Chronic Opioid Use in Rheumatoid Arthritis: Prevalence and Predictors.
The opioid epidemic is a major public health concern. However, little is known about opioid use among rheumatoid arthritis (RA) patients. We undertook this study to examine trends in chronic opioid use in RA patients in 2002-2015 and to identify clinical predictors. RA patients were identified from the Corrona registry. Opioid use was ascertained from surveys obtained at clinical visits as often as every 3 months. Chronic opioid use was defined as any opioid use reported during ≥2 consecutive study visits. Annual prevalence of chronic opioid use was calculated using data from 33,739 RA patients with information on opioid use from ≥2 visits. Among the 26,288 individuals who were not taking opioids at baseline, Cox proportional hazards models identified associations between patient characteristics and incident chronic opioid use. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated. Chronic opioid use increased from 7.4% in 2002 to 16.9% in 2015. Severe pain (HR 2.53 [95% CI 2.19-2.92]) and antidepressant use (HR 1.79 [95% CI 1.64-1.92]) were associated with an increased risk of chronic opioid use. High disease activity (HR 1.55 [95% CI 1.30-1.84]) and a high level of disability (HR 1.45 [95% CI 1.27-1.65]) were also associated with chronic opioid use, whereas Asian ethnicity (HR 0.49 [95% CI 0.36-0.68]) was associated with a decreased risk of chronic opioid use. Among RA patients, chronic opioid use doubled from 2002 to 2015. Pain and antidepressant use were the strongest predictors of chronic opioid use. To curb the rise in chronic opioid use, strategies for stringent control of RA disease activity and management of pain and depression should be research priorities.


Structure and transport properties of polymer grafted nanoparticles.
We perform molecular dynamics simulations on a bead-spring model of pure polymer grafted nanoparticles (PGNs) and of a blend of PGNs with a polymer melt to investigate the correlation between PGN design parameters (such as particle core concentration, polymer grafting density, and polymer length) and properties, such as microstructure, particle mobility, and viscous response. Constant strain-rate simulations were carried out to calculate viscosities and a constant-stress ensemble was used to calculate yield stresses. The PGN systems are found to have less structural order, lower viscosity, and faster diffusivity with increasing length of the grafted chains for a given core concentration or grafting density. Decreasing grafting density causes depletion effects associated with the chains leading to close contacts between some particle cores. All systems were found to shear thin, with the pure PGN systems shear thinning more than the blend; also, the pure systems exhibited a clear yielding behavior that was absent in the blend. Regarding the mechanism of shear thinning at the high shear rates examined, it was found that the shear-induced decrease of Brownian stresses and increase in chain alignment, both correlate with the reduction of viscosity in the system with the latter being more dominant. A coupling between Brownian stresses and chain alignment was also observed wherein the non-equilibrium particle distribution itself promotes chain alignment in the direction of shear.


Defect crystal structure of new TiO(OH)2 hydroxide and related lithium salt Li2TiO3.
Crystal structures of TiO(OH)(2) and Li(2)TiO(3) have been studied in detail and refined using X-ray powder diffraction data. Both compounds possess a high concentration of defects in the structure. The crystal structure of the Li(2)TiO(3) salt obtained at 700 degrees C reveals stacking faults of LiTi(2) metal layers, which leads to the appearance of short-range order in three possible space groups: C2/c, C2/m, P3(1)12. The possibility to stabilise this imperfect state increases the mobility of the Li(+) ions in the structure and allows the complete exchange of lithium by hydrogen in acid water solutions with formation of TiO(OH)(2). The crystal structure of TiO(OH)(2) belongs to the layered double hydroxide structure type with the 3R(1) sequence of oxygen layers and can be described as a stacking of charge-neutral metal oxyhydroxide slabs [(OH)(2)OTi(2)O(OH)(2)]. TiO(OH)(2) is the first layered double hydroxide structure formed by a cation with oxidation state +4 only.


New Progress in Improving the Delivery Methods of Bisphosphonates in the Treatment of Bone Tumors.
Bone tumors are tumors that occur in the bone or its accessory tissues, including primary tumors and metastatic tumors. The main mechanism of bisphosphonate is to inhibit the resorption of destructive bone, inhibit the activity of osteoclasts and reduce the concentration of blood calcium. Therefore, bisphosphonates can be used for malignant hypercalcaemia, pain caused by osteolytic bone metastasis, prevention of osteolytic bone metastasis, multiple myeloma osteopathy, improving radiosensitivity and so on. However, the traditional administration of bisphosphonates can cause a series of adverse reactions. To overcome this disadvantage, it is necessary to develop novel methods to improve the delivery of bisphosphonates. In this paper, the latest research progress of new and improved bisphosphonate drug delivery methods in the treatment of bone tumors is reviewed. At present, the main design idea is to connect bisphosphonate nanoparticles, liposomes, microspheres, microcapsules, couplings, prodrugs and bone tissue engineering to targeted anti-tumors systems, and positive progress has been made in in vitro and animal experiments. However, its safety and effectiveness in human body still need to be verified by more studies.


[Not Available].
Rheumatoid arthritis is the most common chronic inflammatory joint disease. To overcome joint inflammation and eventually induce disease remission, the physician must often use drugs that are more and more toxic. Indications, method of administration, and common adverse effects of non-steroidal anti-inflammatory drugs, local steroid injections, second-line agents, and steroids are reviewed. The author briefly discusses a new therapeutic concept and emphasizes the importance of patient education and early referral to an interdisciplinary rehabilitation team.


A Thalamocortical Neural Mass Model of the EEG during NREM Sleep and Its Response to Auditory Stimulation.
Few models exist that accurately reproduce the complex rhythms of the thalamocortical system that are apparent in measured scalp EEG and at the same time, are suitable for large-scale simulations of brain activity. Here, we present a neural mass model of the thalamocortical system during natural non-REM sleep, which is able to generate fast sleep spindles (12-15 Hz), slow oscillations (<1 Hz) and K-complexes, as well as their distinct temporal relations, and response to auditory stimuli. We show that with the inclusion of detailed calcium currents, the thalamic neural mass model is able to generate different firing modes, and validate the model with EEG-data from a recent sleep study in humans, where closed-loop auditory stimulation was applied. The model output relates directly to the EEG, which makes it a useful basis to develop new stimulation protocols.


Nicotinic receptor fourth transmembrane domain: hydrogen bonding by conserved threonine contributes to channel gating kinetics.
The fourth transmembrane domain (M4) of the nicotinic acetylcholine receptor (AChR) contributes to the kinetics of activation, yet its close association with the lipid bilayer makes it the outermost of the transmembrane domains. To investigate mechanistic and structural contributions of M4 to AChR activation, we systematically mutated alphaT422, a conserved residue that has been labeled by hydrophobic probes, and evaluated changes in rate constants underlying ACh binding and channel gating steps. Aromatic and nonpolar mutations of alphaT422 selectively affect the channel gating step, slowing the rate of opening two- to sevenfold, and speeding the rate of closing four- to ninefold. Additionally, kinetic modeling shows a second doubly liganded open state for aromatic and nonpolar mutations. In contrast, serine and asparagine mutations of alphaT422 largely preserve the kinetics of the wild-type AChR. Thus, rapid and efficient gating of the AChR channel depends on a hydrogen bond involving the side chain at position 422 of the M4 transmembrane domain.


Listeria monocytogenes InlP interacts with afadin and facilitates basement membrane crossing.
During pregnancy, the placenta protects the fetus against the maternal immune response, as well as bacterial and viral pathogens. Bacterial pathogens that have evolved specific mechanisms of breaching this barrier, such as Listeria monocytogenes, present a unique opportunity for learning how the placenta carries out its protective function. We previously identified the L. monocytogenes protein Internalin P (InlP) as a secreted virulence factor critical for placental infection. Here, we show that InlP, but not the highly similar L. monocytogenes internalin Lmo2027, binds to human afadin (encoded by AF-6), a protein associated with cell-cell junctions. A crystal structure of InlP reveals several unique features, including an extended leucine-rich repeat (LRR) domain with a distinctive Ca2+-binding site. Despite afadin's involvement in the formation of cell-cell junctions, MDCK epithelial cells expressing InlP displayed a decrease in the magnitude of the traction stresses they could exert on deformable substrates, similar to the decrease in traction exhibited by AF-6 knock-out MDCK cells. L. monocytogenes ΔinlP mutants were deficient in their ability to form actin-rich protrusions from the basal face of polarized epithelial monolayers, a necessary step in the crossing of such monolayers (transcytosis). A similar phenotype was observed for bacteria expressing an internal in-frame deletion in inlP (inlP ΔLRR5) that specifically disrupts its interaction with afadin. However, afadin deletion in the host cells did not rescue the transcytosis defect. We conclude that secreted InlP targets cytosolic afadin to specifically promote L. monocytogenes transcytosis across the basal face of epithelial monolayers, which may contribute to the crossing of the basement membrane during placental infection.


A web-based clinical decision tool to support treatment decision-making in psychiatry: a pilot focus group study with clinicians, patients and carers.
Treatment decision tools have been developed in many fields of medicine, including psychiatry, however benefits for patients have not been sustained once the support is withdrawn. We have developed a web-based computerised clinical decision support tool (CDST), which can provide patients and clinicians with continuous, up-to-date, personalised information about the efficacy and tolerability of competing interventions. To test the feasibility and acceptability of the CDST we conducted a focus group study, aimed to explore the views of clinicians, patients and carers. The CDST was developed in Oxford. To tailor treatments at an individual level, the CDST combines the best available evidence from the scientific literature with patient preferences and values, and with patient medical profile to generate personalised clinical recommendations. We conducted three focus groups comprising of three different participant types: consultant psychiatrists, participants with a mental health diagnosis and/or experience of caring for someone with a mental health diagnosis, and primary care practitioners and nurses. Each 1-h focus group started with a short visual demonstration of the CDST. To standardise the discussion during the focus groups, we used the same topic guide that covered themes relating to the acceptability and usability of the CDST. Focus groups were recorded and any identifying participant details were anonymised. Data were analysed thematically and managed using the Framework method and the constant comparative method. The focus groups took place in Oxford between October 2016 and January 2017. Overall 31 participants attended (12 consultants, 11 primary care practitioners and 8 patients or carers). The main themes that emerged related to CDST applications in clinical practice, communication, conflicting priorities, record keeping and data management. CDST was considered a useful clinical decision support, with recognised value in promoting clinician-patient collaboration and contributing to the development of personalised medicine. One major benefit of the CDST was perceived to be the open discussion about the possible side-effects of medications. Participants from all the three groups, however, universally commented that the terminology and language presented on the CDST were too medicalised, potentially leading to ethical issues around consent to treatment. The CDST can improve communication pathways between patients, carers and clinicians, identifying care priorities and providing an up-to-date platform for implementing evidence-based practice, with regard to prescribing practices.


A Community-Engaged Assessment of Barriers and Facilitators to Rapid Stroke Treatment.
Treatment for acute ischemic stroke must be initiated within hours of stroke symptom onset, and the sooner it is administered, the better. In South Carolina, 76% of the population can access expert stroke care, and rural hospitals may provide specialized treatment using telemedicine, but many stroke sufferers seek care too late to achieve full benefit. Using a community-engaged approach in a southern rural community, we explored barriers and facilitators to early stroke care and implications for improvement. The Community-Engaged Assessment to facilitate Stroke Elimination (CEASE) study was guided by a community advisory group to ensure community centeredness and local relevance. In a qualitative descriptive study, eight focus groups were conducted including 52 individuals: recent stroke survivors, family members, emergency medical personnel, hospital emergency department staff, primary care providers, and community leaders. From analysis of focus group transcripts came six themes: lack of trust in healthcare system and providers; weak relationships fueled by poor communication; low health literacy; financial limitations related to health care; community-based education; and faith as a message of hope. A hierarchy model for improving early community-based stroke care was developed through consensus dialogue by community representatives and the research team. This model can be used to inform a community-partnered, stakeholder-informed intervention to improve stroke care in a rural southern community with the goal of improving stroke education, care, and outcome. © 2016 Wiley Periodicals, Inc.


Distribution of brain sodium long and short relaxation times and concentrations: a multi-echo ultra-high field 23Na MRI study.
Sodium (23Na) MRI proffers the possibility of novel information for neurological research but also particular challenges. Uncertainty can arise in in vivo 23Na estimates from signal losses given the rapidity of T2* decay due to biexponential relaxation with both short (T2*short) and long (T2*long) components. We build on previous work by characterising the decay curve directly via multi-echo imaging at 7 T in 13 controls with the requisite number, distribution and range to assess the distribution of both in vivo T2*short and T2*long and in variation between grey and white matter, and subregions. By modelling the relationship between signal and reference concentration and applying it to in vivo 23Na-MRI signal, 23Na concentrations and apparent transverse relaxation times of different brain regions were measured for the first time. Relaxation components and concentrations differed substantially between regions of differing tissue composition, suggesting sensitivity of multi-echo 23Na-MRI toward features of tissue composition. As such, these results raise the prospect of multi-echo 23Na-MRI as an adjunct source of information on biochemical mechanisms in both physiological and pathophysiological states.


Identification of kinase-phosphatase signaling modules composed of p70 S6 kinase-protein phosphatase 2A (PP2A) and p21-activated kinase-PP2A.
A growing body of evidence indicates that regulation of protein-serine/threonine phosphatase 2A (PP2A) involves its association with other cellular and viral proteins in multiprotein complexes. PP2A-containing protein complexes may exist that contribute to PP2A's important regulatory role in many cellular processes. To identify such protein complexes, PP2A was partially purified from rat brain soluble extracts following treatment with a reversible cross-linker to stabilize large molecular size forms of PP2A. Compared with native (uncross-linked) PP2A, cross-linked PP2A revealed an enrichment of p70 S6 kinase and two p21-activated kinases (PAK1 and PAK3) in the PP2A complex, indicating these kinases may associate with PP2A. The existence of protein kinase-PP2A complexes in rat brain soluble extracts was further substantiated by the following results: 1) independent immunoprecipitation of the kinases revealed that PP2A co-precipitated with p70 S6 kinase and the two PAK isoforms; 2) glutathione S-transferase fusion proteins of p70 S6 kinase and PAK3 each isolated PP2A; and 3) PAK3 and p70 S6 kinase bound to microcystin-Sepharose (an affinity resin for PP2A-PP1). Cumulatively, these findings provide evidence for association of PP2A with p70 S6 kinase, PAK1, and PAK3 in the context of the cellular environment. Moreover, together with the recent reports describing associations of PP2A with Ca2+/calmodulin-dependent protein kinase IV (Westphal, R. S., Anderson, K. A., Means, A. R., and Wadzinski, B. E. (1998) Science 280, 1258-1261) and casein kinase IIalpha (Heriche, J. K., Lebrin, F., Rabilloud, T., Leroy, D., Chambaz, E. M., and Goldberg, Y. (1997) Science 276, 952-955), the present data provide compelling evidence for the existence of protein kinase-PP2A signaling modules as a new paradigm for the control of various intracellular signaling cascades.


Investigation of optimum roasting conditions to obtain possible health benefit supplement, antioxidants from coffee beans.
In order to investigate the role of roasting conditions in antioxidant formation, methanol and hot water extracts from Robusta coffee beans roasted for various lengths of time and at various temperatures were analyzed for total phenolic acid, chlorogenic acid, and caffeine content, as well as for their antioxidant activities using 1,1-diphenyl-2-picryhydrazyl (DPPH), thiobarbituric acid (TBA), and malonaldehyde/gas chromatography (MA/GC) assays. The amount of total phenolics in methanol extracts decreased linearly over the roasting temperature from 63.51 ± 0.77 mg chlorogenic acid equivalent (CAE)/g coffee beans (roasted at 200°C) to 42.56 ± 0.33 mg CAE/g coffee beans (roasted at 240°C). The total chlorogenic acid content decreased when the roasting time was increased from 78.33 ± 1.41 mg/g (green coffee beans) to 4.31 ± 0.23 mg/g (roasted for 16 min at 250°C). All methanol extracts from roasted coffee beans possessed over 90% antioxidant activities in the DPPH assay. The antioxidant activity of methanol extracts ranged from 41.38 ± 1.77% (roasted at 250°C for 10 min) to 98.20 ± 1.49% (roasted at 230°C for 16 min) as tested by the TBA assay. The antioxidant activity of methanol extracts of green coffee beans and roasted coffee beans ranged from 93.01% (green coffee beans) to 98.62 ± 1.32% (roasted at 250°C for 14 min) in the MA/GC assays. All hot water extracts exhibited moderate pro-oxidant activities in TBA and MA/GC assays. The results indicated that roasting conditions of coffee beans play an important role in the formation of antioxidants in brewed coffee, which can be dietary supplements having beneficial effect to human health.


Staff burnout in paediatric oncology: new tools to facilitate the development and evaluation of effective interventions.
Working in paediatric oncology can be stressful, and staff may need support if they are to avoid burnout, but there is currently no evidence base to guide the development of interventions. As a significant barrier to addressing this gap is a lack of context specific research instruments, a project was undertaken to develop measures of the stressors and rewards experienced by staff. Measure development involved: (1) qualitative interviews with a purposive sample of paediatric oncology staff to develop an 'item pool' (n = 32); (2) selection of items for draft measures; (3) cognitive interviews (n = 7) to gather feedback on draft measures; (4) a survey of staff (n = 203) using the draft and comparator measures; (5) factor and Rasch analysis to determine the scaling properties of the measures; (6) an assessment of construct validity. As a result, the Work Stressors Scale - Paediatric Oncology (WSS-PO) and the Work Rewards Scale - Paediatric Oncology (WRS-PO) were created. Both measures have considerable content validity, and fulfil classical test theory requirements and Rasch model requirements for an interval level scale. These new measures can be used in research and clinical practice to investigate factors associated with burnout, and to facilitate and direct the development of staff interventions.


Dietary fiber, lipid metabolism, and atherosclerosis.
Despite the physiochemical complexity of dietary fibers (plant cell walls) and their individual components, there is substantial epidemiologic, clinical, and experimental evidence that these dietary components may have a role in modifying certain risk factors in coronary heart disease. Particulate fibers, such as wheat bran, do not appear to significantly alter plasma lipids or lipoprotein distributions in humans, or the atherogenicity of diets in experimental animals. Dietary fibers found in fruits, legumes, and vegetables, in contrast, show more definitive responses. Among the fiber isolates, the gelling and mucilaginous fibers, such as pectins and guar gum, predictably decrease circulating lipids in humans and animals and increase excretion of fecal metabolites of cholesterol, the bile acids. These fibers and fiber components can be shown to influence luminal solubility of lipids and the extent of lymphatic absorption of both cholesterol and triglyceride. In addition, these same fibers are effective in reducing postprandial levels of glucose, insulin, and other hormones. These direct effects on lipid absorption, and secondary effects of glucose and insulin on hepatic and peripheral lipoprotein metabolism, can account for many of the hypolipidemic responses to specific dietary fibers or their components, and may be of long-term consequence in coronary heart disease.


Biomarkers of the Physical Function Mobility Domains Among Patients Hospitalized in Internal Medicine.
Hospitalized patients in internal medicine have an increased risk of low physical reserve which further declines during the hospital stay. The diagnosis requires bed-side testing of functional domains or more complex investigations of the muscle mass. Clinically useful biomarkers of functional status are needed, thus we aimed to explore the potential of microRNAs. Among hospitalized patients, we recorded the basic demographics, anthropometrics, nutritional status, and physical function domains: hand-grip strength (HGS, abnormal values M<30 kg, W<20 kg), balance (<30 s), chair-stands speed (CHSS<0.5/s) and gait speed (GS<0.8 m/s). A panel of five micro-RNAs (miRNA 1, miRNA 133a, miRNA 133b, miRNA 29a, miRNA 29b) and basic blood biochemistry and vitamin D values were recorded. We enrolled 80 patients (M40, W40), with a mean age of 68.8±8.4 years. Obesity was observed in 27.5 % and 30 %, low HGS and low CHSS in 65.0, 77.5 %, and 80, 90 % of men and women respectively. The median hospital stay was 6.5 days. MiRNA29a and miRNA29b have the strongest correlation with the triceps skinfold (miRNA 29b, r=0.377, p=0.0006) and CHSS (miRNA 29a, r=0.262, p=0.02). MiRNA 29a, miRNA 29b and 133a levels were significantly higher in patients with CHSS<0.5/s. Other anthropometric parameters, mobility domains, or vitamin D did not correlate. All miRNAs except of miRNA 1, could predict low CHSS (miRNA29b, AUROC=0.736 CI 0.56-0.91, p=0.01), particularly in patients with low HGS (miRNA 29b, AUROC=0.928 CI 0.83-0.98). Among hospitalized patients in internal medicine, low functional status was frequent. MicroRNAs were fair biomarkers of the antigravity domain, but not other domains. Larger studies with clinical endpoints are needed.


Supplemental oxygen may decrease progression of prethreshold disease to threshold retinopathy of prematurity.
The optimum level of oxygen saturation for infants with prethreshold retinopathy of prematurity (ROP) is unknown. We reviewed our conversion rate from prethreshold to threshold ROP between 1985 and 1993 during which time target levels of oxygen saturation rose in a stepwise fashion. A retrospective study of 153 infants with prethreshold ROP was performed at Stanford University between 1985 and 1993 that showed that target minimum oxygen saturation rose from 92% (1985-1987) to 95% (1988) to 96% (1989) to 99% (1990-1993). In addition, we looked at 26 infants between 1994 and 1996 who were excluded from the STOP-ROP study and who were not receiving supplemental oxygen in an effort to maintain equipoise for that study. Infant characteristics were tabulated, and rates of progression from prethreshold to threshold ROP were calculated. Rates of progression to threshold varied little between 1985 and 1989 (average 37%), but dropped to 7% for the period between 1990 and 1993. From 1994 through 1996 the rate of progression to threshold disease rose again, to 38%. Moderate supplemental oxygen (target saturation 99% with PO2 no higher than 100 mm Hg) was associated with regression of prethreshold ROP, without appearing to arrest retinal vascular maturation.


[Soft-tissue contour plastic repair of the maxillofacial area using a biologically compatible polyacrylamide gel].
Polyacrylamide hydrogel was used in contour plastic repair of maxillofacial soft tissues in 161 female patients. The remote results (up to 2 years after the manipulation) demonstrate the advantages of this method over traditional surgery. Biogel preserves the natural appearance of soft tissues of the face; the clinical effect is stable.


[Effects of honokiol on particulate matter 2.5-induced lung injury in asthmatic mice and its mechanisms].
To explore the therapeutic effect of honokiol on particulate matter 2.5 (PM2.5)-induced lung injury in asthmatic mice and the possible mechanisms. Methods: A total of 32 BALB/C mice were randomly divided into four groups: a normal saline group, a model group, a PM2.5 group and a honokiol group (n=8 in each group). The asthma mouse model was established by ovalbumin treatment. The mice were treated with physiological saline, ovalbumin, PM2.5 and honokiol, respectively. Lung tissues and serum were collected. The pathological changes of lung tissues were evaluated. The levels of inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and serum were measured and the expressions of Toll like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), retinoid-related orphan receptor gamma-t (RORγt) and forkhead box protein 3 (Foxp3) in lung tissues were detected. Results: 1) The lung tissues of mice in the asthma group showed obvious pathological changes and inflammatory state, suggesting that the asthma model was established successfully. PM2.5 could aggravate the pathological condition of inflammatory injury in lung tissues in asthmatic mice. 2) Compared to the PM2.5 group, the pathological symptoms in the lung tissues were alleviated in the honokiol group and the percentage of inflammatory cells in BALF and the levels of inflammatory cytokines in BALF and serum were significantly reduced (all P<0.05). 3) Compared to the PM2.5 group, the expressions of TLR4, NF-κB (p-p65) and RORγt in lung tissues were significantly decreased, while the expression of Foxp3 was increased; the ratio of RORγt/Foxp3 was also decreased in the honokiol group (all P<0.05). Conclusion: Honokiol can resist lung injury induced by PM2.5 in asthmatic mice. These effects are through inhibiting TLR4-NF-κB pathway-mediated inflammatory response or regulating the balance of Th17/Treg cells.


Where optics meets electronics: recent progress in decreasing the terahertz gap.
The terahertz region of the electromagnetic spectrum offers considerable opportunities for exploitation. Recent advances in source and coherent-detection technology have enabled advances to be made in a wide range of applications. This article reviews the historical development of the field, summarizes the current state of system technology and outlines a number of current system applications, including medical imaging. The limitations of present-day technology are discussed and some future possible applications are considered.


X-linked markers in the Duchenne muscular dystrophy gene associated with oral clefts.
As part of an international consortium, case-parent trios were collected for a genome-wide association study of isolated, non-syndromic oral clefts, including cleft lip (CL), cleft palate (CP), and cleft lip and palate (CLP). Non-syndromic oral clefts have a complex and heterogeneous etiology. Risk is influenced by genes and environmental factors, and differs markedly by gender. Family-based association tests (FBAT) were used on 14,486 single nucleotide polymorphisms (SNPs) spanning the X chromosome, stratified by type of cleft and racial group. Significant results, even after multiple-comparisons correction, were obtained for the Duchenne muscular dystrophy (DMD) gene, the largest single gene in the human genome, among CL/P (i.e., both CL and CLP combined) trios. When stratified into groups of European and Asian ancestry, stronger signals were obtained for Asian subjects. Although conventional sliding-window haplotype analysis showed no increase in significance, selected combinations of the 25 most significant SNPs in the DMD gene identified four SNPs together that attained genome-wide significance among Asian CL/P trios, raising the possibility of interaction between distant SNPs within the DMD gene.


Single Photon Subradiance: Quantum Control of Spontaneous Emission and Ultrafast Readout.
Recent work has shown that collective single photon emission from an ensemble of resonate two-level atoms, i.e., single photon superradiance, is a rich field of study. The present Letter addresses the flip side of superradiance, i.e., subradiance. Single photon subradiant states are potentially stable against collective spontaneous emission and can have ultrafast readout. In particular it is shown how many atom collective effects provide a new way to control spontaneous emission by preparing and switching between subradiant and superradiant states.


Deep-Brain Subthalamic Nucleus Stimulation Enhances Food-Related Motivation by Influencing Neuroinflammation and Anxiety Levels in a Rat Model of Early-Stage Parkinson's Disease.
Deep-brain subthalamic nucleus stimulation (DBS-STN) has become a well-established therapeutic option for advanced Parkinson's disease (PD). While the motor benefits of DBS-STN are widely acknowledged, the neuropsychiatric effects are still being investigated. Beyond its immediate effects on neuronal circuits, emerging research suggests that DBS-STN might also modulate the peripheral inflammation and neuroinflammation. In this work, we assessed the effects of DBS-STN on food-related motivation, food intake pattern, and the level of anxiety and compared them with markers of cellular and immune activation in nigrostriatal and mesolimbic areas in rats with the 6-OHDA model of early PD. To evaluate the potential mechanism of observed effects, we also measured corticosterone concentration in plasma and leukocyte distribution in peripheral blood. We found that DBS-STN applied during neurodegeneration has beneficial effects on food intake pattern and motivation and reduces anxiety. These behavioral effects occur with reduced percentages of IL-6-labeled cells in the ventral tegmental area and substantia nigra pars compacta in the stimulated brain hemisphere. At the same brain structures, the cFos cell activations were confirmed. Simultaneously, the corticosterone plasma concentration was elevated, and the peripheral blood lymphocytes were reduced after DBS-STN. We believe that comprehending the relationship between the effects of DBS-STN on inflammation and its therapeutic results is essential for optimizing DBS therapy in PD.


[Reversible hyperparathyroid metabolic osteopathy secondary to parathyroid carcinoma].
Parathyroid carcinoma is a rare cause of hyperparathyroidism and metabolic osteopathy. The authors report a patient with parathyroid carcinoma who underwent 99mTc-Sestamibi parathyroid and 99mTc-MDP bone scanning. These techniques showed the parathyroid lesion and typical features of severe metabolic osteopathy respectively. The bone scan performed at only four months after surgery showed near complete resolution.


[Primary prevention of behavioral risky forms in adolescents].
The paper considers the state-of-the-art of adolescents' risky behavior. It is noted that there is a need for designing a more stringent conceptual apparatus and for unifying a diagnostic approach by specialists of various profiles. There is evidence that behavioral phenomena are of different diagnostic value in the historical time range of 17 years. The aims, principles, and technologies of primary psychoprophylaxis are defined. It is concluded that it is necessary to qualitatively improve psychiatric training of pediatricians, school psychologists, and teachers.


Polysome-dependent in vitro translation system capable of peptide chain reinitiation.
A sensitive in vitro translation system has been developed which makes use of cellular polysomes as the source of mRNA and ribosomes. The soluble factors are derived from the preincubated S-30 fraction by centrifugation through a discontinuous sucrose gradient. Of the four fractions tested, fraction 1 (topmost fraction in the gradient) and fraction 2 (fraction sedimenting in 0.5 M sucrose) were stimulatory. These two fractions together yield the highest activity, corresponding to about 125 times the background incorporation. The polysome-directed system exhibits optimal activity in the range 1.8-2 mM Mg2+ and 125-175 mM KCl. The polysome-directed in vitro products exhibit a complexity comparable to the in vivo products resolved on the two-dimensional polyacrylamide gels of O'Farrell [O'Farrell, P. (1975) J. Biol. Chem. 250, 4007-4021]. The system is capable of active chain reinitiation as indicated by partial inhibition by 7-methylguanosine 5'-monophosphate and pactomycin and N-terminal end analysis of in vitro products. This system can also translate polysomes from diverse tissues such as mouse liver, rat liver, and rat brain. The levels and also the authenticity of translation of rat liver albumin and mouse liver carbamoyl phosphate synthetase I were tested by immunoprecipitation with monospecific antibodies. The results show that the major as well as the minor translation products are synthesized in this system at levels comparable to the physiological levels.


The application of nuclear magnetic resonance to the study of cellular physiology.
Nuclear magnetic resonance (NMR) is a form of absorption spectroscopy that can noninvasively monitor the intracellular concentration and several kinetic properties of numerous organic and inorganic compounds. Utilizing these characteristics, investigators have demonstrated that NMR is a useful tool in the study of cellular physiology. In this review, the techniques for using NMR to study isolated cells are outlined with suggestions for the determination of cellular viability within the NMR spectrometer. Whenever feasible, cell preparations that are continuously perfused are preferred, because they can be constantly fed and controlled. Results of various NMR experiments on isolated cells using several nuclides are reviewed to highlight the type of information NMR can provide about cellular physiology. Several important differences between NMR and chemical extraction data are noted. The reason for these differences is probably related to the chemical extraction techniques determining the total amount of a compound within the cell in comparison to NMR, which is somewhat more specific, theoretically, detecting only the free species within the cytosol.


An efficient and universal In silico screening strategy for acquisition of high-affinity Aptamer and its application in analytical utility.
Numerous aptamers against various targets have been identified through the technology of systematic evolution of ligands by exponential enrichment (SELEX), but the affinity of these aptamers are often insufficient due to the limitations of SELEX. Therefore, a more rational in silico screening strategy (ISS) was developed for efficient screening of high affinity aptamers, which took shape complementarity and thermodynamic stability into consideration. Neuron specific enolase (NSE), a tumor marker, was selected as the target molecule. In the screening process, three aptamer candidates with good shape complementarity, lower ΔG values, and higher ZDOCK scores were produced. The dissociation constant (Kd) of these candidates to NSE was determined to be 10.13 nM, 14.82 nM, and 2.76 nM, respectively. Each of them exhibited higher affinity to NSE than the parent aptamer (Kd = 23.83 nM). Finally, an antibody-free fluorescence aptasensor assay, based on the aptamer with the highest affinity, P-5C8G, was conducted, resulting in a limit of detection (LOD) value of 1.8 nM, which was much lower than the parental aptamer (P, LOD = 12.6 nM). The proposed ISS approach provided an efficient and universal strategy to improve the aptamer to have a high affinity and good analytical utility.


Neighbour species richness and local structural variability modulate aboveground allocation patterns and crown morphology of individual trees.
Local neighbourhood interactions are considered a main driver for biodiversity-productivity relationships in forests. Yet, the structural responses of individual trees in species mixtures and their relation to crown complementarity remain poorly understood. Using a large-scale forest experiment, we studied the impact of local tree species richness and structural variability on above-ground wood volume allocation patterns and crown morphology. We applied terrestrial laser scanning to capture the three-dimensional structure of trees and their temporal dynamics. We found that crown complementarity and crown plasticity increased with species richness. Trees growing in species-rich neighbourhoods showed enhanced aboveground wood volume both in trunks and branches. Over time, neighbourhood diversity induced shifts in wood volume allocation in favour of branches, in particular for morphologically flexible species. Our results demonstrate that diversity-mediated shifts in allocation pattern and crown morphology are a fundamental mechanism for crown complementarity and may be an important driver of overyielding.


Predictors of Mortality From a Population-Based Cancer Registry Data in Jos, Nigeria: A Resource-Limited Setting.
Background: It is a well-documented fact that world-wide cancer incidence and mortality remains high in Human Immunodeficiency Virus (HIV) infected population despite potent antiretroviral therapy. With the current capture of HIV status of cancer patients in our cancer registry at Jos Nigeria, this study aims to assess the effect of HIV on cancer mortality outcomes. Methodology: We conducted a 2-year retrospective cohort study of cancer registry data from Jos, north central Nigeria. The cancers were grouped into cervical, breast, liver, hematologic, colonic, AIDS defining, prostate and others in this study. Patients were followed up to determine their patient time contribution from time at initiation of cancer treatment to death or the end of study period. Those lost to follow-up were censored at date of their last known follow-up in clinic. Results: Out of 930 cancer cases evaluated, 52 (5.6%) were HIV positive, 507 (54.5%) were HIV negative and 371 (39.9%) did not know their HIV status. After 525,223 person- days of follow-up, there were 232 deaths leading to a crude mortality rate of 4.3 per 10,000 person-days. Median survival probability for both HIV-infected and HIV uninfected patients were equal (1,013 days). Unadjusted hazard of death was associated with greater age, HR 0.99 (95% CI: 0.98,0.99, p = 0.002); hepatitis virus, HR 2.40 (95% CI: 1.69,3.43, p = 0.001); liver cancer, HR 2.25 (95% CI:1.11,4.55, p = 0.024); prostate cancer, HR 0.17 (95% CI: 0.06,0.393, p = 0.001). In an adjusted model, only prostate cancer AHR 0.23 (95% CI: 0.12, 0.42, p < 0.001) and liver cancer AHR 2.45 (95% CI: 1.78, 5.51, p < 0.001) remained significantly associated with death regardless of HIV status. Conclusion: Having liver cancer increases risk for mortality among our cancer patients. Screening, early detection and treatment are therefore key to improving dismal outcomes.


Pharmaceutical Industry Funding of Health Consumer Groups in Australia: A Cross-sectional Analysis.
Relationships between consumer organizations and pharmaceutical manufacturers are the focus of transparency efforts in some jurisdictions, including Australia. This study describes the frequency and nature of industry sponsorship of Australian health consumer organizations and examines the link between sponsorship of the most highly funded organizations and manufacturers' requests for public reimbursement of products for related health conditions. We downloaded 130 transparency reports covering the period January 2013 to December 2016 from the website of Medicines Australia and carried out a descriptive analysis. For the most heavily funded organizations and their sponsors, we examined Public Summary Documents of the Pharmaceutical Benefits Advisory Committee to identify relevant products under consideration for public reimbursement over the study period. Thirty-four pharmaceutical companies provided 1,482 sponsorships to 230 organizations, spending a total of AU$34,507,810. The top clinical areas in terms of amount of funding received were cancer, eye health, and nervous system disorders. The sponsors of the most highly funded groups were companies that in most cases had drugs under review for public reimbursement for conditions covered by these organizations. Interactions between the pharmaceutical industry and consumer organizations are common and require careful management to prevent biases that may favor sponsors' interests above those of patients and the public.


Desmin and CD31 immunolabeling for detecting venous invasion of the pancreatobiliary tract cancers.
Although venous invasion (VI) is a poor prognostic factor for patients with pancreatobiliary tract cancers, its histopathologic characteristics have not been well described. We evaluated the patterns of VI and the added benefit provided by CD31, desmin, and dual CD31‒desmin immunolabeling for identification of VI. We included 120 surgically resected pancreatobiliary tract cancer cases-59 cases as a test set with known VI and 61 cases as a validation set without information of VI. VI was classified into three patterns: intraepithelial neoplasia-like (IN-like), conventional, and destructive. Hematoxylin and eosin (H&E) staining and CD31, desmin, and dual CD31‒desmin immunolabeling were performed. Foci number and patterns of VI were compared with the test and validation sets. More foci of VI were detected by single CD31 (P = 0.022) than H&E staining in the test set. CD31 immunolabeling detected more foci of the conventional pattern of VI, and desmin immunolabeling detected more foci of the destructive pattern (all, P < 0.001). Dual CD31‒desmin immunolabeling identified more foci of VI (P = 0.012) and specifically detected more foci of IN-like (P = 0.045) and destructive patterns (P < 0.001) than H&E staining in the validation set. However, dual CD31‒desmin immunolabeling was not helpful for detecting the conventional pattern of VI in the validation set. Patients with VI detected by dual CD31‒desmin immunolabeling had shorter disease-free survival (P <0.001) than those without VI. VI detected by dual CD31‒desmin immunolabeling was a worse prognostic indicator (P = 0.009). More foci of VI could be detected with additional single CD31 or dual CD31‒desmin immunolabeling. The precise evaluation of VI with dual CD31‒desmin immunolabeling can provide additional prognostic information for patients with surgically resected pancreatobiliary tract cancers.


Parametric manipulation of working memory load in traumatic brain injury: behavioral and neural correlates.
Traumatic brain injury (TBI) is often associated with enduring impairments in high-level cognitive functioning, including working memory (WM). We examined WM function in predominantly chronic patients with mild, moderate and severe TBI and healthy comparison subjects behaviorally and, in a small subset of moderate-to-severe TBI patients, with event-related functional magnetic resonance imaging (fMRI), using a visual n-back task that parametrically varied WM load. TBI patients showed severity-dependent and load-related WM deficits in performance accuracy, but not reaction time. Performance of mild TBI patients did not differ from controls; patients with moderate and severe TBI were impaired, relative to controls and mild TBI patients, but only at higher WM-load levels. fMRI results show that TBI patients exhibit altered patterns of activation in a number of WM-related brain regions, including the dorsolateral prefrontal cortex and Broca's area. Examination of the pattern of behavioral responding and the temporal course of activations suggests that WM deficits in moderate-to-severe TBI are due to associative or strategic aspects of WM, and not impairments in active maintenance of stimulus representations. Overall, results demonstrate that individuals with moderate-to-severe TBI exhibit WM deficits that are associated with dysfunction within a distributed network of brain regions that support verbally mediated WM.


High therapeutic potential of Spilanthes acmella: A review.
Spilanthes acmella, a well known antitoothache plant with high medicinal usages, has been recognized as an important medicinal plant and has an increasingly high demand worldwide. From its traditional uses in health care and food, extensive phytochemical studies have been reported. This review provides an overview and general description of the plant species, bioactive metabolites and important pharmacological activities including the preparation, purification and in vitro large-scale production. Structure-activity relationships of the bioactive compounds have been discussed. Considering data from the literature, it could be demonstrated that S. acmella possesses diverse bioactive properties and immense utilization in medicine, health care, cosmetics and as health supplements. As a health food, it is enriched with high therapeutic value with high potential for further development.


Virus-Based MicroRNA Silencing and Overexpressing in Common Wheat (Triticum aestivum L.).
MicroRNAs (miRNAs) are a class of endogenous small non-coding RNAs that arise from large RNA precursors with a stem-loop structure and play important roles in plant development and responses to environmental stress. Although a hundred and nineteen wheat miRNAs have been identified and registered in the miRBase (Release 21.0, June, 2014; http://www.mirbase.org), the functional characterization of these miRNAs in wheat growth and development is lagging due to lack of effective techniques to investigate endogenous miRNA functions in wheat. Here we report barley stripe mosaic virus(BSMV)-based miRNA overexpression and silence systems that can be applied to study miRNA functions in wheat. By utilizing the BSMV system, we successfully knocked down endogenous miR156 and miR166 levels and over-expressed endogenous miR156 and artificial miRNA against phytoene desaturase gene PDS (amiR-PDS) in wheat. amiR-PDS expression caused a great reduction in endogenous mRNA abundance of PDS gene in wheat plant, leading to leaf obviously photobleaching. miR156 silencing led to a great increase in the mRNA level of its target gene SPL2, resulting in a leaf-curl phenotype in wheat seedlings. In contrast, overexpression of miR156 led to a significant reduction in the mRNA level of SPL2 in wheat seedlings, resulting in serious delay of the vegetative phase transitions as well as booting and flowering in wheat. These confirmed that miR156 regulates wheat development and booting time through SPL genes. In summary, the BSMV-based miRNA overexpression and silence systems have extraordinary potential not only for functional study of protein-encoding genes but also for miRNA genes in wheat.


The ARE-associated factor AUF1 binds poly(A) in vitro in competition with PABP.
The ARE (AU-rich element) is a post-transcriptional element controlling both mRNA turnover and translation initiation by primarily inducing poly(A) tail shortening. The mechanisms by which the ARE-associated proteins induce deadenylation are still obscure. One possibility among others would be that an ARE-ARE-BP (ARE-binding protein) complex intervenes in the PABP [poly(A)-binding protein]-poly(A) tail association and facilitates poly(A) tail accessibility to deadenylases. Here, we show by several experimental approaches that AUF1 (AU-rich element RNA-binding protein 1)/hnRNP (heterogeneous nuclear ribonucleoprotein) D, an mRNA-destabilizing ARE-BP, can bind poly(A) sequence in vitro. First, endogenous AUF1 proteins from HeLa cells specifically bound poly(A), independently of PABP. Secondly, using polyadenylated RNA probes, we showed that (i) the four recombinant AUF1 isoforms bind poly(A) as efficiently as PABP, (ii) the AUF1 binding to poly(A) does not change when the polyadenylated probe contains the GM-CSF (granulocyte/macrophage-colony stimulating factor) ARE, suggesting that, in vitro, the AUF1-poly(A) association was independent of the ARE sequence itself. In vitro, the binding of AUF1 isoforms to poly(A) displayed oligomeric and co-operative properties and AUF1 efficiently displaced PABP from the poly(A). Finally, the AUF1 molar concentration in HeLa cytoplasm was only 2-fold lower than that of PABP, whereas in the nucleus, its molar concentration was similar to that of PABP. These in vitro results suggest that, in vivo, AUF1 could compete with PABP for the binding to poly(A). Altogether, our results may suggest a role for AUF1 in controlling PABP-poly(A) tail association.


Thrombospondin and the adhesive behavior of platelets.
The adhesion-promoting activity of TSP has been examined in four systems. Both the amino-terminal heparin-binding domain and the large globular carboxy-terminal domains have been implicated in the agglutination of erythrocytes and fixed-activated platelets by TSP. Sulfatides specifically bind TSP and may serve as a membrane receptor for the heparin-binding domain of TSP. The large globular domains of TSP have been implicated in secretion-dependent platelet aggregation. Activation-dependent adhesion of platelets to TSP substrates does not appear to be mediated solely by direct interaction of TSP with platelet membrane components, but appears to be mediated in large part by intervening bridging molecules, such as fibronectin or fibrinogen. Thus, different regions of the complex TSP molecule are of varying importance in the different systems. No single simple system appears adequate for exploration of the adhesion-promoting activity of TSP.


Molecular detection of hepatitis E virus in German domestic pigs.
In industrial countries, Hepatitis E virus (HEV) transmission to humans is predominantly assumed to be a zoonotic infection. Recently, it has been demonstrated that about 50% of domestic pigs in Germany carry HEV-specific antibodies. However, further investigations concerning the distribution of HEV in different age groups of German domestic pigs, phylogenetic analyses and the viral load in the porcine liver are still pending. Liver samples of all age groups from herds in a pig-dense region in north-western Germany were investigated for the presence and quantity of HEV RNA and subsequently genotyped. Out of 251 liver samples, 34 contained ORF2-specific RNA, whereas 19 samples were positive using ORF1-specific primers, resulting in an overall detection rate of 13.5% and 7.6%, respectively. Especially nursery pigs and growers were tested positive for viral RNA. Furthermore, determination of the HEV copy numbers revealed high replication levels. Up to 10(9) genome copies per g of liver tissue could be detected suggesting a likely high degree of viral spread to the environment. In the HEV-positive liver samples we found no hints for pathohistological changes reflecting the HEV status.The HEV sequences showed marked diversity but could be assigned to HEV genotype 3 without exception. However, by comparing two different genomic fragments, we found indications for infections with two different HEV variants in domestic pigs. Apart from this, the current study confirms the outcome of our recent serological HEV survey and for the first time gives direct proof of HEV infections in the German domestic pig population.


Homotypic and heterotypic antibody responses to a 56-kilodalton protein of Orientia tsutsugamushi.
We analyzed homotypic and heterotypic antibody responses to a type-specific antigen (Tsa), a 56-kDa protein of Orientia tsutsugamushi, by using sera from mice immunized with strains Gilliam, Karp, Kato, and Boryong. We generated a series of deletion constructs of the tsa gene and expressed them as MalE fusion proteins. Variable domain I (VD I) showed strong responses to homotypic antibodies. Antigenic domain II (AD II) from Boryong and Karp showed cross-reactivities to each other. VD III showed no responses to any of the antibodies. Sera from Kato-immunized mice showed only homotypic responses to AD III. On the other hand, sera of the mice immunized with Gilliam, Karp, or Boryong showed homotypic as well as heterotypic responses to this region. VD IV showed the strongest heterotypic antibody responses among the fragments tested. These data suggest that VD I is important in homotypic antibody responses and that AD II, AD III, and VD IV are important in heterotypic antibody responses of the mice to Tsa.


Social Support Seeking on Social Media Among Chinese Gay Men Living with HIV/AIDS: The Role of Perceived Threat.
Background: Due to a double stigma against HIV/AIDS and homosexuality, gay men living with HIV/AIDS (GMLHA) have used social media to exchange social support. The current study aims to examine the influence of perceived threat on seeking social support on social media among Chinese GMLHA. Methods: First, Weibo posts from 133 GMLHA were content analyzed to identify the perceived severity of HIV infection and perceived severity of stigma, as well as their social support seeking on Weibo. Then, a 2 × 2 (perceived severity of HIV infection [present, absent] × perceived severity of stigma [present, absent]) between-subject multivariate analysis of variance with social support seeking as the dependent variable was performed. Results: Perceived severity of HIV infection and perceived severity of stigma had main effects on different kinds of social support seeking. Moreover, GMLHA who expressed both perceived severity of HIV infection and perceived severity of stigma on Weibo posted the greatest number of emotional support-seeking messages. Conclusions: This study revealed that perceived threat was one of the motivations of GMLHA to seek online social support.


Assessing patterns of use of cardio-protective polypill component medicines in Australian women.
A low-cost 'polypill' could theoretically be one way of improving medication affordability and compliance for secondary prevention of cardiovascular and cerebrovascular disease. The polypill has also been proposed as a primary prevention strategy. Yet many of the issues surrounding the polypill are still being debated and the underlying assumptions have not been proven. In this paper, we step back from the complexities of the debate and report upon the utilization of polypill component medicines in two population cohorts of Australian women who were aged 56-61 years and 81-86 years in 2007. The aims of this study were firstly, to describe the association between the women's characteristics (health, illness, behavioural, demographic, socioeconomic) and their use of statins and antihypertensive medicines for the treatment of heart disease, and secondly, to discuss possible health and economic benefits for women with these characteristics that may be expected to result from the introduction of a cardio-protective polypill. Survey records from the Australian Longitudinal Study on Women's Health (ALSWH) were linked to 2007 Pharmaceutical Benefits Scheme (PBS) claims for 7,116 mid-aged women and 4,526 older-aged women. Associations between women's characteristics (self-reported in ALSWH surveys) and their use of statins and antihypertensive medicines (measured through PBS claims in 2007) were analysed using Chi-square and multivariate regression techniques. Between 2002 and 2007, the use of statins in combination with antihypertensives by mid- and older-aged Australian women increased. A moderate yet increasing proportion of mid-aged women were taking statins without antihypertensives, and a high proportion of older-aged women were using antihypertensives without statins. A high proportion of women who were prescribed both statins and antihypertensives were in lower socioeconomic groups and reported difficulty managing on their incomes. These results suggest that a polypill may provide an easy-to-take, cheaper alternative for Australian women already taking multiple cardiovascular disease medications, with particular benefits for older women and women in lower socioeconomic groups. Future research is needed to quantify the potential social and economic benefits of the polypill.


Problematics of iodine saturation among children on the vegan diet.
Plant-based diets, which includes veganism, is now rapidly gaining popularity. In the absence of the knowledge how to provide all the risky nutrients, this style of eating can lead to nutritional deficits that result in disruption of the physiological development of the child. One of the risk elements also includes iodine. The vegan population is at risk not only of developing an iodine deficiency, but also of complications from its excessive consumption, since vegan alternatives, such as these made of seaweed, contain an excess amount of it. Iodine is essential for the proper functioning of the thyroid gland, whose hormones are involved in the development of the nervous system during intrauterine and postnatal development, and in the regulation of metabolism, as well as growth in children. Several physical (thyroid palpation), imaging (ultrasound) and laboratory methods (TSH, fT3/fT4 ratio, TG level, median of ioduria) are used to investigate iodine supply. For vegans it is essential to closely monitor iodine saturation and to edify the need to adequately supplement the diet of vegan diets. A possible vegan iodine source are precisely measured doses of mineral water (Vincentka) or iodine tablets. On the contrary, uncontrolled consumption of seaweed must be strictly discouraged. In terms of iodine supply, vegans are a risk group, and pregnant and breastfeeding women and children on vegan diets deserve increased attention.


Superovulatory ovarian response in Mangalica gilts is not influenced by feeding level.
The aim of the study was to compare how different feeding levels affect the ovarian potential of follicular development and oocyte maturation in response to superovulatory treatment in native Mangalica (M, n = 17) compared with Landrace (L, n = 20) pigs. Gilts of both breeds were fed high-energy (HI-2.5 kg) or low-energy (LO - 1.25 kg) feed during oestrus synchronization (15 days of Regumate feeding) till the time of oocyte aspiration (Day 6 after Regumate). Follicular growth was stimulated by the administration of 1000 IU equiue choriou gonadotropiu (eCG) 24 h after Regumate treatment, and ovulation was induced by injection of 750 IU human choriou gonadotropiu (hCG) 80 h after eCG administration. Ultrasound (US) investigation was done three times (4-10 h before, and 40-44 and 72-74 h after eCG administration) for the observation of follicular development. Oocyte and follicular fluid (FF) were collected endoscopically 34 h after hCG injection. Cumulus-oocyte complexes were evaluated, their morphology determined, and thereafter fixed and stained for chromatin evaluation. Oocytes were classified as meiosis-resumed (germinal vesicle breakdown, diakinesis, metaphase I to anaphase I) or matured (telophase I and metaphase II). FF concentrations of oestradiol and progesterone were measured by validated radioimmunoassays. In L gilts, differences were observed between HI and LO in the number of preovulatory follicles (32.3 +/- 10.5 vs 17.1 +/- 12.3, p < 0.05), but not in M (25.3 +/- 2.9 vs 28.8 +/- 7.3, p > 0.05). Initial follicular growth was not affected by feeding levels; however, preovulatory follicle size was larger in M (7.1 +/- 0.9 and 6.9 +/- 1.1 mm vs 5.7 +/- 0.7 and 5.5 +/- 0.8 mm; p < 0.05). No differences were obtained with relation to mature chromatin configuration in both breeds (L gilts: HI - 70% and LO-67% vs M gilts: HI - 67% and LO - 63%). A twofold higher oestradiol concentration was detected in FF of HI-M and LO-M (29.6 +/- 6.8 and 30.9 +/- 10.3 ng/ml respectively) compared with that of L (16.9 +/- 9.7 and 17.9 +/- 3.6 ng/ml, respectively; p < 0.05). The mean FF progesterone level was nearly fivefold higher in M (2020.4 +/- 1056 and 1512.2 +/- 1121.8 ng/ml) compared with L (386.2 +/- 113.7 and 298.8 +/- 125.9 ng/ml, p < 0.05). The results indicate an influence of the feeding of altered energy on the number of recruitable preovulatory follicles in modern Landrace but not in native Mangalica breed. Moreover, the follicular steroid hormone milieu differs between Landrace and Mangalica gilts but not depending on feeding levels. Oocyte maturation was not affected by diet.


Metiram-induced nephrotoxicity in albino mice: effect of licorice aqueous extract.
The present study was designed to estimate the effect of aqueous extract of licorice on metiram toxicity in mice. Treating mice with metiram at a dose level of [1/2] LD(50) daily for 3 weeks induced many histological changes in the kidney cortex. The renal tubules lost their characteristic appearance and their lining epithelial cells were degenerated. The glomeruli were atrophied and the renal blood vessels were congested. The intertubular spaces infiltrated by inflammatory leukocytic cells. Metiram caused an increase in proliferating cell nuclear antigen (PCNA) expression in nuclei of tubular epithelial cells. Metiram also caused marked elevation in serum creatinine and blood urea nitrogen. Treating animals with metiram and licorice aqueous extract led to an improvement, in both biochemical and histopathological alterations. These results proved that licorice had an ameliorative effect against kidney injury induced by metiram and this effect may be attributed to its antioxidant activity.


Utility of the hyperventilation test in the evaluation of the dizzy patient.
The aim of the review is to value the incidence, patterns and temporal characteristics of hyperventilation-induced nystagmus (HVIN) in patients suffering from vestibular diseases, as well as its contribution to the differential diagnosis between vestibular neuritis and schwannoma of the eighth cranial nerve and its behavior in some central vestibular diseases. The hyperventilation test seems to be more useful than other bedside tests in detecting schwannoma of the eighth cranial nerve in the case of sudden monolateral hypacusia. The presence of an excitatory pattern of HVIN in vestibular schwannoma that has undergone to stereotactic surgery reveals that this therapy produces demyelinization in neural fibers. The hyperventilation test is easy to perform, well tolerated and able to reveal latent vestibular asymmetries; it acts both at peripheral and central vestibular levels through metabolic mechanisms or, more rarely, through changes in cerebrospinal fluid pressure. It can provide patterns of oculomotor responses suggesting the execution of gadolinium-enhanced MRI, upon the suspicion of schwannoma of the eighth cranial nerve or of a central disease. In our opinion, the presence of HVIN always needs to be viewed within the more general context of a complete examination of auditory and vestibular systems.


Bulk analysis of tobacco and cigarettes by magnetic resonance imaging.
Proton magnetic resonance imaging of tobacco blends in cigarette rods was investigated to assess the feasibility of various imaging protocols to characterize and quantify the structure and composition of multiphase plant materials in situ. The protocols used to characterize the rigid molecular components (plant cell wall) included single-point imaging (SPI) and a variant experiment, single-point ramped imaging with T(1) enhancement (SPRITE). Both 1D profiles, radially averaged along the length of a cigarette, and 2D maps of proton spin density and relaxation (T(2)) were acquired. Mobile components (tobacco waxes and water) were examined via conventional spin-echo imaging techniques, with 1D, 2D, and 3D data being acquired. Spin-spin relaxation times (T(2)), apparent spin-spin relaxation (T(2)), and spin-lattice (T(1)) relaxation times were measured for selected samples.


Bcl-X(L) is up-regulated by HTLV-I and HTLV-II in vitro and in ex vivo ATLL samples.
Human T lymphotropic virus type I (HTLV-I) is the etiological agent of adult T-cell lymphocytic leukemia (ATLL), whereas HTLV-II has not been associated with hematopoietic malignancies. The control of apoptotic pathways has emerged as a critical step in the development of many cancer types. As a result, the underlying mechanism of long-term survival of HTLV-I and HTLV-II was studied in infected T cells in vitro and in ex vivo ATLL samples. Results indicate that HTLV-I- and HTLV-II-infected T cells in vitro express high levels of the antiapoptotic protein Bcl compared with other human leukemic T cell lines or uninfected peripheral blood mononuclear cells. The levels of proapoptotic proteins Bax, BAD, and Bak were not significantly altered. HTLV-I and HTLV-II viral transactivators, Tax1 and Tax2, are known to increase expression of cellular genes. These proteins were tested for increased transcription from the human Bcl2 and Bcl-X(L) promoters. Whereas no effect was observed on the Bcl2 promoter, both Tax1 and Tax2 increased transcription of the Bcl-X(L) promoter in T cells, although Tax1 appeared to be more efficient than Tax2. The biological significance of these observations was validated by the finding of an increased expression of Bcl-X(L) in ex vivo ATLL cells, especially from patients unresponsive to various chemotherapy regimens. Altogether, these data suggest that overexpression of Bcl-X(L )in vivo( )may be in part responsible for the resistance of ATLL cells to chemotherapy. In addition, inefficient activation of the Bcl-X(L) promoter by Tax2 may result in a shorter survival time of HTLV-II-infected cells in vivo and a diminished risk of leukemia development.


A Jury of Their Peers: A Meta-Analysis of the Effects of Teen Court on Criminal Recidivism.
Juvenile delinquency has been on the decline for a number of years, yet, juvenile courts continue to assess more than 1 million cases per year. Involvement with the juvenile justice system has been linked to a number of risk factors and consequences that may impact positive youth development; however, evidence-based correctional programs that divert juvenile offenders away from formal processing are limited. Teen Court is a specialized diversion intervention that offers an alternative to traditional court processing for juvenile offenders. Despite the rapid expansion of Teen Courts, there is little comprehensive and systematic evidence available to justify this expansion. This meta-analytic study examines the effects of Teen Court on the recidivism of juvenile offenders. The literature search resulted in the selection of 14 studies, which contributed 18 unique effect sizes with a total sample of 2125 treatment group and 979 comparison group youth. The findings suggest that Teen Court is no more effective at reducing recidivism than (a) formal processing or (b) other diversion programs. Implications of formal and informal court processing for low-risk, first-time young offenders are discussed. The authors draw on the Risk-Need-Responsivity model to provide recommendations for policies and practices.


Manipulation of the charge state of single Au atoms on insulating multilayer films.
We show charge-state manipulation of single Au adatoms on 2-11 monolayer (ML) thick NaCl films on Cu surfaces by attaching or detaching single electrons via the tip of an atomic force microscope (AFM). Tristate charge control (neutral, negatively charged, and positively charged) is achieved. On Cu(100) and Cu(111) supports, charge tristability is achieved independently of the NaCl layer thickness. In contrast, on Cu(311), only Au anions are stable on the thinnest NaCl films, but neutral and positive charge states become sufficiently long lived on films thicker than 4 ML to allow AFM-based charge-state-manipulation experiments.


Validity and reliability of GPS units to monitor cricket-specific movement patterns.
The validity and reliability of three commercial global positioning system (GPS) units (MinimaxX, Catapult, Australia; SPI-10, SPI-Pro, GPSports, Australia) were quantified. Twenty trials of cricket-specific locomotion patterns and distances (walking 8800 m, jogging 2400 m, running 1200 m, striding 600 m, sprinting 20- to 40-m intervals, and run-a-three) were compared against criterion measures (400-m athletic track, electronic timing). Validity was quantified with the standard error of the estimate (SEE) and reliability estimated using typical error expressed as a coefficient of variation. The validity (mean +/- 90% confidence limits) for locomotion patterns walking to striding ranged from 0.4 +/- 0.1 to 3.8 +/- 1.4%, whereas for sprinting distances over 20 to 40 m including run-a-three (approx. 50 m) the SEE ranged from 2.6 +/- 1.0 to 23.8 +/- 8.8%. The reliability (expressed as mean [90% confidence limits]) of estimating distance traveled by walking to striding ranged from 0.3 (0.2 to 0.4) to 2.9% (2.3 to 4.0). Similarly, mean reliability of estimating different sprinting distances over 20 to 40 m ranged from 2.0 (1.6 to 2.8) to 30.0% (23.2 to 43.3). The accuracy and bias was dependent on the GPS brand employed. Commercially available GPS units have acceptable validity and reliability for estimating longer distances (600-8800 m) in walking to striding, but require further development for shorter cricket-specific sprinting distances.


[Construction of expression vector pLCK-CD69-IRES-EGFP and generation of CD69 transgenic mice].
To construct the expression vector pLCK-CD69-IRES-EGFP that contains mouse cell surface activation protein CD69 and enhanced green fluorescent protein(EGFP),and to generate CD69 transgenic mice based on this vector. First, RNA was extracted from mouse lung tissue and cDNA was synthesized via reverse transcription. PCR primer was designed through the PubMed searching, then mouse CD69 DNA fragment was amplified with PCR. Second, this DNA fragment was subcloned to the pInsulater-LCK-IRES-EGFP plasmid and constructed the transgenic vector after the verification of nucleotide sequence. Third, the expression vector was then transfected into 293 T cells and its expression in 293 T cells was observed under fluorescence microscope. Last, microinjection was performed to transfer the expression vector pLCK-CD69-IRES-EGFP into fertilized eggs, which were implanted into pseudo-pregnant recipient mice. After birth the tail samples of the pups were obtained for the purpose of genotyping to determine the transgenic founders. Fluorescence microscope and flow cytometer were used to measure the expression of CD69 on cells. The construction of the expression vector pLCK-CD69-IRES-EGFP was verified by enzyme digestion and DNA sequencing. The transfected 293 T cell showed expression of the protein under fluorescence microscope. Identification of PCR for the tail tissue of the pups confirmed the present of CD69 transgene and resting lymphocytes demonstrated the expression of CD69. The construction of expression vector pLCK-CD69-IRES-EGFP and generation of CD69 transgenic mice have been successfully processed, which lays a foundation of the solid pattern studies in inflammatory diseases.


[Diagnosis and treatment of primary liver cancer].
The study group included 43 patients with primary liver cancer. Hepatocellular cancer was detected in 31 cases, cholangiocellular cancer--12, solitary form of tumor--12, nodular--25 and diffuse--in 6 cases. Such procedures as scanning, hepatography involving inflation of the stomach and colon, peritoneography, laparoscopy and examination of vascular system were employed in diagnosis. Out of 34 surgically-treated patients, 7 were operated on radically. Seven patients died postoperatively.


Robust classifiers for data reduced via random projections.
The computational cost for most classification algorithms is dependent on the dimensionality of the input samples. As the dimensionality could be high in many cases, particularly those associated with image classification, reducing the dimensionality of the data becomes a necessity. The traditional dimensionality reduction methods are data dependent, which poses certain practical problems. Random projection (RP) is an alternative dimensionality reduction method that is data independent and bypasses these problems. The nearest neighbor classifier has been used with the RP method in classification problems. To obtain higher recognition accuracy, this study looks at the robustness of RP dimensionality reduction for several recently proposed classifiers--sparse classifier (SC), group SC (along with their fast versions), and the nearest subspace classifier. Theoretical proofs are offered regarding the robustness of these classifiers to RP. The theoretical results are confirmed by experimental evaluations.


Lactosylceramide synthases encoded by B4galt5 and 6 genes are pivotal for neuronal generation and myelin formation in mice.
It is uncertain which β4-galactosyltransferase (β4GalT; gene name, B4galt), β4GalT-5 and/or β4GalT-6, is responsible for the production of lactosylceramide (LacCer) synthase, which functions in the initial step of ganglioside biosynthesis. Here, we generated conditional B4galt5 knockout (B4galt5 cKO) mice, using Nestin-Cre mice, and crossed these with B4galt6 KO mice to generate B4galt5 and 6 double KO (DKO) mice in the central nervous system (CNS). LacCer synthase activity and major brain gangliosides were completely absent in brain homogenates from the DKO mice, although LacCer synthase activity was about half its normal level in B4galt5 cKO mice and B4galt6 KO mice. The DKO mice were born normally but they showed growth retardation and motor deficits at 2 weeks and died by 4 weeks of age. Histological analyses showed that myelin-associated proteins were rarely found localized in axons in the cerebral cortex, and axonal and myelin formation were remarkably impaired in the spinal cords of the DKO mice. Neuronal cells, differentiated from neurospheres that were prepared from the DKO mice, showed impairments in neurite outgrowth and branch formation, which can be explained by the fact that neurospheres from DKO mice could weakly interact with laminin due to lack of gangliosides, such as GM1a. Furthermore, the neurons were immature and perineuronal nets (PNNs) were poorly formed in DKO cerebral cortices. Our results indicate that LacCer synthase is encoded by B4galt5 and 6 genes in the CNS, and that gangliosides are indispensable for neuronal maturation, PNN formation, and axonal and myelin formation.


Retrospective evaluation of the prognostic utility of quick sequential organ failure assessment scores in dogs with surgically treated sepsis (2011-2018): 204 cases.
To assess the prognostic utility of admission quick Sequential Organ Failure Assessment (qSOFA) scores for in-hospital mortality in a population of dogs with surgically treated sepsis. Retrospective cohort study of dogs from January 2011 to January 2018. University teaching hospital. One thousand three hundred nine cases were identified with a clinical diagnosis of sepsis requiring surgical source control. Two hundred and four dogs with surgically treated sepsis met inclusion criteria, defined as: meeting 2 or more systemic inflammatory response syndrome (SIRS) criteria with a documented source of infection. One hundred and forty-three cases of septic peritonitis, 26 cases of septic soft tissue infection, 20 cases of pyometra, and 15 cases of pyothorax were evaluated. None. Overall in-hospital mortality was 63 of 204 (30.9%). Patients with a qSOFA ≥ 2 were more likely to die or be euthanized (odds ratio [OR] 7.1, 95% confidence interval [CI] 2.9-16.4; P < 0.0001). Survivor and nonsurvivor qSOFA scores were significantly different in all categories. Dogs with septic peritonitis and a qSOFA ≥ 2 had an increased risk of postoperative complications (OR 3.9; 95% CI 1.3-11.1; P = 0.02). qSOFA scores were correlated with length of hospitalization in survivors of all-cause surgical sepsis (r = 0.28, P = 0.0007), septic peritonitis (r = 0.33, P = 0.001), and septic soft tissue infection (r = 0.59, P = 0.004). This was the first study to retrospectively evaluate the prognostic utility of qSOFA scores in dogs surgically treated for sepsis. Dogs diagnosed with septic peritonitis and other causes of surgically treated sepsis with a qSOFA ≥ 2 may have a higher risk of in-hospital mortality, although future prospective studies are necessary.


A metabolic reconstruction of Lactobacillus reuteri JCM 1112 and analysis of its potential as a cell factory.
Lactobacillus reuteri is a heterofermentative Lactic Acid Bacterium (LAB) that is commonly used for food fermentations and probiotic purposes. Due to its robust properties, it is also increasingly considered for use as a cell factory. It produces several industrially important compounds such as 1,3-propanediol and reuterin natively, but for cell factory purposes, developing improved strategies for engineering and fermentation optimization is crucial. Genome-scale metabolic models can be highly beneficial in guiding rational metabolic engineering. Reconstructing a reliable and a quantitatively accurate metabolic model requires extensive manual curation and incorporation of experimental data. A genome-scale metabolic model of L. reuteri JCM 1112T was reconstructed and the resulting model, Lreuteri_530, was validated and tested with experimental data. Several knowledge gaps in the metabolism were identified and resolved during this process, including presence/absence of glycolytic genes. Flux distribution between the two glycolytic pathways, the phosphoketolase and Embden-Meyerhof-Parnas pathways, varies considerably between LAB species and strains. As these pathways result in different energy yields, it is important to include strain-specific utilization of these pathways in the model. We determined experimentally that the Embden-Meyerhof-Parnas pathway carried at most 7% of the total glycolytic flux. Predicted growth rates from Lreuteri_530 were in good agreement with experimentally determined values. To further validate the prediction accuracy of Lreuteri_530, the predicted effects of glycerol addition and adhE gene knock-out, which results in impaired ethanol production, were compared to in vivo data. Examination of both growth rates and uptake- and secretion rates of the main metabolites in central metabolism demonstrated that the model was able to accurately predict the experimentally observed effects. Lastly, the potential of L. reuteri as a cell factory was investigated, resulting in a number of general metabolic engineering strategies. We have constructed a manually curated genome-scale metabolic model of L. reuteri JCM 1112T that has been experimentally parameterized and validated and can accurately predict metabolic behavior of this important platform cell factory.


Overactive Bladder Patients With and Without Urgency Incontinence: A Spectrum of One Condition or Different Phenotypes?
The importance of this study is to explore potential differences in pathophysiologies of OAB-wet and OAB-dry. The aim of this study was to define fundamental and unique presenting features of patients exhibiting storage lower urinary tract symptoms (LUTS) with urgency incontinence (OAB-wet) and patients without urgency incontinence (OAB-dry). This was a secondary analysis of cross-sectional data from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases-sponsored Symptoms of Lower Urinary Tract Dysfunction Research Network. Demographic, physical examination, and questionnaire responses were analyzed for women seeking care for LUTS at 6 U.S. centers. Differences between OAB-wet and OAB-dry patients were compared using the Fisher exact test and Mann-Whitney U test. Differences in questionnaire data were assessed using a Benjamini-Hochberg false discovery rate correction. Fifty-six, 84, and 67 women were included in the OAB-dry, wet, and control cohorts, respectively. There was no difference in demographic and physical examination characteristics of the 2 groups. OAB-wet patients reported more urgency incontinence symptoms (LUTS 16a, P < 0.001). OAB-dry reported more bladder pain, feeling of incomplete bladder emptying (LUTS 4, P < 0.001), and a need to strain to urinate (AUA-SI 7, P = 0.003). Sensation of incomplete emptying and straining with urination did not correlate with elevated postvoid residual volumes. Although degrees of symptomatic bother were similar, bother in OAB-dry patients was most closely related to pelvic floor tenderness severity, whereas bother in OAB-wet patients was most related to urgency severity. Women with OAB-dry have distinct presenting features of straining with urination, bladder pain, and a feeling of incomplete emptying. These suggest a unique pathophysiology driving OAB-dry symptoms, which we hypothesize is pelvic floor myofascial dysfunction.


BARREN STALK FASTIGIATE1 is an AT-hook protein required for the formation of maize ears.
Ears are the seed-bearing inflorescences of maize (Zea mays) plants and represent a crucial component of maize yield. The first step in the formation of ears is the initiation of axillary meristems in the axils of developing leaves. In the classic maize mutant barren stalk fastigiate1 (baf1), first discovered in the 1950s, ears either do not form or, if they do, are partially fused to the main stalk. We positionally cloned Baf1 and found that it encodes a transcriptional regulator containing an AT-hook DNA binding motif. Single coorthologs of Baf1 are found in syntenic regions of brachypodium (Brachypodium distachyon), rice (Oryza sativa), and sorghum (Sorghum bicolor), suggesting that the gene is likely present in all cereal species. Protein-protein interaction assays suggest that BAF1 is capable of forming homodimers and heterodimers with other members of the AT-hook family. Another transcriptional regulator required for ear initiation is the basic helix-loop-helix protein BARREN STALK1 (BA1). Genetic and expression analyses suggest that Baf1 is required to reach a threshold level of Ba1 expression for the initiation of maize ears. We propose that Baf1 functions in the demarcation of a boundary region essential for the specification of a stem cell niche.


A mammalian homolog of Drosophila melanogaster transcriptional coactivator intersex is a subunit of the mammalian Mediator complex.
The multiprotein Mediator complex is a coactivator required for transcriptional activation of RNA polymerase II transcribed genes by DNA binding transcription factors. We previously partially purified a Med8-containing Mediator complex from rat liver nuclei (Brower, C. S., Sato, S., Tomomori-Sato, C., Kamura, T., Pause, A., Stearman, R., Klausner, R. D., Malik, S., Lane, W. S., Sorokina, I., Roeder, R. G., Conaway, J. W., and Conaway, R. C. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 10353-10358). Analysis of proteins present in the most highly enriched Mediator fractions by tandem mass spectrometry led to the identification of several new mammalian Mediator subunits, as well as several potential Mediator subunits. Here we identify one of these proteins, encoded by the previously uncharacterized AK000411 open reading frame, as a new subunit of the mammalian Mediator complex. The AK000411 protein, which we designate hIntersex (human Intersex), shares significant sequence similarity with the Drosophila melanogaster intersex protein, which has functional properties expected of a transcriptional coactivator specific for the Drosophila doublesex transactivator. In addition, we show that hIntersex assembles into a subcomplex with Mediator subunits p28b and TRFP. Taken together, our findings identify a new subunit of the mammalian Mediator and shed new light on the architecture of the mammalian Mediator complex.


Inflammatory Myopathy in Horses With Chronic Piroplasmosis.
Horses affected by chronic piroplasmosis may develop poor performance and muscle atrophy. Here we investigate the pathological and immunopathological aspects of myopathy occurring in chronic equine piroplasmosis. The study included 16 horses serologically positive for equine piroplasms presenting with clinical signs and supporting serum biochemical evidence of a myopathy. Skeletal muscle was evaluated by histopathology, immunohistochemistry, indirect immunofluorescence, and molecular detection of piroplasms and inflammatory cytokines in skeletal muscle. Histologic lesions included muscle fiber atrophy (100% of cases), degenerative changes (13/16, 81%), and perivascular perimysial and endomysial lymphocytic infiltrates (81% of cases). In 15 cases (94%), muscle fibers had strong immunostaining for major histocompatibility complex classes I and II. T lymphocyte populations were mainly CD3+, CD8+, and CD4+ in equal proportions, with a lower number of CD79α+ cells. The serum from affected horses was tested by indirect immunofluorescence for binding of IgG, IgM, or IgA to sections of normal equine muscle to detect circulating autoantibodies against muscle antigen(s). In all cases, distinct sarcolemmal staining was detected in sections incubated with serum from affected horses, in contrast to sections incubated with phosphate-buffered saline or equine control sera. Reverse transcription polymerase chain reaction (RT-PCR) testing of muscles from affected animals revealed a significant increase of interferon-γ, interleukin-12, and tumor necrosis factor-α gene expression compared to healthy controls. Theileria equi or Babesia caballi was not detected in samples of affected muscle by RT-PCR. Thus, inflammatory myopathy associated with equine piroplasmosis may involve an autoimmune pathogenesis with upregulation of inflammatory cytokines that may cause myofiber atrophy and degeneration.


ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
In clinical exome and genome sequencing, there is a potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing that emphasized the importance of alerting the patient to the possibility of such results in pretest patient discussions, clinical testing, and reporting of results. The ACMG appointed a Working Group on Incidental Findings in Clinical Exome and Genome Sequencing to make recommendations about responsible management of incidental findings when patients undergo exome or genome sequencing. This Working Group conducted a year-long consensus process, including an open forum at the 2012 Annual Meeting and review by outside experts, and produced recommendations that have been approved by the ACMG Board. Specific and detailed recommendations, and the background and rationale for these recommendations, are described herein. The ACMG recommends that laboratories performing clinical sequencing seek and report mutations of the specified classes or types in the genes listed here. This evaluation and reporting should be performed for all clinical germline (constitutional) exome and genome sequencing, including the "normal" of tumor-normal subtractive analyses in all subjects, irrespective of age but excluding fetal samples. We recognize that there are insufficient data on penetrance and clinical utility to fully support these recommendations, and we encourage the creation of an ongoing process for updating these recommendations at least annually as further data are collected.


Metastatic Conditioning of Myeloid Cells at a Subcutaneous Synthetic Niche Reflects Disease Progression and Predicts Therapeutic Outcomes.
Monitoring metastatic events in distal tissues is challenged by their sporadic occurrence in obscure and inaccessible locations within these vital organs. A synthetic biomaterial scaffold can function as a synthetic metastatic niche to reveal the nature of these distal sites. These implanted scaffolds promote tissue ingrowth, which upon cancer initiation is transformed into a metastatic niche that captures aggressive circulating tumor cells. We hypothesized that immune cell phenotypes at synthetic niches reflect the immunosuppressive conditioning within a host that contributes to metastatic cell recruitment and can identify disease progression and response to therapy. We analyzed the expression of 632 immune-centric genes in tissue biopsied from implants at weekly intervals following inoculation. Specific immune populations within implants were then analyzed by single-cell RNA-seq. Dynamic gene expression profiles in innate cells, such as myeloid-derived suppressor cells, macrophages, and dendritic cells, suggest the development of an immunosuppressive microenvironment. These dynamics in immune phenotypes at implants was analogous to that in the diseased lung and had distinct dynamics compared with blood leukocytes. Following a therapeutic excision of the primary tumor, longitudinal tracking of immune phenotypes at the implant in individual mice showed an initial response to therapy, which over time differentiated recurrence versus survival. Collectively, the microenvironment at the synthetic niche acts as a sentinel by reflecting both progression and regression of disease. SIGNIFICANCE: Immune dynamics at biomaterial implants, functioning as a synthetic metastatic niche, provides unique information that correlates with disease progression. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/3/602/F1.large.jpg.See related commentary by Wolf and Elisseeff, p. 377.


The small-caliber esophagus: radiographic sign of idiopathic eosinophilic esophagitis.
To evaluate a small-caliber esophagus at barium esophagography with idiopathic eosinophilic esophagitis (IEE) and determine if there is a useful threshold diameter for suggesting this diagnosis. The institutional review board approved this retrospective study and waived informed consent. This study was HIPAA compliant. A search of the radiology database (by using the search term small-caliber esophagus) revealed 10 patients with a small-caliber esophagus at barium esophagography who had IEE (defined as more than 20 eosinophils per high-power field in endoscopic biopsy specimens). Images were reviewed to characterize findings and determine the length of narrowing. Luminal diameters were measured at three levels for nine patients and nine control subjects, and mean diameter, range, and standard deviation were determined at each level. An analysis of variance test was performed to determine whether the difference between the range of mean thoracic esophageal diameters in patients with IEE versus that in control subjects was significant. All 10 patients had long-segment but variable-length narrowing of the thoracic esophagus (mean length, 15.4 cm) with tapered margins. The mean diameter at the aortic arch, carina, and one vertebral body above the gastroesophageal junction was 13.9, 14.3, and 15.1 mm, respectively, for patients with small-caliber esophagus versus 20.2, 30.3, and 28.7 mm for control subjects. The mean overall diameter was 14.7 mm for patients with small-caliber esophagus versus 26.3 mm for control subjects. In the nine patients in whom the luminal diameter was measured, the mean thoracic esophageal diameter was 20 mm or less; all nine control subjects had a mean thoracic esophageal diameter greater than 20 mm. The difference in the range of mean thoracic esophageal diameters between these two groups was highly significant (P < .0001), so 20 mm was a useful threshold diameter for suggesting this diagnosis. The small-caliber esophagus of IEE is characterized at barium esophagography by long-segment but variable-length narrowing of the thoracic esophagus, with a mean length of 15.4 cm, a diameter of 20 mm or less, smooth contours, and tapered margins.


Structure and dynamic properties of membrane proteins using NMR.
Integral membrane proteins are one of the most challenging groups of macromolecules despite their apparent conformational simplicity. They manage and drive transport, circulate information, and participate in cellular movements via interactions with other proteins and through intricate conformational changes. Their structural and functional decoding is challenging and has imposed demanding experimental development. Solution nuclear magnetic resonance (NMR) spectroscopy is one of the techniques providing the capacity to make a significant difference in the deciphering of the membrane protein structure-function paradigm. The method has evolved dramatically during the last decade resulting in a plethora of new experiments leading to a significant increase in the scientific repertoire for studying membrane proteins. Besides solving the three-dimensional structures using state-of-the-art approaches, a large variety of developments of well-established techniques are available providing insight into membrane protein flexibility, dynamics, and interactions. Inspired by the speed of development in the application of new strategies, by invention of methods to measure solvent accessibility and describe low-populated states, this review seeks to introduce the vast possibilities solution NMR can offer to the study of membrane protein structure-function analyses with special focus on applicability.


Efficacy of Telitacicept in a systemic lupus erythematosus patient with suboptimal response to Belimumab: A case report.
As a therapeutic treatment for systemic lupus erythematosus (SLE), Belimumab reduces disease relapses and minimizes organ damage. Clinical practice, however, shows that the treatment is ineffective for a number of patients. Treatments for such cases are still lacking. As a biologic agent that targets both BLys and APRIL, Telitacicept inhibits both B cells and plasma cells. This case report describes a 35-year-old female with lupus nephritis (LN) who had previously undergone 10 cycles of Belimumab treatment but remained poorly controlled. Despite this, her condition improved significantly after switching to Telitacicept. This is the first report on the efficacy of Telitacicept in an SLE patient with suboptimal response to Belimumab. Telitacicept's role in this scenario needs more investigation and attention.


Community perceptions on malaria and care-seeking practices in endemic Indian settings: policy implications for the malaria control programme.
The focus of India's National Malaria Programme witnessed a paradigm shift recently from health facility to community-based approaches. The current thrust is on diagnosing and treating malaria by community health workers and prevention through free provision of long-lasting insecticidal nets. However, appropriate community awareness and practice are inevitable for the effectiveness of such efforts. In this context, the study assessed community perceptions and practice on malaria and similar febrile illnesses. This evidence base is intended to direct the roll-out of the new strategies and improve community acceptance and utilization of services. A qualitative study involving 26 focus group discussions and 40 key informant interviews was conducted in two districts of Odisha State in India. The key points of discussion were centred on community perceptions and practice regarding malaria prevention and treatment. Thematic analysis of data was performed. The 272 respondents consisted of 50% females, three-quarter scheduled tribe community and 30% students. A half of them were literates. Malaria was reported to be the most common disease in their settings with multiple modes of transmission by the FGD participants. Adoption of prevention methods was seasonal with perceived mosquito density. The reported use of bed nets was low and the utilization was determined by seasonality, affordability, intoxication and alternate uses of nets. Although respondents were aware of malaria-related symptoms, care-seeking from traditional healers and unqualified providers was prevalent. The respondents expressed lack of trust in the community health workers due to frequent drug stock-outs. The major determinants of health care seeking were socio-cultural beliefs, age, gender, faith in the service provider, proximity, poverty, and perceived effectiveness of available services. Apart from the socio-cultural and behavioural factors, the availability of acceptable care can modulate the community perceptions and practices on malaria management. The current community awareness on symptoms of malaria and prevention is fair, yet the prevention and treatment practices are not optimal. Promoting active community involvement and ownership in malaria control and management through strengthening community based organizations would be relevant. Further, timely availability of drugs and commodities at the community level can improve their confidence in the public health system.