A salvianolic acid B-rich fraction of Salvia miltiorrhiza induces neointimal cell apoptosis in rabbit angioplasty model.
Apoptosis has been suggested to participate in stabilizing cell number in restenosis. Salvia miltiorrhiza (SM) Bunge which is a Chinese herb widely used for the treatment of cardiovascular disorders contains a potent antioxidant, Salvianolic acid B. To determine whether the antioxidant affects vascular apoptosis, the present study examined the frequency of apoptotic cell death in atherosclerotic plaques and in restenotic lesions of cholesterol-fed rabbits. New Zealand White rabbits were treated with a normal diet (normal), a 2% cholesterol diet (HC), a 2% cholesterol diet and endothelial denudation (HC-ED), a 2% cholesterol diet with 5% water-soluble extract of SM (4.8 g/Kg B.W./day) and endothelial denudation (HC-ED-SM), or with a 2% cholesterol diet containing probucol (0.6 g/kg B.W./day) and endothelial denudation (HC-ED-probucol). Apoptosis and associated cell types were examined in serial paraffin sections by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and immunohistochemistry. The expression of p53, an apoptosis-related protein, was also examined. Apoptosis was mainly detected in the neointima of the three groups with endothelial denudation. The percentage of apoptotic cells in SM-treated group (68.5+/-5.9%) was significantly higher than that of normal (0%), HC (1.9+/-1.2%), HC-ED (46.1+/-5.4%), and probucol-treated (32.8+/-3.9%) groups. The SM treatment markedly reduced the thickness of the neointima which was mainly composed of smooth muscle cells with few macrophages. In accordance with the apoptotic cell counts, positive immunoreactivity for p53 was observed in restenotic lesions from HC-ED, SM-treated and probucol-treated groups but not in the intima of the other two groups. These results suggest that the treatment with salvianolic acid B-rich fraction of SM induces apoptosis in neointima which in turn may help prevent the neointimal thickening.


Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial.
Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96-1·28). No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. National Institute for Health Research Health Services and Delivery Research Programme.


Characteristics of successful technological interventions in mental resilience training.
In the last two decades, several effective virtual reality-based interventions for anxiety disorders have been developed. Virtual reality interventions can also be used to build resilience to psychopathology for populations at risk of exposure to traumatic experiences and developing mental disorders as a result, such as for people working in vulnerable professions. Despite the interest among mental health professionals and researchers in applying new technology-supported interventions for pre-trauma mental resilience training, there is a lack of recommendations about what constitutes potentially effective technology-supported resilience training. This article analyses the role of technology in the field of stress-resilience training. It presents lessons learned from technology developers currently working in the area, and it identifies some key clinical requirements for the supported resilience interventions. Two processes made up this research: 1) developers of technology-assisted resilience programs were interviewed regarding human-computer interaction and system development; 2) discussions with clinicians were prompted using technology-centered concept storyboards to elicit feedback, and to refine, validate and extend the initial concepts. A qualitative analysis of the interviews produced a set of development guidelines that engineers should follow and a list of intervention requirements that the technology should fulfill. These recommendations can help bridge the gap between engineers and clinicians when generating novel resilience interventions for people in vulnerable professions.


A Molecular Neurobiological Approach to Understanding the Aetiology of Chronic Fatigue Syndrome (Myalgic Encephalomyelitis or Systemic Exertion Intolerance Disease) with Treatment Implications.
Currently, a psychologically based model is widely held to be the basis for the aetiology and treatment of chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME)/systemic exertion intolerance disease (SEID). However, an alternative, molecular neurobiological approach is possible and in this paper evidence demonstrating a biological aetiology for CFS/ME/SEID is adduced from a study of the history of the disease and a consideration of the role of the following in this disease: nitric oxide and peroxynitrite, oxidative and nitrosative stress, the blood-brain barrier and intestinal permeability, cytokines and infections, metabolism, structural and chemical brain changes, neurophysiological changes and calcium ion mobilisation. Evidence is also detailed for biologically based potential therapeutic options, including: nutritional supplementation, for example in order to downregulate the nitric oxide-peroxynitrite cycle to prevent its perpetuation; antiviral therapy; and monoclonal antibody treatment. It is concluded that there is strong evidence of a molecular neurobiological aetiology, and so it is suggested that biologically based therapeutic interventions should constitute a focus for future research into CFS/ME/SEID.


Regulatory mechanisms and the role of calcium and potassium channels controlling supercontractile crop muscles in adult Phormia regina.
Bioassays and electrophysiological recordings were conducted in the adult blowfly Phormia regina to provide new insights into the regulatory mechanisms governing the crop filling and emptying processes of the supercontractile crop muscles. The cibarial pump drives ingestion. Simultaneous multisite extracellular recordings show that crop lobe (P5) distension during ingestion of a 4.7 μl sugar meal does not require muscle activity by any of the other pumps of the system. Conversely, pumping of fluids toward the anterior of the crop system during crop emptying is brought about by active muscle contraction, in the form of a highly coordinated peristaltic wave starting from P5 and progressively propagating to P6, P4 and P3 pumps, with P5 contracting with a frequency about 3.4 times higher than the other pumps. The crop contraction rate is also modulated by hemolymph-borne factors such as sugars, through ligand recognition at a presumptive receptor site rather than by an osmotic effect, as assessed by both behavioural and electrophysiological experiments. In this respect, sugars of equal osmolarity produce different effects, glucose being inhibitory and mannose ineffective for crop muscles, while trehalose enhances crop activity. Finally, voltage and current clamp experiments show that the muscle action potentials (mAPs) at the P4 pump are sustained by a serotonin-sensitive calcium conductance. Serotonin enhances calcium entry into the muscle cells and this could lead, as an indirect modulatory effect, to activation of a Ca(2+)-activated K(+) conductance (IK(Ca)), which sustains the following mAP repolarization phase in such a way that further mAPs can be generated early and the frequency consequently increased.


Art Meets Sport: What Can Actor Training Bring to Physical Literacy Programs?
The aim of this communication is to highlight synergies and opportunities between the fields of education, sport and health and the performing arts for the promotion of physical literacy. First, physical literacy is introduced and then defined according to the definition used in this communication. Secondly, we highlight the gap in physical literacy interventions, in that they do not address learning based on a holistic comprehensive definition of physical literacy. Then we provide examples of interventions that do borrow from the arts, such as circus arts, and show how these approaches explicitly link to the discipline of arts. This is followed by program examples, which approach motor and language development from discipline-specific perspectives. Then we introduce actor training (within the discipline of arts) in terms of how this approach may be useful to our understanding of physical literacy and how to expand the conception of physical literacy to include affective meaning making, and tolerance for ambiguity and discomfort in not-knowing. Finally, we conclude with the next step for the bridging of disciplines in order to further our journey to understand and improve physical literacy.


Evaluating the impact of a new high dependency unit.
The impact of a new high dependency unit (HDU) that was developed from an adjoining ward was evaluated from both an organizational and consumer perspective. Satisfaction of patients and relatives with nursing care on the ward of origin was measured before and after the development of the HDU, and nurses were surveyed regarding the impact of the change on nursing practices. Patients' perceptions of pain and pain management was compared between patients admitted to the ward prior to the development of the HDU, and a later group admitted to the HDU. Results showed that despite high satisfaction prior to the development of the HDU, satisfaction of patients and relatives improved on the ward after the development of the HDU. Nurses in both areas also described higher satisfaction levels after the change. Patients admitted to the HDU expressed higher levels of satisfaction with nurses' response to analgesia requests and clinical data showed a trend toward lower pain scores in this group compared with pre-HDU patients. The HDU was found to be effective in providing high level care and monitoring for a group of patients at risk of postoperative complications. It was also associated with additional benefits in the running of the adjacent ward.


Histopathologic recognition of involved margins of lentigo maligna excised by staged excision: an interobserver comparison study.
To assess interobserver and intraobserver concordance for identifying positive and negative margins in staged excisions of lentigo maligna and lentigo maligna melanoma and to determine if control biopsy specimens are useful to improve concordance. Retrospective, randomized interobserver and intraobserver comparison study of archived pathologic specimens. The study was conducted in 3 phases, and slides were evaluated blindly and independently by 5 pathologists: in phase 1, all slides were randomized and diagnosed as positive or negative. In phase 2, every third slide was evaluated again and diagnosed as positive or negative. In phase 3, slides were organized into cases, allowing evaluation of each margin in the context of the positive control (tumor from the center of the lesion) and negative control (control biopsy specimen), if available. University referral center. A total of 301 glass microscopic slides from 27 patients who underwent staged excision for lentigo maligna or lentigo maligna melanoma from March 1997 to April 2001. Interobserver and intraobserver concordance between original diagnoses and study diagnoses rendered on all slides by 5 pathologists. Phase 1 and 3 agreement was moderate (kappa range, 0.4-0.5). Phase 2 (intraobserver) agreement was moderate to good for all pathologists (kappa range, 0.6-0.9). Subset analysis revealed a statistically significant increase in agreement with the use of a control strip biopsy specimen for difficult slides. Interobserver concordance for margin analysis in lentigo maligna and lentigo maligna melanoma is moderate, and intraobserver concordance is moderate to good. A control strip biopsy specimen may improve concordance in some cases.


Maternal and amniotic fluid 17 alpha-hydroxyprogesterone levels during pregnancy: diagnosis of congenital adrenal hyperplasia in utero.
17 alpha-Hdroxyprogesterone levels (17 alpha-OHP) were measured in 70 samples of amniotic fluid and 30 samples of maternal serum obtained at different stages of normal pregnancy and in samples of maternal serum and amniotic fluid from a pregnancy with the fetus affected with congenital adrenal hyperplasia. The mean level of 17 alpha-hydroxyprogesterone in the amniotic fluid from control pregnancies was 133.9 +/- 7.6 ng. per 100 ml. (range, 25.1 to 266.6 ng. per 100 ml). The levels were significantly higher in midpregnancy (157.4 +/- 8.4 ng. per 100 ml.) than in late pregnancy (79.2 +/- 6.8 ng. per 100 ml.) (p less than 0.01). Amniotic fluid 17 alpha-OHP levels in the affected pregnancy were significantly higher than the control levels. Mean maternal 17 alpha-OHP level during early pregnancy and midpregnancy was 259.5 +/- 22 ng. per 100 ml. and there was a two-to three-fold increase after 37 weeks (672.2 +/- 61 ng. per 100 ml.) The maternal 17 alpha-OHP levels in the affected pregnancy were significantly higher than the control levels after 34 weeks, but before 34 weeks, the level was within the range seen in control pregnancies. Measurement of 17 alpha-OHP levels in the amniotic fluid before 24 weeks and maternal serum after 34 weeks can be utilized for the prenatal diagnosis of congenital adrenal hyperplasia.


Predicting Anxiety in Routine Palliative Care Using Bayesian-Inspired Association Rule Mining.
We propose a novel knowledge extraction method based on Bayesian-inspired association rule mining to classify anxiety in heterogeneous, routinely collected data from 9,924 palliative patients. The method extracts association rules mined using lift and local support as selection criteria. The extracted rules are used to assess the maximum evidence supporting and rejecting anxiety for each patient in the test set. We evaluated the predictive accuracy by calculating the area under the receiver operating characteristic curve (AUC). The evaluation produced an AUC of 0.89 and a set of 55 atomic rules with one item in the premise and the conclusion, respectively. The selected rules include variables like pain, nausea, and various medications. Our method outperforms the previous state of the art (AUC = 0.72). We analyzed the relevance and novelty of the mined rules. Palliative experts were asked about the correlation between variables in the data set and anxiety. By comparing expert answers with the retrieved rules, we grouped rules into expected and unexpected ones and found several rules for which experts' opinions and the data-backed rules differ, most notably with the patients' sex. The proposed method offers a novel way to predict anxiety in palliative settings using routinely collected data with an explainable and effective model based on Bayesian-inspired association rule mining. The extracted rules give further insight into potential knowledge gaps in the palliative care field.


Purinergic regulation of CFTR and Ca(2+)-activated Cl(-) channels and K(+) channels in human pancreatic duct epithelium.
Purinergic agonists have been considered for the treatment of respiratory epithelia in cystic fibrosis (CF) patients. The pancreas, one of the most seriously affected organs in CF, expresses various purinergic receptors. Studies on the rodent pancreas show that purinergic signaling regulates pancreatic secretion. In the present study we aim to identify Cl(-) and K(+) channels in human pancreatic ducts and their regulation by purinergic receptors. Human pancreatic duct epithelia formed by Capan-1 or CFPAC-1 cells were studied in open-circuit Ussing chambers. In Capan-1 cells, ATP/UTP effects were dependent on intracellular Ca(2+). Apically applied ATP/UTP stimulated CF transmembrane conductance regulator (CFTR) and Ca(2+)-activated Cl(-) (CaCC) channels, which were inhibited by CFTRinh-172 and niflumic acid, respectively. The basolaterally applied ATP stimulated CFTR. In CFPAC-1 cells, which have mutated CFTR, basolateral ATP and UTP had negligible effects. In addition to Cl(-) transport in Capan-1 cells, the effects of 5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one (DC-EBIO) and clotrimazole indicated functional expression of the intermediate conductance K(+) channels (IK, KCa3.1). The apical effects of ATP/UTP were greatly potentiated by the IK channel opener DC-EBIO. Determination of RNA and protein levels revealed that Capan-1 cells have high expression of TMEM16A (ANO1), a likely CaCC candidate. We conclude that in human pancreatic duct cells ATP/UTP regulates via purinergic receptors both Cl(-) channels (TMEM16A/ANO1 and CFTR) and K(+) channels (IK). The K(+) channels provide the driving force for Cl(-)-channel-dependent secretion, and luminal ATP provided locally or secreted from acini may potentiate secretory processes. Future strategies in augmenting pancreatic duct function should consider sidedness of purinergic signaling and the essential role of K(+) channels.


The relational tradition: landscape and canon.
This essay charts the origins, influences, and evolution of the relational tradition in contemporary psychoanalysis. Considering the theoretical and philosophical influences from nineteenth-century Americans like William James and C. S Pierce, and noting the seminal modern work of Steven Mitchell and Jay Greenberg in opening a critique of one-person focused drive theory, the essay follows developments over a quarter century. Hallmarks of the relational approach-social construction, two-person psychologies, multiple self-states, social regulation and construction of identities like gender and sexual orientation, and an evolving theory of clinical practice-are reviewed. New developments in clinical theory, in the study of identity categories, in the work on embodiment and enactment, and in developmental models are also reviewed.


Lead-induced hypertension: role of oxidative stress.
Chronic, low-level lead exposure causes hypertension in both animals and humans. The pathogenesis of lead-induced hypertension is multifactorial, including such diverse mechanisms as: inactivation of endogenous nitric oxide and downregulation of soluble guanylate cyclase by reactive oxygen species (ROS), leading to a functional deficiency in nitric oxide; heightened sympathetic activity and plasma norepinephrine together with depressed vascular and elevated renal beta-adrenergic receptor density; elevated plasma angiotensin-converting enzyme (ACE) activity, plasma renin activity (PRA), angiotensin II (Ang-II), and aldosterone levels; increased kininase I and kininase II activities; lead-induced inhibition of vascular smooth muscle Na(+)-K+ ATPase, leading to a rise in cellular Na+ and, hence, Ca2+; and a possible rise in endothelin and thromboxane generation. In this article, we present an overview of the epidemiology and proposed underlying mechanisms of lead-induced hypertension.


Protective effects of antioxidants against uraemia-induced lipid peroxidation and glutathione depletion in humans.
The effects of uraemias and antioxidant therapy for 40 days with vitamin A, vitamin C and vitamin E on blood and erythrocyte sulfhydryl (glutathione, GSH) content and on erythrocyte glutathione-S transferase (GST), glutathione reductase (GSR) and glutathione peroxidase activities were studied in six uraemic patients maintained on haemodialysis. In addition, the effect of antioxidant therapy on erythrocyte lipid peroxidation was determined, and erythrocyte haemoglobin content was measured. Uraemic patients in dialysis exhibited significant decreases in blood and erythrocyte GSH content as well as significant decreases in the activities of GST, GSR and GSH-peroxidase relative to control subjects. Furthermore, the uraemic patients had elevated erythrocyte malondialdehyde levels. Blood and erythrocyte GSH content from uraemic patients was significantly elevated after 20 days of antioxidant treatment and remained elevated thereafter throughout the remaining 20 days of the study (130% and 173%, respectively). Antioxidant therapy also produced significant increases in GSR and GSH-peroxidase activities after 20 days of treatment which remained relatively constant thereafter. No significant change in GST activity was observed. Erythrocyte malondialdehyde levels, as an index of oxidative tissue damage, exhibited a significant decrease (70%) in the patients after 40 days of antioxidant therapy. A gradual increase in erythrocyte haemoglobin content was observed following treatment of the uraemic subjects (45% at day 40). The results suggest that antioxidant therapy may protect against oxidative stress associated with uraemia.


Typing and clustering of Yersinia pseudotuberculosis isolates by restriction fragment length polymorphism analysis using insertion sequences.
Yersinia pseudotuberculosis is an enteropathogen that has an animal reservoir and causes human infections, mostly in temperate and cold countries. Most of the methods previously used to subdivide Y. pseudotuberculosis were performed on small numbers of isolates from a specific geographical area. One aim of this study was to evaluate the typing efficiency of restriction fragment length polymorphism of insertion sequence hybridization patterns (IS-RFLP) compared to other typing methods, such as serotyping, ribotyping, and multilocus sequence typing (MLST), on the same set of 80 strains of Y. pseudotuberculosis of global origin. We found that IS100 was not adequate for IS-RFLP but that both IS285 and IS1541 efficiently subtyped Y. pseudotuberculosis. The discriminatory index (DI) of IS1541-RFLP (0.980) was superior to those of IS285-RFLP (0.939), ribotyping (0.944), MLST (0.861), and serotyping (0.857). The combination of the two IS (2IS-RFLP) further increased the DI to 0.998. Thus, IS-RFLP is a powerful tool for the molecular typing of Y. pseudotuberculosis and has the advantage of exhibiting well-resolved banding patterns that allow for a reliable comparison of strains of worldwide origin. The other aim of this study was to assess the clustering power of IS-RFLP. We found that 2IS-RFLP had a remarkable capacity to group strains with similar genotypic and phenotypic markers, thus identifying robust populations within Y. pseudotuberculosis. Our study thus demonstrates that 2IS- and even IS1541-RFLP alone might be valuable tools for the molecular typing of global isolates of Y. pseudotuberculosis and for the analysis of the population structure of this species.


Magnetic resonance-coupled fluorescence tomography scanner for molecular imaging of tissue.
A multichannel spectrally resolved optical tomography system to image molecular targets in small animals from within a clinical MRI is described. Long source/detector fibers operate in contact mode and couple light from the tissue surface in the magnet bore to 16 spectrometers, each containing two optical gratings optimized for the near infrared wavelength range. High sensitivity, cooled charge coupled devices connected to each spectrograph provide detection of the spectrally resolved signal, with exposure times that are automated for acquisition at each fiber. The design allows spectral fitting of the remission light, thereby separating the fluorescence signal from the nonspecific background, which improves the accuracy and sensitivity when imaging low fluorophore concentrations. Images of fluorescence yield are recovered using a nonlinear reconstruction approach based on the diffusion approximation of photon propagation in tissue. The tissue morphology derived from the MR images serves as an imaging template to guide the optical reconstruction algorithm. Sensitivity studies show that recovered values of indocyanine green fluorescence yield are linear to concentrations of 1 nM in a 70 mm diameter homogeneous phantom, and detection is feasible to near 10 pM. Phantom data also demonstrate imaging capabilities of imperfect fluorophore uptake in tissue volumes of clinically relevant sizes. A unique rodent MR coil provides optical fiber access for simultaneous optical and MR data acquisition of small animals. A pilot murine study using an orthotopic glioma tumor model demonstrates optical-MRI imaging of an epidermal growth factor receptor targeted fluorescent probe in vivo.


Typing Clostridium difficile strains based on tandem repeat sequences.
Genotyping of epidemic Clostridium difficile strains is necessary to track their emergence and spread. Portability of genotyping data is desirable to facilitate inter-laboratory comparisons and epidemiological studies. This report presents results from a systematic screen for variation in repetitive DNA in the genome of C. difficile. We describe two tandem repeat loci, designated 'TR6' and 'TR10', which display extensive sequence variation that may be useful for sequence-based strain typing. Based on an investigation of 154 C. difficile isolates comprising 75 ribotypes, tandem repeat sequencing demonstrated excellent concordance with widely used PCR ribotyping and equal discriminatory power. Moreover, tandem repeat sequences enabled the reconstruction of the isolates' largely clonal population structure and evolutionary history. We conclude that sequence analysis of the two repetitive loci introduced here may be highly useful for routine typing of C. difficile. Tandem repeat sequence typing resolves phylogenetic diversity to a level equivalent to PCR ribotypes. DNA sequences may be stored in databases accessible over the internet, obviating the need for the exchange of reference strains.


Factors affecting anaemia among women of reproductive age in Nepal: a multilevel and spatial analysis.
The main objective of this study was to explore the factors affecting anaemia among women of reproductive age (WRA) in Nepal using spatial and multilevel epidemiological analysis. This cross-sectional study analysed data from the 2016 Nepal Demographic and Health Survey. Spatial analysis was performed using ArcGIS software V.10.8 to identify the hot and cold spots of anaemia among WRA (15-49 years). Data were analysed using multilevel mixed-effect logistic regression analysis. Nepal. A total of 6414 WRA were included in the analysis. Anaemia defined by WHO as haemoglobin level less than 120 g/L in non-pregnant women and less than 110 g/L in pregnant women. The spatial analysis showed that statistically significant hotspots of anaemia were in the southern Terai region (four districts in province 1, eight districts in province 2, one district in Bagmati province, two districts in province 5 and one district in Sudurpaschim province) of Nepal. At the individual level, women who underwent female sterilisation (adjusted OR, aOR: 3.61, 95% CI 1.10 to 11.84), with no education (aOR: 1.99, 95% CI: 1.17 to 3.39), and from middle socioeconomic class families (aOR: 1.65, 95% CI: 1.02 to 2.68) were more likely to be anaemic, whereas, older women (>35 years) (aOR: 0.51, 95% CI: 0.26 to 0.97) and those women who were using hormonal contraceptives (aOR: 0.63, 95% CI: 0.43 to 0.90) were less likely to be anaemic. At the community level, women from province 2 (aOR=2.97, 95% CI: 1.52 to 5.82) had higher odds of being anaemic. WRA had higher odds of developing anaemia, and it varied by the geographical regions. Nutrition-specific and nutrition-sensitive interventions can be tailored based on the factors identified in this study to curb the high burden of anaemia.


Visual Cues and Food Intake: Distortion Power of Plate and Spoon Size on Overweight and Obese University Staff.
This study was designed to evaluate the effect of the size of plate, spoon, and fork on food and energy intake during a meal in obese or overweight staff. This was a crossover randomized controlled trial that was conducted on 40 obese or overweight clerical staff of the university. The staff was invited to have lunch randomly, receiving either a large or a small set of plate, spoon, and fork. Washout period was 3 weeks, and the participants were then invited to have lunch in a second intervention period and received opposite sizes of dishes compared to the first period sizes. The meal was composed of roasted chicken (kebab), cooked rice, vegetable salad, dairy drink, and soda. Changes in food intake between large and small utensils (plate, spoon, and fork) were analyzed with paired t-test. Rice intake using small or large eating utensils was different (P = 0.02). But total energy intake was not different. The Pearson correlation test demonstrated a positive and significant correlation between rice consumption and waist-to-hip ratio (P = 0.02). Soda (P = 0.02), carbohydrate (P = 0.01), and total energy intake (P = 0.03) were negatively correlated with the age of the participant. It seems that only the amount of grain products consumption changes with changing in dishware size with no significant effect on total energy intake. It is recommended that the independent effect of visual cues on food intake for foods with different textures be investigated in future studies.


Positive and negative gaze perception in autism spectrum conditions.
Eyes are key social features providing a wealth of information about the attention, interest, emotion, and intention of others. Humans are typically very adept at detecting gaze direction, but there is a large decrement in gaze discrimination ability when eye images change from positive to negative polarity. This is thought to show an expert system for gaze perception that applies a contrast-specific heuristic to determine where someone else is looking. Autism spectrum conditions (ASC) are characterized by social deficits including difficulties in face-processing and in the social use of gaze. People with ASC are thought to have less expertise for gaze processing compared to typical controls, though little research has tested this. We investigated gaze direction perception in typical males and females, and males with ASC using facial stimuli with positive or negative polarity of the eyes. Results showed that the ASC group was worse at judging gaze direction with positive stimuli, and showed less of a decrement in performance when eye stimuli changed from positive to negative polarity. The differences in gaze perception for the ASC group were most evident when information from the eyes was more difficult and ambiguous. Typical females performed better at gaze direction detection with positive polarity than typical males, who in turn performed better than males with ASC. This latter finding is consistent with the extreme male brain theory of autism, and with the idea that people with ASC have less gaze expertise.


Exploiting the Genomic Diversity of Rice (Oryza sativa L.): SNP-Typing in 11 Early-Backcross Introgression-Breeding Populations.
This study demonstrates genotyping-by-sequencing-based single-nucleotide polymorphism (SNP)-typing in 11 early-backcross introgression populations of rice (at BC1F5), comprising a set of 564 diverse introgression lines and 12 parents. Sequencing using 10 Ion Proton runs generated a total of ∼943.4 million raw reads, out of which ∼881.6 million reads remained after trimming for low-quality bases. After alignment, 794,297 polymorphic SNPs were identified, and filtering resulted in LMD50 SNPs (low missing data, with each SNP, genotyped in at least 50% of the samples) for each sub-population. Every data point was supported by actual sequencing data without any imputation, eliminating imputation-induced errors in SNP calling. Genotyping substantiated the impacts of novel breeding strategy revealing: (a) the donor introgression patterns in ILs were characteristic with variable introgression frequency in different genomic regions, attributed mainly to stringent selection under abiotic stress and (b) considerably lower heterozygosity was observed in ILs. Functional annotation revealed 426 non-synonymous deleterious SNPs present in 102 loci with a range of 1-4 SNPs per locus and 120 novel SNPs. SNP-typing this diversity panel will further assist in the development of markers supporting genomic applications in molecular breeding programs.


Growth dynamics of gut microbiota in health and disease inferred from single metagenomic samples.
Metagenomic sequencing increased our understanding of the role of the microbiome in health and disease, yet it only provides a snapshot of a highly dynamic ecosystem. Here, we show that the pattern of metagenomic sequencing read coverage for different microbial genomes contains a single trough and a single peak, the latter coinciding with the bacterial origin of replication. Furthermore, the ratio of sequencing coverage between the peak and trough provides a quantitative measure of a species' growth rate. We demonstrate this in vitro and in vivo, under different growth conditions, and in complex bacterial communities. For several bacterial species, peak-to-trough coverage ratios, but not relative abundances, correlated with the manifestation of inflammatory bowel disease and type II diabetes.


Hospital Variation in Health Care Utilization by Children With Medical Complexity.
Although children with medical complexity have high health care needs, little is known about the variation in care provided between centers. This information may be particularly useful in identifying opportunities to improve quality and reduce costs. We conducted a retrospective population-based observational cohort study using all payer claims databases for children aged 30 days to <18 years residing in Maine, New Hampshire, and Vermont from 2007 to 2010. We identified hospital-affiliated cohorts (n = 6) of patients (n = 8216) with medical complexity by using diagnostic codes from both inpatient and outpatient claims. Children were assigned to the hospital where they received the most inpatient days, or their outpatient visits if no hospitalization occurred. Outcomes of interest included patient encounters, medical imaging, and diagnostic testing. Adjusted relative rates were calculated with overdispersed Poisson regression models. Adjusting for patient characteristics, the number of inpatient (relative rate 0.84 vs 2.28) and intensive care days (relative rate 0.45 vs 1.28) varied by more than twofold, whereas office (relative rate 0.77 vs 1.12) and emergency department visits (relative rate 0.71 vs 1.37) varied to a lesser extent. There was also marked variation in the use of imaging, and other diagnostic tests, with particularly high variation in electrocardiography (relative rate 0.35 vs 2.81) and head MRI (relative rate 0.72 vs 2.12). Depending on where they receive care, children with medical complexity experience widely different patterns of utilization. These findings indicate the need for identifying best practices for this growing patient population.


The future of aortic surgery in Europe.
At least every ten years, each specialty should reflect upon its past, its present and its future, in order to be able to reconfirm the direction in which it is headed, to adopt suggestions from inside and outside and, consequently, to improve. As such, the aim of this manuscript is to provide the interested reader with an overview of how aortic surgery and (perhaps more accurately) aortic medicine has evolved in Europe, and its present standing; also to provide a glimpse into the future, trying to disseminate the thoughts of a group of people actively involved in the development of aortic medicine in Europe, namely the Vascular Domain of the European Association of Cardio-Thoracic Surgery (EACTS).


Ambient oxygen promotes tumorigenesis.
Oxygen serves as an essential factor for oxidative stress, and it has been shown to be a mutagen in bacteria. While it is well established that ambient oxygen can also cause genomic instability in cultured mammalian cells, its effect on de novo tumorigenesis at the organismal level is unclear. Herein, by decreasing ambient oxygen exposure, we report a ∼50% increase in the median tumor-free survival time of p53-/- mice. In the thymus, reducing oxygen exposure decreased the levels of oxidative DNA damage and RAG recombinase, both of which are known to promote lymphomagenesis in p53-/- mice. Oxygen is further shown to be associated with genomic instability in two additional cancer models involving the APC tumor suppressor gene and chemical carcinogenesis. Together, these observations represent the first report directly testing the effect of ambient oxygen on de novo tumorigenesis and provide important physiologic evidence demonstrating its critical role in increasing genomic instability in vivo.


Multiplexing of encrypted data using fractal masks.
In this Letter, we present to the best of our knowledge a new all-optical technique for multiple-image encryption and multiplexing, based on fractal encrypting masks. The optical architecture is a joint transform correlator. The multiplexed encrypted data are stored in a photorefractive crystal. The fractal parameters of the key can be easily tuned to lead to a multiplexing operation without cross talk effects. Experimental results that support the potential of the method are presented.


Optical motion control of maglev graphite.
Graphite has been known as a typical diamagnetic material and can be levitated in the strong magnetic field. Here we show that the magnetically levitating pyrolytic graphite can be moved in the arbitrary place by simple photoirradiation. It is notable that the optical motion control system described in this paper requires only NdFeB permanent magnets and light source. The optical movement is driven by photothermally induced changes in the magnetic susceptibility of the graphite. Moreover, we demonstrate that light energy can be converted into rotational kinetic energy by means of the photothermal property. We find that the levitating graphite disk rotates at over 200 rpm under the sunlight, making it possible to develop a new class of light energy conversion system.


Structural characterization of the stem-stem dimerization interface between prolactin receptor chains complexed with the natural hormone.
The most promising approach to targeting the tumor-growth-promoting actions of prolactin (PRL) mediated by its autocrine/paracrine pathway has been the development of specific PRL receptor (PRLR) antagonists. However, the optimization of such antagonists requires a thorough understanding of the activation mechanism of PRLR. We have thus conducted a systematic X-ray crystallographic study in order to visualize the successive steps of PRLR activation by PRL. We report here the structure at 3.35 Å resolution of the 1:2 complex between natural PRL and two PRLR chains (PRLR1 and PRLR2), corresponding to the final activated state of PRLR. Further than our previously published structure involving an affinity-matured PRL variant, this structure allowed to visualize for the first time the loop L5 spanning PRLR2 residues Thr133-Phe140, revealing its central implication for the three intermolecular interfaces of the complex. We equally succeeded in obtaining a comprehensive picture of the PRLR-PRLR dimerization interface, also called stem-stem interface. Site-directed mutagenesis was conducted to probe the energetic importance of stem-stem contacts highlighted by the structure. Surprisingly, in spite of significant structural differences between the PRL/PRLR(2) complex and the 1:2 growth hormone/growth hormone receptor complex, our mutational data suggest that hot-spot residues that stabilize the receptor dimerization interface are equivalent in the two complexes. This study provides a new overall picture of the structural features of PRLR involved in stabilizing its complex with PRL.


Using digital technologies to engage with medical research: views of myotonic dystrophy patients in Japan.
As in other countries, the traditional doctor-patient relationship in the Japanese healthcare system has often been characterised as being of a paternalistic nature. However, in recent years there has been a gradual shift towards a more participatory-patient model in Japan. With advances in technology, the possibility to use digital technologies to improve patient interactions is growing and is in line with changing attitudes in the medical profession and society within Japan and elsewhere. The implementation of an online patient engagement platform is being considered by the Myotonic Dystrophy Registry of Japan. The aim of this exploratory study was to understand patients' views and attitudes to using digital tools in patient registries and engagement with medical research in Japan, prior to implementation of the digital platform. We conducted an exploratory, cross-sectional, self-completed questionnaire with a sample of myotonic dystrophy (MD) patients attending an Open Day at Osaka University, Japan. Patients were eligible for inclusion if they were 18 years or older, and were diagnosed with MD. A total of 68 patients and family members attended the Open Day and were invited to participate in the survey. Of those, 59 % submitted a completed questionnaire (n = 40). The survey showed that the majority of patients felt that they were not receiving the information they wanted from their clinicians, which included recent medical research findings and opportunities to participate in clinical trials, and 88 % of patients indicated they would be willing to engage with digital technologies to receive relevant medical information. Patients also expressed an interest in having control over when and how they received this information, as well as being informed of how their data is used and shared with other researchers. Overall, the findings from this study suggest that there is scope to develop a digital platform to engage with patients so that they can receive information about medical care and research opportunities. While this study group is a small, self-selecting population, who suffer from a particular condition, the results suggest that there are interested populations within Japan that would appreciate enhanced communication and interaction with healthcare teams.


Effect of Tranexamic Acid on Blood Loss, D-Dimer, and Fibrinogen Kinetics in Adult Spinal Deformity Surgery.
Antifibrinolytics such as tranexamic acid reduce operative blood loss and blood product transfusion requirements in patients undergoing surgical correction of scoliosis. The factors involved in the unrelenting coagulopathy seen in scoliosis surgery are not well understood. One potential contributor is activation of the fibrinolytic system during a surgical procedure, likely related to clot dissolution and consumption of fibrinogen. The addition of tranexamic acid during a surgical procedure may mitigate the coagulopathy by impeding the derangement in D-dimer and fibrinogen kinetics. We retrospectively studied consecutive patients who had undergone surgical correction of adult spinal deformity between January 2010 and July 2016 at our institution. Intraoperative hemostatic data, surgical time, estimated blood loss, and transfusion records were analyzed for patients before and after the addition of tranexamic acid to our protocol. Each patient who received tranexamic acid and met inclusion criteria was cohort-matched with a patient who underwent a surgical procedure without tranexamic acid administration. There were 17 patients in the tranexamic acid cohort, with a mean age of 60.7 years, and 17 patients in the control cohort, with a mean age of 60.9 years. Estimated blood loss (932 ± 539 mL compared with 1,800 ± 1,029 mL; p = 0.005) and packed red blood-cell transfusions (1.5 ± 1.6 units compared with 4.0 ± 2.1 units; p = 0.001) were significantly lower in the tranexamic acid cohort. In all single-stage surgical procedures that met inclusion criteria, the rise of D-dimer was attenuated from 8.3 ± 5.0 μg/mL in the control cohort to 3.3 ± 3.2 μg/mL for the tranexamic acid cohort (p < 0.001). The consumption of fibrinogen was 98.4 ± 42.6 mg/dL in the control cohort but was reduced in the tranexamic acid cohort to 60.6 ± 35.1 mg/dL (p = 0.004). In patients undergoing spinal surgery, intravenous administration of tranexamic acid is effective at reducing intraoperative blood loss. Monitoring of D-dimer and fibrinogen during spinal surgery suggests that tranexamic acid impedes the fibrinolytic pathway by decreasing consumption of fibrinogen and clot dissolution as evidenced by the reduced formation of D-dimer. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


The value of blowing up a balloon.
Suboptimal breathing patterns and impairments of posture and trunk stability are often associated with musculoskeletal complaints such as low back pain. A therapeutic exercise that promotes optimal posture (diaphragm and lumbar spine position), and neuromuscular control of the deep abdominals, diaphragm, and pelvic floor (lumbar-pelvic stabilization) is desirable for utilization with patients who demonstrate suboptimal respiration and posture. This clinical suggestion presents a therapeutic exercise called the 90/90 bridge with ball and balloon. This exercise was designed to optimize breathing and enhance both posture and stability in order to improve function and/or decrease pain. Research and theory related to the technique are also discussed.


Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study.
Mosunetuzumab is a CD20 × CD3 T-cell-engaging bispecific monoclonal antibody that redirects T cells to eliminate malignant B cells. In a phase 1 study, mosunetuzumab was well tolerated and active in patients with relapsed or refractory B-cell lymphoma. We, therefore, aimed to evaluate the safety and anti-tumour activity of fixed-duration mosunetuzumab in patients with relapsed or refractory follicular lymphoma who had received two or more previous therapies. We conducted a single-arm, multicentre, phase 2 study at 49 centres in seven countries (Australia, Canada, Germany, South Korea, Spain, UK, and USA). All patients were aged 18 years or older with histologically confirmed follicular lymphoma (grade 1-3a) and an Eastern Cooperative Oncology Group performance status of 0-1. Patients had disease that was relapsed or refractory to two or more previous lines of treatment, including an anti-CD20 therapy and an alkylating agent. Intravenous mosunetuzumab was administered in 21-day cycles with cycle 1 step-up dosing: 1 mg on cycle 1 day 1, 2 mg on cycle 1 day 8, 60 mg on cycle 1 day 15 and cycle 2 day 1, and 30 mg on day 1 of cycle 3 and onwards. Patients with a complete response by investigator assessment using the International Harmonisation Project criteria completed treatment after cycle 8, whereas patients with a partial response or stable disease continued treatment for up to 17 cycles. The primary endpoint was independent review committee-assessed complete response rate (as best response) in all enrolled patients; the primary efficacy analysis compared the observed IRC-assessed complete response rate with a 14% historical control complete response rate in a similar patient population receiving the pan class I PI3K inhibitor copanlisib. Safety was assessed in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02500407, and is ongoing. Between May 2, 2019, and Sept 25, 2020, we enrolled 90 patients. As of the data cutoff date (Aug 27, 2021), the median follow-up was 18·3 months (IQR 13·8-23·3). According to independent review committee assessment, a complete response was recorded in 54 patients (60·0% [95% CI 49·1-70·2]). The observed complete response rate was significantly higher than the historical control complete response rate with copanlisib of 14% (p<0·0001), thereby meeting the primary study endpoint. Cytokine release syndrome was the most common adverse event (40 [44%] of 90 patients) and was predominantly grade 1 (23 [26%] of 90) and grade 2 (15 [17%]), and primarily confined to cycle 1. The most common grade 3-4 adverse events were neutropenia or neutrophil count decreased (24 [27%] of 90 patients), hypophosphataemia (15 [17%]), hyperglycaemia (seven [8%]), and anaemia (seven [8%]). Serious adverse events occurred in 42 (47%) of 90 patients. No treatment-related grade 5 (ie, fatal) adverse event occurred. Fixed-duration mosunetuzumab has a favourable safety profile and induces high rates of complete remissions, allowing potential administration as an outpatient regimen, in patients with relapsed or refractory follicular lymphoma and two or more previous therapies. F Hoffmann-La Roche and Genentech.


Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party.
Measurable residual disease (MRD; previously termed minimal residual disease) is an independent, postdiagnosis, prognostic indicator in acute myeloid leukemia (AML) that is important for risk stratification and treatment planning, in conjunction with other well-established clinical, cytogenetic, and molecular data assessed at diagnosis. MRD can be evaluated using a variety of multiparameter flow cytometry and molecular protocols, but, to date, these approaches have not been qualitatively or quantitatively standardized, making their use in clinical practice challenging. The objective of this work was to identify key clinical and scientific issues in the measurement and application of MRD in AML, to achieve consensus on these issues, and to provide guidelines for the current and future use of MRD in clinical practice. The work was accomplished over 2 years, during 4 meetings by a specially designated MRD Working Party of the European LeukemiaNet. The group included 24 faculty with expertise in AML hematopathology, molecular diagnostics, clinical trials, and clinical medicine, from 19 institutions in Europe and the United States.


Burkholderia pseudomallei in a lowland rice paddy: seasonal changes and influence of soil depth and physico-chemical properties.
Melioidosis, a severe infection with the environmental bacterium Burkholderia pseudomallei, is being recognised increasingly frequently. What determines its uneven distribution within endemic areas is poorly understood. We cultured soil from a rice field in Laos for B. pseudomallei at different depths on 4 occasions over a 13-month period. We also measured physical and chemical parameters in order to identify associated characteristics. Overall, 195 of 653 samples (29.7%) yielded B. pseudomallei. A higher prevalence of B. pseudomallei was found at soil depths greater than the 30 cm currently recommended for B. pseudomallei environmental sampling. B. pseudomallei was associated with a high soil water content and low total nitrogen, carbon and organic matter content. Our results suggested that a sampling grid of 25 five metre square quadrats (i.e. 25 × 25 m) should be sufficient to detect B. pseudomallei at a given location if samples are taken at a soil depth of at least 60 cm. However, culture of B. pseudomallei in environmental samples is difficult and liable to variation. Future studies should both rely on molecular approaches and address the micro-heterogeneity of soil when investigating physico-chemical associations with the presence of B. pseudomallei.


High-level production and optimization of monodispersity of 11beta-hydroxysteroid dehydrogenase type 1.
11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is an intraluminally oriented, endoplasmic reticulum (ER)-bound enzyme catalyzing the interconversion between inactive cortisone and hormonally active cortisol. Heterologous production of 11beta-HSD1, devoid of its N-terminal transmembrane segment, is possible but yields only small amounts of soluble protein. Here we show that the soluble portion of recombinant 11beta-HSD1 produced in E. coli is found mainly as multimeric aggregates in the absence of detergent, and to a large extent associated with the endogenous chaperonin GroEL and other E. coli proteins. By co-overexpressing GroEL/ES and adding an 11beta-HSD1 inhibitor during protein synthesis, we have increased the accumulation of soluble 11beta-HSD1 by more than one order of magnitude. Using monodispersity as a screening criterion, we have also optimized the purification process by evaluating various solubilizing systems for the chromatographic steps, finally obtaining stable monodisperse preparations of both human and guinea pig 11beta-HSD1. By analytical ultracentrifugation, we could demonstrate that 11beta-HSD1 mainly exists as a dimer in the solubilized state. Moreover, active site titration of human 11beta-HSD1 revealed that at least 75% of the protein in a typical preparation represents active enzyme. Equilibrium unfolding experiments indicate that addition of inhibitor and the cofactor NADP(H) can stabilize the conformational stability of this enzyme in an additive manner. The outlined procedure may provide a general method for preparing similar proteins to oligomeric homogeneity and with retained biological activity.


Objective and quantitative definitions of modified food textures based on sensory and rheological methodology.
Patients who suffer from chewing and swallowing disorders, i.e. dysphagia, may have difficulties ingesting normal food and liquids. In these patients a texture modified diet may enable that the patient maintain adequate nutrition. However, there is no generally accepted definition of 'texture' that includes measurements describing different food textures. Objectively define and quantify categories of texture-modified food by conducting rheological measurements and sensory analyses. A further objective was to facilitate the communication and recommendations of appropriate food textures for patients with dysphagia. About 15 food samples varying in texture qualities were characterized by descriptive sensory and rheological measurements. Soups were perceived as homogenous; thickened soups were perceived as being easier to swallow, more melting and creamy compared with soups without thickener. Viscosity differed between the two types of soups. Texture descriptors for pâtés were characterized by high chewing resistance, firmness, and having larger particles compared with timbales and jellied products. Jellied products were perceived as wobbly, creamy, and easier to swallow. Concerning the rheological measurements, all solid products were more elastic than viscous (G'>G''), belonging to different G' intervals: jellied products (low G') and timbales together with pâtés (higher G'). By combining sensory and rheological measurements, a system of objective, quantitative, and well-defined food textures was developed that characterizes the different texture categories.


Novel role of PKR in inflammasome activation and HMGB1 release.
The inflammasome regulates the release of caspase activation-dependent cytokines, including interleukin (IL)-1β, IL-18 and high-mobility group box 1 (HMGB1). By studying HMGB1 release mechanisms, here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. Exposure of macrophages to inflammasome agonists induced PKR autophosphorylation. PKR inactivation by genetic deletion or pharmacological inhibition severely impaired inflammasome activation in response to double-stranded RNA, ATP, monosodium urate, adjuvant aluminium, rotenone, live Escherichia coli, anthrax lethal toxin, DNA transfection and Salmonella typhimurium infection. PKR deficiency significantly inhibited the secretion of IL-1β, IL-18 and HMGB1 in E. coli-induced peritonitis. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. PKR autophosphorylation in a cell-free system with recombinant NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC, also known as PYCARD) and pro-caspase-1 reconstitutes inflammasome activity. These results show a crucial role for PKR in inflammasome activation, and indicate that it should be possible to pharmacologically target this molecule to treat inflammation.


Longitudinal relationship between sleep deficiency and pain symptoms among community-dwelling older adults in Japan and Singapore.
The association of sleep with pain is well documented among adult populations. Even though both sleep problems and pain are prevalent in older adults, the longitudinal and bidirectional relationship between sleep deficiency (i.e. insufficient and poor sleep) and pain is less well established. This study investigated the association between sleep deficiency and pain among community-dwelling adults aged 65 years and older across a 2- to 3-year period. We analyzed cross-country data from the Nihon University Japanese Longitudinal Study of Aging (N = 2888) and the Panel on Health and Aging of Singaporean Elderly (N = 2111). Sleep deficiency was operationalized as self-reported short sleep duration (<6 hours), frequent restlessness during the night, and/or non-restorative sleep. Pain was characterized in terms of any pain, multiple pain locations, and pain-related disability. Demographics, smoking, nap duration, depressive symptoms, chronic conditions, and body mass index were included as covariates. Baseline sleep deficiency was associated with any pain, multiple pain locations, and pain-related disability among older adults at follow-up, although differences by country of residence were observed. In Singaporeans, sleep deficiency predicted the new onset of any pain, and any pain also predicted the new emergence of sleep deficiency. Improving sleep of older adults may improve pain-related symptoms and help intervene on the vicious cycle of pain and sleep deficiency.


Improving compliance with central venous catheter care bundles using electronic records.
Health care associated infections are a major contributor to avoidable harm experienced by patients in modern health care settings. Recent reports suggest that electronic checklists for the documentation of a central line bundle may significantly enhance documented process compliance and help to reduce catheter-related bloodstream infection rates. This paper describes the use of our electronic tool to monitor and feedback process compliance in conjunction of introducing bespoke central line insertion packs to tackle catheter-related bloodstream infections in our intensive care unit in a medium-sized district general hospital. Continuous quality improvement programme with 'Plan-Do-Study-Act' cycles was implemented. The central venous catheter insertion and maintenance bundle was rolled out in 2007. To monitor compliance with the bundle elements, an electronic tool was designed as part of our bedside Clinical Information System. From 2009, regular quarterly feedback was provided on the number of central venous catheter lines inserted, compliance with the insertion and maintenance bundle and catheter-related bloodstream infection rate using the data collected through the Clinical Information System. We have also introduced dedicated line insertion trolleys and factory-prepared insertion packs. We used segmented regression analysis to assess the changes in the catheter-related bloodstream infection rate before and after implementation of the central venous catheter bundle. Bundle compliance increased during the implementation period and reached over 95% within 6 months. We observed a significant reduction in the catheter-related bloodstream infection rate from 15.6/1000 days to 0.4/1000 days. Regression analysis showed that only the compliance had significant effect on the number and prevalence of catheter-related bloodstream infections. Implementation of evidence-based care bundles reinforced by real-time feedback on the performance of caregivers can significantly reduce the rate of catheter-related bloodstream infection in the intensive care unit. Ensuring that change processes are seamlessly integrated in the workflow with minimal administrative burden is crucial to the quality improvement process.


Exenatide reduces oxidative stress and cell death in testis in iron overload rat model.
Glucagon-like peptide-1 (GLP-1) has been demonstrated to affect the oxidative stress status in several in vitro, in vivo and clinical studies. The aim of the present study was to evaluate the effect of a GLP-1 analogue, exenatide, on oxidative stress parameters and apoptotic markers in testicular cells in an iron overload rat model. To obtain this model, the animals were randomly divided into three groups (n=6/group). Rats in the control group received intraperitoneal injections of saline. Intraperitoneal iron dextran (60 mg/kg/day) was given to Group FE for 5 days a week for 4 weeks. The third group (Group Fe +E) was given subcutaneous injections of 10 µg/kg exenatide in two divided doses for 4 weeks in addition to iron dextran. Testes of all rats were immediately removed for immunohistochemical staining and to measure the malondialdehyde level and superoxide dismutase enzyme activity. A significant reduction was observed in caspase-8 and -3 enzyme staining in testicular stromal and endothelial cells in exenatide injected iron overloaded rats when compared with controls. Oxidative stress markers malondialdehyde levels and superoxide dismutase enzyme activities were also significantly lower in exenatide-injected rats when compared with controls. These findings indicate that exenatide may be protective against the harmful effects of iron accumulation in testis. Further studies are required to evaluate how exenatide reduces oxidative stress and cell death in iron overloaded testis tissue.


Initial analysis of the international association for the study of lung cancer mesothelioma database.
The current staging system for malignant pleural mesothelioma (MPM) is controversial. To plan revisions of this system, the International Association for the Study of Lung Cancer Staging Committee developed an international database. Initial analyses focus on patients managed surgically. Participation was solicited from centers known to have MPM registries. Common data elements were analyzed by the International Association for the Study of Lung Cancer Staging Committee Statistical Center. Survival was analyzed by the Kaplan-Meier method, prognostic factors by log rank and Cox regression model. p Value less than 0.05 was significant. Data included 3101 patients (15 centers, 4 continents). median age 63 years, 79% men, 62.3% epithelioid tumor. Best tumor, node, metastasis (bTNM) stages were: I (11%), II, (21%), III (48%), and IV (20%). Curative-intent surgery was performed in 1494 patients (64.5%). Median survivals by clinical TNM and pathological TNM were similar: stage I, 21 months; stage II, 19 months; stage III, 16 months; and stage IV, 12 months. Median survival by histology: epithelioid 19 months, biphasic 13 months, and sarcomatoid 8 months. By multivariable analyses, significant differences in overall survival were seen for: T4 versus T3 and T3 versus T2 but not T2 versus T1; N0 versus N1 and N2 but not N1 versus N2; stages III and IV versus I but not II versus I; epithelioid histology versus other; age of female versus age of male; and palliative versus curative-intent surgery. This is the largest international database examining outcomes in surgically managed MPM patients. Survival differences reported from smaller databases are confirmed but suggest the need to revise tumor and node staging.


Automatic computation of optical focal surfaces.
The use of automatically computed aberration coefficients of arbitrary order for an exact determination of the surface of best focus of a symmetrical system, by minimizing the gyration radius of the spot diagram, is demonstrated. For the two optical systems studied, a Schmidt camera and a Ritchey-Chrétien telescope, the results from the exact model are found to be significantly different from the paraxial approximation predictions.


Glucose utilization and lactate production by Helicobacter pylori.
The transport and incorporation of D-glucose into the human pathogen Helicobacter pylori was investigated employing radioactive tracer analysis and 1H and 13C nuclear magnetic resonance spectroscopy. The bacterium was found to utilize D-glucose contrary to the accepted view that it cannot catabolize carbohydrates. Under the experimental conditions employed, the rate of transport of [14C]glucose was 3.24 mmol min-1 (g protein)-1, and the rate of incorporation into the cellular mass was 1.06 mumol h-1 (g protein)-1. The utilization of [13C]glucose showed biphasic characteristics with a slower initial period followed by a phase with a rate of utilization at least an order of magnitude faster. The apparent rates of decline of glucose levels during both phases varied between strains and depended on the growth conditions of the bacteria prior to harvesting. The main product of glucose catabolism was identified as lactate. These findings provide new perspectives into the physiology of H. pylori and have implications for the active search to develop appropriate therapies for the micro-organism.


Mastering variation: variance components and personalised medicine.
Various sources of variation in observed response in clinical trials and clinical practice are considered, and ways in which the corresponding components of variation might be estimated are discussed. Although the issues have been generally well-covered in the statistical literature, they seem to be poorly understood in the medical literature and even the statistical literature occasionally shows some confusion. To increase understanding and communication, some simple graphical approaches to illustrating issues are proposed. It is also suggested that reducing variation in medical practice might make as big a contribution to improving health outcome as personalising its delivery according to the patient. It is concluded that the common belief that there is a strong personal element in response to treatment is not based on sound statistical evidence.


Plant poisoning in domestic animals: epidemiological data from an Italian survey (2000-2011).
An Italian epidemiological study based on the human Poison Control Centre of Milan (Centro Antiveleni di Milano (CAV)) data related to domestic animal poisoning by exposure to plants, was carried out in collaboration with the Veterinary Toxicology Section of the University of Milan. It encompasses a 12-year period, from the beginning of 2000 to the end of 2011. Calls related to toxic plants accounted for 5.7 per cent of total inquiries (2150) received by CAV. The dog was the most commonly poisoned species (61.8 per cent of calls) followed by the cat (26 per cent). Little information was recorded for other species. Most exposures (73.8 per cent) resulted in mild to moderate clinical signs. The outcome was reported in only 53.7 per cent of cases, and fatal poisoning accounted for 10.6 per cent of these cases. Glycoside, alkaloid, oxalate, toxalbumin, saponin, terpene and terpenoid-containing plants were recorded and found to be responsible for intoxication. Cycas revoluta, Euphorbia pulcherrima, Hydrangea macrophylla, Nerium oleander, Rhododendron species and Prunus species were the plants most frequently involved. Epidemiological data from this Italian survey provide useful information on animal exposure to plants and confirm the importance of plants as causative agents of animal poisoning.


Climate-driven diversification in two widespread Galerida larks.
The major impact of Plio-Pleistocene climatic oscillations on the current genetic structure of many species is widely recognised but their importance in driving speciation remains a matter of controversies. In addition, since most studies focused on Europe and North America, the influence of many other biogeographic barriers such as the Sahara remains poorly understood. In this paper, climate-driven diversification was investigated by using a comparative phylogeographic approach in combination with phenotypic data in two avian species groups distributed on both sides of the deserts belt of Africa and Asia. In particular, we tested whether: 1) vicariance diversification events are concomitant with past climatic events; and 2) current ecological factors (using climate and competition as proxies) contribute to phenotypic divergence between allopatric populations. Mitochondrial and nuclear sequence data indicated that the crested and Thekla lark species groups diverged in the early Pliocene and that subsequent speciation events were congruent with major late Pliocene and Pleistocene climatic events. In particular, steep increase in aridity in Africa near 2.8 and 1.7 million years ago were coincident with two north-south vicariance speciation events mediated by the Sahara. Subsequent glacial cycles of the last million years seem to have shaped patterns of genetic variation within the two widespread species (G. cristata and G. theklae). The Sahara appears to have allowed dispersal from the tropical areas during climatic optima but to have isolated populations north and south of it during more arid phases. Phenotypic variation did not correlate with the history of populations, but was strongly influenced by current ecological conditions. In particular, our results suggested that (i) desert-adapted plumage evolved at least three times and (ii) variation in body size was mainly driven by interspecific competition, but the response to competition was stronger in more arid areas. Climatic fluctuations of the Plio-Pleistocene strongly impacted diversification patterns in the Galerida larks. Firstly, we found that cladogenesis coincides with major climatic changes, and the Sahara appears to have played a key role in driving speciation events. Secondly, we found that morphology and plumage were strongly determined by ecological factors (interspecific competition, climate) following vicariance.


Modulation of Pro-Oxidant and Pro-Inflammatory Activities of M1 Macrophages by the Natural Dipeptide Carnosine.
Carnosine is a natural endogenous dipeptide widely distributed in mammalian tissues, existing at particularly high concentrations in the muscles and brain and possesses well-characterized antioxidant and anti-inflammatory activities. In an in vitro model of macrophage activation, induced by lipopolysaccharide + interferon-gamma (LPS + IFN-γ), we here report the ability of carnosine to modulate pro-oxidant and pro-inflammatory activities of macrophages, representing the primary cell type that is activated as a part of the immune response. An ample set of parameters aimed to evaluate cytotoxicity (MTT assay), energy metabolism (HPLC), gene expressions (high-throughput real-time PCR (qRT-PCR)), protein expressions (western blot) and nitric oxide production (qRT-PCR and HPLC), was used to assess the effects of carnosine on activated macrophages challenged with a non cytotoxic LPS (100 ng/mL) + IFN-γ (600 U/mL) concentration. In our experimental model, main carnosine beneficial effects were: (1) the modulation of nitric oxide production and metabolism; (2) the amelioration of the macrophage energy state; (3) the decrease of the expressions of pro-oxidant enzymes (Nox-2, Cox-2) and of the lipid peroxidation product malondialdehyde; (4) the restoration and/or increase of the expressions of antioxidant enzymes (Gpx1, SOD-2 and Cat); (5) the increase of the transforming growth factor-β1 (TGF-β1) and the down-regulation of the expressions of interleukins 1β and 6 (IL-1β and IL-6) and 6) the increase of the expressions of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1). According to these results carnosine is worth being tested in the treatment of diseases characterized by elevated levels of oxidative stress and inflammation (atherosclerosis, cancer, depression, metabolic syndrome, and neurodegenerative diseases).


Influence of acidosis, hypoxemia, and hypotension on neurodevelopmental outcome in very low birth weight infants.
We previously demonstrated that acidosis (pH < 7.15) predicts poor motor outcome in very low birth weight (VLBW) infants. The present study was undertaken to examine the association between acidosis and developmental outcome in more detail and to better understand the interrelationship of acidosis with related factors such as hypoxemia and hypotension. The nursery records of 191 infants enrolled in our VLBW follow-up study were reviewed to identify the type of acidosis (metabolic or respiratory) present, measure the duration of single and cumulative episodes, and examine the interaction of acidosis with hypoxemia and hypotension. The Bayley Scales of Infant Development and a detailed neurologic examination were performed at 6 (n = 158) and 24 (n = 106) months corrected age. At 6 months, both respiratory and metabolic acidosis as well as the total duration and longest single episode of acidosis were significantly correlated with cognitive, motor, and neurologic outcome (P < .0001). By 24 months, only the association of the metabolic component of acidosis with all three outcome measures remained significant. Duration of hypotension independently correlated with outcome at both testing periods (P < .002) but isolated hypoxemia did not. The metabolic component of acidosis and isolated hypotension contributed significantly to the variance in all three outcome measures (P < .05). Duration of hypoxemia, but not hypotension, contributed significantly (53%) to the variance in the metabolic component of acidosis. We conclude that it is the metabolic component of acidosis that is important in predicting poor developmental outcome in VLBW infants. The detrimental effect of hypoxemia appears to be closely related to the occurrence of metabolic acidosis while hypotension has an independent effect on outcome.


Multi-laboratory validation of a standard method for quantifying proanthocyanidins in cranberry powders.
The objective of this study was to validate an improved 4-dimethylaminocinnamaldehyde (DMAC) colorimetric method using a commercially available standard (procyanidin A2), for the standard method for quantification of proanthocyanidins (PACs) in cranberry powders, in order to establish dosage guidelines for the uropathogenic bacterial anti-adhesion effect of cranberry. Commercially available cranberry samples were obtained (five from U.S. sources and six from European sources) for PAC quantification in five different analytical laboratories. Each laboratory extracted and analyzed the samples using the improved DMAC method. Within-laboratory variation (mean +/- SD) was 4.1 +/- 1.7% RSD (range, 2.3-6.1% RSD) and the between laboratory variability was 16.9 +/- 8.5% RSD (range, 8-32% RSD). For comparative purposes, the cranberry samples were alternatively quantified using weights of extracted PACs (gravimetric). The correlation coefficient between the two methods was 0.989. This improved DMAC method provides a simple, robust and relatively specific spectrophotometric assay for total PACs in cranberry samples using commercially available procyanidin A2 dimer as a standard. DMAC is most useful within a given type of food such as cranberries, but may not be appropriate for comparing concentrations across different food types, particularly in those cases where large differences exist among the relative amounts of each oligomer and polymer.


Dietary xylo-oligosaccharide stimulates intestinal bifidobacteria and lactobacilli but has limited effect on intestinal integrity in rats.
Consumption of prebiotics may modulate gut microbiota, subsequently affecting the bacterial composition, metabolite profile, and human health. Previous studies indicate that also changes in intestinal integrity may occur. In order to explore this further we have investigated the effect of the putative prebiotic xylo-oligosaccharides (XOS) on the gut microbiota and intestinal integrity in male Wistar rats. As changes in intestinal integrity may be related to the expected bifidogenic effect of XOS, we additionally addressed effects of supplementation with a commensal Bifidobacterium pseudolongum (BIF) isolated from the same breed of laboratory rats. Changes in faecal and caecal bacterial composition determined by 16S rRNA gene sequencing and quantitative PCR for selected bacterial groups revealed that the overall bacterial composition did not differ markedly between the control (CON), XOS, and BIF groups, when correcting for multiple comparisons. However as hypothesised, the relative abundance of Bifidobacterium spp. was increased in XOS-fed rats as compared to CON in faecal samples after the intervention. Also Lactobacillus spp. was increased in both the XOS and BIF groups in caecum content compared to CON. Intestinal permeability determined in vivo by FITC-dextran permeability and in vitro using extracted caecum water in trans-epithelial resistance (TER) assay showed no effect on intestinal integrity in either the XOS or the BIF groups. However, the expression of occludin, which is part of the tight junction complex, was increased in the XOS group compared to the CON group. Supplementation with XOS or a commensal Bifidobacterium pseudolongum had very limited effects on intestinal integrity in rats as only significant change in expression of a single tight junction protein gene was found for the XOS group.


Gold-catalyzed conversion of lignin to low molecular weight aromatics.
A heterogeneous catalyst system, employing Au nanoparticles (NPs) and Li-Al (1 : 2) layered double hydroxide (LDH) as support, showed excellent activity in aerobic oxidation of the benzylic alcohol group in β-O-4 linked lignin model dimers to the corresponding carbonyl products using molecular oxygen under atmospheric pressure. The synergistic effect between Au NPs and the basic Li-Al LDH support induces further reaction of the oxidized model compounds, facilitating facile cleavage of the β-O-4 linkage. Extension to oxidation of γ-valerolactone (GVL) extracted lignin and kraft lignin using Au/Li-Al LDH under similar conditions produced a range of aromatic monomers in high yield. Hydrolysis of the Au/Li-Al LDH oxidized lignin was found to increase the degree of lignin depolymerization, with monomer yields reaching 40% for GVL extracted lignin. Based on these results, the Au/Li-Al LDH + O2 catalyst system shows potential to be an environmentally friendly means of depolymerizing lignin to low molecular weight aromatics under mild conditions.


Naturally occurring variations in the human 5-HT3A gene profoundly impact 5-HT3 receptor function and expression.
The serotonin [5-hydroxytryptamine (5-HT)]-gated ion channel 5-HT3 is involved in the mediation of postoperative and radiotherapy/chemotherapy-induced nausea/emesis and in irritable bowel syndrome. It has also been suggested to play a role in various psychiatric diseases. Five naturally occurring single nucleotide polymorphisms leading to amino acid changes have been identified in the human 5-HT3A gene. We investigated the functional effects of these polymorphisms on the 5-HT3A receptor using fluorescence-based cellular assays. Notably, variants A33T, S253N, and M257I displayed 5-HT-induced maximal responses of 3-64% of the wild-type response, whereas R344H and P391R exhibited wild-type-like function. All variants displayed wild-type-like potencies of 5-HT and three 5-HT3 antagonists. Furthermore, all variants displayed Kd values similar to that of the wild-type receptor in a [H]GR65630-binding assay. The surface expression of A33T, M257I, and R344H was reduced 2-4-fold compared with the wild-type, despite similar total expression levels. Finally, coexpression of wild-type 5-HT3A or 5-HT3B subunits with 5-HT3A variants A33T, S253N, or M257I resulted in mixed or heteromeric receptors, characterized by significantly reduced maximal responses to 5-HT compared with the wild-type receptors. Three polymorphisms of the 5-HT3A gene gave rise to functionally impaired receptors whose function could not be rescued by either wild-type 5-HT3A or 5-HT3B. Three of the variant receptors were surface-expressed at reduced levels in spite of total expression levels similar to wild-type, indicating that these variants affect receptor biogenesis and/or trafficking. These severe single nucleotide polymorphism effects hold promise for identification of new 5-HT3A gene-disease causalities.


Imaging histamine H1 receptors in the living human brain with carbon-11-pyrilamine.
The brain distribution and kinetics of the H1 receptor antagonist, carbon-11-pyrilamine (11C-pyrilamine) were examined in vivo in two baboons and one human by positron emission tomography. After i.v. administration of the tracer, brain activity peaked within 20 min after injection and subsequently decreased, reflecting reversible binding to the receptor. Pretreatment with 1 mg/kg diphenhydramine reduced the brain activity at 70 min by 33%, 29%, 26%, and 23% of the control values in frontal cortex, temporal cortex, hippocampus, and cerebellum, respectively. Coinjection of 1 and 5 mg/kg cold pyrilamine reduced the activity at 70 min by 40%, 36%, 34%, and 30% in frontal, temporal, hippocampus and cerebellum, respectively. The in vivo specific binding to the H1 receptors in different brain regions at 70 min after injection correlated with the in vitro H1 histamine receptors distribution in human brain tissue obtained at autopsy, with high values in the frontal and temporal cortex and low values in cerebellum and brain stem. In the healthy human volunteer study, the value of washout of radioactivity increased by about 50% after injection of 0.7 mg/kg diphenhydramine.


Age- and Maturity-Related Variations in Morphology, Body Composition, and Motor Fitness among Young Female Tennis Players.
The purpose of this study was to examine the effects of age and maturity on anthropometric and various fitness characteristics in young competitive female tennis players. Sixty-one players, aged 10.4-13.2 years (11.8 ± 0.8) were measured for standing and sitting heights, body mass, skinfolds, grip strength, and agility, and dichotomized into two age (U12 and U14) and maturity (earliest and latest) groups according to their chronological age and maturity status. The results revealed significant age effects for stature, sitting height, leg length, and hand grip in favor of the older players. Girls contrasting in maturation differed significantly for all anthropometric and physical performance variables except for body mass index (BMI), body fat percentage (BF%), and hexagon agility test. The earliest maturing group showed significantly higher values for anthropometric measures and better results in the hand grip test than the latest maturing group. After controlling for chronological age, differences were revealed between contrasting maturity groups in stature, sitting height, BF%, and the hand grip test. The findings highlight the age- and maturity-related trends in body size and muscular strength among young female tennis players in the pubertal period. Nevertheless, the differences in the body composition and agility of the contrasting age and maturity groups were negligible.


Cometary science. The organic-rich surface of comet 67P/Churyumov-Gerasimenko as seen by VIRTIS/Rosetta.
The VIRTIS (Visible, Infrared and Thermal Imaging Spectrometer) instrument on board the Rosetta spacecraft has provided evidence of carbon-bearing compounds on the nucleus of the comet 67P/Churyumov-Gerasimenko. The very low reflectance of the nucleus (normal albedo of 0.060 ± 0.003 at 0.55 micrometers), the spectral slopes in visible and infrared ranges (5 to 25 and 1.5 to 5% kÅ(-1)), and the broad absorption feature in the 2.9-to-3.6-micrometer range present across the entire illuminated surface are compatible with opaque minerals associated with nonvolatile organic macromolecular materials: a complex mixture of various types of carbon-hydrogen and/or oxygen-hydrogen chemical groups, with little contribution of nitrogen-hydrogen groups. In active areas, the changes in spectral slope and absorption feature width may suggest small amounts of water-ice. However, no ice-rich patches are observed, indicating a generally dehydrated nature for the surface currently illuminated by the Sun.


It Is All in the Right Amygdala: Increased Synaptic Plasticity and Perineuronal Nets in Male, But Not Female, Juvenile Rat Pups after Exposure to Early-Life Stress.
Early-life stress (ELS) is associated with increased vulnerability to mental disorders. The basolateral amygdala (BLA) plays a critical role in fear conditioning and is extremely sensitive to ELS. Using a naturalistic rodent model of ELS, the limited bedding paradigm (LB) between postnatal days 1-10, we previously documented that LB male, but not female preweaning rat pups display increased BLA neuron spine density paralleled with enhanced evoked synaptic responses and altered BLA functional connectivity. Since ELS effects are often sexually dimorphic and amygdala processes exhibit hemispheric asymmetry, we investigated changes in synaptic plasticity and neuronal excitability of BLA neurons in vitro in the left and right amygdala of postnatal days 22-28 male and female offspring from normal bedding or LB mothers. We report that LB conditions enhanced synaptic plasticity in the right, but not the left BLA of males exclusively. LB males also showed increased perineuronal net density, particularly around parvalbumin (PV) cells, and impaired fear-induced activity of PV interneurons only in the right BLA. Action potentials fired from right BLA neurons of LB females displayed slower maximal depolarization rates and decreased amplitudes compared with normal bedding females, concomitant with reduced NMDAR GluN1 subunit expression in the right BLA. In LB males, reduced GluA2 expression in the right BLA might contribute to the enhanced LTP. These findings suggest that LB differentially programs synaptic plasticity and PV/perineuronal net development in the left and right BLA. Furthermore, our study demonstrates that the effects of ELS exposure on BLA synaptic function are sexually dimorphic and possibly recruiting different mechanisms.SIGNIFICANCE STATEMENT Early-life stress (ELS) induces long-lasting consequences on stress responses and emotional regulation in humans, increasing vulnerability to the development of psychopathologies. The effects of ELS in a number of brain regions, including the amygdala, are often sexually dimorphic, and have been reproduced using the rodent limited bedding paradigm of early adversity. The present study examines sex differences in synaptic plasticity and cellular activation occurring in the developing left and right amygdala after limited bedding exposure, a phenomenon that could shape long-term emotional behavioral outcomes. Studying how ELS selectively produces effects in one amygdala hemisphere during a critical period of brain development could guide further investigation into sex-dependent mechanisms and allow for more targeted and improved treatment of stress-and emotionality-related disorders.


In vitro anticholinesterase activity of various alkaloids.
In the current study, a number of alkaloids including retamine, cytisine, and sparteine (quinolizidine-type), yohimbine and vincamine (indole-type), scopolamine and atropine (tropane-type), colchicine (tropolone-type), allantoin (imidazolidine-type), trigonelline (pyridine-type) as well as octopamine, synephrine, and capsaicin (exocyclic amine-type) were tested in vitro for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) at 1 mg/ml concentration by the Ellman method using an ELISA microplate reader. Among the alkaloids tested, only capsaicin exerted a remarkable inhibitory effect towards both AChE and BChE [(62.7 +/- 0.79)% and (75.3 +/- 0.98)%, respectively]. While the rest of the alkaloids did not show any significant inhibition against AChE, three of the alkaloids, namely retamine, sparteine, and yohimbine, exerted a noteworthy anti-BChE effect as compared to galanthamine, the reference drug.


Fat-Bone Interactions in Adults With Spina Bifida.
Spina bifida (SB) can lead to changes in body composition and bone mineral density (BMD) through diminished ambulation, renal impairment, and anticonvulsant medication. With increased life expectancy, diseases such as obesity and osteoporosis are emerging comorbidities in SB, with limited data to guide management. To examine the relationship between cardiometabolic factors, body composition, BMD, and minimal trauma fractures (MTFs) in adults with SB. Retrospective cross-sectional study. Forty-nine adults with SB (median age, 32.7 years; interquartile range, 22.6 to 39.0) who had undergone dual-energy x-ray absorptiometry imaging at a single tertiary hospital from 2004 to 2015. The mean body mass index was 31.7 ± 7.5 kg/m2; 26 (53.1%) were obese. Using age- and sex-matched fat percentiles from the National Health and Nutrition Examination Survey III, 62.5% had a total body percentage fat greater than the 95th percentile. Low bone mass (defined as a Z-score of ≤-2.0) was present in 21.9% at the L1 vertebra and in 35.1% at the femoral neck. Ten (20.4%) had a history of MTFs. A BMD or Z-score at L1, femoral neck, or total body site did not correlate with the occurrence of MTF. Fat mass was significantly and positively associated with BMD after adjustment for age, sex, and height and accounted for 18.6% of the variance in BMD (P = 0.005). The prevalence of metabolic comorbidities, such as hypertension (20.4%) and obstructive sleep apnea (16.3%), was high. Obesity and low BMD are common in young adults with SB. An increased fat mass correlated significantly with BMD. The prevalence of metabolic complications in patients with SB is increased and deserves further study.


Both low birthweight and high birthweight are associated with cognitive impairment in persons with schizophrenia and their first-degree relatives.
Both low birthweight and high birthweight have been associated with an increased risk for schizophrenia and cognitive impairments in the general population. We assessed the association between birthweight and cognitive performance in persons with schizophrenia and their unaffected first-degree relatives. We investigated a population-based family sample comprising persons with schizophrenia (n = 142) and their unaffected first-degree relatives (n = 277). Both patients and relatives were interviewed with the Structured Clinical Interview for DSM-IV Axis I Disorders, Clinician Version (SCID-CV) and a comprehensive neuropsychological test battery was administered. Information on birthweight was obtained from obstetric records. We used generalized estimating equation (GEE) models to investigate the effect of birthweight, as a continuous variable, on cognitive functioning, adjusting for within-family correlation and relevant covariates. Both low birthweight and high birthweight were associated with lower performance in visuospatial reasoning, processing speed, set-shifting and verbal and visual working memory among persons with schizophrenia and their unaffected first-degree relatives compared to individuals with birthweight in the intermediate range. The group × birthweight interactions were non-significant. Both low birthweight and high birthweight are associated with deficits in cognition later in life. Schizophrenia does not seem to modify the relationship between birthweight and cognition in families with schizophrenia.


Optical photon transport in powdered-phosphor scintillators. Part 1. Multiple-scattering and validity of the Boltzmann transport equation.
In Part 1 of this two-part work, predictions for light transport in powdered-phosphor screens are made, based on three distinct approaches. Predictions of geometrical optics-based ray tracing through an explicit microscopic model (EMM) for screen structure are compared to a Monte Carlo program based on the Boltzmann transport equation (BTE) and Swank's diffusion equation solution. The purpose is to: (I) highlight the additional assumptions of the BTE Monte Carlo method and Swank's model (both previously used in the literature) with respect to the EMM approach; (II) demonstrate the equivalences of the approaches under well-defined conditions and; (III) identify the onset and severity of any discrepancies between the models. A package of computer code (called phsphr) is supplied which can be used to reproduce the BTE Monte Carlo results presented in this work. The EMM geometrical optics ray-tracing model is implemented for hypothesized microstructures of phosphor grains in a binder. The BTE model is implemented as a Monte Carlo program with transport parameters, derived from geometrical optics, as inputs. The analytical solution of Swank to the diffusion equation is compared to the EMM and BTE predictions. Absorbed fractions and MTFs are calculated for a range of binder-to-phosphor relative refractive indices (n = 1.1-5.0), screen thicknesses (t = 50-200 μm), and packing fill factors (pf = 0.04-0.54). Disagreement between the BTE and EMM approaches increased with n and pf. For the largest relative refractive index (n = 5) and highest packing fill (pf = 0.5), the BTE model underestimated the absorbed fraction and MTF50, by up to 40% and 20%, respectively. However, for relative refractive indices typical of real phosphor screens (n ≤ 2), such as Gd2O2S:Tb, the BTE and EMM predictions agreed well at all simulated packing densities. In addition, Swank's model agreed closely with the BTE predictions when the screen was thick enough to be considered turbid. Although some assumptions of the BTE are violated in realistic powdered-phosphor screens, these appear to lead to negligible effects in the modeling of optical transport for typical phosphor and binder refractive indices. Therefore it is reasonable to use Monte Carlo codes based on the BTE to treat this problem. Furthermore, Swank's diffusion equation solution is an adequate approximation if a turbidity condition, presented here, is satisfied.


Insulin Protects Cardiac Myocytes from Doxorubicin Toxicity by Sp1-Mediated Transactivation of Survivin.
Insulin inhibits ischemia/reperfusion-induced myocardial apoptosis through the PI3K/Akt/mTOR pathway. Survivin is a key regulator of anti-apoptosis against doxorubicin-induced cardiotoxicity. Insulin increases survivin expression in cardiac myocytes to mediate cytoprotection. However, the mechanism by which survivin mediates the protective effect of insulin against doxorubicin-associated injury remains to be determined. In this study, we demonstrated that pretreatment of H9c2 cardiac myocytes with insulin resulted in a significant decrease in doxorubicin-induced apoptotic cell death by reducing cytochrome c release and caspase-3 activation. Doxorubicin-induced reduction of survivin mRNA and protein levels was also significantly perturbed by insulin pretreatment. Reducing survivin expression with survivin siRNA abrogated insulin-mediated inhibition of caspase-3 activation, suggesting that insulin signals to survivin inhibited caspase-3 activation. Interestingly, pretreatment of H9c2 cells with insulin or MG132, a proteasome inhibitor, inhibited doxorubicin-induced degradation of the transcription factor Sp1. ChIP assay showed that pretreatment with insulin inhibited doxorubicin-stimulated Sp1 dissociation from the survivin promoter. Finally using pharmacological inhibitors of the PI3K pathway, we showed that insulin-mediated activation of the PI3K/Akt/mTORC1 pathway prevented doxorubicin-induced proteasome-mediated degradation of Sp1. Taken together, insulin pretreatment confers a protective effect against doxorubicin-induced cardiotoxicity by promoting Sp1-mediated transactivation of survivin to inhibit apoptosis. Our study is the first to define a role for survivin in cellular protection by insulin against doxorubicin-associated injury and show that Sp1 is a critical factor in the transcriptional regulation of survivin.