Alpha1A-adrenergic receptor-directed autoimmunity induces left ventricular damage and diastolic dysfunction in rats.
Agonistic autoantibodies to the alpha(1)-adrenergic receptor occur in nearly half of patients with refractory hypertension; however, their relevance is uncertain. We immunized Lewis rats with the second extracellular-loop peptides of the human alpha(1A)-adrenergic receptor and maintained them for one year. Alpha(1A)-adrenergic antibodies (alpha(1A)-AR-AB) were monitored with a neonatal cardiomyocyte contraction assay by ELISA, and by ERK1/2 phosphorylation in human alpha(1A)-adrenergic receptor transfected Chinese hamster ovary cells. The rats were followed with radiotelemetric blood pressure measurements and echocardiography. At 12 months, the left ventricles of immunized rats had greater wall thickness than control rats. The fractional shortening and dp/dt(max) demonstrated preserved systolic function. A decreased E/A ratio in immunized rats indicated a diastolic dysfunction. Invasive hemodynamics revealed increased left ventricular end-diastolic pressures and decreased dp/dt(min). Mean diameter of cardiomyocytes showed hypertrophy in immunized rats. Long-term blood pressure values and heart rates were not different. Genes encoding sarcomeric proteins, collagens, extracellular matrix proteins, calcium regulating proteins, and proteins of energy metabolism in immunized rat hearts were upregulated, compared to controls. Furthermore, fibrosis was present in immunized hearts, but not in control hearts. A subset of immunized and control rats was infused with angiotensin (Ang) II. The stressor raised blood pressure to a greater degree and led to more cardiac fibrosis in immunized, than in control rats. We show that alpha(1A)-AR-AB cause diastolic dysfunction independent of hypertension, and can increase the sensitivity to Ang II. We suggest that alpha(1A)-AR-AB could contribute to cardiovascular endorgan damage.


HIV: The deadly passenger in dendritic cells.
A picture is emerging of how HIV subverts a normal immunological surveillance mechanism to establish primary infection. This involves the infection of dendritic cells at mucosal surfaces: as these cells then mature, they transport the virus to lymphoid tissue, where viral replication begins and infection of CD4(+) T cells occurs.


The applicability of holography in forensic identification: a fusion of the traditional optical technique and digital technique.
In this study, the applicability of holography in the 3-dimensional recording of forensic objects such as skulls and mandibulae, and the accuracy of the reconstructed 3-D images, were examined. The virtual holographic image, which records the 3-dimensional data of the original object, is visually observed on the other side of the holographic plate, and reproduces the 3-dimensional shape of the object well. Another type of holographic image, the real image, is focused on a frosted glass screen, and cross-sectional images of the object can be observed. When measuring the distances between anatomical reference points using an image-processing software, the average deviations in the holographic images as compared to the actual objects were less than 0.1 mm. Therefore, holography could be useful as a 3-dimensional recording method of forensic objects. Two superimposition systems using holographic images were examined. In the 2D-3D system, the transparent virtual holographic image of an object is directly superimposed onto the digitized photograph of the same object on the LCD monitor. On the other hand, in the video system, the holographic image captured by the CCD camera is superimposed onto the digitized photographic image using a personal computer. We found that the discrepancy between the outlines of the superimposed holographic and photographic dental images using the video system was smaller than that using the 2D-3D system. Holography seemed to perform comparably to the computer graphic system; however, a fusion with the digital technique would expand the utility of holography in superimposition.


Semiconductor laser to single-mode fiber coupler.
Promising results of various coupling experiments between laser diodes and single-mode fibers to determine the optimum coupling method are reported. The cylindrical lens method is shown to be most efficient, with a coupling loss of 1.8 dB under optimum alignment conditions. More than -2 dB coupling efficiency is attained with a cylindrical lens whose radius is less than 8 microm. The laser to fiber coupling characteristics are estimated by Gaussian beam approximation. The optimum radius of a cylindrical lens, which gives maximum coupling efficiency, is derived by theoretical calculation, using the ray matrix method. The cylindrical lens alignment tolerance is also shown theoretically and experimentally.


Occurrence and Genetic Diversity of Protist Parasites in Captive Non-Human Primates, Zookeepers, and Free-Living Sympatric Rats in the Córdoba Zoo Conservation Centre, Southern Spain.
Little information is currently available on the epidemiology of parasitic and commensal protist species in captive non-human primates (NHP) and their zoonotic potential. This study investigates the occurrence, molecular diversity, and potential transmission dynamics of parasitic and commensal protist species in a zoological garden in southern Spain. The prevalence and genotypes of the main enteric protist species were investigated in faecal samples from NHP (n = 51), zookeepers (n = 19) and free-living rats (n = 64) by molecular (PCR and sequencing) methods between 2018 and 2019. The presence of Leishmania spp. was also investigated in tissues from sympatric rats using PCR. Blastocystis sp. (45.1%), Entamoeba dispar (27.5%), Giardia duodenalis (21.6%), Balantioides coli (3.9%), and Enterocytozoon bieneusi (2.0%) (but not Troglodytella spp.) were detected in NHP. Giardia duodenalis (10.5%) and Blastocystis sp. (10.5%) were identified in zookeepers, while Cryptosporidium spp. (45.3%), G. duodenalis (14.1%), and Blastocystis sp. (6.25%) (but not Leishmania spp.) were detected in rats. Blastocystis ST1, ST3, and ST8 and G. duodenalis sub-assemblage AII were identified in NHP, and Blastocystis ST1 in zookeepers. Giardia duodenalis isolates failed to be genotyped in human samples. In rats, four Cryptosporidium (C. muris, C. ratti, and rat genotypes IV and V), one G. duodenalis (assemblage G), and three Blastocystis (ST4) genetic variants were detected. Our results indicate high exposure of NHP to zoonotic protist species. Zoonotic transmission of Blastocysts ST1 was highly suspected between captive NHP and zookeepers.


Radiative properties of dense nanofluids.
The radiative properties of dense nanofluids are investigated. For nanofluids, scattering and absorbing of electromagnetic waves by nanoparticles, as well as light absorption by the matrix/fluid in which the nanoparticles are suspended, should be considered. We compare five models for predicting apparent radiative properties of nanoparticulate media and evaluate their applicability. Using spectral absorption and scattering coefficients predicted by different models, we compute the apparent transmittance of a nanofluid layer, including multiple reflecting interfaces bounding the layer, and compare the model predictions with experimental results from the literature. Finally, we propose a new method to calculate the spectral radiative properties of dense nanofluids that shows quantitatively good agreement with the experimental results.


Impact of Routine Plain X-ray on Postoperative Management in Cochlear Implantation.
To determine the benefit of a routine plain radiography (X-ray) for confirming the optimal electrode position in cochlear implant surgery. In total, 245 patients (135 males and 111 females) who underwent cochlear implantation in a single tertiary referral center were included in this study. Postoperative plain X-ray findings and electrophysiological tests were retrospectively analyzed. The mean age was 11.4±14.6 years (range, 1-70 years). Overall, 196 (80%) patients were pediatric patients (age, <18 years) and 49 (20%) were adults (age, >18 years). The mean rotation of electrode arrays was 1.03±0.17 turns. The plain X-ray revealed that electrode misplacement was present in 5 patients (2%); incomplete insertion in 3 patients, and tip rollover and electrode migration in 1 patient each. A revision was performed for the last patient who had an extracochlear electrode position in the plain X-ray. Postoperative imaging is mostly used to confirm the electrode array position after cochlear implant surgery. In addition, intraoperative evaluations have low positive predictive value and sensitivity. Thus, this study revealed that postoperative radiological imaging should be considered even when all intraoperative electrophysiological measures and surgical reports are normal.


Clinicoradiographic evaluation of hyaluronan-nano hydroxyapatite composite graft in the management of periodontal infrabony defects.
Hyaluronan is a naturally occurring polysaccharide in the extracellular matrix of the connective tissue. It imparts antibacterial and osteogenic properties to the nano hydroxyapatite bone graft (NHA). This study aims to evaluate the efficacy of hyaluronan-NHA (H-NHA) composite in the treatment of infrabony defects in chronic periodontitis patients. Eight systemically healthy chronic periodontitis patients with 32 graftable sites were included in the study. After flap reflection and debridement, the defect sites in the test quadrant were filled with H-NHA graft and those in the control quadrant were filled with NHA graft alone. Clinical parameters such as probing pocket depth (PPD) and clinical attachment level (CAL) were assessed at baseline and 3, 6, 9, and 12 months; bone probing depth (BPD) and radiographic parameters such as amount and percentage of defect depth reduction (DDR, PDDR) and change in alveolar crest level (ALR) were assessed at baseline and 6 and 12 months. Descriptive statistics, one-way analysis of variance, and Student's t-test were used for statistical analysis. At the end of 12 months, H-NHA group showed a greater reduction in PPD (5.06 ± 0.582 mm), BPD (4.22 ± 0.371 mm), and gain in CAL (4.00 ± 0.421 mm) as compared to the NHA group (3.21 ± 0.648 mm, 3.21 ± 0.047 mm, and 2.86 ± 0.127 mm, respectively). In addition, DDR, PDDR, and ALR were better in H-NHA group (1.92 ± 0.647 mm 48.22 ± 31.561 mm, and 1.22 ± 0.808 mm, respectively) as compared to the NHA group (1.14 ± 0.602 mm, 20.14 ± 25.349 mm, and 0.89 ± 0.626 mm, respectively). Statistically significant improvements in all the parameters were seen in the test sites when compared to control sites at 12 months. H-NHA composite graft can be considered a promising periodontal regenerative material.


Substituent Effects in the Noncovalent Bonding of SO2 to Molecules Containing a Carbonyl Group. The Dominating Role of the Chalcogen Bond.
The SO2 molecule is paired with a number of carbonyl-containing molecules, and the properties of the resulting complexes are calculated by high-level ab initio theory. The global minimum of each pair is held together primarily by a S···O chalcogen bond wherein the lone pairs of the carbonyl O transfer charge to the π* antibonding SO orbital, supplemented by smaller contributions from weak CH···O H-bonds. The binding energies vary between 4.2 and 8.6 kcal/mol, competitive with even some of the stronger noncovalent forces such as H-bonds and halogen bonds. The geometrical arrangement places the carbonyl O atom above the plane of the SO2 molecule, consistent with the disposition of the molecular electrostatic potentials of the two monomers. This S···O bond differs from the more commonly observed chalcogen bond in both geometry and origin. Substituents exert their influence via inductive effects that change the availability of the carbonyl O lone pairs as well as the intensity of the negative electrostatic potential surrounding this atom.


Traumatic brain injury, dry eye and comorbid pain diagnoses in US veterans.
The purpose of the study is to evaluate the relationship between dry eye (DE) and pain diagnoses in US veterans with and without traumatic brain injury (TBI). Retrospective cohort study of veterans who were seen in the Veterans Administration Hospital (VA) between 1 January 2010 and 31 December 2014. Veterans were separated into two groups by the presence or absence of an International Classification of Diseases, Ninth Revision diagnosis of TBI and assessed for DE and other comorbidities. A dendrogram was used to investigate the linkage between TBI, DE, chronic pain and other comorbid conditions. Of the 3 265 894 veterans seen during the 5-year period, 3.97% carried a diagnosis of TBI. Veterans with TBI were more likely to have a diagnosis of DE compared with their counterparts without TBI (37.2% vs 29.1%, p<0.0005). The association was stronger between TBI and ocular pain (OR 3.08; 95% CI 3.03 to 3.13) compared with tear film dysfunction (OR 1.09; 95% CI 1.07 to 1.10). Those with TBI were also about twice as likely to have a diagnosis of chronic pain, headache, depression or post-traumatic stress disorder compared with their counterparts without TBI. Cluster analysis of TBI, DE and pain diagnoses of interest revealed that central pain syndrome, cluster headache, sicca syndrome, keratoconjunctivitis sicca and late effect of injury to the nervous system (as can be seen after TBI) were all closely clustered together. DE and pain disorders occur at higher frequencies in patients with a diagnosis of TBI, suggesting a common underlying pathophysiology.


Servo control of an optical trap.
A versatile optical trap has been constructed to control the position of trapped objects and ultimately to apply specified forces using feedback control. While the design, development, and use of optical traps has been extensive and feedback control has played a critical role in pushing the state of the art, few comprehensive examinations of feedback control of optical traps have been undertaken. Furthermore, as the requirements are pushed to ever smaller distances and forces, the performance of optical traps reaches limits. It is well understood that feedback control can result in both positive and negative effects in controlled systems. We give an analysis of the trapping limits as well as introducing an optical trap with a feedback control scheme that dramatically improves an optical trap's sensitivity at low frequencies.


Boron di- and tri-cations.
Previous work on boron di- and tri-cations is reviewed. The structural chemistry of representative examples of these classes of compound has been probed by determination of the single-crystal X-ray structures of [(4-Mepy)4B]Br3 and [py3BH]Br2. The electronic structures of the polycations [(py)3BH]2+, [(py)3BBr]2+, [(4-Mepy)3BH]2+, [(4-Mepy)4B]3+, [(Me3P)3BH]2+ and [(Me3P)4B]3+ have been examined by DFT methods. The atomic charges on these cations were evaluated by Mulliken, natural population analysis (NPA), Hirschfeld and Voronoi deformation density (VDD) methods.


Crystal structure of ATP sulfurylase from the bacterial symbiont of the hydrothermal vent tubeworm Riftia pachyptila.
In sulfur chemolithotrophic bacteria, the enzyme ATP sulfurylase functions to produce ATP and inorganic sulfate from APS and inorganic pyrophosphate, which is the final step in the biological oxidation of hydrogen sulfide to sulfate. The giant tubeworm, Riftia pachyptila, which lives near hydrothermal vents on the ocean floor, harbors a sulfur chemolithotroph as an endosymbiont in its trophosome tissue. This yet-to-be-named bacterium was found to contain high levels of ATP sulfurylase that may provide a substantial fraction of the organisms ATP. We present here, the crystal structure of ATP sulfurylase from this bacterium at 1.7 A resolution. As predicted from sequence homology, the enzyme folds into distinct N-terminal and catalytic domains, but lacks the APS kinase-like C-terminal domain that is present in fungal ATP sulfurylase. The enzyme crystallizes as a dimer with one subunit in the crystallographic asymmetric unit. Many buried solvent molecules mediate subunit contacts at the interface. Despite the high concentration of sulfate needed for crystallization, no ordered sulfate was observed in the sulfate-binding pocket. The structure reveals a mobile loop positioned over the active site. This loop is in a "closed" or "down" position in the reported crystal structures of fungal ATP sulfurylases, which contained bound substrates, but it is in an "open" or "up" position in the ligand-free Riftia symbiont enzyme. Thus, closure of the loop correlates with occupancy of the active site, although the loop itself does not interact directly with bound ligands. Rather, it appears to assist in the orientation of residues that do interact with active-site ligands. Amino acid differences between the mobile loops of the enzymes from sulfate assimilators and sulfur chemolithotrophs may account for the significant kinetic differences between the two classes of ATP sulfurylase.


The Rho pathway mediates transition to an alveolar type I cell phenotype during static stretch of alveolar type II cells.
Stretch is an essential mechanism for lung growth and development. Animal models in which fetal lungs have been chronically over or underdistended demonstrate a disrupted mix of type II and type I cells, with static overdistention typically promoting a type I cell phenotype. The Rho GTPase family, key regulators of cytoskeletal signaling, are known to mediate cellular differentiation in response to stretch in other organs. Using a well-described model of alveolar epithelial cell differentiation and a validated stretch device, we investigated the effects of supraphysiologic stretch on human fetal lung alveolar epithelial cell phenotype. Static stretch applied to epithelial cells suppressed type II cell markers (SP-B and Pepsinogen C, PGC), and induced type I cell markers (Caveolin-1, Claudin 7 and Plasminogen Activator Inhibitor-1, PAI-1) as predicted. Static stretch was also associated with Rho A activation. Furthermore, the Rho kinase inhibitor Y27632 decreased Rho A activation and blunted the stretch-induced changes in alveolar epithelial cell marker expression. Together these data provide further evidence that mechanical stimulation of the cytoskeleton and Rho activation are key upstream events in mechanotransduction-associated alveolar epithelial cell differentiation.


Can increased dietary fibre level and a single enrichment device reduce the risk of tail biting in undocked growing-finishing pigs in fully slatted systems?
This study evaluated the effectiveness of combined dietary and enrichment strategies to manage tail biting in pigs with intact tails in a conventional fully-slatted floor housing system. A 2 × 2 × 2 factorial design was used. Pigs had either a high fibre (weaner 5.3% and finisher 11.6% of crude fibre) or standard fibre diet (weaner 3.7% and finisher 5.9% of crude fibre). In the weaner stage, pigs had either a spruce wooden post (supplied in a wall-mounted dispenser) or a rubber floor toy as a enrichment device, and in the finisher stage, they had either the same or alternate enrichment item. Six hundred and seventy-two pigs were assigned to 48 pens of 14 pigs and followed from weaning until slaughter. Individual tail lesion scores and pen level behaviours were directly recorded every 2 weeks. Twenty-six pens had tail biting outbreaks and 161 injured pigs needed removal for treatment. Pigs fed with the high fibre diet performed more tail biting (p < 0.05) and tended to have a worse tail damage scores than those fed the standard fibre diet (p = 0.08). Pigs which had the floor toy as weaners and wood as finishers tended to have fewer tail lesions in the finisher stage than their counterparts (p = 0.06). Pigs receiving the floor toy as enrichment interacted with the enrichment more frequently overall (p < 0.001) and performed fewer harmful behaviours in the weaner stage (p < 0.05). Overall, higher fibre in the diet in a relatively barren environment did not help reduce tail biting or tail lesions. Altering the fibre level in the pigs' diet and providing a single enrichment device to undocked pigs on fully slatted floors resulted in a high level of tail biting and a large proportion of pigs with partial tail amputation.


Lower Extremity Stiffness Changes after Concussion in Collegiate Football Players.
Recent research indicates that a concussion increases the risk of musculoskeletal injury. Neuromuscular changes after concussion might contribute to the increased risk of injury. Many studies have examined gait postconcussion, but few studies have examined more demanding tasks. This study compared changes in stiffness across the lower extremity, a measure of neuromuscular function, during a jump-landing task in athletes with a concussion (CONC) to uninjured athletes (UNINJ). Division I football players (13 CONC and 26 UNINJ) were tested pre- and postseason. A motion capture system recorded subjects jumping on one limb from a 25.4-cm step onto a force plate. Hip, knee, and ankle joint stiffness were calculated from initial contact to peak joint flexion using the regression line slopes of the joint moment versus the joint angle plots. Leg stiffness was (peak vertical ground reaction force [PVGRF]/lower extremity vertical displacement) from initial contact to peak vertical ground reaction force. All stiffness values were normalized to body weight. Values from both limbs were averaged. General linear models compared group (CONC, UNINJ) differences in the changes of pre- and postseason stiffness values. Average time from concussion to postseason testing was 49.9 d. The CONC group showed an increase in hip stiffness (P = 0.03), a decrease in knee (P = 0.03) and leg stiffness (P = 0.03), but no change in ankle stiffness (P = 0.65) from pre- to postseason. Lower extremity stiffness is altered after concussion, which could contribute to an increased risk of lower extremity injury. These data provide further evidence of altered neuromuscular function after concussion.


Peridomicilary habitat and risk factors for Triatoma infestation in a rural community of the Mexican occident.
An examination of peridomestic area organization and triatomine collection in an endemic village for Chagas disease (Jalisco State) identified the habitat of Triatoma longipennis (dominant species) and the risk factors of peridomestic infestation. In 100 visited peridomestic areas, 369 structures (permanent, temporary, and natural) were submitted to active manual research of triatomines. Storage shelters had a higher infestation of T. longipennis than piles of brick and tile; baked clay material had higher degrees of infestation than others. The secondary species Triatoma barberi shares a wide range of peridomicilary habitats with T. longipennis. Peridomestic area infestation risks (evaluated with multivariate logistic regression analysis) are number of closed storage shelters, number of brick and tile piles, number of houses per peridomestic areas, and distance of peridomicile from natural environment. Because both species present great adaptability to different artificial habitats, strategies of control must involved improving the overall management of peridomestic areas to prevent stable colonization.


Act local, think global: how the Malawi experience of scaling up antiretroviral treatment has informed global policy.
The scale-up of antiretroviral therapy (ART) in Malawi was based on a public health approach adapted to its resource-poor setting, with principles and practices borrowed from the successful tuberculosis control framework. From 2004 to 2015, the number of new patients started on ART increased from about 3000 to over 820,000. Despite being a small country, Malawi has made a significant contribution to the 15 million people globally on ART and has also contributed policy and service delivery innovations that have supported international guidelines and scale up in other countries. The first set of global guidelines for scaling up ART released by the World Health Organization (WHO) in 2002 focused on providing clinical guidance. In Malawi, the ART guidelines adopted from the outset a more operational and programmatic approach with recommendations on health systems and services that were needed to deliver HIV treatment to affected populations. Seven years after the start of national scale-up, Malawi launched a new strategy offering all HIV-infected pregnant women lifelong ART regardless of the CD4-cell count, named Option B+. This strategy was subsequently incorporated into a WHO programmatic guide in 2012 and WHO ART guidelines in 2013, and has since then been adopted by the majority of countries worldwide. In conclusion, the Malawi experience of ART scale-up has become a blueprint for a public health response to HIV and has informed international efforts to end the AIDS epidemic by 2030.


Tobacco use among individuals with intellectual or developmental disabilities: a brief review.
Tobacco use is the leading preventable cause of death in the United States. Although few tobacco control efforts target individuals with intellectual and/or developmental disabilities, this population may be especially vulnerable to the deleterious effects of tobacco use and dependence. Individuals with intellectual and developmental disabilities suffer from the health, financial, and stigmatizing effects of tobacco use. The present review examined the current literature with respect to the prevalence and patterns of tobacco use in individuals with intellectual and developmental disabilities, the importance of addressing tobacco use in these smokers, and policies surrounding tobacco use in this population. Suggestions for additional avenues of inquiry as well as modifications to current cessation treatments are proposed.


Documenting the Welfare and Role of Working Equids in Rural Communities of Portugal and Spain.
Recently, the need for a more holistic approach to welfare assessment has been highlighted. This is particularly pertinent in the case of working equids who provide vital support for human livelihoods, often in low- to middle-income countries, yet suffer from globally low standards of welfare. This study aimed to provide insight into the welfare status and traditional use of working equids in rural Western European communities using the new EARS welfare tool, designed to provide a broad view of the welfare of working equids and the context in which they are found. Other questions on the topics of equid management practices, social transmission of expertise, environmental stressors, and traditions, alongside physical and behavioural welfare assessments were also included to explore the impact of these wide-ranging factors on an understudied population of working equids. The protocol was trialled on 60 working equid owners from communities in Portugal and Spain where, despite the decline in traditional agricultural practices and livestock keeping, donkeys and mules remain working animals. Many owners stated that the help donkeys provided was invaluable, and donkeys were considered to be important for both farming and daily life. However, participants also recognised that the traditional agricultural way of life was dying out, providing insights into the traditional practices, community structure, and beliefs of equid owners. Questions investigating the social networks and social transfer of information within the villages were effective in finding local sources of equid knowledge. Overall, welfare was deemed fair, and the protocol enabled the identification of the most prevalent welfare problems within the communities studied, in this case obesity and the use of harmful practices. The findings suggest that the new protocol was feasible and detail how contextual factors may influence equid welfare. Increasing understanding of the cultural context, social structure, and attitudes within a community, alongside more traditional investigations of working practices and animal management, may, in the future, help to make equid welfare initiatives more effective.


Upper respiratory viral load in asymptomatic individuals and mildly symptomatic patients with SARS-CoV-2 infection.
Asymptomatic individuals with SARS-CoV-2 infection have viable viral loads and have been linked to several transmission cases. However, data on the viral loads in such individuals are lacking. We assessed the viral loads in asymptomatic individuals with SARS-CoV-2 infection in comparison with those in symptomatic patients with COVID-19. Study participants were recruited from a community facility designated for the isolation of patients with mild COVID-19 in South Korea. The presence of symptoms was evaluated with a questionnaire-based survey. Viral loads in the upper respiratory tract were measured with real-time reverse transcription-PCR (RT-PCR) targeting the E, RdRp and N genes of SARS-CoV-2, with a cycle threshold (Ct) value of 40 for determining positivity. In 213 patients with SARS-CoV-2 infection, 41 (19%) had remained asymptomatic from potential exposure to laboratory confirmation and admission; of them, 39 (95%) underwent follow-up RT-PCR testing after a median 13 days. In 172 symptomatic patients, 144 (84%) underwent follow-up RT-PCR testing. Twenty-one (54%) asymptomatic individuals and 92 (64%) symptomatic patients tested positive for SARS-CoV-2 at follow-up. Asymptomatic individuals and symptomatic patients did not show any significant differences in the mean Ct values of the E (31.15 vs 31.43; p>0.99), RdRp (32.26 vs 32.93; p=0.92) and N (33.05 vs 33.28; p>0.99) genes. Approximately one-fifth of the individuals without severe symptoms were asymptomatic, and their viral loads were comparable to those in symptomatic patients. A large proportion of mildly symptomatic patients with COVID-19 or asymptomatic individuals with SARS-CoV-2 showed persistent positive upper respiratory RT-PCR results at follow-up.


Risperidone and haloperidol in first-episode psychosis: a long-term randomized trial.
The first episode of psychotic illness is a key intervention point. The initial experience with medication can affect willingness to accept treatment. Further, relapse prevention is a treatment cornerstone during the first years of illness because active psychotic illness may affect lifetime outcomes. Thus, initial treatment of active symptoms and subsequent relapse prevention are central goals of pharmacotherapy. This study compared long-term effectiveness of risperidone versus haloperidol in first-episode psychosis patients. First-episode psychosis patients (N=555, mean age=25.4 years) participated in a double-blind, randomized, controlled flexible-dose trial that compared risperidone (mean modal dose=3.3 mg) and haloperidol (mean modal dose=2.9 mg). The median treatment length was 206 days (maximum=1,514). Positive and Negative Syndrome Scale scores and Clinical Global Impression ratings improved significantly relative to baseline, with no significant differences between groups. Three-quarters of the patients achieved initial clinical improvement, defined as >20% reduction in total Positive and Negative Syndrome Scale score. However, among those who achieved clinical improvement, 42% of the risperidone group experienced a relapse compared with 55% of the haloperidol group. The median time to relapse was 466 days for risperidone-treated subjects and 205 days for those given haloperidol. These differences were statistically significant based on Kaplan-Meier survival analysis. Adverse effects distinguished the treatments: there were significantly more extrapyramidal signs and symptoms and adjunctive medication use in the haloperidol group and greater prolactin elevation in the risperidone group. There was less weight gain with haloperidol initially but no significant differences between groups at endpoint. Relatively low doses of antipsychotic drugs lead to significant symptom amelioration in the majority of first-episode psychosis patients. In the long term, risperidone prevents relapse in more patients and for a longer time and also induces less abnormal movements than haloperidol.


The origin of the synergistic effect of muramyl dipeptide with endotoxin and peptidoglycan.
Although the basis for the high mortality rate for patients with mixed bacterial infections is likely to be multifactorial, there is evidence for a synergistic effect of muramyldipeptide (MDP) with lipopolysaccharide (LPS) on the synthesis of proinflammatory cytokines by mononuclear phagocytes. In this study, co-incubation of human Mono Mac 6 cells with MDP and either LPS or peptidoglycan (PGN) resulted in an apparent synergistic effect on tumor necrosis factor-alpha (TNF-alpha) secretion. Although incubation of cells with MDP alone produced minimal TNF-alpha, it caused significant expression of TNF-alpha mRNA. These findings suggest that the majority of TNF-alpha mRNA induced by MDP alone is not translated into protein. Furthermore, simultaneous incubation of cells with MDP and either LPS or PGN resulted in TNF-alpha mRNA expression that approximated the sum of the amounts expressed in response to MDP, LPS, and PGN individually. These findings indicate that the apparent synergistic effect of MDP on TNF-alpha production induced by either LPS or PGN is due to removal of a block in translation of the mRNA expressed in response to MDP. In subsequent studies, the effects of MDP alone and its effect on the production of TNF-alpha by LPS and PGN were determined to be independent of CD14, Toll-like receptor 2, and Toll-like receptor 4. These findings indicate that MDP acts through receptor(s) other than those primarily responsible for transducing the effects of LPS and PGN. Successful treatment of patients having mixed bacterial infections is likely to require interventions that address the mechanisms involved in responses induced by a variety of bacterial cell wall components.


Chronic Angiotensin-(1-7) Improves Insulin Sensitivity in High-Fat Fed Mice Independent of Blood Pressure.
Angiotensin-(1-7) improves glycemic control in animal models of cardiometabolic syndrome. The tissue-specific sites of action and blood pressure dependence of these metabolic effects, however, remain unclear. We hypothesized that Ang-(1-7) improves insulin sensitivity by enhancing peripheral glucose delivery. Adult male C57BL/6J mice were placed on standard chow or 60% high-fat diet for 11 weeks. Ang-(1-7) (400 ng/kg per minute) or saline was infused subcutaneously during the last 3 weeks of diet, and hyperinsulinemic-euglycemic clamps were performed at the end of treatment. High-fat fed mice exhibited modest hypertension (systolic blood pressure: 137 ± 3 high fat versus 123 ± 5 mm Hg chow;P=0.001), which was not altered by Ang-(1-7) (141 ± 4 mm Hg;P=0.574). Ang-(1-7) did not alter body weight or fasting glucose and insulin in chow or high-fat fed mice. Ang-(1-7) increased the steady-state glucose infusion rate needed to maintain euglycemia in high-fat fed mice (31 ± 5 Ang-(1-7) versus 16 ± 1 mg/kg per minute vehicle;P=0.017) reflecting increased whole-body insulin sensitivity, with no effect in chow-fed mice. The improved insulin sensitivity in high-fat fed mice was because of an enhanced rate of glucose disappearance (34 ± 5 Ang-(1-7) versus 20 ± 2 mg/kg per minute vehicle;P=0.049). Ang-(1-7) enhanced glucose uptake specifically into skeletal muscle by increasing translocation of glucose transporter 4 to the sarcolemma. Our data suggest that Ang-(1-7) has direct insulin-sensitizing effects on skeletal muscle, independent of changes in blood pressure. These findings provide new insight into mechanisms by which Ang-(1-7) improves insulin action, and provide further support for targeting this peptide in cardiometabolic disease.


Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15.
Under homeostatic conditions, animals use well-defined hypothalamic neural circuits to help maintain stable body weight, by integrating metabolic and hormonal signals from the periphery to balance food consumption and energy expenditure. In stressed or disease conditions, however, animals use alternative neuronal pathways to adapt to the metabolic challenges of altered energy demand. Recent studies have identified brain areas outside the hypothalamus that are activated under these 'non-homeostatic' conditions, but the molecular nature of the peripheral signals and brain-localized receptors that activate these circuits remains elusive. Here we identify glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as a brainstem-restricted receptor for growth and differentiation factor 15 (GDF15). GDF15 regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses; we show that Gfral knockout mice are hyperphagic under stressed conditions and are resistant to chemotherapy-induced anorexia and body weight loss. GDF15 activates GFRAL-expressing neurons localized exclusively in the area postrema and nucleus tractus solitarius of the mouse brainstem. It then triggers the activation of neurons localized within the parabrachial nucleus and central amygdala, which constitute part of the 'emergency circuit' that shapes feeding responses to stressful conditions. GDF15 levels increase in response to tissue stress and injury, and elevated levels are associated with body weight loss in numerous chronic human diseases. By isolating GFRAL as the receptor for GDF15-induced anorexia and weight loss, we identify a mechanistic basis for the non-homeostatic regulation of neural circuitry by a peripheral signal associated with tissue damage and stress. These findings provide opportunities to develop therapeutic agents for the treatment of disorders with altered energy demand.


Central serotonergic mechanisms in hypertension.
Serotonin-containing neurons in the central nervous system are grouped into a number of discrete and distinctive collections with cell bodies in the brainstem and projections passing to many regions of the brain and spinal cord. Evidence is presented that activation of one projection of serotonin-containing neurons from the midbrain to the hypothalamus elevates arterial pressure. Evidence is also presented that activation of a projection descending from the lateral B3 serotonin cell group to the spinal cord elicits a pressor response that is accompanied by increased release of serotonin in the spinal cord and is independent of the C1 adrenaline-containing neurons that lie close by. In contradistinction, experiments are described demonstrating that activation of the midline group of B3 serotonin cells in the raphe nucleus causes a fall in arterial pressure, consistent with the view that different groups of serotonin neurons in the brain and spinal cord participate in the control of blood pressure in diverse ways and can have different effects on blood pressure. Finally, experiments are described showing that the hypotensive action of methyldopa is mediated in part through central serotonin nerves.


Spermine uptake is necessary to induce haemoglobin synthesis in murine erythroleukaemia cells.
To determine whether intracellular uptake of spermine is necessary to induce haemoglobin synthesis in murine erythroleukaemia (MEL) DS 19 cells, we used single-step selection for resistance to N1,N12-bis(ethyl)spermine (BESM), a cytotoxic spermine analogue, to isolate clones deficient in polyamine transport. The cells were approximately 500-fold more resistant to BESM than parental cells and were unable to accumulate BESM, putrescine, spermidine or spermine. Addition of spermine to the polyamine-transport-deficient cells failed to induce haemoglobin synthesis. Hexamethylene-1,6-bisacetamide, a well-known differentiating agent, induced haemoglobin synthesis in both parental and resistant cells. Polyamine-transport-deficient cells transfected with DNA purified from the parental cell line were further selected for their ability to grow in the presence of alpha-difluoromethylornithine and putrescine. The transfectants had an active transport system for polyamines, and spermine added to their culture medium accumulated inside the cells and induced haemoglobin production. These findings indicate that intracellular spermine uptake is required to induce haemoglobin production in MEL cells.


Spontaneous Partial Regression of a Carcinoid Tumor: Radiology May Not Capture the Real Picture.
A partial or complete resolution of the neoplastic lesion, either spontaneously or in the presence of therapy that is considered inadequate to exert significant influence on the growth of the neoplastic lesion, is considered a spontaneous regression. This phenomenon is extremely rare in lung neoplasms. A close follow up with imaging along with bronchoscopy and a biopsy of the lesion is essential, as they may have potential for distant spread even during radiological regression. Here, we report a case of a partial resolution of a bronchial carcinoid tumor that had a high mitotic activity and was resected.


Brief exposure to Swedish snus causes divergent vascular responses in healthy male and female volunteers.
The use of Swedish oral moist snuff, known as snus, has for a long time been limited to the Scandinavian countries. With declining cigarette sales in the western world, tobacco companies have looked to the development of alternative tobacco products. In 2006 snus products were launched in the US. Even though several studies have demonstrated negative health effects, snus is often depicted as harmless. The aim of the present study was to investigate acute vascular effects of snus as measured by arterial stiffness as well as blood pressure and heart rate. Two separate randomized double-blind crossover studies with the same study design were pooled for analysis. Twenty-nine healthy snus-users (17 females, 12 males) were included. Snus (Göteborgs Rapé) and tobacco free snus (Onico) were administered in a randomized order at two separate visits. Arterial stiffness, blood pressure and heart rate were measured at baseline as well as every five minutes for 40 minutes during exposure. Following snus removal, measurements continued for 30 minutes post exposure. Arterial stiffness was measured using pulse wave velocity (Vicorder) and pulse wave analysis (Sphygmocor). Compared to placebo, snus significantly increased systolic and diastolic blood pressure as well as heart rate, however, only in females (p = 0.004, p = 0.006 and p<0.001 respectively). No changes were seen in arterial stiffness measurements in either gender. We observed an increase in blood pressure and heart rate only in females, but not in males due to snus usage as compared to placebo. This novel finding was surprising and needs to be further investigated considering most of the earlier studies have mainly focused on male snus users and the increasing usage of snus among females.


Anisotropic tissue motion induced by acupuncture needling along intermuscular connective tissue planes.
Acupuncture needle manipulation causes mechanical deformation of connective tissue, which in turn results in mechanical stimulation of fibroblasts, with active changes in cell shape and autocrine purinergic signaling. We have previously shown using ultrasound elastography in humans that acupuncture needle manipulation causes measurable movement of tissue up to several centimeters away from the needle. The goal of this study was to quantify the spatial pattern of tissue displacement and deformation (shear strain) in response to acupuncture needling along an intermuscular connective tissue plane compared with needling over the belly of a muscle. Eleven (11) healthy human subjects underwent a single testing session during which robotic acupuncture needling was performed while recording tissue displacement using ultrasound. Outcome measures were axial and lateral tissue displacement as well as lateral shear strain calculated using ultrasound elastography postprocessing. Tissue displacement and strain extended further in the longitudinal direction when needling between muscles, and in the transverse direction when needling over the belly of a muscle. The anisotropic tissue motion observed in this study may influence the spatial distribution of local connective tissue cellular responses following acupuncture needle manipulation.


The critical care management of spontaneous intracranial hemorrhage: a contemporary review.
Spontaneous intracerebral hemorrhage (ICH), defined as nontraumatic bleeding into the brain parenchyma, is the second most common subtype of stroke, with 5.3 million cases and over 3 million deaths reported worldwide in 2010. Case fatality is extremely high (reaching approximately 60 % at 1 year post event). Only 20 % of patients who survive are independent within 6 months. Factors such as chronic hypertension, cerebral amyloid angiopathy, and anticoagulation are commonly associated with ICH. Chronic arterial hypertension represents the major risk factor for bleeding. The incidence of hypertension-related ICH is decreasing in some regions due to improvements in the treatment of chronic hypertension. Anticoagulant-related ICH (vitamin K antagonists and the newer oral anticoagulant drugs) represents an increasing cause of ICH, currently accounting for more than 15 % of all cases. Although questions regarding the optimal medical and surgical management of ICH still remain, recent clinical trials examining hemostatic therapy, blood pressure control, and hematoma evacuation have advanced our understanding of ICH management. Timely and aggressive management in the acute phase may mitigate secondary brain injury. The initial management should include: initial medical stabilization; rapid, accurate neuroimaging to establish the diagnosis and elucidate an etiology; standardized neurologic assessment to determine baseline severity; prevention of hematoma expansion (blood pressure management and reversal of coagulopathy); consideration of early surgical intervention; and prevention of secondary brain injury. This review aims to provide a clinical approach for the practicing clinician.


Ectopic expression of the nude gene induces hyperproliferation and defects in differentiation: implications for the self-renewal of cutaneous epithelia.
Nude mice are characterized by the absence of visible hair, epidermal defects, and the failure to develop a thymus. This phenotype results from loss-of-function mutations in Whn (Hfh11), a winged-helix transcription factor. In murine epidermis and hair follicles, endogenous whn expression is induced as epithelial cells initiate terminal differentiation. Using the promoter for the differentiation marker involucrin, transgenic mice that ectopically express whn in stratified squamous epithelia, hair follicles, and the transitional epithelium of the urinary tract were generated. Transgenic epidermis and hair follicles displayed impaired terminal differentiation and a subset of hair defects, such as delayed growth, a waved coat, and curly whiskers, correlated with decreased transforming growth factor (TGF)-alpha expression. The exogenous Whn protein also stimulated epithelial cell multiplication. In the epidermis, basal keratinocytes exhibited hyperproliferation, though transgene expression was restricted to suprabasal, postmitotic cells. Hair follicles failed to enter telogen (a resting period) and remained continuously in an abnormal anagen (the growth phase of the hair cycle). Ureter epithelium developed severe hyperplasia, leading to the obstruction of urine outflow and death from hydronephrosis. Though an immune infiltrate was present occasionally in transgenic skin, the infiltrate was not the primary cause of the epithelial hyperproliferation, as the immune reaction was not observed in all affected transgenics, and the transgene induced identical skin and urinary tract abnormalities in immunodeficient Rag1-null mice. Given the effects of the transgene on cell proliferation and TGFalpha expression, the results suggest that Whn modulates growth factor production by differentiating epithelial cells, thereby regulating the balance between proliferative and postmitotic populations in self-renewing epithelia.


STAT3/p53 pathway activation disrupts IFN-β-induced dormancy in tumor-repopulating cells.
Dynamic interaction with the immune system profoundly regulates tumor cell dormancy. However, it is unclear how immunological cues trigger cancer cell-intrinsic signaling pathways for entering into dormancy. Here, we show that IFN-β treatment induced tumor-repopulating cells (TRC) to enter dormancy through an indolamine 2,3-dioxygenase/kynurenine/aryl hydrocarbon receptor/p27-dependent (IDO/Kyn/AhR/p27-dependent) pathway. Strategies to block this metabolic circuitry did not relieve dormancy, but led to apoptosis of dormant TRCs in murine and human melanoma models. Specifically, blocking AhR redirected IFN-β signaling to STAT3 phosphorylation through both tyrosine and serine sites, which subsequently facilitated STAT3 nuclear translocation and subsequent binding to the p53 promoter in the nucleus. Upregulation of p53 in turn disrupted the pentose phosphate pathway, leading to excessive ROS production and dormant TRC death. Additionally, in melanoma patients, high expression of IFN-β correlated with tumor cell dormancy. Identification of this mechanism for controlling TRC dormancy by IFN-β provides deeper insights into cancer-immune interaction and potential new cancer immunotherapeutic modalities.


An empirically grounded agent based model for modeling directs, conflict detection and resolution operations in air traffic management.
We present an agent based model of the Air Traffic Management socio-technical complex system aiming at modeling the interactions between aircraft and air traffic controllers at a tactical level. The core of the model is given by the conflict detection and resolution module and by the directs module. Directs are flight shortcuts that are given by air controllers to speed up the passage of an aircraft within a certain airspace and therefore to facilitate airline operations. Conflicts between flight trajectories can occur for two main reasons: either the planning of the flight trajectory was not sufficiently detailed to rule out all potential conflicts or unforeseen events during the flight require modifications of the flight plan that can conflict with other flight trajectories. Our model performs a local conflict detection and resolution procedure. Once a flight trajectory has been made conflict-free, the model searches for possible improvements of the system efficiency by issuing directs. We give an example of model calibration based on real data. We then provide an illustration of the capability of our model in generating scenario simulations able to give insights about the air traffic management system. We show that the calibrated model is able to reproduce the existence of a geographical localization of air traffic controllers' operations. Finally, we use the model to investigate the relationship between directs and conflict resolutions (i) in the presence of perfect forecast ability of controllers, and (ii) in the presence of some degree of uncertainty in flight trajectory forecast.


Characteristics of 36 subjects reporting compulsive sexual behavior.
The authors describe the sociodemographic features, phenomenology, and psychiatric comorbidity of 36 subjects reporting compulsive sexual behavior. Twenty-eight men and eight women who responded to advertisements for "persons ... who have a problem with compulsive sexual behavior" completed structured and semistructured assessments, including the Diagnostic Interview Schedule for DSM-III-R disorders (axis I) and the Structured Interview for DSM-III-R Personality Disorders, Revised (axis II). The typical subject was a 27-year-old man who reported experiencing compulsive sexual behavior for nearly 9 years. Sexual behavior was described as excessive and poorly controlled and was associated with either subjective distress or impairment in interpersonal or occupational functioning or as overly time-consuming. Fourteen subjects (39%) reported a history of major depression or dysthymia, 15 (42%) a history of phobic disorder, and 23 (64%) a history of substance use disorder. Personality disorders were quite frequent, particularly the paranoid, histrionic, obsessive-compulsive, and passive-aggressive subtypes. The compulsive sexual behavior was quite varied and included both paraphilic (e.g., cross-dressing) and nonparaphilic (e.g., compulsive masturbation) types. Compulsive sexual behavior may be a clinically useful concept, but it describes a heterogeneous group of individuals with substantial psychiatric comorbidity and diverse behavioral problems.


Mold metabolites drive rheumatoid arthritis in mice via promotion of IFN-gamma- and IL-17-producing T cells.
Environmental factors have been discussed as triggers for autoimmune diseases like rheumatoid arthritis (RA). However, the role of chemical exposures in activation or exacerbation of RA is not clarified yet. Exposure of DBA/1 mice to the mold metabolites ochratoxin A (OTA) or deoxynivalenol (DON) increased the prevalence and the clinical severity of RA compared to un-exposed mice using an experimental collagen-induced arthritis model. Mycotoxin-exposed mice showed enhanced serum IgG1 and IgG2a levels and an elevated production of IL-1β and IL-6 in inflamed joints and of IFN-γ and IL-17 in splenocytes. Additionally, OTA and DON increased the release of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α in activated murine macrophages and supported the differentiation of naïve T cells into Th1 cells, while treatment of CD4+T cells with the supernatant from mycotoxin-exposed macrophages induced IL-17 production. Furthermore, exposure of mice to OTA or DON enhanced the gene expression of Stat1, Stat3 and Stat4 in the spleen while the collagen-induced increase of Socs1 and Socs3 was abolished. Our results demonstrate that mycotoxins increase the susceptibility to develop RA via an enhanced stimulation of macrophages and promotion of Th1/Th17 cell differentiation by induction of Stat signalling pathways and down-regulation of the Socs-mediated feedback inhibition.


Comparative plasma disposition, bioavailability and efficacy of ivermectin following oral and pour-on administrations in horses.
Pour-on formulations of endectocides decrease the risk of injury for both user and animal, and are particularly convenient for animal owners who can apply the product. This study was designed to investigate the plasma disposition and efficacy of ivermectin (IVM) following pour-on, per os and intravenous administrations. Eighteen female horses weighing 510-610 kg were used in this study. The animals were allocated into three groups (per os, pour-on and intravenous groups). The equine paste, bovine pour-on and bovine injectable formulations of IVM were administered orally, topically and intravenously at the dose rates of 0.2, 0.5 and 0.2mg/kg bodyweight, respectively. Heparinized blood samples and hair samples were collected at various times between 1h and 40 days. The samples were analysed by high performance liquid chromatography with fluorescence detector. Faecal strongyle egg counts (EPG) were performed by a modified McMaster's technique before and at weekly intervals during 10 weeks after treatment. The results indicated that the plasma concentration and systemic availability of IVM was lower but the plasma persistence was prolonged after pour-on administration compared with per os route. IVM (paste) reduced the EPG by >95% for 10 weeks, whereas the reduction in pour-on group varied from 82 to 97%. EPG reduction in pour-on group was lower than that of per os group. Degradation on the application site, cutaneous biotransformation, binding of IVM to the haircoat and/or sebum are probably responsible for the relatively lower bioavailability of IVM in horses after pour-on administration. In conclusion, the poor plasma availability observed after pour-on administration could result in subtherapeutic plasma concentrations, which may promote the development of drug resistance in parasites.


Bile duct injury after laparoscopic cholecystectomy: the value of endoscopic retrograde cholangiopancreatography.
This study describes the value of endoscopic retrograde cholangiopancreatography (ERCP) in patients with bile duct injury after laparoscopic cholecystectomy. Twelve consecutive patients were studied over a one year period. In all patients the biliary tree was visualised during ERCP. Four patients had complete bile duct obstruction, seven patients had a stricture (two with concomitant leakage), and one patient had leakage from a hepatic branch. Three patients with complete obstruction, presented with a relatively prolonged symptom free, 'silent' period before diagnosis. In all four patients with complete transection, a proximal hepaticojejunostomy was performed. In one patient with a tough fibrous stricture, secondary to incorrect clip placement, passage of the guidewire was impossible, leaving surgical reconstruction as the only therapeutic option. All remaining seven patients with leakage or strictures, or both were successfully treated by endoscopic sphincterotomy only (n = 1) or sphincterotomy and subsequent stent placement (n = 6). When patients do not recover uneventfully after laparoscopic cholecystectomy even without cholestasis or jaundice, early ERCP is recommended as a safe and valuable method to detect bile duct injury and to suggest treatment. Subsequently, more than half of such patients can be treated endoscopically. Extended follow up is needed to evaluate the longterm results.


The efficacy of lumbar discectomy and single-level fusion for spondylolisthesis: results from the NeuroPoint-SD registry: clinical article.
There is significant practice variation and considerable uncertainty among payers and other major stakeholders as to whether many surgical treatments are effective in actual US spine practice. The aim of this study was to establish a multicenter cooperative research group and demonstrate the feasibility of developing a registry to assess the efficacy of common lumbar spinal procedures using prospectively collected patient-reported outcome measures. An observational prospective cohort study was conducted at 13 US academic and community sites. Unselected patients undergoing lumbar discectomy or single-level fusion for spondylolisthesis were included. Patients completed the 36-item Short-Form Survey Instrument (SF-36), Oswestry Disability Index (ODI), and visual analog scale (VAS) questionnaires preoperatively and at 1, 3, 6, and 12 months postoperatively. Power analysis estimated a sample size of 160 patients: 125 patients with lumbar disc herniation, and 35 with lumbar spondylolisthesis. All patient data were entered into a secure Internet-based data management platform. Of 249 patients screened, there were 198 enrolled over 1 year. The median age of the patients was 45.0 years (49% female) for lumbar discectomy (n = 148), and 58.0 years (58% female) for lumbar spondylolisthesis (n = 50). At 30 days, 12 complications (6.1% of study population) were identified. Ten patients (6.8%) with disc herniation and 1 (2%) with spondylolisthesis required reoperation. The overall follow-up rate for the collection of patient-reported outcome data over 1 year was 88.3%. At 30 days, both lumbar discectomy and single-level fusion procedures were associated with significant improvements in ODI, VAS, and SF-36 scores (p ≤ 0.0002), which persisted over the 1-year follow-up period (p < 0.0001). By the 1-year follow-up evaluation, more than 80% of patients in each cohort who were working preoperatively had returned to work. It is feasible to build a national spine registry for the collection of high-quality prospective data to demonstrate the effectiveness of spinal procedures in actual practice. Clinical trial registration no.: 01220921 (ClinicalTrials.gov).


Tub has a key role in insulin and leptin signaling and action in vivo in hypothalamic nuclei.
Mutation of tub gene in mice induces obesity, suggesting that tub could be an important regulator of energy balance. In the current study, we investigated whether insulin, leptin, and obesity can modulate Tub in vivo in hypothalamic nuclei, and we investigated possible consequences on energy balance, neuropeptide expression, and hepatic glucose metabolism. Food intake, metabolic characteristics, signaling proteins, and neuropeptide expression were measured in response to fasting and refeeding, intracerebroventricular insulin and leptin, and Tub antisense oligonucleotide (ASO). Tub tyrosine phosphorylation (Tub-p-tyr) is modulated by nutritional status. Tub is a substrate of insulin receptor tyrosine kinase (IRTK) and leptin receptor (LEPR)-Janus kinase 2 (JAK2) in hypothalamic nuclei. After leptin or insulin stimulation, Tub translocates to the nucleus. Inhibition of Tub expression in hypothalamus by ASO increased food intake, fasting blood glucose, and hepatic glucose output, decreased O(2) consumption, and blunted the effect of insulin or leptin on proopiomelanocortin, thyroid-releasing hormone, melanin-concentrating hormone, and orexin expression. In hypothalamus of mice administered a high-fat diet, there is a reduction in leptin and insulin-induced Tub-p-tyr and nuclear translocation, which is reversed by reducing protein tyrosine phosphatase 1B expression. These results indicate that Tub has a key role in the control of insulin and leptin effects on food intake, and the modulation of Tub may contribute to insulin and leptin resistance in DIO mice.


Natural gas vaporization in a nanoscale throat connected model of shale: multi-scale, multi-component and multi-phase.
Production of hydrocarbons from shale is a complex process that necessitates the extraction of multi-component hydrocarbons trapped in multi-scale nanopores. While advances in nanofluidics have allowed researchers to probe thermodynamics and transport in single, discrete nanochannels, these studies present a highly simplified version of shale reservoirs with homogeneous pore structures and/or single-component fluid compositions. In this study, we develop and apply a 30 000-pore nanomodel that captures the inherent heterogeneity in reservoir pore sizes (100 nm pores gated by 5 nm-pores) to study vaporization of a representative natural gas hydrocarbon mixture. The nanomodel matches major North American formations in the volumetric and number contributions of the pore sizes, porosity (10.5%), and ultra-low permeability (44 nD). Combined experimental and analytical results show 3000× slower vaporization owing to the nanoscale throat bottlenecks. At low temperatures, mixture effects reduce rates further with stochastic vaporization of light components in large pores dominating. Collectively this approach captures the coupled complexity of multicomponent, multiphase fluids in multiscale geometries that is inherent to this resource.


Plants growing on contaminated and brownfield sites appropriate for use in Organisation for Economic Co-operation and Development terrestrial plant growth test.
The Organisation for Economic Co-operation and Development (OECD) terrestrial plant test is often used for the ecological risk assessment of contaminated land. However, its origins in plant protection product testing mean that the species recommended in the OECD guidelines are unlikely to occur on contaminated land. Six alternative species were tested on contaminated soils from a former Zn smelter and a metal fragmentizer with elevated concentrations of Cd, Cu, Pb, and Zn. The response of the alternative species was compared with that of two species recommended by the OECD: Lolium perenne (perennial ryegrass) and Trifolium pratense (red clover). Urtica dioica (stinging nettle) and Poa annua (annual meadowgrass) had low emergence rates in the control soil and so may be considered unsuitable. Festuca rubra (Chewings fescue), Holcus lanatus (Yorkshire fog), Senecio vulgaris (common groundsel), and Verbascum thapsus (great mullein) offer good alternatives to the OECD species. In particular, H. lanatus and S. vulgaris were more sensitive to the soils with moderate concentrations of Cd, Cu, Pb, and Zn than the OECD species.


Inulin coated plasmonic gold nanoparticles as a tumor-selective tool for cancer therapy.
Polymer coated gold nanospheres are proposed as a tumor selective carrier for the anticancer drug doxorubicin. Thiolated polyethyleneglycol (PEG-SH) and an inulin-amino derivative based copolymer (INU-EDA) were used as stabilizing and coating materials for 40 nm gold nanospheres. The resulting polymer coated gold nanospheres (Au@PEG-INU) showed excellent physicochemical stability and potential stealth like behavior. The system was loaded with doxorubicin (Au@PEG-INU/Doxo) and its cytotoxicity profile was evaluated on human cervical cancer cells (HeLa) and lung cancer cells (A549), as compared to Au@PEG-INU and doxorubicin alone. Cytotoxicity assays showed that the system is able to drastically reduce cell viability upon incubation for 3 days. This result was supported by the ability of Au@PEG-INU/Doxo to be internalized by cancer cells and to release doxorubicin, as assessed by fluorescence microscopy. Finally, a cancer/non cancer cell co-culture model was used to display the advantageous therapeutic effects of the proposed system with respect to doxorubicin alone, thereby demonstrating the ability of Au@PEG-INU/Doxo to preferentially accumulate in tumor cells due to their enhanced metabolism, and to selectively kill target cells.


Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis.
To describe the relative risk for serious gastrointestinal complications due to non-aspirin nonsteroidal anti-inflammatory drug (NSAID) exposure among NSAID users as well as in selected subgroups. Overview and meta-analysis. A literature search of English-language studies examining the association between NSAIDs and adverse gastrointestinal events for the period 1975 to 1990 identified using MEDLINE and communicating with three internationally recognized experts. A qualitative summary of study characteristics and a critical appraisal of study quality were done. The results of 16 primary studies were selected and combined statistically. Summary estimates were weighted by sample size and quality score. The overall odds ratio of the risk for adverse gastrointestinal events related to NSAID use, summarized from 16 studies (9 case-control and 7 cohort) was 2.74 (95% Cl, 2.54 to 2.97). The summary odds ratios were as follows: elderly patients, (aged greater than or equal to 60 years), 5.52 (Cl, 4.63 to 6.60); patients under 65 years of age, 1.65 (Cl, 1.08 to 2.53); women, 2.32 (Cl, 1.91 to 2.82); and men, 2.40 (Cl, 1.85 to 3.11). The summary odds ratio for NSAID users receiving concomitant corticosteroids compared with NSAID users not receiving corticosteroids was 1.83 (Cl, 1.20 to 2.78). The summary odds ratio for the first gastrointestinal event was 2.39 (Cl, 2.16 to 2.65). The relative risk for a subsequent or unspecified gastrointestinal event was 4.76 (Cl, 4.05 to 5.59). The summary odds ratio for less than 1 month of NSAID exposure was 8.00 (Cl, 6.37 to 10.06); for more than 1 month but less than 3 months of exposure, the summary odds ratio was 3.31 (Cl, 2.27 to 4.82); and for more than 3 months of exposure, the summary odds ratio was 1.92 (Cl, 1.19 to 3.13). Users of NSAIDs are at approximately three times greater relative risk for developing serious adverse gastrointestinal events than are nonusers. Additional risk factors include age greater than 60 years, previous history of gastrointestinal events, and concomitant corticosteroid use. Another possible risk factor is the first 3 months of NSAID therapy. The risk for serious gastrointestinal events appears to be equal among men and women. These data represent summary statistics from 16 studies and cannot be considered generalizable to all NSAID users.


Splenic angiosarcoma: a clinicopathologic and immunophenotypic study of 28 cases.
Primary angiosarcoma of the spleen is a rare neoplasm that has not been well characterized. We describe the clinical, morphologic, and immunophenotypic findings of 28 cases of primary splenic angiosarcoma, including one case that shares features of lymphangioma/lymphangiosarcoma. The patients included 16 men and 12 women, aged 29 to 85 years, with a mean of 59 years and median of 63 years. The majority of patients (75%) complained of abdominal pain, and 25% presented with splenic rupture. The most common physical finding was splenomegaly (71%). Seventeen of 21 patients were reported to have anemia. Macroscopic examination showed splenomegaly in 85% cases. Sectioning revealed discrete lesions in 88% of cases, ranging from well-circumscribed firm nodules to poorly delineated foci of necrosis and hemorrhage associated with cystic spaces. Microscopically, the tumors were heterogenous; however, all cases demonstrated at least a focal vasoformative component lined by atypical endothelial cells. Solid sarcomatous, papillary, and epithelioid growth patterns were observed. The solid sarcomatous component resembled fibrosarcoma in two cases and malignant fibroushistiocytoma in one case. Hemorrhage, necrosis, hemosiderin, extramedullary hematopoiesis, and intracytoplasmic hyaline globules were frequently identified. A panel of immunohistochemical studies revealed that the majority of tumors were immunoreactive for at least two markers of vascular differentiation (CD34, FVIIIRAg, VEGFR3, and CD31) and at least one marker of histiocytic differentiation (CD68 and/or lysozyme). Metastases developed in 100% of patients during the course of their disease. Twenty-six patients died of disease despite aggressive therapy, whereas only two patients are alive at last follow-up, one with disease at 8 years and the other without disease at 10 years. In conclusion, primary splenic angiosarcoma is an extremely aggressive neoplasm that is almost universally fatal. The majority of splenic angiosarcomas coexpress histiocytic and endothelial markers by immunohistochemical analysis, which suggest that some tumors may originate from splenic lining cells.


Exposure to Gambling Advertisements and Gambling Behavior in Young People.
A cross-sectional survey of 4617 adolescents and young adults from 38 schools in two German states was conducted in 2014 to assess the association between gambling advertisements and gambling behavior. Exposure to ten gambling advertisements was measured with masked ad images; students indicated contact frequency and brand recall. Main outcomes were several gambling behaviors including probable pathological gambling assessed with the South Oaks Gambling Screen (SOGS ≥ 5). A total of 65.4 % of the students reported gambling at least once in their life; 42.2 % gambled in the last 12 months; 6.9 % gambled in the last week, and 2.8 % reported probable pathological gambling. The average frequency that one of the selected ads had been seen at least once was 29.5 %, the average brand recall rate was 9.4 %. After adjustment for confounding, multilevel mixed-effects logistic regressions revealed that high gambling ad exposure was positively related to all assessed gambling outcomes, with the strongest association for weekly gambling. Future studies need to clarify the temporal sequence and specificity of these associations.


A comparison of self-report and antiretroviral detection to inform estimates of antiretroviral therapy coverage, viral load suppression and HIV incidence in Kwazulu-Natal, South Africa.
Accurately identifying individuals who are on antiretroviral therapy (ART) is important to determine ART coverage and proportion on ART who are virally suppressed. ART is also included in recent infection testing algorithms used to estimate incidence. We compared estimates of ART coverage, viral load suppression rates and HIV incidence using ART self-report and detection of antiretroviral (ARV) drugs and we identified factors associated with discordance between the methods. Cross-sectional population-based survey in KwaZulu-Natal, South Africa. Individuals 15-59 years were eligible. Interviews included questions about ARV use. Rapid HIV testing was performed at the participants' home. Blood specimens were collected for ARV detection, LAg-Avidity HIV incidence testing and viral load quantification in HIV-positive individuals. Multivariate logistic regression models were used to identify socio-demographic covariates associated with discordance between self-reported ART and ARV detection. Of the 5649 individuals surveyed, 1423 were HIV-positive. Median age was 34 years and 76.3% were women. ART coverage was estimated at 51.4% (95%CI:48.5-54.3), 53.1% (95%CI:50.2-55.9) and 56.1% (95%CI:53.5-58.8) using self-reported ART, ARV detection and both methods combined (classified as ART exposed if ARV detected and/or ART reported) respectively. ART coverage estimates using the 3 methods were fairly similar within sex and age categories except in individuals aged 15-19 years: 33.3% (95%CI:23.3-45.2), 33.8% (95%CI:23.9-45.4%) and 44.3% (95%CI:39.3-46.7) using self-reported ART, ARV detection and both methods combined. Viral suppression below 1000cp/mL in individuals on ART was estimated at 89.8% (95%CI:87.3-91.9), 93.1% (95%CI:91.0-94.8) and 88.7% (95%CI:86.2-90.7) using self-reported ART, ARV detection and both methods combined respectively. HIV incidence was estimated at 1.4 (95%CI:0.8-2.0) new cases/100 person-years when employing no measure of ARV use, 1.1/100PY (95%CI:0.6-1.7) using self-reported ART, and 1.2/100PY (95%CI:0.7-1.7) using ARV detection. In multivariate analyses, individuals aged 15-19 years had a higher risk of discordance on measures of ARV exposure (aOR:9.4; 95%CI:3.9-22.8), while migrants had a lower risk (aOR:0.3; 95%CI:0.1-0.6). In KwaZulu-Natal, the method of identifying ARV use had little impact on estimates of ART coverage, viral suppression rate and HIV incidence. However, discordant results were more common in younger individuals. This may skew estimates of ART coverage and viral suppression, particularly in adolescent surveys.


A novel machine learning-derived radiotranscriptomic signature of perivascular fat improves cardiac risk prediction using coronary CT angiography.
Coronary inflammation induces dynamic changes in the balance between water and lipid content in perivascular adipose tissue (PVAT), as captured by perivascular Fat Attenuation Index (FAI) in standard coronary CT angiography (CCTA). However, inflammation is not the only process involved in atherogenesis and we hypothesized that additional radiomic signatures of adverse fibrotic and microvascular PVAT remodelling, may further improve cardiac risk prediction. We present a new artificial intelligence-powered method to predict cardiac risk by analysing the radiomic profile of coronary PVAT, developed and validated in patient cohorts acquired in three different studies. In Study 1, adipose tissue biopsies were obtained from 167 patients undergoing cardiac surgery, and the expression of genes representing inflammation, fibrosis and vascularity was linked with the radiomic features extracted from tissue CT images. Adipose tissue wavelet-transformed mean attenuation (captured by FAI) was the most sensitive radiomic feature in describing tissue inflammation (TNFA expression), while features of radiomic texture were related to adipose tissue fibrosis (COL1A1 expression) and vascularity (CD31 expression). In Study 2, we analysed 1391 coronary PVAT radiomic features in 101 patients who experienced major adverse cardiac events (MACE) within 5 years of having a CCTA and 101 matched controls, training and validating a machine learning (random forest) algorithm (fat radiomic profile, FRP) to discriminate cases from controls (C-statistic 0.77 [95%CI: 0.62-0.93] in the external validation set). The coronary FRP signature was then tested in 1575 consecutive eligible participants in the SCOT-HEART trial, where it significantly improved MACE prediction beyond traditional risk stratification that included risk factors, coronary calcium score, coronary stenosis, and high-risk plaque features on CCTA (Δ[C-statistic] = 0.126, P < 0.001). In Study 3, FRP was significantly higher in 44 patients presenting with acute myocardial infarction compared with 44 matched controls, but unlike FAI, remained unchanged 6 months after the index event, confirming that FRP detects persistent PVAT changes not captured by FAI. The CCTA-based radiomic profiling of coronary artery PVAT detects perivascular structural remodelling associated with coronary artery disease, beyond inflammation. A new artificial intelligence (AI)-powered imaging biomarker (FRP) leads to a striking improvement of cardiac risk prediction over and above the current state-of-the-art.


Flame-Retardant Paper from Wood Fibers Functionalized via Layer-by-Layer Assembly.
The highly flammable character of cellulose-rich fibers from wood limits their use in some advanced materials. To suppress the flammability and introduce flame-retardant properties to individual pulp fibers, we deposited nanometer thin films consisting of cationic chitosan (CH) and anionic poly(vinylphosphonic acid) (PVPA) on fibers using the layer-by-layer (LbL) technique. The buildup of the multilayer film was investigated in the presence and absence of salt (NaCl) using model cellulose surfaces and a quartz crystal microbalance technique. Fibers were then treated with the same strategy, and the treated fibers were used to prepare paper sheets. A horizontal flame test (HFT) and cone calorimetry were conducted to evaluate the combustion behavior of paper sheets as a function of the number of bilayers deposited on fibers. In HFT, paper made of fibers coated with 20 CH/PVPA bilayers (BL), self-extinguished the flame, while uncoated fibers were completely consumed. Scanning electron microscopy of charred paper after HFT revealed that a thin shell of the charred polymeric multilayer remained after the cellulose fibers had been completely oxidized. Cone calorimetry demonstrated that the phosphorus-containing thin films (20 BL is ∼25 nm) reduced the peak heat release rate by 49%. This study identifies a unique and highly effective way to impart flame-retardant characteristic to pulp fibers and the papers made from these fibers.


Dimensionality and measurement invariance in the Satisfaction with Life Scale in Norway.
Results from previous studies examining the dimensionality and factorial invariance of the Satisfaction with Life Scale (SWLS) are inconsistent and often based on small samples. This study examines the factorial structure and factorial invariance of the SWLS in a Norwegian sample. Confirmatory factor analysis (AMOS) was conducted to explore dimensionality and test for measurement invariance in factor structure, factor loadings, intercepts, and residual variance across gender and four age groups in a large (N = 4,984), nationally representative sample of Norwegian men and women (15-79 years). The data supported a modified unidimensional structure. Factor loadings could be constrained to equality between the sexes, indicating metric invariance between genders. Further testing indicated invariance also at the strong and strict levels, thus allowing analyses involving group means. The SWLS was shown to be sensitive to age, however, at the strong and strict levels of invariance testing. In conclusion, the results in this Norwegian study seem to confirm that a unidimensional structure is acceptable, but that a modified single-factor model with correlations between error terms of items 4 and 5 is preferred. Additionally, comparisons may be made between the genders. Caution must be exerted when comparing age groups.


Machine Learning Prediction Models for Chronic Kidney Disease Using National Health Insurance Claim Data in Taiwan.
Chronic kidney disease (CKD) represents a heavy burden on the healthcare system because of the increasing number of patients, high risk of progression to end-stage renal disease, and poor prognosis of morbidity and mortality. The aim of this study is to develop a machine-learning model that uses the comorbidity and medication data obtained from Taiwan's National Health Insurance Research Database to forecast the occurrence of CKD within the next 6 or 12 months before its onset, and hence its prevalence in the population. A total of 18,000 people with CKD and 72,000 people without CKD diagnosis were selected using propensity score matching. Their demographic, medication and comorbidity data from their respective two-year observation period were used to build a predictive model. Among the approaches investigated, the Convolutional Neural Networks (CNN) model performed best with a test set AUROC of 0.957 and 0.954 for the 6-month and 12-month predictions, respectively. The most prominent predictors in the tree-based models were identified, including diabetes mellitus, age, gout, and medications such as sulfonamides and angiotensins. The model proposed in this study could be a useful tool for policymakers in predicting the trends of CKD in the population. The models can allow close monitoring of people at risk, early detection of CKD, better allocation of resources, and patient-centric management.


The prevalence of diabetes-specific emotional distress in people with Type 2 diabetes: a systematic review and meta-analysis.
Psychological comorbidity, such as depression and/or diabetes-specific emotional distress (diabetes distress), is widespread in people with Type 2 diabetes and is associated with poorer treatment outcomes. Although extensive research into the prevalence of depression has been conducted, the same attention has not been given to diabetes distress. The aim of this systematic review was to determine the overall prevalence of diabetes distress in people with Type 2 diabetes. Seven databases were searched to identify potentially relevant studies; eligible studies (adult population aged > 18 years with Type 2 diabetes and an outcome measure of diabetes distress) were selected and appraised independently by two reviewers. Multiple fixed- and random-effects meta-analyses were performed to synthesize the data; with primary analyses to determine the overall prevalence of diabetes distress in people with Type 2 diabetes, and secondary meta-analyses and meta-regression to explore the prevalence across different variables. Fifty-five studies (n = 36 998) were included in the meta-analysis and demonstrated an overall prevalence of 36% for diabetes distress in people with Type 2 diabetes. Prevalence of diabetes distress was significantly higher in samples with a higher prevalence of comorbid depressive symptoms and a female sample majority. Diabetes distress is a prominent issue in people with Type 2 diabetes that is associated with female gender and comorbid depressive symptoms. It is important to consider the relationship between diabetes distress and depression, and the significant overlap between conditions. Further work is needed to explore psychological comorbidity in Type 2 diabetes to better understand how best to identify and appropriately treat individuals.


Prevalence of occult celiac disease in patients with iron-deficiency anemia: a prospective study.
Occult celiac disease has been reported in 0 to 6% of adults presenting with iron-deficiency anemia. Most prior studies have been retrospective or screened only a selected population of patients with small bowel biopsies. To more accurately define the true prevalence of this disorder in patients presenting with iron-deficiency anemia (with or without stool hemoccult positivity), we initiated this prospective study. Esophagogastroduodenoscopy with small bowel biopsies and colonoscopy were performed in all iron-deficiency anemia patients (including those with hemoccult-positive stools) referred to the gastroenterology service during a 2-year period (1998-2000). Inclusion criteria included iron-deficiency anemia as defined by a serum ferritin < 25 ng/ml and anemia with hemoglobin < 12 g/dl. Patients were excluded for documented prior erosive, ulcerative, or malignant disease of the gastrointestinal tract, previous gastrointestinal surgery, overt gastrointestinal bleeding within the past 3 months, or inability to access the duodenum for biopsy. All patients underwent upper endoscopy with more than two biopsies of the distal duodenum and colonoscopy. A serum immunoglobulin A antiendomysial antibody test was to be performed in those patients with a positive small bowel biopsy to confirm the diagnosis of celiac disease. One hundred five of 139 consecutive patients with iron-deficiency anemia met the inclusion criteria and were enrolled in the study. Fifty-seven men (mean age, 51.6 yr) and 48 women (mean age, 54.1 yr) constituted the study population. The demographics of this study population included 36 blacks, 38 Hispanics, and 22 whites. Nine patients were of mixed or unknown ethnic background. Forty-three and eight-tenths percent of the men and 37.5% of women had hemoccult-positive stools, accounting for a total of 40.9% of the study patients. Upper endoscopic findings included gastritis in 22.8%, gastric ulcers in 9.5%, duodenitis in 8.5%, esophagitis in 7.6%, Barrett's ulcer in 2.8%, duodenal ulcer in 2.8%, gastric polyp in 2.8%, and celiac disease in 2.8%. Colonoscopic findings included colon polyps in 21.9%, diverticula in 10.4%, and hemorrhoids in 16.1%. Multiple findings were found in 32.3% of patients, and there were no findings in 28.5% of patients. The prevalence of occult celiac disease in this prospective study of patients presenting with iron-deficiency anemia was 2.8%. A significant number of other gastrointestinal lesions amenable to therapy were also found on upper and lower endoscopy in these patients. Given the treatable nature of celiac disease, it should be screened for in patients with unexplained iron-deficiency anemia with or without hemoccult-positive stools.


The fimbrial protein FlfA from Gallibacterium anatis is a virulence factor and vaccine candidate.
The Gram-negative bacterium Gallibacterium anatis is a major cause of salpingitis and peritonitis in egg-laying chickens, leading to decreased egg production worldwide. Widespread multidrug resistance largely prevents treatment of this organism using traditional antimicrobial agents, while antigenic diversity hampers disease prevention by classical vaccines. Thus, insight into its pathogenesis and knowledge about important virulence factors is urgently required. A key event during the colonization and invasion of mucosal surfaces is adherence, and recently, at least three F17-like fimbrial gene clusters were identified in the genomes of several G. anatis strains. The objective of this study was to characterize the putative F17-like fimbrial subunit protein FlfA from G. anatis 12656-12 and determine its importance for virulence. In vitro expression and surface exposure of FlfA was demonstrated by flow cytometry and immunofluorescence microscopy. The predicted function of FlfA as a fimbrial subunit protein was confirmed by immunogold electron microscopy. An flfA deletion mutant (ΔflfA) was generated in G. anatis 12656-12, and importantly, this mutant was significantly attenuated in the natural chicken host. Furthermore, protection against G. anatis 12656-12 could be induced by immunizing chickens with recombinant FlfA. Finally, in vitro expression of FlfA homologs was observed in a genetically diverse set of G. anatis strains, suggesting the potential of FlfA as a serotype-independent vaccine candidate This is the first study describing a fimbrial subunit protein of G. anatis with a clear potential as a vaccine antigen.


Application of MRI of the wrist for age determination in international U-17 soccer competitions.
To guarantee equal chances for different age groups, age-related tournaments for male and female players have been established in soccer. However, as registration at birth is not compulsory in some countries, other methods of age determination are needed to prevent participation in the incorrect age group. To evaluate the age of soccer players of international U-17 competitions from the degree of fusion of the distal radius and to compare the findings with an age-related normative population. MRI scans of the wrist of a representative sample of 189 players from four U-17 competitions (FIFA U-17 World Cups 2003 and 2005, and Asian (AFC) U-17 championships 2004 and 2006) were analysed using a previously published grading system. Because of different regulations, all players in the AFC U-17 championships were younger than 17 years, whereas 71% of the players in the FIFA U-17 World Cup competitions were 17 years old. The distal radius of 15% of players from the AFC U-17 tournaments and 27% of the players from the FIFA U-17 tournaments were graded as completely fused on the MRI scans, which is a substantially higher percentage than in the respective age groups of a previously published normative population of soccer players. Furthermore, in contrast with the normative population, no significant correlation between the age category and the fusion grading (r = 0.13) was observed in U-17 players. From the MRI results, U-17 soccer players seem to be more mature than a normative population of the same age category. However, the lack of correlation between age category and degree of fusion in U-17 players supports the suspicion that the age stated in the official documents of the U-17 players examined might not be correct in all cases.


Experimental models and tools to tackle glioblastoma.
Glioblastoma multiforme (GBM) is one of the deadliest human cancers. Despite increasing knowledge of the genetic and epigenetic changes that underlie tumour initiation and growth, the prognosis for GBM patients remains dismal. Genome analysis has failed to lead to success in the clinic. Fresh approaches are needed that can stimulate new discoveries across all levels: cell-intrinsic mechanisms (transcriptional/epigenetic and metabolic), cell-cell signalling, niche and microenvironment, systemic signals, immune regulation, and tissue-level physical forces. GBMs are inherently extremely challenging: tumour detection occurs too late, and cells infiltrate widely, hiding in quiescent states behind the blood-brain barrier. The complexity of the brain tissue also provides varied and complex microenvironments that direct cancer cell fates. Phenotypic heterogeneity is therefore superimposed onto pervasive genetic heterogeneity. Despite this bleak outlook, there are reasons for optimism. A myriad of complementary, and increasingly sophisticated, experimental approaches can now be used across the research pipeline, from simple reductionist models devised to delineate molecular and cellular mechanisms, to complex animal models required for preclinical testing of new therapeutic approaches. No single model can cover the breadth of unresolved questions. This Review therefore aims to guide investigators in choosing the right model for their question. We also discuss the recent convergence of two key technologies: human stem cell and cancer stem cell culture, as well as CRISPR/Cas tools for precise genome manipulations. New functional genetic approaches in tailored models will likely fuel new discoveries, new target identification and new therapeutic strategies to tackle GBM.


Right Colon Resection: Evolution and Surgical Technique.
This review aims to provide succinct insight into the past, present and near-future of right colon resection. The history of right colon resection as well as the evolution of a laparoscopic approach are described. Standardization of the surgical technique, indications for medial-to-lateral and lateral-to medial mobilization, D2 and D3 lymphadenectomy, iso-peristaltic and antiperistaltic anastomotic configurations, intracorporeal and extracorporeal anastomosis, totally stapled and stapled handsewn techniques, laparoscopic and robotic suturing, mucosa eversion and inversion, and specimen extraction sites are discussed. In addition, totally intracorporeal robotic right colectomy for cancer is described. This review concludes that, whether it is hindered or assisted, gasless or "con gas", multiple- or single-port, extra- or intracorporeal, iso- or anti-peristaltic, right colon resection is still evolving.


"This body does not want free medicines": South African consumer perceptions of drug quality.
OBJECTIVES Like many other developing countries, South Africa provides free medicines through its public health care facilities. Recent policies encourage generic substitution in the private sector. This study explored South African consumer perceptions of drug quality and whether these perceptions influenced how people procured and used their medicines. METHODS The study was undertaken in Durban, Cape Town and Johannesburg in South Africa between December 2005 and January 2006. A combination of purposive and snowball sampling was used to recruit participants from low and middle socio-economic groups as well as the elderly and teenagers. Data were collected through 12 focus group discussions involving a total of 73 participants. Interviews were tape-recorded. Thematic analysis was performed on the transcripts. RESULTS Irrespective of socio-economic status, respondents described medicine quality in terms of the effect the medicine produced on felt symptoms. Generic medicines, as well as medicines supplied without charge by the state, were considered to be poor quality and treated with suspicion. Respondents obtained medicines from three sources: public sector hospitals and/or clinics, dispensing doctors and community pharmacies. Cost, avoidance of feeling 'second-class', receiving individualized care and choice in drug selection were the main determinants influencing their procurement behaviour. Selection of over-the-counter medicines was influenced by prior knowledge of products, through advertising and previous use. Participants perceived that they had limited influence on selection of prescription medicines. Generic substitution would be supported if the doctor, rather than the pharmacist, recommended it. CONCLUSIONS Our findings emphasize the importance of meaningful consumer involvement in the development of national medicines policies, and strategic campaigns targeting consumers and prescribers regarding the quality of generic and essential medicines. Where consumers perceive free or generic medicines as inferior, this could significantly undermine attempts to implement national medicines policies aimed to improve access to medicines.


Genomic signatures of relaxed disruptive selection associated with speciation reversal in whitefish.
Speciation reversal: the erosion of species differentiation via an increase in introgressive hybridization due to the weakening of previously divergent selection regimes, is thought to be an important, yet poorly understood, driver of biodiversity loss. Our study system, the Alpine whitefish (Coregonus spp.) species complex is a classic example of a recent postglacial adaptive radiation: forming an array of endemic lake flocks, with the independent origination of similar ecotypes among flocks. However, many of the lakes of the Alpine radiation have been seriously impacted by anthropogenic nutrient enrichment, resulting in a collapse in neutral genetic and phenotypic differentiation within the most polluted lakes. Here we investigate the effects of eutrophication on the selective forces that have shaped this radiation, using population genomics. We studied eight sympatric species assemblages belonging to five independent parallel adaptive radiations, and one species pair in secondary contact. We used AFLP markers, and applied FST outlier (BayeScan, Dfdist) and logistic regression analyses (MatSAM), to identify candidate regions for disruptive selection in the genome and their associations with adaptive traits within each lake flock. The number of outlier and adaptive trait associated loci identified per lake were then regressed against two variables (historical phosphorus concentration and contemporary oxygen concentration) representing the strength of eutrophication. Whilst we identify disruptive selection candidate regions in all lake flocks, we find similar trends, across analysis methods, towards fewer disruptive selection candidate regions and fewer adaptive trait/candidate loci associations in the more polluted lakes. Weakened disruptive selection and a concomitant breakdown in reproductive isolating mechanisms in more polluted lakes has lead to increased gene flow between coexisting Alpine whitefish species. We hypothesize that the resulting higher rates of interspecific recombination reduce either the number or extent of genomic islands of divergence surrounding loci evolving under disruptive natural selection. This produces the negative trend seen in the number of selection candidate loci recovered during genome scans of whitefish species flocks, with increasing levels of anthropogenic eutrophication: as the likelihood decreases that AFLP restriction sites will fall within regions of heightened genomic divergence and therefore be classified as F(ST) outlier loci. This study explores for the first time the potential effects of human-mediated relaxation of disruptive selection on heterogeneous genomic divergence between coexisting species.


Induction of the RNA regulator LIN28A is required for the growth and pathogenesis of RESTless breast tumors.
The transcription factor RE1 silencing transcription factor (REST) is lost in approximately 20% of breast cancers. Although it is known that these RESTless tumors are highly aggressive and include all tumor subtypes, the underlying tumorigenic mechanisms remain unknown. In this study, we show that loss of REST results in upregulation of LIN28A, a known promoter of tumor development, in breast cancer cell lines and human breast tumors. We found that LIN28A was a direct transcriptional target of REST in cancer cells and that loss of REST resulted in increased LIN28A expression and enhanced tumor growth both in vitro and in vivo, effects that were dependent on heightened LIN28A expression. Tumors lacking REST expression were locally invasive, consistent with the increased lymph node involvement observed in human RESTless tumors. Clinically, human RESTless breast tumors also displayed significantly enhanced LIN28A expression when compared with non-RESTless tumors. Our findings therefore show a critical role for the REST-LIN28A axis in tumor aggression and suggest a causative relationship between REST loss and tumorigenicity in vivo.