Changes in treatment for multidrug-resistant tuberculosis according to national income.
The aim of this study was to analyse temporal changes in treatments for and outcomes of multidrug-resistant (MDR)/rifampin-resistant (RR)-tuberculosis (TB) in the context of national economic status.We analysed data collected by the Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB Treatment on MDR/RR-TB patients from 37 countries. The data were stratified by three national income levels (low-/lower-middle, upper-middle and high) and grouped by time of treatment initiation (2001-2003, 2004-2006, 2007-2009, 2010-2012 and 2013-2015). Temporal trends over the study period were analysed. The probability of treatment success in different income groups over time was calculated using generalised linear mixed models with random effects.In total, 9036 patients were included in the analysis. Over the study period, use of group A drugs (levofloxacin/moxifloxacin, bedaquiline and linezolid) recommended by the World Health Organization increased and treatment outcomes improved in all income groups. Between 2001-2003 and 2013-2015, treatment success rates increased from 60% to 78% in low-/lower-middle-income countries, from 40% to 67% in upper-middle-income countries, and from 73% to 81% in high-income countries. In earlier years, the probability of treatment success in upper-middle-income countries was lower than that in low-/lower-middle-income countries, but no difference was observed after 2010. However, high-income countries had persistently higher probability of treatment success compared to upper-middle income countries.Improved treatment outcomes and greater uptake of group A drugs were observed over time for patients with MDR/RR-TB at all income levels. However, treatment outcomes are still unsatisfactory, especially in upper-middle-income countries.


Europium nanoparticle-based high performing immunoassay for the screening of treponemal antibodies.
Treponema pallidum subspecies pallidum (Tp) is the causative agent of syphilis which mainly spreads through sexual contact, blood transfusion and perinatal route. In order to curtail the spread of the infection and to clinically manage the disease, timely, accurate and reliable diagnosis is very important. We have developed an immunoassay for the detection of treponemal antibodies in human serum or plasma samples. In vivo biotinylated and non-biotinylated versions of the recombinant antigen were designed by the fusion of three Tp-specific antigens namely Tp15, Tp17 and Tp47. These fusion antigens were expressed in E. coli and purified using single-step metal affinity chromatography. Biotinylated fusion antigen immobilized on streptavidin coated plate was used to capture the treponemal antibodies and the non-biotinylated antigen coated on europium nanoparticles was used as tracer. Assays with two different incubation times of 10 min and 1 h were developed, and following the incubation the europium fluorescence was measured using time-resolved fluorometry. The developed time-resolved fluorometric (TRF) immunoassays were evaluated with in-house and commercial serum/plasma sample panels. For well-established treponemal antibodies positive or negative samples, the sensitivity of TRF immunoassay with 10 min incubation time was 97.4%, and of TRF immunoassay with 1 h incubation time was 98.7%, and the specificities of both the TRF immunoassays were 99.2%. For the samples with discordant results with the reference assays, both the TRF immunoassays showed better specificity than the Enzygnost syphilis enzyme immunoassay as a screening test. The two different incubation times did not have any significant effect on the signal to cutoff (S/Co) ratios obtained with the two immunoassays (p=0.06). Our results indicate that the developed immunoassay with a short incubation time of 10 min has the potential to be used in clinical laboratories and in blood-bank settings as a screening test for treponemal antibodies.


Human rights and rehabilitation outcomes.
The aim of this article is to introduce rehabilitation professionals to the rapidly growing literature on human rights particularly as it relates to health and rehabilitation. The article aims to stimulate further discussion and debate concerning the place of human rights in rehabilitation practice. Some important milestones in the recent history of the human rights movement are briefly outlined, and some important terms in the rights literature are explained. The Ward and Birgden model of the structure of human rights is then described as an example of a rights perspective that might have particular relevance for health and social services and rehabilitation. A rehabilitation case study is presented as an example of how the Ward and Birgden model could have practical relevance when deciding on the most important outcomes for an individual in rehabilitation. Human rights are playing an increasing role in the struggle to improve health and healthcare globally. They also have important implications for rehabilitation practitioners and researchers and should form the core of any ethical framework for rehabilitation. It might even be argued that rights and dignity are themselves valued outcomes for rehabilitation.


Deducing CO2 motion, adsorption locations and binding strengths in a flexible metal-organic framework without open metal sites.
Microporous metal-organic frameworks (MOFs) have high surface areas and porosities, and are well-suited for CO2 capture. MIL-53 features corner-sharing MO4(OH)2 (M = Al, Ga, Cr, etc.) octahedra interconnected by benzenedicarboxylate linkers that form one-dimensional rhombic tunnels, and exhibits an excellent adsorption ability for guest molecules such as CO2. Studying the behavior of adsorbed CO2 in MIL-53 via solid-state NMR (SSNMR) provides rich information on the dynamic motion of guest molecules as well as their binding strengths to the MOF host, and sheds light on the specific guest adsorption mechanisms. Variable-temperature (13)C SSNMR spectra of (13)CO2 adsorbed within various forms of MIL-53 are acquired and analyzed. CO2 undergoes a combination of two motions within MIL-53; we report the types of motion present, their rates, and rotational angles. (1)H-(13)C CP SSNMR experiments are used to examine the proximity of (1)H atoms in the MOF to (13)C atoms in CO2 guests. By replacing (1)H with (2)H in MIL-53, the location of the CO2 adsorption site in MIL-53 is experimentally confirmed by (1)H-(13)C CP SSNMR. The binding strength of CO2 within these MIL-53 MOFs follows the order MIL-53-NH2 (Al) > MIL-53-NH2 (Ga) > MIL-53 (Al) > MIL-53 (Ga).


Development of platelet inhibition by cAMP during megakaryocytopoiesis.
Prostacyclin is a potent inhibitor of agonist-induced Ca2+ increases in platelets, but in the megakaryocytic cell line MEG-01 this inhibition is absent. Using human megakaryocytic cell lines representing different stages in megakaryocyte (Mk) maturation as well as stem cells and immature and mature megakaryocytes, we show that the inhibition by prostacyclin develops at a late maturation stage shortly before platelets are formed. This late appearance is not caused by insufficient cAMP formation or absent protein kinase A (PKA) activity in immature cells. Instead, the appearance of Ca2+ inhibition by prostacyclin is accompanied by a sharp increase in the expression of the catalytic subunit of PKA (PKA-C) but not by changes in the expression of the PKA-regulatory subunits Ialpha/beta, IIalpha, and IIbeta. Overexpression of PKA-C in the megakaryocytic cell line CHRF-288-11 potentiates the Ca2+ inhibition by prostacyclin. Thus, up-regulation of PKA-C appears to be a key step in the development of Ca2+ inhibition by prostacyclin in platelets.


One year in review 2020: vasculitis.
Systemic vasculitides are a group of diseases that could potentially affect any organ with heterogeneous clinical manifestations that usually depend on the size of the most involved vessels. These diseases could be associated with a relevant burden of mortality and morbidity if not early recognised and treated. Moreover, even if they are usually rare diseases, their incidence and prevalence seem to be increasing in the last decade, partially because of improved awareness and management of vasculitis from physicians. Like in the previous annual reviews of this series, in this paper we revised the most recent literature on pathogenesis, clinical manifestations and treatment options in small- and large-vessel vasculitis.


The Conflict in East Ukraine: A Growing Need for Addiction Research and Substance Use Intervention for Vulnerable Populations.
Security and trauma challenges in Ukraine have been constantly evolving since the 2014 Russian military incursion of Crimea and War in Donbass. One long-term consequence of the conflict in East Ukraine is the toll of substance and alcohol use and addictions that may have been triggered by the conflict among the veterans, internally displaced peoples, and civilian survivors. Further funding and research on substance and alcohol addiction with these vulnerable populations affected by the ongoing Ukrainian conflict should be examined. Are people from fragile states and conflict zones more susceptible to co-morbidity with substance abuse and addiction?


MIXED MATING SYSTEMS IN HAWAIIAN BIDENS (ASTERACEAE).
Floral features related to the breeding system were studied for 11 species of Hawaiian Bidens. Protandry and male sterility promote outcrossing, while self-compatibility and geitonogamy contribute to inbreeding. The combination of these floral mechanisms results in a mixed mating system in all species studied. Outcrossing rates of 15 populations of these species ranged from 0.43 to 0.88, averaging 0.65. Apparent selling rates of females ranged from 0 to 0.25 in seven gynodioecious populations surveyed, suggesting that there is variation in the level of biparental inbreeding among populations. The presence of females increased the level of outcrossing by an average of 9% in gynodioecious populations. This study indicates that the efficiency of gynodioecy as an outcrossing mechanism largely depends on the current outcrossing rate of hermaphrodites, the frequency of females, and the extent of genetic substructuring in populations. On average, autogamy contributed 4%, geitonogamy contributed 24%, and consanguineous mating contributed 15% to the realized selfing rate (43%) in the hermaphrodites of these species.


Discovery of the role of wall shear in atherosclerosis.
The suggestion was made in the 1870s that mechanical irritation of the arterial wall is a cause of atherosclerosis, because the changes were chiefly found at points "exposed to the full stress and impact of the blood." The mechanical damage theory persisted until well into the 20th century when, with interest increasing in multidisciplinary research, two fluid mechanical proposals were advanced for the patchy distribution of the lesions. One advocated high- and the other low-wall shear. Arterial wall shear stress levels appeared, however, insufficiently high to damage the endothelium. In contrast, examination of cadaver human arteries, combined with flow studies in models and casts of arteries, implied that the lesions occurred preferentially in regions expected to experience low-wall shear; a mechanism, involving arterial wall lipid metabolism and shear-dependent blood-wall mass transport, was suggested to account for that distribution. These proposals helped stimulate extensive investigation of arterial fluid mechanics/mass transport and vascular biology/pathology, revealing mechanisms that may explain the now widely confirmed preferred occurrence of atherosclerosis in low wall shear regions in adult human beings.


The Invisible Burden of Violence Against Girls and Young Women in Mexico: 1990 to 2015.
The increasing burden of interpersonal violence in women in Mexico is a neglected social and health problem that competes with other leading causes of premature death, disability, and health losses in young women. In this article, we focus on revealing the burden of violence in girls and young women and its implications for public policy. This study presents the subnational analysis of Mexico from the Global Burden of Disease study (1990-2015). The global study harmonized information of 195 countries and 79 risk factors. The study analyzed the deaths, years of life lost to premature death (YLL), years lived with disability (YLD), and the healthy years of life lost or disability-adjusted life year (DALY) related to violence. Nationwide, violence in young women accounts for 7% of all deaths in the 10 to 29 years age group and arises as the second most important cause of death in all age groups, except 10 to 14 years old, where it stands in the seventh position from 1990 to 2015. The health losses and social impact related to violence in young women demands firm actions by the government and society. It is urgent for health institutions to focus on the health of girls and young women because gender inequities have an enormous effect on their lives. Girls and women are nearly universally less powerful, less privileged, and have fewer opportunities than men.


Microwave-assisted synthesis, anticonvulsant activity and quantum mechanical modelling of N-(4-bromo-3-methylphenyl) semicarbazones.
To study the effect of halo substitution on disubstituted aryl semicarbazones on the anticonvulsant potential and model the activity based on quantum mechanics. A series of twenty-six compounds of N(4)-(4-bromo-3-methylphenyl) semicarbazones were synthesized and evaluated for the anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. Some potential compounds were also tested in the subcutaneous strychnine (scSTY) and subcutaneous picrotoxin (scPIC) seizure threshold tests. The synthesized compounds were tested for behavioral impairment and CNS (central nervous system) depression in mice. Quantum mechanical modelling was carried out on these compounds to gain understanding on the structural features essential for activity. Some compounds possessed broad spectrum anticonvulsant activity as indicated by their effect in pentylenetetrazole, strychnine, picrotoxin and maximal electroshock seizures models in resemblance to other aryl semicarbazone derivatives reported earlier. The higher the difference in HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) energy levels was, the greater was the activity profile. The pharmacophoric requirements for compounds to exhibit anticonvulsant activity that includes one aryl unit in proximity to a hydrogen donor-acceptor domain and an electron donor have been justified with the molecular orbital surface analysis of the synthesized compounds.


Experimental investigation of pneumatic soil vapor extraction.
Soil Vapor Extraction (SVE) is a common remediation technique for removing volatile organic compounds from unsaturated contaminated soils. Soil heterogeneities can however cause serious limitations to the applicability of SVE due to air bypassing low permeable areas of the soil, leading to diffusion limitation of the remediation. To enhance removal from areas subject to diffusion limitation a new remediation technique, pneumatic soil vapor extraction, is proposed. In contrast to traditional SVE, in which soil vapor is extracted continuously by a vacuum pump, pneumatic SVE is based on enforcing a sequence of large pressure drops on the system to enhance the recovery from the low-permeable areas. The pneumatic SVE technique was investigated in the laboratory using TCE as a model contaminant. 2D-laboratory tank experiments were performed on homogeneous and heterogeneous sand packs. The heterogeneous packs consisted of a fine sand lens surrounded by a coarser sand matrix. As expected when using traditional SVE, the removal of TCE from the low permeable lens was extremely slow and subject to diffusion limitation. In contrast when pneumatic venting was used removal rates increased by up to 77%. The enhanced removal was hypothesized to be attributed to mixing of the contaminated air inside the lens and generation of net advective transport out of the lens due to air expansion.


The management of unstable angina and non-ST-segment elevation myocardial infartion.
Patients presenting with unstable angina and non-ST elevation myocardial infarction (UA/NSTEM) have a highly variable course. Optimal management is critical because of the high risk of death or myocardial infarction (MI) in the ensuing 30 days. In this article, we review the therapeutic options available to clinicians. Anti-ischemic therapy with beta-blockers and nitrates should be considered in all patients without contraindications. Aspirin remains a cornerstone of antiplatelet therapy and has been shown to substantially reduce the risk of death or MI. Although the data are less robust, unfractionated heparin (UFH) also appears to be efficacious, and the low-molecular-weight heparin (LMWH) enoxaparin appears to be superior to UFH. The GP IIb/IIIa inhibitors, highly beneficial in the setting of percutaneous coronary intervention (PCI), should be considered in patients with continuing ischemia or other high-risk features. The ADP receptor blocker clopidogrel has been shown to be beneficial in patients who are managed conservatively and in those who undergo PCI. Lastly, a strategy of early angiography should be considered in patients with recurrent ischemia or in those who present with high-risk features such as elevated troponins or ST deviation. Thus, early risk stratification using clinical features, electrocardiographic data, and biomarkers allows identification of subgroups of patients who are not only at high risk but also enjoy the greatest benefits from these aggressive therapies and thereby enables clinicians to target these interventions most effectively.


Positive efficacy of Lactiplantibacillus plantarum MH-301 as a postoperative adjunct to endoscopic sclerotherapy for internal hemorrhoids: a randomized, double-blind, placebo-controlled trial.
Background: Endoscopic sclerotherapy is a widely used minimally invasive procedure for internal hemorrhoids, yet postoperative symptoms remain a concern. The purpose of this study is to investigate the postoperative adjuvant efficacy of Lactiplantibacillus plantarum. Method: In this study, patients (≥18 years) with internal hemorrhoids that conformed to Goligher's classification of grade I-III received administration of L. plantarum MH-301 for 4 weeks following endoscopic sclerotherapy. The primary clinical endpoint in this study was the improvement rate, which was defined as the percentage of patients whose n-HDSS score decreased to 0 following the procedure. Stools were collected for high-throughput sequencing analysis post operation. Result: A total of 103 participants (51 in the LP group and 52 in the C group) were recruited, with 96 completing the entire trial (49 in the LP group and 47 in the C group). The primary clinical endpoint showed a higher improvement rate in the LP group (87.8% vs. 70.2%, P = 0.045). High-throughput sequencing analysis demonstrated that the LP group had a greater diversity of intestinal microbiota and a higher relative abundance of beneficial bacteria such as Bifidobacterium, Megamonas, and Lactobacillus. No significant difference in postoperative complications and adverse events was found. Conclusion: This paper concludes that the administration of L. plantarum MH-301 after endoscopic sclerotherapy can further increase the efficacy of the procedure and improve bowel movements. Regulation of intestinal microbiota may be the potential mechanism for the efficacy of L. plantarum MH-301.


Monitoring the lactic acid bacterial diversity during shochu fermentation by PCR-denaturing gradient gel electrophoresis.
The presence of lactic acid bacteria (LAB) during shochu fermentation was monitored by PCR-denaturing gradient gel electrophoresis (DGGE) and by bacteriological culturing. No LAB were detected from fermented mashes by PCR-DGGE using a universal bacterial PCR primer set. However, PCR-DGGE using a new primer specific for the 16S rDNA of Lactococcus, Streptococcus, Tetragenococcus, Enterococcus, and Vagococcus and two primers specific for the 16S rDNA of Lactobacillus, Pediococcus, Leuconostoc, and Weissella revealed that Enterococcus faecium, Lactobacillus casei, Lactobacillus fermentum, Lactobacillus nagelii, Lactobacillus plantarum, Lactococcus lactis, Leuconostoc citreum, Leuconostoc mesenteroides, and Weissella cibaria inhabited in shochu mashes. It was also found that the LAB community composition during shochu fermentation changed after the main ingredient and water were added during the fermentation process. Therefore, we confirmed that PCR-DGGE using all three primers specific for groups of LAB together was well suited to the study of the LAB diversity in shochu mashes. The results of DGGE profiles were similar to the results of bacteriological culturing. In conclusion, LAB are present during shochu fermentation but not dominant.


Hyperhomocysteinemia relates to the subtype of antiphospholipid antibodies in non-SLE patients.
Abnormal increases of antiphospholipid antibody and plasma homocysteine levels are recently emerging as nonlipidic risk factors for cerebral atherogenesis and thrombosis. Both antiphospholipid antibody and homocysteine share many similar bioeffects in hemostasis, but their interaction is still inconsistent. In this study, we examined the relation between the plasma homocysteine level and lupus anticoagulant, anticardiolipin antibody, and anti-beta2-glycoprotein I antibody in patients with noncardiac cerebral ischemia. Systemic lupus erythrematosus patients were excluded. The results showed a higher frequency of moderate hyperhomocysteinemia in patients with an abnormal increase of lupus anticoagulant only. Neither the serum folate and cobalamin levels nor methylenetetrahydrofolate reductase allele mutation contributes to this result. Accordingly, homocysteine interacts with lupus anticoagulant to promote cerebral atherosclerosis and ischemia. The role of vasculopathic or prothrombotic autoantibody generation in response to specific pathological change such as hyperhomocysteinemia warrants further investigation.


Meta-analysis of the efficacy of ebastine 20 mg compared to loratadine 10 mg and placebo in the symptomatic treatment of seasonal allergic rhinitis.
Few randomized studies have compared the efficacy of ebastine and loratadine in the symptomatic treatment of seasonal allergic rhinitis (SAR). A meta-analysis was performed on data from four randomized, double-blind, placebo-controlled, parallel-group clinical trials comparing the efficacy of ebastine 20 mg once daily versus loratadine 10 mg once daily in the symptomatic treatment of SAR symptoms. Primary efficacy variable was the mean change in the overall mean daily reflective total symptom score (TSS), i.e. the sum of five rhinitis symptom scores: nasal discharge, nasal congestion, nasal itching, sneezing and total eye symptoms (itchy/watery eyes) over the first 2 weeks of treatment compared to baseline. There were 2,089 patients in the population analyzed: 749, 739 and 601 patients in the ebastine 20 mg, loratadine 10 mg and placebo groups, respectively. Compared to baseline, overall mean daily reflective TSS over the first 2 weeks of treatment was -3.61 (35.4% reduction from baseline) in the ebastine group, -3.05 (29.0% reduction) in the loratadine group and -2.30 (22.7% reduction) in the placebo group. Statistically significant differences in the mean change from baseline were found when comparing ebastine and loratadine (p<0.001), ebastine and placebo (p<0.0001), and loratadine and placebo (p<0.0001). The global effect (i.e. the difference in overall mean daily reflective TSS over the first 2 weeks of treatment) of ebastine compared with loratadine over the first 2 weeks of treatment was -0.56 (95% confidence interval, CI, -0.86 to -0.26), and it was sustained during the whole (4-week) period studied. The global effects of ebastine and loratadine compared with placebo were -1.30 (95% CI, -1.61 to -0.99) and -0.74 (95% CI, -1.05 to -0.43), respectively. Secondary variables (reflective and snapshot individual symptom scores) showed the same trend. This meta-analysis confirms that ebastine 20 mg has a good efficacy profile, inducing a greater decrease from baseline in mean rhinitis symptom scores than loratadine 10 mg or placebo.


Cytokines involved in interferon-gamma production by human macrophages.
Interferon (IFN)-gamma is important to the immune defense against intracellular pathogens and specifically the ability of macrophages to control Mycobacterium tuberculosis (MTB). Increasing evidence has accumulated to support the idea that macrophages produce IFN-gamma. We describe here the cytokine interactions that determine IFN-gamma expression and secretion during MTB infection of human macrophages. Detection of biologically important IFN-gamma levels in culture supernatants of MTB-infected human macrophages requires the addition of interleukin (IL)-12. IL-18 augmented IFN-gamma production from human macrophages in response to the combination of MTB and supplemental IL-12. Although IL-18 gene expression was generally unchanged, IL-18 protein secretion was enhanced by the combination of MTB and IL-12, and functioned primarily to stimulate IFN-gamma release. Importantly, IL-27 induced by MTB infection opposed IFN-gamma production by antagonizing IL-18 activity in human macrophages. Neutralization of IL-27 increased the expression of the IL-18 receptor beta-chain. Additionally, IL-27 blocked NF-kappaB activation in response to IL-18. These results define the signals required for IFN-gamma production by human macrophages and highlight the interactions between cytokines produced during MTB infection. Together, they identify a novel role for IL-27 in regulating macrophage function by disrupting IL-18 activity.


A Fas-associated death domain protein/caspase-8-signaling axis promotes S-phase entry and maintains S6 kinase activity in T cells responding to IL-2.
Fas-associated death domain protein (FADD) constitutes an essential component of TNFR-induced apoptotic signaling. Paradoxically, FADD has also been shown to be crucial for lymphocyte development and activation. In this study, we report that FADD is necessary for long-term maintenance of S6 kinase (S6K) activity. S6 phosphorylation at serines 240 and 244 was only observed after long-term stimulation of wild-type cells, roughly corresponding to the time before S-phase entry, and was poorly induced in T cells expressing a dominantly interfering form of FADD (FADDdd), viral FLIP, or possessing a deficiency in caspase-8. Defects in S6K1 phosphorylation were also observed. However, defective S6K1 phosphorylation was not a consequence of a wholesale defect in mammalian target of rapamycin function, because 4E-BP1 phosphorylation following T cell activation was unaffected by FADDdd expression. Although cyclin D3 up-regulation and retinoblastoma hypophosphorylation occurred normally in FADDdd T cells, cyclin E expression and cyclin-dependent kinase 2 activation were markedly impaired in FADDdd T cells. These results demonstrate that a FADD/caspase-8-signaling axis promotes T cell cycle progression and sustained S6K activity.


Cost-effectiveness of physical activity programs and services for older adults: a scoping review.
Evidence supporting physical activity for older adults is strongly positive. Implementation and scale-up of these interventions need to consider the value for money. This scoping review aimed to assess the volume of (i) systematic review evidence regarding economic evaluations of physical activity interventions, and (ii) of cost utility analysis (CUA) studies (trial- or model-based) of physical activity interventions for older people. We searched five databases (January 2010 to February 2022) for systematic reviews of economic evaluations, and two databases (1976 to February 2022) for CUA studies of physical activity interventions for any population of people aged 60+ years. We found 12 potential reviews, two of which were eligible for inclusion. The remaining 10 reviews included eligible individual studies that were included in this review. All individual studies from the 12 reviews (n = 37) investigated the cost-effectiveness of structured exercise and most showed the intervention was more costly but more effective than no intervention. We identified 27 CUA studies: two investigated a physical activity promotion program and the remainder investigated structured exercise. Most interventions (86%) were more costly but more effective, and the remaining were cost-saving compared to no intervention. There is a scarcity of reviews investigating the value for money of physical activity interventions for older adults. Most studies investigated structured exercise. Physical activity interventions were generally more effective than no intervention but more costly. As such an intervention could be cost-effective and therefore worthy of wider implementation, but there is a need for more frequent economic evaluation in this field.


Mapping the cytochrome C folding landscape.
The solution to the riddle of how a protein folds is encoded in the conformational energy landscape for the constituent polypeptide. Employing fluorescence energy transfer kinetics, we have mapped the S.cerevisiae iso-1 cytochrome c landscape by monitoring the distance between a C-terminal fluorophore and the heme during folding. Within 1 ms after denaturant dilution to native conditions, unfolded protein molecules have evolved into two distinct and rapidly equilibrating populations: a collection of collapsed structures with an average fluorophore-heme distance (r) of 27 A and a roughly equal population of extended polypeptides with r > 50 A. Molecules with the native fold appear on a time scale regulated by heme ligation events ( approximately 300 ms, pH 7). The experimentally derived landscape for folding has a narrow central funnel with a flat upper rim on which collapsed and extended polypeptides interchange rapidly in a search for the native structure.


Mitotic kinesin Eg5 overcomes inhibition to the phase I/II clinical candidate SB743921 by an allosteric resistance mechanism.
Development of drug resistance during cancer chemotherapy is one of the major causes of chemotherapeutic failure for the majority of clinical agents. The aim of this study was to investigate the underlying molecular mechanism of resistance developed by the mitotic kinesin Eg5 against the potent second-generation ispinesib analogue SB743921 (1), a phase I/II clinical candidate. Biochemical and biophysical data demonstrate that point mutations in the inhibitor-binding pocket decrease the efficacy of 1 by several 1000-fold. Surprisingly, the structures of wild-type and mutant Eg5 in complex with 1 display no apparent structural changes in the binding configuration of the drug candidate. Furthermore, ITC and modeling approaches reveal that resistance to 1 is not through conventional steric effects at the binding site but through reduced flexibility and changes in energy fluctuation pathways through the protein that influence its function. This is a phenomenon we have called "resistance by allostery".


First Reported Case of Anti-Ampa Receptor Encephalitis in a Vietnamese Adolescent.
Autoimmune encephalitis refers to a group of diseases characterized by the presence of antibodies that directly attack receptors on the neuron surface and are associated with cognitive and behavioral disorders. Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor autoimmune encephalitis is very rare and has been reported in only a few individual cases, with little clinical experience. We describe the clinical manifestation and disease course of the first diagnosed case of anti-AMPA receptor encephalitis at the Neurology Department of Children's Hospital 2 in November 2020. A previously healthy 10-year-old presented with symptoms over 2 periods. During each period, the patient presented with multiple focal seizures, a cognitive-behavioral disorder, and amnesia. The brain magnetic resonance imaging (MRI) results were persistently normal. Electroencephalography (EEG) recorded many focal spikes and spike waves. Antibodies against N-methyl D-aspartate (NMDA) were not detected. Antibodies against AMPA receptors were detected in the serum and cerebrospinal fluid using an indirect fluorescent antibody test. This patient was treated with immunotherapy, including methylprednisolone and intravenous immunoglobulin (IVIG), and antiepileptic drugs, such as oxcarbazepine, topiramate, and levetiracetam. The seizures were controlled, but the cognitive-behavioral disorder was only partially resolved. This case report contributes to the clinical understanding of anti-AMPA receptor encephalitis disease manifestation, the response to the immunotherapy, and relapse.


Knowing so much, yet knowing so little: a scoping review of interventions that address the stigma of mental illness in the Canadian context.
Stigma can have detrimental effects on the health and wellbeing of individuals living with a mental illness. This scoping review describes the nature, range, and extent of intervention research aimed at reducing public and self-stigma of mental illness in the Canadian context. The review was guided by Arksey and O'Malley's framework. A search of databases and relevant websites identified 35 primary studies. Most studies used quantitative research methods and included predominantly youth or middle-aged adults, women, and white Canadian-born people. Guided by different conceptualizations of stigma, direct or indirect contact, education, and advocacy-focused interventions, aimed to provide information, and/or develop skills to address self and public stigma. Most studies evaluated interventions' effectiveness short-term. Of the few studies that followed-up participants long-term, some were able to reduce stigmatizing attitudes post-intervention, however, these targeted only specific groups such as students or health care professionals. Lack of diversity among the samples, and limited evidence of long-term effectiveness of interventions, were some of the studies' limitations. What is currently known about interventions aimed at reducing the stigma of mental illness in the Canadian context is not informed by research among vulnerable groups, such as people living with a mental illness, older adults, immigrants, and people of diverse ethnic backgrounds. Interventions that are informed by clear conceptualizations of stigma and rigorously evaluated in a range of ethno-cultural groups would create a knowledge base that is useful for policy-makers, community leaders, and agencies serving various ethnic communities in Canada.


Interventional Treatment of Pulmonary Valve Stenosis: A Single Center Experience.
Percutaneous pulmonary valvuloplasty is well established treatment of choice in pulmonary valve stenosis. The aim of our study was to present our experience with the interventional technique, its immediate and mid-term effectiveness as well as its complication rate. The study included 43 patients, where 33 (74%) of them were children between the age of 1 month and 15 years. The procedure was successful in 38 patients or 90%. Mean peak to peak transvalvular gradient was reduced from 91.2 mmHg (55-150 mmHg) to 39.1 mmHg (20-80 mmHg). Follow- up of patients was between 2 and 13 years and included echocardiographic evaluation of pulmonary valve gradient, right heart dimensions and function as well as assessment of pulmonary regurgitation. We experienced one major complication pericardial effusion in a 5 months old child that required pericardiocenthesis. Six patients (13.9%) required a second intervention. During the follow up period there was significant improvement of right heart function and echocardiography parameters. Mild pulmonary regurgitation was noted in 24 (55%) patients, and four (9%) patients developed moderate regurgitation, without affecting the function of the right ventricle. Percutaneous pulmonary valvuloplasty is an effective procedure in treatment of pulmonary stenosis with good short and mid-term results.


Avoiding drug errors.
Although no statistics are available, medication errors occur relatively frequently and should be a target for Clinical Governance activities. Organisations need to create a culture where risk management regarding medication is incorporated.


Focus on Basal cell carcinoma.
Nonmelanoma skin cancers (NMSCs), which include basal and squamous cell cancers are the most common human cancers. BCCs have a relatively low metastatic rate and slow growth and are frequently underreported. Whilst there is a definite role of sunexposure in the pathogenesis of BCC, several additional complex genotypic, phenotypic and environmental factors are contributory. The high prevalence and the frequent occurrence of multiple primary BCC in affected individuals make them an important public health problem. This has led to a substantial increase in search for newer noninvasive treatments for BCC. Surgical excision with predetermined margins remains the mainstay treatment for most BCC. Of the newer non-invasive treatments only photodynamic therapy and topical imiquimod have become established in the treatment of certain BCC subtypes, while the search for other more effective and tissue salvaging therapies continues. This paper focuses on the pathogenesis and management of BCC.


Development of a commercial cigarette "market map" comparison methodology for evaluating new or non-conventional cigarettes.
A "market map" comparison methodology for cigarette smoke chemistry yields is presented. Federal Trade Commission machine-method smoke chemistry was determined for a range of filtered cigarettes from the US marketplace. These data were used to develop illustrative market maps for each smoke constituent as analytical tools for comparing new or non-conventional cigarettes to a sampling of the broader range of marketplace cigarettes. Each market map contained best-estimate "market-means," showing the relationship between commercial cigarette constituent and tar yields, and yield "market ranges" defined by prediction intervals. These market map means and ranges are the basis for comparing new cigarette smoke yields to those of conventional cigarettes. The potential utility of market maps for evaluating differences in smoke chemistry was demonstrated with 1R4F and 2R4F Kentucky reference cigarettes, an Accord cigarette, and an Advance cigarette. Conventional cigarette tobacco nicotine, nitrate, soluble ammonia, and tobacco specific nitrosamine levels are reported. Differences among conventional cigarette constituent yields at similar tar levels were explained in part by the chemical composition range of those cigarette tobaccos. The study also included a comparison of smoke constituent yields and in vitro smoke cytotoxicity and mutagenicity assay results for the 1R4F Kentucky reference cigarette and its replacement 2R4F. Significant smoke yield differences were noted for lead, NNK, and NNN. The majority of their smoke constituent yields were within the market range developed from the sampled conventional cigarettes. Within the sensitivity and specificity of the in vitro bioassays used, smoke toxic activity differences for the two reference cigarettes were not statistically significant. These results add to the limited information available for the 2R4F reference cigarette.


Neurologic illness associated with occupational exposure to the solvent 1-bromopropane--New Jersey and Pennsylvania, 2007-2008.
1-Bromopropane (1-BP) (n-propyl bromide) is a solvent increasingly used as a substitute for ozone-depleting chloro-fluorocarbons and similar regulated compounds. 1-BP is used in vapor and immersion degreasing operations and other manufacturing processes, and as a solvent in industries using aerosol-applied adhesives. In some states, 1-BP is used as a solvent in dry cleaning because of restrictions on use of perchloroethylene (tetrachloroethylene), a possible human carcinogen. Published studies of workers exposed to 1-BP have raised concerns about occupational health risks associated with exposure. This report describes two cases involving workers exposed to 1-BP and diagnosed with clinical manifestations of neurotoxicity. The cases, when coupled with previously reported studies of workers exposed to 1-BP, illustrate potential health risks of 1-BP exposure. Clinicians and public health professionals should be alert to potential health effects among workers exposed to 1-BP, particularly in dry cleaning and other workplaces where 1-BP use might be increasing, and effective control methods to limit exposure to 1-BP should be implemented at worksites.


Endothelin antagonism prevents early EGFR transactivation but not increased matrix metalloproteinase activity in diabetes.
Although past studies have demonstrated decreased renal matrix metalloproteinase (MMP) activity in type 1 diabetes and in mesangial cells grown under high glucose conditions, renal MMP expression and activity in type 2 diabetes and the regulation of MMPs by profibrotic factors involved in diabetic renal complications such as endothelin-1 (ET-1) remained unknown. The renal expression and activity of MMPs in type 2 diabetic Goto-Kakizaki (GK) rats treated with vehicle or ET(A) receptor selective antagonist ABT-627 for 4 wk were assessed by gelatin zymography, fluorogenic gelatinase assay, and immunoblotting. In addition, expression and phosphorylation of epidermal growth factor receptor (EGFR) and connective tissue growth factor were evaluated by immunoblotting. Renal sections stained with Masson trichrome were used to investigate kidney structure. MMP-2 activity and protein levels were significantly increased in both cortical and medullary regions in the GK rats. Membrane-bound MMP (MT1-MMP), MMP-9, and fibronectin levels were also increased, and ABT-627 treatment did not have an effect on MMP activity and expression. Histological analysis of kidneys did not reveal any structural changes. Phosphorylation of EGFR was significantly increased in the diabetic animals, and ABT-627 treatment prevented this increase, suggesting ET-1-mediated transactivation of EGFR. These results suggest that there is early upregulation of renal MMPs in the absence of any kidney damage. Although the ET(A) receptor subtype is not involved in the early activation of MMPs in type 2 diabetes, ET-1 contributes to transactivation of growth-promoting and profibrotic EGFR.


Tandem Rh-Catalyzed [4 + 2] Vinylic C-H O-Annulation of Exocyclic Enones with Alkynes and 1,5-H Shift.
Active pyrylium intermediates are in situ generated by a Rh-catalyzed vinylic C-H annulation reaction between exocyclic α,β-enones and alkynes, which undergo a base-promoted rearrangement via 1,5-H shift to form 1H-benzo[f]chromene derivatives.


Design, synthesis, and antiproliferative activity of some new pyrazole-fused amino derivatives of the pyranoxanthenone, pyranothioxanthenone, and pyranoacridone ring systems: a new class of cytotoxic agents.
A series of novel pyranoxanthenones, pyranothioxanthenones, and pyranoacridones have been designed and synthesized as analogues of the acridone alkaloid acronycine, and their DNA binding and in vitro cytotoxicities have been investigated. The title compounds were derived by reaction of the corresponding 6-tosylates 5a-e with 2-hydroxyethylhydrazine, followed by conversion of the free hydroxyl of the substituted ethanols 6a-e to the corresponding mesylates, which were then treated with the suitably substituted secondary amines to provide the target derivatives 8-27. An alternative synthetic procedure for the preparation of these types of compounds is also developed, which resulted in an improvement of the overall yield. The new compounds exhibited interesting cytotoxic activity against the murine leukemia L1210 cell line, being more active than the parent compound, and a number of them possessed cytotoxicity against some human solid tumor cell lines. Especially in the case of a colon adenocarcinoma cell line, their IC(50) values were comparable to that of mitoxantrone. The results of this study indicate that the incorporation of an amino-substituted pyrazole ring into the acronycine chromophore, or into its isosteres, results in an improvement of the lead compound's activity, and therefore, it may be of use in the search of new anticancer agents derived from this natural product.


Methylation Profile of Cancer Testis Antigens in Colorectal Cancer.
Cancer testis antigens (CTAs) are a class of immune-stimulating antigens often overexpressed in many types of cancers. The usage of the CTAs as immunotherapy targets have been widely investigated in different cancers including melanoma, hematological malignancies, and colorectal cancer. Studies have indicated that the epigenetic regulation of the CTAs such as the methylation status may affect the expression of the CTAs. However, the report on the methylation status of the CTAs is conflicting. The general methylation profile of the CTAs, especially in colorectal cancer, is still elusive. To determine the methylation profile of the selected CTAs in our colorectal cancer patients. A total of 54 pairs of colorectal cancer samples were subjected to DNA methylation profiling using the Infinium Human Methylation 450K bead chip. We found that most of the CTAs were hypomethylated, and CCNA1 and TMEM108 genes were among the few CTAs that were hypermethylated. Overall, our brief report has managed to show the overall methylation profile in over the 200 CTAs in colorectal cancer and this could be used for further refining any immunotherapy targets.


IL-1 and T Helper Immune Responses.
CD4 T cells play a critical role in mediating adaptive immunity to a variety of pathogens as well as in tumor immunity. If not adequately regulated, CD4 T cells can be also involved in autoimmunity, asthma, and allergic responses. During TCR activation in a particular cytokine milieu, naïve CD4 T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, and Th17, as defined by their pattern of cytokine production and function. IL-1, the prototypic proinflammatory cytokine, has been shown to influence growth and differentiation of immunocompetent lymphocytes. The differential expression of IL-1RI on human CD4 T cell subsets confers distinct capacities to acquire specific effector functions. In this review, we summarize the role of IL-1 on CD4 T cells, in terms of differentiation, activation, and maintenance or survival.


Delivering Simulation Activities Safely: What if We Hurt Ourselves?
Although a focus on the learner rightly remains in any teaching environment, the psychological safety of everyone involved in the conduct of experiential learning and critical academic scholarship is important. Education literature suggests that faculty are just as prone to psychological harm as their learners. This commentary describes adverse experiences from a simulation-based education event that took place at an Australasian interprofessional and cross-domain simulation workshop. Event facilitators explored the notion of the "safe container" but, in the process, were themselves exposed to psychological injury. We summarize an ostensibly complex simulation activity with unintended sequelae, the ethical concerns surrounding the faculty care, and from lessons learned, present an extended conceptualization of the safe container including broader parameters around the preparation of all involved in the delivery of simulation-based activities. Our goals in sharing this case is to encourage the community to become more vigilant regarding the unintended consequences of our simulation activities and to encourage open reporting and discussion of such incidents for the betterment of the field.


Peptide backbone circularization enhances antifreeze protein thermostability.
Antifreeze proteins (AFPs) are a class of ice-binding proteins that promote survival of a variety of cold-adapted organisms by decreasing the freezing temperature of bodily fluids. A growing number of biomedical, agricultural, and commercial products, such as organs, foods, and industrial fluids, have benefited from the ability of AFPs to control ice crystal growth and prevent ice recrystallization at subzero temperatures. One limitation of AFP use in these latter contexts is their tendency to denature and irreversibly lose activity at the elevated temperatures of certain industrial processing or large-scale AFP production. Using the small, thermolabile type III AFP as a model system, we demonstrate that AFP thermostability is dramatically enhanced via split intein-mediated N- and C-terminal end ligation. To engineer this circular protein, computational modeling and molecular dynamics simulations were applied to identify an extein sequence that would fill the 20-Å gap separating the free ends of the AFP, yet impose little impact on the structure and entropic properties of its ice-binding surface. The top candidate was then expressed in bacteria, and the circularized protein was isolated from the intein domains by ice-affinity purification. This circularized AFP induced bipyramidal ice crystals during ice growth in the hysteresis gap and retained 40% of this activity even after incubation at 100°C for 30 min. NMR analysis implicated enhanced thermostability or refolding capacity of this protein compared to the noncyclized wild-type AFP. These studies support protein backbone circularization as a means to expand the thermostability and practical applications of AFPs.


Comparing the Personality Traits of Patients with an Eating Disorder versus a Dual Diagnosis.
Objectives: This cross-sectional study explored personality traits of individuals receiving treatment in a private clinic for an eating disorder (ED) compared to those receiving treatment for a dual diagnosis (DD; defined as an addiction to illegal drugs and/or alcohol along with a mental illness, in this case an ED). The aims of this study were to: (a) assess the personality profiles and differentiating traits between the ED and DD groups, (b) analyze differences in personality traits of restrictive ED versus bingeing ED profiles, and lastly (c) compare the individuals Temperament and Character Inventory-Revised (TCI-R) results to their personality clusters as per the Diagnostic and Statistical Manual of Mental Disorders - 5th edition (DSM-5). Methods: The TCI-R is a self-report questionnaire consisting of seven scales, each with their own subscales, which provide a fuller understanding of each temperament and character trait evaluated. This questionnaire was given to patients (n = 67) receiving treatment at a private institute specialized in eating disorders in Barcelona, Spain and the surrounding areas, along with the State-Trait Anxiety Inventory (STAI), Beck Depression Inventory-II (BDI-II), and the Barratt Impulsiveness Scale-11 (BIS-11). These subsequent questionnaires were given as they are often found to be comorbidities of ED. Results: The ED group (n = 41), regarding the TCI-R scales, showed higher scores in harm avoidance (HA), reward dependence (RD), persistence (P), cooperativeness (C) and self-directedness (SD). Whereas, the DD (n = 26) group, showed higher scores in novelty seeking (NS) and self-transcendence (ST). Also, there was a significant positive correlation between the DD group and the extravagance (NS3) subscale of novelty seeking across models. When comparing the two ED groups, the restrictive profile (RP) to the bingeing profile (BP), there were significant negative correlations in the TCI-R subscales of dependence (RD4) and perfectionism (P4) whereas there were positive correlations in the TCI-R subscale of responsibility (SD1). Conclusions: These results support previous studies and help to appraise differences in personality traits between specific groups in a clinical setting.


Impact of Implicit Abdominal Aortic Aneurysm Screening in the Veterans Affairs Health Care System Over 10 Years.
Background Abdominal aortic aneurysm (AAA) screening programs have been active in the United States since 2005, but are not the only way AAAs are detected. AAA management and outcomes have not been investigated broadly in the context of "implicit AAA screening," whereby radiologic examinations not intended for focused screening can identify AAAs. Methods and Results We examined the association between imaging-based AAA screening, both explicit and implicit, and various outcomes for ≈1.6 million veterans in the Veterans Affairs health care system from 2005 to 2015. Screened-positive, screened-negative, and unscreened veterans were identified in the overall cohort and within a subgroup of veterans aged 65 years in 2005. The yearly composite screening rate increased over 10 years, from 11.7% to 18.3%, whereas the screened-positive rate decreased from 7.3% to 4.9%. Only 12.9% of screening examinations were explicit AAA screening ultrasounds. The subgroup's composite screening rate was 74% within its 10-year eligibility window, with implicit screening accounting for 91.8% of examinations. In the 2005 subgroup, all-cause mortality and Charlson comorbidity scores were higher for veterans who underwent screening compared with those unscreened (31.2% versus 23.1% and 0.47 versus 0.25, respectively; P<0.001). AAA rupture rates were similar between those unscreened and screened-negative individuals. Conclusions Accounting for both explicit and implicit screening, AAA screening in the Veterans Affairs population has moderate reach. Efforts to expand explicit AAA screening are not likely to impact either all-cause mortality or AAA rupture on the population scale as significantly as a careful accounting for and use of implicit screening data.


Induction of MHC-unrestricted cytolytic CD4+ T cells against virally infected target cells by cross-linking CD4 molecules.
Cross-linking CD4 molecules with the use of specific mAbs induced Ag-nonspecific, MHC-unrestricted killing by human or bovine CD4+ T cells and human allospecific T cell clones against virally infected (bovine herpesvirus-1 and herpes simplex virus-1) target cells. Heat-aggregated goat IgG anti-mouse IgG elevated CD4 cross-linking efficiency, resulting in augmented killing activity by effector cells. However, Ab-activated effector cells failed to kill tumor target cell lines, e.g., K562, Daudi (human), and BL3 (bovine). The result supports the hypotheses that the CD4 molecule plays an important role in activating CD4 cytotoxic cells and that viral glycoproteins participate in conjugating target cells with activated effector cells in two species. The herpesviruses eliciting killing represent potential natural infections for each species. The relationship between a cytolytic response and cell proliferation was independent because cross-linking of CD4 molecules induced cytotoxicity but not T cell proliferation, in contrast to cross-linking CD3 molecules. Our findings of non-MHC-restricted cytotoxic lymphocytes induced by cross-linking CD4 molecules identify an activation mechanism of antiviral cytotoxicity.


Reusable amine-based structural motifs for green house gas (CO2) fixation.
A series of compounds with an amine based structural motif (ASM) have been synthesized for efficient atmospheric CO(2) fixation. The H-bonded ASM-bicarbonate complexes were formed with an in situ generated HCO(3)(-) ion. The complexes have been characterized by IR, (13)C NMR, and X-ray single-crystal structural analysis. ASM-bicarbonate salts have been converted to pure ASMs in quantitative yield under mild conditions for recycling processes.


Suppression of voluntary motor activity revealed using transcranial magnetic stimulation of the motor cortex in man.
1. Suppression of voluntary muscle activity of hand and arm muscles in response to transcranial magnetic stimulation (TMS) of the motor cortex has been investigated in man. 2. Suppression could be elicited by low levels of TMS without any prior excitatory response. The latency of the suppression was 3-8 ms longer than the excitation observed at a higher stimulus intensity. The duration of the suppression ranged from 8 to 26 ms. 3. A circular stimulating coil was used to determine threshold intensity for excitation and suppression of contraction of thenar muscles in response to TMS at different locations over the motor cortex. The locations for lowest threshold excitation coincided with those for lowest threshold suppression. Suppression was elicited at a lower threshold than excitation at all locations. 4. A figure-of-eight stimulating coil was positioned over the left motor cortex at the lowest threshold point for excitation of the right thenar muscles. The orientation for the lowest threshold excitatory and inhibitory responses was the same for all subjects. That orientation induced a stimulating current travelling in an antero-medial direction. Suppression was invariably elicited at lower thresholds than excitation. 5. When antagonistic muscles (second and third dorsal interosseus) were co-contracted, TMS evoked coincident suppression of voluntary EMG in the two muscles without prior excitation of either muscle. This suggests that the suppression is not mediated via corticospinal activation of spinal interneurones. 6. Test responses to electrical stimulation of the cervical spinal cord were evoked in both relaxed and activated thenar muscles. In the relaxed muscle, prior TMS at an intensity that would suppress voluntary activity failed to influence the test responses, suggesting absence of inhibition at a spinal level. However, in the activated muscle, prior TMS could reduce the test response. This may be explained by disfacilitation of motoneurones due to inhibition of corticospinal output. 7. We propose that suppression of voluntary muscle activity by TMS is due in large part to activation of a mechanism within the motor cortex that reduces the corticospinal output to the muscle. It is concluded that TMS evokes excitation and inhibition via neuronal structures lying close to one another and having similar orientations.


Wave-vector-dependent exciton exchange interaction.
The exchange interaction for the yellow 1S orthoexciton in Cu2O is derived up to the order K2. The resulting exchange splittings are verified experimentally using high resolution spectroscopy. In agreement with theory the fine structure shows a characteristic dependence on the direction of the wave vector.


Brain mast cells and therapeutic potential of vasoactive intestinal peptide in a Parkinson's disease model in rats: brain microdialysis, behavior, and microscopy.
In the present study, the effect of systemically administered vasoactive intestinal peptide (VIP) (25 ng/kg i.p.) was investigated on drug-induced rotational behavior, extra-cellular dopamine levels and histology of corpus striatum in a 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease. After 15 days of 6-OHDA lesion, apomorphine-induced (0.05 mg/kg s.c.) rotational behavior of the animals significantly increased and extra-cellular dopamine levels of corpus striatum were significantly reduced. VIP reversed the rotational deficits but did not alter the decrease in striatal dopamine levels. On the other hand, histological data indicate that VIP significantly reduced neuronal death and demyelination. Electron microscopic appearance of mast cells showed ultra-structural variety between VIP-treated and 6-OHDA lesioned groups. VIP activates mast cells without any evidence of typical exocytosis, and possibly mast cells could participate in neuroprotection. Our results suggest that systemically administered VIP can attenuate the motor response changes, neuronal cell death, and myelin sheet loss characteristically associated with 12 microg 6-OHDA administration into the rat striatum. Brain mast cells seem to participate in neuronal protection. Possibly, protective cues could be produced by brain mast cells.


Clinical validation of a blood-based classifier for diagnostic evaluation of asymptomatic individuals with pulmonary nodules.
The number of pulmonary nodules detected in the US is expected to increase substantially following recent recommendations for nationwide CT-based lung cancer screening. Given the low specificity of CT screening, non-invasive adjuvant methods are needed to differentiate cancerous lesions from benign nodules to help avoid unnecessary invasive procedures in the asymptomatic population. We have constructed a serum-based multi-biomarker panel and assessed its clinical accuracy in a retrospective analysis of samples collected from participants with suspicious radiographic findings in the Prostate, Lung, Chest and Ovarian (PLCO) cancer screening trial. Starting with a set of 9 candidate biomarkers, we identified 8 that exhibited limited pre-analytical variability with increasing clotting time, a key pre-analytical variable associated with the collection of serum. These 8 biomarkers were evaluated in a training study consisting of 95 stage I NSCLC patients and 186 smoker controls where a 5-biomarker pulmonary nodule classifier (PNC) was selected. The clinical accuracy of the PNC was determined in a blinded study of asymptomatic individuals comprising 119 confirmed malignant nodule cases and 119 benign nodule controls selected from the PLCO screening trial. A PNC comprising 5 biomarkers: CEA, CYFRA 21-1, OPN, SCC, and TFPI, was selected in the training study. In an independent validation study, the PNC resolved lung cancer cases from benign nodule controls with an AUC of 0.653 (p < 0.0001). CEA and CYFRA 21-1, two of the markers included in the PNC, also accurately distinguished malignant lesions from benign controls. A 5-biomarker blood test has been developed for the diagnostic evaluation of asymptomatic individuals with solitary pulmonary nodules.


The Role of Perceived Social Norms in Rural Sanitation: An Explorative Study from Infrastructure-Restricted Settings of South Ethiopia.
The perception of social sanitation norms (PSSNs) around unacceptability of open defecation has been a key aspect of recent sanitation interventions. However, underlying mechanisms through which "reconstructed" PSSNs affect sanitation outcomes have been a black box. This explorative cross-sectional study examines direct and indirect links between PSSNs and sanitation safety using data from structured interviews and observations in 368 households in rural South Ethiopia. In addition to a positive association between PSSNs and sanitation safety, we propose and examine the following two mechanisms: First, we confirm a potentially adverse feedback of PSSNs on future sanitation safety by enhancing the emotional satisfaction with current sanitation practice (satisfaction independent of the functionality of sanitation facilities). Second, inspired by the social amplification/attenuation of risk framework, we demonstrate that PSSNs work as a "social filter" that can amplify or attenuate the effects of other variables targeted in sanitation interventions such as perceived health-related and non-health risks and benefits associated with open defecation and private latrine ownership, respectively, and factual hygiene and sanitation knowledge. These findings imply that PSSNs are not only important per se, but they are also important instrumentally because sanitation outcomes depend upon the capacity of social influences to shape the perception of sanitation risks and benefits and sanitation-related awareness in desirable ways. The mechanisms outlined in this paper as well as the sustainability of sanitation outcomes depend on whether and how social sanitation norms are internalized.


[Giovanni Gigli. The Nephrological School of Pisa from Tuscany to Umbria].
Giovanni Gigli (1913-1988) can be considered one of the pioneers of Italian nephrology. Years before the foundation of the Italian Society of Nephrology (SIN), Gigli was engaged in research into renal function and renal disease. He published an important monograph on the study of renal function in 1953. In addition to his scientific interests, Gigli was involved in the clinical aspects of renal disease and in popularizing the new concepts in this field. Of particular value in his career were the foundation of a school of nephrology and the introduction of a chronic dialysis treatment program at the Institute of Medical Pathology in Perugia.


A comparison of nontransmural and transmural myocardial infarction.
This report compares the past history, hospital course and follow-up of 70 patients with nontransmural myocardial infarction compared to 259 patients with transmural myocardial infarction. The pre-infarction history in the two groups is similar with respect to angina and infarction. The hospital course for non-transmural myocardial infarction is not a guide for future cardiac events and the post-hospital prognosis in the two groups is similar. Nontransmural myocardial infarction has a lower hospital mortality (P less than 0.05). Patients in whom nontransmural myocardial infarction is a first coronary event have a lower incidence of subsequent angina (P less than 0.05). The study demonstrates that myocardial infarction without development of q waves does not have an unfavourable long term outlook when compared to transmural infarction. This finding is contrary to reports which suggest a poor prognosis and recommend early coronary anteriography with a view to aorto-coronary bypass in patients with nontransmural infarction.


Child Abuse Training, Comfort, and Knowledge Among Emergency Medicine, Family Medicine, and Pediatric Residents.
To assess the training, comfort, and knowledge related to the medical management of child abuse among emergency medicine, family medicine, and pediatric residents. In 2004, a 25-item survey was distributed to 274 pediatric, emergency medicine, and family medicine residents at two medical schools in Norfolk, Virginia and Dallas, Texas. Analyses focused on identifying differences in training, comfort, and knowledge by specialty and site, and identifying factors associated with greater knowledge and comfort. Pediatric residents reported receiving the most hours of instruction in child abuse during residency. Training experiences of family medicine residents differed significantly by site. Clinical and overall knowledge and comfort with handling exams correlated strongly with the number of abuse patients seen during residency. On both clinical and overall knowledge, family medicine residents performed significantly worse than pediatric and emergency medicine residents. Knowledge of genital anatomy and comfort with sexual abuse exams was poor among all specialties. The results support the need for improvements in and a more systematic approach to residency training in child abuse.


Application of Mobile Phases Containing Ionic Liquid for HPLC Analysis of Selected Isoquinoline Alkaloids.
An HPLC procedure on a polar reversed-phase column with mobile phases containing ionic liquid (IL) was developed for the analysis of selected alkaloids from different chemical groups. We aimed to obtain optimal conditions for the separation of alkaloids because widely used silica-based stationary phases exhibit a silanol effect, rendering analysis of basic analytes extremely difficult. Retention, separation selectivity, peak symmetry, and system efficiency were examined in various eluent systems containing different concentrations of IL and acetonitrile. The obtained results revealed substantial influence from the concentrations of IL, the organic modifier, and temperature on the retention behavior of the investigated alkaloids. The most selective and efficient chromatographic systems were applied for the analysis of several alkaloids in a plant extract.


Child protection and adult depression: evaluating the long-term consequences of evacuating children to foster care during World War II.
This paper combined data collected from war time government records with survey data including background characteristics, such as factors that affected eligibility, to examine the adult depression outcomes of individuals who were evacuated from Finland to temporary foster care in Sweden during World War II. Using war time government records and survey data for a random sample of 723 exposed individuals and 1321 matched unexposed individuals, the authors conducted least squares adjusted means comparison to examine the association between evacuation and adult depression (Beck Depression Inventory). The random sample was representative for the whole population of evacuees who returned to their biological families after World War II. The authors found no statistically significant difference in depressive symptoms during late adulthood between the two groups; for example, the exposed group had a 0.41 percentage points lower average Beck Depression Inventory score than the unexposed group (p = 0.907). This study provides no support for family disruption during early childhood because of the onset of sudden shocks elevating depressive symptoms during late adulthood.


Operative anatomy and classification of the sylvian veins for the distal transsylvian approach.
Methods for preservation of the sylvian veins in the transsylvian approach have not been established because of the considerable variations. This study attempted to classify the sylvian veins to facilitate systematic dissection of the sylvian fissure for sylvian veins to be preserved. The operative anatomy of the sylvian vein was examined in 82 hemispheres. The type of drainage and the pattern of branching were investigated. The superficial sylvian vein (SSV) was classified into three types according to the number of stems draining into the dural sinus on the inner surface of the sphenoid bone: The SSV was absent or hypoplastic in eight cases, the SSV was single in 38 cases, and the SSV was double in 36 cases. The SSV drained into neither the sphenoparietal sinus nor the cavernous sinus in nine cases. An anastomosis between the SSV and the deep middle cerebral vein (DMCV) was observed in 42 cases. The frontobasal bridging vein (FBBV) drained into the sphenoparietal sinus in 47 cases. The type of connection was further subdivided into four types according to the connections with the DMCV and FBBV. The venous anatomy of sylvian fissure indicates that dissection (skeletonization) of the main stem of sylvian veins from the temporal lobe should be performed to preserve the tributaries from the frontal lobe.


Body image, emotional intelligence and quality of life in peritoneal dialysis patients.
End-stage-renal-disease is one of the most common chronic diseases, and peritoneal dialysis constitutes one of the replacement therapies. The aim of this study was to investigate the views of patients on peritoneal dialysis regarding their body image, to assess their quality of life and level of emotional intelligence. A cross-sectional study was performed with structured questionnaires. The sample of the study was the patients undergoing peritoneal dialysis and monitored by the nephrology clinics of 7 public hospitals in Greece. A total of 102 completed questionnaires were collected and analyzed (68% response rate). The participants showed moderate degree of body-image dysphoria (mean = 1.29, SD = 0.94), moderate levels of emotional intelligence and experienced moderate quality of life. According to the statistical analysis, women reported worse body image (p = 0.013) and university graduates showed higher levels of emotionality (p = 0.016). The correlations between the quality of life questionnaire subscales and demographic characteristics revealed statistically significant relationships between marital status and the Physical Functionality subscale, where unmarried people had a better quality of life in this subscale (p = 0.042) and between postgraduate/doctoral degree holders and the subscale Patient Satisfaction (p = 0.035). Also, statistically significant relationships were found between occupation and the Social Interaction subscale, where those engaged in household activities and were unemployed (p = 0.022) showed better quality of life. Participants living in semi-urban areas had better quality of life on the subscale Burden of Kidney Disease (p = 0.034). ESRD patients on peritoneal dialysis suffer significant limitations related to disease and treatment modality. According to our findings, these affect both their body image as well as their quality of life. Improvement in emotional intelligence is the factor which plays an important mediating role in improving both body image and quality of life in patients on peritoneal dialysis.


HR MAS 1H NMR and chemometrics as useful tool to assess the geographical origin of cocoa beans - Comparison with HR 1H NMR.
Chocolate and cocoa-based products are among the goods with higher added value. A current trend of the cocoa market is to offer to the consumers high quality cocoa products, namely mono-origin cocoa. However, a reliable analytical method able to trace the geographical origin of cocoa is lacking. In this work we tested the capability of HR MAS 1H NMR combined with chemometrics to assess the geographical origins of 60 fermented and dried cocoa beans of 23 different cocoa producing countries from the three major crop-growing areas (Africa, Central/South America, Asia/Oceania). Metabolic profiling was determined by HR MAS 1H NMR directly on cocoa powder after the method optimization. The same samples were also subjected to extraction and analysis with HR 1H NMR. HR MAS 1H NMR, as 1H NMR analysis, allowed the simultaneous detection of amino acids, polyalcohols, organic acids, sugars, methylxanthines, catechins. Moreover, HR MAS allows the detection of lipids, not present in the aqueous extract utilized for 1H NMR. The data set obtained is therefore representative of all classes of cocoa compounds. Untargeted HR MAS 1H NMR and 1H NMR datasets were utilized as fingerprint of the samples and elaborated with multivariate statistical methods. A targeted quantitative approach of selected metabolites was possible only with HR 1H NMR data, because HR MAS 1H NMR does not give reliable quantitative results. All the approaches adopted showed a discrimination of the cocoa origins. HR MAS presents the advantages to obtain a very rapid picture of the samples, comprising both lipophilic and hydrophilic components, avoiding any sample manipulation.


FK506 potentiates NGF-induced neurite outgrowth via the Ras/Raf/MAP kinase pathway.
Nerve growth factor (NGF) and other members of the neurotrophin family are critical for the survival and differentiation of neurons within the peripheral and central nervous systems. Neurophilin ligands, including FK506, potentiate NGF-induced neurite outgrowth in several experimental models, although the mechanism of this potentiation is unclear. Therefore, we tested which signaling pathways were involved in FK506-potentiated neurite outgrowth in SH-SY5Y neuroblastoma cells using specific pharmacological inhibitors of various signaling molecules. Inhibitors of Ras (lovastatin), Raf (GW5074), or MAP kinase (PD98059 and U0126) blocked FK506 activity, as did inhibitors of phospholipase C (U73122) and phosphatidylinositol 3' kinase (LY294002). Protein kinase C inhibitors (Go6983 and Ro31-8220) slightly but significantly inhibited neurite outgrowth, whereas inhibitors of p38 MAPK (SB203580) or c-Jun N-terminal kinase (SP600125) had no effect. These data suggest that FK506 potentiates neurite outgrowth through the Ras/Raf/MAP kinase signaling pathway downstream of phospholipase C and phosphatidylinositol 3' kinase.


N-arachidonoyl-serotonin, a dual FAAH and TRPV1 blocker, inhibits the retrieval of contextual fear memory: Role of the cannabinoid CB1 receptor in the dorsal hippocampus.
Anandamide, an endocannabinoid, inhibits aversive responses by activating the CB1 cannabinoid receptor. At high concentrations, however, anandamide may exert pro-aversive activities mediated by the transient receptor potential vanilloid type-1 channel (TRPV1). Accordingly, N-arachidonoyl-serotonin (AA-5-HT), a dual blocker of the anandamide-hydrolysing enzyme fatty acid amide hydrolase (FAAH) and the TRPV1 channel, induces anxiolytic-like effects. Here we tested the hypothesis that AA-5-HT inhibits the expression of contextual fear conditioning by facilitating CB1 receptor signalling in the dorsal hippocampus of mice. Intraperitoneal injection of AA-5-HT (0.1, 0.3, 1 mg/kg) inhibited the retrieval of contextual fear memory (freezing response). The effect of AA-5-HT (0.3 mg/kg) was prevented by systemic injection of the CB1 receptor antagonist, AM251 (1.0 mg/kg), and mimicked by simultaneous FAAH inhibition (URB597, 0.3 mg/kg) and TRPV1 blockage (SB366791, 1 mg/kg). Injection of AA-5-HT (0.125, 0.25, 0.5 nmol) into the dorsal hippocampus also reduced freezing. Finally, the effect of systemic AA-5-HT (0.3 mg/kg) was prevented by intra-hippocampal injection of AM251 (1 nmol). In conclusion, dual FAAH and TRPV1 blockage inhibits contextual fear memory by facilitating anandamide-induced CB1 receptor activation in the dorsal hippocampus. This approach may lead to new pharmacological treatments for traumatic memories and related psychiatric disorders.


The DNA-binding efficiency of Sp1 is affected by redox changes.
We have previously demonstrated that the DNA-binding efficiency of Sp1 is greatly decreased in nuclear extracts from 30-month-old rat tissues compared to those from young ones, although its gene appears to be normally expressed. As reactive oxygen intermediates are known to accumulate in aged animals, we investigated the effect of oxidation on the Sp1 DNA-binding activity. Electrophoretic mobility shift assays and DNase I footprintings showed that high concentrations of dithiothreitol, added to the aged tissue extracts, fully restore the Sp1 DNA-binding efficiency. However, in young nuclear extracts hydrogen peroxide treatment strongly decreases the Sp1 DNA-binding activity that is restored by the treatment with high dithiothreitol concentrations. To ascertain whether the oxidative stress is directed toward the Sp1 molecule alone, or whether it acts on unknown Sp1 cofactor(s) necessary for DNA binding, we purified Sp1 from young rat liver and demonstrated that when the purified protein is added to aged nuclear extracts, it efficiently binds to its DNA cis-element. Moreover, purified Sp1 treated with hydrogen peroxide lost its ability to bind its cis-element and the DNA-binding efficiency was fully restored after incubation with dithiothreitol.


Cortical changes in cerebral small vessel diseases: a 3D MRI study of cortical morphology in CADASIL.
Brain atrophy represents a key marker of disease progression in cerebrovascular disorders. The 3D changes of cortex morphology occurring during the course of small vessel diseases of the brain (SVDB) remain poorly understood. The objective of this study was to assess the changes affecting depth and surface area of cortical sulci and their clinical and radiological correlates in a cohort of patients with cerebral autosomal dominant arteriolopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic SVDB. Data were obtained from a series of 69 CADASIL patients. Validated methods were used to determine depth and surface area of four cortical sulci. The ratio of brain to intracranial cavity volumes (brain parenchymal fraction--BPF), volume of lacunar lesions (LL) and of white matter hyperintensities, number of cerebral microhaemorrhages, and mean apparent diffusion coefficient were also measured. Association between depth and surface area of the cortical sulci and BPF, clinical status and subcortical MRI lesions were tested. Depth and surface area of cortical sulci obtained in 54 patients were strongly correlated with both cognitive score and disability scales. Depth was related to the extent of subcortical lesions, surface area was related only to age. In additional analyses, the depth of the cingular sulcus was independently associated with the volume of LL (P = 0.001), and that of the superior frontal sulcus with the mean apparent diffusion coefficient (P = 0.003). In CADASIL, important morphological changes of cortical sulci occur in association with clinical worsening, extension of subcortical tissue damage and progression of global cerebral atrophy. These results suggest that the examination of cortical morphology may be of high clinical relevance in SVDB.


More than skin deep. Ten year follow-up of delayed cutaneous adverse drug reactions (CADR).
To determine the gaps in practice regarding appropriate ADR documentation and risk communication for patients diagnosed with severe cutaneous adverse drug reactions (CADR). This was a retrospective observational cohort study conducted using hospital coding and databases to identify inpatients diagnosed with CADR from January 2004 to August 2014. Hospital discharge summaries, ADR reports and pharmacy dispensing records were reviewed for ADR documentation. Patients still living in Australia and who did not opt out of being contacted were invited to be surveyed by telephone to determine their understanding of recommendations, re-exposure rates and long-term effects. Of 85 patients identified, median age was 59 (IQR 44-72) years and 47.1% were male. The most common diagnosis was TENS (49.4%). Ten patients (11.8%) died as inpatients. Of the 81 patients with a drug-related causality, 47 (58%) had appropriate documentation in all three required medical record platforms. Of the 56 eligible patients, 38 (67.9%) were surveyed; 13% had no information provided upon discharge and 26.3% patients had a mismatch in knowledge of implicated medications. No surveyed patient had a relapse of CADR, but 23.7% had a subsequent unrelated allergic reaction. Thirteen patients (34.2%) reported long-term effects. We found gaps in the accuracy of ADR documentation and communication of risk at discharge, which indicated risks to patient safety. Electronic systems are being developed to improve documentation. Written information about CADR is being provided at discharge to improve patient understanding and knowledge.


Depth-of-field expansion method based on multidimensional structure and edge-guided correction.
Multi-focus image fusion is a method to extend the depth of field to generate fully focused images. The effective detection of image focusing pixels and the optimization of image regions are the key to it. A method based on multidimensional structure and edge-guided correction (MSEGC) is proposed. The pixel-level focusing evaluation function is redesigned to preserve image details and non-texture regions. Edge-guided decision correction is used to suppress edge artifacts. With public data and semiconductor detection images for verification, the results show that compared with other methods, the objective evaluation is improved by 22-50%, providing better vision.


Tyrosine 125 of alpha-synuclein plays a critical role for dimerization following nitrative stress.
alpha-Synuclein is a major component of Lewy bodies in Parkinson's disease, dementia with Lewy bodies, and glial cytoplasmic inclusions in multiple system atrophy. Increasing evidence suggests that the nitration of tyrosine residues in alpha-synuclein induced by oxidative injury is involved in the formation of inclusions characteristic to these synucleinopathies. Exposure of alpha-synuclein to peroxynitrite induces nitration of tyrosine residues, thereby forming alpha-synuclein oligomers. However, the contribution of tyrosine residues to either the nitration or the oligomerization is currently unknown. The present study used recombinant wild-type and mutant alpha-synuclein proteins to investigate the role of each alpha-synuclein tyrosine residue in the in vitro formation of alpha-synuclein oligomers under nitrative stress. Confocal microscopic analysis revealed that wild-type alpha-synuclein protein was able to accumulate and form an inclusion-like structure in the cytoplasm of living cells upon introduction by streptolysin O. Authentic peroxynitrite induced nitration of tyrosine residues in alpha-synuclein protein, as well as dimerization of alpha-synuclein. The formation of both SDS- and heat-stable dimers suggests cross-linking between nitrated tyrosine residues. Nonetheless, dimerization of alpha-synuclein proteins lacking tyrosine 125 was significantly decreased compared with alpha-synuclein proteins lacking tyrosine residues at positions 39, 133, or 136. Presumably, tyrosine 125 plays a critical role for alpha-synuclein dimerization under nitrative stress.


Preparation of Plasma Membrane Vesicles from Bone Marrow Mesenchymal Stem Cells for Potential Cytoplasm Replacement Therapy.
We have previously reported on the generation of plasma membrane vesicles (PMVs) through the mechanical extrusion of mammalian cells. The fusion of PMVs with mitochondrial deficient Rho0 cells restored mitotic activity under normal culture conditions. Atherosclerosis, type 2 diabetes, Alzheimer's disease, and cancer are age-related diseases that have been reported to be associated with multiple mechanical and functional defects in the cytosol and organelles of a variety of cell types. Bone marrow mesenchymal stem cells (BMSCs) represent a unique cell population from the bone marrow that possess self-renewal capabilities while maintaining their multipotency. The supplementation of senescence cells with young cytoplasm from autologous BMSCs via the fusion of PMVs provides a promising approach to ameliorate or even reverse age-associated phenotypes. This protocol describes how to prepare PMVs from BMSCs via extrusion through a polycarbonate membrane with 3 µm pores, determine the existence of mitochondria and examine the maintenance of membrane potential within PMVs using a confocal microscope, concentrate PMVs by centrifugation, and carry out the in vivo injection of PMVs into the gastrocnemius muscle of mice.


Role of precision medicine in obstructive sleep apnoea.
Obstructive sleep apnoea is a substantial clinical and public health problem because it contributes to harmful effects on quality of life, daytime symptoms, road traffic incidents, and cardiometabolic disease. Increasingly, obstructive sleep apnoea is recognised as a heterogeneous disease, and patients have varied susceptibility to long term complications and different responses to treatment. This narrative review summarises the current knowledge of precision medicine in obstructive sleep apnoea, particularly the role of symptom clusters, polysomnogram phenotypes, physiological endotypes, and circulating biomarkers in defining subtypes. In the near future, the prognostic accuracy of these measures in predicting long term complications in obstructive sleep apnoea will likely be improved, together with better matching of treatments to disease subtypes.


Histopathological Experience of Primary Adrenal Lymphoma From Two Tertiary Hospitals.
Primary adrenal lymphoma (PAL) is a rare tumor. The aim of this study was to demonstrate the histopathological features of PAL at two tertiary hospitals. All PALs diagnosed between January 2003 and February 2023 were retrieved. Pathology and immunohistochemistry slides were reviewed. Additional immunohistochemical markers were done in selected cases. Follow-up data were obtained. There were 7 cases of PAL. The age range of the patients was 52 to 73 years (median 64 years; mean 63.3 years). There were 4 males (57.1%) and 3 females (42.9%). The clinical manifestations included abdominal pain nausea, vomiting, and loss of weight. There were 4 cases of diffuse large B-cell lymphoma (DLBCL), 2 cases of high-grade B-cell lymphomas, and 1 case of follicular lymphoma. There were 5 cases that were unilateral and 2 cases that were bilateral, and both were high-grade B-cell lymphoma. During follow-up, the 1-year and 2-year overall survival rates were 50% and 33%, respectively. PAL is a disease of the elderly, and DLBCL is the most common pathological type. The prognosis is generally poor. Further reporting of PAL cases might help in understanding this disease and could lead to improvement in its management.


Relationship between Conformation Traits and Lifetime Production Efficiency of Cows.
Analysis was made of the relationship between conformation traits and lifetime production efficiency of the cows that first calved in 2000 and represented the active population in the Pomorze and Kujawy regions of Poland. The CORR Pearson procedures of SAS package were used in the statistical calculations. It was found that there is a statistically significant relationship, weak or low on the Guilford scale, between conformation traits and lifetime production efficiency of the cows, which is slightly higher for milk yield than for longevity. The type and conformation traits appear to be more suitable than the detailed traits for predicting the lifetime production efficiency of cows. Lifetime performance was most strongly related to the overall score and udder score (r = 0.22), followed by the scores for type and conformation and legs and feet (r = 0.13), and detailed traits such as udder width and dairy character (r = 0.14). The highest positive effect on longevity was exerted by udder score and legs and feet (r = 0.11) and among detailed traits by udder placement (r = 0.14) and fore udder attachment (r = 0.10).


Dutch-Cantonese Bilinguals Show Segmental Processing during Sinitic Language Production.
This study addressed the debate on the primacy of syllable vs. segment (i.e., phoneme) as a functional unit of phonological encoding in syllabic languages by investigating both behavioral and neural responses of Dutch-Cantonese (DC) bilinguals in a color-object picture naming task. Specifically, we investigated whether DC bilinguals exhibit the phonemic processing strategy, evident in monolingual Dutch speakers, during planning of their Cantonese speech production. Participants named the color of colored line-drawings in Cantonese faster when color and object matched in the first segment than when they were mismatched (e.g., , /laam4/ /lok3to4/, "blue camel;" , /hung4/ /lok3to4/, "red camel"). This is in contrast to previous studies in Sinitic languages that did not reveal such phoneme-only facilitation. Phonemic overlap also modulated the event-related potentials (ERPs) in the 125-175, 200-300, and 300-400 ms time windows, suggesting earlier ERP modulations than in previous studies with monolingual Sinitic speakers or unbalanced Sinitic-Germanic bilinguals. Conjointly, our results suggest that, while the syllable may be considered the primary unit of phonological encoding in Sinitic languages, the phoneme can serve as the primary unit of phonological encoding, both behaviorally and neurally, for DC bilinguals. The presence/absence of a segment onset effect in Sinitic languages may be related to the proficiency in the Germanic language of bilinguals.


Characterization of a Powdery Mildew Resistance Gene in Wheat Breeding Line 10V-2 and Its Application in Marker-Assisted Selection.
Powdery mildew, caused by Blumeria graminis f. sp. tritici, is a serious disease of wheat (Triticum aestivum L.) throughout the world. Host resistance is the most effective and preferred means for managing this disease. Line 10V-2, a wheat breeding line with superior agronomic performance, shows broad-spectrum seedling resistance to powdery mildew. Genetic analysis demonstrated that its resistance was controlled by a single dominant gene, tentatively designated Pm10V-2. This gene was localized near the documented Pm2 locus on chromosome 5DS using the simple sequence repeat (SSR) marker Cfd81. To saturate the marker map of Pm10V-2, more markers were developed using bulked segregant RNA-Seq. Two single-nucleotide polymorphism (SNP) markers (Swgi047 and Swgi064), three expressed sequence tag markers (Swgi007, Swgi029, and Swgi038), and one SSR marker (Swgi066) were polymorphic between the resistant and susceptible bulks and showed tightly linked to the Pm10V-2 gene. Pm10V-2 was flanked by the new developed markers Swgi064 and Swgi066 at genetic distances of 0.4 and 1.2 centimorgans (cM), respectively, and cosegregated with Swgi007 and Swgi038. The homologous sequence of Pm2a was cloned from 10V-2 based on a recent study. Although the sequence cloned from 10V-2 was completely identical to that of the reported Pm2a-related gene, they did not cosegregate but were separated at a genetic distance of 1.6 cM, indicating that Pm10V-2 was different from the reported of Pm2a-related gene. When inoculated with multiple B. graminis f. sp. tritici isolates, Pm10V-2 had a significantly different resistance spectrum from Pm2a and other powdery mildew (Pm) resistance genes at or near the Pm2 locus. Therefore, Pm10V-2 may be a new Pm2 allele or Pm2-linked gene. To use Pm10V-2 in marker-assisted selection (MAS) breeding, seven markers applicable for MAS were confirmed, including three newly developed markers (Swgi029, Swgi038, and Swgi064) in the present work. Using these markers, a great number of resistant lines with desirable agronomic performance were selected from crosses involving 10V-2, including the breeding line KM5016, which has been entered in the Regional trials in Hebei Province, China.


Comparison of some risk factors for diabetes across different social groups: a cross-sectional study.
In fast, developing economies such as India, the population is undergoing rapid social transition, which can increase the risk profile for diabetes. Market forces promoting lifestyles such as sedentary habits, alcohol and tobacco use, which earlier were more prevalent among affluent urban populations are now trickling into the urban poor and rural populations. The aim of the present research was to compare the prevalence of risk factors for diabetes among three distinct social groups-the urban affluent, the urban poor and the rural poor. A total of 775 adult population over 18 years and belonging to both genders were surveyed for prevalence of some of the risk factors for diabetes such as physical inactivity, obesity, alcohol, and tobacco use. The sample comprised of three distinct social groups as follows; 125 medical students representing the affluent, 400 subjects from urban slums, and 250 subjects from rural areas. Obesity was measured by body mass index (BMI) while central obesity was ascertained by waist hip ratio (WHR). Alcohol and tobacco use were elicited by interview. The overall response rate was 88.52% (686/775). Medical students were more sedentary with mean hours spent each day sitting or reclining at 10.47 (3.25) h, compared to corresponding figures of 6.34 (3.1) h and 7.49 (3.74) h for the rural and urban slum residents respectively (P < 0.001). However, all types of leisure time physical activities were significantly more among the medical students compared to the other groups (P < 0.001). BMI was significantly highest among the rural population with mean of 24.22 (4.17) kg/m(2) when compared to the other groups, (P < 0.001). Villagers also had higher WHR and had a higher proportion of persons above the WHR cut-off for gender (P < 0.001). Experimentation with alcohol was more prevalent among the medical students while the urban slum residents were more frequent and heavy drinkers. Smoking was most prevalent among the medical students, while smokeless tobacco use was more among the other groups. Physical inactivity, obesity, including central obesity, alcohol and tobacco use were found in various degrees in the study samples. An important finding was that both obesity and central obesity ascertained by BMI and WHR respectively were highest among the rural population implying the impact of social change on diabetic risk factors.


Long-term outcome of a residual scar from myocardial infarction after coronary artery bypass grafting: a 100-month study using myocardial perfusion scintigraphy.
The prognosis for patients with a residual scar from myocardial infarction (MI) after coronary artery bypass grafting surgery (CABG) has not been fully evaluated, so the present study retrospectively evaluated such patients with stress myocardial single photon emission computed tomography (SPECT) at 100 months after CABG. The study group consisted of 24 subjects (23 males, 1 female; mean age, 59+/-9 years) in whom CABG had been performed more than 100 months (mean follow-up period 135+/-25 months) previously. The 24 subjects were classified into 3 groups according to their summed stress score (SSS) and summed reversibility score (SRS) in the early period after CABG. Eight subjects with MI (SSS> or =2 and SRS<2) were classified into the group MI, 8 subjects with ischemic myocardium (SSS> or =2 and SRS> or =2) was classified into the group RE, and 8 subjects with normal perfusion (SSS<2 and SRS<2) was classified into group N. None of the subjects in group MI required revascularization. Cardiac events occurred in 4 of the group RE patients and all required revascularization. As to the SPECT scoring system, the long-term SSS of group MI (6.4+/-3.1) was not different from that in the early periods (4.3+/-4.0; NS). However, the long-term SSS values of group RE (8.8+/-6.2) were significantly greater than those soon after CABG (3.4+/-1.8; p=0.03). In group N, there was also no difference in the SSS values between the early period (0.3+/-0.5) and the long-term period (0.0+/-0.0; NS). Patients with a residual scar from MI in the early period after CABG did not worsen over a period of 100 months. Moreover, there was no significant difference in the SPECT score in the segment with the residual scar in the short or long term after CABG. However, the extent of reversibility was directly associated with the presence of clinical events. Therefore scintigraphic imaging remains an important and clinically relevant risk stratification tool. Stress myocardial SPECT, early after CABG, can be used to predict the possibility of future cardiac events or the need for revascularization.