Substituted ferrocenes and iodine as synergistic thermoelectrochemical heat harvesting redox couples in ionic liquids.
Combining ferrocene and iodine results in enhanced thermoelectrochemical (or thermogalvanic) waste heat harvesting abilities, for both the Seebeck coefficient and the overall power output. All systems displayed a mixture of ferrocene, ferrocenium, iodine and triiodide. The observed enhancement correlates with lower electron-density on the ferrocene; the synergistic improvement observed for mixtures of substituted ferrocenes and iodine is attributed to the formation of charge-transfer complexes. Combining dibutanoylferrocene and iodine resulted in the highest Seebeck coefficient of 1.67 mV K(-1).


Development of Cell-Derived Matrices for Three-Dimensional In Vitro Cancer Cell Models.
Most morphogenetic and pathological processes are driven by cells responding to the surrounding matrix, such as its composition, architecture, and mechanical properties. Despite increasing evidence for the role of extracellular matrix (ECM) in tissue and disease development, many in vitro substitutes still fail to effectively mimic the native microenvironment. We established a novel method to produce macroscale (>1 cm) mesenchymal cell-derived matrices (CDMs) aimed to mimic the fibrotic tumor microenvironment surrounding epithelial cancer cells. CDMs are produced by human adipose mesenchymal stem cells cultured in sacrificial 3D scaffold templates of fibronectin-coated poly-lactic acid microcarriers (MCs) in the presence of macromolecular crowders. We showed that decellularized CDMs closely mimic the fibrillar protein composition, architecture, and mechanical properties of human fibrotic ECM from cancer masses. CDMs had highly reproducible composition made of collagen types I and III and fibronectin ECM with tunable mechanical properties. Moreover, decellularized and MC-free CDMs were successfully repopulated with cancer cells throughout their 3D structure, and following chemotherapeutic treatment, cancer cells showed greater doxorubicin resistance compared to 3D culture in collagen hydrogels. Collectively, these results support the use of CDMs as a reproducible and tunable tool for developing 3D in vitro cancer models.


Expression of caveolin-3 in skeletal, cardiac, and smooth muscle cells. Caveolin-3 is a component of the sarcolemma and co-fractionates with dystrophin and dystrophin-associated glycoproteins.
Caveolae are microdomains of the plasma membrane that have been implicated in signal transduction. Caveolin, a 21-24-kDa integral membrane protein, is a principal component of the caveolae membrane. Recently, we and others have identified a family of caveolin-related proteins; caveolin has been retermed caveolin-1. Caveolin-3 is most closely related to caveolin-1, but caveolin-3 mRNA is expressed only in muscle tissue types. Here, we examine (i) the expression of caveolin-3 protein in muscle tissue types and (ii) its localization within skeletal muscle fibers by immunofluorescence microscopy and subcellular fractionation. For this purpose, we generated a novel monoclonal antibody (mAb) probe that recognizes the unique N-terminal region of caveolin-3, but not other members of the caveolin gene family. A survey of tissues and muscle cell types by Western blot analysis reveals that the caveolin-3 protein is selectively expressed only in heart and skeletal muscle tissues, cardiac myocytes, and smooth muscle cells. Immunolocalization of caveolin-3 in skeletal muscle fibers demonstrates that caveolin-3 is localized to the sarcolemma (muscle cell plasma membrane) and coincides with the distribution of another muscle-specific plasma membrane marker protein, dystrophin. In addition, caveolin-3 protein expression is dramatically induced during the differentiation of C2C12 skeletal myoblasts in culture. Using differentiated C2C12 skeletal myoblasts as a model system, we observe that caveolin-3 co-fractionates with cytoplasmic signaling molecules (G-proteins and Src-like kinases) and members of the dystrophin complex (dystrophin, alpha-sarcoglycan, and beta-dystroglycan), but is clearly separated from the bulk of cellular proteins. Caveolin-3 co-immunoprecipitates with antibodies directed against dystrophin, suggesting that they are physically associated as a discrete complex. These results are consistent with previous immunoelectron microscopic studies demonstrating that dystrophin is localized to plasma membrane caveolae in smooth muscle cells.


Characterization and reactivity of photodimers of dihydroneopterin and dihydrobiopterin.
7,8-Dihydrobiopterin (H(2)Bip) and 7,8-dihydroneopterin (H(2)Nep) belong to a class of heterocyclic compounds present in a wide range of living systems. H(2)Bip accumulates in the skin of patients suffering from vitiligo, whereas H(2)Nep is secreted by human macrophages when the cellular immune system is activated. We have investigated the photochemical reactivity of both compounds upon UV-A irradiation (320-400 nm), the chemical structures of the products and their thermal stability. The study was performed in neutral aqueous solutions. The reactions were followed by UV/Visible spectrophotometry and HPLC and the products were analyzed by means of electrospray ionization mass spectrometry and (1)H-NMR. Excitation of H(2)Bip and H(2)Nep leads to the formation, in each case, of two main isomeric dimers. The latter compounds undergo a thermal process that may consist in a retro [2 + 2]-cycloaddition and hydrolysis to yield the reactant (H(2)Bip or H(2)Nep) and a product that has incorporated a molecule of H(2)O.


Local neurons play key roles in the mammalian olfactory bulb.
Over the past few decades, research exploring how the brain perceives, discriminates, and recognizes odorant molecules has received a growing interest. Today, olfaction is no longer considered a matter of poetry. Chemical senses entered the biological era when an increasing number of scientists started to elucidate the early stages of the olfactory pathway. A combination of genetic, biochemical, cellular, electrophysiological and behavioral methods has provided a picture of how odor information is processed in the olfactory system as it moves from the periphery to higher areas of the brain. Our group is exploring the physiology of the main olfactory bulb, the first processing relay in the mammalian brain. From different electrophysiological approaches, we are attempting to understand the cellular rules that contribute to the synaptic transmission and plasticity at this central relay. How olfactory sensory inputs, originating from the olfactory epithelium located in the nasal cavity, are encoded in the main olfactory bulb remains a crucial question for understanding odor processing. More importantly, the persistence of a high level of neurogenesis continuously supplying the adult olfactory bulb with newborn local neurons provides an attractive model to investigate how basic olfactory functions are maintained when a large proportion of local neurons are continuously renewed. For this purpose, we summarize the current ideas concerning the molecular mechanisms and organizational strategies used by the olfactory system to encode and process information in the main olfactory bulb. We discuss the degree of sensitivity of the bulbar neuronal network activity to the persistence of this high level of neurogenesis that is modulated by sensory experience. Finally, it is worth mentioning that analyzing the molecular mechanisms and organizational strategies used by the olfactory system to transduce, encode, and process odorant information in the olfactory bulb should aid in understanding the general neural mechanisms involved in both sensory perception and memory. Due to space constraints, this review focuses exclusively on the olfactory systems of vertebrates and primarily those of mammals.


Xenacoelomorpha is the sister group to Nephrozoa.
The position of Xenacoelomorpha in the tree of life remains a major unresolved question in the study of deep animal relationships. Xenacoelomorpha, comprising Acoela, Nemertodermatida, and Xenoturbella, are bilaterally symmetrical marine worms that lack several features common to most other bilaterians, for example an anus, nephridia, and a circulatory system. Two conflicting hypotheses are under debate: Xenacoelomorpha is the sister group to all remaining Bilateria (= Nephrozoa, namely protostomes and deuterostomes) or is a clade inside Deuterostomia. Thus, determining the phylogenetic position of this clade is pivotal for understanding the early evolution of bilaterian features, or as a case of drastic secondary loss of complexity. Here we show robust phylogenomic support for Xenacoelomorpha as the sister taxon of Nephrozoa. Our phylogenetic analyses, based on 11 novel xenacoelomorph transcriptomes and using different models of evolution under maximum likelihood and Bayesian inference analyses, strongly corroborate this result. Rigorous testing of 25 experimental data sets designed to exclude data partitions and taxa potentially prone to reconstruction biases indicates that long-branch attraction, saturation, and missing data do not influence these results. The sister group relationship between Nephrozoa and Xenacoelomorpha supported by our phylogenomic analyses implies that the last common ancestor of bilaterians was probably a benthic, ciliated acoelomate worm with a single opening into an epithelial gut, and that excretory organs, coelomic cavities, and nerve cords evolved after xenacoelomorphs separated from the stem lineage of Nephrozoa.


Towards understanding the gliotoxin detoxification mechanism: in vivo thiomethylation protects yeast from gliotoxin cytotoxicity.
Gliotoxin (GT) is a mycotoxin produced by some species of ascomycete fungi including the opportunistic human pathogen Aspergillus fumigatus. In order to produce GT the host organism needs to have evolved a self-protection mechanism. GT contains a redox-cycling disulfide bridge that is important in mediating toxicity. Recently is has been demonstrated that A. fumigatus possesses a novel thiomethyltransferase protein called GtmA that has the ability to thiomethylate GT in vivo, which aids the organism in regulating GT biosynthesis. It has been suggested that thiomethylation of GT and similar sulfur-containing toxins may play a role in providing self-protection in host organisms. In this work we have engineered Saccharomyces cerevisiae, a GT-naïve organism, to express A. fumigatus GtmA. We demonstrate that GtmA can readily thiomethylate GT in yeast, which results in protection of the organism from exogenous GT. Our work has implications for understanding the evolution of GT self-protection mechanisms in organisms that are GT producers and non-producers.


The mediating role of risk perception in the association between industry-related air pollution and health.
Heavy industry emits many potentially hazardous pollutants into the air which can affect health. Awareness about the potential health impacts of air pollution from industry can influence people's risk perception. This in turn can affect (self-reported) symptoms. Our aims were to investigate the associations of air pollution from heavy industry with health symptoms and to evaluate whether these associations are mediated by people's risk perception about local industry. A cross-sectional questionnaire study was conducted among children (2-18 years) and adults (19 years and above) living in the direct vicinity of an area with heavy industry. A dispersion model was used to characterize individual-level exposures to air pollution emitted from the industry in the area. Associations between PM2.5 and NOX with presence of chronic diseases (adults) and respiratory symptoms (adults and children) were investigated by logistic regression analysis. Risk perception was indirectly measured by worries about local industry (0-10 scale). Mediation analyses were performed to investigate the role of mediation by these worries. The response was 54% (2,627/4,877). In adults exposure to modelled PM2.5 from industry (per μg/m3) was related with reported high blood pressure (OR 1.56, 95% CI 1.13-2.15) and exposure to modelled NOX (per μg/m3) was inversely related with cardiovascular diseases (OR 0.91, 95% CI 0.84-0.98). In children higher PM2.5 and NOX concentrations (per μg/m3) were related with wheezing (OR 2.00, 95% CI 1.24-3.24 and OR 1.13, 95% CI 1.06-1.21 respectively) and dry cough (OR 2.33, 95% CI 1.55-3.52 and OR 1.16, 95% CI 1.10-1.22 respectively). Parental worry about local industry was an important mediator in exposure-health relations in children (indirect effect between 19-28%). Exposure from industry was associated with self-reported reported high blood pressure among adults and respiratory symptoms among their children. Risk perception was found to mediate these associations for children.


Probiotics to minimize the disruption of faecal microbiota in healthy subjects undergoing antibiotic therapy.
A novel combination of culturing and DNA-based terminal restriction fragment length polymorphism (TRFLP) analysis was used to investigate the effect of probiotics on antibiotic-induced gut microbiota alterations to determine if a probiotic preparation containing bifidobacteria and lactobacilli, taken during and after antibiotic therapy, can minimize antibiotic disturbance of faecal microbiota. Healthy subjects administered amoxicillin/clavulanate were randomized and concomitantly received a placebo or probiotic mixture. The primary end point was similarity of faecal microbiota as determined by culturing and TRFLP from subjects taking probiotics compared to those taking a placebo measured by comparing data from baseline to post-treatment for each subject. TRFLP analysis revealed a high subject to subject variation in the baseline faecal microbiota. The most common antibiotic-induced disturbance was a relative increase in Clostridium, Eubacterium, Bacteroides and Enterobacteraceae. The mean similarity to the baseline increased over time in both treatment groups, although the probiotic group was less disturbed according to both TRFLP and culture data. The culture method revealed that post-antibiotic faecal microbiota in probiotic-consuming subjects were more similar to the baseline microbiota than the control group (P=0.046). Changes in Enterobactereaceae (P=0.006) and Bifidobacterium (P=0.030) counts were significantly different between the groups. Analysis of TRFLP data reinforced the trend between groups but was not statistically significant (P=0.066). This study indicates this mixture of probiotics promotes a more rapid return to pre-antibiotic baseline faecal bacterial microbiota.


Activity of Polish unifloral honeys against pathogenic bacteria and its correlation with colour, phenolic content, antioxidant capacity and other parameters.
The use of honey as an antimicrobial agent gains importance due to often ineffectiveness of conventional treatment. However, activity of honey depends mainly on its botanical and geographical origin. To date, antimicrobial potential of Polish honeys has not yet been entirely investigated. In this study, 37 unifloral samples of 14 honey types (including rare varieties) from Poland were analysed and compared with manuka honey. The most active were cornflower, thyme and buckwheat honeys. Their MICs ranged from 3·12 to 25·00%, (depending on tested micro-organism) and often were lower than for manuka honey. Additionally, colour, antioxidant activity, total phenols, pH and conductivity were assessed and significant correlations (P < 0·05) of MICs with several parameters were found. The most active were darker honeys, with strong yellow colour component, rich in phenolics, with high conductivity and water content. The honey antibacterial properties depended mainly on peroxide mechanism and were vulnerable to excessive heating, but quite stable during storage in cold. A number of honey samples showed potential as effective antimicrobial agents. The observed correlations of MICs and physical-chemical parameters help to understand better the factors impacting the antibacterial activity. Honey is a promising agent in the treatment of non-healing infected wounds. Thirty-seven unifloral samples of 14 honey varieties from Poland were analysed for their antimicrobial activity and compared with manuka honey. Several honey types exert even higher antimicrobial potential and could be introduced to wound therapy. Additionally, positive correlations of the antimicrobial activity were found, especially with yellow colour and could be important in the search and screening of the honey active against Escherichia coli.


Increased rate of hair regrowth in mice with constitutive overexpression of Del1.
Developmental endothelial locus (Del)1 is a secreted extracellular matrix-associated protein that stimulates angiogenesis through integrin binding and is implicated in vasculogenesis. We hypothesized that increased expression of an angiogenic factor would lead to enhanced wound healing. Transgenic mice had Del1 cloned behind a keratin 14 promoter (K14-Del1) to drive constitutive expression in basal keratinocytes. Transgenic animals and wild-type litter mates underwent excisional wounding or depilation, and tissues were harvested at various time points. Wound healing and hair regrowth were assessed by photography, histology, and immunohistochemistry. For injection experiments, purified Del1 protein was injected in the flanks of wild-type mice with carrier on the contralateral flank as a control. Del1 expression during hair development was performed using transgenic mice with a LacZ cassette introduced downstream from the native promoter. K14-Del1 animals appeared normal and healed excisional wounds normally but demonstrated an increased rate of hair regrowth after wound healing. Using depilation experiments to specifically address hair follicle growth, we found increased hair regrowth was independent of wounding. This was confirmed by injection of purified Del1 protein. During normal hair anagenesis, Del1 is expressed in the root of the hair follicle. Constitutive expression of Del1 in skin does not affect skin vascularity or improve wound healing. Surprisingly, we found the primary effect of constitutive Del1 expression in the basal keratinocytes was increased hair growth following induction of anagenesis. During normal hair anagenesis, we see expression of Del1 in the root of the hair follicle suggesting it may function there to stimulate hair growth.


Plasma metabolomic profiles reflective of glucose homeostasis in non-diabetic and type 2 diabetic obese African-American women.
Insulin resistance progressing to type 2 diabetes mellitus (T2DM) is marked by a broad perturbation of macronutrient intermediary metabolism. Understanding the biochemical networks that underlie metabolic homeostasis and how they associate with insulin action will help unravel diabetes etiology and should foster discovery of new biomarkers of disease risk and severity. We examined differences in plasma concentrations of >350 metabolites in fasted obese T2DM vs. obese non-diabetic African-American women, and utilized principal components analysis to identify 158 metabolite components that strongly correlated with fasting HbA1c over a broad range of the latter (r = -0.631; p<0.0001). In addition to many unidentified small molecules, specific metabolites that were increased significantly in T2DM subjects included certain amino acids and their derivatives (i.e., leucine, 2-ketoisocaproate, valine, cystine, histidine), 2-hydroxybutanoate, long-chain fatty acids, and carbohydrate derivatives. Leucine and valine concentrations rose with increasing HbA1c, and significantly correlated with plasma acetylcarnitine concentrations. It is hypothesized that this reflects a close link between abnormalities in glucose homeostasis, amino acid catabolism, and efficiency of fuel combustion in the tricarboxylic acid (TCA) cycle. It is speculated that a mechanism for potential TCA cycle inefficiency concurrent with insulin resistance is "anaplerotic stress" emanating from reduced amino acid-derived carbon flux to TCA cycle intermediates, which if coupled to perturbation in cataplerosis would lead to net reduction in TCA cycle capacity relative to fuel delivery.


Thiamin function, metabolism, uptake, and transport.
Vitamins are crucial components in the diet of animals and many other living organisms. One of these essential nutrients, thiamin, is known to be involved in several cell functions, including energy metabolism and the degradation of sugars and carbon skeletons. Other roles that are connected to this vitamin are neuronal communication, immune system activation, signaling and maintenance processes in cells and tissues, and cell-membrane dynamics. Because of the key functions of thiamin, uptake and transport through the body are crucial. Its uptake route is relatively complex, encompassing a variety of protein families, including the solute carrier anion transporters, the alkaline phosphatase transport system, and the human extraneuronal monoamine transporter family, some of which are multispecific proteins. There are two known structures of protein (subunits) involved in thiamin uptake in prokaryotes. Binding of thiamin to these proteins is strongly guided by electrostatic interactions. The lack of structural information about thiamin binding proteins for higher organisms remains a bottleneck for understanding the uptake process of thiamin in atomic detail. This review includes recent data on thiamin metabolism, related deficiencies and pathologies, and the latest findings on thiamin binding transporters.


Eight-year outcomes of a competency-based residency training program in orthopedic surgery.
Background: The Division of Orthopaedic Surgery at the University of Toronto implemented a pilot residency training program that used a competency-based framework in July of 2009. The competency-based curriculum (CBC) deployed an innovative, modularized approach that dramatically intensified both the structured learning elements and the assessment processes. Methods: This paper discusses the initial curriculum design of the CBC pilot program; the refinement of the curriculum using curriculum mapping that allowed for efficiencies in educational delivery; details of evaluating resident competence; feedback from external reviews by accrediting bodies; and trainee and program outcomes for the first eight years of the program's implementation. Results: Feedback from the residents, the faculty, and the postgraduate residency training accreditation bodies on the CBC has been positive and suggests that the essential framework of the program may provide a valuable tool to other programs that are contemplating embarking on transition to competency-based education. Conclusions: While the goal of the program was not to shorten training per se, efficiencies gained through a modular, competency-based program have resulted in shortened time to completion of residency training for some learners.


E2F8 is a nonreceptor activator of heterotrimeric G proteins.
Heterotrimeric G proteins are important for numerous signaling events in eukaryotes, serving primarily to transduce signals that are initiated by G protein-coupled receptors. It has recently become clear that nonreceptor activators can regulate the level of heterotrimeric G protein signaling and, in some cases, drive cycles of receptor-independent G protein activation. In this study, we used a yeast expression cloning strategy to identify novel nonreceptor activators of heterotrimeric G proteins in a human adipocyte cDNA library. The human transcription factor E2F8 was found to activate heterotrimeric G proteins, suggesting a specific biological role for this recently described member of the E2F family. Epistasis studies showed that E2F8 acted at the level of G proteins and was specific for G alpha(i) over Gpa1. E2F8 augmented receptor-driven signaling, but also activated G proteins in the absence of a receptor. The GTPase-activating protein RGS4 antagonized the effect of E2F8, showing that E2F8's effect on G alpha involved nucleotide turnover. The entire E2F8 protein was required for full activity, but the majority of the signaling activity appeared to reside in the first 200 residues. In yeast, E2F8 is a guanine nucleotide exchange factor (GEF) for the alpha subunit of heterotrimeric G proteins. The molecular mechanism and biological significance of this effect remain to be determined.


Childhood socioeconomic position and objectively measured physical capability levels in adulthood: a systematic review and meta-analysis.
Grip strength, walking speed, chair rising and standing balance time are objective measures of physical capability that characterise current health and predict survival in older populations. Socioeconomic position (SEP) in childhood may influence the peak level of physical capability achieved in early adulthood, thereby affecting levels in later adulthood. We have undertaken a systematic review with meta-analyses to test the hypothesis that adverse childhood SEP is associated with lower levels of objectively measured physical capability in adulthood. Relevant studies published by May 2010 were identified through literature searches using EMBASE and MEDLINE. Unpublished results were obtained from study investigators. Results were provided by all study investigators in a standard format and pooled using random-effects meta-analyses. 19 studies were included in the review. Total sample sizes in meta-analyses ranged from N = 17,215 for chair rise time to N = 1,061,855 for grip strength. Although heterogeneity was detected, there was consistent evidence in age adjusted models that lower childhood SEP was associated with modest reductions in physical capability levels in adulthood: comparing the lowest with the highest childhood SEP there was a reduction in grip strength of 0.13 standard deviations (95% CI: 0.06, 0.21), a reduction in mean walking speed of 0.07 m/s (0.05, 0.10), an increase in mean chair rise time of 6% (4%, 8%) and an odds ratio of an inability to balance for 5s of 1.26 (1.02, 1.55). Adjustment for the potential mediating factors, adult SEP and body size attenuated associations greatly. However, despite this attenuation, for walking speed and chair rise time, there was still evidence of moderate associations. Policies targeting socioeconomic inequalities in childhood may have additional benefits in promoting the maintenance of independence in later life.


The role of shortening procedures for the surgical therapy of Peyronie's disease.
In this article we briefly review the current surgical treatment options for Peyronie's disease (PD) in its stable phase. We emphasize the important role of tunical shortening procedures which account for the major share of operations for PD. Shortening procedures provide excellent curvature correction combined with a very low risk of new erectile dysfunction. Since erectile function is already heavily impaired by the disease and its comorbidities in many patients with PD, tunical shortening procedures often are the treatment of choice for the correction of penile curvature. While there is no hard evidence for the superiority of a specific shortening procedure, several authors prefer the classical Nesbit technique over simple plication techniques. We also present our experiences with the Tunica albuginea underlap technique (TAU-technique), a new modification of the Nesbit procedure, that might add further surgical advantages while preserving the strength of the classical Nesbit technique.


Neuropathic pain: an updated grading system for research and clinical practice.
The redefinition of neuropathic pain as "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system," which was suggested by the International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG) in 2008, has been widely accepted. In contrast, the proposed grading system of possible, probable, and definite neuropathic pain from 2008 has been used to a lesser extent. Here, we report a citation analysis of the original NeuPSIG grading paper of 2008, followed by an analysis of its use by an expert panel and recommendations for an improved grading system. As of February, 2015, 608 eligible articles in Scopus cited the paper, 414 of which cited the neuropathic pain definition. Of 220 clinical studies citing the paper, 56 had used the grading system. The percentage using the grading system increased from 5% in 2009 to 30% in 2014. Obstacles to a wider use of the grading system were identified, including (1) questions about the relative significance of confirmatory tests, (2) the role of screening tools, and (3) uncertainties about what is considered a neuroanatomically plausible pain distribution. Here, we present a revised grading system with an adjusted order, better reflecting clinical practice, improvements in the specifications, and a word of caution that even the "definite" level of neuropathic pain does not always indicate causality. In addition, we add a table illustrating the area of pain and sensory abnormalities in common neuropathic pain conditions and propose areas for further research.


Acute kidney injury in patients hospitalized with COVID-19.
The rate of acute kidney injury (AKI) associated with patients hospitalized with Covid-19, and associated outcomes are not well understood. This study describes the presentation, risk factors and outcomes of AKI in patients hospitalized with Covid-19. We reviewed the health records for all patients hospitalized with Covid-19 between March 1, and April 5, 2020, at 13 academic and community hospitals in metropolitan New York. Patients younger than 18 years of age, with end stage kidney disease or with a kidney transplant were excluded. AKI was defined according to KDIGO criteria. Of 5,449 patients admitted with Covid-19, AKI developed in 1,993 (36.6%). The peak stages of AKI were stage 1 in 46.5%, stage 2 in 22.4% and stage 3 in 31.1%. Of these, 14.3% required renal replacement therapy (RRT). AKI was primarily seen in Covid-19 patients with respiratory failure, with 89.7% of patients on mechanical ventilation developing AKI compared to 21.7% of non-ventilated patients. 276/285 (96.8%) of patients requiring RRT were on ventilators. Of patients who required ventilation and developed AKI, 52.2% had the onset of AKI within 24 hours of intubation. Risk factors for AKI included older age, diabetes mellitus, cardiovascular disease, black race, hypertension and need for ventilation and vasopressor medications. Among patients with AKI, 694 died (35%), 519 (26%) were discharged and 780 (39%) were still hospitalized. AKI occurs frequently among patients with Covid-19 disease. It occurs early and in temporal association with respiratory failure and is associated with a poor prognosis.


Aberration evaluation of alignment optics in lithographic tools by use of a step-height structure highly sensitive to the asymmetry of an optical image.
To satisfy the increasing demand for extremely tight overlay accuracy in semiconductor manufacturing processes, all the measurement error factors in alignment systems and overlay measurement tools need be identified and eliminated. The principle of most alignment systems is based on image processing of target marks on the wafer under bright-field illumination. Although the phenomenon that the sensitivity to the alignment error varies with the step height (SH) of the mark has been known and used for evaluating the performance of the alignment optics, no investigation has been made into the origin and the physical mechanism of the phenomenon. We propose a simplified optical model that can account for the origin of the asymmetric image and clarify its relation to the SHs. The model is validated with simulation and experimental results. The improved performance of an alignment system using marks with optimally designed SHs is demonstrated.


Hypertension, antihypertensive treatment and cancer incidence and mortality: a pooled collaborative analysis of 12 Australian and New Zealand cohorts.
Observational studies examining associations between hypertension and cancer are inconsistent. We explored the association of hypertension, graded hypertension and antihypertensive treatment with cancer incidence and mortality. Eighty-six thousand five hundred and ninety-three participants from the Australian and New Zealand Diabetes and Cancer Collaboration were linked to the National Death Index and Australian Cancer Database. Cox proportional hazards models estimated hazard ratios and 95% confidence intervals (95% CI) for the association of treated and untreated hypertension with cancer incidence and mortality. Over a median follow-up of 15.1 years, 12 070 incident and 4350 fatal cancers were identified. Untreated and treated hypertension, compared with normotension, were associated with an increased risk for cancer incidence [hazard ratio 1.06, 95% CI (1.00-1.11) and 1.09 (1.02-1.16) respectively], and cancer mortality (1.07, 0.98-1.18) and (1.15, 1.03-1.28), respectively. When compared with untreated hypertension, treated hypertension did not have a significantly greater risk for cancer incidence (1.03, 0.97-1.10) or mortality (1.07, 0.97-1.19). A significant dose-response relationship was observed between graded hypertension and cancer incidence and mortality; Ptrend = 0.053 and Ptrend = 0.001, respectively. When stratified by treatment status, these relationships remained significant in untreated, but not in treated, hypertension. Hypertension, both treated and untreated, is associated with a modest increased risk for cancer incidence and mortality. Similar risks in treated and untreated hypertension suggest that the increased cancer risk is not explained by the use of antihypertensive treatment.


Different approaches in the treatment of obstructive pulmonary diseases.
Advances in drug formulation, inhalation device design and disease management are generating new opportunities for patients suffering from obstructive pulmonary diseases. This article provides a comprehensive review of the different promising pulmonary drug delivery technologies in the treatment of obstructive pulmonary diseases, particularly with regard to the treatment of asthma and chronic pulmonary diseases (COPD), which are increasing day by day due to increasing environmental pollution and its harmful and toxic contaminants. In the recent years, a better knowledge has been gained regarding the mechanism of action of glucocorticoids and how they suppress the chronic inflammation. New etiology has been brought into light regarding the inactivity of glucocorticoids in some patients having asthma and COPDs even though the inflammatory genes are triggered by similar molecules in both the diseases. This new knowledge has given a new platform to improve glucocorticoids and their resistance also how other combination therapy can be used for these diseases. It has also led to the quest for improving and developing other alternatives such as anti-leukotriene agents, muscarinic inhibitors, combination therapy, as well as biologic immune-modulators in the treatment of the different pulmonary diseases. Several new combinations of glucocorticoids are available in the global market for the use in pulmonary diseases especially asthma although their availability fluctuates between continents. There has been several studies done regarding the variation of effectiveness of the different inhaled glucocorticoids and hence it is important to take into consideration the different delivery systems and the methods which are used to treat the patients.


The state of population health surveillance using electronic health records: a narrative review.
Electronic health records (EHRs) are transforming the practice of clinical medicine, but the extent to which they are being harnessed to advance public health goals remains uncertain. Data extracted from integrated EHR networks offer the potential for almost real-time determination of the health status of populations in care, for targeting interventions to vulnerable populations, and for monitoring the impact of such initiatives over time. This is especially true in ambulatory care settings, which are uniquely suited for monitoring population health indicators including risk factors and disease management indicators associated with chronic diseases. As efforts gather steam to integrate health data across delivery systems, large networks of electronic patient information are increasingly emerging. Few of the national population health surveillance systems that rely on EHR data have progressed beyond laying groundwork to launch and maintain EHR-based surveillance, but a limited number of more focused or local efforts have demonstrated innovation in population health surveillance. Common challenges include incompleteness of population coverage, lack of interoperability across data systems, and variable data quality. This review defines progress, opportunities, and challenges in using EHR data for population health surveillance.


Halothane induced hepatic necrosis in rats: the role of in vivo lipid peroxidation.
Hepatic damage was induced in phenobarbitone pretreated male Fischer 344 rats by the administration of 1% halothane in 14% oxygen for either 1 or 2 hours. Ethane production during the exposure period was not significantly different between the halothane and non-halothane exposed groups. Animals were sacrificed 1, 2, 6 and 24 hrs from commencement of anaesthesia and the hepatic microsomal fraction analyzed for diene conjugates, lipid hydroperoxides, total lipid content and fatty acid composition. Animals exposed to halothane and sacrificed at 2 and 24 hrs had significantly elevated levels of diene conjugates (P less than 0.05), while lipid hydroperoxide concentration and serum alanine aminotransferase increased in only those animals sacrificed at 24 hrs. Alterations in total lipid content and hepatic microsomal fatty acid composition were not observed in animals sacrificed after 1 and 2 hrs. A significant reduction in total lipid and arachidonic acid content occurred only in those animals sacrificed 24 hrs after exposure, however a concomitant increase in the saturated fatty acid fraction was not observed. It is proposed that alterations in fatty acid composition in vivo and evidence of lipid peroxidation occur as a result of cell death rather than an initiating event in halothane induced hepatic necrosis in rats.


Oxidative Stress Induces Expression of the Toll-Like Receptors (TLRs) 2 and 4 in the Human Peripheral Blood Mononuclear Cells: Implications for Metabolic Inflammation.
Innate immune toll-like receptors (TLRs) are emerging as nutrient sensors. Oxidative stress in the adipose tissue in obesity acts as a critical early trigger of altered pathophysiology. TLR2/TLR4 adipose upregulation has been associated with insulin resistance in humans; however, it remains unclear whether oxidative stress can modulate expression of TLR2/4 and related immune-metabolic regulators (IRF3/5) in immune cells. We, therefore, assessed their expression along with proinflammatory cytokines in the human PBMC following induction of oxidative stress. PBMC were isolated from blood of healthy donors using Ficoll-Paque method and cells were treated with H2O2 to induce oxidative stress. ROS was measured by DCFH-DA assay. Target gene and protein expression was determined using real-time RT-PCR and flow cytometry/confocal microscopy, respectively. TLR2/4 expression by H2O2 in presence of ROS-inhibitors or leptin/LPS/fatty acids was also assessed. Expression of phosphorylated/total ERK1/2, c-Jun, p38, and NF-κB was determined by western blotting. The data (mean±SEM) were compared using unpaired student's t-test or ANOVA; all P-values <0.05 were considered significant. TLR2/4 mRNA/protein expression was elevated by oxidative stress in PBMC compared to controls (P<0.001). This induction was abrogated by apocynin/N-acetyl cysteine treatments (P<0.01). H2O2-induced TLR2/4 gene expression was further enhanced by leptin, LPS, oleate, or palmitate (P<0.05). Oxidative stress also promoted expression of IRF3/5 and proinflammatory cytokines including IFN-γ, IL-1β, IL-6, TNF-α, and MCP-1/CCL2. This oxidative stress in PBMC involved MAPK/NF-κB dependent signaling. Taken together, oxidative stress upregulates expression of TLR2/4, IRF3/5 and signature proinflammatory cytokines in PBMC, involving MAPK/NF-κB dependent signaling, all of which may have implications for metabolic inflammation.


Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial.
Acute promyelocytic leukaemia is a chemotherapy-sensitive subgroup of acute myeloid leukaemia characterised by the presence of the PML-RARA fusion transcript. The present standard of care, chemotherapy and all-trans retinoic acid (ATRA), results in a high proportion of patients being cured. In this study, we compare a chemotherapy-free ATRA and arsenic trioxide treatment regimen with the standard chemotherapy-based regimen (ATRA and idarubicin) in both high-risk and low-risk patients with acute promyelocytic leukaemia. In the randomised, controlled, multicentre, AML17 trial, eligible patients (aged ≥16 years) with acute promyelocytic leukaemia, confirmed by the presence of the PML-RARA transcript and without significant cardiac or pulmonary comorbidities or active malignancy, and who were not pregnant or breastfeeding, were enrolled from 81 UK hospitals and randomised 1:1 to receive treatment with ATRA and arsenic trioxide or ATRA and idarubicin. ATRA was given to participants in both groups in a daily divided oral dose of 45 mg/m(2) until remission, or until day 60, and then in a 2 weeks on-2 weeks off schedule. In the ATRA and idarubicin group, idarubicin was given intravenously at 12 mg/m(2) on days 2, 4, 6, and 8 of course 1, and then at 5 mg/m(2) on days 1-4 of course 2; mitoxantrone at 10 mg/m(2) on days 1-4 of course 3, and idarubicin at 12 mg/m(2) on day 1 of the final (fourth) course. In the ATRA and arsenic trioxide group, arsenic trioxide was given intravenously at 0·3 mg/kg on days 1-5 of each course, and at 0·25 mg/kg twice weekly in weeks 2-8 of course 1 and weeks 2-4 of courses 2-5. High-risk patients (those presenting with a white blood cell count >10 × 10(9) cells per L) could receive an initial dose of the immunoconjugate gemtuzumab ozogamicin (6 mg/m(2) intravenously). Neither maintenance treatment nor CNS prophylaxis was given to patients in either group. All patients were monitored by real-time quantitative PCR. Allocation was by central computer minimisation, stratified by age, performance status, and de-novo versus secondary disease. The primary endpoint was quality of life on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 global health status. All analyses are by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN55675535. Between May 8, 2009, and Oct 3, 2013, 235 patients were enrolled and randomly assigned to ATRA and idarubicin (n=119) or ATRA and arsenic trioxide (n=116). Participants had a median age of 47 years (range 16-77; IQR 33-58) and included 57 high-risk patients. Quality of life did not differ significantly between the treatment groups (EORTC QLQ-C30 global functioning effect size 2·17 [95% CI -2·79 to 7·12; p=0·39]). Overall, 57 patients in the ATRA and idarubicin group and 40 patients in the ATRA and arsenic trioxide group reported grade 3-4 toxicities. After course 1 of treatment, grade 3-4 alopecia was reported in 23 (23%) of 98 patients in the ATRA and idarubicin group versus 5 (5%) of 95 in the ATRA and arsenic trioxide group, raised liver alanine transaminase in 11 (10%) of 108 versus 27 (25%) of 109, oral toxicity in 22 (19%) of 115 versus one (1%) of 109. After course 2 of treatment, grade 3-4 alopecia was reported in 25 (28%) of 89 patients in the ATRA and idarubicin group versus 2 (3%) of 77 in the ATRA and arsenic trioxide group; no other toxicities reached the 10% level. Patients in the ATRA and arsenic trioxide group had significantly less requirement for most aspects of supportive care than did those in the ATRA and idarubicin group. ATRA and arsenic trioxide is a feasible treatment in low-risk and high-risk patients with acute promyelocytic leukaemia, with a high cure rate and less relapse than, and survival not different to, ATRA and idarubicin, with a low incidence of liver toxicity. However, no improvement in quality of life was seen.


Association of maternal and nutrient supply line factors with DNA methylation at the imprinted IGF2/H19 locus in multiple tissues of newborn twins.
Epigenetic events are crucial for early development, but can be influenced by environmental factors, potentially programming the genome for later adverse health outcomes. The insulin-like growth factor 2 (IGF2)/H19 locus is crucial for prenatal growth and the epigenetic state at this locus is environmentally labile. Recent studies have implicated maternal factors, including folate intake and smoking, in the regulation of DNA methylation at this locus, although data are often conflicting in the direction and magnitude of effect. Most studies have focused on single tissues and on one or two differentially-methylated regions (DMRs) regulating IGF2/H19 expression. In this study, we investigated the relationship between multiple shared and non-shared gestational/maternal factors and DNA methylation at four IGF2/H19 DMRs in five newborn cell types from 67 pairs of monozygotic and 49 pairs of dizygotic twins. Data on maternal and non-shared supply line factors were collected during the second and third trimesters of pregnancy and DNA methylation was measured via mass spectrometry using Sequenom MassArray EpiTyper analysis. Our exploratory approach showed that the site of umbilical cord insertion into the placenta in monochorionic twins has the strongest positive association with methylation in all IGF2/H19 DMRs (p<0.05). Further, evidence for tissue- and locus-specific effects were observed, emphasizing that responsiveness to environmental exposures in utero cannot be generalized across genes and tissues, potentially accounting for the lack of consistency in previous findings. Such complexity in responsiveness to environmental exposures in utero has implications for all epigenetic studies investigating the developmental origins of health and disease.


Probing the role of backbone hydrogen bonds in protein-peptide interactions by amide-to-ester mutations.
One of the most frequent protein-protein interaction modules in mammalian cells is the postsynaptic density 95/discs large/zonula occludens 1 (PDZ) domain, involved in scaffolding and signaling and emerging as an important drug target for several diseases. Like many other protein-protein interactions, those of the PDZ domain family involve formation of intermolecular hydrogen bonds: C-termini or internal linear motifs of proteins bind as β-strands to form an extended antiparallel β-sheet with the PDZ domain. Whereas extensive work has focused on the importance of the amino acid side chains of the protein ligand, the role of the backbone hydrogen bonds in the binding reaction is not known. Using amide-to-ester substitutions to perturb the backbone hydrogen-bonding pattern, we have systematically probed putative backbone hydrogen bonds between four different PDZ domains and peptides corresponding to natural protein ligands. Amide-to-ester mutations of the three C-terminal amides of the peptide ligand severely affected the affinity with the PDZ domain, demonstrating that hydrogen bonds contribute significantly to ligand binding (apparent changes in binding energy, ΔΔG = 1.3 to >3.8 kcal mol(-1)). This decrease in affinity was mainly due to an increase in the dissociation rate constant, but a significant decrease in the association rate constant was found for some amide-to-ester mutations suggesting that native hydrogen bonds have begun to form in the transition state of the binding reaction. This study provides a general framework for studying the role of backbone hydrogen bonds in protein-peptide interactions and for the first time specifically addresses these for PDZ domain-peptide interactions.


Profiles of family caregivers of patients at the end of life at home: a Q-methodological study into family caregiver' support needs.
Family caregivers of patients at the end of life often experience care-related burden. To prevent caregiver burden and to enhance the capacity to provide care it is important to have insight in their support needs. The purpose of this study was to identify profiles of family caregivers who provide care to patients at the end of life at home. A Q-methodological study was conducted in which family caregivers ranked 40 statements on support needs and experiences with caregiving. Thereafter they explained their ranking in an interview. By-person factor analysis was used to analyse the rankings and qualitative data was used to support the choice of profiles. A set of 41 family caregivers with a variety on background characteristics who currently or recently provided care for someone at the end of life at home were included. Four distinct profiles were identified; profile (1) those who want appreciation and an assigned contact person; profile (2) was bipolar. The positive pole (2+) comprised those who have supportive relationships and the negative pole (2-) those who wish for supportive relationships; profile (3) those who want information and practical support, and profile (4) those who need time off. The profiles reflect different support needs and experiences with caregiving. Family caregivers of patients at the end of life have varying support needs and one size does not fit all. The profiles are relevant for healthcare professionals and volunteers in palliative care as they provide an overview of the main support needs among family caregivers of patients near the end of life. This knowledge could help healthcare professionals giving support.


Assessing Severity in Pediatric Pneumonia: Predictors of the Need for Major Medical Interventions.
The aim of this study was to determine potential predictors of the need for major medical interventions in the context of assessing severity in pediatric pneumonia. This was a prospective, cohort study of previously healthy children and adolescents younger than 18 years presenting to the pediatric emergency room with clinically suspected pneumonia and examining both the full cohort and those with radiologically confirmed pneumonia. The presence of hypoxemia (peripheral oxygen saturation ≤92%), age-specific tachypnea, high temperature (≥38.5°C), chest retraction score, modified Pediatric Early Warning Score, age, C-reactive protein, white blood cell (WBC) count, and chest radiograph findings at first assessment were analyzed by univariate and multivariate analyses to examine their predictive ability for the need for major medical interventions: supplemental oxygen, supplemental fluid, respiratory support, intensive care, or treatment for complications during admission. Fifty percent of the 394 cases of suspected pneumonia and 60% of the 265 cases of proven pneumonia were in need of 1 or more medical interventions. In multivariate logistic regression, only the presence of hypoxemia (odds ratios, 3.66 and 3.83 in suspected and proven pneumonia, respectively) and chest retraction score (odds ratios, 1.21 and 1.31, respectively for each 1-point increase in the score) significantly predicted the need for major medical interventions in both suspected and proven pneumonia. Specificity of 94% or greater, positive likelihood ratio of 6.4 or greater, and sensitivity of less than 40% were found for both hypoxemia and chest retraction score in predicting major medical interventions. C-reactive protein and white blood cell count were not associated with the need for these interventions, whereas multifocal radiographic changes were. Hypoxemia and an assessment of chest retractions were the predictors significantly able to rule in more severe pneumonia, but with a limited clinical utility given their poor ability to rule out the need for major medical interventions. Future validation of these findings is needed.


Systematic review and meta-analysis: influence of smoking cessation on incidence of pneumonia in HIV.
Smoking is common in people infected with HIV but cessation support is not a routine part of clinical care. The aim was to assess whether smoking is a risk factor for pneumonia in people with HIV and whether smoking cessation ameliorates excess risk. We performed MEDLINE and Embase database searches and included cohort or case-control studies conducted in adult patients infected with HIV extracting a hazard ratio (HR) or odds ratio (OR) that compared the incidence of bacterial pneumonia or pneumonia caused by Pneumocystis jiroveci (PCP) between two smoking categories. Studies were appraised for quality and combined using inverse variance meta-analysis. Fourteen cohort and case-control studies were included. Assessment of outcome was good, but assessment of exposure status was poor. Current smokers were at higher risk of bacterial pneumonia than former smokers: HR 1.37 (95% confidence interval (CI): 1.06, 1.78). There was no evidence that former smokers were at higher risk than never smokers: HR 1.24 (95%CI: 0.96, 1.60). Current smokers were at higher risk of bacterial pneumonia than current non-smokers: HR of 1.73 (95%CI: 1.44, 2.06). There was no evidence that smoking increased the incidence of PCP. The HR for current versus non-smokers was 0.94 (95%CI: 0.79, 1.12), but from case-control studies the OR was 1.76 (95%CI: 1.25, 2.48) with heterogeneity. Confined to higher quality studies, the OR was 0.97 (95%CI: 0.81, 1.16). Residual confounding is possible, but available data suggest this is not an adequate explanation. Smoking is a risk factor for bacterial pneumonia but not PCP and smoking cessation reduces this risk.See related article: http://www.biomedcentral.com/1741-7015/11/16.


Prophylactic effect of N-acetylcysteine against sodium fluoride-induced blood oxidative stress in mice.
Ninety female Balb/c mice were used. The animals were allocated to evenly six groups. While the first group was maintained as control, Groups 3, 4, 5, and 6 were administered 750 ppm, 1500 ppm, 3000 ppm, and 6000 ppm of N-acetylcysteine, respectively, for a period of 15 days. After day 15, Groups 2-6 were administered sodium fluoride, containing 100 ppm fluoride in drinking water, for another 15 days. Plasma malondialdehyde (MDA) levels and erythrocyte superoksid dismutase (SOD) and catalase (CAT) activities were determined at the beginning of the trial and on days 15 and 30. According to the data obtained in the present study, N-acetylcysteine, when administered at the indicated doses, did not produce a significant alteration in any of the three parameters investigated. On the other hand, while the plasma MDA level was determined to have increased significantly, erythrocyte SOD and CAT activities were ascertained to have decreased significantly in the group, which was administered sodium fluoride alone on day 30. In the groups, which were administered N-acetylcysteine prior to sodium fluoride, however, it was observed that, after sodium fluoride administration, plasma MDA levels and erythrocyte SOD and CAT activities drew closer to the values of the control group.


NMR of hyperpolarized (129)Xe in the canine chest: spectral dynamics during a breath-hold.
One of the major goals of hyperpolarized-gas MR imaging has been to obtain (129)Xe dissolved-phase images in humans. Since the dissolved-phase signal is much weaker than the gas-phase signal, highly optimized MR pulse sequences are required to obtain adequate images during a single breath-hold. In particular, a solid understanding of the temporal dynamics of xenon as it passes from the lung gas spaces into the parenchyma, the blood and other downstream compartments is absolutely essential. Spectroscopy experiments were performed in the canine chest to elucidate the behavior of xenon exchange in the lung. The experiments covered a time range from 1 ms to 9 s and therefore considerably extend the data currently available in the literature. It was found that the integrals of the dissolved-phase resonances approached plateau values within approximately 200 ms, and then increased again after approximately 1 s. This behavior suggests an early saturation of the parenchyma before xenon reaches downstream compartments. Mono-exponential recovery curves with time constants on the order of 100 ms were fit to the data. These results potentially provide information on several underlying physiological parameters of the lung, including the parenchymal and blood volumes as well as the diffusion properties of lung tissue.


Music training for the development of speech segmentation.
The role of music training in fostering brain plasticity and developing high cognitive skills, notably linguistic abilities, is of great interest from both a scientific and a societal perspective. Here, we report results of a longitudinal study over 2 years using both behavioral and electrophysiological measures and a test-training-retest procedure to examine the influence of music training on speech segmentation in 8-year-old children. Children were pseudo-randomly assigned to either music or painting training and were tested on their ability to extract meaningless words from a continuous flow of nonsense syllables. While no between-group differences were found before training, both behavioral and electrophysiological measures showed improved speech segmentation skills across testing sessions for the music group only. These results show that music training directly causes facilitation in speech segmentation, thereby pointing to the importance of music for speech perception and more generally for children's language development. Finally these results have strong implications for promoting the development of music-based remediation strategies for children with language-based learning impairments.


Precision control of flow rate in microfluidic channels using photoresponsive soft polymer actuators.
A novel approach that allows control of flow in microfluidic channels with unsurpassed performance using light is described. Valve structures have been created using photoresponsive hydrogels based on spiropyran-functionalised pNIPAAm hydrogels photopolymerised around pillar structures within the channels. Valve actuation is controlled from outside the fluidic system using externally located LEDs. Highly precise and accurate flow rates can be selected by passing real-time flow rate measurements into a PID algorithm. The optimised algorithm also minimises overshoot of the selected flow rate, eliminates flow rate drift, and improves the system response time. In addition to the dramatic improvements in flow rate control, the set up enables the polymer actuation behaviour to be rapidly characterised. The power supply to the LED also provides a useful system diagnostic for monitoring the performance of the valve over time. For example, degradation in the valve actuation due to photodegradation will manifest as an increasing power requirement over time, enabling predictive failure thresholds to be established for particular actuator designs and polymer compositions.


In vivo hepatogenic capacity and therapeutic potential of stem cells from human exfoliated deciduous teeth in liver fibrosis in mice.
Liver transplantation is a gold standard treatment for intractable liver diseases. Because of the shortage of donor organs, alternative therapies have been required. Due to their potential to differentiate into a variety of mature cells, stem cells are considered feasible cell sources for liver regeneration. Stem cells from human exfoliated deciduous teeth (SHED) exhibit hepatogenic capability in vitro. In this study, we investigated their in vivo capabilities of homing and hepatocyte differentiation and therapeutic efficacy for liver disorders in carbon tetrachloride (CCl4)-induced liver fibrosis model mice. We transplanted SHED into CCl4-induced liver fibrosis model mice through the spleen, and analyzed the in vivo homing and therapeutic effects by optical, biochemical, histological, immunological and molecular biological assays. We then sorted human leukocyte antigen-ABC (HLA-ABC)-positive cells from primary CCl4-damaged recipient livers, and analyzed their fusogenicity and hepatic characteristics by flow cytometric, genomic DNA, hepatocyte-specific gene assays. Furthermore, we examined the treatment effects of HLA-positive cells to a hepatic dysfunction by a secondary transplantation into CCl4-treated mice. Transplanted SHED homed to recipient livers, and expressed HLA-ABC, human hepatocyte specific antigen hepatocyte paraffin 1 and human albumin. SHED transplantation markedly recovered liver dysfunction and led to anti-fibrotic and anti-inflammatory effects in the recipient livers. SHED-derived HLA-ABC-positive cells that were sorted from the primary recipient liver tissues with CCl4 damage did not fuse with the host mouse liver cells. Sorted HLA-positive cells not only expressed human hepatocyte-specific genes including albumin, cytochrome P450 1A1, fumarylacetoacetase, tyrosine aminotransferase, uridine 5'-diphospho-glucuronosyltransferase, transferrin and transthyretin, but also secreted human albumin, urea and blood urea nitrogen. Furthermore, SHED-derived HLA-ABC-positive cells were secondary transplanted into CCl4-treated mice. The donor cells homed into secondary recipient livers, and expressed hepatocyte paraffin 1 and human albumin, as well as HLA-ABC. The secondary transplantation recovered a liver dysfunction in secondary recipients. This study indicates that transplanted SHED improve hepatic dysfunction and directly transform into hepatocytes without cell fusion in CCl4-treated mice, suggesting that SHED may provide a feasible cell source for liver regeneration.


Urologic complications of HIV and AIDS.
In recent years the nature of HIV infection has been dramatically transformed from an invariably fatal disease to a chronic disorder with a relatively benign course. Disease progression from HIV to AIDS and HIV-related mortality can be reduced effectively by several years of treatment with highly active antiretroviral therapy (HAART). For patients who do not have access to HAART, HIV infection continues to be a lethal disorder characterized by opportunistic infection with uncommon organisms (e.g. mycobacteria, fungi, parasites and viruses), as well as lethal malignancies such as Kaposi sarcoma, non-Hodgkin lymphoma and squamous cell carcinoma of the penis or cervix. In patients receiving HAART, urologic complications are likely to be caused by adverse effects of antiretroviral medication (e.g. indinavir urolithiasis) or disorders associated with aging, such as benign prostatic hyperplasia and prostate cancer. Prospective clinical trials have shown that adult male circumcision can reduce the rate of female to male HIV transmission by more than 50%; however, the development of preventive or curative modalities with 100% efficacy remains elusive.


Healing effect of sea buckthorn, olive oil, and their mixture on full-thickness burn wounds.
The purpose of this study is to evaluate the healing effect of silver sulfadiazine (SSD), sea buckthorn, olive oil, and 5% sea buckthorn and olive oil mixture on full-thickness burn wounds with respect to both gross and histopathologic features. Full-thickness burns were induced on 60 rats; the rats were then were divided into 5 groups and treated with sea buckthorn, olive oil, a 5% sea buckthorn/olive oil mixture, SSD, and normal saline (control). They were observed for 28 days, and the wounds' healing process was evaluated. Wound contraction occurred faster in sea buckthorn, olive oil, and the sea buckthorn/olive oil mixture groups compared with the SSD and control groups. The volume of the exudates was controlled more effectively in wounds treated with the sea buckthorn/olive oil mixture. Purulent exudates were observed in the control group, but the others did not show infection. The group treated with sea buckthorn/olive oil mixture revealed more developed re-epithelialization with continuous basement membrane with a mature granulation tissue, whereas the SSD-treated group showed ulceration, necrosis, and immature granulation. The results show that sea buckthorn and olive oil individually are proper dressing for burn wounds and that they also show a synergetic effect when they are used together. A sea buckthorn and olive oil mixture could be considered as an alternative dressing for full-thickness burns because of improved wound healing characteristics and antibacterial property.


Limbic encephalitis and small cell lung cancer. Clinical and immunological features.
Paraneoplastic limbic encephalitis (LE) is considered a particular manifestation of paraneoplastic encephalomyelitis (PEM), a remote effect of cancer almost always associated with anti-neuronal antibodies (anti-Hu; also called ANNA 1) and small cell lung carcinoma (SCLC). In order to define the frequency of anti-Hu antibodies in LE with SCLC and to analyse possible clinical differences between patients with and without anti-Hu antibodies, the charts of 16 patients with LE and SCLC were reviewed. Eight patients (50%) had anti-Hu antibodies (anti-Hu+) whereas eight patients (50%) had no detectable anti-neuronal antibodies (anti-Hu-). The clinical and laboratory features of LE and time to diagnosis of SCLC were similar in the anti-Hu+ and anti-Hu- groups. Involvement of other areas of the nervous system compatible with the diagnosis of PEM was observed in seven (87.5%) patients of the anti-Hu+ group but in only one (12.5%) of the anti-Hu- group (P = 0.012). Five patients, including four of the anti-Hu- group, had a partial improvement of the LE after treatment of the SCLC. Another anti-Hu- patient improved spontaneously. Six patients of the anti-Hu+ group died from the neurological disorder, whereas in the anti-Hu- group the cause of death was progression of the SCLC in the three patients who died. The results of this study indicate that the absence of anti-Hu antibodies does not rule out the presence of an underlying SCLC in patients with a clinical diagnosis of LE. Patients with LE and SCLC who are without anti-Hu antibodies are less likely to develop PEM and seem to improve more often after treatment of the cancer than those who present anti-Hu antibodies.


A Danish population-based twin study on general health in the elderly.
To study the relative influence of genetic and environmental factors on self-rated health and hospitalization patterns in the elderly. A survey among all 3,099 Danish twins ages 75 years and older identified in the Danish Twin Registry. An interview was conducted with 77% of the twins. The number of hospitalizations in the previous 18 years was obtained through register linkage, thereby obtaining health information on 96% of the study population, including all nonresponders. Structural equation modeling suggested that approximately a quarter of the variation in the liability to self-reported health and the number of hospitalizations could be attributed to genetic factors. The remaining variation was most likely due to nonfamilial environment. Analyses of the hospitalization patterns of proxy responders and nonresponders suggest that the estimates of the genetic influence on health outcomes in the study are conservative. The present study indicates that variation in general health among the elderly is partly explained by genetic factors.


Editorial: The rising prevalence of autism.
The first autism surveys were simple head counts of children already diagnosed with a severe autism phenotype and residing in small, circumscribed geographical areas. Prevalence was low, ranging from 0.4 to 2/1,000 in the 1960's and 1970's. Today, the methodology of surveys has become more complex; studies include large populations, multiple sites, stratified samples and rely on intricate sets of screening activities followed by some form of diagnostic confirmation procedures. Yet, and as surprising as it may be, there is no standardization of autism survey methodology. Each survey has unique design features that reflect the local educational and health services infrastructure and current social policies for children with disabilities, they include or not parents, teachers and subjects with Autism Spectrum Disorder (ASD), and rely on variable screening and diagnostic instruments and methods. As such, prevalence differences between studies are hazardous to evaluate and whether observed discrepancies are due to method factors or true differences in population parameters, cannot be determined.


Retinal protective effects of resveratrol via modulation of nitric oxide synthase on oxygen-induced retinopathy.
Retinopathy of prematurity (ROP) is one of the leading causes of blindness, with retinal detachment occurring due to oxygen toxicity in preterm infants. Recently, advances in neonatal care have led to improved survival rates for preterm infants, and ROP has increased in incidence. In the present study, we aimed to determine whether or not resveratrol exhibits protective effects in an animal model of ROP and in primary retinal cell cultures of neonatal rat via nitric oxide (NO)-modulating actions using western blotting and real-time PCR with inducible nitric oxide synthase (iNOS), endothelial NOS (eNOS) and neuronal NOS (nNOS) antibodies and mRNAs. In an in vivo oxygen-induced retinopathy (OIR) model, cyclic hyperoxia was induced with 80% O(2) for one day and 21% O(2) for one day from P1 to P14 in newborn Sprague-Dawley (SD) rats. Resveratrol was injected intravitreally for seven days and rats were sacrificed at P21. In vitro OIR primary retinal cell culture was performed using P0-2 SD rats. Hyperoxia injuries were induced through 100% O(2) exposure for six hours. Western blotting and real-time PCR using iNOS, eNOS, nNOS antibodies and primers were performed in the rat model of ROP and the dispersed retinal cell culture. In both in vivo and in vitro OIR, the expression of iNOS antibody and mRNA was increased and of eNOS and nNOS were reduced in the resveratrol-treated group. In conclusion, resveratrol appeared to exert retinal protective effects via modulation of NO-mediated mechanism in in vivo and in vitro OIR models.


Combined coherent anti-Stokes Raman spectroscopy and linear Raman spectroscopy for simultaneous temperature and multiple species measurements.
The simultaneous application of pure rotational coherent anti-Stokes Raman spectroscopy (CARS) and vibrational linear Raman spectroscopy (LRS) for the measurement of temperature and species concentrations in combustion systems is demonstrated. In addition to the standard rotational CARS experimental setup, only one detection system (spectrometer and intensified CCD camera) for the collection of the LRS signals was applied. The emission of the broadband dye laser used for CARS was shifted to the deep red to avoid interferences with the LRS signals located in the visible region. First experimental results from a vaporizing propane spray using an engine injection system are shown.


Brevibacterium fuscum protocatechuate 3,4-dioxygenase. Purification, crystallization, and characterization.
A protocatechuate 3,4-dioxygenase with exceptionally sharp spectral features and a new subunit composition has been purified and crystallized from the Gram-positive organism Brevibacterium fuscum. EPR spectra show that the catalytically essential Fe3+ resides in a site of almost the maximal rhombicity (E/D = 0.333 +/- 0.003). The spectral line widths (1.4 milliTesla at g = 9.67) are the smallest reported for any biological high spin Fe3+ complex and suggest that the enzyme is quite homogeneous in the vicinity of the Fe site. The same conclusion is drawn from Mössbauer spectra measured with enzyme prepared from cells cultured in 57Fe-enriched media as well as from resonance Raman and optical spectra. In contrast, EPR and Mössbauer spectra of the anaerobic complex with protocatechuate (PCA) are complex and demonstrate that multiple species with markedly different electronic symmetries and both positive and negative zero field splittings are present. The Mr = 315,000 enzyme has a composition of (alpha beta Fe)5 (Mr(alpha) = 22,500; Mr (beta) = 40,000). Amino acid analysis shows that neither subunit contains cysteine, thus eliminating this amino acid as a possible Fe ligand. The general features of the structure, spectra, and catalyzed reaction of this enzyme appear to be very similar to those of protocatechuate 3,4-dioxygenase isolated from Gram-negative organisms. However, the kinetic parameters (Km(PCA) = 125 microM, Km(O2) = 800 microM, turnover number = 25,000 min-1 at infinite PCA and O2 concentrations) are 5- to 50-fold higher. The sharp spectra and the kinetic properties facilitate mechanistic studies described in this and the following reports.


A Bayesian approach to inferring population structure from dominant markers.
Molecular markers derived from polymerase chain reaction (PCR) amplification of genomic DNA are an important part of the toolkit of evolutionary geneticists. Random amplified polymorphic DNA markers (RAPDs), amplified fragment length polymorphisms (AFLPs) and intersimple sequence repeat (ISSR) polymorphisms allow analysis of species for which previous DNA sequence information is lacking, but dominance makes it impossible to apply standard techniques to calculate F-statistics. We describe a Bayesian method that allows direct estimates of FST from dominant markers. In contrast to existing alternatives, we do not assume previous knowledge of the degree of within-population inbreeding. In particular, we do not assume that genotypes within populations are in Hardy-Weinberg proportions. Our estimate of FST incorporates uncertainty about the magnitude of within-population inbreeding. Simulations show that samples from even a relatively small number of loci and populations produce reliable estimates of FST. Moreover, some information about the degree of within-population inbreeding (FIS) is available from data sets with a large number of loci and populations. We illustrate the method with a reanalysis of RAPD data from 14 populations of a North American orchid, Platanthera leucophaea.


Synthesis of inorganic-organic layered compounds using immiscible liquid-liquid systems under the distribution law.
A method for synthesizing inorganic-organic layered compounds is proposed using a biphasic liquid-liquid system in one pot. Layered basic zinc benzoate (LBZB) compounds were chosen, and their formation was investigated starting from a xylene-water system. In a typical synthesis, a xylene phase dissolving benzoic acid was allowed to stand in contact with an equal amount of an aqueous phase dissolving zinc nitrate hexahydrate and urea. A role of urea is to supply OH(-) gradually by hydrolysis at an elevated temperature. The biphasically separated solutions were maintained at 80 °C, and then LBZB was obtained in the aqueous phase. Two kinds of layered structures with a basal spacing of 27.14 and 14.77 Å were formed by changing a C(6)H(5)COOH/Zn molar ratio. Chemical compositions of the 27.14 and the 14.77 Å layered phases were estimated to be Zn(OH)(1.74)(C(6)H(5)COO)(0.26)·0.29H(2)O and Zn(OH)(1.12)(C(6)H(5)COO)(0.88)·0.21H(2)O, respectively. The 27.14 Å phase could also be deposited as a film on substrates by heterogeneous nucleation. The film consisted of standing platelike particles and exhibited a two-dimensional structure, which could be converted to ZnO by heating. The relationship between the initial solution compositions and the final solid products was systematically examined on the basis of distribution law for benzoic acid in the xylene-water system.


Demarcated redness associated with increased vascular density/size: a useful marker of flat-type dysplasia in patients with ulcerative colitis.
Background and study aims Recent advances in endoscopic equipment and diagnostic techniques have improved the detection of dysplasia in the inflamed mucosa of patients with ulcerative colitis (UC). However, it remains difficult to endoscopically identify flat-type dysplasia which has been formerly recognized as invisible dysplasia. Patients and methods In this retrospective, single-center study, we endoscopically identified 10 cases of flat-type-predominant dysplasia by targeted biopsy among 38 intramucosal dysplasia lesions from patients with UC who underwent surgical or endoscopic resection from 2007 to 2017. Their endoscopic and histological features were examined, including color changes, intramucosal vascular density/size, and vascular endothelial growth factor (VEGF) expression. Results All flat-type-predominant dysplasias were endoscopically recognized as demarcated red-colored areas and histologically diagnosed as low- (LGDs) or high-grade dysplasias (HGDs). Immunohistochemical examination using resected specimens revealed that flat-type dysplasia was characterized by significantly increased CD34-positive vascular density (LGDs, 1.7-fold, P < 0.01; HGDs, 2.2-fold, P < 0.01) and size (LGDs, 1.03-fold, P < 0.01; HGDs, 1.11-fold, P < 0.01) in the mucosa, compared to adjacent non-neoplastic areas. Increased numbers of vessels were observed at the base of the mucosa in LGDs, whereas HGDs contained increased/enlarged vessels throughout the mucosa. Moreover, VEGF expression was elevated in all dysplastic epithelia. Conclusions Demarcated red-colored areas, histologically characterized by an increased vascular density/size in the mucosa, are an endoscopic sign of formerly invisible flat-type dysplasia in patients with UC and should be considered for targeted biopsy. Prospective studies focusing on the mucosal color change for their early detection would be desirable in the future.


[Existential hope: a phenomenological key to understanding depression?]
Researchers that try to identify the relationship between hope and mental health often lack a conceptual understanding of 'hope'. Nonetheless, experiences of despair that are central in depression seem to surpass our everyday understanding of hope and hopelessness. How can this despair be understood and recognized? OBJECTIVE To describe depression through a phenomenological understanding of hope and to explore how this insight relates to our current definition of depression as a mood disorder, as well as to clinical practice.
 RESULTS: Existential hope arises spontaneously in our experience of the world and through the relationship with significant others. A significant part of the experience of depression amounts to the loss of existential hope. Depressive despair features a radically shifted experiential structure, which seems to be absent in demoralisation; this advocates the view of depression as a 'disorder of attunement'. A therapeutic relationship can recover the loss by cultivating a new sense of possibilities.
 CONCLUSION: The idea of existential hope provides a new conceptual framework to understand the experience of depression as well as the possibility for its recovery.


Unraveling Mobile Health Exercise Interventions for Adults: Scoping Review on the Implementations and Designs of Persuasive Strategies.
It is unclear why some physical activity (PA) mobile health (mHealth) interventions successfully promote PA whereas others do not. One possible explanation is the variety in PA mHealth interventions-not only do interventions differ in the selection of persuasive strategies but also the design and implementation of persuasive strategies can vary. However, limited studies have examined the different designs and technical implementations of strategies or explored if they indeed influenced the effectiveness of the intervention. This scoping review sets out to explore the different technical implementations and design characteristics of common and likely most effective persuasive strategies, namely, goal setting, monitoring, reminders, rewards, sharing, and social comparison. Furthermore, this review aims to explore whether previous mHealth studies examined the influence of the different design characteristics and technical operationalizations of common persuasive strategies on the effectiveness of the intervention to persuade the user to engage in PA. An unsystematic snowball and gray literature search was performed to identify the literature that evaluated the persuasive strategies in experimental trials (eg, randomized controlled trial, pre-post test). Studies were included if they targeted adults, if they were (partly) delivered by a mobile system, if they reported PA outcomes, if they used an experimental trial, and when they specifically compared the effect of different designs or implementations of persuasive strategies. The study methods, implementations, and designs of persuasive strategies, and the study results were systematically extracted from the literature by the reviewers. A total of 29 experimental trials were identified. We found a heterogeneity in how the strategies are being implemented and designed. Moreover, the findings indicated that the implementation and design of the strategy has an influence on the effectiveness of the PA intervention. For instance, the effectiveness of rewarding was shown to vary between types of rewards; rewarding goal achievement seems to be more effective than rewarding each step taken. Furthermore, studies comparing different ways of goal setting suggested that assigning a goal to users might appear to be more effective than letting the user set their own goal, similar to using adaptively tailored goals as opposed to static generic goals. This study further demonstrates that only a few studies have examined the influence of different technical implementations on PA behavior. The different implementations and designs of persuasive strategies in mHealth interventions should be critically considered when developing such interventions and before drawing conclusions on the effectiveness of the strategy as a whole. Future efforts are needed to examine which implementations and designs are most effective to improve the translation of theory-based persuasive strategies into practical delivery forms.


Infant formula containing galacto-and fructo-oligosaccharides and Bifidobacterium breve M-16V supports adequate growth and tolerance in healthy infants in a randomised, controlled, double-blind, prospective, multicentre study.
The objective of the present study was to evaluate the growth and tolerance in healthy, term infants consuming a synbiotic formula with daily weight gain as the primary outcome. In a randomised, controlled, double-blind, multicentre, intervention study infants were assigned to an extensively hydrolysed formula containing a specific combination of Bifidobacterium breve M-16V and a prebiotic mixture (short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides in a 9:1 ratio; scGOS/lcFOS; synbiotic group), or the same formula without this synbiotic concept for 13 weeks (control group). Anthropometry, formula intake, tolerance, stool characteristics, blood parameters, faecal microbiota and metabolic faecal profile were assessed. Medically confirmed adverse events were recorded throughout the study. Equivalence in daily weight gain was demonstrated for the intention-to-treat (ITT) population (n 211). In the per-protocol (PP) population (n 102), the 90 % CI of the difference in daily weight gain slightly crossed the lower equivalence margin. During the intervention period, the mean weight-for-age and length-for-age values were close to the median of the WHO growth standards in both groups, indicating adequate growth. The number of adverse events was not different between both groups. No relevant differences were observed in blood parameters indicative for liver and renal function. At 13 weeks, an increased percentage of faecal bifidobacteria (60 v. 48 %) and a reduced percentage of Clostridium lituseburense/C. histolyticum (0·2 v. 2·6 %) were observed in the synbiotic group (n 19) compared with the control group (n 27). In conclusion, this study demonstrates that an extensively hydrolysed formula with B. breve M-16V and the prebiotic mixture scGOS/lcFOS (9:1) supports an adequate infant growth.


The role of oncologists in multidisciplinary cancer teams in the UK: an untapped resource for team leadership?
In the UK, cancer care is managed via multidisciplinary teams (MDT). Core members of these teams are typically surgeons, oncologists, radiologists, pathologists and clinical nurse specialists (with other health care professionals potentially present). Good teamwork, including team communication and leadership, has been shown to be a prerequisite for safe care delivery in other health care contexts, but cancer MDT team working processes are yet to be fully explored. This study aimed to assess the self-perceived contribution of oncologists to MDTs, with emphasis on their potential role as team leaders. Data were collected at the British Uro-oncology Group 6th Annual Meeting (Sep 11-12 2009, York, UK). Respondents completed various items related to their perceived contribution to MDTs, aspects of current and potential MDT leadership, team decision making in these meetings, and also demographic information. Seventy-seven oncologists attended the meeting, of whom 61 fully completed the survey (response rate 79%). Oncologists reported that their contribution to the MDT discussion carries equal weight to those of surgeons, radiologists and pathologists. Whereas 83% of respondents reported that MDT chairmanship could rotate, only 39% reported that it does in their own MDTs. More than 90% of respondents thought that oncologists (clinical or medical) could chair these meetings, but only 25% of them had ever chaired their own MDT. Despite a high level of contribution to MDTs and the respect of their colleagues, oncologists are not taking leadership roles within MDTs at the level that they expect. This study raises the question of whether a re-evaluation the leadership of MDTs is required with clinicians from a variety of specialities being given opportunities to develop skills necessary to lead cancer MDTs and improve team performance and ultimately cancer care.


Crystal structure of the PHF8 Jumonji domain, an Nepsilon-methyl lysine demethylase.
Crystallographic analysis of the catalytic domain of PHD finger protein 8 (PHF8), an N(epsilon)-methyl lysine histone demethylase associated with mental retardation and cleft lip/palate, reveals a double-stranded beta-helix fold with conserved Fe(II) and cosubstrate binding sites typical of the 2-oxoglutarate dependent oxygenases. The PHF8 active site is highly conserved with those of the FBXL10/11demethylases, which are also selective for the di-/mono-methylated lysine states, but differs from that of the JMJD2 demethylases which are selective for tri-/di-methylated states. The results rationalize the lack of activity for the clinically observed F279S PHF8 variant and they will help to identify inhibitors selective for specific N(epsilon)-methyl lysine demethylase subfamilies.


Patients' experiences from symptom onset to initial treatment for atrial fibrillation.
To describe patients' experiences from symptom onset to initial treatment for atrial fibrillation. The estimated number of individuals with atrial fibrillation globally in 2010 was 33·5 million. World-wide, each year, new cases of atrial fibrillation approach 5 million, and prevalence will increase 2·5-fold by 2050. As a result, clinicians worldwide will treat a growing number of patients with atrial fibrillation. Early intervention to promote atrial fibrillation self-management is critical to reduce associated complications of stroke and heart failure. Greater understanding of patients' experiences from symptom onset to initial treatment for atrial fibrillation is needed to guide development of interventions to promote early effective self-management. A descriptive qualitative design was used. Twenty females and 21 males at an academic medical centre were interviewed using open-ended questions to explore their experiences from symptom onset to initial treatment for atrial fibrillation. Data were analysed using qualitative content analysis. Participants' mean age was 64·3 (SD = 10·1) years. Four themes were identified: (1) misinterpreting symptoms; (2) discovering the meaning of atrial fibrillation; (3) facing fears, uncertainty, and moving to acceptance; and (4) receiving validation and reassurance. Participants lacked knowledge of atrial fibrillation and took cues from providers' responses to appraise symptoms and diagnosis. Fear and uncertainty were reduced when providers initiated prompt treatment and took time to explain atrial fibrillation. Patients appreciated receiving clear information about atrial fibrillation, were engaged in learning, and motivated to participate in their care. Providers played a critical role in helping patients to develop an accurate understanding of atrial fibrillation, to cope with the new diagnosis, and motivated them to engage in effective self-management. Insight into participant experiences from symptom onset to initial treatment for atrial fibrillation may inform development of interventions to promote effective atrial fibrillation self-management.


Screening methods for waterlogging tolerance in lucerne: comparative analysis of waterlogging effects on chlorophyll fluorescence, photosynthesis, biomass and chlorophyll content.
Waterlogging is a serious environmental stress on lucerne (Medicago sativa) affecting its agronomic performance. To facilitate the breeding process, efficient tools to screen a population of lucerne cultivars are needed. In this study, a comparative analysis of waterlogging effects on leaf photosynthesis, pigment composition, PSII photochemistry, and plant growth characteristics was undertaken using four different lucerne cultivars (Aurora, Hunter River, L153 and Sequel HR). Two-month-old plants, grown in half-strength Hoagland nutrient solution, were waterlogged for 16 days, and plant physiological characteristics were monitored at regular intervals (every few days). All cultivars had significantly reduced fresh and dry weight for both shoots and roots after 16 days of waterlogging. Root biomass showed a greater percentage of reduction than did shoot biomass. As waterlogging stress developed, chlorophyll content, CO2 assimilation rate, transpiration rate, stomatal conductance and maximal quantum efficiency of PSII (Fv/Fm) decreased significantly. Chlorophyll a and b content gradually decreased over the time of the experiment in the stressed cultivars, and leaf chlorosis became increasingly evident. Although most of the parameters showed significant changes as waterlogging progressed, limitations render some of them inapplicable for screening. It is concluded that for practical screening purposes, the Fv/Fm ratio is the most appropriate. A significant difference between control and waterlogged plants became evident as early as day 7. Possible physiological mechanisms involved are discussed.


Identification of counterfeit medicines for erectile dysfunction from an illegal supply chain.
The appearance of counterfeit medicines in supply chains is a global public health problem that may seriously affect patients. Counterfeit drugs do not meet quality standards and do not declare their real composition and/or source for the purposes of fraud. They may be generic or innovative, they may contain genuine constituents in a fake packaging, or wrong ingredients, or inactive ingredients, or an incorrect quantity of the active substance. In Croatia, no cases of counterfeit medicines have been detected so far, but the Agency for Medicinal Products and Medical Devices has received 34 samples of medicines and other products for testing from Zagreb City Police. The samples included medicines for erectile dysfunction: sildenafil, tadalafil, and vardenafil. Twenty-three samples of tablets without marketing authorisation in Croatia were tested with high-performance liquid chromatography (HPLC) for the declared sildenafil and tadalafil content. Samples labelled 1 (batch T/33), 3 (batch T/33), 5 (batch 4), 6 (batch M0016J), 10 (batch T-070235), 12 (batch T-070544), 15 (batch 314833201), 16 (batch 832718474), and 17 (batch 504830028) containing sildenafil and samples labelled 20 (batch 070356), 21 (batch 05668), and 22 (batch T 378 5) containing tadalafil did not contain the active substance within the acceptable 95 % to 105 % margin of deviation from the declared content. While most samples cannot be described as fake with a reasonable amount of certainty, there is still a suspicion of counterfeit. A correct conclusion can be drawn only with the assistance of the manufacturers and by conducting additional laboratory tests.


A Robust Encoding Scheme for Delivering Artificial Sensory Information via Direct Brain Stimulation.
Innovations for creating somatosensation via direct electrical stimulation of the brain will be required for the next generation of bi-directional cortical neuroprostheses. The current lack of tactile perception and proprioceptive input likely imposes a fundamental limit on speed and accuracy of brain-controlled prostheses or re-animated limbs. This study addresses the unique challenge of identifying a robust, high bandwidth sensory encoding scheme in a high-dimensional parameter space. Previous studies demonstrated single dimensional encoding schemes delivering low bandwidth sensory information, but no comparison has been performed across parameters, nor with update rates suitable for real-time operation of a neuroprosthesis. Here, we report the first comprehensive measurement of the resolution of key stimulation parameters such as pulse amplitude, pulse width, frequency, train interval and number of pulses. Surprisingly, modulation of stimulation frequency was largely undetectable. While we initially expected high frequency content to be an ideal candidate for passing high throughput sensory signals to the brain, we found only modulation of very low frequencies were detectable. Instead, the charge-per-phase of each pulse yields the highest resolution sensory signal, and is the key parameter modulating perceived intensity. The stimulation encoding patterns were designed for high-bandwidth information transfer that will be required for bi-directional brain interfaces. Our discovery of the stimulation features which best encode perceived intensity have significant implications for design of any neural interface seeking to convey information directly to the brain via electrical stimulation.


Effects of prenatal exposure to cocaine and associated risk factors on language development.
During the past decade there has been a dramatic increase in the number of children born with prenatal exposure to cocaine. However, there is very little hard data concerning the later development of these children. The purpose of this preliminary study was to compare the language development profiles of 5 children prenatally exposed to cocaine and associated risk factors to the language development profiles of a matched non-exposed control group in terms of analyses of the discourse-pragmatic, semantic, and form components of language. The language evaluation was based on the analysis of a 30-minute language sample. The results suggested differences between the two groups as well as differences within the cocaine-exposed group. The major differences between the two groups were in discourse-pragmatics although less marked differences in syntactic development were also found. The results are discussed in relation to the potential contribution of pertinent medical and environmental risk factors. The study suggests that for children with prenatal exposure to cocaine in combination with multiple associated risk factors, language development may be compromised.


Free-Radical Concentrations and Other Properties of Pile-Irradiated Coals.
Five coals reacted quite differently when they were exposed to pileirradiation. Little or no change was found in free-radical content for the three coals of lowest carbon content, whereas the two coals of highest carbon content were found to have a considerable increase in free-radical content. The infrared spectra and the apparent hardness of the irradiated coals of higher carbon content indicate that polymerization occurred. Radiation of these coals in chemical reagents may promote reactivity.


Efficacy and safety of ginsenoside-Rd for acute ischaemic stroke: a randomized, double-blind, placebo-controlled, phase II multicenter trial.
Ginsenoside-Rd is a selective competitive Ca2+ receptor antagonist. A phase II randomized, double-blind, placebo-controlled, multicenter study was conducted to examine the efficacy and safety of ginsenoside-Rd in patients with acute ischaemic stroke. A total of 199 patients were randomized equally to receive a 14-day infusion of placebo (group B), ginsenoside-Rd 10 mg (group A) or ginsenoside-Rd 20 mg (group C). Primary end-points were National Institutes of Health Stroke Scale (NIHSS) scores at 15 days. Secondary end-points were NIHSS scores and the Barthel Index at 8 days, the Barthel Index and the modified Rankin scale at 15 days and 90 days. The safety end-points included serious and non-serious adverse events, laboratory values and vital signs. Analysis was by intention to treat. For the primary study outcome, there is significant difference amongst the three groups at 15 days in NIHSS scores (P = 0.0003). Comparing group A with B and group B with C, the difference in the mean for NIHSS was significant in statistics (P = 0.0004, P = 0.0009 respectively). This is no significant difference between group A and C (P = 0.9640). For the secondary study outcome, ginsenoside-Rd did not improve neurological functioning. Incidence of serious and non-serious adverse events was similar amongst the three groups. Ginsenoside-Rd may be of some benefit in acute ischaemic stroke.