Usage criminel de substances psycho-actives : le problème de la durée de détection.
On a regular basis, the media presents the potential risks of the use of psycho-active compounds, including misused pharmaceuticals (flunitrazepam, GHB) or drugs of abuse (cannabis, LSD, ecstasy). Ethanol is also frequently encountered. These drugs can be used for recreational purposes by addicts or can be observed after sexual assaults (drugs spiked in food). Forensic toxicology can be involved in several situations to document impairment, such as : crime under influence, date rape, driving under influence, phsychiatric disorders, determination of the cause of death … In some particular situations, it can be very cautious to investigate exposure to psycho-active drugs, due to late sampling of biological specimens. To enhance the window of detection of 3 specific drugs, the authors propose the following : 1. Use of an ultra-sensitive technique, such as GC/MS/MS/NCI for 7-aminoflunitrazepam; 2. Use of a cumulative specimen, such as sweat for GHB and 3. Use of a metabolite with a long half-life, such as ethyl glucuronide for ethanol.


A novel counterbalanced implementation study design: methodological description and application to implementation research.
Implementation research is increasingly being recognised for optimising the outcomes of clinical practice. Frequently, the benefits of new evidence are not implemented due to the difficulties applying traditional research methodologies to implementation settings. Randomised controlled trials are not always practical for the implementation phase of knowledge transfer, as differences between individual and organisational readiness for change combined with small sample sizes can lead to imbalances in factors that impede or facilitate change between intervention and control groups. Within-cluster repeated measure designs could control for variance between intervention and control groups by allowing the same clusters to receive a sequence of conditions. Although in implementation settings, they can contaminate the intervention and control groups after the initial exposure to interventions. We propose the novel application of counterbalanced design to implementation research where repeated measures are employed through crossover, but contamination is averted by counterbalancing different health contexts in which to test the implementation strategy. In a counterbalanced implementation study, the implementation strategy (independent variable) has two or more levels evaluated across an equivalent number of health contexts (e.g. community-acquired pneumonia and nutrition for critically ill patients) using the same outcome (dependent variable). This design limits each cluster to one distinct strategy related to one specific context, and therefore does not overburden any cluster to more than one focussed implementation strategy for a particular outcome, and provides a ready-made control comparison, holding fixed. The different levels of the independent variable can be delivered concurrently because each level uses a different health context within each cluster to avoid the effect of treatment contamination from exposure to the intervention or control condition. An example application of the counterbalanced implementation design is presented in a hypothetical study to demonstrate the comparison of 'video-based' and 'written-based' evidence summary research implementation strategies for changing clinical practice in community-acquired pneumonia and nutrition in critically ill patient health contexts. A counterbalanced implementation study design provides a promising model for concurrently investigating the success of research implementation strategies across multiple health context areas such as community-acquired pneumonia and nutrition for critically ill patients.


Characterization of a novel influenza A virus hemagglutinin subtype (H16) obtained from black-headed gulls.
In wild aquatic birds and poultry around the world, influenza A viruses carrying 15 antigenic subtypes of hemagglutinin (HA) and 9 antigenic subtypes of neuraminidase (NA) have been described. Here we describe a previously unidentified antigenic subtype of HA (H16), detected in viruses circulating in black-headed gulls in Sweden. In agreement with established criteria for the definition of antigenic subtypes, hemagglutination inhibition assays and immunodiffusion assays failed to detect specific reactivity between H16 and the previously described subtypes H1 to H15. Genetically, H16 HA was found to be distantly related to H13 HA, a subtype also detected exclusively in shorebirds, and the amino acid composition of the putative receptor-binding site of H13 and H16 HAs was found to be distinct from that in HA subtypes circulating in ducks and geese. The H16 viruses contained NA genes that were similar to those of other Eurasian shorebirds but genetically distinct from N3 genes detected in other birds and geographical locations. The European gull viruses were further distinguishable from other influenza A viruses based on their PB2, NP, and NS genes. Gaining information on the full spectrum of avian influenza A viruses and creating reagents for their detection and identification will remain an important task for influenza surveillance, outbreak control, and animal and public health. We propose that sequence analyses of HA and NA genes of influenza A viruses be used for the rapid identification of existing and novel HA and NA subtypes.


Human positron emission tomographic [18F]fluorodopa studies correlate with dopamine cell counts and levels.
Postmortem counts of dopaminergic cell densities in the substantia nigra (5 subjects) and striatal levels of dopamine (DA) and its metabolites (6 subjects) were determined on 1 parkinsonian (PD), 3 progressive supranuclear palsy (PSP), 1 amyotrophic lateral sclerosis, and 1 Alzheimer's case who had been positron emission tomography scanned with 6-[18F]fluorodopa during life. [18F]Fluorodopa uptake rate constants, which presumably depend on the number of functioning striatal DA terminals, were strictly proportional to cell densities (significant correlation with zero intercept) and also correlated significantly with striatal DA levels but with an intercept indicating greater losses of DA than of terminals in PSP and PD. Postmortem data on 6 PD, 1 PSP, and 9 neuronally normal controls substantiated the significant correlation between cell counts and DA levels, with the latter being the more depressed in pathological cases.


Long-term stable and efficient degradation of ornidazole with minimized by-product formation by a biological sulfidogenic process based on elemental sulfur.
Conventional biological treatment processes cannot efficiently and completely degrade nitroimidazole antibiotics, due to the formation of highly antibacterial and carcinogenic nitroreduction by-products. This study investigated the removal of a typical nitroimidazole antibiotic (ornidazole) during wastewater treatment by a biological sulfidogenic process based on elemental sulfur (S0-BSP). Efficient and stable ornidazole degradation and organic carbon mineralization were simultaneously achieved by the S0-BSP in a 798-day bench-scale trial. Over 99.8 % of ornidazole (200‒500 μg/L) was removed with the removal rates of up to 0.59 g/(m3·d). Meanwhile, the efficiencies of organic carbon mineralization and sulfide production were hardly impacted by the dosed ornidazole, and their rates were maintained at 0.15 kg C/(m3·d) and 0.49 kg S/(m3·d), respectively. The genera associated with ornidazole degradation were identified (e.g., Sedimentibacter, Trichococcus, and Longilinea), and their abundances increased significantly. Microbial degradation of ornidazole proceeded by several functional genes, such as dehalogenases, cysteine synthase, and dioxygenases, mainly through dechlorination, denitration, N-heterocyclic ring cleavage, and oxidation. More importantly, the nucleophilic substitution of nitro group mediated by in-situ formed reducing sulfur species (e.g., sulfide, polysulfides, and cysteine hydropolysulfides), instead of nitroreduction, enhanced the complete ornidazole degradation and minimized the formation of carcinogenic and antibacterial nitroreduction by-products. The findings suggest that S0-BSP can be a promising approach to treat wastewater containing multiple contaminants, such as emerging organic pollutants, organic carbon, nitrate, and heavy metals.


Functional analysis of the human cytomegalovirus immune evasion protein, pUS3(22kDa).
Human cytomegalovirus (HCMV) is an important opportunistic pathogen that infrequently causes disease in individuals with mature immune systems. The HCMV US3 gene encodes a 22-kDa protein that interferes with immune recognition of virally infected cells. The 22-kDa US3 protein binds to major histocompatibility complex (MHC) class I complexes, retaining them in the endoplasmic reticulum (ER), thereby decreasing the presentation of viral antigen to cytotoxic T cells. Our studies demonstrate that correct folding of the ER lumenal domain of the US3 protein is essential, but insufficient for interactions with MHC class I complexes. We demonstrate a requirement for the transmembrane domain of the 22-kDa US3 protein, confirming the results of others, and also show that the cytosolic carboxyl-terminal tail influences the function of the protein. Anchoring of the ER-lumenal immunoglobulin-like fold of the US3 protein to the membrane of the endoplasmic reticulum is critical for the binding and retention of MHC class I complexes.


Influences of ethnicity on perinatal and child mortality in the Netherlands.
To investigate the differences in perinatal death and child mortality between different ethnic groups in the Netherlands. Retrospective analysis of data collected between 1990 and 1993 in the national obstetric registry comprising 569 743 births. Retrospective analysis of all death certificates of 0 to 15 year old children routinely collected between 1979 and 1993, comprising 20 211 deaths. Black mothers had the highest perinatal death rate compared with indigenous Dutch mothers (odds ratio 2.2). Hindustanis (West Indian Asians) had an odds ratio of 1.4 and Mediterraneans 1.3. The increased rate for black and Hindustani women could be fully explained by preterm birth. In the Mediterranean group the differences were explained by teenage pregnancy, grand multiparity, and socioeconomic status rather than prematurity. The death rate of Turkish and Moroccan children was twice as high as that of native Dutch children. For the different diagnostic categories this was: infectious diseases, relative risk (RR) 2.2; hereditary (metabolic) disorders, RR 2.0; accidents and drowning, RR 1.9. One quarter of the Turkish and Moroccan children died while on holiday in their country of origin. Sudden infant death syndrome was twice as high for Turkish infants as for Dutch children and four times higher than for Moroccan infants. Ethnic minorities in the Netherlands have a higher perinatal and child mortality rate than the indigenous Dutch. Apart from socioeconomic differences, sociocultural and lifestyle factors play an important role.


Geometric feature extraction by a multimarked point process.
This paper presents a new stochastic marked point process for describing images in terms of a finite library of geometric objects. Image analysis based on conventional marked point processes has already produced convincing results but at the expense of parameter tuning, computing time, and model specificity. Our more general multimarked point process has simpler parametric setting, yields notably shorter computing times, and can be applied to a variety of applications. Both linear and areal primitives extracted from a library of geometric objects are matched to a given image using a probabilistic Gibbs model, and a Jump-Diffusion process is performed to search for the optimal object configuration. Experiments with remotely sensed images and natural textures show that the proposed approach has good potential. We conclude with a discussion about the insertion of more complex object interactions in the model by studying the compromise between model complexity and efficiency.


Fungi associated with the hemlock woolly adelgid, Adelges tsugae, and assessment of entomopathogenic isolates for management.
Fungi associated with the hemlock wooly adelgid, Adelges tsugae Annand (Hemiptera: Adelgidae), were collected throughout the eastern USA and southern China. Twenty fungal genera were identified, as were 79 entomopathogenic isolates, including: Lecanicillium lecanii (Zimmermann) (Hypocreales: Insertae sedis), Isaria farinosa (Holm: Fries.) (Cordycipitaceae), Beauveria bassiana (Balasamo) (Hyphomycetes), and Fusarium spp (Nectriaceae). The remaining fungal genera associated with insect cadavers were similar for both the USA and China collections, although the abundance of Acremonium (Hypocreaceae) was greater in China. The entomopathogenic isolates were assayed for efficacy against Myzus persicae (Sulzer) (Homoptera: Aphididae) and yielded mortality ranging from 3 to 92%. Ten isolates demonstrating the highest efficacy were further assessed for efficacy against field-collected A. tsugae under laboratory conditions. Overall, two B. bassiana, one L. lecanii, and a strain of Metarhizium anisopliae (Metchnikoff) (Hypocreales: Clavicipitaceae), demonstrated significantly higher efficacy against A. tsugae than the others. Isolates were further evaluated for conidial production, germination rate and colony growth at four temperatures representative of field conditions. All isolates were determined to be mesophiles with optimal temperature between 25-30 degrees C. In general, conidial production increased with temperature, though two I. farinosa produced significantly more conidia at cooler temperatures. When efficacy values were compared with conidial production and temperature tolerances, Agricultural Research Service Collection of Entomopathogenic Fungi (ARSEF) 1080, 5170, and 5798 had characteristics comparable to the industrial B. bassiana strain GHA.


Radio-opacity of fishbones.
Bones are the largest group of foreign bodies found in the air and food passages. Fishbones which lodge in the tonsil can be easily seen and removed relatively easily. Those lodging in the pyriform fossa are well localized by the patient and can usually be seen on mirror examination. It would be useful to know which types of fishbones are radio-opaque and therefore likely to be shown by radiographs when mirror examination is difficult or fails to reveal a foreign body. Therefore a study was undertaken to ascertain the radio-opacity of the bones of ten different species of fish eaten in the British Isles.


Brief alcohol interventions for adolescents and young adults: a systematic review and meta-analysis.
This study reports findings from a meta-analysis summarizing the effectiveness of brief alcohol interventions for adolescents (age 11-18) and young adults (age 19-30). We identified 185 eligible study samples using a comprehensive literature search and synthesized findings using random-effects meta-analyses with robust standard errors. Overall, brief alcohol interventions led to significant reductions in alcohol consumption and alcohol-related problems among adolescents (g = 0.27 and g = 0.19) and young adults (g = 0.17 and g = 0.11). These effects persisted for up to 1 year after intervention and did not vary across participant demographics, intervention length, or intervention format. However, certain intervention modalities (e.g., motivational interviewing) and components (e.g., decisional balance, goal-setting exercises) were associated with larger effects. We conclude that brief alcohol interventions yield beneficial effects on alcohol-related outcomes for adolescents and young adults that are modest but potentially worthwhile given their brevity and low cost.


The role of tumor-stroma interactions on desmoplasia and tumorigenicity within a microengineered 3D platform.
The tumor microenvironment has been demonstrated to play a crucial role in modulating cancer progression. Amongst various cell types within the tumor microenvironment, cancer associated fibroblasts (CAFs) are in abundance, serving to modulate the biophysical properties of the stromal matrix, through excessive deposition of extracellular matrix (ECM) proteins that leads to enhanced tumor progression. There is still a critical need to develop a fundamental framework on the role of tumor-stromal cell interactions on desmoplasia and tumorigenicity. Herein, we developed a 3D microengineered organotypic tumor-stroma model incorporated with breast cancer cells surrounded by CAF-embedded collagen matrix. We further integrated our platform with atomic force microscopy (AFM) to study the dynamic changes in stromal stiffness during active tumor invasion. Our findings primarily demonstrated enhanced tumor progression in the presence of CAFs. Furthermore, we highlighted the crucial role of crosstalk between tumor cells and CAFs on stromal desmoplasia, where we identified the role of tumor-secreted PDGF-AA/-BB on elevated matrix stiffness. Inhibition of the activity of PDGFRs in CAFs led to attenuation of stromal stiffness. Overall, our work presents a well-controlled tumor microenvironment model capable of dissecting specific biophysical and biochemical signaling cues which lead to stromal desmoplasia and tumor progression.


Inhibitory Effects of Urolithins, Bioactive Gut Metabolites from Natural Polyphenols, against Glioblastoma Progression.
We previously reported that proinflammatory cytokines, particularly tumor necrosis factor (TNF)-α, promoted tumor migration, invasion, and proliferation, thus worsening the prognosis of glioblastoma (GBM). Urolithins, the potent metabolites produced by the gut from pomegranate polyphenols, have anticancer properties. To develop an effective therapy for GBM, this study aimed to study the effects of urolithins against GBM. Urolithin A and B significantly reduced GBM migration, reduced epithelial-mesenchymal transition, and inhibited tumor growth. Moreover, urolithin A and B inhibited TNF-α-induced vascular cell adhesion molecule (VCAM)-1 and programmed death ligand 1 (PD-L1) expression, thereby reducing human monocyte (HM) binding to GBM cells. Aryl hydrocarbon receptor (AhR) level had higher expression in patients with glioma than in healthy individuals. Urolithins are considered pharmacological antagonists of AhR. We demonstrated that the inhibition of AhR reduced TNF-α-stimulated VCAM-1 and PD-L1 expression. Furthermore, human macrophage condition medium enhanced expression of PD-L1 in human GBM cells. Administration of the AhR antagonist attenuated the enhancement of PD-L1, indicating the AhR modulation in GBM progression. The modulatory effects of urolithins in GBM involve inhibiting the Akt and epidermal growth factor receptor pathways. The present study suggests that urolithins can inhibit GBM progression and provide valuable information for anti-GBM strategy.


Does the oral apparatus of the ciliate Stentor inhibit oral development by release of a diffusible substance?
In the ciliate Stentor, many thousands of basal bodies assemble on the ventral cell surface to form a new oral apparatus during cell division, regeneration and reorganization (oral replacement during interphase). During interphase, oral development is normally inhibited by the presence of the anteriorly placed oral apparatus. A glass needle was used to cut the oral apparatus of interphase stentors in two so that the parts remained intact but separate at the anterior end of the cell. These cells initiated basal body assembly and oral development, usually within 8 h. Basal body assembly can therefore result from disconnection of fibrous structures within the oral apparatus but is unlikely to be regulated by an inhibitor diffusing from it.


[Taxonomic study of Pseudomonas aurantiaca Nakhimovskaya, 1948 and the proposal of a neotype strain of this species].
The type strain of Pseudomonas aurantiaca VKM B-876 (NCIB 10068) was shown to be identical to P. aureofaciens in its biological properties, G + C--content of DNA and chemical nature of produced pigments. Its genome relatedness value with the type strain of P. aureofaciens was found to be 82%. The properties of 36 orange-pigmented fluorescent bacterial strains corresponding with the special description of P. aurantiaca, are presented. Their DNA homology values with other fluorescent species and with the majority of P. fluorescens biotypes ranged from 0 to 49%. At the same time this bacterial group showed a considerable phenotypic similarity and high DNA homology values (90-100%) with the strains of P. fluorescens biotype II (B). The ability to produce a complex of antibiotics, phloroglucinol derivatives, is also their mutual distinctive characteristic. The unification of orange-pigmented microorganisms and the strains of P. fluorescens biotype B under the specific name P. aurantiaca is proposed, regarding the strains of biotype B as the pigmentless variants of this species. The amended description of P. aurantiaca Nakhimovskaya, 1948 is presented. The neotype strain P. aurantiaca VKM B-1524 is proposed.


Ouabain exerts biphasic effects on connexin functionality and expression in vascular smooth muscle cells.
1. We have compared the effects of ouabain on the maintenance of gap junctional communication in rat aortic A7r5 smooth muscle cells, monkey COS-1 fibroblasts and human HeLa epithelial cells. 2. Ouabain (1 mM) interrupted dye coupling between confluent A7r5 cells within approximately 1 h, and high concentrations of ouabain were similarly required to reduce coupling between COS-1 cells selected to express the rat alpha1 Na+/K+-ATPase subunit, which is ouabain resistant. By contrast, low concentrations of ouabain (1-10 microM) attenuated dye transfer in wild-type COS-1 and HeLa cells, whose endogenous alpha1 subunits possess relatively high affinity for the glycoside (Ki approximately 0.3 vs approximately 100 microM) Ouabain-induced reductions in dye transfer therefore correlated with the ability of the glycoside to bind to the Na+/K+-ATPase isoenzymes expressed in these different cell lines. 3. No consistent relationship between inhibition of intercellular dye transfer and secondary changes in [Ca2+]i or pHi could be identified following incubation with ouabain. 4. In separate experiments, the effects of ouabain on real-time trafficking of connexin protein were monitored by time-lapse microscopy of A7r5 cells transfected to express a fluorescent Cx43-green fluorescent protein (GFP) and the ability of the glycoside to modulate endogenous expression of connexins (Cx) 40 and 43 evaluated in A7r5 cells by immunochemical and Western blot analysis. 5. Ouabain (1 mM) depressed vesicular trafficking of Cx43-GFP after approximately 1 h, and caused a time-dependent loss of endogenous Cx40 and Cx43 protein that was first evident at 2 h and almost complete after 4 h. These effects of ouabain on Cx expression were reversed approximately 90 min following washout of the glycoside. 6. We conclude that ouabain exerts biphasic effects on the intercellular communication that involve an initial decrease in gap junctional permeability followed by a global reduction in the expression of Cx protein. Further studies are necessary to establish to what extent these actions of ouabain reflect inversion of the normal [Na+]i/[K+]i ratio and/or conversion of the Na+/K+-ATPase into a general signal transducer that regulates downstream protein synthesis.


Evaluation of changes in the secretion of immunoactive inhibin by adult rat seminiferous tubules in vitro as an indicator of early toxicant action on spermatogenesis.
A method for culturing isolated seminiferous tubules (ST) from adult rats for 1-3 days has been developed and optimized rigorously on the basis of the secretion of immunoactive inhibin under basal conditions and after maximal stimulation with rat FSH or dibutyryl cyclic AMP. The effect on these cultures of three known testicular toxicants was assessed. Of these, two are thought to act on the Sertoli cell, meta-dinitrobenzene (mDNB) and nitrobenzene (NB), while the third, methoxy acetic acid (MAA), is thought to act on pachytene spermatocytes. In addition, the effect of a possible testicular toxicant, 3-mononitrotoluene (3-MNT), was investigated. These data were compared with those obtained using cultures of immature rat Sertoli cells (SC) or SC + germ cells and with data on the effect of equivalent doses of the compounds on the secretion of immunoactive inhibin in vivo. In studies designed to optimize conditions for the secretion of immunoactive inhibin by ST in culture, significant effects were found of the type of culture medium used, the duration of culture, the total and individual length of tubules used, etc. All subsequent studies with toxicants utilized optimal conditions. Addition of either mDNB or NB to ST cultures at 10(-5) or 10(-3) M, or MAA at 10(-4) M, stimulated basal secretion of immunoactive inhibin by two- to fourfold on Days 1, 2, or 3 of culture while FSH or dibutyryl cyclic AMP-stimulated secretion of immunoactive inhibin was either unaffected or was enhanced to a small extent. At the same doses, mDNB or NB also enhanced secretion of immunoactive inhibin by SC cultures. although these effects were more variable and of smaller magnitude than the effects on ST cultures. In contrast, addition of up to 10(-3) MAA to cocultures of SC + germ cells had no effect on the secretion of immunoactive inhibin. Exposure of rats in vivo to levels of mDNB, NB, or MAA similar to those which stimulated secretion of immunoactive inhibin in vitro resulted in a two- to fourfold increase in the levels of immunoactive inhibin in testicular interstitial fluid (IF) at 1 and 3 days post-treatment, and this was associated with early impairment of spermatogenesis (as judged by testis weight). In contrast to these effects, addition of 3-MNT to ST or SC cultures had no effect except at 10(-3) M, when the secretion of immunoactive inhibin was increased marginally.(ABSTRACT TRUNCATED AT 400 WORDS)


Age-related changes of protein SUMOylation balance in the AβPP Tg2576 mouse model of Alzheimer's disease.
Alzheimer's disease (AD) is a complex disorder that affects the central nervous system causing a severe neurodegeneration. This pathology affects an increasing number of people worldwide due to the overall aging of the human population. In recent years SUMO protein modification has emerged as a possible cellular mechanism involved in AD. Some of the proteins engaged in the physiopathological process of AD, like BACE1, GSK3-β tau, AβPP, and JNK, are in fact subject to protein SUMO modifications or interactions. Here, we have investigated the SUMO/deSUMOylation balance and SUMO-related proteins during the onset and progression of the pathology in the Tg2576 mouse model of AD. We examined four age-stages (1.5, 3, 6, 17 months old) and observed shows an increase in SUMO-1 protein conjugation at 3 and 6 months in transgenic mice with respect to WT in both cortex and hippocampus. Interestingly this is paralleled by increased expression levels of Ubc9 and SENP1 in both brain regions. At 6 months of age also the SUMO-1 mRNA resulted augmented. SUMO-2-ylation was surprisingly decreased in old transgenic mice and was unaltered in the other time windows. The fact that alterations in SUMO/deSUMOylation equilibrium occur from the early phases of AD suggests that global posttranslational modifications may play an important role in the mechanisms underlying disease pathogenesis, thus providing potential targets for pharmacological interventions.


Individualized analysis of skin thermosensory thresholds and sensitivity in heat-sensitive people with multiple sclerosis.
We investigated whether and how multiple sclerosis (MS) alters thresholds for perceiving increases and decreases in local skin temperature, as well as the sensitivity to progressively greater temperature stimuli, amongst heat-sensitive people with MS. Eleven MS patients (5 M/6 F; 51.1 ± 8.6 y, EDSS 5.7 ± 1.9) and 11 healthy controls (CTR; 7 M/4 F; 50.3 ± 9.0 y) performed warm and cold threshold tests on a hairy skin site, on both sides of the body. They also underwent a thermosensitivity test where they rated (visual analogue scale) perceived magnitude of 4 local skin stimuli (i.e. 22, 26, 34, 38°C). Individual thresholds and slopes of linear regression for thermosensitivity were z-transformed for each MS patient, and used to determine individual thermosensory abnormalities. When considering both threshold and thermosensitivity, six out of our 11 heat-sensitive patients (54.5%) exhibited skin thermosensory abnormalities. Those abnormalities varied amongst patients in terms of type (threshold vs. thermosensitivity), quality (warm vs. cold), location (left vs. right side of the body) and extent. Each of those six patients presented unique thermosensory profiles. While some patients experienced thermosensory loss in both thresholds and sensitivity and on both sides of the body, others experienced cold thermosensory loss on one side of the body only. The observed individual variability in thermosensory function among heat-sensitive MS patients highlight the need for a patient-centered approach to assessing thermosensory dysfunction and its potential implications for heat stress vulnerability in this patient group.


Plasma and urinary endothelin-1 concentrations in asphyxiated newborns [corrected].
The aim of this study was to determine if there is any correlation between the hypoxia induced deterioration of renal functions and urinary excretions of endothelin (ET). Therefore using a sensitive and specific radioimmunoassay, we have investigated plasma ET-1 concentrations and urine ET-1 excretions in healthy and asphyxiated newborns. Sixteen newborns (10 boys, 6 girls) with perinatal asphyxia or hypoxia of variable seriousness which were followed at Newborn Intensive Care Unit in Eskisehir Osmangazi University Faculty of Medicine were enrolled. Simultaneously, gestation and weight matched 10 newborns (6 boys, 4 girls) with no asphyxia (first minute Apgar score >7) were enrolled as controls. Plasma ET-1 concentrations of the asphyxiated infants (61.8+/-79.3 pg/ml, between 23.4-125.2 pg/ml) were higher than in the control group (29.3+/-22.1 pg/ml, between 12.3 and 50.8 pg/ml, p<0.05). However creatinine clearance values were not different between the two groups (p>0.05), mean fractional excretion of sodium levels (FeNa%) were higher in the study group than the controls (p<0.01). Urinary ET-1 concentrations in the asphyxiated infants were 144.6+/-63.4 pg/ml versus 70.1+/-27.7 pg/ml in the control group (p<0.001). The ET clearance were more elevated in the asphyxiated newborns than in the healthy infants (p<0.05). Urinary ET-1/Cr ratio in the hypoxic infants were significantly elevated in the first day of life when compared with those of healthy infants (p<0.05). Total ET excretion was negatively correlated with FeNa (%) (r=-0.603, p<0.05). Plasma ET-1 concentrations of the asphyxiated infants reduced at 48 hours of age (p<0.001). Fifth minute Apgar score was negatively correlated with urinary ET-1 levels (r=-0.615, p<0.01), urinary Na excretion (r=-0.583, p<0.01), FeNa (%) (r=-0.597, p<0.01) and total ET excretion (r=-0.560, p<0.01) and positively correlated with ET clearance (r=0.559, p<0.05). Urinary ET-1 levels were negatively correlated with umbilical artery BE levels (r=-0.612, p<0.05). To our study, elevated urinary ET-1 levels were observed during perinatal asphyxia and urinary ET-1 levels were negatively correlated with 5th minute Apgar score and cord blood base excess levels. For this reason urinary ET-1 levels could be a marker of perinatal asphyxia as cord blood ET-1 levels. With investigations showing renal production is independent from plasma and increased urinary ET-1/Cr levels in newborn with perinatal asphyxia and also negative correlation between the total ET excretion and FeNa, urinary ET-1 levels could be served as a useful marker to detecting also impaired renal functions in infants with perinatal asphyxia.


O-GlcNAcylation of Neuronal Proteins: Roles in Neuronal Functions and in Neurodegeneration.
O-GlcNAc is the attachment of β-N-acetylglucosamine to the hydroxyl group of serine and threonine in nuclear and cytoplasmic proteins. It is generally not further elongated but exists as a monosaccharide that can be rapidly added or removed. Thousands of proteins involved in gene transcription, protein translation, and degradation as well as the regulation of signal transduction contain O-GlcNAc. Brain is one of the tissues where O-GlcNAc is most highly expressed and deletion of neuronal O-GlcNAc leads to death early in development. O-GlcNAc is also important for normal adult brain function, where dynamic processes like learning and memory at least in part depend on the modification of specific proteins by O-GlcNAc. Conversely, too much or too little O-GlcNAc on other proteins participates in neurodegenerative processes underlying diseases such as Alzheimer's and Parkinson's. In this chapter, we describe the expression and regulation of O-GlcNAc in the nervous system.


Gene activation in the amphibian mesoderm.
Cell potency is progressively restricted in amphibian development by a series of cellular interactions called inductions. The mesoderm is believed to develop in response to the earliest known induction, in which vegetal cells of the blastula divert overlying animal hemisphere cells away from epidermal and towards mesodermal fates. We describe two early markers of mesodermal differentiation in Xenopus laevis, both mRNAs that encode DNA-binding proteins of the helix-loop-helix family. One is a frog homologue of MyoD, a gene that in transfection experiments can convert cultured fibroblasts into myoblasts. Xenopus MyoD (XMyoD) is expressed in the early myotomes, from which the axial musculature develops. The accumulation of XMyoD RNA precedes that of transcripts from the cardiac actin gene, until now the earliest known marker of the muscle lineage, this result indicating that XMyoD could play a role in initiating muscle differentiation in normal development. We show by microinjection of synthetic RNA that XMyoD can indeed activate muscle-specific gene expression in animal cap cells, which would normally form only ectoderm. However, the XMyoD-injected animal caps did not produce differentiated muscle, suggesting that additional specific factors are required for full myogenesis. The other mRNA is a relative of the twist gene of Drosophila, which is required for mesodermal differentiation in flies. This gene (Xtwi) is expressed widely in the early frog mesoderm, but not, however, in the myotomes, where XMyoD is expressed. Later, the Xtwi gene is activated, in response to a second induction, in the developing neural crest.


Multilayer Density Analysis of Cellulose Thin Films.
An approach for the multilayer density analysis of polysaccharide thin films at the example of cellulose is presented. In detail, a model was developed for the evaluation of the density in different layers across the thickness direction of the film. The cellulose thin film was split into a so called "roughness layer" present at the surface and a "bulk layer" attached to the substrate surface. For this approach, a combination of multi-parameter surface plasmon resonance spectroscopy (SPR) and atomic force microscopy (AFM) was employed to detect changes in the properties, such as cellulose content and density, thickness and refractive index, of the surface near layer and the bulk layer. The surface region of the films featured a much lower density than the bulk. Further, these results correlate to X-ray reflectivity studies, indicating a similar layered structure with reduced density at the surface near regions. The proposed method provides an approach to analyse density variations in thin films which can be used to study material properties and swelling behavior in different layers of the films. Limitations and challenges of the multilayer model evaluation method of cellulose thin films were discussed. This particularly involves the selection of the starting values for iteration of the layer thickness of the top layer, which was overcome by incorporation of AFM data in this study.


Paracetamol versus ibuprofen in treating episodic tension-type headache: a systematic review and network meta-analysis.
Tension-type headache (TTH) is the most common type of headache worldwide. It is defined and classified according to the International Classification of Headache Disorders. TTH is treated with over-the-counter medications, mostly paracetamol or ibuprofen. The purpose was to assess the effectiveness of paracetamol versus ibuprofen in treating episodic tension-type headache (ETTH) through direct and indirect comparisons of randomized controlled trials (RCTs). We included RCTs comparing paracetamol with a placebo, ibuprofen with a placebo, or paracetamol with ibuprofen for acute ETTH treatment that were published between 1988 and 2022. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and the Web of Science. The Cochrane Collaboration risk of bias tool was used to assess the risk of bias. We identified 14 studies including 6521 people with ETTH. None of the studies had a low risk of bias for all domains; this was most likely due to inadequate reporting and a small sample size. Ibuprofen (odds ratio (OR): 1.73, 95% confidence interval (CI): 1.17-2.56) showed better efficacy than paracetamol (OR: 1.62, 95% CI 1.24-2.13) for pain-free status at 2 h, while paracetamol (OR: 1.42, 95% CI 0.87-2.30) showed better efficacy than ibuprofen (OR: 1.20, 95% CI 0.58-2.48) for pain-free status at 1 h. Paracetamol was associated with the lowest likelihood of rescue medication use (OR: 0.49, 95% CI 0.37-0.65). Ibuprofen was associated with a lower likelihood of the occurrence of any events and gastrointestinal adverse events compared with placebo and paracetamol (OR: 0.95, 95% CI 0.64-1.41 and OR: 0.81, 95% CI 0.44-1.50, respectively). Paracetamol and ibuprofen showed better efficacy than placebo in treating ETTH; there was no statistically significant difference in efficacy between the two drugs. For individuals at a higher risk (like renal insufficiency or risk of GI bleeding), paracetamol may be considered as a preferred option instead of Ibuprofen. Further meta-analyses of head-to-head trials are needed for direct comparisons in the future.PROSPERO registration number: CRD42022340936.


NEIL3 promotes hepatoma epithelial-mesenchymal transition by activating the BRAF/MEK/ERK/TWIST signaling pathway.
Hepatocellular carcinoma (HCC) is among the most prevalent visceral neoplasms. So far, reliable biomarkers for predicting HCC recurrence in patients undergoing surgery are far from adequate. In the aim of searching for genetic biomarkers involved in HCC development, we performed analyses of cDNA microarrays and found that the DNA repair gene NEIL3 was remarkably overexpressed in tumors. NEIL3 belongs to the Fpg/Nei protein superfamily, which contains DNA glycosylase activity required for the base excision repair for DNA lesions. Notably, the other Fpg/Nei family proteins NEIL1 and NEIL2, which have the same glycosylase activity as NEIL3, were not elevated in HCC; NEIL3 was specifically induced to participate in HCC development independently of its glycosylase activity. Using RNA-seq and invasion/migration assays, we found that NEIL3 elevated the expression of epithelial-mesenchymal transition (EMT) factors, including the E/N-cadherin switch and the transcription of MMP genes, and promoted the invasion, migration, and stemness phenotypes of HCC cells. Moreover, NEIL3 directly interacted with the key EMT player TWIST1 to enhance invasion and migration activities. In mouse orthotopic HCC studies, NEIL3 overexpression also caused a prominent E-cadherin decrease, tumor volume increase, and lung metastasis, indicating that NEIL3 led to EMT and tumor metastasis in mice. We further found that NEIL3 induced the transcription of MDR1 (ABCB1) and BRAF genes through the canonical E-box (CANNTG) promoter region, which the TWIST1 transcription factor recognizes and binds to, leading to the BRAF/MEK/ERK pathway-mediated cell proliferation as well as anti-cancer drug resistance, respectively. In the HCC cohort, the tumor NEIL3 level demonstrated a high positive correlation with disease-free and overall survival after surgery. In conclusion, NEIL3 activated the BRAF/MEK/ERK/TWIST pathway-mediated EMT and therapeutic resistances, leading to HCC progression. Targeted inhibition of NEIL3 in HCC individuals with NEIL3 induction is a promising therapeutic approach. © 2022 The Pathological Society of Great Britain and Ireland.


CHOICES for sickle cell reproductive health: A protocol of a randomized preconception intervention model for a single gene disorder.
Our long-term goal is to foster genetically informed reproductive health knowledge and behaviors among young adults with sickle cell disease (SCD) or sickle cell trait (SCT) with a web-based, tailored, multimedia intervention called CHOICES. CHOICES is designed to help young adults with SCD or SCT preconception to gain knowledge of genetic inheritance, specify their reproductive health intentions (their parenting plan), and engage in reproductive health behaviors concordant with their parenting plan. In a previous study, we found high acceptability of both the e-Book (usual care control) and CHOICES interventions. We also found sustained (24 months), significant effects on knowledge but not on behavior, most likely because half of the recruited group was not at risk for their children inheriting SCD. Hence, we propose an adequately powered randomized controlled trial with the CHOICES intervention and an e-Book control to compare their effects on genetic inheritance knowledge and at-risk reproductive health behaviors (immediate posttest and at 6, 12, 18, and 24 months). We will conduct subgroup analyses to provide insight into the baseline knowledge and behavior as well as the intervention effects in different demographic or acceptability groups. Given the scalability and low cost of CHOICES, if proved to be effective, it can reach the affected population at low cost.


The in vivo immunomodulatory effects of recombinant interferon gamma plus recombinant tumor necrosis factor-alfa.
We conducted a phase I study in which an intramuscular injection of interferon gamma (IFN gamma) at 10, 50, or 100 micrograms/m2 was followed 5 minutes later by an intramuscular injection of 10, 50, or 100 micrograms/m2 of tumor necrosis factor-alfa (TNF alpha) at another site every other day for 20 days (10 doses). The addition of TNF alpha to IFN gamma reduced both the magnitude and duration of IFN gamma-mediated effects on peripheral blood monocyte expression of Fc receptors (FcRs) and HLA-DR and production of hydrogen peroxide. This inhibition was related to the dose of TNF alpha. On the other hand, TNF alpha and IFN gamma appeared to have an additive stimulatory effect on the production of neopterin by monocytes. The highest serum levels of neopterin were detected in patients who received the highest doses of both IFN gamma and TNF alpha. Thus, conflicting conclusions regarding the effect of the combination on immune activation are possible. If the activation of peripheral blood monocytes is the appropriate surrogate measure of the immune enhancement of the combination, then the simultaneous administration of IFN gamma and TNF alpha is ineffective, and future attempts to exploit the potential additive or synergistic effects of this combination of cytokines in humans may need to explore sequential administration schemata. On the other hand, if serum neopterin levels are a more reliable index of immune activation, simultaneous administration of 100 micrograms/m2 IFN gamma and 50 micrograms/m2 TNF alpha every other day (the maximally tolerated dose [MTD]) should be used in phase II testing. This dilemma points out the limitations of currently available methods of human immune assessment and the inadequacies in our capacity to gauge what particular immune measure or set of measures predict for in vivo antitumor effects.


ADCY5 mutations are another cause of benign hereditary chorea.
To determine the contribution of ADCY5 mutations in cases with genetically undefined benign hereditary chorea (BHC). We studied 18 unrelated cases with BHC (7 familial, 11 sporadic) who were negative for NKX2-1 mutations. The diagnosis of BHC was based on the presence of a childhood-onset movement disorder, predominantly characterized by chorea and no other major neurologic features. ADCY5 analysis was performed by whole-exome sequencing or Sanger sequencing. ADCY5 and NKX2-1 expression during brain development and in the adult human brain was assessed using microarray analysis of postmortem brain tissue. The c.1252C>T; p.R418W mutation was identified in 2 cases (1 familial, 1 sporadic). The familial case inherited the mutation from the affected father, who had a much milder presentation, likely due to low-grade somatic mosaicism. The mutation was de novo in the sporadic case. The clinical presentation of these cases featured nonparoxysmal generalized chorea, as well as dystonia in the most severely affected, but no facial myokymia. We observed significant progression of symptoms in ADCY5 mutation carriers, in contrast to BHC secondary to NKX2-1 mutations. The difference in the clinical course is mirrored by the brain expression data, showing increasing ADCY5 expression in the striatum during brain development, whereas NKX2-1 shows an opposite trend. Our study identifies mutations in ADCY5, the gene previously linked to familial dyskinesia with facial myokymia, as a cause of familial and sporadic BHC. ADCY5 genetic analysis should be performed in cases with a benign choreiform movement disorder even in the absence of facial myokymia.


Prognostic Impact of Presurgical CA19-9 Level in Pancreatic Adenocarcinoma: A Pooled Analysis.
Presurgical carbohydrate antigen 19-9 (CA19-9) level predicts overall survival (OS) in resected pancreatic adenocarcinoma (PaC). The aim of this pooled analysis was to evaluate if presurgical CA19-9 level can also predict local control (LC) and distant metastasis-free survival (DMFS). Seven hundred patients with PaC from eight institutions who underwent surgical resection ± adjuvant treatment between 2000 and 2014 were analyzed. Patients were divided based on four presurgical CA19-9 level cutoffs (5, 37, 100, 353 U/ml). Weibull regression model to identify independent predictors of OS on 404 patients with complete information was fitted. Median follow-up was 17 months (range: 2-225 months). Univariate analysis showed a better prognosis in pT1-2, pN0, diameter <30 mm, or grade 1 tumors and in patients undergoing R0 resection, distal pancreatectomy, or adjuvant chemotherapy and with lower CA19-9 levels. Five-year OS, LC, and DMFS were as follows: CA19-9 <5.0: 5.7%, 47.2%, 17.0%; CA19-9 5.1-37.0: 37.9%, 63.3%, 46.0%; CA19-9 37.1-100.0: 27.1%, 59.4%, 39.0%; CA19-9 100.1-353.0: 17.4%, 43.4%, 26.7%; CA19-9 >353.1: 10.9%, 50.2%, and 23.4%, respectively. At multivariate analysis, CA19-9 >100 and <353 level (P=.002), CA19-9 ≥353.1 (P<.001) level, G3 tumor (P=.002), and tumor diameter >30 mm (P<.001) correlated with worse OS. Patients treated with postoperative chemoradiation doses >50.0 Gy showed improved OS (P<.001). Presurgical CA19-9 predicts both OS and pattern of failure. Therefore, CA19-9 should be included in predictive models in order to customize treatments based on prognostic factors. Moreover, future studies should stratify patients according to presurgical CA19-9 level.


Walking casts: effect on plantar foot pressures.
Pressure measurements were made at four sites on the right foot of six normal subjects while they walked in a standard shoe, conventional padded cast, total contact cast, and again in a shoe. No differences in mean relative pressure were found between the padded cast and the total-contact cast. Significant reductions in mean relative pressure were found between the standard shoe and walking casts at the first and third metatarsal head. This study supported the use of walking casts in the management of plantar ulcers. The effectiveness of the cast in reducing plantar pressure was not found to be dependent on the cast padding technique.


Cell-mediated lympholysis. Importance of serologically defined H-2 regions.
The cell-mediated lympholytic capability of mouse spleen cells stimulated in mixed lymphocyte culture is related to the major histocompatibility complex genotype on target lymphocytes. The strain combinations AQR-B10. T(6R) and B10.A(4R)-B10.A(2R) that result in significant mixed lymphocyte culture activation do not mediate cell-mediated lympholysis on sensitizing target lymphocytes; serologically defined regions (H-2K and H-2D) are identical within each combination. H-2K or H-2D region disparity alone does not cause cell-mediated lympholysis. However after mixed lymphocyte culture activation as seen with B10.A-B10.T(6R), a target cell bearing only an H-2K region difference from the effector cell is sensitive to cell-mediated lympholysis. Likewise an H-2D region difference is an adequate target after mixed lymphocyte culture activation of the effector cell in the combination B10.A(2R)-B10.D2.


[Tuberculosis and its control--lessons from the past and future prospect].
Koch R reported the discovery of tubercle bacilli on March 24, 1882, and the numbers of death from phthisis were collected in the vital statistics from the latter half of 1883 in Japan. Tuberculosis death was officially adopted in the Japanese vital statistics from 1899, and there was certain disagreement existed between the numbers of death from TB and phthisis in 1899, the analysis on the trend of TB in Japan was done based on TB death. Trend of TB in Japan in the past 100 years could be divided into five phases. In phase 1 (1899-1918), TB mortality had increased with the first industrialization of Japan with main focus on the weaving industry. During this period, TB mortality of female was higher than that of male and then major victims of TB were young girls born from 1890 to 1925. In phase 2 (1918-1930), TB mortality decreased through excess death of TB cases by the influenza pandemic in 1918. This decline due to influenza pandemic was seen all over the world, and in the European countries and the U.S., the decline continued up to 1945 while in Japan, TB had increased again in the phase 3 (1930-1945) mainly due to second industrialization with main focus on heavy industry and the impact of quasi-war and war conditions. In phase 4 (1945-mid 1970s), TB started to decline fast due to the excess death of TB cases during the World War II and then, the application of modern TB control started from early 1950s. In phase 5 (from mid 1970s until now), decline of TB has showed down. Increase or slowdown of TB decline was seen nearly all countries of the world, however, its causes were different from country to country. In case of Japan, slowdown was caused by the rapid ageing of the population, in developing countries mainly by the impact of HIV epidemic and in industrialized countries, mainly by the migration of the population and partly by the HIV epidemic. Contribution of phthisiology in Japan to the global progress of phthisiology could be summarized as follows: elucidation of the pathogenesis of TB when TB was highly prevalent in Japan by high incidence of TB from primarily infected youth, the development of mass screening for TB using radiophotography technique developed in Japan, completion of the interpretation method of chest X-ray findings, first success in the mass production of freeze-dried BCG vaccine in the world, the first implementation of the TB prevalence survey using random sampling method in 1953, and the development of a new drug for TB, kanamycin. Phthisiology also contributed to the progress of international health. As the objective index to measure the magnitude of TB problem, the concept of annual risk of TB infection (ARTI) was introduced by Sutherland and Styblo, and by using ARTI, the epidemiological situation of TB could be divided into 3 categories; high prevalence country with ARTI above 1%, low prevalence country below 0.05-0.1%, and middle prevalence country inbetween. To reduce the burden of TB in high prevalence countries, so-called DOTS strategy of TB control was introduced and has been applied in most developing countries, and the gap between high and low prevalence countries has reduced in the past decade. Cooperation in global TB control has also been done actively from the government and NGOs of industrialized countries under the strong leadership of WHO. For the success of TB control, the transmission of tubercle bacilli in a community should be cut either infection, onset of TB or the progress of TB. Prevention of TB infection could be achieved by the early detection of TB cases and their cure by the treatment. To encourage early visit to doctors for those with symptoms suggesting TB and adequate examinations at medical institutions for these persons would be a major tool of early detection of TB cases in Japan in the future. In addition, there is no doubt to intensify contacts examinations and source investigations. It is hoped to elucidate recent pathogenesis of TB by applying new technologies such as QFT and RFLP. Prevention of onset of TB will be focused on the preventive use of TB drugs, however, development of new vaccine better than BCG is also encouraged for the developing countries where the risk of TB infection is remained high. TB is now a curable disease, and the duration of treatment has been shortened to 6 months. If new more potent TB drugs were developed, and the total duration of treatment could be shortened, the global TB control could be done much more easily, and also most MDRTB cases could be cured. Otsuka Pharmaceutical Company is now developing a new potent drug which has no cross resistance with existing TB drugs. This new drug is now on the clinical trial phase II, and it is hoped that Japan can make another great contribution to the global TB control. It is my sincere wish that the government continues to assist the research to develop new TB drugs and new technologies used in TB control, and in future, if it is needed to change the current policy of TB control, a new policy should be tried in a pilot area before its introduction on national level. The Japanese Society for TB is a key organization in developing further research and the training of new personnel engaging in TB research and control, and I sincerely hope further development of the Society.


Clinical characterization of colitis arising from anti-PD-1 based therapy.
Colitis is a frequent, clinically-significant immune-related adverse event caused by anti-programmed death-1 (PD-1). The clinical features, timing, and management of colitis with anti-PD-1-based regimens are not well-characterized. Patients with advanced melanoma that received either anti-PD-1 monotherapy ("monotherapy") or combined with ipilimumab ("combination therapy") were screened from 8 academic medical centers, to identify those with clinically-relevant colitis (colitis requiring systemic steroids). Of 1261 patients who received anti-PD-1-based therapy, 109 experienced colitis. The incidence was 3.2% (30/937) and 24.4% (79/324) in the monotherapy and combination therapy cohorts, respectively. Patients with colitis from combination therapy had significantly earlier symptom onset (7.2 weeks vs 25.4 weeks, p < 0.0001), received higher steroid doses (median prednisone equivalent 1.5 mg/kg vs 1.0 mg/kg, p = 0.0015) and experienced longer steroid tapers (median 6.0 vs 4.0 weeks, p = 0.0065) compared to monotherapy. Infliximab use and steroid-dose escalation occurred more frequently in the combination therapy cohort compared to monotherapy. Nearly all patients had resolution of their symptoms although one patient died from complications. Anti-PD-1 associated colitis has a variable clinical presentation, and is more frequent and severe when associated with combination therapy. This variability in checkpoint-inhibitor associated colitis suggests that further optimization of treatment algorithms is needed.


The effect of physician-nurse substitution in primary care in chronic diseases: a systematic review.
Chronically ill and ageing populations demand increasing human resources who can provide on-going and frequent follow-up care. We performed a systematic review to assess the effect of physician-nurse substitution on process care outcomes. We searched OVID Medline, Embase, CINAHL and The Cochrane Library for all available dates up to August 2012 and updated in February 2014. We selected and critically appraised published randomised controlled trials (RCT) and followed the PRISMA guidelines for the reporting of systematic reviews. A total of 14 RCTs comprising 10,743 participants met the inclusion criteria. Studies were generally small and suffered from attrition of ≥20% and selection biases. There were 53 process measurements investigated in the 14 RCTs, many of which were unique to specific conditions. Accounts of nurses' roles, responsibilities, tasks, qualifications and training content/components were not described in sufficient detail. Most study estimates showed no significant differences between nurse-led care and physician-led care while less than a half (~40%) favoured nurse-led care. Despite the methodological limitations and the varying nurses' roles and competencies across studies, specially trained nurses can provide care that is at least as equivalent to care provided by physicians for the management of chronic diseases, in terms of process of care. Future, larger studies with better quality methods are needed and should report and assess whether the differences in effects vary due to diversity in roles, qualifications, training competencies and characteristics of clinicians delivering substitution of care.


Successful Pregnancy after Treatment with Chinese Herbal Medicine in a 43-Year-Old Woman with Diminished Ovarian Reserve and Multiple Uterus Fibrosis: A Case Report.
To highlight a natural approach to coexisting oligomenorrhea, subfertility, luteal phase insufficiency and multiple fibroids cohesively when in vitro fertilisation (IVF) has failed. A 43-year-old woman with diminished ovarian reserve and multiple uterine fibroids had previously been advised to discontinue IVF treatment. According to Chinese Medicine diagnosis, herbal formulae were prescribed for improving age-related ovarian insufficiency as well as to control the growth of fibroids. After 4 months of treatment, the patient's menstrual cycle became regula r and plasma progesterone one week after ovulation increased from 10.9 nmol/L to 44.9 nmol/L. After 6 months, she achieved a natural conception, resulting in a live birth of a healthy infant at an estimated gestational age of 40 weeks. The successful treatment with Chinese Herbal Medicine for this case highlights a natural therapy to manage infertility due to ovarian insufficiency and multiple fibroids after unsuccessful IVF outcome.


Pressure-driven phase transitions and reduction of dimensionality in 2D silicon nanosheets.
In-situ high-pressure synchrotron X-ray powder diffraction studies up to 21 GPa of CVD-grown silicon 2D-nanosheets establish that the structural phase transitions depend on size and shape. For sizes between 9.3(7) nm and 15.2(8) nm we observe an irreversible phase transition sequence from I (cubic) → II (tetragonal) → V (hexagonal) during pressure increase and during decompression below 8 GPa the emergence of an X-ray amorphous phase. High-angle annular dark field scanning transmission electron microscopy (HAADF-STEM) and atomic force microscopy (AFM) images of this X-ray amorphous phase reveal the formation of significant numbers of 1D nanowires with aspect ratios > 10, which are twinned and grow along the <111> direction. We discovered a reduction of dimensionality under pressure from a 2D morphology to a 1D wire in a material with a diamond structure. MD simulations indicate the reduction of thermal conductivity in such nanowires.


Efficacy of Ferric carboxymaltose in heart failure with iron deficiency: an individual patient data meta-analysis.
Whereas a beneficial effect of intravenous ferric carboxymaltose (FCM) on symptoms and exercise capacity among patients with iron deficiency (ID) and heart failure (HF) has been consistently demonstrated, the effects of treatment on clinical events remain the subject of research. This meta-analysis aimed to characterize the effects of FCM therapy on hospitalizations and mortality. Patient-level data from randomized, placebo-controlled FCM trials including adults with HF and ID with ≥52 weeks follow-up were analysed. The co-primary efficacy endpoints were (1) composite of total/recurrent cardiovascular hospitalizations and cardiovascular death, and (2) composite of total HF hospitalizations and cardiovascular death, through 52 weeks. Key secondary endpoints included individual composite endpoint components. Event rates were analysed using a negative binomial model. Treatment-emergent adverse events were also examined. Three FCM trials with a total of 4501 patients were included. FCM was associated with a significantly reduced risk of co-primary endpoint 1 (rate ratio [RR] 0.86; 95% confidence interval [CI] 0.75-0.98; P=0.029; Cochran Q: 0.008), with a trend towards a reduction of co-primary endpoint 2 (RR 0.87; 95% CI 0.75-1.01; P=0.076; Cochran Q: 0.024). Treatment effects appeared to result from reduced hospitalization rates, not improved survival. Treatment appeared to have a good safety profile and was well-tolerated. In iron-deficient patients with HF with reduced left ventricular ejection fraction, intravenous FCM was associated with significantly reduced risk of hospital admissions for HF and cardiovascular causes, with no apparent effect on mortality.


Physiological synaptic interactions mediated by potassium ions.
We present experiments indicating that specific and efficient interactions among neurons can be mediated by the increase in extracellular potassium ion concentration as a consequence of a single action potential in one neuron. Intracellular recording and stimulation from adjacent giant interneurons (GIN) of the cockroach Periplaneta americana reveals reciprocal synaptic interactions at the level of the metathoracic ganglion (T3). The reciprocal synaptic interaction (GGSP) is characterized by: a short synaptic delay (1 ms), fast rise time (1-1.5 ms), an amplitude of 5-8 mV and a long decay time (60-100 ms). The GGSP is not blocked by the addition of 5 mM cobalt ions and is insensitive to trans membrane voltage. The possibility that the GGSP is mediated by an electrotonic synapse was ruled out by experiments which showed that no direct current spread takes place between adjacent giant axons. Intracellular injection of TEA caused prolongation of the action potential of the injected fiber. The rate of rise and amplitude of the GGSP in the second fiber was significantly reduced. These results are consistent with the interpretation that the GGSP is mediated by the accumulation of potassium ions in the extracellular space. Serial cross sections for electron microscope reveal that the plasma membrane of adjacent GINS comes into close proximity (7-10 nm). These regions may serve as the site for the potassium mediated interactions.


Continuous recordings of brain regional circulation during sleep/wake state transitions in rats.
Continuous measurement of regional blood flow (RBF) in the brain of a freely behaving rat was attained by a combination of laser-Doppler (LD) flowmetry and our originally devised apparatus, which had been developed for the automatic releasing of the twisting of lines connected between experimental apparatus and the freely behaving animal. RBF changes were studied in a ventral region of the rostral basal forebrain along with sleep-wake states. When compared with the RBF level during slow-wave sleep (SWS), levels of RBF during paradoxical sleep (PS) and wakefulness were higher by 24 (P = 0.0001) and 9% (P < 0.05), respectively. The LD signals suggested that the RBF elevation during PS was produced by dilation of both the large brain arteries and small vessels, whereas the elevation during wakefulness was caused by dilation of small vessels that was counteracted by contraction of large arteries. It was noticed that the original circulation tended to begin changing before the onset of SWS. A circadian rhythm was also demonstrated for the RBF, which largely decreased around the onset of the light period and returned to the high level before the beginning of the dark period. Thus continuous and real-time recordings of regional circulation were performed with satisfactorily precision in freely behaving rats.


miRNA-503 Promotes Tumor Progression and Is Associated with Early Recurrence and Poor Prognosis in Human Colorectal Cancer.
MicroRNA (miR)-503 is downregulated in several cancers and plays a tumor-suppressive role in carcinogenesis. However, the miR-503 expression pattern, its clinical significance and its molecular mechanism in colorectal cancer (CRC) have not been investigated. We analyzed miR-503 expression in normal mucosa (n = 20), adenoma (n = 27) and CRC (n = 20). We quantified miR-503 expression in an independent cohort (n = 191) and investigated the clinical significance of miR-503 in CRC. CRC cell lines were transfected with anti-miR-503 to assess its function and target gene. miR-503 expression increased according to the adenoma-carcinoma sequence. High miR-503 expression was significantly associated with large tumor size, serosal invasion, lymphatic and venous invasion as well as lymph node metastasis. CRC patients with high miR-503 expression had significantly earlier relapse and poorer prognosis than those with low expression. miR-503 was an independent recurrence marker in stage I/II CRC. In vitro, attenuated miR-503 expression resulted in inhibition of proliferation, invasion and migration and acquisition of anoikis of CRC cells. The putative target gene (calcium-sensing receptor) was significantly upregulated after miR-503 attenuation. miR-503 acts as an 'onco-miR' in CRC. High miR-503 expression is associated with early recurrence and poor prognosis in CRC.


The relationship between default mode network connectivity and social functioning in individuals at familial high-risk for schizophrenia.
Unaffected first-degree relatives of individuals with schizophrenia (i.e., those at familial high-risk [FHR]), demonstrate social dysfunction qualitatively similar though less severe than that of their affected relatives. These social difficulties may be the consequence of genetically conferred disruption to aspects of the default mode network (DMN), such as the dMPFC subsystem, which overlaps with the network of brain regions recruited during social cognitive processes. In the present study, we investigate this possibility, testing DMN connectivity and its relationship to social functioning in FHR using resting-state fMRI. Twenty FHR individuals and 17 controls underwent fMRI during a resting-state scan. Hypothesis-driven functional connectivity analyses examined ROI-to-ROI correlations between the DMN's hubs, and regions of the dMPFC subsystem and MTL subsystem. Connectivity values were examined in relationship to a measure of social functioning and empathy/perspective-taking. Results demonstrate that FHR exhibit reduced connectivity specifically within the dMPFC subsystem of the DMN. Certain ROI-to-ROI correlations predicted aspects of social functioning and empathy/perspective-taking across all participants. Together, the data indicate that disruption to the dMPFC subsystem of the DMN may be associated with familial risk for schizophrenia, and that these intrinsic connections may carry measurable consequences for social functioning.


Fast parallelized sampling of Bayesian regression models for whole-genome prediction.
Bayesian regression models are widely used in genomic prediction, where the effects of all markers are estimated simultaneously by combining the information from the phenotypic data with priors for the marker effects and other parameters such as variance components or membership probabilities. Inferences from most Bayesian regression models are based on Markov chain Monte Carlo methods, where statistics are computed from a Markov chain constructed to have a stationary distribution that is equal to the posterior distribution of the unknown parameters. In practice, chains of tens of thousands steps are typically used in whole-genome Bayesian analyses, which is computationally intensive. In this paper, we propose a fast parallelized algorithm for Bayesian regression models called independent intensive Bayesian regression models (BayesXII, "X" stands for Bayesian alphabet methods and "II" stands for "parallel") and show how the sampling of each marker effect can be made independent of samples for other marker effects within each step of the chain. This is done by augmenting the marker covariate matrix by adding p (the number of markers) new rows such that columns of the augmented marker covariate matrix are orthogonal. Ideally, the computations at each step of the MCMC chain can be accelerated by k times, where k is the number of computer processors, up to p times, where p is the number of markers. We demonstrate the BayesXII algorithm using the prior for BayesC[Formula: see text], a Bayesian variable selection regression method, which is applied to simulated data with 50,000 individuals and a medium-density marker panel ([Formula: see text] 50,000 markers). To reach about the same accuracy as the conventional samplers for BayesC[Formula: see text] required less than 30 min using the BayesXII algorithm on 24 nodes (computer used as a server) with 24 cores on each node. In this case, the BayesXII algorithm required one tenth of the computation time of conventional samplers for BayesC[Formula: see text]. Addressing the heavy computational burden associated with Bayesian methods by parallel computing will lead to greater use of these methods.


Respective role of antithrombin III and heparin cofactor II in the in vitro anticoagulant effect of heparin and of various sulphated polysaccharides.
The in vitro anticoagulant effects of standard heparin (SH) and of seven other sulphated polysaccharides (SPS) were investigated by measuring activated partial thromboplastin time (APTT) prolongation of normal plasma and of plasmas selectively depleted of antithrombin III (AT III), of heparin cofactor II (HC II) and of both heparin cofactors. This allowed the determination of the relative contribution of each of the two heparin cofactors to the SPS anticoagulant effect. The SPS varied in their relative activities as catalysts of thrombin inhibition by purified AT III or HC II. The anticoagulant activities of heparin and dermatan sulphate were primarily attributable to their ability to enhance thrombin inhibition by AT III and HC II respectively. Heparin had an additional minor anticoagulant activity which was independent of both AT III and HC II. Pentosan polysulphate, high molecular weight dextran sulphate, heparin with low affinity for AT III and a sulphated heparin derivative had weaker anticoagulant activities in normal plasma than standard heparin. The anticoagulant activities of these last four SPS in plasma depleted of both AT III and HC II were similar to their respective activities in normal plasma. This suggests that these SPS act by directly preventing thrombin generation rather than by enhancing thrombin inhibition.


New insight into the potential energy landscape and relaxation pathways of photoexcited aniline from CASSCF and XMCQDPT2 electronic structure calculations.
There have been a number of recent experimental investigations of the nonadiabatic relaxation dynamics of aniline following excitation to the first three singlet excited states, 1(1)ππ*, 1(1)π3s/πσ* and 2(1)ππ*. Motivated by differences between the interpretations of experimental observations, we have employed CASSCF and XMCQDPT2 calculations to explore the potential energy landscape and relaxation pathways of photoexcited aniline. We find a new prefulvene-like MECI connecting the 1(1)ππ* state with the GS in which the carbon-atom carrying the amino group is distorted out-of-plane. This suggests that excitation above the 1(1)π3s/πσ* vertical excitation energy could be followed by electronic relaxation from the 1(1)ππ* state to the ground-electronic state through this MECI. We find a MECI connecting the 1(1)π3s/πσ* and 1(1)ππ* states close to the local minimum on 1(1)π3s/πσ* which suggests that photoexcitation to the 1(1)π3s/πσ* state could be followed by relaxation to the 1(1)ππ* state and to the dissociative component of the 1(1)π3s/πσ* state. We also find evidence for a new pathway from the 2(1)ππ* state to the ground electronic state that is likely to pass through a three-state conical intersection involving the 2(1)ππ*, 1(1)π3s/πσ* and 1(1)ππ* states.


Systematic review and meta-analysis of the impact of deviations from a clinical pathway on outcomes following pancreatoduodenectomy.
Enhanced recovery after surgery is steadily gaining importance in patients undergoing pancreatic surgery, including pancreatoduodenectomy (PD). While clinical pathways targeting enhanced-recovery can achieve their intended outcome in reducing length of stay, compliance to these pathways, and their relevance is poorly understood. The aim of this systematic review was to assess the impact of deviations from/non-compliance to a clinical pathway on post-PD outcomes. To assess the impact of deviations from/non-compliance to a clinical pathway on post-PD outcomes. A systematic review of major reference databases was undertaken, according to preferred reporting items for systematic reviews and meta-analysis guidelines, between January 2000 and November 2020 relating to compliance with clinical pathways and its impact on outcomes in patients undergoing PD. A meta-analysis was performed using fixed-effects or random-effects models. Eleven studies including 1852 patients were identified. Median overall compliance to all components of the clinical pathway was 65.7% [interquartile range (IQR): 62.7%-72.3%] with median compliance to post-operative parameters of the clinical pathway being 44% (IQR: 34.5%-52.25%). Meta-analysis using a fixed-effects model showed that ≥ 50% compliance to a clinical pathway predicted significantly fewer post-operative complications [pooled odds ratio (OR): 9.46, 95% confidence interval (CI): 5.00-17.90; P < 0.00001] and a significantly shorter length of hospital stay [pooled mean difference (MD): 4.32, 95%CI: -3.88 to -4.75; P < 0.0001]. At 100% compliance which was associated with significantly fewer post-operative complications (pooled OR: 11.25, 95%CI: 4.71-26.84; P < 0.00001) and shorter hospital stay (pooled MD of 4.66, 95%CI: 2.81-6.51; P < 0.00001). Compliance to post-PD clinical pathways remains low. Deviations are associated with an increased risk of complications and length of hospital stay. Under-standing the relevance of deviations to clinical pathways post-PD presents pancreatic surgeons with opportunities to actively pursue an enhanced-recovery of their patients.


Peptidoglycan editing in non-proliferating intracellular Salmonella as source of interference with immune signaling.
Salmonella enterica causes intracellular infections that can be limited to the intestine or spread to deeper tissues. In most cases, intracellular bacteria show moderate growth. How these bacteria face host defenses that recognize peptidoglycan, is poorly understood. Here, we report a high-resolution structural analysis of the minute amounts of peptidoglycan purified from S. enterica serovar Typhimurium (S. Typhimurium) infecting fibroblasts, a cell type in which this pathogen undergoes moderate growth and persists for days intracellularly. The peptidoglycan of these non-proliferating bacteria contains atypical crosslinked muropeptides with stem peptides trimmed at the L-alanine-D-glutamic acid-(γ) or D-glutamic acid-(γ)-meso-diaminopimelic acid motifs, both sensed by intracellular immune receptors. This peptidoglycan has a reduced glycan chain average length and ~30% increase in the L,D-crosslink, a type of bridge shared by all the atypical crosslinked muropeptides identified. The L,D-transpeptidases LdtD (YcbB) and LdtE (YnhG) are responsible for the formation of these L,D-bridges in the peptidoglycan of intracellular bacteria. We also identified in a fraction of muropeptides an unprecedented modification in the peptidoglycan of intracellular S. Typhimurium consisting of the amino alcohol alaninol replacing the terminal (fourth) D-alanine. Alaninol was still detectable in the peptidoglycan of a double mutant lacking LdtD and LdtE, thereby ruling out the contribution of these enzymes to this chemical modification. Remarkably, all multiple mutants tested lacking candidate enzymes that either trim stem peptides or form the L,D-bridges retain the capacity to modify the terminal D-alanine to alaninol and all attenuate NF-κB nuclear translocation. These data inferred a potential role of alaninol-containing muropeptides in attenuating pro-inflammatory signaling, which was confirmed with a synthetic tetrapeptide bearing such amino alcohol. We suggest that the modification of D-alanine to alaninol in the peptidoglycan of non-proliferating intracellular S. Typhimurium is an editing process exploited by this pathogen to evade immune recognition inside host cells.


Downscaling climate information for local disease mapping.
The study of the impacts of climate on human health requires the interdisciplinary efforts of health professionals, climatologists, biologists, and social scientists to analyze the relationships among physical, biological, ecological, and social systems. As the disease dynamics respond to variations in regional and local climate, climate variability affects every region of the world and the diseases are not necessarily limited to specific regions, so that vectors may become endemic in other regions. Climate data at local level are thus essential to evaluate the dynamics of vector-borne disease through health-climate models and most of the times the climatological databases are not adequate. Climate data at high spatial resolution can be derived by statistical downscaling using historical observations but the method is limited by the availability of historical data at local level. Since the 90s', the statistical interpolation of climate data has been an important priority of the Agrometeorology Group of the Food and Agriculture Organization of the United Nations (FAO), as they are required for agricultural planning and operational activities at the local level. Since 1995, date of the first FAO spatial interpolation software for climate data, more advanced applications have been developed such as SEDI (Satellite Enhanced Data Interpolation) for the downscaling of climate data, LOCCLIM (Local Climate Estimator) and the NEW_LOCCLIM in collaboration with the Deutscher Wetterdienst (German Weather Service) to estimate climatic conditions at locations for which no observations are available. In parallel, an important effort has been made to improve the FAO climate database including at present more than 30,000 stations worldwide and expanding the database from developing countries coverage to global coverage.


Base of skull internal carotid and internal jugular gunshot wounds treated conservatively: inadequate treatment, or was well enough left alone?
Zone three carotid injuries present problems of access in emergency situations. Not only are the methods time consuming, but they also put certain structures in the neck at risk. A patient was treated at this institution with a large calibre gunshot injury of the right internal carotid and internal jugular vein. He was neurologically intact and his bleeding had been completely controlled. A decision was made to treat him conservatively and he recovered uneventfully with no neurological deficit and no further bleeding. Emergency exposure of the distal carotid artery involves dislocating the mandible, putting the facial nerve and parotid gland at risk of injury. Base of skull carotid injuries are best treated expectantly if there is no active bleeding or progressive neurological impairment. Careful follow-up is required to diagnose and treat carotid-jugular fistulas, false aneurysms and stenoses early.


Clinical pathology reference ranges of laboratory animals. Working Group II, Nonclinical Safety Evaluation Subcommittee of the Japan Pharmaceutical Manufacturers Association.
We analyzed historical control data of clinical pathology testings provided by sixty-seven member companies of the Japan Pharmaceutical Manufacturers Association covering study populations of approximately 7,000 rats/sex, 5,000 dogs/sex, and 700 monkeys/sex. This paper assesses the relationship between conditions of sample collection, methods of measurement, etc. and potential factors contributing to variations in reference data, based on weighted means and standard deviations thereof derived from data for rats, dogs and monkeys for those parameters measured using methods most common to the participating facilities. Parameters included erythrocyte count (RBC), hematocrit (Ht), hemoglobin concentration(Hb), reticulocyte count (Rt), platelet count, total leukocyte count (WBC), differential leukocyte count (%WBC), coagulation time (activated partial thromboplastin time: APTT, prothrombin time: PT), and serum/plasma levels of GOT, GPT, ALP, LDH, glucose, cholesterol, triglycerides (TG), total protein, albumin, urea nitrogen (UN), creatinine, sodium (Na), potassium (K), calcium (Ca), chloride (Cl), inorganic phosphorus (Ip), and CPK. Analyses of the data revealed species differences in RBC, Ht, Rt, platelet count, WBC, %WBC, ALP, LDH, glucose, cholesterol, TG, total protein, UN, creatinine, Ca, Ip, and CPK. There were strain differences in rats in platelet count, WBC, GOT, ALP, UN, creatinine, and CPK. Sex differences were noted for Hb, Ht, WBC, ALP, glucose, cholesterol, TG, total protein, A/G ratio, UN, and Ip. Age differences were observed with RBC, Hb, Ht, Rt, %WBC, GOT, GPT, ALP, LDH, cholesterol, TG total protein, Ip, and CPK. APTT, PT, ALP, glucose, TG and UN were found to be subject to the influence of fasting/feeding. In rats, Ht, WBC, CPK and K showed differences by the site of bleeding. Observed values for LDH and CPK varied with specimen type, plasma or serum; serum assay values showed greater variation than plasma values.


The syrphids of Serra do Courel, Northern Spain and description of a new Cheilosia Meigen species (Diptera: Syrphidae).
The syrphids (Syrphidae) of Serra do Courel, a mountainous locality of just over 20,000ha at the west end of the Cantabrian Mountains, northern Spain are poorly known. The Scottish based, Malloch Society visited the locality in May 2012 and collected a total of 462 specimens of 98 syrphid species and 36 genera. These represent the first syrphid records from Serra do Courel. The area has many meadows and small woodlands or 'soutos' and these habitats combined were the most productive, 69 spp. recorded. Cheilosia lucense Ricarte sp. nov. is described from Courel and compared with other species of the alpina group. Six other syrphid species were new to the Iberian Peninsula, three of which belong to the saproxylic genus, Brachyopa. In common with studies elsewhere in the Cantabrian Mountains, Cheilosia was the most diverse genus and 21 species were recorded. The syrphid fauna of the Cantabrian Mountains includes 203 species of which 24 are here added and a species checklist provided.


Association of a Simulated Institutional Gender Equity Initiative With Gender-Based Disparities in Medical School Faculty Salaries and Promotions.
Despite progress in narrowing gender-based salary gaps, notable disparities persist in the scientific community. The significance of pay difference may be underestimated, with little data evaluating its effect on lifetime wealth after accounting for factors like time to promotion and savings. To characterize gender disparities in salary and assess the outcomes associated with a gender equity initiative (GEI). Quality improvement study with simulations of salary and additional accumulated wealth (AAW) using retrospectively reviewed Johns Hopkins University School of Medicine annual salary and promotion data. All academic faculty were included in the faculty salary analysis from 2005 (n = 1481) and 2016 (n = 1885). Salary and longitudinal promotion data from 2005 to 2016 were used to estimate gender-based differences in salary and time to promotion. The effect of these differences on total salary and AAW, including retirement and salary-based investments, was simulated for a representative male and female faculty member over a 30-year career in 3 scenarios: (1) pre-GEI, (2) post-GEI, and (3) in real time for GEI, beginning with and progressing through these initiatives. Analyses of salaries of 1481 faculty (432 women) in 2005 and 1885 faculty (742 women) in 2016 revealed that a decade after GEI implementation, the overall mean (SE) salary gap by gender decreased from -2.6% (1.2%) (95% CI, -5.6% to -0.3%) to -1.9% (1.1%) (95% CI, -4.1% to 0.3%). Simulation of pre-GEI disparities correlated with male faculty collecting an average lifetime AAW of $501 416 more than the equivalent woman, with disparities persisting past retirement. The AAW gap decreased to $210 829 in the real-time GEI simulation and to $66 104 using post-GEI conditions, reflecting success of GEI efforts. Even small gender-based salary gaps are associated with substantial differences in lifetime wealth, but an institutional commitment to achieving equitable promotion and compensation for women can appreciably reduce these disparities. The findings of this study support broad implementation of similar initiatives without delay, as results may take more than a decade to emerge. A modifiable version of the simulation is provided so that external users may assess the potential disparities present within their own institutions.


Correlation between Mechanical Properties and Collagen Degeneration in Fibrous Tissue.
Fibrosis is a disease that causes abnormal accumulation of collagen and other extracellular matrix components. It can lead to organ failure and is responsible for one-third of all deaths worldwide. However, there is no cure for this disease, and the development of minimally invasive therapies is urgently needed. We have previously reported techniques for adjusting the shape and flexibility of fibrous tissue by traction while denaturing it with heat. However, studies comparing heat and traction on fibrous tissue are limited, so this paper examined that. Applying heat and traction to bovine Achilles tendon tissue has been shown to cause the denaturation of collagen molecules to accumulate in the tissue in response to these loads. Heat-induced collagen denaturation was nondirectional and omnidirectional, whereas mechanical stress-induced collagen denaturation was concentrated in the direction of traction. When both heat and traction were applied, collagen denaturation increased more than under a single load, indicating a synergistic effect.


Therapeutic education in atopic dermatitis: A position paper from the International Eczema Council.
Atopic dermatitis (AD) is a chronic, inflammatory skin disease that affects as many as 12.5% of children aged 0-17 years and 3% of the adult population. In the United States, 31.6 million children and adults are estimated to be living with AD. Therapeutic patient education (TPE) has proven its value in the management of chronic diseases for which adherence to therapy is suboptimal. This article explores experts' opinions and treatment practices to determine if TPE is a recommended and effective method for treating AD. Forty-two (51%) of 82 Councilors and Associates of the International Eczema Council (IEC), an international group with expertise in AD, responded to an electronic survey on TPE and AD. Most respondents (97.5%) agreed that TPE should play an important role in the management of AD. Many respondents (82.9%) believed that all patients with AD, regardless of disease severity, could benefit from TPE. The International Eczema Council survey lacks specific information on AD severity. Publications have shown the positive effect of TPE on the course of the disease, the prevention of complications, and the autonomy and quality of patient life. Survey respondents agreed that TPE can improve the quality of patient care and patient satisfaction with care.


A cellular coevolutionary algorithm for image segmentation.
Clustering is inherently a difficult problem, both with respect to the definition of adequate models as well as to the optimization of the models. We present a model for the cluster problem that does not need knowledge about the number of clusters a priori. This property is among others useful in the image segmentation domain, which we especially address. Further, we propose a cellular coevolutionary algorithm for the optimization of the model. Within this scheme multiple agents are placed in a regular two-dimensional (2-D) grid representing the image, which imposes neighboring relations on them. The agents cooperatively consider pixel migration from one agent to the other in order to improve the homogeneity of the ensemble of the image regions they represent. If the union of the regions of neighboring agents is homogeneous then the agents form alliances. On the other hand, if an agent discovers a deviant subject, it isolates the subject. In the experiments we show the effectiveness of the proposed method and compare it to other segmentation algorithms. The efficiency can easily be improved by exploiting the intrinsic parallelism of the proposed method.


A Modulated Wideband Converter Model Based on Linear Algebra and Its Application to Fast Calibration.
In the context of cognitive radio, smart cities and Internet-of-Things, the need for advanced radio spectrum monitoring becomes crucial. However, surveillance of a wide frequency band without using extremely expensive high sampling rate devices is a challenging task. The recent development of compressed sampling approaches offers a promising solution to these problems. In this context, the Modulated Wideband Converter (MWC), a blind sub-Nyquist sampling system, is probably the most realistic approach and was successfully validated in real-world conditions. The MWC can be realized with existing analog components, and there exist calibration methods that are able to integrate the imperfections of the mixers, filters and ADCs, hence allowing its use in the real world. The MWC underlying model is based on signal processing concepts such as filtering, modulation, Fourier series decomposition, oversampling and undersampling, spectrum aliasing, and so on, as well as in-flow data processing. In this paper, we develop an MWC model that is entirely based on linear algebra, matrix theory and block processing. We show that this approach has many interests: straightforward translation of mathematical equations into simple and efficient software programming, suppression of some constraints of the initial model, and providing a basis for the development of an extremely fast system calibration method. With a typical MWC acquisition device, we obtained a speed-up of the calibration computation time by a factor greater than 20 compared with a previous implementation.


Impact of a pedometer program on nurses working in a health-promoting hospital.
The aim of this research was to describe the impact of a pedometer-based activity program on a subset of nurses in a university-affiliated, multisite health care center in Canada. This study used a longitudinal design with preintervention-postintervention (8 weeks) and follow-up (6 months). At baseline, 60 nurses participated; 51 (85%) remained for the postprogram assessment and 33 (55%) also completed the follow-up questionnaire. Data were collected through self-administered questionnaires (weight, height, fatigue, insomnia, stress and step data) and blood tests (total cholesterol and low-density lipoprotein and high-density lipoprotein cholesterol). At postprogram, participants reported 12 thinsp;912 steps on average per day. At follow-up, 79% of participants indicated that they maintained their physical activity after the pedometer program. A significant decrease in insomnia was evident in postprogram scores compared with baseline scores, and this decrease was maintained at follow-up. A significant decrease in minutes spent sitting per week was also observed from baseline to postprogram and also maintained at follow-up. Participants' stress and low-density lipoprotein cholesterol levels decreased from baseline to postprogram (marginally significant). Finally, their weight decreased from baseline to follow-up (marginally significant). The pedometer program generated some positive outcomes for nurses after 6 months.


Comparison of the stimulation of inositol phospholipid hydrolysis and of cyclic GMP formation by neurotensin, some of its analogs, and neuromedin N in neuroblastoma clone N1E-115.
Neurotensin, some of its analogs, and neuromedin N were examined for comparison of their potencies at stimulating inositol phospholipid hydrolysis and cyclic GMP synthesis in intact murine neuroblastoma cells (clone N1E-115). Neurotensin(8-13) and acetylneurotensin(8-13) had the highest potencies for the stimulation of the hydrolysis of inositol phospholipid, which were about three times as potent as neurotensin (EC50 = 0.9 nM). On the other hand, fragments of the amino-terminal portion of neurotensin, such as neurotensin(1-6), neurotensin(1-8) and neurotensin(1-11), showed no ability to stimulate this hydrolysis. Neuromedin N, which is similar in structure to neurotensin(8-13) and which has been demonstrated to stimulate cyclic GMP formation [J.A. Gilbert and E. Richelson, Eur. J. Pharmac. 129, 379 (1986)], had EC50 values of 2.5 and 4.5 nM for release of [3H]inositol phosphates and stimulation of cyclic [3H]GMP respectively. A strong correlation was obtained between the EC50 values for neurotensin and several analogs in the stimulation of the release of inositol phosphates and the EC50 values for these peptides in the stimulation of cyclic GMP formation in neuroblastoma clone N1E-115 cells under similar experimental conditions. Thus, these two different biochemical effects of neurotensin and its analogs appear to be mediated by the same receptor site, which may also have been the site of action of neuromedin N in these cells.


Intranasal adenovirus-vectored vaccine for induction of long-lasting humoral immunity-mediated broad protection against influenza in mice.
Influenza vaccines aimed at inducing antibody (Ab) responses against viral surface hemagglutinin (HA) and neuraminidase (NA) provide sterile immunity to infection with the same subtypes. Vaccines targeting viral conserved determinants shared by the influenza A viruses (IAV) offer heterosubtypic immunity (HSI), a broad protection against different subtypes. We proposed that vaccines targeting both HA and the conserved ectodomain of matrix protein 2 (M2e) would provide protection against infection with the same subtype and also HSI against other subtypes. We report here that single intranasal immunization with a recombinant adenovirus (rAd) vector encoding both HA of H5 virus and M2e (rAdH5/M2e) induced significant HA- and M2e-specific Ab responses, along with protection against heterosubtypic challenge in mice. The protection is superior compared to that induced by rAd vector encoding either HA (rAdH5), or M2e (rAdM2e). While protection against homotypic H5 virus is primarily mediated by virus-neutralizing Abs, the cross-protection is associated with Abs directed to conserved stalk HA and M2e that seem to have an additive effect. Consistently, adoptive transfer of antisera induced by rAdH5/M2e provided the best protection against heterosubtypic challenge compared to that provided by antisera derived from mice immunized with rAdH5 or rAdM2e. These results support the development of rAd-vectored vaccines encoding both H5 and M2e as universal vaccines against different IAV subtypes. Current licensed influenza vaccines provide protection limited to the infection with same virus strains; therefore, the composition of influenza vaccines has to be revised every year. We have developed a new universal influenza vaccine that is highly efficient in induction of long-lasting cross-protection against different influenza virus strains. The cross-protection is associated with a high level of vaccine-induced antibodies against the conserved stalk domain of influenza virus hemagglutinin and the ectodomain of matrix protein. The vaccine could be used to stimulate cross-protective antibodies for the prevention and treatment of influenza with immediate effect for individuals who fail to respond to or receive the vaccine in due time. The vaccine offers a new tool to control influenza outbreaks, including pandemics.


Increase of IFN-γ and TNF-α production in CD107a + NK-92 cells co-cultured with cervical cancer cell lines pre-treated with the HO-1 inhibitor.
Natural killer (NK) cells eliminate virus-infected and tumor cells through the release of perforins and granzymes; they also produce Interferon gamma (IFN-γ) and Tumor necrosis factor alpha (TNF-α), which induce apoptosis in target cells. Many tumors express Heme oxygenase 1 (HO-1), and this expression has been associated with avoiding immunosuppression and apoptosis. In this work, HO-1+ Cervical cancer cell (CCC) lines were pre-treated with HO-1 inhibitor and we assessed whether this inhibition enhanced the sensitivity of CCC to NK cell activity. We assessed the expression of HO-1 in HeLa, SiHa, and C-33A CCC by Flow cytometry (FC). CCC were pre-treated with SnPP or ZnPP HO-1 inhibitors. After that, NK-92 cells were co-cultured with HeLa, SiHa, and C-33A CCC pre-treated or not with HO-1 inhibitors, and the expression of IFN-γ, TNF-α, CD107a, Granzyme B, NKp44, NKp46, NKp30, and NKG2D was evaluated by FC. CCC lines HeLa, SiHa, and C-33A expressed HO-1. Inhibition of HO-1 in these cells increased the expression of IFN-γ and TNF-α in CD107a + NK-92 cells. We observed a reduction in the expression of NKG2D, NKp46, and NKp30 in NK cells co-cultured with HeLa and SiHa cells, and when HeLa and SiHa cells were pre-treated with the HO-1 inhibitors, the expression of NKG2D and NKp30 in NK cells was restored. We observed a similar effect in NK cells co-cultured with C-33A cells in NKp30 expression. Inhibition of HO-1 in CCC induces an increase in IFN-γ and TNF-α production in CD107a + NK-92 cells and restores NKG2D, NKp46 and NKp30 downmodulation in NK cells.