the dominant communication performances enacted by dialysis staff members, including registered nurses, patient care technicians, technical aides, a social worker, and a dietitian. Findings suggest a dialectic between extreme routinization of care and continual adaptation. The dominant routine involved repeating the same preparation, treatment, and discharge process 3 shifts per day, thrice weekly for each patient. At the same time, near-constant adjustments to scheduling, coordination of tasks, and problem solving were needed to maintain the performance of repetition. The balancing of this dialectic has significant implications for new staff training and socialization, understanding the role of technology and routine in dialysis and in health care systems more generally, and in further theorizing the role of unbounded communication interactions in health care.


Reliable confirmation of antibodies to human immunodeficiency virus type 1 (HIV-1) with an enzyme-linked immunoassay using recombinant antigens derived from the HIV-1 gag, pol, and env genes.
An enzyme-linked immunoassay (ELISA) using six recombinant proteins corresponding to large segments of the human immunodeficiency virus type 1 (HIV-1) gag, pol, and env gene products (HIVAGEN; SmithKline Bio-Science Laboratories, Van Nuys, Calif.) was developed to confirm the presence of antibodies to HIV-1 in sera reactive in the whole-cell-derived virion screening ELISAs. Serum samples for testing were obtained from healthy seronegative blood donors and from the different categories of HIV-infected individuals (asymptomatic, acquired immunodeficiency syndrome [AIDS]-related complex, and AIDS). A positive reaction was defined as reactivity against an env and at least one other (either gag or pol) HIV-1 gene product; negative was defined as no reaction with any antigen; and indeterminate was defined as reactivity with gag or pol (or both) or with env alone. None of the 1,180 serum samples from healthy seronegative blood donors gave a positive result, and only 49 of these samples (4%) gave indeterminate results. The recombinant HIV-1 antigen ELISA panel identified seropositive individuals with a high degree of accuracy, as a positive reaction was seen with 99.3% of asymptomatic healthy seropositive individuals, 98.1% of patients with AIDS-related complex, and 90.4% of patients with AIDS. None of the 725 HIV-1-seropositive subjects had a negative test result. Reactivity with the Kp41 antigen, corresponding to an amino-terminal portion of the gp41 envelope glycoprotein, by itself demonstrated 100% sensitivity and specificity in distinguishing seronegative from seropositive sera. A subset of seronegative and seropositive samples were tested both with the recombinant HIV-1 antigen ELISA panel and by Western blot (Du Pont Co.). The recombinant HIV-1 antigen ELISA panel accurately identified more seropositive and seronegative samples and had fewer indeterminate results than did Western blot (interpreted by Du Pont criteria).


Burn and scald injuries.
Burns are one of the most harmful physical and psychological traumas. Infection is the major cause of morbidity and mortality in burns. Infections acquired from hospital or from the patient's own endogenous flora have a significant prevalence after burns. Pseudomonas aeruginosa and Staphylococcus aureus are the most frequent colonizing agents whereas group A beta-haemolytic streptococci are the most virulent bacteria. Anaerobic bacteria and fungi are also prevalent. Viral infection is less frequent. Aggressive resuscitation, nutritional support, thorough surgical excision of infected wounds, early wound closure, grafting and the development of effective topical and systemic chemotherapy have largely improved morbidity and mortality rates of burn patients.


Bisacylphosphane oxides as photo-latent cytotoxic agents and potential photo-latent anticancer drugs.
Bisacylphosphane oxides (BAPOs) are established as photoinitiators for industrial applications. Light irradiation leads to their photolysis, producing radicals. Radical species induce oxidative stress in cells and may cause cell death. Hence, BAPOs may be suitable as photolatent cytotoxic agents, but such applications have not been investigated yet. Herein, we describe for the first time a potential use of BAPOs as drugs for photolatent therapy. We show that treatment of the breast cancer cell lines MCF-7 and MDA-MB-231 and of breast epithelial cells MCF-10A with BAPOs and UV irradiation induces apoptosis. Cells just subjected to BAPOs or UV irradiation alone are not affected. The induction of apoptosis depend on the BAPO and the irradiation dose. We proved that radicals are the active species since cells are rescued by an antioxidant. Finally, an optimized BAPO-derivative was designed which enters the cells more efficiently and thus leads to stronger effects at lower doses.


Impact of PrEP on a STI clinic in a Belgian context: a provider's perspective.
Objectives: To assess the impact of Pre-Exposure Prophylaxis (PrEP) to avoid HIV infection as an additional service in a routine Sexually Transmitted Infections (STI) clinic.Methods: We used routinely obtained retrospective data to estimate the increased workload on the existing facilities. We focussed on STI registration through the laboratory registration system and put this in a national perspective. A critical appraisal was made of the national HIV notifications, as an indicator of the impact of PrEP. Additional challenges were identified via face-to-face interviews with clinicians with at least five years experience in the STI clinic.Results: PrEP delivery puts a substantial burden on a routine STI clinic, in terms of counselling users and prescribing drugs, and regular screening and treating of STIs. Psycho-social aspects need to be incorporated as part of a comprehensive approach of the PrEP user. This requires skills and resources that are not yet always available in a clinic, specialised in HIV and STI care. The increasing demand for this service calls for a careful and critical appraisal of the existing service model.Conclusion: PrEP has gained an important and irreplaceable position in the prevention of HIV infection. New models of care need to be studied, preferably in close collaboration with the users, to make this intervention sustainable for the health system in which it is introduced.


Does this patient have erythema migrans?
Erythema migrans, while not pathognomonic, is the most common manifestation of early Lyme disease. Accurate diagnosis of this rash is essential to initiating appropriate antibiotic therapy. To determine the sensitivity of history and physical examination characteristics for the diagnosis of erythema migrans. Structured MEDLINE searches of articles written only in English, 1966 through March 2007. Studies were included if they enrolled at least 15 consecutive patients with the diagnosis of erythema migrans and reported original data regarding the history and physical examination characteristics of the patients. One author abstracted data from the studies. We separately analyzed the studies from Europe and analyzed both Lyme-endemic and nonendemic areas of the United States to search for potential differences in the clinical presentation. Thirty-two studies from Europe, 20 studies from the United States, and 1 from Europe and the United States met inclusion criteria for a total of 8493 patients. Sensitivity was calculated for each of the variables. No studies included patients without erythema migrans, so specificity data and likelihood ratios could not be determined. Many patients do not recall a tick bite. Associated systemic symptoms, such as fever and headache, are frequently reported. Nausea and vomiting are rare. A solitary lesion is the most frequent presentation in both US (81%; 95% confidence interval [CI], 72%-87%) and European patients (88%; 95% CI, 81%-93%). Central clearing is less common in the endemic United States (19%; 95% CI, 11%-32%) vs Europe (79%; 95% CI, 69%-86%) and the nonendemic United States (80%; 95% CI, 63%-90%). Our analysis of the current available literature suggests that there is no single element in the history or physical examination that is highly sensitive by itself for the diagnosis of erythema migrans. Clinicians should be aware of the wide variability in the clinical presentation of erythema migrans and the need to factor in multiple components of the clinical examination and epidemiological context.


Lipid peroxidation during myocardial ischaemia induced by pacing.
Oxygen derived free radical generation can be shown in experimental models of myocardial ischaemia and reperfusion and may cause cellular damage by peroxidizing polyunsaturated membrane phospholipids. An attempt was made to quantify human intracardiac lipid peroxidation during transient myocardial ischaemia by measuring the aortic and coronary sinus concentrations of malondialdehyde (a marker of lipid peroxidation) before, during, and after incremental pacing. Twenty six patients were paced until they had severe chest pain or 2 mm ST segment depression or they reached a paced rate of 180 beats/min. They were divided into two groups according to whether or not lactate was produced during pacing. Twelve patients (group 1), all with coronary artery disease, produced myocardial lactate during pacing. None of the other 14 patients (group 2), half of whom had coronary disease, produced lactate during pacing. Concentrations of malondialdehyde in the aorta and coronary sinus were significantly higher in group 1 than in group 2. Five minutes after the end of pacing coronary sinus malondialdehyde concentrations in group 1 had increased significantly from baseline values. There were no changes with time in the coronary sinus concentration of malondialdehyde in group 2 or in the aorta in either group. The negative malondialdehyde extraction ratio in group 1 suggests that intracardiac lipid peroxidation occurs during transient human myocardial ischaemia.


Evaluation of serum concentrations of biomarkers of skeletal metabolism and results of radiography as indicators of severity of osteochondrosis in foals.
To determine whether serum concentrations of biomarkers of skeletal metabolism can, in conjunction with radiographic evaluation, indicate severity of osteochondrosis in developing horses. 43 Dutch Warmblood foals with varying severity of osteochondrosis. 24 foals were monitored for 5 months and 19 foals were monitored for 11 months. Monthly radiographs of femoropatellar-femorotibial and tibio-tarsal joints were graded for osteochondral abnormalities. Serial blood samples were assayed for 8 cartilage and bone biomarkers. At the end of the monitoring period, foals were examined for macroscopic osteochondrosis lesions. Temporal relationships were evident between certain serum biomarkers and osteochondrosis severity in foals during their first year. Biomarkers of collagen degradation (collagenase-generated neoepitopes of type-II collagen fragments, type-I and -II collagen fragments [COL2-3/4C(short)], and cross-linked telopeptide fragments of type-I collagen) and bone mineralization (osteocalcin) were positive indicators of osteochondrosis severity at 5 months of age. In foals with lesions at 11 months of age, osteochondrosis severity correlated negatively with COL2-3/4C(short) and osteocalcin and positively with C-propeptide of type-II procollagen (CPII), a collagen synthesis marker. Radiographic grading of osteochondrosis lesions significantly correlated with macroscopic osteochondrosis severity score at both ages and was strongest when combined with osteocalcin at 5 months and CPII at 11 months. The ability of serum biomarkers to indicate osteochondrosis severity appears to depend on stage of disease and is strengthened with radiography. In older foals with more permanent lesions, osteochondrosis severity is significantly related to biomarker concentrations of decreased bone formation and increased cartilage synthesis.


Expression of the hMSH6 mismatch-repair protein in colon cancer and HeLa cells.
10 to 15% of human colon cancers are associated with an inherited or somatic defect of the DNA Mismatch Repair (MMR) system, which has evolved to correct biosynthetic errors such as nucleotide mis-incorporations or misalignments arising during DNA replication in the S phase of the cell-cycle. Although expression of the MMR genes was expected to be cell-cycle dependent, we and others observed that the MMR proteins hMSH2 and hMLH1 are expressed constitutively in proliferating cells. In this study we extend our observations to another essential MMR protein, hMSH6. We used immunohistochemistry to evaluate the expression pattern of this protein in human colorectal mucosa and tumours, as well as in synchronised HeLa-S3 cells, in which we analysed its steady-state levels during the cell-cycle. We show that the immunohistochemical pattern of expression of hMSH6 in normal colorectal crypts and in colon cancers differs significantly from that of the other MMR proteins, with a much lower percentage of replicating cells being hMSH6-positive. This implies that hMSH6 could be cell-cycle regulated. In order to test this hypothesis in a model system, we synchronised HeLa-S3 cells with mitotic shake-off and found that the hMSH6 protein was detectable throughout the cell-cycle, but that its steady-state level increased when cells progressed from G1 to S-phase. The increase of hMSH6 steadystate level when cells enter S-phase was expected, since MMR acts during DNA replication. However, the overall low level of oscillations of hMSH6 during the cell-cycle in this cellular model apparently does not fit the immunohistochemical phenotype. We believe that this discrepancy is due to the fact that human cell lines proliferate at a much higher rate than normal and neoplastic colorectal cells in vivo.


A combined analysis of the short-term effects of photochemical air pollutants on mortality within the EMECAM project.
In recent years, some epidemiologic studies have attributed adverse effects of air pollutants on health not only to particles and sulfur dioxide but also to photochemical air pollutants (nitrogen dioxide and ozone). The effects are usually small, leading to some inconsistencies in the results of the studies. Furthermore, the different methodologic approaches of the studies used has made it difficult to derive generic conclusions. We provide here a quantitative summary of the short-term effects of photochemical air pollutants on mortality in seven Spanish cities involved in the EMECAM project, using generalized additive models from analyses of single and multiple pollutants. Nitrogen dioxide and ozone data were provided by seven EMECAM cities (Barcelona, Gijón, Huelva, Madrid, Oviedo, Seville, and Valencia). Mortality indicators included daily total mortality from all causes excluding external causes, daily cardiovascular mortality, and daily respiratory mortality. Individual estimates, obtained from city-specific generalized additive Poisson autoregressive models, were combined by means of fixed effects models and, if significant heterogeneity among local estimates was found, also by random effects models. Significant positive associations were found between daily mortality (all causes and cardiovascular) and NO(2), once the rest of air pollutants were taken into account. A 10 microg/m(3) increase in the 24-hr average 1-day NO(2)level was associated with an increase in the daily number of deaths of 0.43% [95% confidence interval (CI), -0.003-0.86%] for all causes excluding external. In the case of significant relationships, relative risks for cause-specific mortality were nearly twice as much as that for total mortality for all the photochemical pollutants. Ozone was independently related only to cardiovascular daily mortality. No independent statistically significant relationship between photochemical air pollutants and respiratory mortality was found. The results in this study suggest that, given the present levels of photochemical pollutants, people living in Spanish cities are exposed to health risks derived from air pollution.


Childhood pegboard task predicts adult-onset psychosis-spectrum disorder among a genetic high-risk sample.
Motor abnormalities have been established as a core aspect of psychosis-spectrum disorders, with numerous studies identifying deficits prior to clinical symptom presentation. Additional research is needed to pinpoint standardized motor assessments associated with psychosis-spectrum disorders prior to illness onset to enhance prediction and understanding of etiology. With a long history of findings among people with diagnosable psychosis-spectrum disorders, but little research conducted during the premorbid phase, pegboard tasks are a viable and understudied measure of premorbid for psychosis motor functioning. In the current study, examining data from the Copenhagen Perinatal Cohort, the Simultaneous Pegs Test was performed with children (n=244, aged 10-13) at genetic high risk for psychosis (n=94) and controls (n=150). Findings suggest that children who eventually developed a psychosis-spectrum disorder (n=33) were less likely to successfully complete the task within time limit relative to controls (χ2(2, N=244)=6.94, p=0.03, ϕ=0.17). Additionally, children who eventually developed a psychosis-spectrum disorder took significantly longer to complete the task relative to controls (χ2(2, N=244)=7.06, p=0.03, ϕ=0.17). As pegboard performance is thought to tap both diffuse and specific brain networks, findings suggest that pegboard tests may be useful premorbid measures of motor functioning among those on a trajectory towards a psychosis-spectrum disorder.


Effect of plant growth regulators on leaf anatomy of the has mutant of Arabidopsis thaliana.
In this study, the effect of plant growth regulators on leaf morphogenesis of the recessive T-DNA insertion mutant of Arabidopsis thaliana was analyzed. The morpho-anatomical analysis revealed that leaves of the has mutant are small and narrow, with lobed blades and disrupted tissue organization. When has plants were grown on the medium supplied with plant growth regulators: benzylaminopurine (BAP) or ethylene precursor, 1-aminocyclopropane-1-carboxylic acid (ACC), the leaf anatomy was partially restored to the wild type, although plants still exhibited morphological abnormalities.


Neural decoding of expressive human movement from scalp electroencephalography (EEG).
Although efforts to characterize human movement through electroencephalography (EEG) have revealed neural activities unique to limb control that can be used to infer movement kinematics, it is still unknown the extent to which EEG can be used to discern the expressive qualities that influence such movements. In this study we used EEG and inertial sensors to record brain activity and movement of five skilled and certified Laban Movement Analysis (LMA) dancers. Each dancer performed whole body movements of three Action types: movements devoid of expressive qualities ("Neutral"), non-expressive movements while thinking about specific expressive qualities ("Think"), and enacted expressive movements ("Do"). The expressive movement qualities that were used in the "Think" and "Do" actions consisted of a sequence of eight Laban Effort qualities as defined by LMA-a notation system and language for describing, visualizing, interpreting and documenting all varieties of human movement. We used delta band (0.2-4 Hz) EEG as input to a machine learning algorithm that computed locality-preserving Fisher's discriminant analysis (LFDA) for dimensionality reduction followed by Gaussian mixture models (GMMs) to decode the type of Action. We also trained our LFDA-GMM models to classify all the possible combinations of Action Type and Laban Effort quality (giving a total of 17 classes). Classification accuracy rates were 59.4 ± 0.6% for Action Type and 88.2 ± 0.7% for Laban Effort quality Type. Ancillary analyses of the potential relations between the EEG and movement kinematics of the dancer's body, indicated that motion-related artifacts did not significantly influence our classification results. In summary, this research demonstrates that EEG has valuable information about the expressive qualities of movement. These results may have applications for advancing the understanding of the neural basis of expressive movements and for the development of neuroprosthetics to restore movements.


The Impact of Concurrent Antiretroviral Therapy and MDR-TB Treatment on Adverse Events.
South Africa has among the highest incidence of multidrug-resistant tuberculosis (MDR-TB) and more than 70% of patients are HIV co-infected. MDR-TB treatment is associated with frequent adverse events (AEs). Although guidelines recommend concurrent treatment of MDR-TB and HIV, safety data on concurrent therapy are limited. We conducted a prospective observational study of MDR-TB patients with and without HIV-coinfection in South Africa between 2011 and 2015. Participants received standardized MDR-TB and HIV regimens. Participants were followed monthly for the duration of MDR-TB therapy and screened for clinical and laboratory AEs. Audiometry was performed monthly during the intensive phase; color discrimination testing was performed every 2 months. We enrolled 150 HIV-infected and 56 HIV-uninfected participants. Nearly all experienced at least one clinical (93%) or laboratory (96%) AE. The most common clinical AEs were peripheral neuropathy (50%) and difficulty sleeping (48%); the most common laboratory AEs were hypokalemia (47%) and decreased creatinine clearance (46%). Among 19 clinical and lab AEs examined, there were no differences by HIV status, except for diarrhea (27% HIV-infected vs. 13% HIV-uninfected, P = 0.03). Hearing loss was experienced by 72% of participants (8% severe loss). Fourteen percent experienced color discrimination loss (4% severe loss). There were no differences in frequency or severity of hearing or vision loss by HIV status. AEs were common, but not more frequent or severe among MDR-TB/HIV co-infected participants receiving concurrent antiretroviral therapy. Given the favorable treatment outcomes associated with concurrent treatment, antiretroviral therapy initiation should not be delayed in MDR-TB patients with HIV-coinfection.