Aspiration Risk Factors, Microbiology, and Empiric Antibiotics for Patients Hospitalized With Community-Acquired Pneumonia.
Aspiration community-acquired pneumonia (ACAP) and community-acquired pneumonia (CAP) in patients with aspiration risk factors (AspRFs) are infections associated with anaerobes, but limited evidence suggests their pathogenic role. What are the aspiration risk factors, microbiology patterns, and empiric anti-anaerobic use in patients hospitalized with CAP? This is a secondary analysis of GLIMP, an international, multicenter, point-prevalence study of adults hospitalized with CAP. Patients were stratified into three groups: (1) ACAP, (2) CAP/AspRF+ (CAP with AspRF), and (3) CAP/AspRF- (CAP without AspRF). Data on demographics, comorbidities, microbiological results, and anti-anaerobic antibiotics were analyzed in all groups. Patients were further stratified in severe and nonsevere CAP groups. We enrolled 2,606 patients with CAP, of which 193 (7.4%) had ACAP. Risk factors independently associated with ACAP were male, bedridden, underweight, a nursing home resident, and having a history of stroke, dementia, mental illness, and enteral tube feeding. Among non-ACAP patients, 1,709 (70.8%) had CAP/AspRF+ and 704 (29.2%) had CAP/AspRF-. Microbiology patterns including anaerobes were similar between CAP/AspRF-, CAP/AspRF+ and ACAP (0.0% vs 1.03% vs 1.64%). Patients with severe ACAP had higher rates of total gram-negative bacteria (64.3% vs 44.3% vs 33.3%, P = .021) and lower rates of total gram-positive bacteria (7.1% vs 38.1% vs 50.0%, P < .001) when compared with patients with severe CAP/AspRF+ and severe CAP/AspRF-, respectively. Most patients (>50% in all groups) independent of AspRFs or ACAP received specific or broad-spectrum anti-anaerobic coverage antibiotics. Hospitalized patients with ACAP or CAP/AspRF+ had similar anaerobic flora compared with patients without aspiration risk factors. Gram-negative bacteria were more prevalent in patients with severe ACAP. Despite having similar microbiological flora between groups, a large proportion of CAP patients received anti-anaerobic antibiotic coverage.


Annular Eruptive Pseudoangiomatosis and Adenovirus Infection: A Novel Clinical Variant of Paraviral Exanthems and a Novel Virus Association.
Eruptive pseudoangiomatosis is a distinct exanthem thought to be caused by viruses. The usual rash configu-ration is erythematous papules and macules. An association with echovirus infection has been reported. We present here one adult and one child with this exanthem, supported by clinical, histopathological, and immunohistochemical findings. Both patients presented with prodromal symptoms, widespread angioma-like macules in annular configuration, blanchable telangiectasia, followed by spontaneous remission in 6-8 weeks. Lesional histopathology of the adult patient revealed dilated dermal blood vessels and lymphohistiocytic infiltrates predominated by CD4+ lymphocytes with a 5:1 ratio of CD4:CD8 lymphocytes. No B cells or CD56+ natural killer cells were found. Serology of both patients revealed evidence of active infections by adenoviruses, and a range of other viruses were excluded. We believe that these 2 patients manifested annular eruptive pseudoangio-matosis, a novel variant of the rash with a probable adenovirus association that has not yet been reported.


Link between risk of colorectal cancer and serum vitamin E levels: A meta-analysis of case-control studies.
The effect of low serum vitamin E levels on the risk of colorectal cancer (CRC) remains inconclusive. This meta-analysis aims to synthesize relevant studies to evaluate the association between serum vitamin E and the risk of CRC based on case-control studies. Potentially relevant studies were selected by searching PubMed, EMBASE, and China National Knowledge Infrastructure databases according to inclusion and exclusion criteria. The association between serum vitamin E levels and CRC was estimated by the weighted mean difference (WMD) and 95% confidence interval (CI) using a random-effects model. Heterogeneity was evaluated using Q test and I statistic. Subgroup analysis was conducted to explore sources of heterogeneity. Sensitivity analysis was performed to reveal stability and reliability. A total of 10 papers with 11 studies, including 6431 subjects with 520 CRC patients and 5981 controls, were included in this present meta-analysis. The results indicated that compared with healthy controls, patients with CRC showed lower concentrations of serum vitamin E (WMD = -2.994 μmol/L, 95% CI = -4.395 to -1.593). Ethnicity subgroup analysis indicated that the serum vitamin E levels were lower in European (WMD = -1.82 μmol/L, 95% CI = -3.00 to -0.65), but not in Asian. Control-source subgroup analysis revealed that a significant association was observed in subgroup with hospital-based controls (WMD = -3.43 μmol/L, 95% CI = -6.27 to -0.59), but not in those with population-based controls. Sensitivity analysis suggested no significant difference in the pooled estimates, indicating stable results. CRC is associated with a lower concentration of serum vitamin E. However, necessary prospective cohort studies should be conducted to assess the effect of serum vitamin E on the risk of CRC in the future.


Induction of tolerance in peripheral T cells with monoclonal antibodies.
Our goal has been to develop ways to tolerize the mature immune system to any defined antigen. In this report we show that peripheral (post-thymic) T cells of mice can become tolerant to a range of antigens (human and rat immunoglobulins, and bone marrow and skin grafts that differ at multiple minor transplantation antigens). In the case of human gamma globulin (HGG), this required that the antigen be given under the cover of a short course of non-depleting anti-CD4 antibody, while for tolerance to skin and marrow grafts anti-CD8 antibody was also required. Tolerance to HGG could be reinforced by repeated injections of HGG, but was lost in the absence of any further exposure to antigen. This reversal of tolerance with time was due to new T cells being exported from the thymus, as it was not observed in tolerized, adult thymectomized mice. In contrast, tolerance to marrow and skin grafts was permanent, presumably because the established grafts acted as a continuous source of antigen to reinforce the tolerant state. Tolerance could not be broken by the infusion of unprimed spleen cells and in one example (tolerance to Mls-1a) there was clear evidence that specific peripheral T cells were anergic. We propose that anergic cells may themselves participate in reinforcing the tolerant state by competing at sites of antigen presentation.


Feather mites and internal parasites in small ground finches (Geospiza fuliginosa, Emberizidae) from the Galapagos Islands (Equador).
During a parasite survey, we collected data on the presence and distribution of feather mites, intestinal parasites, and blood parasites of small ground finches (Geospiza fuliginosa) from 4 islands in the Galapagos. We recorded 4 species of feather mites, with the most common species, Trouessartia geospiza, present on the majority (77% [308/400]) of individuals. Birds with high loads of T. geospiza came from larger islands and had higher body masses. We identified 3 species of intestinal Isospora (Isospora fragmenta, Isospora temeraria, and Isospora exigua) in fecal samples that showed a diurnal pattern of oocyst release. Among samples collected in the afternoon, infection prevalence was 61% (11/18), while only 0.5% (1/192) contained oocysts in the morning. We screened 40 individuals from one island (Isabela) for blood parasites using molecular markers. Although no parasites of Haemoproteus, Leucocytozoon, or Plasmodium were detected, a high proportion of birds (80% [32/40]) had systemic Isospora spp. infections. A high infection prevalence (74% [20/27]), but low infection intensity, was confirmed using optical microscopy. This result could either be due to the detection of a previously unidentified systemic Isospora sp. parasite, or a result of the previously described Isospora spp. parasites causing systemic infections.


Isolation and characterization of Schizosaccharomyces pombe mutants affected in mitotic recombination.
A haploid Schizosaccharomyces pombe strain carrying a heteroallelic duplication of the ade6 gene was used to isolate mitotic recombination-deficient mutants. Recombination between the different copies of the ade6 gene can lead to Ade+ segregants. These are observed as growing papillae when colonies of a suitable size are replicated onto selective medium. We isolated mutants which show an altered papillation phenotype. With two exceptions, they exhibit a decrease in the frequency of mitotic recombination between the heteroalleles of the duplication. The two other mutants display a hyper-recombination phenotype. The 12 mutations were allocated to at least nine distinct loci by recombination tests. Of the eight rec mutants analyzed further, six were also affected in mitotic intergenic recombination in the intervals cen2-mat or cen3-arg 1. No effect on mitotic intragenic recombination was observed. These data suggest that mitotic gene conversion and crossing over can be separated mutationally. Meiotic recombination occurs at the wild-type frequency in all mutants investigated.


From Reef to Table: Social and Ecological Factors Affecting Coral Reef Fisheries, Artisanal Seafood Supply Chains, and Seafood Security.
Ocean and coastal ecosystems provide critical fisheries, coastal protection, and cultural benefits to communities worldwide, but these services are diminishing due to local and global threats. In response, place-based strategies involve communities and resource users in management have proliferated. Here, we present a transferable community-based approach to assess the social and ecological factors affecting resource sustainability and food security in a small-scale, coral reef fishery. Our results show that this small-scale fishery provides large-scale benefits to communities, including 7,353 ± 1547 kg yr(-1) (mean ± SE) of seafood per year, equating to >30,000 meals with an economic value of $78,432. The vast majority of the catch is used for subsistence, contributing to community food security: 58% is kept, 33.5% is given away, and 8.5% is sold. Our spatial analysis assesses the geographic distribution of community beneficiaries from the fishery (the "food shed" for the fishery), and we document that 20% of seafood procured from the fishery is used for sociocultural events that are important for social cohesion. This approach provides a method for assessing social, economic, and cultural values provided by small-scale food systems, as well as important contributions to food security, with significant implications for conservation and management. This interdisciplinary effort aims to demonstrate a transferable participatory research approach useful for resource-dependent communities as they cope with socioeconomic, cultural, and environmental change.


Geographical influences on content of 10-hydroxy-trans-2-decenoic acid in royal jelly in China.
The content of 10-hydroxy-trans-2-decenoic acid (10-HDA), a marker compound in royal jelly (RJ), is the most important criterion in grading RJ for commercial trade and varies with its origin. To identify the effect of geographical origin on 10-HDA content in RJ, 138 samples were collected from 19 provinces of China (divided into three groups) produced by either Apis mellifera ligustica Spinola, 1806 or a hybrid of A. m. ligustica and Apis mellifera carnica Pollman, 1879 and analyzed for moisture, sugar, crude protein, ash, acid, and 10-HDA concentration. The results show that RJ from western China has a significantly higher 10-HDA level (2.01 +/- 0.05%) than those from northeastern (1.87 +/- 0.05%) and eastern (1.75 +/- 0.03%) China. RJ secreted by hybrid bees contained more 10-HDA (1.89 +/- 0.03%) than that secreted by A. m. ligustica (1.78 +/- 0.03%). The 10-HDA content of RJ produced during flowering of rape (Brassica campestris L.), lime (Tilia amurensis Ruprecht), and vitex (Vitex negundo L. variety heterophylla (Franch.) Rehder) was 1.92, 1.80, and 1.68%, respectively. The results would be helpful during the process of price determination of RJ by providing some basis of geographical, bee strain, and botanical information for commercial trade.


Commitment to change statements can predict actual change in practice.
Statements of commitment to change are advocated both to promote and to assess continuing education interventions. However, most studies of commitment to change have used self-reported outcomes, and self-reports may significantly overestimate actual performance. As part of an educational randomized controlled trial, this study documented changes that family physicians committed to make in their prescribing and then used third-party data to examine actual changes. Following participation in a continuing medical education program using interactive small groups, physicians were asked to identify changes that they planned to make in their practices. For prescribing changes related to four conditions, data from a provincial pharmacy registry were analyzed for 6-month periods before and after the educational intervention. A total of 207 physicians participated in the project, which involved monthly meetings of 30 peer learning groups. Ninety-nine physicians received experimental case-based educational modules +/- personal prescribing feedback, and 91 of these indicated that they planned to make at least one change in practice. Of the 209 intended changes, 71% were directly related to the prescribing messages in the materials. In three of four indicator conditions, physicians who expressed a commitment to change were significantly more likely to change their actual prescribing for the target medications in the following 6 months. The percentage of physicians who did change their prescribing varied significantly by condition. Further study of the process of translating commitment to change into real practice change is needed.


Impact of multiple micronutrient versus iron-folic acid supplements on maternal anemia and micronutrient status in pregnancy.
Multiple micronutrient supplements could increase hemoglobin and improve micronutrient status of pregnant women more than iron supplements alone or iron with folic acid. To compare the effects of multiple micronutrients with those of iron supplements alone or iron with folic acid, on hemoglobin and micronutrient status of pregnant women. Studies were identified in which pregnant women were randomized to treatment with multiple micronutrients, or with iron with or without folic acid. A pooled analysis was conducted to compare the effects of these supplements on maternal hemoglobin, anemia, and micronutrient status. Effect size was calculated for individual and combined studies, based on mean change from baseline to final measure in the group receiving iron, with or without folic acid, minus the mean change in the group, divided by the pooled standard deviation of the two groups. The effect on the relative risk of anemia or iron deficiency was calculated as the probability of anemia or iron deficiency in the group receiving multiple micronutrients divided by the probability in the group receiving iron, with or without folic acid. Multiple micronutrient supplements had the same impact on hemoglobin and iron status indicators as iron with or without folic acid. There was no overall effect on serum retinol or zinc. In the only study in which status of other micronutrients was analyzed, a high prevalence of multiple deficiencies persisted in the group receiving multiple micronutrients provided with daily recommended intakes of each nutrient. Multiple micronutrient supplements increased hemoglobin synthesis to the same extent as supplementation with iron with or without folic acid, although often they contained lower amounts of iron. The amount of supplemental iron and other nutrients that can enable pregnant women with micronutrient deficiencies to achieve adequate status remains to be determined.


Heart failure with preserved left ventricular systolic function among patients with non-ST-segment elevation acute coronary syndromes.
Previous studies of non-ST-segment elevation acute coronary syndromes (NSTE ACSs) complicated by heart failure (HF) have focused primarily on patients with left ventricular systolic dysfunction defined by an ejection fraction (EF) <40%. Little is known about HF with preserved systolic function (EF > or =40%) in the NSTE ACS population. We identified high-risk patients with NSTE ACS (ischemic electrocardiographic changes and/or positive cardiac markers) from the CRUSADE quality improvement initiative who had an EF recorded and who had information on HF status. Management and outcomes were analyzed and compared based on the presence or absence of HF and whether left ventricular EF was > or =40%. Of 94,558 patients with NSTE ACS, 21,561 (22.8%) presented with signs of HF, and most had HF with preserved systolic function (n = 11,860, 55%). Mortality rates were 10.7% for HF/systolic dysfunction, 5.8% for HF/preserved systolic function, 5.7% for no HF/systolic dysfunction, and 1.5% for no HF/preserved systolic function. Use of guideline-recommended medical therapies and interventions was frequently significantly lower in those with HF regardless of EF compared with those without HF, except for use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. In conclusion, NSTE ACS complicated by HF with preserved systolic function is common and associated with a 2.3-fold higher mortality compared with NSTE ACS without HF or systolic dysfunction. Guideline-recommended therapies and interventions are under-utilized in patients with NSTE ACS and HF, with and without preserved systolic function, compared with those without HF.


Foley catheter vs oral misoprostol for induction of labor: individual participant data meta-analysis.
To compare the effectiveness and safety of Foley catheter and oral misoprostol for induction of labor (IOL). The Cochrane Review on Mechanical Methods for Induction of Labour and Ovid MEDLINE, EMBASE via Ovid, Ovid Emcare, CINAHL Plus, ClinicalTrials.gov and Scopus, from inception to April 2019, were searched for randomized controlled trials (RCTs) comparing Foley catheter to oral misoprostol for IOL in viable singleton gestations. Eligible trials for which raw data were obtained were included and individual participant data meta-analysis was performed. Primary outcomes were vaginal birth, a composite of adverse perinatal outcome (including stillbirth, neonatal death, neonatal seizures, admission to the neonatal intensive care unit, severe respiratory compromise or meconium aspiration syndrome) and a composite of adverse maternal outcome (including admission to the intensive care unit, maternal infection, severe postpartum hemorrhage, maternal death or uterine rupture). The quality of the included RCTs was assessed using the Cochrane Risk of Bias 2 tool and the certainty of evidence was evaluated using the GRADE approach. A two-stage random-effects model was used for meta-analysis according to the intention-to-treat principle and interactions between treatment and baseline characteristics were assessed. Of seven eligible trials, four provided individual participant data for a total of 2815 participants undergoing IOL, of whom 1399 were assigned to Foley catheter and 1416 to oral misoprostol. All four trials provided data for each of the primary outcomes in all 2815 women. Compared with those receiving oral misoprostol, Foley catheter recipients had a slightly decreased chance of vaginal birth (risk ratio (RR), 0.95 (95% CI, 0.91-0.99); I2 , 2.0%; moderate-certainty evidence). A trend towards a lower rate of composite adverse perinatal outcome was found in women undergoing IOL using a Foley catheter compared with oral misoprostol (RR, 0.71 (95% CI, 0.48-1.05); I2 , 14.9%; low-certainty evidence). Composite adverse maternal outcome did not differ between the groups (RR, 1.00 (95% CI, 0.97-1.03); I2 , 0%; moderate-certainty evidence). Meta-analyses of effect modifications did not show significant interactions between intervention and parity or gestational age for any of the primary outcomes. For women undergoing IOL, Foley catheter is less effective than oral misoprostol, as it was associated with fewer vaginal births. However, while we found no significant difference in maternal safety, Foley catheter induction may reduce adverse perinatal outcomes. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.


Activity of mesenchymal stem cells in therapies for chronic skin wound healing.
Chronic or non-healing skin wounds present an ongoing challenge in advanced wound care, particularly as the number of patients increases while technology aimed at stimulating wound healing in these cases remains inefficient. Mesenchymal stem cells (MSCs) have proved to be an attractive cell type for various cell therapies due to their ability to differentiate into various cell lineages, multiple donor tissue types, and relative resilience in ex-vivo expansion, as well as immunomodulatory effects during transplants. More recently, these cells have been targeted for use in strategies to improve chronic wound healing in patients with diabetic ulcers or other stasis wounds. Here, we outline several mechanisms by which MSCs can improve healing outcomes in these cases, including reducing tissue inflammation, inducing angiogenesis in the wound bed, and reducing scarring following the repair process. Approaches to extend MSC life span in implant sites are also examined.


Parental Understanding of Tuberous Sclerosis Complex.
Tuberous sclerosis complex is a genetic disorder with multisystem involvement that poses significant challenges to the affected child and family. Caregiver knowledge in the South African population has not previously been reported. A prospective study of the parents of 21 children with tuberous sclerosis complex was undertaken. Median parental age was 38 (interquartile range 34.5-45) years. Parents were randomly allocated to receive written information about the condition, or to receive verbal counseling already established in clinic. A significant difference (P = .001) was observed in the change in the mean knowledge scores for the parent group that received written information (34.2 at baseline, 51.7 at the second visit. This impact was higher in parents with an education level of at least grade 8 (P = .003). Parental understanding of tuberous sclerosis complex can be improved by provision of written information and should be routinely available in a readily understandable format.


Late complications of newborn circumcision: a common and avoidable problem.
The purpose of this paper is to study the types of operative and post-operative late complications resulting from newborn circumcisions and to make recommendations to prevent them. After obtaining IRB approval, a retrospective review of the late complications resulting from newborn circumcisions treated at the MassGeneral Hospital for Children from January 2003 to December 2007 was undertaken. The source used was the consultation notes and operative reports of affected patients. Additionally, cases seen in the outpatient Pediatric Urology Clinic from April 2007 to April 2008 were reviewed. A total of 8,967 children were operated during the study period, of which 424 (4.7%) were for complications resulting from previous neonatal circumcision. Penile adhesions, skin bridges, meatal stenosis, redundant foreskin (incomplete circumcision with uncircumcised appearance), recurrent phimosis, buried penis and penile rotation were the most frequent complications. At the outpatient clinic of the Section of Pediatric Urology, 127 boys with concerns following newborn circumcision were evaluated, representing 7.4% of the total volume of cases seen in this clinic. Our results indicate the need to undertake a collaborative study to define the incidence of complications following newborn circumcisions, which should be performed by practitioners with adequate training in the technique of their choice and its post-operative care.


Polyethylene glycol 4000 as a continuously administered non-absorbable faecal marker for metabolic balance studies in human subjects.
The use of polyethylene glycol 4000 as a non-absorbable, continuously fed faecal marker is described. The intestinal handling and transit of polyethylene glycol is compared with that of chromium sesquioxide and barium sulphate. Polyethylene glycol is an acceptable non-absorbable faecal marker for calcium, phosphorus, and fatty acids, and has several features which commend its use in preference to insoluble chromium sesquioxide and barium sulphate particularly when marking water-soluble dietary constituents.


Gout-causing Q141K mutation in ABCG2 leads to instability of the nucleotide-binding domain and can be corrected with small molecules.
The multidrug ATP-binding cassette, subfamily G, 2 (ABCG2) transporter was recently identified as an important human urate transporter, and a common mutation, a Gln to Lys substitution at position 141 (Q141K), was shown to cause hyperuricemia and gout. The nature of the Q141K defect, however, remains undefined. Here we explore the Q141K ABCG2 mutation using a comparative approach, contrasting it with another disease-causing mutation in an ABC transporter, the deletion of Phe-508 (ΔF508) in the cystic fibrosis transmembrane conductance regulator (CFTR). We found, much like in ΔF508 CFTR, that the Q141K mutation leads to instability in the nucleotide-binding domain (NBD), a defect that translates to significantly decreased protein expression. However, unlike the CFTR mutant, the Q141K mutation does not interfere with the nucleotide-binding domain/intracellular loop interactions. This investigation has also led to the identification of critical residues involved in the protein-protein interactions necessary for the dimerization of ABCG2: Lys-473 (K473) and Phe-142 (F142). Finally, we have demonstrated the utility of using small molecules to correct the Q141K defect in expression and function as a possible therapeutic approach for hyperuricemia and gout.


Three-dimensional MR coronary angiography using the navigator technique compared with conventional coronary angiography.
We evaluated the diagnostic accuracy of three-dimensional (3D) MR coronary angiography with the navigator technique for the detection of coronary artery stenoses in comparison with that of conventional radiographic angiography. Thirty patients with coronary artery disease were examined with an ECG-triggered 3D fast low-angle shot sequence using retrospective respiratory gating and the navigator technique on a 1.5-T MR scanner. The data set was evaluated as a 3D view with a surface rendering technique. Imaging of the proximal coronary arteries was possible in all patients. The average visualized lengths of the left main, left anterior descending, left circumflex, and right coronary arteries were 1.9+/-0.5 cm (mean +/- SD), 5.2+/-2.3 cm, 4.2+/-1.9 cm, and 5.2+/-2.5 cm, respectively. Irregular breathing reduced image quality in seven of the 30 patients, making diagnosis of stenoses impossible. In the 77% of patients whose examinations resulted in high-quality images, the sensitivity and specificity for detection of significant stenoses and occlusions in all four main coronary arteries were 81% and 89%, respectively. The navigator technique allows reproducible imaging of the proximal course of coronary arteries. This technique obviates breath-hold studies, thus allowing more patients to be examined. In patients whose examinations resulted in high-quality images, significant coronary artery lesions could be seen. However, for widespread clinical use, further technical improvement is necessary to increase sensitivity and specificity.


Alleviative effect of Ruellia tuberosa L. on NAFLD and hepatic lipid accumulation via modulating hepatic de novo lipogenesis in high-fat diet plus streptozotocin-induced diabetic rats.
Ruellia tuberosa L. (RTL) exhibits phytochemical activities and has been used as a folk medicine for curing diabetes mellitus in East Asia for decades. This study investigated the effect of RTL aqueous and ethanolic extracts on nonalcoholic fatty liver disease (NAFLD) and hepatic lipid accumulation in high-fat diet (HFD) and streptozotocin (STZ)-induced type 2 diabetes mellitus (T2DM) rats. Administration of RTL aqueous extract (RTLW) or ethanolic extract (RTLE) at dosage of 100 or 400 mg/kg body weight for 4 weeks was carried out in HFD/STZ-induced T2DM rats. Liver weight, adipose (epididymal and perirenal adipose tissues) weight, hepatic triglyceride level, and de novo lipogenesis (DNL)-associated protein expression were monitored after scarification. The results revealed that RTLW and RTLE reduced relative liver weight and relative fat weights in HFD/STZ-induced T2DM rats. RTLW and RTLE also ameliorated NAFLD and hepatic triglyceride (TG) accumulation in diabetic rats. Moreover, hepatic DNL-regulated enzymes such as sterol regulatory element-binding protein-1 (SREBP1) and fatty acid synthase (FAS) expression were significantly suppressed by RTLE (100 and 400 mg/kg body weight) in diabetic rats. The evidences of this study suggest that RTL possesses potential on alleviating NAFLD and lipid accumulation via regulating DNL in the liver of HFD/STZ-induced T2DM rats.


Elevated intraocular pressure causes inner retinal dysfunction before cell loss in a mouse model of experimental glaucoma.
We assessed the relationship among intraocular pressure (IOP), histology, and retinal function changes in a mouse model of induced, chronic, mild ocular hypertension. IOP was elevated experimentally via anterior chamber injection of polystyrene beads and measured twice weekly with a rebound tonometer. Histology was assessed with a combination of neurobiotin (NB) retrograde labeling of retinal ganglion cells (RGCs) and TO-PRO3 staining. Retinal function was assessed with serial dark-adapted electroretinograms (ERGs) optimized for detection of the a-wave, b-wave, and positive and negative scotopic threshold responses (pSTR, nSTR). Comparisons between bead-injected and saline-injected (control) eyes were conducted. IOP remained elevated for at least 3 months following a single injection of polystyrene beads. Elevated IOP resulted in a mild, progressive reduction of RGCs, and a mild increase in axial length at 6 and 12 weeks after bead injection. The raw b-wave amplitude was increased shortly after IOP elevation, but the raw a-wave, pSTR, and nSTR amplitudes were unchanged. pSTR and nSTR amplitudes were normalized to the increased b-wave. With this normalization, the pSTR amplitude was decreased shortly after IOP elevation. Polystyrene bead injection results in a mild, chronic elevation of IOP that recapitulates several critical aspects of human ocular hypertension and glaucoma, and results in early changes in retinal electrical function that precede histologic changes. It is possible that glaucoma associated with elevated IOP involves the early disruption of a complex combination of retinal synapses.


Who attracts whom to rural general practice? Variation in temperament and character profiles of GP registrars across different vocational training pathways.
The ongoing rural doctor workforce shortage continues to stimulate interest in new strategies to alleviate the situation. Alongside increasingly promising approaches is the notion that attracting and nurturing the 'right' individuals may be paramount to achieving long-term success in recruitment and retention. This study compares the patterns of demographic and temperament and character trait profiles of general practice registrars in training across three Australian vocational training pathways: the Australian College of Rural and Remote Medicine independent rural pathway, and the rural and general pathways of Australian general practice training. The aim is to describe the predominant personalities of existing trainees. At its foundation, this study strives to obtain more information about those individuals choosing rural practice, which may inform ways to enhance future recruitment and training into rural medicine. This rationale has been explored with medical students using intention as the dependent variable, but registrars are that much closer to their final career choice, and therefore may provide more practical and reliable indicators of the notion of who attracts whom into rural practice. A cross-sectional design sampled four registrar training groups: one from the Australian College of Rural and Remote Medicine, one Australian general practice training rural only, and two Australian general practice training rural and general pathway regional training providers. Registrars (451) completed a questionnaire that gathered basic demographics and a personality trait profile using the Temperament and Character Inventory plus a measure of resilience. Statistical analysis explored the relationships between variables (multivariate analyses of variance) and compared levels of traits between registrar groups (analyses of variance). Registrars training via the Australian College of Rural and Remote Medicine pathway were more likely to be male, older, have a definite interest in or already practising in a rural area and were significantly (with moderate effect sizes) lower in levels of harm avoidance and higher in persistence, self-directedness and resilience compared to the other training pathways. The implications of the data to the recruitment and training of general practice registrars goes further than identifying groups of individuals with similar temperament and character trait patterns. This sample is portrayed as relatively homogenous in light of their overall trait levels as compared to population norms. However, it is the combination of the levels of individual traits that suggests a profile that differs between registrars on a rural or general training path. Importantly the combination of trait levels that tend to differentiate registrars (low harm avoidance, high self-directedness and persistence) correlates strongly with high levels of resilience. Doctors and medical students benefit from a high level of resilience to cope with and manage the challenges of the profession and arguably more so in rural practice. Along with certain demographic characteristics, the combination and levels of temperament (stable) and character (developmental) traits support the notion of a mixture of personal traits that may be indicative of individuals best suited to rural and remote medicine. Further investigation is needed to determine whether individuals with a certain pattern of personal traits are attracted to rural practice training or whether the training itself, in part by exposure to rural life and rural medical practice, selects for those who are most suited to and will eventually choose to practice in a rural location.


Adaptation and Assessment of a Text Messaging Smoking Cessation Intervention in Vietnam: Pilot Randomized Controlled Trial.
Text message (ie, short message service, SMS) smoking cessation interventions have demonstrated efficacy in high-income countries but are less well studied in low- and middle-income countries, including Vietnam. The goal of the research is to assess the feasibility, acceptability, and preliminary efficacy of a fully automated bidirectional SMS cessation intervention adapted for Vietnamese smokers. The study was conducted in 3 phases. In phase 1, we adapted the SMS library from US-based SMS cessation programs (ie, SmokefreeTXT and Text2Quit). The adaptation process consisted of 7 focus groups with 58 smokers to provide data on culturally relevant patterns of tobacco use and assess message preferences. In phase 2, we conducted a single-arm pilot test of the SMS intervention with 40 smokers followed by in-depth interviews with 10 participants to inform additional changes to the SMS library. In phase 3, we conducted a 2-arm pilot randomized controlled trial (RCT) with 100 smokers. Participants received either the SMS program (intervention; n=50) or weekly text assessment on smoking status (control; n=50). The 6-week SMS program consisted of a 2-week prequit period and a 4-week postquit period. Participants received 2 to 4 automated messages per day. The main outcomes were engagement and acceptability which were assessed at 6 weeks (end of intervention). We assessed biochemically confirmed smoking abstinence at 6 weeks and 12 weeks. Postintervention in-depth interviews explored user experiences among a random sample of 16 participants in the intervention arm. Participants in both arms reported high levels of engagement and acceptability. Participants reported using the program for an average of 36.4 (SD 3.4) days for the intervention arm and 36.0 (SD 3.9) days for the control arm. Four of the 50 participants in the intervention arm (8%) reset the quit date and 19 (38%) texted the keyword TIPS. The majority of participants in both arms reported that they always or usually read the text messages. Compared to the control arm, a higher proportion of participants in the intervention arm reported being satisfied with the program (98% [49/50] vs 82% [41/50]). Biochemically verified abstinence was higher in the intervention arm at 6 weeks (20% [10/50] vs 2% [1/50]; P=.01), but the effect was not significant at 12 weeks (12% [6/50] vs 6% [3/50]; P=.49). In-depth interviews conducted after the RCT suggested additional modifications to enhance the program including tailoring the timing of messages, adding more opportunities to interact with the program, and placing a greater emphasis on messages that described the harms of smoking. The study supported the feasibility and acceptability of an SMS program adapted for Vietnamese smokers. Future studies need to assess whether, with additional modifications, the program is associated with prolonged abstinence. ClinicalTrials.gov NCT03219541; https://clinicaltrials.gov/ct2/show/NCT03219541.


Synthesis of a Cu-infiltrated Zr-doped SBA-15 catalyst for CO2 hydrogenation into methanol and dimethyl ether.
A catalytically active nanoassembly comprising Cu-nanoparticles grown on integrated and active supports (large pore Zr-doped mesoporous SBA-15 silica) has been synthesized and used to promote CO2 hydrogenation. The doped mesoporous material was synthesized using a sol-gel method, in which the pore size was tuned between 11 and 15 nm while maintaining a specific surface area of about 700 m2 g-1. The subsequent Cu nanoparticle growth was achieved by an infiltration process involving attachment of different functional groups on the external and internal surfaces of the mesoporous structure such that 7-10 nm sized Cu nanoparticles grew preferentially inside the pores. Chemisorption showed improved absorption of both CO2 and H2 for the assembly compared to pure SBA-15 and 15% of the total CO2 was converted to methanol and dimethyl ether at 250 °C and 33 bar.


Deep genealogical lineages in the widely distributed African helmeted terrapin: evidence from mitochondrial and nuclear DNA (Testudines: Pelomedusidae: Pelomedusa subrufa).
We investigated the phylogeographic differentiation of the widely distributed African helmeted terrapin Pelomedusa subrufa based on 1503 base pairs of mitochondrial DNA (partial cyt b and ND4 genes with adjacent tRNAs) and 1937 bp of nuclear DNA (partial Rag1, Rag2, R35 genes). Congruent among different analyses, nine strongly divergent mitochondrial clades were found, representing three major geographical groupings: (1) A northern group which includes clades I from Cameroon, II from Ghana and Ivory Coast, III from Benin, Burkina Faso and Niger, IV from the Central African Republic, and V from Kenya, (2) a northeastern group consisting of clades VI from Somalia, and VII from Saudi Arabia and Yemen, and (3) a southern group comprising clade VIII from Botswana, the Democratic Republic of Congo, Madagascar and Malawi, and clade IX from South Africa. Malagasy and continental African populations were not clearly differentiated, indicating very recent arrival or introduction of Pelomedusa in Madagascar. The southern group was in some phylogenetic analyses sister to Pelusios, rendering Pelomedusa paraphyletic with respect to that genus. However, using partitioned Bayesian analyses and sequence data of the three nuclear genes, Pelomedusa was monophyletic, suggesting that its mitochondrial paraphyly is due to either ancient introgressive hybridization or phylogenetic noise. Otherwise, nuclear sequence data recovered a lower level of divergence, but corroborated the general differentiation pattern of Pelomedusa as revealed by mtDNA. This, and the depth of the divergences between clades, indicates ancient differentiation. The divergences observed fall within, and in part exceed considerably, the differentiation typically occurring among chelonian species. To test whether Pelomedusa is best considered a single species composed of deep genealogical lineages, or a complex of up to nine distinct species, we suggest a future taxonomic revision that should (1) extend the geographical sampling of molecular data, specifically focusing on contact zones and the possible sympatric occurrence of lineages without admixture, and (2) evaluate the morphology of the various genealogical lineages using the type specimens or topotypical material of the numerous junior synonyms of P. subrufa.


The clinical picture of pancreatic insufficiency.
Minor degrees of pancreatic insufficiency may go unrecognized. There is a paucity of symptoms and physical findings in mild and moderate degrees of insufficiency and in such circumstances laboratory methods are necessary to determine the presence of insufficiency. The clinical picture when insufficiency is well established may be characterized by loss in weight; vague indigestion; voluminous, light-colored, glistening stools in which fat globulets may be seen; changes in the concentration of pancreatic enzymes in the blood indicative of lowered pancreatic function; diminished amounts of pancreatic enzymes in the duodenal juice, and the related poor digestion of fat and protein in the food. Lowered tolerance of carbohydrate, as found in diabetes mellitus, may or may not be present. The location and character of the disease in the pancreas causing the insufficiency may or may not be apparent.


Multicenter validation of a reproducible flow cytometric score for the diagnosis of low-grade myelodysplastic syndromes: results of a European LeukemiaNET study.
The current World Health Organization classification of myelodysplastic syndromes is based morphological evaluation of bone marrow dysplasia. In clinical practice, the reproducibility of the recognition of dysplasia is usually poor especially in cases that lack specific markers such as ring sideroblasts and clonal cytogenetic abnormalities. We aimed to develop and validate a flow cytometric score for the diagnosis of myelodysplastic syndrome. Four reproducible parameters were analyzed: CD34(+) myeloblast-related and B-progenitor-related cluster size (defined by CD45 expression and side scatter characteristics CD34(+) marrow cells), myeloblast CD45 expression and granulocyte side scatter value. The study comprised a "learning cohort" (n=538) to define the score and a "validation cohort" (n=259) to confirm its diagnostic value. With respect to non-clonal cytopenias, patients with myelodysplastic syndrome had increased myeloblast-related cluster size, decreased B-progenitor-related cluster size, aberrant CD45 expression and reduced granulocyte side scatter (P<0.001). To define the flow cytometric score, these four parameters were combined in a regression model and the weight for each variable was estimated based on coefficients from that model. In the learning cohort a correct diagnosis of myelodysplastic syndrome was formulated in 198/281 cases (sensitivity 70%), while 18 false-positive results were noted among 257 controls (specificity 93%). Sixty-five percent of patients without specific markers of dysplasia (ring sideroblasts and clonal cytogenetic abnormalities) were correctly classified. A high value of the flow cytometric score was associated with multilineage dysplasia (P=0.001), transfusion dependency (P=0.02), and poor-risk cytogenetics (P=0.04). The sensitivity and specificity in the validation cohort (69% and 92%, respectively) were comparable to those in the learning cohort. The likelihood ratio of the flow cytometric score was 10. A flow cytometric score may help to establish the diagnosis of myelodysplastic syndrome, especially when morphology and cytogenetics are indeterminate.


Trends in adults receiving a recommendation for exercise or other physical activity from a physician or other health professional.
The Healthy People 2020 objectives for physical activity include two objectives for increasing the proportion of physician office visits that include counseling or education related to exercise (see http://www.healthypeople.gov/2020/default.aspx). Physician counseling for exercise has not previously been tracked by the Healthy People initiative. The present report looks at this emerging health issue from the vantage point of adults in the general population who had seen a physician or other health professional in the past 12 months and had been advised to begin or continue to do exercise or other physical activity. About 8 in 10 adults had seen a health professional in the past 12 months during 2000 (80.6%), 2005 (81.2%), and 2010 (79.8%), although estimates varied by demographic subgroups (10–12). Over time, estimates of the percentage of adults being advised to exercise could be influenced by major changes in the characteristics of adults seeing a health professional. In 2010, about one in three adults (32.4%) who had seen a physician or other health professional in the past year had been advised to exercise or do other physical activity, which reflects an upward trend since 2000, moving in the direction of meeting Healthy People 2020 goals. In relative terms, there has been more than a 40% increase—from 22.6% of adults in 2000 to 32.4% in 2010. Although increases were noted for every population and health condition group studied, these increases were larger for some groups than others. The increase in the percentage of adults receiving exercise advice is particularly noteworthy for the oldest age group. In 2000, 15.3% of adults aged 85 and over had been advised to exercise; by 2010, the percentage had increased to 28.9%. Across the chronic health conditions studied, adults with diabetes were the most likely, and those with cancer were the least likely, to have been advised by their physician to exercise. An upward trend of 8–10 percentage points, however, was seen among adults with each of the chronic diseases examined. Adults who were overweight or obese saw among the largest increases over the decade in the percentage receiving a physician's advice to exercise. The percentage of healthy weight adults receiving exercise advice also increased over the decade, but to a lesser extent. Trends over the past 10 years suggest that the medical community is increasing its efforts to recommend participation in exercise and other physical activity that research has shown to be associated with substantial health benefits. Still, the prevalence of receiving this advice remains well below one-half of U.S. adults and varies substantially across population subgroups.


Cellular Blue Nevomelanocytic Lesions: Analysis of Clinical, Histological, and Outcome Data in 37 Cases.
Cellular blue nevomelanocytic lesions (CBNLs) frequently pose diagnostic problems to pathologists, and their biological potential may be difficult to establish. In this study, the authors have analyzed the clinical, histological, and outcome data of 37 cellular blue nevomelanocytic lesions and the molecular characteristics of 4 lesions. The cohort of cases comprised 8 cellular blue nevi (CBNs), 17 atypical cellular blue nevi (ACBNs), and 12 blue-nevus-like melanomas (BNLMs) with a mean follow-up of 5 years. The average age at diagnosis was 25.9 years for patients with ACBN, versus 30.4 years for CBN, and 44.6 years for BNLM. Both CBN and ACBN occurred most frequently on the trunk or extremities, whereas BNLM primarily involved the scalp. Histologically, CBN and ACBN were characterized by a mean diameter of <1 cm, absence of necrosis, low mitotic rate (mean: 1-2 mitotic figures/mm), little or no infiltrative properties, and usually low-grade cytologic atypia. In contrast, BNLM had a mean diameter of 1.6 cm, necrosis, tissue infiltration, greater mitotic activity (mean: 6 mitotic figures/mm), and high-grade cytologic atypia. ACBNs often were larger, more densely cellular, exhibited higher mitotic counts, and were cytologically more atypical than CBN. Seven CBN cases with follow-up had a benign clinical course (average follow-up of 4.7 years). Among 6 patients with ACBN who underwent sentinel lymph node (SLN) biopsy, 3 were positive, and a single additional case had 1 positive non-SLN (this patient did not have a SLN biopsy performed). All 14 cases of ACBN with follow-up were alive and without recurrence with mean follow-up of 5 years. Of the 9 melanoma cases with follow-up, 3 patients with SLN and non-SLN involvement died from their disease (average follow-up of 4.8 years). Array comparative genomic hybridization was performed on 2 ACBNs and 1 BNLM: One of the 2 ACBNs showed chromosomal aberrations and 1 BNLM showed multiple chromosomal gains and losses. Multiplex polymerase chain reaction was performed on 1 ACBN, and no mutations were found. From these results, the authors conclude that ACBN occupy an intermediate position within the spectrum of CBN and BNLM, yet many lesions cannot be reliably distinguished from either CBN or BNLM because of overlapping histologic features. However, in general, ACBNs seem to aggregate more closely with CBN in terms of clinical, histological, molecular profile (limited data), and biological behavior.


Psilocybin: From Serendipity to Credibility?
Psilocybin has a long history of non-medical use and some seem to infer from this that it has therapeutic utility. Early phase clinical trials with psilocybin are encouraging, but suggest only that larger, multicentre trials are required. These are ongoing but will take many years to complete. Meanwhile, retreat centers offering paid experiences with psilocybin truffles have opened in some countries, often using early phase clinical trial data as a basis for bold, public facing claims. This seems unwise. Early phase trials are not designed for their results to be generalized outside the setting they were undertaken in. To do so risks being misleading. Providing what may be seen as an unregulated drug intervention as a paid service is difficult to reconcile with long-held ethical principles underpinning human research and treatment development that were laid down by the 1947 Nuremberg Code and the 1962 Kefauver Harris Amendments. By using psilocybin before it has been properly tested, retreat centers may be undermining their own credibility and the credibility of the wider field.


Dual roles of dissolved organic matter as sensitizer and quencher in the photooxidation of tryptophan.
The photooxidation processes of tryptophan (Trp) in the presence of dissolved organic matter (DOM) were identified and quantified by steady-state photolysis experiments, laser spectroscopy and kinetic modeling. In sunlight, Trp photooxidation is dominated by the reaction with excited triplet DOM ((3)DOM), accounting for approximately 50-70% of the total degradation, depending on the DOM concentration and source. Reaction with singlet oxygen and direct photolysis are secondary processes that are both still more important than the reaction with hydroxyl radical. Both direct photolysis and reaction with (3)DOM form Trp radical cation (Trp(•+)) via Trp photoionization and direct oxidation, respectively. The Trp(•+) can be converted back to Trp by suitable electron or hydrogen atom donors. Transient absorption spectroscopy shows that DOM itself and low-molecular-weight analogues of redox-active moieties can reduce the lifetime of photochemically produced Trp(•+) and thus quench Trp degradation. This study demonstrates that DOM plays dual roles in the photodegradation of Trp acting as a sensitizer and quencher. The photochemistry of Trp and the participation of DOM have direct implications for photochemical reactions in extracellular proteins as well as for organic compounds in aquatic systems with similar photoionization processes.


Portable spherical array probe for volumetric real-time optoacoustic imaging at centimeter-scale depths.
We report on a novel hand-held imaging probe for real-time optoacoustic visualization of deep tissues in three dimensions. The system incorporates an annular two-dimensional array of ultrasonic sensors densely distributed on a spherical surface. Simultaneous recording and processing of time-resolved data from all the channels enables acquisition of entire volumetric data sets for each illumination laser pulse. The proposed solution utilizes a transparent membrane in order to allow efficient coupling of optoacoustically generated waves to the ultrasonic detectors while avoiding direct contact of the imaged object with the coupling medium. The hand-held approach further allows convenient handling of both pre-clinical experiments as well as clinical measurements in human subjects. Here we demonstrate an imaging speed of 10 volumetric frames per second with spatial resolution down to 200 micrometers in the imaged region while also achieving imaging depth of more than 1.5 cm in living tissues without signal averaging.


Altered regulation of in-vivo coagulation in orthopedic patients prior to knee or hip replacement surgery.
Up to 20% of patients develop venographically proven deep-vein thrombosis after elective orthopedic surgery even under the cover of heparin or low molecular weight heparin. The extent to which the chronic inflammation of osteoarthritis requiring elective orthopedic surgery alters in-vivo coagulation and whether any specific alteration influences the development of postoperative thrombosis are unknown. This study compared the concentrations of activated factor VII (FVIIa), tissue factor pathway inhibitor (TFPI), activated factor X (FXa)-TFPI, thrombin-antithrombin, and prothrombin fragment 1+2 (F1+2) in plasmas of 535 healthy individuals (ages 17-76) with those in the preoperative plasmas of 306 arthritis patients (ages 30-92) scheduled for elective knee or hip replacement surgery. C-reactive protein was also measured in the plasmas of approximately 15% of the participants. Age-adjusted concentrations of FVIIa, F1+2, and C-reactive protein were higher in patients than controls, while the concentrations of thrombin-antithrombin, TFPI and FXa-TFPI were similar. Chronic inflammation in the patients was thus associated with increased coagulation in vivo. Without compensatory increases in the concentrations of TFPI (natural inhibitor of prothrombinase), the elevated concentrations of FVIIa in the preoperative plasmas and the trauma associated with surgery may enhance the risk for developing postoperative deep-vein thrombosis.


Heparin binding epidermal growth factor in renal ischaemia/reperfusion injury.
The epidermal growth factor (EGF) receptor and its ligands are crucially involved in the renal response to ischaemia. We studied the heparin binding-epidermal growth factor (HB-EGF), a major ligand for the EGF receptor, in experimental and human ischaemia/reperfusion injury (IRI). HB-EGF mRNA and protein expression was studied in rat kidneys and cultured human tubular (HK-2) cells that were subjected to IRI and in human donor kidneys during transplantation. The effect of EGF receptor inhibition was investigated in vivo and in vitro. Furthermore, urinary HB-EGF protein excretion was studied after renal transplantation. Finally, HB-EGF KO and WT mice were subjected to IRI to study the role of HB-EGF in renal injury. HB-EGF mRNA was significantly up-regulated in the early phase of IRI in rats, cells, and human donor biopsies. Treatment with PKI-166 reduces macrophage accumulation and interstitial alpha-SMA in the early phase of IRI in rats. In vitro, PKI-166 causes a marked reduction in HB-EGF-induced cellular proliferation. Urinary HB-EGF is increased after transplantation compared with control urines from healthy subjects. HB-EGF KO mice subjected to IRI revealed significantly less morphological damage after IRI, compared with WT mice. We conclude that IRI results in early induction of HB-EGF mRNA and protein in vivo and in vitro. Absence of HB-EGF and inhibition of the EGF receptor in the early phase of IRI has protective effects, suggesting a modulating role for HB-EGF.


Large-scale brain networks account for sustained and transient activity during target detection.
Target detection paradigms have been widely applied in the study of human cognitive functions, particularly those associated with arousal, attention, stimulus processing and memory. In EEG recordings, the detection of task-relevant stimuli elicits the P300 component, a transient response with latency around 300 ms. The P300 response has been shown to be affected by the amount of mental effort and learning, as well as habituation. Furthermore, trial-by-trial variability of the P300 component has been associated with inter-stimulus interval, target-to-target interval or target probability; however, understanding the mechanisms underlying this variability is still an open question. In order to investigate whether it could be related to the distinct cortical networks in which coherent intrinsic activity is organized, and to understand the contribution of those networks to target detection processes, we carried out a simultaneous EEG-fMRI study, collecting data from 13 healthy subjects during a visual oddball task. We identified five large-scale networks, that largely overlap with the dorsal attention, the ventral attention, the core, the visual and the sensory-motor networks. Since the P300 component has been consistently associated with target detection, we concentrated on the first two brain networks, the time-course of which showed a modulation with the P300 response as detected in simultaneous EEG recordings. A trial-by-trial EEG-fMRI correlation approach revealed that they are involved in target detection with different functional roles: the ventral attention network, dedicated to revealing salient stimuli, was transiently activated by the occurrence of targets; the dorsal attention network, usually engaged during voluntary orienting, reflected sustained activity, possibly related to search for targets.


Genetically Encoded Fragment-Based Discovery from Phage-Displayed Macrocyclic Libraries with Genetically Encoded Unnatural Pharmacophores.
Genetically encoded macrocyclic peptide libraries with unnatural pharmacophores are valuable sources for the discovery of ligands for many targets of interest. Traditionally, generation of such libraries employs "early stage" incorporation of unnatural building blocks into the chemically or translationally produced macrocycles. Here, we describe a divergent late-stage approach to such libraries starting from readily available starting material: genetically encoded libraries of peptides. A diketone linchpin 1,5-dichloropentane-2,4-dione converts peptide libraries displayed on phage to 1,3-diketone bearing macrocyclic peptides (DKMP): shelf-stable precursors for Knorr pyrazole synthesis. Ligation of diverse hydrazine derivatives onto DKMP libraries displayed on phage that carries silent DNA-barcodes yields macrocyclic libraries in which the amino acid sequence and the pharmacophore are encoded by DNA. Selection of this library against carbonic anhydrase enriched macrocycles with benzenesulfonamide pharmacophore and nanomolar Kd. The methodology described in this manuscript can graft diverse pharmacophores into many existing genetically encoded phage libraries and significantly increase the value of such libraries in molecular discoveries.


A phase 1 open-label, sequential dose-escalation study investigating the safety, tolerability, and pharmacokinetics of intravenous TLC388 administered to patients with advanced solid tumors.
The first-in-human phase 1 trial examined the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetic profile, and antitumor activity of TLC388, a novel camptothecin with a unique lactone ring modification, in patients with advanced solid tumors. TLC388 was administered intravenously to patients with metastatic chemotherapy refractory solid tumors on days 1, 8, and 15 of a 28-day cycle. Patients underwent tumor assessments every other cycle. Pharmacokinetic samples were drawn on days 1, 8, and 15 of cycles 1 and 2. Fifty-four patients were enrolled at doses ranging from 1.5 to 60.0 mg/m(2) over 12 cohorts. Treatment was generally well-tolerated and no cumulative toxicity observed. Two of six patients treated at 60.0 mg/m(2) developed DLTs of grade 3 neutropenia causing dose delay and grade 3 febrile neutropenia. The next lower dose, 50.0 mg/m(2), was declared as MTD. Treatment-related grade 3-4 hematologic toxicities included neutropenia (19 %), leukopenia (15 %), anemia (9 %), and thrombocytopenia (7 %). Grade 3-4 nonhematologic toxicities included diarrhea (2 %) and hyponatremia (4 %). Pharmacokinetics of both diastereomers (S,R and S,S) of TLC388, a mixture of two diastereomers, was dose independent; mean (SD) values for the volume of distribution at steady-state and clearance were 857 (1122) L/m(2) for S,R and 996 (1333) L/m(2) for S,S, and 2174 (2526) L/h-m(2) for S,R and 2670 (2988) L/h-m(2) for S,S, respectively. The half-life values averaged 0.67 (1.15) hours for S,R and 0.64 (1.11) hours for S,S. The best overall response was stable disease in 21 (39 %) patients. Prolonged (≥ 6 months) stable disease was noted in eight patients. TLC388 at 50 mg/m(2) on the current treatment schedule is generally safe and well tolerated.


Fragment Quantum Mechanical Method for Large-Sized Ion-Water Clusters.
Fragmentation methods have been widely studied for computing quantum mechanical (QM) energy of medium-sized water clusters, but less attention has been paid to large-sized ion-water clusters, in which many-body QM interaction is more significant, because of the charge-transfer effect between ions and water molecules. In this study, we utilized electrostatically embedded generalized molecular fractionation (EE-GMF) method for full QM calculation of the large-sized ion-water clusters (up to 15 Na+ and 15 Cl- ions solvated with 119 water molecules). Through systematic validation using different fragment sizes, we show that, by using distance thresholds of 6 Å for both the two-body and three-body QM interactions, the EE-GMF method is capable of providing accurate ground-state energies of large-sized ion-water clusters at different ab initio levels (including HF, B3LYP, M06-2X, and MP2) with significantly reduced computational cost. The deviations of EE-GMF from full system calculations are within a few kcal/mol. The result clearly shows that the calculated energies of the ion-water clusters using EE-GMF are close to converge after the distance thresholds are larger than 6 Å for both the two-body and three-body QM interactions. This study underscores the importance of the three-body interactions in ion-water clusters. The EE-GMF method can also accurately reproduce the relative energy profiles of the ion-water clusters.


Racial disparities in job strain among American and immigrant long-term care workers.
Nursing homes are occupational settings, with an increasing minority and immigrant workforce where several psychosocial stressors intersect. This study aimed to examine racial/ethnic differences in job strain between Black (n = 127) and White (n = 110) immigrant and American direct-care workers at nursing homes (total n = 237). Cross-sectional study with data collected at four nursing homes in Massachusetts during 2006-2007. We contrasted Black and White workers within higher-skilled occupations such as registered nurses or licensed practical nurses (n = 82) and lower-skilled staff such as certified nursing assistants (CNAs, n = 155). Almost all Black workers (96%) were immigrants. After adjusting for demographic and occupational characteristics, Black employees were more likely to report job strain, compared with Whites [relative risk (RR): 2.9, 95% confidence interval (CI) 1.3 to 6.6]. Analyses stratified by occupation showed that Black CNAs were more likely to report job strain, compared with White CNAs (RR: 3.1, 95% CI: 1.0 to 9.4). Black workers were also more likely to report low control (RR: 2.1, 95% CI: 1.1 to 4.0). Additionally, Black workers earned $2.58 less per hour and worked 7.1 more hours per week on average, controlling for potential confounders. Black immigrant workers were 2.9 times more likely to report job strain than White workers, with greater differences among CNAs. These findings may reflect differential organizational or individual characteristics but also interpersonal or institutional racial/ethnic discrimination. Further research should consider the role of race/ethnicity in shaping patterns of occupational stress.


Autophagy is required for CSF-1-induced macrophagic differentiation and acquisition of phagocytic functions.
Autophagy is the process by which superfluous or damaged macromolecules or organelles are degraded by the lysosome. Pharmacologic and genetic evidence indicates that autophagy plays pleiotropic functions in cellular homeostasis, development, survival, and differentiation. The differentiation of human blood monocytes into macrophages is a caspase-dependent process when triggered ex vivo by colony stimulating factor-1. We show here, using pharmacologic inhibitors, siRNA approaches, and Atg7-/- mice, that autophagy initiated by ULK1 is required for proper colony stimulating factor-1-driven differentiation of human and murine monocytes. We also unravel a role for autophagy in macrophage acquisition of phagocytic functions. Collectively, these findings highlight an unexpected and essential role of autophagy during monocyte differentiation and acquisition of macrophage functions.


A novel online Food Recall Checklist for use in an undergraduate student population: a comparison with diet diaries.
University students are commonly overlooked when diet of populations is measured and there is a lack of comprehensive dietary assessment in whole university student populations. To measure diet of undergraduate students, a new online 121-item Food Recall Checklist (FoRC) was designed as an alternative to a non-weighed record (food diary). This article reports the comparison between the new dietary assessment method (FoRC) and the food diary as a measure of energy (kJ), fat (g), Non-Starch Polysaccharide (NSP) (g), fruit and vegetables (g), breakfast cereal (g) and bread (g) and alcohol (units) intake. Fifty-three students at the University of Aberdeen completed four days of FoRC then four days food diary. Median agreement and correlation between the two methods was assessed for foods and nutrients using the Spearman's rank correlation co-efficient and the Wilcoxon signed ranks test. Agreement between FoRC and food diary was assessed using the Bland-Altman method. The mean time taken to complete FoRC for one day was 7.4 minutes. Intakes of fat (g and % food energy), NSP and bread were similar between FoRC and the food diary. Median energy intake was 8185 kJ in the food diary and 8007 kJ in FoRC. However, FoRC recorded significantly lower intakes of energy and alcohol and significantly higher intakes of fruit and vegetables and breakfast cereal compared with the food diary. There was considerable variation in agreement between methods at the individual level. For all variables except alcohol and percentage energy from fat, correlation co-efficients were statistically significant and greater than 0.5. At the group level, four days of FoRC showed good median agreement with the food diary and there was high correlation between methods for most foods and nutrients. This suggests that this novel method of assessing diet can provide a useful alternative for assessing group mean intakes but that individual intakes may need to be interpreted with care.


Four-year outcomes from a multiparametric magnetic resonance imaging (MRI)-based active surveillance programme: PSA dynamics and serial MRI scans allow omission of protocol biopsies.
To report outcomes from a multiparametric (mp) magnetic resonance imaging (MRI)-based active surveillance programme that did not include performing protocol biopsies after the first confirmatory biopsy. All patients diagnosed with Gleason 3 + 3 prostate cancer because of a raised PSA level who underwent mpMRI after diagnosis were included. Patients were recorded in a prospective clinical database and followed up with PSA monitoring and repeat MRI. In patients who remained on active surveillance after the first MRI (with or without confirmatory biopsy), we investigated PSA dynamics for association with subsequent progression. Comparison between first and second MRI scans was undertaken. Outcomes assessed were: progression to radical therapy at first MRI/confirmatory biopsy and progression to radical therapy in those who remained on active surveillance after first MRI. A total of 211 patients were included, with a median of 4.2 years of follow-up. The rate of progression to radical therapy was significantly greater at all stages among patients with visible lesions than in those with initially negative MRI (47/125 (37.6%) vs 11/86 (12.8%); odds ratio 4.1 (95% CI 2.0-8.5), P < 0.001). Only 1/56 patients (1.8%) with negative initial MRI scans who underwent a confirmatory systematic biopsy had upgrading to Gleason 3 + 4 disease. PSA velocity was significantly associated with subsequent progression in patients with negative initial MRI (area under the curve 0.85 [95% CI 0.75-0.94]; P <0.001). Patients with high-risk visible lesions on first MRI who remained on active surveillance had a high risk of subsequent progression 19/76 (25.0%) vs 9/84 (10.7%) for patients with no visible lesions, despite reassuring targeted and systematic confirmatory biopsies and regardless of PSA dynamics. Men with low-risk Gleason 3 + 3 prostate cancer on active surveillance can forgo protocol biopsies in favour of MRI and PSA monitoring with selective re-biopsy.


One-year investigator-blind randomized multicenter trial comparing Asacol 2.4 g once daily with 800 mg three times daily for maintenance of remission in ulcerative colitis.
Mesalazine (Asacol) is still widely prescribed in divided doses for ulcerative colitis (UC), despite evidence that adherence is improved by once-daily (OD) prescribing. We aimed to investigate whether OD Asacol was as effective as three times (TDS) daily dosing, and to evaluate the role of treatment adherence. An investigator-blind randomized trial was undertaken comparing OD Asacol (three 800 mg tablets) versus one 800 mg TDS in maintenance of remission of UC over 1 year. The primary endpoint was relapse rate, and noninferiority would be concluded if the lower limit of the two-sided 95% confidence interval (CI) of the difference in proportions relapsing (TDS-OD) exceeded -10%. Adherence was measured by tablet counts and self-reported adherence. A subgroup of patients used a bottle cap that recorded all bottle opening events. In all, 213 patients were randomized. In the intention-to-treat (ITT) population, relapse rates were 31% (95% CI 22%-40%) in the OD and 45% (95% CI 35%-54%) in the TDS group. Primary analysis confirmed the noninferiority of OD dosing. Two of the study populations, ITT and per-protocol (PP), showed potential superiority of OD dosing. All measures of adherence showed that it was significantly better in the OD group. Multivariate analysis, however, showed OD dosing was associated with lower relapse risk independently of adherence. OD dosing with Asacol 2.4 g is as safe and effective as TDS dosing, and secondary analysis confirmed significantly reduced relapse rates. The benefit, however, was clinically borderline and may relate in part to ease of adherence.


Quetiapine, QTc interval prolongation, and torsade de pointes: a review of case reports.
Recently, both the manufacturer of quetiapine and the US Food and Drug Administration warned healthcare providers and patients about quetiapine-induced QTc interval prolongation and torsade de pointes (TdP) when using this drug within the approved labeling. We reviewed the case-report literature and found 12 case reports of QTc interval prolongation in the setting of quetiapine administration. There were no cases of quetiapine-induced TdP or sudden cardiac death (SCD) among patients using quetiapine appropriately and free of additional risk factors for QTc interval prolongation and TdP. Among the 12 case reports risk factors included female sex (nine cases), coadministration of a drug associated with QTc interval prolongation (eight cases), hypokalemia or hypomagnesemia (six cases) quetiapine overdose (five cases), cardiac problems (four cases), and coadministration of cytochrome P450 3A4 inhibitors (two cases). There were four cases of TdP. As drug-induced TdP is a rare event, prospective studies to evaluate the risk factors associated with QTc prolongation and TdP are difficult to design, would be very costly, and would require very large samples to capture TdP rather than its surrogate markers. Furthermore, conventional statistical methods may not apply to studies of TdP, which is rare and an 'outlier' manifestation of QTc prolongation. We urge drug manufacturers and regulatory agencies to periodically publish full case reports of psychotropic drug-induced QTc interval prolongation, TdP, and SCD so that clinicians and investigators may better understand the clinical implications of prescribing such drugs as quetiapine.


The role of mitogen-activated protein kinase and protein kinase C in fibronectin production in human vascular smooth muscle cells.
After evaluating various growth factors, cytokines, and extracellular matrix (ECM) proteins, we found that the most potent agonists of smooth muscle cell (SMC) fibronectin (Fn) production were transforming growth factor-beta (TGF-beta) and epidermal growth factor (EGF). To determine the possible signaling pathways involved in the production of this matrix protein, we investigated the role of the intracellular proteins, protein kinase C (PKC) and mitogen-activated protein kinase (MAP-K), in TGF-beta- and EGF-induced human vascular SMC Fn production. After stimulation of human SMCs with TGF-beta (10 ng/ml) and EGF (100 ng/ml), Fn in the cell medium was assayed by immunoblotting using a specific antibody. PKC was activated by brief stimulation of SMC with phorbol 12,13-dibutyrate (PDBu) and inhibited by downregulation with PDBu or the inhibitor, GF109203X. MAP-K was inhibited with PD098059. PKC activation increased basal and synergistically enhanced TGF-beta- and EGF-induced Fn production. However, inhibition of PKC by downregulation and GF109203X did not diminish Fn production by TGF-beta and EGF. Surprisingly, these two methods of inhibition slightly increased basal and agonist-induced Fn production. The MAP-K kinase inhibitor, PD098059, produced an almost complete inhibition of EGF and a partial inhibition of TGF-beta-induced Fn production. Activation of PKC stimulates Fn production; however, neither TGF-beta nor EGF produce Fn through a PKC-dependent pathway. EGF and TGF-beta both stimulate Fn production at least in part through the intracellular signaling protein MAP-K. Understanding the signaling pathways involved in extracellular matrix protein production will allow the design of specific inhibitors of intimal hyperplasia.


[Brain MRI findings in Japanese patients with clinically isolated syndrome].
Treatment of patients with clinically isolated syndrome (CIS) with disease modifying drugs including interferon β delays conversion to clinically definite multiple sclerosis (MS). However, CIS patients do not necessarily develop MS even after 20 years. Brain MRI lesions were required for CIS patients to include in clinical trials such as CHAMPS study and BENEFIT study. CIS patients with brain MRI lesions compatible to MS were considered as high risk to convert to MS in western countries. Previously we reported that asymptomatic enhancing brain lesions (AEBLs) were found in 9/23 (39.1%) of MS patients who had suffered at least one relapse in the preceding year or two relapses in the preceding 2 years, and the number of AEBLs per scan was 0.37, suggesting low disease activity of Japanese MS patients. We examined brain MRI findings in Japanese CIS patients and compared with those of Japanese MS patients at the first presentation. We reviewed brain MRI of 23 CIS visited our clinic from December 2007 to October 2010 who fulfilled the criteria proposed by Kappos et al. (2006) and Dalton et al (2002). Thirty two clinically definite MS (CDMS) patients fulfilled the first McDonald criteria (two or more attacks and objective clinical evidence of two or more lesions) proposed by Polman et al. (2005). Patients with neuromyelitis optica (NMO) and patients with NMO spectrum proposed by Wingerchuk et al. (2006) and Wingerchuk et al. (2007), respectively, were excluded. Patients with anti-aquaporin4 antibodies or with contiguous spinal cord lesion extending over three vertebral segments on MRI were also excluded. We could not obtain MRI of 11 patients with CDMS because of very long disease course, and 2 CIS and 13 CDMS patients had not been examined with MRI. So we examined 21 CIS and 8 CDMS patients at the first presentation using Paty criteria and Barkhof criteria. Eleven CIS patients did not meet any of the Barkhof criteria. Seven and 3 CIS patients met one and two of Barkhof criteria, respectively. No CIS patients showed fulfilled more than 3 of Barkhof criteria. Seven of eight CDMS patients at the first presentation showed more than one of the Barkhof criteria, however, only one CDMS patient at the onset fulfilled more than 3 of the Barkhof criteria. Japanese CIS patients seemed to show less brain lesions than those in western countries.


IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses.
IL-6 is induced often together with the proinflammatory cytokines TNFalpha and IL-1 in many alarm conditions, and circulating IL-6 plays an important role in the induction of acute phase reactions. However, whether this endogenous IL-6 plays any additional pro- or antiinflammatory roles in local or systemic responses remains unclear. In this study, the role of IL-6 in acute inflammatory responses was investigated in animal models of endotoxic lung or endotoxemia by using IL-6+/+ and IL-6-/- mice. Aerosol exposure of endotoxin induced increased IL-6 and proinflammatory cytokines TNFalpha and MIP-2 and a neutrophilic response in the lung of IL-6+/+ mice. However, the levels of TNFalpha and MIP-2 and neutrophilia were significantly higher in the lung of IL-6-/- mice. The rate of neutrophil apoptosis in these mice was similar to that in IL-6+/+ mice. A low constitutive level of antiinflammatory cytokine IL-10 was not enhanced by endotoxin and remained similar in the lung in both IL-6+/+ and IL-6-/- mice. Systemically, intraperitoneal delivery of endotoxin resulted in much more pronounced circulating levels of TNFalpha, MIP-2, GM-CSF, and IFNgamma in IL-6-/- mice than in IL-6+/+ mice, and administration of recombinant IL-6 to IL-6-/- mice abolished these differences. In contrast, circulating IL-10 levels were induced to a similar degree in both IL-6+/+ and IL-6-/- mice. Thus, our studies reveal that endogenous IL-6 plays a crucial antiinflammatory role in both local and systemic acute inflammatory responses by controlling the level of proinflammatory, but not antiinflammatory, cytokines, and that these antiinflammatory activities by IL-6 cannot be compensated for by IL-10 or other IL-6 family members.


Three stage AIDS incubation period: a worst case scenario using addict-needle interaction assumptions.
In this paper we develop and analyse a model for the spread of HIV/AIDS amongst a population of injecting drug users. We start off with a brief literature survey and review; this is followed by the derivation of a model which allows addicts to progress through three distinct stages of variable infectivity prior to the onset of full blown AIDS and where the class of infectious needles is split into three according to the different levels of infectivity in addicts. Given the structure of this model we are required to make assumptions regarding the interaction of addicts and needles of different infectivity levels. We deliberately choose these assumptions so that our model serves as an upper bound for the prevalence of HIV under the assumption of a three stage AIDS incubation period. We then perform an equilibrium and stability analysis on this model. We find that there is a critical threshold parameter R(0) which determines the behaviour of the model. If R(0)< or =1, then irrespective of the initial conditions of the system HIV will die out in all addicts and all needles. If R(0)>1, then there is a unique endemic equilibrium which is locally stable if, as is realistic, the time scale on which addicts inject is much shorter than that of the other epidemiological and demographic processes. Simulations indicate that if R(0)>1, then provided that disease is initially present in at least one addict or needle it will tend to the endemic equilibrium. In addition we derive conditions which guarantee this. We also find that under calibration the long term prevalence of disease in our variable infectivity model is always greater than in an equivalent constant infectivity model. These results are confirmed and explored further by simulation. We conclude with a short discussion.


S100A13 participates in the release of fibroblast growth factor 1 in response to heat shock in vitro.
S100A13, a member of the S100 gene family of Ca(2+)-binding proteins has been previously characterized as a component of a brain-derived heparin-binding multiprotein aggregate/complex containing fibroblast growth factor 1 (FGF1). We report that while expression of S100A13 in NIH 3T3 cells results in the constitutive release of S100A13 into the extracellular compartment at 37 degrees C, co-expression of S100A13 with FGF1 represses the constitutive release of S100A13 and enables NIH 3T3 cells to release S100A13 in response to temperature stress. S100A13 release in response to stress occurs with kinetics similar to that observed for the stress-induced release of FGF1, but S100A13 expression is able to reverse the sensitivity of FGF1 release to inhibitors of transcription and translation. The release of FGF1 and S100A13 in response to heat shock results in the solubility of FGF1 at 100% (w/v) ammonium sulfate saturation, and the expression of a S100A13 deletion mutant lacking its novel basic residue-rich domain acts as a dominant negative effector of FGF1 release in vitro. Surprisingly, the expression of S100A13 also results in the stress-induced release of a Cys-free FGF1 mutant, which is normally not released from NIH 3T3 cells in response to heat shock. These data suggest that S100A13 may be a component of the pathway for the release of the signal peptide-less polypeptide, FGF1, and may involve a role for S100A13 in the formation of a noncovalent FGF1 homodimer.


Mammography screening among Mexican, Central-American, and South-American women.
Cancer and cancer screening disparities exist across Latino subgroups; however the reasons for these disparities are not fully known. This study examines (1) mammography screening among Latinas born in Mexico, Central-America and South-America and (2) the impact of birthplace and acculturation on mammography screening. Data were derived from the California Health Interview Survey 2007. Analyses included 1,675 Latina women 40 years of age and older. Multivariate logistic regression examined predictors of mammography screening. Mexican and Central-American women were less likely to report ever receiving a mammogram while Mexican women were less likely to report a recent mammogram. Low-acculturated women were less likely to report ever receiving a mammogram and less likely to report recent mammography. Different screening patterns across Latina subgroups were observed. Differences in screening patterns and the factors associated with screening highlight the need for unique intervention strategies tailored specifically to Latinas.


Controlled pixelation of inverse opaline structures towards reflection-mode displays.
Pixelated inverse opals with red, green, and blue colors were prepared by hybridizing convective assembly of colloidal particles and photolithography techniques. The brilliant structural colors, high mechanical stability, and small feature size of the pixels were simultaneously accomplished, thereby providing color reflectors potentially useful for display devices. Moreover, this hybridized method provides a general means to create multi-colored photonic crystals.


Technology Ready to be Launched, but is there a Payer? Challenges for Implementing eHealth in Sweden.
The development of a sustainable, high-quality, affordable health care is today a high priority for many actors in the society. This is to ensure that we will continue to afford to care for the growing portion of elderly in our population. One solution is to enable the individual's power over her own health or illness, and participation in her own care. There are evidently opportunities with the rapid development of eHealth and wearable sensors. Tracking and measuring vital data can help to keep people out of the hospital. Loads of data is generated to help us understand disease, to provide us with early diagnostics and warnings. It is providing us with possibilities to collect and capture the true health status of individuals. Successful technologies demonstrate savings, acceptance among users and improved access to healthcare. But there are also challenges. Implementing new technologies in health care is difficult. Researchers from around the world are reporting on similar problems, such as reimbursement, interoperability, usability and regulatory issues. This paper will discuss a few of these implementation challenges as well as a few of the efforts in meeting them. To conclude, eHealth solutions can contribute to patient empowerment and a sustainable health care. Our assumption is however, that as long as we do not face the implementation challenges and invest in overcoming the pressing obstacles, society will not be able, or willing, to pay for the solutions.


New mechanism of nerve injury in Alzheimer's disease: β-amyloid-induced neuronal pyroptosis.
The present study was designed to investigate the role of β-amyloid (Aβ1-42 ) in inducing neuronal pyroptosis and its mechanism. Mice cortical neurons (MCNs) were used in this study, LPS + Nigericin was used to induce pyroptosis in MCNs (positive control group), and Aβ1-42 was used to interfere with MCNs. In addition, propidium iodide (PI) staining was used to examine cell permeability, lactate dehydrogenase (LDH) release assay was employed to detect cytotoxicity, immunofluorescence (IF) staining was used to investigate the expression level of the key protein GSDMD, Western blot was performed to detect the expression levels of key proteins, and enzyme-linked immunosorbent assay (ELISA) was utilized to determine the expression levels of inflammatory factors in culture medium, including IL-1β, IL-18 and TNF-α. Small interfering RNA (siRNA) was used to silence the mRNA expression of caspase-1 and GSDMD, and Aβ1-42 was used to induce pyroptosis, followed by investigation of the role of caspase-1-mediated GSDMD cleavage in pyroptosis. In addition, necrosulfonamide (NSA), an inhibitor of GSDMD oligomerization, was used for pre-treatment, and Aβ1-42 was subsequently used to observe the pyroptosis in MCNs. Finally, AAV9-siRNA-caspase-1 was injected into the tail vein of APP/PS1 double transgenic mice (Alzheimer's disease mice) for caspase-1 mRNA inhibition, followed by observation of behavioural changes in mice and measurement of the expression of inflammatory factors and pyroptosis-related protein. As results, Aβ1-42 could induce pyroptosis in MCNs, increase cell permeability and enhance LDH release, which were similar to the LPS + Nigericin-induced pyroptosis. Meanwhile, the expression levels of cellular GSDMD and p30-GSDMD were up-regulated, the levels of NLRP3 inflammasome and GSDMD-cleaved protein caspase-1 were up-regulated, and the levels of inflammatory factors in the medium were also up-regulated. siRNA intervention in caspase-1 or GSDMD inhibited Aβ1-42 -induced pyroptosis, and NSA pre-treatment also caused the similar inhibitory effects. The behavioural ability of Alzheimer's disease (AD) mice was relieved after the injection of AAV9-siRNA-caspase-1, and the expression of pyroptosis-related protein in the cortex and hippocampus was down-regulated. In conclusion, Aβ1-42 could induce pyroptosis by GSDMD protein, and NLRP3-caspase-1 signalling was an important signal to mediate GSDMD cleavage, which plays an important role in Aβ1-42 -induced pyroptosis in neurons. Therefore, GSDMD is expected to be a novel therapeutic target for AD.


Universal definition of perioperative bleeding in adult cardiac surgery.
Perioperative bleeding is common among patients undergoing cardiac surgery; however, the definition of perioperative bleeding is variable and lacks standardization. We propose a universal definition for perioperative bleeding (UDPB) in adult cardiac surgery in an attempt to precisely describe and quantify bleeding and to facilitate future investigation into this difficult clinical problem. The multidisciplinary International Initiative on Haemostasis Management in Cardiac Surgery identified a common definition of perioperative bleeding as an unmet need. The functionality and usefulness of the UDPB for clinical research was then tested using a large single-center, nonselected, cardiac surgical database. A multistaged definition for perioperative bleeding was created based on easily measured clinical end points, including total blood loss from chest tubes within 12 hours, allogeneic blood products transfused, surgical reexploration including cardiac tamponade, delayed sternal closure, and the need for salvage treatment. Depending on these components, bleeding is graded as insignificant, mild, moderate, severe, or massive. When applied to an established cardiac surgery dataset, the UDPB provided insight into the incidence and outcome of bleeding after cardiac surgery. The proposed UDPB in adult cardiac surgery provides a precise classification of bleeding that is useful in everyday practice as well as in clinical research. Once fully validated, the UDPB may be useful as an institutional quality measure and serve as an important end point in future cardiac surgical research.


Targeted adenovirus gene transfer to endothelial and smooth muscle cells by using bispecific antibodies.
A major hurdle to adenovirus (Ad)-mediated gene transfer is that the target issue lacks sufficient levels of receptors to mediate vector attachment via its fiber coat protein. Endothelial and smooth muscle cells are primary targets in gene therapy approaches to prevent restenosis following angioplasty or to promote or inhibit angiogenesis. However, Ad poorly binds and transduces these cells because of their low or undetectable levels of functional Ad fiber receptor. The Ad-binding deficiency of these cells was overcome by targeting Ad binding to alpha v integrin receptors that are sufficiently expressed by these cells. In order to target alpha v integrins, a bispecific antibody (bsAb) that comprised a monoclonal Ab to the FLAG peptide epitope, DYKDDDDK, and a monoclonal Ab to alpha v integrins was constructed. In conjunction with the bsAb, a new vector, AdFLAG, which incorporated the FLAG peptide epitope into its penton base protein was constructed. Complexing AdFLAG with the bsAb increased the beta-glucuronidase transduction of human venule endothelial cells and human intestinal smooth muscle cells by seven- to ninefold compared with transduction by AdFLAG alone. The increased transduction efficiency was shown to occur through the specific interaction of the complex with alpha v integrins. These results demonstrate that bsAbs can be successfully used to target Ad to a specific cellular receptor and thereby increase the efficiency of gene transfer.


1H, 13C and 15N resonance assignments for the oxidized and reduced states of the N-terminal domain of DsbD from Escherichia coli.
Viability and pathogenicity of Gram-negative bacteria is linked to the cytochrome c maturation and the oxidative protein folding systems in the periplasm. The transmembrane reductant conductor DsbD is a unique protein which provides the necessary reducing power to both systems through thiol-disulfide exchange reactions in a complex network of protein-protein interactions. The N-terminal domain of DsbD (nDsbD) is the delivery point of the reducing power originating from cytoplasmic thioredoxin to a variety of periplasmic partners. Here we report (1)H, (13)C and (15)N assignments for resonances of nDsbD in its oxidized and reduced states. These assignments provide the starting point for detailed investigations of the interactions of nDsbD with its protein partners.


Use of CO2 in video assisted thoracic surgery and single-lumen endotracheal tube-a new less invasive approach.
Carbon dioxide (CO2) has been extensively used to allow laparoscopic procedures, due to its extensive advantages in obtaining a fairly innocuous pneumoperitoneum to allow visceral dissection. Its use in video assisted thoracic surgery (VATS) has seldom been described. We present our experience in more than 100 patients, operated for various thoracic pathologies, in whom we created a surgical pneumothorax to allow different surgeries to be undertaken.


Different factors affecting human ANP amyloid aggregation and their implications in congestive heart failure.
Atrial Natriuretic Peptide (ANP)-containing amyloid is frequently found in the elderly heart. No data exist regarding ANP aggregation process and its link to pathologies. Our aims were: i) to experimentally prove the presumptive association of Congestive Heart Failure (CHF) and Isolated Atrial Amyloidosis (IAA); ii) to characterize ANP aggregation, thereby elucidating IAA implication in the CHF pathogenesis. A significant prevalence (85%) of IAA was immunohistochemically proven ex vivo in biopsies from CHF patients. We investigated in vitro (using Congo Red, Thioflavin T, SDS-PAGE, transmission electron microscopy, infrared spectroscopy) ANP fibrillogenesis, starting from α-ANP as well as the ability of dimeric β-ANP to promote amyloid formation. Different conditions were adopted, including those reproducing β-ANP prevalence in CHF. Our results defined the uncommon rapidity of α-ANP self-assembly at acidic pH supporting the hypothesis that such aggregates constitute the onset of a fibrillization process subsequently proceeding at physiological pH. Interestingly, CHF-like conditions induced the production of the most stable and time-resistant ANP fibrils suggesting that CHF affected people may be prone to develop IAA. We established a link between IAA and CHF by ex vivo examination and assessed that β-ANP is, in vitro, the seed of ANP fibrils. Our results indicate that β-ANP plays a crucial role in ANP amyloid deposition under physiopathological CHF conditions. Overall, our findings indicate that early IAA-related ANP deposition may occur in CHF and suggest that these latter patients should be monitored for the development of cardiac amyloidosis.


Women and tobacco: a call for including gender in tobacco control research, policy and practice.
Female smoking is predicted to double between 2005 and 2025. There have been numerous calls for action on women's tobacco use over the past two decades. In the present work, evidence about female tobacco use, progress, challenges and ways forward for developing gendered tobacco control is reviewed. Literature on girls, women and tobacco was reviewed to identify trends and determinants of tobacco use and exposure, the application of gender analysis, tobacco marketing, the impact of tobacco control on girls and women and ways to address these issues particularly in low-income and middle-income countries. Global female tobacco use is increasingly complex, involving diverse products and factors including tobacco marketing, globalisation and changes in women's status. In high-income countries female smoking is declining but is increasingly concentrated among disadvantaged women. In low-income and middle-income countries the pattern is more complex; in several regions the gap between girls' and boys' smoking is narrow. Gendered analyses and approaches to tobacco control are uncommon, especially in low-income and middle-income countries. Tobacco control has remained largely gender blind, with little recognition of the importance of understanding the context and challenges of girl's and women's smoking and secondhand smoke exposure. There has been little integration of gender considerations in research, policy and programmes. The present work makes a case for gender and diversity analyses in tobacco control to reflect and identify intersecting factors affecting women's tobacco use. This will help animate the WHO Framework Convention on Tobacco Control's concern for gender specificity and women's leadership, and reduce the impact of tobacco on women.