Optimized versus corrected peak power during friction-braked cycle ergometry in males and females.
The aim of this study was to compare optimization and correction procedures for the determination of peak power output during friction-loaded cycle ergometry. Ten male and 10 female sports students each performed five 10-s sprints from a stationary start on a Monark 864 basket-loaded ergometer. Resistive loads of 5.0, 6.5, 8.0, 9.5, and 11.0% body weight were administered in a counterbalanced order, with a recovery period of 10 min between sprints. Peak power was greater and occurred earlier, with less work having been done before the attainment of peak power, when the data were corrected to account for the inertial and frictional characteristics of the ergometer. Corrected peak power was independent of resistive load (P > 0.05), whereas uncorrected peak power varied as a quadratic function of load (P < 0.001). For males and females, optimized peak power (971 +/- 122 and 668 +/- 37 W) was lower (P < 0.01) than either the highest (1074 +/- 111 and 754 +/- 56 W respectively) or the mean (1007 +/- 125 and 701 +/- 45 W respectively) of the five values for corrected peak power. Optimized and mean corrected peak power were highly correlated both in males (r = 0.97, P < 0.001) and females (r = 0.96, P < 0.001). The difference between optimized and mean corrected peak power was 37 +/- 30 W in males and 33 +/- 14 W in females, of which approximately 15 W was due to the correction for frictional losses. We conclude that corrected peak power is independent of resistive load in males and females.


The regulation of function, growth and survival of GLP-1-producing L-cells.
Glucagon-like peptide-1 (GLP-1) is a peptide hormone, released from intestinal L-cells in response to hormonal, neural and nutrient stimuli. In addition to potentiation of meal-stimulated insulin secretion, GLP-1 signalling exerts numerous pleiotropic effects on various tissues, regulating energy absorption and disposal, as well as cell proliferation and survival. In Type 2 Diabetes (T2D) reduced plasma levels of GLP-1 have been observed, and plasma levels of GLP-1, as well as reduced numbers of GLP-1 producing cells, have been correlated to obesity and insulin resistance. Increasing endogenous secretion of GLP-1 by selective targeting of the molecular mechanisms regulating secretion from the L-cell has been the focus of much recent research. An additional and promising strategy for enhancing endogenous secretion may be to increase the L-cell mass in the intestinal epithelium, but the mechanisms that regulate the growth, survival and function of these cells are largely unknown. We recently showed that prolonged exposure to high concentrations of the fatty acid palmitate induced lipotoxic effects, similar to those operative in insulin-producing cells, in an in vitro model of GLP-1-producing cells. The mechanisms inducing this lipototoxicity involved increased production of reactive oxygen species (ROS). In this review, regulation of GLP-1-secreting cells is discussed, with a focus on the mechanisms underlying GLP-1 secretion, long-term regulation of growth, differentiation and survival under normal as well as diabetic conditions of hypernutrition.


207Pb and 119Sn solid-state NMR and relativistic density functional theory studies of the historic pigment lead-tin yellow type I and its reactivity in oil paintings.
Lead soaps (lead carboxylates) have been detected in traditional oil paintings in layers containing the pigment lead-tin yellow type I (LTY-I). LTY-I has been used by artists from at least the second quarter of the 15th century until the first half of the 18th century. Soap formation can lead to protrusions in paint layers and increased transparency, causing the paint support to become visible. We have characterized LTY-I by (119)Sn and (207)Pb solid-state NMR (ssNMR) spectroscopy. Using a combination of NMR techniques and DFT molecular cluster calculations, we identify the individual species in LTY-I and determine their (119)Sn and (207)Pb chemical-shift tensors. The presence of starting materials from the synthesis, minium, and tin(IV) oxide was also verified. Knowledge of the chemical-shift tensor components and the impurities in LTY-I is important for examining the chemistry of degradation processes and soap formation. We demonstrate that ssNMR can be used to detect reaction between Pb2SnO4 and added palmitic acid in a model paint sample containing LTY-I.


Using an adoption design to separate genetic, prenatal, and temperament influences on toddler executive function.
Poor executive functioning has been implicated in children's concurrent and future behavioral difficulties, making work aimed at understanding processes related to the development of early executive function (EF) critical for models of developmental psychopathology. Deficits in EF have been associated with adverse prenatal experiences, genetic influences, and temperament characteristics. However, our ability to disentangle the predictive and independent effects of these influences has been limited by a dearth of genetically informed research designs that also consider prenatal influences. The present study examined EF and language development in a sample of 361 toddlers who were adopted at birth and reared in nonrelative adoptive families. Predictors included genetic influences (as inherited from birth mothers), prenatal risk, and growth in child negative emotionality. Structural equation modeling indicated that the effect of prenatal risk on toddler effortful attention at age 27 months became nonsignificant once genetic influences were considered in the model. In addition, genetic influences had unique effects on toddler effortful attention. Latent growth modeling indicated that increases in toddler negative emotionality from 9 to 27 months were associated with poorer delay of gratification and poorer language development. Similar results were obtained in models incorporating birth father data. Mechanisms of intergenerational transmission of EF deficits are discussed.


Biological Consequences of Dysfunctional HDL.
Epidemiological studies have suggested an inverse correlation between high-density lipoprotein (HDL) cholesterol levels and the risk of cardiovascular disease. HDLs promote reverse cholesterol transport (RCT) and possess several putative atheroprotective functions, associated to the anti-inflammatory, anti-thrombotic and anti-oxidant properties as well as to the ability to support endothelial physiology. The assumption that increasing HDL-C levels would be beneficial on cardiovascular disease (CVD), however, has been questioned as, in most clinical trials, HDL-C-raising therapies did not result in improved cardiovascular outcomes. These findings, together with the observations from Mendelian randomization studies showing that polymorphisms mainly or solely associated with increased HDL-C levels did not decrease the risk of myocardial infarction, shift the focus from HDL-C levels toward HDL functional properties. Indeed, HDL from atherosclerotic patients not only exhibit impaired atheroprotective functions but also acquire pro-atherogenic properties and are referred to as "dysfunctional" HDL; this occurs even in the presence of normal or elevated HDL-C levels. Pharmacological approaches aimed at restoring HDL functions may therefore impact more significantly on CVD outcome than drugs used so far to increase HDL-C levels. The aim of this review is to discuss the pathological conditions leading to the formation of dysfunctional HDL and their role in atherosclerosis and beyond.


Complete chloroplast genome sequence of the red silk cotton tree (Bombax ceiba).
Bombax ceiba L. is a beautiful and deciduous tree with great ecological and economic importance. The third generation sequencing of chloroplast genome of B. ceiba was conducted on the PacBio sequencing platform (Pacific Biosciences). The complete chloroplast genome was 158,997 bp, which contains a large single-copy (LSC) region (89,021 bp), a small single-copy (SSC) region (21,110 bp), and two inverted repeats (IRs) (24,433 bp). In total, 116 genes were annotated, including 81 protein-coding genes, eight rRNA genes, and 27 tRNA genes. The phylogenetic tree showed that B. ceiba was closely clustered with one clade of Malvaceae.


The onset of grapevine berry ripening is characterized by ROS accumulation and lipoxygenase-mediated membrane peroxidation in the skin.
The ripening of fleshy fruits is a complex developmental program characterized by extensive transcriptomic and metabolic remodeling in the pericarp tissues (pulp and skin) making unripe green fruits soft, tasteful and colored. The onset of ripening is regulated by a plethora of endogenous signals tuned to external stimuli. In grapevine and tomato, which are classified as non-climacteric and climacteric species respectively, the accumulation of hydrogen peroxide (H2O2) and extensive modulation of reactive oxygen species (ROS) scavenging enzymes at the onset of ripening has been reported, suggesting that ROS could participate to the regulatory network of fruit development. In order to investigate this hypothesis, a comprehensive biochemical study of the oxidative events occurring at the beginning of ripening in Vitis vinifera cv. Pinot Noir has been undertaken. ROS-specific staining allowed to visualize not only H2O2 but also singlet oxygen (1O2) in berry skin cells just before color change in distinct subcellular locations, i.e. cytosol and plastids. H2O2 peak in sample skins at véraison was confirmed by in vitro quantification and was supported by the concomitant increase of catalase activity. Membrane peroxidation was also observed by HPLC-MS on galactolipid species at véraison. Mono- and digalactosyl diacylglycerols were found peroxidized on one or both α-linolenic fatty acid chains, with a 13(S) absolute configuration implying the action of a specific enzyme. A lipoxygenase (PnLOXA), expressed at véraison and localizing inside the chloroplasts, was indeed able to catalyze membrane galactolipid peroxidation when overexpressed in tobacco leaves. The present work demonstrates the controlled, harmless accumulation of specific ROS in distinct cellular compartments, i.e. cytosol and chloroplasts, at a definite developmental stage, the onset of grape berry ripening. These features strongly candidate ROS as cellular signals in fruit ripening and encourage further studies to identify downstream elements of this cascade. This paper also reports the transient galactolipid peroxidation carried out by a véraison-specific chloroplastic lipoxygenase. The function of peroxidized membranes, likely distinct from that of free fatty acids due to their structural role and tight interaction with photosynthesis protein complexes, has to be ascertained.


A Carotenoid-Deficient Mutant in Pantoea sp. YR343, a Bacteria Isolated from the Rhizosphere of Populus deltoides, Is Defective in Root Colonization.
The complex interactions between plants and their microbiome can have a profound effect on the health and productivity of the plant host. A better understanding of the microbial mechanisms that promote plant health and stress tolerance will enable strategies for improving the productivity of economically important plants. Pantoea sp. YR343 is a motile, rod-shaped bacterium isolated from the roots of Populus deltoides that possesses the ability to solubilize phosphate and produce the phytohormone indole-3-acetic acid (IAA). Pantoea sp. YR343 readily colonizes plant roots and does not appear to be pathogenic when applied to the leaves or roots of selected plant hosts. To better understand the molecular mechanisms involved in plant association and rhizosphere survival by Pantoea sp. YR343, we constructed a mutant in which the crtB gene encoding phytoene synthase was deleted. Phytoene synthase is responsible for converting geranylgeranyl pyrophosphate to phytoene, an important precursor to the production of carotenoids. As predicted, the ΔcrtB mutant is defective in carotenoid production, and shows increased sensitivity to oxidative stress. Moreover, we find that the ΔcrtB mutant is impaired in biofilm formation and production of IAA. Finally we demonstrate that the ΔcrtB mutant shows reduced colonization of plant roots. Taken together, these data suggest that carotenoids are important for plant association and/or rhizosphere survival in Pantoea sp. YR343.


Physician and Nurse Research in Multidisciplinary Intensive Care Units.
Although clinical care is multidisciplinary, intensive care unit research commonly focuses on single-discipline themes. We sought to characterize intensive care unit research conducted by physicians and nurses. One hundred randomly selected reports of clinical studies published in critical care medical and nursing journals were reviewed. Of the 100 articles reviewed, 50 were published in medical journals and 50 were published in nursing journals. Only 1 medical study (2%) used qualitative methods, compared with 9 nursing studies (18%) (P = .02). The distribution of quantitative study designs differed between medical and nursing journals (P < .001), with medical journals having a predominance of cohort studies (29 articles [58%]). Compared with medical journal articles, nursing journal articles had significantly fewer authors (median [interquartile range], 5 [3-6] vs 8 [6-10]; P < .001) and study participants (94 [51-237] vs 375 [86-4183]; P < .001) and a significantly lower proportion of male study participants (55% [26%-65%] vs 60% [51%-65%]; P = .02). Studies published in medical journals were much more likely than those published in nursing journals to exclusively involve patients as participants (47 [94%] vs 25 [50%]; P < .001). Coauthorship between physicians and nurses was evident in 14 articles (14%), with infrequent inclusion of authors from other health care disciplines. Physician research and nurse research differ in several important aspects and tend to occur within silos. Increased interprofessional collaboration is possible and worthwhile.


Mapping community determinants of heat vulnerability.
The evidence that heat waves can result in both increased deaths and illness is substantial, and concern over this issue is rising because of climate change. Adverse health impacts from heat waves can be avoided, and epidemiologic studies have identified specific population and community characteristics that mark vulnerability to heat waves. We situated vulnerability to heat in geographic space and identified potential areas for intervention and further research. We mapped and analyzed 10 vulnerability factors for heat-related morbidity/mortality in the United States: six demographic characteristics and two household air conditioning variables from the U.S. Census Bureau, vegetation cover from satellite images, and diabetes prevalence from a national survey. We performed a factor analysis of these 10 variables and assigned values of increasing vulnerability for the four resulting factors to each of 39,794 census tracts. We added the four factor scores to obtain a cumulative heat vulnerability index value. Four factors explained > 75% of the total variance in the original 10 vulnerability variables: a) social/environmental vulnerability (combined education/poverty/race/green space), b) social isolation, c) air conditioning prevalence, and d) proportion elderly/diabetes. We found substantial spatial variability of heat vulnerability nationally, with generally higher vulnerability in the Northeast and Pacific Coast and the lowest in the Southeast. In urban areas, inner cities showed the highest vulnerability to heat. These methods provide a template for making local and regional heat vulnerability maps. After validation using health outcome data, interventions can be targeted at the most vulnerable populations.


Phospholipase D family member 4, a transmembrane glycoprotein with no phospholipase D activity, expression in spleen and early postnatal microglia.
Phospholipase D (PLD) catalyzes conversion of phosphatidylcholine into choline and phosphatidic acid, leading to a variety of intracellular signal transduction events. Two classical PLDs, PLD1 and PLD2, contain phosphatidylinositide-binding PX and PH domains and two conserved His-x-Lys-(x)(4)-Asp (HKD) motifs, which are critical for PLD activity. PLD4 officially belongs to the PLD family, because it possesses two HKD motifs. However, it lacks PX and PH domains and has a putative transmembrane domain instead. Nevertheless, little is known regarding expression, structure, and function of PLD4. PLD4 was analyzed in terms of expression, structure, and function. Expression was analyzed in developing mouse brains and non-neuronal tissues using microarray, in situ hybridization, immunohistochemistry, and immunocytochemistry. Structure was evaluated using bioinformatics analysis of protein domains, biochemical analyses of transmembrane property, and enzymatic deglycosylation. PLD activity was examined by choline release and transphosphatidylation assays. Results demonstrated low to modest, but characteristic, PLD4 mRNA expression in a subset of cells preferentially localized around white matter regions, including the corpus callosum and cerebellar white matter, during the first postnatal week. These PLD4 mRNA-expressing cells were identified as Iba1-positive microglia. In non-neuronal tissues, PLD4 mRNA expression was widespread, but predominantly distributed in the spleen. Intense PLD4 expression was detected around the marginal zone of the splenic red pulp, and splenic PLD4 protein recovered from subcellular membrane fractions was highly N-glycosylated. PLD4 was heterologously expressed in cell lines and localized in the endoplasmic reticulum and Golgi apparatus. Moreover, heterologously expressed PLD4 proteins did not exhibit PLD enzymatic activity. Results showed that PLD4 is a non-PLD, HKD motif-carrying, transmembrane glycoprotein localized in the endoplasmic reticulum and Golgi apparatus. The spatiotemporally restricted expression patterns suggested that PLD4 might play a role in common function(s) among microglia during early postnatal brain development and splenic marginal zone cells.


Ion cyclotron resonance as a tool in regenerative medicine.
The identification of suitable stem cell cultures and differentiating conditions that are free of xenogenic growth supplements is an important step in finding the clinical applicability of cell therapy in two important fields of human medicine: heart failure and bone remodeling, growth and repair. We recently demonstrated the possibility of obtaining cardiac stem cells (CSCs) from human endomyocardial biopsy specimens. CSCs self-assemble into multi-cellular clusters known as cardiospheres (CSps) that engraft and partially regenerate infarcted myocardium. CSps and cardiosphere-derived-cells (CDCs) were exposed for five days in an incubator regulated for temperature, humidity, and CO(2) inside a solenoid system. This system was placed in a magnetically shielded room. The cells were exposed simultaneously to a static magnetic field (MF) and a parallel low-alternating frequency MF, close to the cyclotron frequency corresponding to the charge/mass ratio of the Ca(++) ion. In this exposure condition, CSps and CDCs modulate their differentiation turning on cardiogenesis and turning off vasculogenesis. Cardiac markers such as troponin I (TnI) and myosin heavy chain (MHC) were up-regulated. Conversely, angiogenic markers such as vascular endothelial growth factor (VEGF) and kinase domain receptor (KDR) were down-regulated as evidenced by immunocytochemistry. Exposure to the 7 Hz calcium ion cyclotron resonance (ICR) frequency can modulate the cardiogenic vs. angiogenic differentiation process of ex vivo expanded CSCs. This may pave the way for novel approaches in tissue engineering and cell therapy. With regard to bone remodeling, it has been suggested that bone marrow-derived mesenchymal stem cells (MSC) may be considered as a potential therapeutic tool. Using the Ca(++)-dependent specific differentiation potential of the ELF-MF 7 Hz ICR, we show here that exposure of human MSC to these same MF conditions enhanced the expression of osteoblast differentiation markers such as alkaline phosphatase, osteocalcin, and osteopontin, as analyzed by real-time quantitative PCR, without affecting cell proliferation. As expected, while the differentiation marker factors were up regulated, the ICR electromagnetic field down regulated osteoprotegerin gene expression, a critical regulator of postnatal skeletal development and homeostasis in humans as well as mice.


Role of the Drug Transporter ABCC3 in Breast Cancer Chemoresistance.
Increased expression of ABC-family of transporters is associated with chemotherapy failure. Although the drug transporters ABCG2, ABCB1 and ABCC1 have been majorly implicated in cancer drug resistance, recent studies have associated ABCC3 with multi drug resistance and poor clinical response. In this study, we have examined the expression of ABCC3 in breast cancers and studied its role in drug resistance and stemness of breast cancer cells in comparison with the more studied ABCC1. We observed that similar to ABCC1, the transcripts levels of ABCC3 was significantly high in breast cancers compared to adjacent normal tissue. Importantly, expression of both transporters was further increased in chemotherapy treated patient samples. Consistent with this, we observed that treatment of breast cancer cell lines with anti-cancer agents increased their mRNA levels of both ABCC1 and ABCC3. Further, similar to knockdown of ABCC1, knockdown of ABCC3 also significantly increased the retention of chemotherapeutic drugs in breast cancer cells and rendered them more chemo-sensitive. Interestingly, ABCC1 and ABCC3 knockdown cells also showed reduction in the expression of stemness genes, while ABCC3 knockdown additionally led to a reduction in the CD44high/CD24low breast cancer stem-like subpopulation. Consistent with this, their ability to form primary tumours was compromised. Importantly, down-modulation of ABCC3 rendered these cells increasingly susceptible to doxorubicin in xenograft mice models in vivo. Thus, our study highlights the importance of ABCC3 transporters in drug resistance to chemotherapy in the context of breast cancer. Further, these results suggest that combinatorial inhibition of these transporters together with standard chemotherapy can reduce therapy-induced resistance in breast cancer.


Transcriptome characterization of moso bamboo (Phyllostachys edulis) seedlings in response to exogenous gibberellin applications.
Moso bamboo (Phyllostachys edulis) is a well-known bamboo species of high economic value in the textile industry due to its rapid growth. Phytohormones, which are master regulators of growth and development, serve as important endogenous signals. However, the mechanisms through which phytohormones regulate growth in moso bamboo remain unknown to date. Here, we reported that exogenous gibberellins (GA) applications resulted in a significantly increased internode length and lignin condensation. Transcriptome sequencing revealed that photosynthesis-related genes were enriched in the GA-repressed gene class, which was consistent with the decrease in leaf chlorophyll concentrations and the lower rate of photosynthesis following GA treatment. Exogenous GA applications on seedlings are relatively easy to perform, thus we used 4-week-old whole seedlings of bamboo for GA- treatment followed by high throughput sequencing. In this study, we identified 932 cis-nature antisense transcripts (cis-NATs), and 22,196 alternative splicing (AS) events in total. Among them, 42 cis-nature antisense transcripts (cis-NATs) and 442 AS events were differentially expressed upon exposure to exogenous GA3, suggesting that post-transcriptional regulation might be also involved in the GA3 response. Targets of differential expression of cis-NATs included genes involved in hormone receptor, photosynthesis and cell wall biogenesis. For example, LAC4 and its corresponding cis-NATs were GA3-induced, and may be involved in the accumulation of lignin, thus affecting cell wall composition. This study provides novel insights illustrating how GA alters post-transcriptional regulation and will shed light on the underlying mechanism of growth modulated by GA in moso bamboo.


The distribution and identification of dangerously venomous Australian terrestrial snakes.
The identification of dangerous Australian snakes is important in instituting therapy for envenomation. Despite the availability of a number of identification guides with varying degrees of generality, identification can be problematic for several reasons. These include a diversity of common names, many of which are inappropriate or regionally applied to different species, identification keys that focus on variable features, intraspecific variation and interspecific convergence in colouration, and recent changes in scientific nomenclature of species and genera. Geographic distribution of the dangerously venomous species can be a useful aid to identification, by limiting the range of options in a region. However, delineation of the limits of distribution relies on fine scale mapping beyond the resolution of most identification guides. This article provides a summary of the geographic limits of the dangerously venomous Australian snakes, with particular emphasis on major population centres, and clarifies some problems in identification, particularly among brown-coloured snakes.


Neutral glycolipids of atherosclerotic plaques and unaffected human aorta tissue.
The composition, structure and localization of neutral glycosphingolipids of human aorta taken from subjects who had died after myocardial infarction were studied. Individual glycosphingolipids were purified by high-performance liquid chromatography and were characterized on the basis of their chromatographic mobility, carbohydrate composition, methylation analysis and by 1H-NMR spectroscopy. The main aortic glycosphingolipids were identified as glucosylceramide, lactosylceramide, globotriaosylceramide and globotetraosylceramide. Significant differences in the neutral glycosphingolipid composition of intima and media were detected. The neutral glycosphingolipid profile of medial plaques resembled that of unaffected media; however, significant differences were detected between intimal plaques and unaffected intima. Whereas the latter contained trihexosylceramide and globoside as the only neutral glycolipids, the intimal plaque glycolipids consisted mainly of glucosylceramide and also contained appreciable amounts of lactosylceramide which were completely absent in the unaffected intima. In comparison to intimal plaques, unaffected intima is characterized by a much higher content of cerebrosides terminating by beta-galactosyl residues which are known to interact with growth factors and other external stimuli. It thus seems possible that the proliferative activity of smooth muscle cells in atherosclerotic diseases is to some extent associated with their neutral glycolipid profile.


Cosmetic benefits of astaxanthin on humans subjects.
Two human clinical studies were performed. One was an open-label non-controlled study involving 30 healthy female subjects for 8 weeks. Significant improvements were observed by combining 6 mg per day oral supplementation and 2 ml (78.9 μM solution) per day topical application of astaxanthin. Astaxanthin derived from the microalgae, Haematococcus pluvialis showed improvements in skin wrinkle (crow's feet at week-8), age spot size (cheek at week-8), elasticity (crow's feet at week-8), skin texture (cheek at week-4), moisture content of corneocyte layer (cheek in 10 dry skin subjects at week-8) and corneocyte condition (cheek at week-8). It may suggest that astaxanthin derived from H. pluvialis can improve skin condition in all layers such as corneocyte layer, epidermis, basal layer and dermis by combining oral supplementation and topical treatment. Another was a randomized double-blind placebo controlled study involving 36 healthy male subjects for 6 weeks. Crow's feet wrinkle and elasticity; and transepidermal water loss (TEWL) were improved after 6 mg of astaxanthin (the same as former study) daily supplementation. Moisture content and sebum oil level at the cheek zone showed strong tendencies for improvement. These results suggest that astaxanthin derived from Haematococcus pluvialis may improve the skin condition in not only in women but also in men.


Activation of cardiac vagal afferents in ischemia and reperfusion. Prostaglandins versus oxygen-derived free radicals.
Myocardial ischemia and reperfusion can evoke excitation of cardiac vagal nerve endings and activation of a cardiogenic depressor reflex (Bezold-Jarisch effect). We postulate that oxygen-derived free radicals, which are known to be produced during prolonged ischemia and reperfusion, contribute to this afferent excitation. We recorded activity from 47 chemosensitive vagal afferent fibers in 31 rats; the endings of these fibers were located in the left ventricle. Chemosensitive endings were identified with topical applications of capsaicin (10 micrograms) to the surface of the heart. Reactivity of the endings to oxygen-derived free radicals was assessed by topical application of H2O2 (3 to 9 mumol). Activity of the vagal fibers was recorded during 30 minutes of occlusion of the left anterior descending coronary artery (LAD) and 10 minutes of subsequent reperfusion. The activity of chemosensitive endings within the ischemic zone increased in the first 2 minutes of LAD occlusion from 2.2 +/- 0.4 to 4.3 +/- 0.9 impulses per second (107 +/- 30% increase, P < .05). This increased activity waned after 3 to 5 minutes of occlusion. Endings outside the ischemic zone did not increase, their activity at the beginning of ischemia. Reperfusion caused a rapid elevation of activity only in chemosensitive fibers whose endings were found to respond to topical H2O2. The reperfusion-sensitive endings were located both within and outside the ischemic zone of the left ventricle. Indomethacin (5 mg/kg i.v., 20 minutes before occlusion) effectively prevented activation of chemosensitive afferent endings at the beginning of LAD occlusion regardless of their sensitivity to H2O2 but had no effect on the activation at reperfusion.


Leukocyte composition of human breast cancer.
Retrospective clinical studies have used immune-based biomarkers, alone or in combination, to predict survival outcomes for women with breast cancer (BC); however, the limitations inherent to immunohistochemical analyses prevent comprehensive descriptions of leukocytic infiltrates, as well as evaluation of the functional state of leukocytes in BC stroma. To more fully evaluate this complexity, and to gain insight into immune responses after chemotherapy (CTX), we prospectively evaluated tumor and nonadjacent normal breast tissue from women with BC, who either had or had not received neoadjuvant CTX before surgery. Tissues were evaluated by polychromatic flow cytometry in combination with confocal immunofluorescence and immunohistochemical analysis of tissue sections. These studies revealed that activated T lymphocytes predominate in tumor tissue, whereas myeloid lineage cells are more prominant in "normal" breast tissue. Notably, residual tumors from an unselected group of BC patients treated with neoadjuvant CTX contained increased percentages of infiltrating myeloid cells, accompanied by an increased CD8/CD4 T-cell ratio and higher numbers of granzyme B-expressing cells, compared with tumors removed from patients treated primarily by surgery alone. These data provide an initial evaluation of differences in the immune microenvironment of BC compared with nonadjacent normal tissue and reveal the degree to which CTX may alter the complexity and presence of selective subsets of immune cells in tumors previously treated in the neoadjuvant setting.


Immunomodulatory roles of lymphatic vessels in cancer progression.
Lymphatic vessels in the tumor microenvironment are known to foster tumor metastasis in many cancers, and they can undergo activation, hyperplasia, and lymphangiogenesis in the tumor microenvironment and in the tumor-draining lymph node. The mechanism underlying this correlation was originally considered as lymphatic vessels providing a physical route for tumor cell dissemination, but recent studies have highlighted new roles of the lymphatic endothelium in regulating host immunity. These include indirectly suppressing T-cell function by secreting immunosuppressive factors and inhibiting dendritic cell (DC) maturation, as well as directly driving T-cell tolerance by antigen presentation in the presence of inhibitory ligands. Furthermore, lymphatic endothelium scavenges and regulates transendothelial transport actively, controlling the sustained delivery of lymph-borne antigens from chronically inflamed tissues to draining lymph nodes where immature DCs, in the absence of danger signals, along with lymph node stromal cells present these antigens to T cells for maintenance of peripheral tolerance to self-antigens, a mechanism that may be hijacked by some tumors. This Masters of Immunology primer aims to present an overview of research in this area and highlight emerging evidence that suggests lymphatic vessels, and lymphangiogenesis, play important immunomodulatory roles in the tumor microenvironment.


Preoperative antiplatelet and statin treatment was not associated with reduced myocardial infarction after high-risk vascular operations in the Vascular Quality Initiative.
Medical management with antiplatelet (AP) and statin therapy is recommended for nearly all patients undergoing vascular surgery to reduce cardiovascular events. We assessed the association between preoperative use of AP and statin medications and postoperative in-hospital myocardial infarction (MI) in patients undergoing high-risk open surgery. We studied patients who underwent elective suprainguinal (n = 3039) and infrainguinal (n = 8323) bypass and open infrarenal abdominal aortic aneurysm repair (n = 3007) in the Vascular Quality Initiative (VQI, 2005-2014). We assessed the association between AP or statin use and in-hospital postoperative MI and MI/death. Multivariable logistic analyses were performed to identify the patient, procedure, and preoperative medication factors associated with postoperative MI and MI/death across procedures and patient cardiac risk strata. Secondary end points included bleeding, transfusion, and thrombotic complications. Most patients were taking both AP and statin preoperatively (56% both agents vs 19% AP only, 13% statin only, and 12% neither agent). Use of both agents was more common for patients in the highest cardiac risk stratum (low, 54%; intermediate, 59%; high, 61%; P < .01). Increased cardiac risk was associated with higher MI rates (1.8% vs 3.8% vs 6.5% for low, intermediate, and high risk; P < .01). By univariate analysis, MI rate was paradoxically higher for patients taking both agents (3.7%, vs statin only 2.8%, AP only 2.6%, or neither AP nor statin 2.4%; P = .003). After multivariable adjustment, rates of MI in patients taking preoperative AP only (odds ratio [OR], 0.9; 95% confidence interval [CI], 0.7-1.2) and statin only (OR, 0.8; 95% CI, 0.6-1.2) were not different from those in patients taking either or neither medication (neither agent compared with taking both agents: OR, 1.0; 95% CI, 0.7-1.4; P > .05 for all). Similarly, rates of MI/death were not associated with medication status after multivariable adjustment. Estimated blood loss >1 liter (OR, 2.4; 95% CI, 1.6-3.7; P < .01) and transfusions of 1 or 2 units (OR, 2.5; 95% CI, 2.0-3.3; P < .01) and ≥3 units (OR, 4.0; 95% CI, 3.1-5.3; P < .01) were highly associated with MI, with similar findings related to composite MI/death in multivariable analysis. Rates of blood loss were slightly higher with AP use for all procedures; however, increased transfusions occurred only for infrainguinal bypass with AP use. Rates of reoperation for bleeding, graft thrombosis, or graft revision did not differ by preoperative AP use. Preoperative AP and statin medications as used in VQI were not associated with the rate of in-hospital MI/death after major open vascular operations. Rather, predicted cardiac risk and operative blood loss were significantly associated with in-hospital MI or MI/death. AP and statin medications appear to be more useful in reducing late mortality than early postoperative MI/death in VQI. However, they were not harmful, so their long-term benefit argues for continued use.


The HEADS-ED: Evaluating the Clinical Use of a Brief, Action-Oriented, Pediatric Mental Health Screening Tool.
This effectiveness study aimed to evaluate the clinical use of the HEADS-ED tool for patients presenting to a pediatric emergency department (PED) for mental health (MH) care. In this pragmatic trial, PED physicians used the HEADS-ED to guide their assessment and identify areas of MH need in 639 patients (mean [SD], 15.16 [1.40] years; female, 72.6%) who presented to the emergency department with MH concerns between May 2013 and March 2014. The HEADS-ED guided consultation to psychiatry/crisis, with 86% receiving a recommended consult. Those with a HEADS-ED score of greater than or equal to 8 and suicidality of 2 (relative risk, 2.64; confidence interval, 2.28-3.06) had a 164% increased risk of physicians requesting a consult compared with those with a score of less than 8 or greater than or equal to 8 with no suicidality of 2. The HEADS-ED mean score was significantly higher for those who received a consult (M = 6.91) than those who did not (M = 4.70; P = 0.000). Similarly, the mean score for those admitted was significantly higher (M = 7.21) than those discharged (M = 5.28; P = 0.000). Agreement on needs requiring action between PED physicians and crisis intervention workers was obtained for a subset of 140 patients and ranged from 62% to 93%. Results support the HEADS-ED's use by PED physicians to help guide the assessment and referral process and for discussing the clinical needs of patients among health care providers using a common action-oriented language.


Studies on the density, distribution, and surface phenotype of intraepithelial class II major histocompatibility complex antigen (Ia)-bearing dendritic cells (DC) in the conducting airways.
Conventional immunohistochemical analysis of airway intraepithelial class II major histocompatibility complex (Ia) expression demonstrates a morphologically heterogeneous pattern of staining, suggestive of the presence of a mixed population of endogenous antigen presenting cells. Employing a novel tissue sectioning technique in conjunction with optimal surface antigen fixation, we now demonstrate that virtually all intraepithelial Ia staining throughout the respiratory tree in the normal rat, can be accounted for by a network of cells with classical dendritic cell (DC) morphology. The density of DC varies from 600-800 per mm2 epithelial surface in the large airways, to 75 per mm2 in the epithelium of the small airways of the peripheral lung. All the airway DC costain for CD4, with low-moderate expression of a variety of other leukocyte surface markers. Both chronic (eosinophilic) inflammation and acute (neutrophilic) inflammation, caused respectively by inhalation of chemical irritants in dust or aerosolised bacterial lipopolysaccharide (LPS), are shown to be accompanied by increased intraepithelial DC density in the large airways (in the order of 50%) and up to threefold increased expression of activation markers, including the beta chain of CD11/18. The kinetics of the changes in the DC network in response to LPS mirrored those of the transient neutrophil influx, suggesting that airway intraepithelial DC constitute a dynamic population which is rapidly upregulated in response to local inflammation. These findings have important theoretical implications for research on T cell activation in the context of allergic and infectious diseases in the respiratory tract.


BarkBase: Epigenomic Annotation of Canine Genomes.
Dogs are an unparalleled natural model for investigating the genetics of health and disease, particularly for complex diseases like cancer. Comprehensive genomic annotation of regulatory elements active in healthy canine tissues is crucial both for identifying candidate causal variants and for designing functional studies needed to translate genetic associations into disease insight. Currently, canine geneticists rely primarily on annotations of the human or mouse genome that have been remapped to dog, an approach that misses dog-specific features. Here, we describe BarkBase, a canine epigenomic resource available at barkbase.org. BarkBase hosts data for 27 adult tissue types, with biological replicates, and for one sample of up to five tissues sampled at each of four carefully staged embryonic time points. RNA sequencing is complemented with whole genome sequencing and with assay for transposase-accessible chromatin using sequencing (ATAC-seq), which identifies open chromatin regions. By including replicates, we can more confidently discern tissue-specific transcripts and assess differential gene expression between tissues and timepoints. By offering data in easy-to-use file formats, through a visual browser modeled on similar genomic resources for human, BarkBase introduces a powerful new resource to support comparative studies in dogs and humans.


Counter-regulation of opioid analgesia by glial-derived bioactive sphingolipids.
The clinical efficacy of opiates for pain control is severely limited by analgesic tolerance and hyperalgesia. Herein we show that chronic morphine upregulates both the sphingolipid ceramide in spinal astrocytes and microglia, but not neurons, and spinal sphingosine-1-phosphate (S1P), the end-product of ceramide metabolism. Coadministering morphine with intrathecal administration of pharmacological inhibitors of ceramide and S1P blocked formation of spinal S1P and development of hyperalgesia and tolerance in rats. Our results show that spinally formed S1P signals at least in part by (1) modulating glial function because inhibiting S1P formation blocked increased formation of glial-related proinflammatory cytokines, in particular tumor necrosis factor-α, interleukin-1βα, and interleukin-6, which are known modulators of neuronal excitability, and (2) peroxynitrite-mediated posttranslational nitration and inactivation of glial-related enzymes (glutamine synthetase and the glutamate transporter) known to play critical roles in glutamate neurotransmission. Inhibitors of the ceramide metabolic pathway may have therapeutic potential as adjuncts to opiates in relieving suffering from chronic pain.


Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix.
There is increasing evidence that hypoxia-regulated gene expression influences tumor aggressiveness, contributing to the poorer outcome of patients with hypoxic tumors. The role of the transcriptional complex hypoxia-inducible factor-1 as an important mediator of hypoxia-regulated gene expression is one of the best documented pathways. Recently, it has emerged that certain tumor-associated carbonic anhydrases (CAs) can be added to the list of known hypoxia-inducible factor-responsive genes. Here we show that the immunohistochemical expression of the tumor-associated CA IX is correlated with the level of hypoxia in human cervical tumors. We performed a prospective study in 68 patients where needle electrodes were used to make direct measurements of tumor oxygenation levels. CA IX expression was evaluated immunohistochemically in pretreatment tumor biopsies. There was a significant positive correlation between the level of tumor hypoxia (HP5) and the extent of CA IX expression. A retrospective study of 130 squamous cell cervical carcinomas demonstrated that a semiquantitative immunohistochemical analysis of CA IX expression in tumor biopsies is a significant and independent prognostic indicator of overall survival and metastasis-free survival after radiation therapy. These studies provide clinical evidence that CA IX expression is up-regulated in hypoxic human cervical tumors and is associated with a poor prognosis. CA IX may act as an intrinsic marker of tumor hypoxia and poor outcome after radiation therapy. The level of CA IX expression may be used to aid in the selection of patients who would benefit most from hypoxia-modification therapies or bio-reductive drugs.


Investigation of repressive and enhancive effects of fruit extracts on the activity of glucose-6-phophatase.
Glucose-6-phosphatase is a key enzyme of glucose metabolic pathways. Deficiency of this enzyme leads to glycogen storage disease. This enzyme also plays a negative role in diabetes mellitus disorder in which the catalytic activity of this enzyme increases. Thus there is need for activators to enhance the activity of glucose-6-phosphatase in glycogen storage disease of type 1b while in diabetes mellitus repressors are needed to reduce its activity. Crude extracts of apricot, fig, mulberry and apple fruits were investigated for their repressive/enhancive effects on glucose-6-phosphatase in vivo. Albino mice were used as experimental animal. All the selected extracts showed depressive effects on glucose-6-phosphatase, which shows that all these extracts can be used as antidiabetic supplement of food. The inhibitory pattern was competitive one, which was evident from the effect of increasing dose from 1g/Kg body weight to 3g/Kg body weight for all the selected fruit extracts. However fig and apple fruit extracts showed high repressive effects for high doses as compared to apricot and mulberry fruit extracts. None of these selected fruit extracts showed enhancive effect on glucose-6-phosphatase activity. All these fruits or their extracts can be used as antidiabetic dietary supplement for diabetes mellitus.


Use of a novel porcine collagen paste as a dermal substitute in full-thickness wounds.
A commercially available porcine collagen sheet material has been found previously to be useful as an implant for reconstructive surgery. However, its use as a dermal substitute has been hindered by slow cell penetration and vascularization. A novel paste formulation of this material was investigated for its potential role as a dermal substitute in full-thickness wounds. A porcine punch biopsy model was initially used to assess the integration of a wide range of material formulations. Selected formulations were then assessed further in a larger wound-chamber model. Paste formulations were compared with those of sheet and another commercially available dermal regeneration template. The porcine collagen paste became integrated into full-thickness wounds without rejection and without excessive inflammation. It was detected in wounds up to day 27 postimplantation. Porcine collagen paste was readily infiltrated by host cells by day 2 and supported migrating keratinocytes on its surface. Staining for endothelial cells indicated neovasculature formation as early as day 4 and functional newly formed microvessels were noted at day 7. This was comparable with neovascularization of an alternative and clinically proven dermal regeneration template and was significantly superior to the sheet material formulation at the same time points. Our findings suggest that porcine collagen paste may be suitable as an alternative to current dermal substitutes in full-thickness wounds.


A 6-month analysis of training-intensity distribution and physiological adaptation in Ironman triathletes.
In the present study, we analysed the training-intensity distribution and physiological adaptations over a 6-month period preceding an Ironman triathlon race. Ten athletes (mean ± s: age 43 ± 3 years, mass 78.3 ± 10.3 kg, stature 1.79 ± 0.05 m) participated in the study. The study consisted of three training periods (A, B, C), each of approximately 2 months' duration, and four testing weeks. Testing consisted of incremental tests to exhaustion for swimming, cycling and running, and assessments for anthropometry plus cardiovascular and pulmonary measures. The lactate threshold and the lactate turnpoint were used to demarcate three discipline-specific, exercise-intensity zones. The mean percentage of time spent in zones 1, 2, and 3 was 69 ± 9%, 25 ± 8%, and 6 ± 2% for periods A-C combined. Only modest physiological adaptation occurred throughout the 6-month period, with small to moderate effect sizes at best. Relationships between the training volume/training load and the training-intensity distribution with the changes in key measures of adaptation were weak and probably reflect differences in initial training status. Our results suggest that the effects of intensity distribution are small over short-term training periods and future experimental research is needed to clarify the potential impact of intensity distribution on physiological adaptation.


Risk factors for recoarctation of aorta after Norwood procedure in patients with hypoplastic left heart syndrome.
Recoarctation (reCoA) of the aorta is a common complication afer the Norwood procedure. Untreated, it can lead to failure of the systemic ventricle and death. The main goal of the study is to define risk factors of reCoA after the Norwood procedure in hypoplastic left heart syndrome (HLHS). We retrospectively analyzed the pre-, intra- and postoperative data of 96 successive patients who underwent the Norwood procedure between 2007 and 2011. In case of reCoA balloon angioplasty was performed. We analyzed and compared the data of the patients with reCoA and without reCoA using the StatSo STATISTICA TM 10 software. ReCoA was noted in 23 patients (33.3%). This complication was diagnosed 95.1 days (49-156 days) on the average a er the Norwood procedure. Balloon angioplasty successfully allowed for decreasing the mean gradient across the site of the narrowing from the average 27.5 mmHg to the average 9.7 mmHg (p = 0.008) and enlarged the neo-isthmus by the average of 2 mm (p <0.05). The risks factors seemed to be the diameter of the ascending aorta OR = 7.82 (p = 0.001), atresia of the mitral valve OR = 7.00 (p = 0.003) and atresia of the aortic valve - OR = 6.22 (p = 0.002). Balloon angioplasty seems to be an effective intervention in case of reCoA. A low diameter of the native ascending aorta (<=3mm) and the presence of atresia of the mitral and/or aortic valve should intensify the vigilance of a cardiologist in the search for signs of reCoA of the aorta.


Acute anterior myocardial infarction in the 36th week of pregnancy: A successful stepwise treatment approach.
Acute myocardial infarction (AMI) is associated with a high incidence of maternal and fetal complications when it develops during pregnancy or the early postpartum period. The pathophysiology involves various factors, including alterations in the vascular wall and hypercoagulability as a result of the hormonal and hemodynamic effects of pregnancy. It frequently occurs due to the development of a thrombus following a ruptured plaque. In addition, coronary artery dissection constitutes a significant cause of AMI in pregnancy. In the literature, the therapeutic approach covers a wide spectrum, ranging from conservative follow-up to percutaneous coronary intervention, urgent bypass surgery, and occasionally, thrombolytic therapy. The success rate is often low; however, maternal and fetal complications are seen more frequently during invasive interventions and bypass surgeries because of the structural changes in the coronary intima and media wall. Presently described is the case of a woman in the 36th week of pregnancy who presented with AMI. The occlusion could not be detected during the primary percutaneous intervention, and thrombolytic treatment and a stepwise percutaneous intervention were performed with a successful result.


Antistaphylococcal activity of bacteriophage derived chimeric protein P128.
Bacterial drug resistance is one of the most significant challenges to human health today. In particular, effective antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA) are urgently needed. A causal relationship between nasal commensal S. aureus and infection has been reported. Accordingly, elimination of nasal S. aureus reduces the risk of infection. Enzymes that degrade bacterial cell walls show promise as antibacterial agents. Bacteriophage-encoded bacterial cell wall-degrading enzymes exhibit intrinsic bactericidal activity. P128 is a chimeric protein that combines the lethal activity of the phage tail-associated muralytic enzyme of Phage K and the staphylococcal cell wall targeting-domain (SH3b) of lysostaphin.Here we report results of in vitro studies evaluating the susceptibility of staphylococcal strains to this novel protein. Using the broth microdilution method adapted for lysostaphin, we found that P128 is effective against S. aureus clinical strains including MRSA, methicillin-sensitive S. aureus (MSSA), and a mupirocin-resistant S. aureus. Minimum bactericidal concentrations and minimum inhibitory concentrations of P128 (1-64 μg/mL) were similar across the 32 S. aureus strains tested, demonstrating its bactericidal nature.In time-kill assays, P128 reduced colony-forming units by 99.99% within 1 h and inhibited growth up to 24 h.In an assay simulating topical application of P128 to skin or other biological surfaces, P128 hydrogel was efficacious when layered on cells seeded on solid media. P128 hydrogel was lethal to Staphylococci recovered from nares of healthy people and treated without any processing or culturing steps, indicating its in situ efficacy. This methodology used for in vitro assessment of P128 as an agent for eradicating nasal carriage is unique. The novel chimeric protein P128 is a staphylococcal cell wall-degrading enzyme under development for clearance of S. aureus nasal colonization and MRSA infection. The protein is active against globally prevalent antibiotic-resistant clinical isolates and other clinically significant staphylococcal species including S. epidermidis. The P128 hydrogel formulation was bactericidal against Staphylococci including S. aureus recovered from the nares of 31 healthy people, demonstrating its in situ efficacy.


Maximizing the value of mobile health monitoring by avoiding redundant patient reports: prediction of depression-related symptoms and adherence problems in automated health assessment services.
Interactive voice response (IVR) calls enhance health systems' ability to identify health risk factors, thereby enabling targeted clinical follow-up. However, redundant assessments may increase patient dropout and represent a lost opportunity to collect more clinically useful data. We determined the extent to which previous IVR assessments predicted subsequent responses among patients with depression diagnoses, potentially obviating the need to repeatedly collect the same information. We also evaluated whether frequent (ie, weekly) IVR assessment attempts were significantly more predictive of patients' subsequent reports than information collected biweekly or monthly. Using data from 1050 IVR assessments for 208 patients with depression diagnoses, we examined the predictability of four IVR-reported outcomes: moderate/severe depressive symptoms (score ≥10 on the PHQ-9), fair/poor general health, poor antidepressant adherence, and days in bed due to poor mental health. We used logistic models with training and test samples to predict patients' IVR responses based on their five most recent weekly, biweekly, and monthly assessment attempts. The marginal benefit of more frequent assessments was evaluated based on Receiver Operator Characteristic (ROC) curves and statistical comparisons of the area under the curves (AUC). Patients' reports about their depressive symptoms and perceived health status were highly predictable based on prior assessment responses. For models predicting moderate/severe depression, the AUC was 0.91 (95% CI 0.89-0.93) when assuming weekly assessment attempts and only slightly less when assuming biweekly assessments (AUC: 0.89; CI 0.87-0.91) or monthly attempts (AUC: 0.89; CI 0.86-0.91). The AUC for models predicting reports of fair/poor health status was similar when weekly assessments were compared with those occurring biweekly (P value for the difference=.11) or monthly (P=.81). Reports of medication adherence problems and days in bed were somewhat less predictable but also showed small differences between assessments attempted weekly, biweekly, and monthly. The technical feasibility of gathering high frequency health data via IVR may in some instances exceed the clinical benefit of doing so. Predictive analytics could make data gathering more efficient with negligible loss in effectiveness. In particular, weekly or biweekly depressive symptom reports may provide little marginal information regarding how the person is doing relative to collecting that information monthly. The next generation of automated health assessment services should use data mining techniques to avoid redundant assessments and should gather data at the frequency that maximizes the value of the information collected.


Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation.
Th17 cells are a subset of CD4+ T cells with an important role in clearing certain bacterial and fungal pathogens. However, they have also been implicated in autoimmune diseases such as multiple sclerosis. Exposure of naive CD4+ T cells to IL-6 and TGF-β leads to Th17 cell differentiation through a process in which many proteins have been implicated. We report here that ectopic expression of liver X receptor (LXR) inhibits Th17 polarization of mouse CD4+ T cells, while LXR deficiency promotes Th17 differentiation in vitro. LXR activation in mice ameliorated disease in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, whereas LXR deficiency exacerbated disease. Further analysis revealed that Srebp-1, which is encoded by an LXR target gene, mediated the suppression of Th17 differentiation by binding to the E-box element on the Il17 promoter, physically interacting with aryl hydrocarbon receptor (Ahr) and inhibiting Ahr-controlled Il17 transcription. The putative active site (PAS) domain of Ahr and the N-terminal acidic region of Srebp-1 were essential for this interaction. Additional analyses suggested that similar LXR-dependent mechanisms were operational during human Th17 differentiation in vitro. This study reports what we believe to be a novel signaling pathway underlying LXR-mediated regulation of Th17 cell differentiation and autoimmunity.


Outcomes From a Patient-Centered, Interprofessional, Palliative Consult Team in Oncology.
Background: Palliative care aims to improve suffering and quality of life for patients with life-limiting disease. This study evaluated an interdisciplinary palliative consultation team for outpatients with advanced cancer at the Tom Baker Cancer Centre. This team traditionally offered palliative medicine and recently integrated a specialized psychosocial clinician. Historic patient-reported clinical outcomes were reviewed. There were no a priori hypotheses. Methods: A total of 180 chart reviews were performed in 8 sample months in 2015 and 2016; 114 patients were included. All patients were referred for management of complex cancer symptomatology by oncology or palliative care clinicians. Patients attended initial interviews in person; palliative medicine follow-ups were largely performed by telephone, and psychosocial appointments were conducted in person for those who were interested and had psychosocial concerns. Chart review included collection of demographics, medical information, and screening for distress measures at referral, initial consult, and discharge. Results: A total of 51% of the patient sample were men, 81% were living with a partner, and 87% had an advanced cancer diagnosis. Patients were grouped based on high, moderate, or low scores for 5 symptoms (pain, fatigue, depression, anxiety, and well-being). High scores on all 5 symptoms decreased from referral to discharge. Pain and anxiety decreased in the moderate group. All 5 low scores increased significantly. Sleep, frustration/anger, sense of burdening others, and sensitivity to cold were less frequently endorsed by discharge. Conclusions: Patients who completed this interdisciplinary palliative consult service appeared to experience a reduction in their most severe symptoms. Visits to patients during existing appointments or having them attend a half-day clinic appears to have reached those referred. With interdisciplinary integration, clinicians are able to collaborate to address patient care needs. Considerations include how to further integrate palliative and psychosocial care to achieve additional benefits and ongoing monitoring of changes in symptom burden.


An Anode-Free Zn-MnO2 Battery.
Aqueous Zn-based batteries are attractive because of the low cost and high theoretical capacity of the Zn metal anode. However, the Zn-based batteries developed so far utilize an excess amount of Zn (i.e., thick Zn metal anode), which decreases the energy density of the whole battery. Herein, we demonstrate an anode-free design (i.e., zero-excess Zn), which is enabled by employing a nanocarbon nucleation layer. Electrochemical studies show that this design allows for uniform Zn electrodeposition with high efficiency and stability over a range of current densities and plating capacities. Using this anode-free configuration, we showcase a Zn-MnO2 battery prototype, showing 68.2% capacity retention after 80 cycles. Our anode-free design opens a new direction for implementing aqueous Zn-based batteries in energy storage systems.


Glutamine administration ameliorates sepsis-induced kidney injury by downregulating the high-mobility group box protein-1-mediated pathway in mice.
Acute kidney injury (AKI) is a severe complication of sepsis. High-mobility group box (HMGB)-1 was implicated as a late mediator of lethal systemic inflammation in sepsis. Since glutamine (GLN) was shown to have anti-inflammatory and antioxidant properties, we hypothesized that GLN administration may downregulate an HMGB-1-mediated pathway and thus ameliorate sepsis-induced AKI. Mice were randomly assigned to a normal group (NC), a septic saline group (SS), or a septic GLN group (SG). Sepsis was induced by cecal ligation and puncture (CLP). The SS group was injected with saline, and the SG group was given 0.75 g GLN/kg body wt once via a tail vein 1 h after CLP. Mice were killed 2, 6, and 24 h after CLP, and blood and kidneys of the animals were harvested for further analysis. The results showed that sepsis resulted in higher mRNA and/or protein expressions of kidney HMGB-1, toll-like receptor (TLR) 4, myeloid differentiation primary-response protein (MyD) 88, and receptor of advanced glycation end products (RAGE) compared with normal mice. Septic mice with GLN administration exhibited decreased HMGB-1, TLR4, RAGE, and phosphorylated NF-κB p65 protein expressions and reduced nitrotyrosine levels in kidney tissues. The histological findings showed that damage to the kidneys was less severe, and survival improved in the SG group. These results indicated that a single dose of GLN administered after the initiation of sepsis plays a prophylactic role in downregulating the expressions of HMGB-1-related mediators and decreasing oxidative stress in the kidneys, which may consequently have ameliorated AKI induced by sepsis.


Notch signaling represses GATA4-induced expression of genes involved in steroid biosynthesis.
Notch2 and Notch3 and genes of the Notch signaling network are dynamically expressed in developing follicles, where they are essential for granulosa cell proliferation and meiotic maturation. Notch receptors, ligands, and downstream effector genes are also expressed in testicular Leydig cells, predicting a potential role in regulating steroidogenesis. In this study, we sought to determine if Notch signaling in small follicles regulates the proliferation response of granulosa cells to FSH and represses the up-regulation steroidogenic gene expression that occurs in response to FSH as the follicle grows. Inhibition of Notch signaling in small preantral follicles led to the up-regulation of the expression of genes in the steroid biosynthetic pathway. Similarly, progesterone secretion by MA-10 Leydig cells was significantly inhibited by constitutively active Notch. Together, these data indicated that Notch signaling inhibits steroidogenesis. GATA4 has been shown to be a positive regulator of steroidogenic genes, including STAR protein, P450 aromatase, and 3B-hydroxysteroid dehydrogenase. We observed that Notch downstream effectors HEY1, HEY2, and HEYL are able to differentially regulate these GATA4-dependent promoters. These data are supported by the presence of HEY/HES binding sites in these promoters. These studies indicate that Notch signaling has a role in the complex regulation of the steroidogenic pathway.


Cognitive ability in adolescents born small for gestational age: Associations with fetal growth velocity, head circumference and postnatal growth.
Small size at birth may be associated with impaired cognitive ability later in life. The aim of this study was to examine the effect of being born small for gestational age (SGA), with or without intrauterine growth restriction (IUGR) on cognitive ability in late adolescence. A follow-up study of a former cohort included 123 participants (52 males); 47 born SGA and 76 born appropriate for gestational age (AGA). Fetal growth velocity (FGV) was determined by serial ultrasound measurements during the third trimester. A control group matched for age and birthplace was included. The original Wechsler Adult Intelligence Scale (WAIS) was administered, and verbal, performance and full-scale Intelligence Quotient (IQ) scores were calculated. There was no difference in IQ between adolescents born SGA and AGA. FGV or IUGR during the third trimester did not influence cognitive ability in late adolescence. Full-scale IQ was positively related to head circumference (HC) in adolescence (B: 1.30, 95% CI: 0.32-2.28, p=0.01). HC at birth and three months was positively associated with full-scale IQ. Catch-up growth in the group of SGA children was associated with a significantly increased height, larger HC, increased levels of insulin-like growth factor-I (IGF-I) and increased full-scale IQ compared to those born SGA without catch-up growth. SGA and IUGR may not be harmful for adult cognitive ability, at least not in individuals born at near-term. However, known risk factors of impaired fetal growth may explain the link between early growth and cognitive ability in adulthood.


Cell dispersion patterns in different cortical regions studied with an X-inactivated transgenic marker.
Inactivation of the X-linked lacZ transgene provides a novel and powerful way of distinguishing between clonally related cellular populations in X inactivation mosaics. This ability to distinguish between clonal populations of cells in the mature cortex permits inferences to be made about cellular dispersion patterns during cortical development. The present study addresses the extent to which radial and tangential dispersion patterns contribute to different regions of the cerebral cortex by quantifying the extent of cellular mixing between clonally distinct cells in separate domains of the medial, dorsolateral and lateral cortices. We show that stripes running perpendicular to the cortical layers are more likely to be seen in the medial and dorsolateral regions, and that the appearance of a stripe is attributed to about two-thirds of the cells being of the same colour. Both neurons and glia appeared to exhibit the same ratio of cell mixing. In the lateral regions of the cortex, stripes were not apparent, and cell mixing was roughly equal. In the barrel-field region of the somatosensory cortex we looked for a correspondence between cytoarchitectural features and clonal borders but found no correlation. These results demonstrate, first, that although there is widespread radial dispersion, no cortical region is composed of radially arrayed stripes of cells in which all members of a stripe are derived from a single progenitor. Second, they demonstrate that, within regions containing a sizeable fraction of cells that do migrate radially, the boundaries of individual stripes do not always coincide with single anatomical units of cortical specialization, such as individual barrels.


Fast test for assessing the susceptibility of Mycobacterium tuberculosis to isoniazid and rifampin by real-time PCR.
Mycobacterium tuberculosis is the bacterium that causes tuberculosis (TB), a leading cause of death from infectious disease worldwide. Rapid diagnosis of resistant strains is important for the control of TB. Real-time polymerase chain reaction (RT-PCR) assays may detect all of the mutations that occur in the M. tuberculosis 81-bp core region of the rpoB gene, which is responsible for resistance to rifampin (RIF) and codon 315 of the katG gene and the inhA ribosomal binding site, which are responsible for isoniazid (INH). The goal of this study was to assess the performance of RT-PCR compared to traditional culture-based methods for determining the drug susceptibility of M. tuberculosis. BACTEC TM MGIT TM 960 was used as the gold standard method for phenotypic drug susceptibility testing. Susceptibilities to INH and RIF were also determined by genotyping of katG, inhA and rpoB genes. RT-PCR based on molecular beacons probes was used to detect specific point mutations associated with resistance. The sensitivities of RT-PCR in detecting INH resistance using katG and inhA targets individually were 55% and 25%, respectively and 73% when combined. The sensitivity of the RT-PCR assay in detecting RIF resistance was 99%. The median time to complete the RT-PCR assay was three-four hours. The specificities for tests were both 100%. Our results confirm that RT-PCR can detect INH and RIF resistance in less than four hours with high sensitivity.


Global Prevalence and Potential Influencing Factors of COVID-19 Vaccination Hesitancy: A Meta-Analysis.
Countries worldwide have deployed mass COVID-19 vaccination drives, but there are people who are hesitant to receive the vaccine. Studies assessing the factors associated with COVID-19 vaccination hesitancy are inconclusive. This study aimed to assess the global prevalence of COVID-19 vaccination hesitancy and determine the potential factors associated with such hesitancy. We performed an organized search for relevant articles in PubMed, Scopus, and Web of Science. Extraction of the required information was performed for each study. A single-arm meta-analysis was performed to determine the global prevalence of COVID-19 vaccination hesitancy; the potential factors related to vaccine hesitancy were analyzed using a Z-test. A total of 56 articles were included in our analysis. We found that the global prevalence of COVID-19 vaccination hesitancy was 25%. Being a woman, being a 50-year-old or younger, being single, being unemployed, living in a household with five or more individuals, having an educational attainment lower than an undergraduate degree, having a non-healthcare-related job and considering COVID-19 vaccines to be unsafe were associated with a higher risk of vaccination hesitancy. In contrast, living with children at home, maintaining physical distancing norms, having ever tested for COVID-19, and having a history of influenza vaccination in the past few years were associated with a lower risk of hesitancy to COVID-19 vaccination. Our study provides valuable information on COVID-19 vaccination hesitancy, and we recommend special interventions in the sub-populations with increased risk to reduce COVID-19 vaccine hesitancy.


Subtype-specific actions of beta-amyloid peptides on recombinant human neuronal nicotinic acetylcholine receptors (alpha7, alpha4beta2, alpha3beta4) expressed in Xenopus laevis oocytes.
Two-electrode voltage-clamp electrophysiology has been used to study the actions of two amyloid peptides (Abeta(1-42), Abeta(1-40)) on alpha7, alpha4beta2 and alpha3beta4 recombinant human neuronal nicotinic acetylcholine receptors (nicotinic AChRs), heterologously expressed in Xenopus laevis oocytes. The application of Abeta(1-42) or Abeta(1-40) (1 pM-100 nM) for 5 s does not directly activate expressed human alpha7, alpha4beta2 or alpha3beta4 nicotinic AChRs.Abeta(1-42) and Abeta(1-40) are antagonists of alpha7 nicotinic AChRs. For example, 10 nM Abeta(1-42) and Abeta(1-40) both reduced the peak amplitude of currents recorded (3 mM ACh) to 48+/-5 and 45+/-10% (respectively) of control currents recorded in the absence of peptide. In both the cases the effect is sustained throughout a 30 min peptide application and is poorly reversible.Abeta(1-42) and Abeta(1-40) (10 nM) enhance currents recorded in response to ACh (3 mM) from oocytes expressing alpha4beta2 nicotinic AChRs by 195+/-40 and 195+/-41% respectively. This effect is transient, reaching a peak after 3 min and returning to control values after a 24 min application of 10 nM Abeta(1-42). We observe an enhancement of 157+/-22% of control ACh-evoked current amplitude in response to 100 nM Abeta(1-42) recorded from oocytes expressing alpha4beta2 nicotinic AChRs.Abeta(1-42) and Abeta(1-40) (10 nM) were without antagonist actions on the responses of alpha3beta4 nicotinic AChRs to ACh (1 nM-3 mM).


Immunization of melanoma patients with BEC2 anti-idiotypic monoclonal antibody that mimics GD3 ganglioside: enhanced immunogenicity when combined with adjuvant.
Previous attempts to immunize melanoma patients against GD3 ganglioside have been unsuccessful because of the poor immunogenicity of GD3. BEC2, an anti-idiotypic monoclonal antibody that mimics GD3, can induce anti-GD3 IgG in rabbits. Since clinical trials with BEC2 in melanoma patients demonstrated that BEC2 alone is not highly immunogenic, we have carried out sequential clinical trials exploring the use of two immunological adjuvants, BCG and QS21, administered with BEC2. Melanoma patients free of disease after surgical resection but at high risk for recurrence were immunized either with BEC2/BCG (14 patients) or BEC2/QS21 (6 patients). All patients developed high-titer IgG antibodies against BEC2, demonstrating that both adjuvants effectively enhanced the immunogenicity of BEC2. Anti-GD3 antibodies were induced in 3 of 14 patients immunized with BEC2/BCG; no patient immunized with BEC2/QS21 developed detectable anti-GD3 antibodies. After a median follow-up of 2.4 years, 71% of the patients immunized with BEC2/BCG remain alive and 64% are free of disease. In patients immunized with BEC2/BCG, no apparent association was observed between class II HLA type and either development of anti-GD3 antibodies or survival. We are encouraged by the results with BEC2/BCG, which suggest that further enhancement of the immune response to BEC2 will result in more frequent anti-GD3 antibody responses among immunized patients.


Hepatotoxicity after long-term methotrexate therapy.
To reassess the need for repeat liver biopsies in patients receiving long-term methotrexate therapy, we reviewed the results of 15 biopsies in 14 such patients seen from 1979 to 1984 at the Medical University of South Carolina. Significant changes in liver histology were found in seven patients. These findings did not correlate with biochemical abnormalities, presence of anemia or obesity, or age when methotrexate therapy was initiated. Four of the 15 biopsies (27%) showed grade III or IV histologic changes (fibrosis or cirrhosis), which led to discontinuance of treatment. The single most significant factor predisposing to toxicity appeared to be the duration of therapy, though the cumulative doses, no patient with grade III or IV histology had been treated for less than five years. Thus, surveillance liver biopsies at suitable intervals are advisable once the patient has been treated for five years or more. Conversely, liver biopsies within the first five years of treatment with methotrexate appear not to be necessary, though these results should be confirmed in a larger patient group.


Toward designed singlet fission: electronic states and photophysics of 1,3-diphenylisobenzofuran.
Single crystal molecular structure and solution photophysical properties are reported for 1,3-diphenylisobenzofuran (1), of interest as a model compound in studies of singlet fission. For the ground state of 1 and of its radical cation (1(+*)) and anion (1(-*)), we report the UV-visible absorption spectra, and for neutral 1, also the magnetic circular dichroism (MCD) and the decomposition of the absorption spectrum into purely polarized components, deduced from fluorescence polarization. These results were used to identify a series of singlet excited states. For the first excited singlet and triplet states of 1, the transient visible absorption spectra, S(1) --> S(x) and sensitized T(1) --> T(x), and single exponential lifetimes, tau(F) = approximately 5.3 ns and tau(T) = approximately 200 micros, are reported. The spectra and lifetimes of S(1) --> S(0) fluorescence and sensitized T(1) --> T(x) absorption of 1 were obtained in a series of solvents, as was the fluorescence quantum yield, Phi(F) = 0.95-0.99. No phosphorescence has been detected. The first triplet excitation energy of solid 1 (11,400 cm(-1)) was obtained by electron energy loss spectroscopy, in agreement with previously reported solution values. The fluorescence excitation spectrum suggests an onset of a nonradiative channel at approximately 37,000 cm(-1). Excitation energies and relative transition intensities are in agreement with those of ab initio (CC2) calculations after an empirical 3000 cm(-1) adjustment of the initial state energy to correct differentially for a better quality description of the initial relative to the terminal state of an absorption transition. The interpretation of the MCD spectrum used the semiempirical PPP method, whose results for the S(0) --> S(x) spectrum require no empirical adjustment and are otherwise nearly identical with the CC2 results in all respects including the detailed nature of the electronic excitation. The ground state geometry of 1 was also calculated by the MP2, B3LYP, and CAS methods. The calculations provided a prediction of changes of molecular geometry upon excitation or ionization and permitted an interpretation of the spectra in terms of molecular orbitals involved. Computations suggest that 1 can exist as two nearly isoenergetic conformers of C(2) or C(s) symmetry. Linear dichroism measurements in stretched polyethylene provide evidence for their existence and show that they orient to different degrees, permitting a separation of their spectra in the region of the purely polarized first absorption band. Their excitation energies are nearly identical, but the Franck-Condon envelopes of their first transition differ to a surprising degree.


Phosphorylation at Ser-129 but not the phosphomimics S129E/D inhibits the fibrillation of alpha-synuclein.
alpha-Synuclein (alpha-syn) phosphorylation at serine 129 is characteristic of Parkinson disease (PD) and related alpha-synulceinopathies. However, whether phosphorylation promotes or inhibits alpha-syn aggregation and neurotoxicity in vivo remains unknown. This understanding is critical for elucidating the role of alpha-syn in the pathogenesis of PD and for development of therapeutic strategies for PD. To better understand the structural and molecular consequences of Ser-129 phosphorylation, we compared the biochemical, structural, and membrane binding properties of wild type alpha-syn to those of the phosphorylation mimics (S129E, S129D) as well as of in vitro phosphorylated alpha-syn using a battery of biophysical techniques. Our results demonstrate that phosphorylation at Ser-129 increases the conformational flexibility of alpha-syn and inhibits its fibrillogenesis in vitro but does not perturb its membrane-bound conformation. In addition, we show that the phosphorylation mimics (S129E/D) do not reproduce the effect of phosphorylation on the structural and aggregation properties of alpha-syn in vitro. Our findings have significant implications for current strategies to elucidate the role of phosphorylation in modulating protein structure and function in health and disease and provide novel insight into the underlying mechanisms that govern alpha-syn aggregation and toxicity in PD and related alpha-synulceinopathies.


Oxygen affinity in vivo and in vitro in chronic ventilatory failure.
1. The oxygen affinity in vitro, haematological indices, erythrocyte 2,3-diphosphoglycerate and plasma inorganic phosphate were determined in 20 patients with chronic ventilatory failure and in 20 healthy non-smokers of similar age. 2. No significant difference was observed between the mean oxygen affinity or phosphate concentrations of the patients and healthy subjects but the mean haemoglobin and packed cell volume were significantly higher in the patients. 3. There was a positive correlation between plasma and intraerythrocytic pH which was similar in both patients and healthy subjects. 4. The arteriovenous difference in oxygen saturation in vivo (directly measured at cardiac catheterization) correlated closely with that calculated from the individual patient's oxygen affinity determined in vitro and arterial and mixed venous oxygen and carbon dioxide tensions, suggesting that oxygen affinity in vitro accurately reflects the curve in vivo.


A systematic review and meta-analysis of somatic and germline DNA sequence biomarkers of esophageal cancer survival, therapy response and stage.
There is an urgent need for biomarkers to help predict prognosis and guide management of esophageal cancer. This review identifies, evaluates and meta-analyses the evidence for reported somatic and germline DNA sequence biomarkers of outcome and stage. A systematic review was carried out of the PubMed, EMBASE and Cochrane databases (20 August 2014), in conjunction with the ASCO Level of Evidence scale for biomarker research. Meta-analyses were carried out for all reported markers associated with outcome measures by more than one study. Four thousand and four articles were identified, 762 retrieved and 182 studies included. There were 65 reported markers of survival or recurrence 12 (18.5%) were excluded due to multiple comparisons. Following meta-analysis, significant associations were seen for six tumor variants (mutant TP53 and PIK3CA, copy number gain of ERBB2/HER2, CCND1 and FGF3, and chromosomal instability/ploidy) and seven germline polymorphisms: ERCC1 rs3212986, ERCC2 rs1799793, TP53 rs1042522, MDM2 rs2279744, TYMS rs34743033, ABCB1 rs1045642 and MTHFR rs1801133. Twelve germline markers of treatment complications were reported; 10 were excluded. Two tumor and 15 germline markers (11 excluded) of chemo (radio)therapy response were reported. Following meta-analysis, associations were demonstrated for mutant TP53, ERCC1 rs11615 and XRCC1 rs25487. There were 41 tumor/germline reported markers of stage; 27 (65.9%) were excluded. Numerous DNA markers of outcome and stage have been reported, yet few are backed by high-quality evidence. Despite this, a small number of variants appear reliable. These merit evaluation in prospective trials, within the context of high-throughput sequencing and gene expression.


An unbiased template of the Drosophila brain and ventral nerve cord.
The fruit fly Drosophila melanogaster is an important model organism for neuroscience with a wide array of genetic tools that enable the mapping of individual neurons and neural subtypes. Brain templates are essential for comparative biological studies because they enable analyzing many individuals in a common reference space. Several central brain templates exist for Drosophila, but every one is either biased, uses sub-optimal tissue preparation, is imaged at low resolution, or does not account for artifacts. No publicly available Drosophila ventral nerve cord template currently exists. In this work, we created high-resolution templates of the Drosophila brain and ventral nerve cord using the best-available technologies for imaging, artifact correction, stitching, and template construction using groupwise registration. We evaluated our central brain template against the four most competitive, publicly available brain templates and demonstrate that ours enables more accurate registration with fewer local deformations in shorter time.


Bone morphogenetic protein 2 activates Smad6 gene transcription through bone-specific transcription factor Runx2.
BMP-2 plays an essential role in osteoblast and chondrocyte differentiation, but its signaling mechanism has not been fully defined. In the present studies, we investigated the mechanism through which BMP-2 activates the Smad6 gene. A -2006/+45 Smad6 promoter-luciferase construct was generated along with deletions and Runx2 binding site mutations to examine the role of Smad1 and Runx2 signaling following BMP-2 stimulation in osteoblasts. Transfection of Runx2 or treatment with BMP-2-stimulated promoter activity of the -2006/+45 and -1191/+45 reporters but not the -829/+45 and -374/+45 reporters. No Smad1/5 binding site is present in the -1191/-829 region of the Smad6 promoter. Mutation of the OSE2-a site (-1036/-1031) completely abolished the stimulatory effect of Runx2 as well as BMP-2 on the -2006/+45 and -1191/+45 Smad6 reporters. Gel shift and chromatin immunoprecipitation (ChIP) assays showed that Runx2 binds the OSE2-a element. ChIP assays demonstrated that Smad1 also interacts with the OSE2-a site at the Smad6 promoter through Runx2. The protein degradation of Runx2 is mediated by the E3 ubiquitin ligase Smurf1. In the present studies, we found that Smurf1 binds the OSE2-a site through Runx2 and inhibits Smad6 gene transcription. Treatment with BMP-2 and transfection of Smad1 abolished Smurf1 binding to the OSE2 site. These results show that Smad1 binding excludes Smurf1 interaction with the OSE2 site and promotes Smad6 gene transcription.


A histopathologic study of a choroideremia carrier.
We have examined eyes from a heterozygote (carrier) of choroideremia, an X-linked disease. Gross examination revealed irregular pigmentation at the level of the retinal pigment epithelium (RPE) except at the posterior pole, and islands of well defined depigmentation of 1-4 mm in diameter in the midperiphery. The optic nerve and retinal blood vessels appeared normal, and there was minimal pigment migration into the retina. Histopathologic examination showed normal photoreceptors in the posterior and anterior fundus, but the outer segments were short or absent in much of the equatorial region. Little gliosis was noted in areas of retinal atrophy. The RPE was abnormal, with irregular thickness and pigmentation associated with variable lipofuscin content from one RPE cell to another, as shown by fluorescence microscopy. There were areas of profound atrophy in the equatorial region, with abrupt transitions between relatively normal RPE and photoreceptors, and retina devoid of RPE and photoreceptors. Bruch's membrane was thickened to a greater extent than is common in age-related change. The choriocapillaris was normal in areas with normal photoreceptors, except for widening of the intercapillary pillars. In those regions with abnormal photoreceptors, choroidal capillaries were fewer in number, had reduced luminal diameter, and fenestrae were sparse. In some areas of intense atrophy, there were no choroidal capillaries. The findings are compatible with the primary defect residing in the RPE. The Lyon hypothesis of X-chromosome inactivation and mosaicism could explain the irregularity of change and areas of intense atrophy, but abrupt demarcation between grossly abnormal, and relatively well preserved retina also occurs in hemizygotes (affected males).


Assessment of the relationship between the maxillary sinus floor and maxillary posterior teeth roots using cone beam computed tomography.
This study was conducted to assess the vertical and horizontal relationship between the maxillary sinus floor and maxillary posterior teeth roots using cone beam computed tomography. In this cross-sectional study, the CBCT images presented in the radiology department of Hamadan dental school was used. From 450 observed CBCT, 340 of them did not have the inclusion criteria of the study and ultimately 110 CBCT were selected. Totally 214 first premolars, 217 second premolars, 220 first molars and 220 second molars were included. For evaluating the relationship between the maxillary sinus floor and the posterior maxillary teeth, the classification implemented in the study of Jung in 2009 was used. The relation was evaluated by two radiologists twice with a 2-week time interval. One hundred and ten patients with a mean age of 31.06 ± 9.7 years were assessed. Type 0 relationship (the maxillary sinus floor is located above the root tip) was most frequently observed with the first and second premolars. The most common type observed in the first and second molars was type 3 (apical protrusion is seen over the maxillary sinus floor). The relation between different types and gender was statistically meaningful, while no statistically significant difference was found between the right and left side assessments. This study showed that although most of the teeth did not have contact with the sinus floor, but the more posterior the maxillary teeth, the more probability for root protruding into the maxillary sinus. It also confirmed that protrusion of teeth roots into the maxillary sinus is more common in male than female. Knowing the anatomical relation between the posterior teeth and the maxillary sinus, help the clinician in preoperative treatment planning of the posterior maxillary teeth and avoid problems that may occur during dental practice.


Stump nerve signals during transcranial magnetic motor cortex stimulation recorded in an amputee via longitudinal intrafascicular electrodes.
Do central and peripheral motor pathways associated with an amputated limb retain at least some functions over periods of years? This problem could be addressed by evaluating the response patterns of nerve signals from peripheral motor fibers during transcranial magnetic stimulation (TMS) of corticospinal tracts. The aim of this study was to record for the first time TMS-related responses from the nerves of a left arm stump of an amputee via intrafascicular longitudinal flexible multi-electrodes (tfLIFE4) implanted for a prosthetic hand control. After tfLIFE4 implant in the stump median and ulnar nerves, TMS impulses of increasing intensity were delivered to the contralateral motor cortex while tfLIFE4 recordings were carried out. Combining TMS of increasing intensity and tfLIFE4 electrodes recordings, motor nerve activity possibly related to the missing limb motor control and selectively triggered by brain stimulation without significant electromyographic contamination was identified. These findings are entirely original and indicate that tfLIFE4 signals are clearly driven from M1 stimulation, therefore witnessing the presence in the stump nerves of viable motor signals from the CNS possibly useful for artificial prosthesis control.


A study on Nim expression in Bacteroides fragilis.
Members of the genus Bacteroides, mainly Bacteroides fragilis, can cause severe disease in man, especially after intestinal perforation in the course of abdominal surgery. Treatment is based on a small number of antibiotics, including metronidazole, which has proved to be highly reliable throughout the last 40 to 50 years. Nevertheless, metronidazole resistance does occur in Bacteroides and has been mainly attributed to Nim proteins, a class of proteins with a suggested nitroreductase function. Despite the potentially high importance of Nim proteins for human health, information on the expression of nim genes in B. fragilis is still lacking. It was the aim of this study to demonstrate expression of nim genes in B. fragilis at the protein level and, furthermore, to correlate Nim levels with the magnitude of metronidazole resistance. By the application of 2D gel electrophoresis, Nim proteins could be readily identified in nim-positive strains, but their levels were not elevated to a relevant extent after induction of resistance with high doses of metronidazole. Thus, the data herein do not provide evidence for Nim proteins acting as nitroreductases using metronidazole as a substrate, because no correlation between Nim levels and levels of metronidazole resistance could be observed. Furthermore, no evidence was found that Nim proteins protect B. fragilis from metronidazole by sequestering the activated antibiotic.


Interleukin 17A: toward a new understanding of psoriasis pathogenesis.
Molecular and cellular understanding of psoriasis pathogenesis has evolved considerably over the last 30 years beginning in the early 1980s when psoriasis was thought to be a skin disease driven by keratinocyte hyperproliferation. During the next 20 years, the role of the immune system and T-helper (Th) cells in psoriasis pathogenesis was recognized. The presence of the interleukin (IL)-12 cytokine in psoriatic lesions led to the postulate that psoriasis is mediated by Th1 cells. Recent evidence has revealed a role for Th17 cells, and other immune cells, as proximal regulators of psoriatic skin inflammation. IL-17A, the principal effector cytokine of Th17 cells, stimulates keratinocytes to produce chemokines, cytokines, and other proinflammatory mediators thereby enabling IL-17A to bridge the innate and adaptive immune systems to sustain chronic inflammation. This model underlies the rationale for inhibiting IL-17A signaling as a potential therapeutic approach to disrupt the psoriatic inflammatory loop. Several monoclonal antibodies that inhibit the IL-17 pathway are in clinical development. These agents exhibit promising clinical efficacy and tolerability profiles including immunohistochemical improvement in psoriatic plaques. Results from clinical trials with IL-17 pathway inhibitors are refining our understanding of psoriasis pathogenesis and may provide a new therapeutic approach for patients with moderate to severe psoriasis.


Latent structure of the Hospital Anxiety And Depression Scale: a 10-year systematic review.
To systematically review the latent structure of the Hospital Anxiety and Depression Scale (HADS). A systematic review of the literature was conducted across Medline, ISI Web of Knowledge, CINAHL, PsycInfo and EmBase databases spanning articles published between May 2000 and May 2010. Studies conducting latent variable analysis of the HADS were included. Twenty-five of the 50 reviewed studies revealed a two-factor structure, the most commonly found HADS structure. Additionally, five studies revealed unidimensional, 17 studies revealed three-factor, and two studies revealed four-factor structures. One study provided equal support for two- and three-factor structures. Different latent variable analysis methods revealed correspondingly different structures: exploratory factor analysis studies revealed primarily two-factor structures, confirmatory factor analysis studies revealed primarily three-factor structures, and item response theory studies revealed primarily unidimensional structures. The heterogeneous results of the current review suggest that the latent structure of the HADS is unclear, and dependent on statistical methods invoked. While the HADS has been shown to be an effective measure of emotional distress, its inability to consistently differentiate between the constructs of anxiety and depression means that its use needs to be targeted to more general measurement of distress.


Evaluating forest fragmentation and its tree community composition in the tropical rain forest of Southern Western Ghats (India) from 1973 to 2004.
A majority of the research on forest fragmentation is primarily focused on animal groups rather than on tree communities because of the complex structural and functional behavior of the latter. In this study, we show that forest fragmentation provokes surprisingly rapid and profound alterations in tropical tree community. We examine forest fragments in the tropical region using high-resolution satellite imagery taken between 1973 and 2004 in the Southern Western Ghats (India) in relation to landscape patterns and phytosociological datasets. We have distinguished fragmentation in six categories--interior, perforated, edge, transitional, patch, and undetermined--around each forested pixel. Furthermore, we have characterized each of the fragment class in the evergreen and semi-evergreen forest in terms of its species composition and richness, its species similarity and abundance, and its regeneration status. Different landscape metrics have been used to infer patterns of land-use changes. Contiguous patches of >1,000 ha covered 90% of evergreen forest in 1973 with less porosity and minimal plantation and anthropogenic pressures; whereas in 2004, the area had 67% forest coverage and a high level of porosity, possibly due to Ochlandra spread and increased plantations which resulted in the loss of such contiguous patches. Results highlight the importance of landscape metrics in monitoring land-cover change over time. Our main conclusion was to develop an approach, which combines information regarding land cover, degree of fragmentation, and phytosociological inputs, to conserve and prioritize tropical ecosystems.


Elongation rate and average length of amyloid fibrils in solution using isotope-labelled small-angle neutron scattering.
We demonstrate a solution method that allows both elongation rate and average fibril length of assembling amyloid fibrils to be estimated. The approach involves acquisition of real-time neutron scattering data during the initial stages of seeded growth, using contrast matched buffer to make the seeds effectively invisible to neutrons. As deuterated monomers add on to the seeds, the labelled growing ends give rise to scattering patterns that we model as cylinders whose increase in length with time gives an elongation rate. In addition, the absolute intensity of the signal can be used to determine the number of growing ends per unit volume, which in turn provides an estimate of seed length. The number of ends did not change significantly during elongation, demonstrating that any spontaneous or secondary nucleation was not significant compared with growth on the ends of pre-existing fibrils, and in addition providing a method of internal validation for the technique. Our experiments on initial growth of alpha synuclein fibrils using 1.2 mg ml-1 seeds in 2.5 mg ml-1 deuterated monomer at room temperature gave an elongation rate of 6.3 ± 0.5 Å min-1, and an average seed length estimate of 4.2 ± 1.3 μm.