Understanding the clinical handoff perspective of pediatric emergency nurses.
In 2007, The Joint Commission began requiring health care organizations to develop and implement a standardized approach to clinical handoff. The goal is to improve patient safety across the health care continuum. While accurate and complete handoff communication is essential in all areas of patient care, it is of critical importance where patients require the most complex care, such as in the emergency department. This quality improvement study used a focus group to begin to understand the clinical handoff perspective of pediatric emergency nurses. Eight nurses of varying levels of practice who work a variety of shifts participated to explore the clinical handoff process in the emergency department of a pediatric teaching hospital. Perceptions and beliefs regarding the process of clinical handoff (who is involved, what variations exist, where they occur) and barriers to the clinical handoff process were explored. Recurring themes included provider-directed handoff, interruptions--impediment to care, and envisioning the ideal process.


Differences in kinetic properties of phospho and dephospho forms of fructose-6-phosphate, 2-kinase and fructose 2,6-bisphosphatase.
Fructose-6-P,2-kinase:fructose 2,6-bisphosphatase has been purified to homogeneity. The ratio of the activities of fructose-6-P,2-kinase to fructose 2,6-bisphosphatase is 1.2. The enzyme ("native") contains 0.2 mol of phosphate/mol of subunit, and it is fully phosphorylated to 0.96 mol of phosphate/mol of subunit by cAMP-dependent protein kinase. Kinetic behavior of the native and phosphorylated forms of these enzymes was investigated. Both native and phosphofructose-6-P,2-kinase show sigmoidal kinetics with respect to fructose-6-P with an apparent K0.5 of 15 microM and 50 microM, respectively. The Hill coefficients are also increased from 1.3 to 2 by phosphorylation. The initial velocity patterns with respect to ATP follows Michaelis-Menten kinetics but the K0.5 of the phosphoenzyme (0.5 mM) is higher than that of the native enzyme (0.25 mM). The native fructose 2,6-bisphosphatase shows a biphasic saturation curve with respect to fructose-2,6-P2 which appears to be negatively cooperative. The phosphofructose 2,6-bisphosphatase, however, exhibits no cooperativity, and the apparent K0.5 for the substrate is 0.5 microM. Both forms of the phosphatase show the same Vmax. Based on these results possible allosteric regulation of fructose-6-P, 2-kinase and fructose 2,6-bisphosphatase in a reciprocal manner in vivo is discussed.


HTLV-1 intragenic viral enhancer influences immortalization phenotype in vitro, but is dispensable for persistence and disease development in animal models.
Human T-cell leukemia virus type 1 (HTLV-1) is the causative infectious agent of adult T-cell leukemia/lymphoma (ATL) and chronic neurological disease. The disparity between silenced sense transcription versus constitutively active antisense (Hbz) transcription from the integrated provirus is not fully understood. The presence of an internal viral enhancer has recently been discovered in the Tax gene near the 3' long terminal repeat (LTR) of HTLV-1. In vitro, this enhancer has been shown to bind SRF and ELK-1 host transcription factors, maintain chromatin openness and viral gene transcription, and induce aberrant host gene transcription near viral integration sites. However, the function of the viral enhancer in the context of early HTLV-1 infection events remains unknown. In this study, we generated a mutant Enhancer virus (mEnhancer) and evaluated its effects on HTLV-1-mediated in vitro immortalization, establishment of persistent infection with an in vivo rabbit model, and disease development in a humanized immune system (HIS) mouse model. The mEnhancer virus was able to establish persistent infection in rabbits, and there were no significant differences in proviral load or HTLV-1-specific antibody responses over a 25-week study. However, rabbits infected with the mEnhancer virus had significantly decreased sense and antisense viral gene expression at 12-weeks post-infection. HIS mice infected with wt or mEnhancer virus showed similar disease progression, proviral load, and viral gene expression. While mEnhancer virus was able to sufficiently immortalize primary T-lymphocytes in cell culture, the immortalized cells had an altered phenotype (CD8+ T-cells), decreased proviral load, decreased sense and anti-sense gene expression, and altered cell cycle progression compared to HTLV-1.wt immortalized cells (CD4+ T-cells). These results suggest that the HTLV-1 enhancer element alone does not determine persistence or disease development but plays a pivotal role in regulating viral gene expression.


Crosstalk control and limits of physiological c-Jun N-terminal kinase activity for cell viability and neurite stability in differentiated PC12 cells.
The c-Jun N-terminal kinases (JNKs) are important mediators of cell viability and structural integrity in postmitotic neurons, which is required for maintaining synaptic connections and neural plasticity. In the present study, we chose differentiated PC12 cells as a well-characterised neuronal model system to selectively examine the regulation of basal JNK activity by extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt. We detected a complex interaction between the kinases to prevent cell death and neurite loss. Especially the appropriate level of JNK activation determined cellular survival. Basal activity of ERK1/2 attenuated the potentiation of JNK phosphorylation and thereby the induction of apoptosis. Importantly, when JNK activity was too low, cell viability and the number of neurite-bearing cells also decreased, even though the activation of ERK1/2 was enhanced. In this case, the JNK-mediated survival signals via activating transcription factor-3 (ATF3) were inhibited. Furthermore, the phosphorylation of ERK1/2 induced by the JNK inhibitor SP600125 inhibited the basal activity of Akt, which normally supported cell viability. Thus, controlling JNK activity is crucial to promote survival and neurite stability of differentiated neuronal cells.


Positive and negative roles for soybean MPK6 in regulating defense responses.
It has been well established that MPK6 is a positive regulator of defense responses in model plants such as Arabidopsis and tobacco. However, the functional importance of soybean MPK6 in disease resistance has not been investigated. Here, we showed that silencing of GmMPK6 in soybean using virus-induced gene silencing mediated by Bean pod mottle virus (BPMV) caused stunted growth and spontaneous cell death on the leaves, a typical phenotype of activated defense responses. Consistent with this phenotype, expression of pathogenesis-related (PR) genes and the conjugated form of salicylic acid were significantly increased in GmMPK6-silenced plants. As expected, GmMPK6-silenced plants were more resistant to downy mildew and Soybean mosaic virus compared with vector control plants, indicating a negative role of GmMPK6 in disease resistance. Interestingly, overexpression of GmMPK6, either transiently in Nicotiana benthamiana or stably in Arabidopsis, resulted in hypersensitive response (HR)-like cell death. The HR-like cell death was accompanied by increased PR gene expression, suggesting that GmMPK6, like its counterpart in other plant species, also plays a positive role in cell death induction and defense response. Using bimolecular fluorescence complementation analysis, we determined that GmMKK4 might function upstream of GmMPK6 and GmMKK4 could interact with GmMPK6 independent of its phosphorylation status. Taken together, our results indicate that GmMPK6 functions as both repressor and activator in defense responses of soybean.


Polysaccharides from waste Zingiber mioga leaves: Ultrasonic-microwave-assisted extraction, characterization, antioxidant and anticoagulant potentials.
Zingiber mioga is a highly economic crop that is used to produce vegetables, spices and herbal pharmaceuticals. Its edible flower bud contributes most to the economic value, but the big leaves were discarded as agricultural waste, which urgently needs to be exploited. In this work, polysaccharides from waste Z. mioga leaves (PWZMLs) were extracted using ultrasonic-microwave-assisted extraction (UMAE). After purification and characterization, the antioxidation and anticoagulation of PWZMLs were evaluated to appraise the potential in cardiovascular protection. Under the liquid-solid ratio of 26: 1 mL/g, after ultrasonication at 495 W for 10 min, followed by microwaving at 490 W for 5 min, the yield of PWZMLs achieved to 6.22 ± 0.14 %, notably higher (P < 0.01) than other methods, and ultrasound contributed more to the yield than microwave. Various analyses confirmed that PWZMLs were negatively charged polysaccharides with galacturonic acid the dominant uronic acid. PWZMLs exerted excellent antioxidant capacity, especially for scavenging 1, 1-diphenyl-2-picrylhydrazyl radical. PWZMLs also elicited promising anticoagulant property, particularly for prolonging activated partial thromboplastin time and lowering fibrinogen, which were almost equivalent to heparin at the same concentration. PWZMLs contained two polysaccharide fractions (199.53 and 275.42 kDa) that could synergistically contribute to the pronounced antioxidant and anticoagulant activities. The PWZMLs extracted with optimized UMAE have great potential in cardiovascular protection.


Human extracellular vesicles and correlation with two clinical forms of toxoplasmosis.
This study analyzed microvesicles and exosomes, called as extracellular vesicles (EVs) excreted in serum and cerebrospinal fluid (CSF) from patients with cerebral or gestational toxoplasmosis. Clinical samples from 83 individuals were divided into four groups. Group I, 20 sera from healthy individuals and pregnant women (seronegative for toxoplasmosis); group II, 21 sera from seropositive patients for toxoplasmosis (cerebral or gestational forms); group III, 26 CSF samples from patients with cerebral toxoplasmosis/HIV co-infection (CT/HIV) (seropositive for toxoplasmosis); and group IV, 16 CSF samples from seronegative patients for toxoplasmosis, but with HIV infection and other opportunistic infections (OI/HIV). Serum and CSF samples were ultracentrifuged to recover EVs. Next, vesicle size and concentration were characterized by Nanoparticle Tracking Analysis (NTA). Concentrations of serum-derived EVs from toxoplasmosis patients (mean: 2.4 x 1010 EVs/mL) were statically higher than of non-infected individuals (mean: 5.9 x 109 EVs/mL). Concentrations of CSF-derived EVs were almost similar in both groups. CT/HIV (mean: 2.9 x 109 EVs/mL) and OI/HIV (mean: 4.8 x 109 EVs/mL). Analyses by NTA confirmed that CSF-derived EVs and serum-derived EVs had size and shape similar to microvesicles and exosomes. The mean size of EVs was similar in serum and CSF. Thus, the concentration, and not size was able distinguish patients with toxoplasmosis than healthy individuals. Presence of exosomes was also confirmed by transmission electron microscopy and evidence of tetraspanins CD63 and CD9 in immunoblotting. Relative expressions of miR-146a-5p, miR-155-5p, miR-21-5p, miR-29c-3p and miR-125b-5p were estimated in exosomal miRNA extracted of EVs. Serum-derived EVs from group II (cerebral and gestational toxoplasmosis) up-expressed miR-125b-5p and miR-146a-5p. CSF-derived EVs from CT/HIV patients) up-expressed miR-155-5p and miR-21-5p and were unable to express miR-29c-3p. These data suggest the participation of EVs and exosomal miRNAs in unbalance of immune response as elevation of TNF-α, IL-6; and downregulation of IFN-γ in cerebral and gestational forms of toxoplasmosis.


Coombs-positive Paroxysmal Nocturnal Haemoglobinuria.
Autoimmune haemolytic anaemia (AIHA) and paroxysmal nocturnal haemoglobinuria (PNH) are two distinct causes of haemolytic anaemia. They have different mechanisms that underpin their pathogenesis and, therefore, require different treatment strategies. The direct antiglobulin test (DAT) or Coombs test is positive in cases of immune-mediated haemolytic anaemia and, thus, is positive in AIHA but negative in PNH. We report a case of a woman presenting with a haemolytic anaemia who was found to have concomitant evidence of AIHA and PNH. The case highlights the importance of carrying out a comprehensive haemolysis work-up in patients who present with haemolytic anaemia.


Determinants of job satisfaction in foreign domestic helpers caring for people with dementia in Hong Kong.
The job satisfaction of live-in foreign domestic helpers (FDHs) may influence their caring motivation and the quality of care they provide, which may in turn affect the health status of care recipients. This study identifies the factors affecting job satisfaction of FDHs caring for people with dementia in Hong Kong, focusing especially on the role of FDHs' adaptation status, job self-efficacy and care recipients' situation. A total of 152 FDHs taking care of people with dementia were recruited from 6 day care centres for elderly people in Hong Kong when they attended with their care recipients. Data were collected from February to August 2011 and the response rate was 95%. Participants completed questionnaires which included measures of care recipients' dementia severity and disruptive behaviours, FDHs' demographic factors, personal adaptation status, caregiving self-efficacy and job satisfaction. Hierarchical regression analysis was conducted to analyse the data. The results showed that longer stay in Hong Kong, better fluency in Cantonese (local dialect), greater satisfaction in living conditions, higher caregiving self-efficacy and less disruptive behaviour of care recipients were independently associated with stronger job satisfaction in FDHs looking after people with dementia. On the basis of these findings, we would suggest that employers should consider helpers who have been in Hong Kong for a longer period of time and speak fluent Cantonese, and have previous experience of taking care of people with dementia. In addition, FDHs caring for people with dementia may benefit from carer training which improves their self-efficacy in dementia care.


Predicting the Presence of Active Schools: A National Survey of School Principals in the United States.
Principals are key to the promotion of physical activity (PA) in schools. The purpose of this study was to understand how school principals' PA values, behaviors, and individual and school characteristics were associated with the presence of an active school. A representative sample of 1019 school principals in the United States was surveyed. Survey items addressed principals' values and behaviors associated with PA, individual and school demographic factors, such as years of experience and school level, and a single item asking whether principals perceived their school to be an active school (ie, provides students with opportunities to be physically active before, during, and after the school day). Significant variables from a cross-tabulation and chi-square analysis were added to a hierarchical logistic regression model to assess the predictive properties of principal values and behaviors as they relate to the presence of an active school. Approximately half of principals (47%) reported having an active school. The model significantly predicted the presence of an active school but accounted for only 6.6% of the total variance. Although values toward PA and more frequent personal PA behaviors were associated with the presence of an active school within the cross-tabulation and chi-square analysis, neither variable emerged as a significant predictor in the regression model. Principals' personal PA values and behaviors contribute to the presence of an active school, but other variables, including years of experience and school contextual factors, are more powerful predictors.


Sex differences in the cholinergic basal forebrain in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease.
In the Down syndrome (DS) population, there is an early incidence of dementia and neuropathology similar to that seen in sporadic Alzheimer's disease (AD), including dysfunction of the basal forebrain cholinergic neuron (BFCN) system. Using Ts65Dn mice, a model of DS and AD, we examined differences in the BFCN system between male and female segmentally trisomic (Ts65Dn) and disomic (2N) mice at ages 5-8 months. Quantitative stereology was applied to BFCN subfields immunolabeled for choline acetyltransferase (ChAT) within the medial septum/vertical limb of the diagonal band (MS/VDB), horizontal limb of the diagonal band (HDB) and nucleus basalis of Meynert/substantia innominata (NBM/SI). We found no sex differences in neuron number or subregion area measurement in the MS/VDB or HDB. However, 2N and Ts65Dn females showed an average 34% decrease in BFCN number and an average 20% smaller NBM/SI region area compared with genotype-matched males. Further, relative to genotype-matched males, female mice had smaller BFCNs in all subregions. These findings demonstrate that differences between the sexes in BFCNs of young adult Ts65Dn and 2N mice are region and genotype specific. In addition, changes in post-processing tissue thickness suggest altered parenchymal characteristics between male and female Ts65Dn mice.


Cost-effective analysis of teaching pelvic examination skills using Gynaecology Teaching Associates (GTAs) compared with manikin models (The CEAT Study).
To determine the cost-effectiveness of Gynaecology Teaching Associate (GTA) teaching versus conventional pelvic model (manikin) teaching of pelvic examination skills for final year medical students within a UK undergraduate obstetrics and gynaecology (O&G) curriculum. An economic evaluation was carried out alongside a randomised controlled trial involving 492 final year medical students. 240 students received manikin teaching, and 241 GTA-led teaching. 418 (85%) students completed their assessment. Proficiency in gynaecological pelvic examination on GTAs was estimated by a senior clinical examiner, blinded to the method of teaching, using a standardised assessment tool. University of Birmingham Medical School thresholds were applied to determine proficiency levels; competence (pass) 50%, merit 60% and distinction 70%. Costs incurred in the delivery of both the educational pathways (control and intervention) were combined. All costs are reported in 2013-2014 prices and earlier costs adjusted using inflation indices. Cost per student competent in pelvic examination at completion of a 5-week clinical O&G placement. GTA teaching was more effective compared with conventional teaching with 12 more students considered competent at pass level and 28 more students competent at merit and distinction levels, respectively. However, the average cost of GTA teaching was £45.06 per student compared with £7.40 per student for conventional teaching, with an increased cost of £37.66 per student. The incremental cost-effectiveness ratio demonstrated that it cost an additional £640.20 per competent student and £274.37 per student competent at merit level and £274.37 at distinction level compared with conventional manikin-based teaching. GTA teaching of female pelvic examination at the start of undergraduate medical student O&G clinical placements is shown to cost more and be more effective. GTA teaching is likely to be considered cost-effective in the context of other tests, and over the lifespan of a competent doctor's career. NCT01944592.


The new modified ABCD method for gastric neoplasm screening.
The ABCD screening method was developed for risk stratification of gastric cancer. It is unclear whether the ABCD method can predict the risk of gastric neoplasms, including gastric adenomas, as observed for gastric cancer. We aimed to devise a modified ABCD method for predicting gastric neoplasms. We reviewed 562 patients who had undergone upper gastrointestinal tract endoscopy and whose serum IgG anti-Helicobacter pylori antibody, gastrin, and pepsinogen (PG) I and PG II data were available. Patients were classified into the following four groups: H. pylori antibody negative and normal PG level (group A), H. pylori antibody positive and normal PG level (group B), H. pylori antibody positive and low PG level (group C), and H. pylori antibody negative and low PG level (group D). The PG I/PG II ratio was lower in patients with gastric neoplasms than in patients without these lesions (gastric adenoma vs gastric cancer vs no neoplasm, 3.7 ± 2.0 vs 3.8 ± 1.8 vs 4.9 ± 2.1, P < 0.001). The optimal cutoff values of the PG I/PG II ratio for predicting gastric neoplasms were 3.1 for H. pylori antibody negative patients and 4.1 for H. pylori antibody positive patients. A higher group grade was associated with a significantly higher proportion of gastric neoplasms [odds ratio (95 % confidence interval), group A, reference; group B, 1.783 (1.007-3.156); group C, 3.807 (2.382-6.085); and group D, 5.862 (2.427-14.155)]. The modified ABCD method using two different cutoff values according to the H. pylori antibody status was useful for predicting the presence of gastric neoplasms. This method might be a supplementary screening tool for both gastric adenoma and gastric cancer. However, further studies will be required to provide a definitive conclusion.


Auditory and vestibular function in hyperbaric oxygen.
The therapeutic value of high partial pressures of oxygen is limited by the toxicity of oxygen. Pulmonary damage, visual impairment, and convulsions are known hazards during hyperoxic exposure, but dose-effect relationships have not been quantified for specific organs or functions. As part of an integrated study of organ oxygen tolerance in man (Predictive Study V of the Institute for Environmental Medicine), auditory and vestibular function was evaluated in man before, during, and after exposure to 100% oxygen at 3 atmospheres absolute pressure for 2 to 3.5 hours. No alterations in hearing or equilibrium were detected, suggesting that ototoxicity is not a factor that would limit exposure under these conditions.


One-carbon chemistry of oxalate oxidoreductase captured by X-ray crystallography.
Thiamine pyrophosphate (TPP)-dependent oxalate oxidoreductase (OOR) metabolizes oxalate, generating two molecules of CO2 and two low-potential electrons, thus providing both the carbon and reducing equivalents for operation of the Wood-Ljungdahl pathway of acetogenesis. Here we present structures of OOR in which two different reaction intermediate bound states have been trapped: the covalent adducts between TPP and oxalate and between TPP and CO2. These structures, along with the previously determined structure of substrate-free OOR, allow us to visualize how active site rearrangements can drive catalysis. Our results suggest that OOR operates via a bait-and-switch mechanism, attracting substrate into the active site through the presence of positively charged and polar residues, and then altering the electrostatic environment through loop and side chain movements to drive catalysis. This simple but elegant mechanism explains how oxalate, a molecule that humans and most animals cannot break down, can be used for growth by acetogenic bacteria.


Streptococcus pneumoniae DNA initiates type I interferon signaling in the respiratory tract.
The mucosal epithelium is the initial target for respiratory pathogens of all types. While type I interferon (IFN) signaling is traditionally associated with antiviral immunity, we demonstrate that the extracellular bacterial pathogen Streptococcus pneumoniae activates the type I IFN cascade in airway epithelial and dendritic cells. This response is dependent upon the pore-forming toxin pneumolysin. Pneumococcal DNA activates IFN-β expression through a DAI/STING/TBK1/IRF3 cascade. Tlr4(-/-), Myd88(-/-), Trif(-/-), and Nod2(-/-) mutant mice had no impairment of type I IFN signaling. Induction of type I IFN signaling contributes to the eradication of pneumococcal carriage, as IFN-α/β receptor null mice had significantly increased nasal colonization with S. pneumoniae compared with that of wild-type mice. These studies suggest that the type I IFN cascade is a central component of the mucosal response to airway bacterial pathogens and is responsive to bacterial pathogen-associated molecular patterns that are capable of accessing intracellular receptors. The bacterium Streptococcus pneumoniae is a leading cause of bacterial pneumonia, leading to upwards of one million deaths a year worldwide and significant economic burden. Although it is known that antibody is critical for efficient phagocytosis, it is not known how this pathogen is sensed by the mucosal epithelium. We demonstrate that this extracellular pathogen activates mucosal signaling typically activated by viral pathogens via the pneumolysin pore to activate intracellular receptors and the type I interferon (IFN) cascade. Mice lacking the receptor to type I IFNs have a reduced ability to clear S. pneumoniae, suggesting that the type I IFN cascade is central to the mucosal clearance of this important pathogen.


Isolation of lipopolysaccharide from the walls of Micropolyspora faeni: chemical composition and serological reactivity.
Extraction of mycelium or walls of Micropolyspora faeni with cold or hot aqueous phenol yielded a lipopolysaccharide consisting of lipid A, phosphate, galactose, arabinose, glucose, glucosamine, and a dideoxy sugar. Extraction with trichloroacetic acid (TCA) yielded an incomplete molecule lacking lipid A. Part of an O-chain was secreted into the culture medium. Phenol and TCA extracts gave three lines of precipitation with human serum from cases of farmer's lung disease, and one of these was given by the culture medium polysaccharide. Serologically-reactive sugars were arabinose, galactose and glucose. The lipopolysaccharide fixed on to red cells which agglutinated in the presence of specific antibody and lysed on the addition of complement. The lipopolysaccharide appeared to elicit mainly IgM antibodies in animals, but IgM and IgG antibodies in humans.


A GA-based method for constructing fuzzy systems directly from numerical data.
A method based on the concepts of genetic algorithm (GA) and recursive least-squares method is proposed to construct a fuzzy system directly from some gathered input-output data of the discussed problem. The proposed method can find an appropriate fuzzy system with a low number of rules to approach an identified system under the condition that the constructed fuzzy system must satisfy a predetermined acceptable performance. In this method, each individual in the population is constructed to determine the number of fuzzy rules and the premise part of the fuzzy system, and the recursive least-squares method is used to determine the consequent part of the constructed fuzzy system described by this individual. Finally, three identification problems of nonlinear systems are utilized to illustrate the effectiveness of the proposed method.


A comparative study of electroporation and iontophoresis for percutaneous penetration of naproxen.
Using side-by-side compartment diffusion cell and rat skin, the in vitro percutaneous penetration of naproxen by electroporation and iontophoresis with different energy was investigated and compared. Both electroporation and iontophoresis could obviously increase the penetration of naproxen through rat skin. The enhancing effect of electroporation was not always better than that of iontophoresis. The enhancing effect was dependent on the energy of the electrical field.


Communication with teenagers who are significantly affected by sexually transmitted infections (STIs) is essential for the sake of prevention. The aim of this study is to develop a specific questionnaire for surveying the degree of knowledge, behavior, and attitudes of current teenagers and young adults on STIs to come up with the proper training tools. We conducted the study following the Delphi method, a 2-round critical assessment score (from 1 to 9) of all domains and items. Only domains and items with median scores ≥ 8 were selected. A total of 8 panelists were involved in this survey. After establishing a median score ≥ 8, a total of 14 domains and 40 items were eventually selected. This is the first questionnaire ever conducted to study the knowledge, habits, and attitudes of contemporary teenagers and young adults on STIs, and stands as a valuable tool for future training on STI prevention in teenagers and young adults.


Effect of C4-, C8- and C18-alkylation of poly(vinyl alcohol) hydrogels on the adsorption of albumin and fibrinogen from buffer and plasma: limited correlation with platelet interactions.
Polyvinyl alcohol (PVA) hydrogel was partially alkylated with short (C4), intermediate (C8) and long (C18) alkyl chains to test the hypothesis that an alkylated surface might promote enhanced interaction with albumin and thus exhibit low platelet thrombogenicity. PVA hydrogel was reacted with alkyl halides (C4, C8 or C18) and coated onto polyethylene. The effect of surface alkylation (extent of alkylation and alkyl chain length) on the adsorption of human serum albumin and fibrinogen to these surfaces was investigated in both buffer and plasma. Platelet interactions were investigated in vitro using flow cytometry methods. The maximum surface concentrations of albumin and fibrinogen adsorbed from buffer onto PVA and alkylated PVA were characteristic of monolayers. At low concentrations differences in adsorption among the surfaces appeared to be related to hydrophobicity as determined by dynamic advancing water contact angle, and to degree of alkylation as determined by angle dependent XPS analysis. Alkyl chain length dependence was not observed. Adsorption from plasma was considerably lower than from buffer, except for albumin on C8-PVA where monolayer adsorption was observed. Fibrinogen adsorption from plasma was similar on PVA, C8-PVA and C18-PVA, but was higher on C4-PVA. For albumin adsorption from plasma, the initial slope of the adsorption-concentration curve was highest for C18-PVA, suggesting higher albumin affinity despite the low degree of substitution of the C18-PVA material. These data suggest possible selectivity of the C18 alkylated PVA for albumin. Platelet studies showed that C4-PVA was the least platelet reactive (microparticle generation and P-selectin expression) of the alkyl derivatized materials.


Symphysis-fundal height predicts difficult evolution of induced labours.
Symphysis-fundal-height (SFH) could be prove useful for the management of labour. This study aims to assess the behaviour of induced labours in relationship with SFH values. Prospective observational study in a sample of 158 women underwent induction with intravaginal dinoprostone for different indications. SFH, SFH corrected for station, gestational age and parity were considered independent variables in multivariable models. Vaginal delivery, operative vaginal delivery, Cesarean section, Cesarean section for dystocia, Cesarean section for cardiotochographyc abnormalities, oxytocin infusion (for potentiating labour), need of Kristeller's maneuvre, epidural anesthesia (on demand), episiotomy, time from the first dose of dinoprostone to delivery, and time of active phase of labour were considered dependent variables in multivariable models. SFH >34 cm (both uncorrected and corrected for station) independently associates with an increase of odds ratio for operative vaginal birth, Kristeller's maneuver, oxytocin use, episiotomy. Additionally, SFH >34 cm (corrected for station) seems to correlate with increasing time of active phase of labour. SFH >34 cm (both corrected and uncorrected for station) predicts difficult vaginal deliveries and operative vaginal deliveries in induced labours.


Exosome-like Nanozyme Vesicles for H2O2-Responsive Catalytic Photoacoustic Imaging of Xenograft Nasopharyngeal Carcinoma.
Photoacoustic imaging (PAI) is an attractive imaging modality, which is promising for clinical cancer diagnosis due to its advantages on deep tissue penetration and fine spatial resolution. However, few tumor catalytic/responsive PAI strategies are developed. Here, we design an exosome-like nanozyme vesicle for in vivo H2O2-responsive PAI of nasopharyngeal carcinoma (NPC). The intrinsic peroxidase-like activity of graphene quantum dot nanozyme (GQDzyme) effectively converts the 2,2'-azino- bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) into its oxidized form in the presence of H2O2. The oxidized ABTS exhibits strong near-infrared (NIR) absorbance, rendering it to be an ideal contrast agent for PAI. Thus, GQDzyme/ABTS nanoparticle is a novel type of catalytic PAI contrast agent, which is sensitive to H2O2 produced from NPC cells. Furthermore, we develop an approach to construct exosome-like nanozyme vesicle via biomimetic functionalization of GQDzyme/ABTS nanoparticle with natural erythrocyte membrane modified with folate acid. In vivo animal experiments demonstrated that this exosome-like nanozyme vesicle effectively accumulated in NPC and selectively triggered catalytic PAI for NPC. In addition, our nanozyme vesicle exhibits excellent biocompatibility and stealth ability for long blood circulation. Together, we demonstrate that GQDzyme/ABTS based exosome-like nanozyme vesicle is an ideal nanoplatform for developing deep-tissue tumor-targeted catalytic PAI in vivo.


Bipolar spin switch.
A thin ferromagnetic film can be used to polarize the spin axes of the electrons carrying an electric current in a manner loosely analogous with a light polarizer. When such a film is fabricated on a gold film, a nonequilibrium population of spin-polarized electrons is built up in the gold causing a "spin bottleneck" effect. The addition of a second ferromagnetic film results in a device whose output voltage depends on the orientation of the spins.


Rapid, ultra-sensitive detection of gas phase elemental mercury under atmospheric conditions using sequential two-photon laser induced fluorescence.
We have examined the sensitivity of sequential two photon laser induced fluorescence (LIF) detection of elemental mercury, Hg(0) in the gas phase. The most sensitive approach involves an initial laser excitation of the 6(3)P1-6(1)S0 transition at 253.7 nm, followed by excitation with a second laser to the 7(1)S0 level. Blue shifted fluorescence is observed on the 6(1)P1-6(1)S0 transition at 184.9 nm. The excitation scheme, involving sequential excitation of two atomic transitions, followed by detection of the emission from a third is extremely specific and precludes detection of anything other than atomic mercury. Using our 10 Hz laser system we have achieved a detection sensitivity of 0.1 ng m(-3) at a sampling rate of 0.1 Hz, i.e. averaging 100 laser shots at a pressure of one atmosphere in air. At low concentrations we sampled simultaneously with an automated mercury analyzer (Tekran 2537A), to ensure accuracy. We have examined the linearity of the technique, generating flows containing mercury concentrations between 1 and 10,000 ng m(-3) using a permeation tube and dynamic dilution, but relying on the concentrations given by the Tekran at low levels and the concentration calculated from dilution at high levels. We find that the detection is linear over the five orders of magnitude that we were able to vary the concentration. Our measured detection limits in He and Ar are much lower as these gases are inefficient fluorescence quenchers.


The ice in voices: Understanding negative content in auditory-verbal hallucinations.
Negative voice-content is the best sole predictor of whether the hearer of an auditory-verbal hallucination will experience distress/impairment necessitating contact with mental health services. Yet, what causes negative voice-content and how interventions may reduce it remains poorly understood. This paper offers definitions of negative voice content and considers what may cause negative voice-content. We propose a framework in which adverse life-events may underpin much negative voice-content, a relation which may be mediated by mechanisms including hypervigilance, reduced social rank, shame and self-blame, dissociation, and altered emotional processing. At a neurological level, we note how the involvement of the amygdala and right Broca's area could drive negative voice-content. We observe that negative interactions between hearers and their voices may further drive negative voice-content. Finally, we consider the role of culture in shaping negative voice-content. This framework is intended to deepen and extend cognitive models of voice-hearing and spur further development of psychological interventions for those distressed by such voices. We note that much of the relevant research in this area remains to be performed or replicated. We conclude that more attention needs to be paid to methods for reducing negative voice-content, and urge further research in this important area.


Can verbal working memory training improve reading?
The aim of the current study was to determine whether poor verbal working memory is associated with poor word reading accuracy because the former causes the latter, or the latter causes the former. To this end, we tested whether (a) verbal working memory training improves poor verbal working memory or poor word reading accuracy, and whether (b) reading training improves poor reading accuracy or verbal working memory in a case series of four children with poor word reading accuracy and verbal working memory. Each child completed 8 weeks of verbal working memory training and 8 weeks of reading training. Verbal working memory training improved verbal working memory in two of the four children, but did not improve their reading accuracy. Similarly, reading training improved word reading accuracy in all children, but did not improve their verbal working memory. These results suggest that the causal links between verbal working memory and reading accuracy may not be as direct as has been assumed.


Water radiolysis products and nucleotide damage in gamma-irradiated DNA.
The radiation chemistry of nucleotide damage introduction into DNA gamma-irradiated in dilute aqueous solution has been studied with a damage-specific DNA binding protein. Irradiation in air, N2 or N2O in the presence and absence of free radical scavengers revealed that protein-recognizable lesions were introduced both by the hydrated electron and by the combination of the hydroxyl radical and superoxide anion radical, but not by the hydroxyl radical alone. In addition, nucleotide damage was introduced into DNA by an enzymatic superoxide-generating system.


Possible predictors of phenoconversion in isolated REM sleep behaviour disorder: a systematic review and meta-analysis.
A number of promising biomarkers for predicting imminent α-synucleinopathies have been suggested in isolated rapid eye movement sleep behaviour disorder (iRBD). However, existing evidence is conflicting without quantitative evaluation. PubMed, Web of Science and ClinicalTrials.gov were searched through June 2021 to identify possible predictors of phenoconversion from iRBD to Parkinson's disease (PD). The pooled HRs and standardised mean differences (SMDs) with 95% CIs were calculated using fixed-effects or random-effects model. A total of 123 studies were included in the meta-analysis. Significant motor dysfunction (HR 1.83, 95% CI 1.33 to 2.51, I2=86.8%, p<0.001), constipation (HR 1.52, 95% CI 1.26 to 1.84, I2=8.3%, p=0.365), orthostatic hypotension (HR 1.93, 95% CI 1.05 to 3.53, I2=54.9%, p=0.084), hyposmia (HR 2.78, 95% CI 1.83 to 4.23, I2=23.9%, p=0.255), mild cognitive impairment (HR 2.27, 95% CI 1.58 to 3.27, I2=0%, p=0.681) and abnormal colour vision (SMD -0.34, 95% CI -0.63 to -0.05, I2=45.6%, p=0.087) correlated with susceptibility to PD. The process can also be traced by putaminal dopamine transporter imaging (HR 2.60, 95% CI 1.94 to 3.48, I2=0%, p=0.781) and tonic electromyographic activity (HR 1.50, 95% CI 1.04 to 2.15, I2=70%, p=0.018). The predictive value of each biomarker was initially highlighted with comprehensive evaluation. Combining specific predictors with high sensitivity is promising for detecting phenoconversion in the prodromal stage. Large-scale and multicentre studies are pivotal to extend our findings.


An Electrical Stimulation Device For In Vitro Neural Engineering.
Due to the intrinsically low turnover of neural tissues, regenerative therapies have gained significant interest in the context of degenerative diseases and injury to the central and peripheral nervous systems. Although a range of neuroregenerative strategies involving cell transplants and drugs have been explored, these are often limited by low efficacy and unwanted side effects. Electrical stimulation (ES) is thought to modulate the proliferation and differentiation of neural stem cells (NSCs), and thus it represents a promising strategy for neuroregenerative therapies. However, its influence on the biology of endogenous and exogenous NSCs, and the effect of different stimulation paradigms remains unexplored. Additionally, the variability of stimulation platforms and parameters employed in previous studies prevents reliable and reproducible discoveries. Therefore, there is a need to develop versatile and robust tools to study the effect of electrical stimulation on NSC fate in vitro. This paper outlines the development and functional application of a standardised, electrically stable, and easily reproducible ES platform for in vitro neuroregeneration applications.Clinical Relevance- The elucidation of the cellular and molecular mechanisms underlying the effect of ES paradigms on NSCs proliferation and differentiation holds great potential for the development of neuroregenerative therapies.


Temporal perturbation of tyrosine phosphoproteome dynamics reveals the system-wide regulatory networks.
Signal transduction systems are known to widely regulate complex biological events such as cell proliferation and differentiation. Because phosphotyrosine-dependent networks play a key role in transmitting signals, a comprehensive and fine description of their dynamic behavior can lead us to systematically analyze the regulatory mechanisms that result in each biological effect. Here we established a mass spectrometry-based framework for analyzing tyrosine phosphoproteome dynamics through temporal network perturbation. A highly time-resolved description of the epidermal growth factor-dependent signaling pathways in human A431 cells revealed a global view of their multiphase network activation, comprising a spike signal transmission within 1 min of ligand stimulation followed by the prolonged activation of multiple Src-related molecules. Temporal perturbation of Src family kinases with the corresponding inhibitor PP2 in the prolonged activation phase led to the down-regulation of the molecules related to cell adhesion and receptor degradation, whereas the canonical cascades as well as the epidermal growth factor receptor relatively maintained their activities. Our methodology provides a system-wide view of the regulatory network clusters involved in signal transduction that is essential to refine the literature-based network structures for a systems biology analysis.


[Socio-anthropological contributions to public nutrition: why, how and under which conditions?].
Socio-anthropological research is being increasingly recognised as important in public nutrition research. It helps to understand practices and behaviours the significance of which can partially escape the nutritionist. It also permits to increase knowledge about food systems and their underlying social dynamics and representations and therefore contributes to the understanding of often neglected aspects of nutritional problems. In this paper the authors highlight how their discipline and its main research techniques can be efficiently involved in public nutrition research, without however neglecting their own specific methodological requirements. The first objective of the paper is to draw methodological lessons from experiences. A second objective is to familiarise researchers, who are not specialised in social sciences, with the main techniques used in the discipline. After a brief presentation of the underlying principles and objectives of socio-anthropological research, the main data collection techniques used by socio-anthropologists (observation, interview, focus groups) are described and their use is illustrated by concrete research examples from Congo, Bolivia, Nepal and Tunisia. A special emphasis is put on the requirements of qualitative data analysis. The discussion focuses on the choice of techniques, the enhancement of quality in qualitative research and on the main constraints and difficulties encountered in involving socio-anthropology in public nutrition. The limits, constraints and conditions of this implication and contribution are discussed. For the authors the issue of involving socio-anthropology in public nutrition should not be viewed in terms of instrumentalisation of one discipline by the other. The main avenue to reach a fruitful and efficient collaboration is respect and recognition of the methodological approaches (and underlying epistemological assumptions) of socio-anthropology (qualification of researchers, quality criteria, etc.). These requirements are necessary for socio-anthropology to produce qualitatively sound data and analysis. More important, the set up of common conceptual frameworks on the basis of an interdisciplinary dialogue has to be established from conception of the research up to its conclusion.


Phylogeography of sexual Heteronotia binoei (Gekkonidae) in the Australian arid zone: climatic cycling and repetitive hybridization.
The biota of much of continental Australia have evolved within the context of gradual aridification of the region over several million years, and more recently of climatic cycling between relatively dry and humid conditions. We performed a phylogeographical study of three sexual chromosome races of the Heteronotia binoei complex of geckos found throughout the Australian arid zone. Two of these three races were involved in two separate hybridization events leading to parthenogenetic lineages (also H. binoei), and the third is widespread and broadly sympatric with the parthenogens. Based on our analyses, the three sexual races diversified approximately 6 million years ago in eastern Australia, during a period of aridification, then each moved west through northern, southern, and central dispersal corridors to occupy their current ranges. In each case, the timing of major phylogeographical inferences corresponds to inferred palaeoclimatic changes in continental Australia. This scenario provides a simple explanation for diversification, secondary contact, and hybridization between the races. However, data presented elsewhere indicate that formation of the parthenogens was considerably more recent than the westward expansion of the hybridizing races, and that multiple hybridization events were geographically and temporally distinct. We suggest that cyclical climate changes may have led to regional range changes that facilitated hybridization between the races, which are not currently known to be in sympatry.


Frontally mediated inhibitory processing and white matter microstructure: age and alcoholism effects.
The NOGO P3 event-related potential is a sensitive marker of alcoholism, relates to EEG oscillation in the δ and θ frequency ranges, and reflects activation of an inhibitory processing network. Degradation of white matter tracts related to age or alcoholism should negatively affect the oscillatory activity within the network. This study aims to evaluate the effect of alcoholism and age on δ and θ oscillations and the relationship between these oscillations and measures of white matter microstructural integrity. Data from ten long-term alcoholics to 25 nonalcoholic controls were used to derive P3 from Fz, Cz, and Pz using a visual GO/NOGO protocol. Total power and across trial phase synchrony measures were calculated for δ and θ frequencies. DTI, 1.5 T, data formed the basis of quantitative fiber tracking in the left and right cingulate bundles and the genu and splenium of the corpus callosum. Fractional anisotropy and diffusivity (λL and λT) measures were calculated from each tract. NOGO P3 amplitude and δ power at Cz were smaller in alcoholics than controls. Lower δ total power was related to higher λT in the left and right cingulate bundles. GO P3 amplitude was lower and GO P3 latency was longer with advancing age, but none of the time-frequency analysis measures displayed significant age or diagnosis effects. The relation of δ total power at CZ with λT in the cingulate bundles provides correlational evidence for a functional role of fronto-parietal white matter tracts in inhibitory processing.


Rational drug therapy education in clinical phase carried out by task-based learning.
Irrational drug use results in drug interactions, treatment noncompliance, and drug resistance. Rational pharmacotherapy education is being implemented in many faculties of medicine. Our aim is to introduce rational pharmacotherapy education by clinicians and to evaluate task-based rational drug therapy education in the clinical context. The Kirkpatrick's evaluation model was used for the evaluation of the program. The participants evaluated the program in terms of constituents of the program, utilization, and contribution to learning. Voluntary participants responded to the evaluation forms after the educational program. Data are evaluated using both quantitative and qualitative tools. SPSS (version 21) used for quantitative data for determining mean and standard deviation values. Descriptive qualitative analysis approach is used for the analysis of open-ended questions. It was revealed that the program and its components have been favorable. A total 95.9% of the students consider the education to be beneficial. Simulated patients practice and personal drug choice/problem-based learning sessions were appreciated by the students in particular. 93.9% of the students stated that all students of medicine should undergo this educational program. Among the five presentations contained in the program, "The Principles of Prescribing" received the highest points (9 ± 1.00) from participating students in general evaluation of the educational program. This study was carried out to improve task-based rational drug therapy education. According to feedback from the students concerning content, method, resource, assessment, and program design; some important changes, especially in number of facilitators and indications, are made in rational pharmacotherapy education in clinical task-based learning program.


Regional, disease specific patterns of smoking-attributable mortality in 2000.
Smoking has been causally associated with increased mortality from several diseases, and has increased considerably in many developing countries in the past few decades. Mortality attributable to smoking in the year 2000 was estimated for adult males and females, including estimates by age and for specific diseases in 14 epidemiological subregions of the world. Lung cancer mortality was used as an indirect marker of the accumulated hazard of smoking. Never-smoker lung cancer mortality was estimated based on the household use of coal with poor ventilation. Estimates of mortality caused by smoking were made for lung cancer, upper aerodigestive cancer, all other cancers, chronic obstructive pulmonary disease (COPD), other respiratory diseases, cardiovascular diseases, and selected other medical causes. Estimates were limited to ages 30 years and above. In 2000, an estimated 4.83 million premature deaths in the world were attributable to smoking, 2.41 million in developing countries and 2.43 million in industrialised countries. There were 3.84 million male deaths and 1.00 million female deaths attributable to smoking. 2.69 million smoking attributable deaths were between the ages of 30-69 years, and 2.14 million were 70 years of age and above. The leading causes of death from smoking in industrialised regions were cardiovascular diseases (1.02 million deaths), lung cancer (0.52 million deaths), and COPD (0.31 million deaths), and in the developing world cardiovascular diseases (0.67 million deaths), COPD (0.65 million deaths), and lung cancer (0.33 million deaths). The share of male and female deaths and younger and older adult deaths, and of various diseases in total smoking attributable deaths exhibited large inter-regional heterogeneity, especially in the developing world. Smoking was an important cause of global mortality in 2000, affecting a large number of diseases. Age, sex, and disease patterns of smoking-caused mortality varied greatly across regions, due to both historical and current smoking patterns, and the presence of other risk factors that affect background mortality from specific diseases.


Integrin fibronectin receptors in matrix metalloproteinase-1-dependent invasion by breast cancer and mammary epithelial cells.
Integrins contribute to progression in many cancers, including breast cancer. For example, the interaction of alpha(5)beta(1) with plasma fibronectin causes the constitutive invasiveness of human prostate cancer cells. Inhibition of this process reduces tumorigenesis and prevents metastasis and recurrence. In this study, naturally serum-free basement membranes were used as invasion substrates. Immunoassays were used to compare the roles of alpha(5)beta(1) and alpha(4)beta(1) fibronectin receptors in regulating matrix metalloproteinase (MMP)-1-dependent invasion by human breast cancer and mammary epithelial cells. We found that a peptide consisting of fibronectin PHSRN sequence, Ac-PHSRN-NH(2), induces alpha(5)beta(1)-mediated invasion of basement membranes in vitro by human breast cancer and mammary epithelial cells. PHSRN-induced invasion requires interstitial collagenase MMP-1 activity and is suppressed by an equimolar concentration of a peptide consisting of the LDV sequence of the fibronectin connecting segment, Ac-LHGPEILDVPST-NH(2), in mammary epithelial cells, but not in breast cancer cells. This sequence interacts with alpha(4)beta(1), an integrin that is often down-regulated in breast cancer cells. Immunoblotting shows that the PHSRN peptide stimulates MMP-1 production by serum-free human breast cancer and mammary epithelial cells and that the LDV peptide represses PHSRN-stimulated MMP-1 production only in mammary epithelial cells. Furthermore, PHSRN stimulates MMP-1 activity in breast cancer cells and mammary epithelial cells with a time course that closely parallels invasion induction. Thus, down-regulation of surface alpha(4)beta(1) during oncogenic transformation may be crucial for establishment of the alpha(5)beta(1)-induced, MMP-1-dependent invasive phenotype of breast cancer cells.


Thrombin down-regulates the TGF-beta-mediated synthesis of collagen and fibronectin by human proximal tubule epithelial cells through the EPCR-dependent activation of PAR-1.
Human proximal tubule (HK-2) cells are commonly used as cellular models to understand the mechanism by which inflammatory mediators cause renal injury. It has been observed that thrombin stimulates the expression of TGF-beta, extracellular matrix (ECM) proteins and proinflammatory cytokines by HK-2 cells. These in vitro responses correlate well with the pathology of glomerular and tubular diseases observed in acute renal injury. HK-2 cells express PAR-1 and the thrombin activation of this receptor has been reported to up-regulate the TGF-beta-mediated expression of ECM proteins, suggesting a possible pathogenic role for PAR-1 signaling by thrombin in acute renal injury. On the other hand, several recent studies have indicated that activated protein C plays a renoprotective role, thus inhibiting the inflammatory responses and attenuating renal injury, presumably by activating the same cell surface receptor. In this study, we show that HK-2 cells express endothelial protein C receptor (EPCR) and that the occupancy of this receptor by protein C switches the signaling specificity of thrombin so that the activation of PAR-1 by thrombin inhibits the TNF-alpha-mediated synthesis of IL-6 and IL-8 and down-regulates the TGF-beta-mediated expression of ECM proteins. These results suggest a possible protective role for EPCR in acute kidney injury.


5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5-HT(1A) receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release.
Atypical antipsychotic drugs (APDs), all of which are relatively more potent as serotonin (5-HT)(2A) than dopamine D(2) antagonists, may improve negative symptoms and cognitive dysfunction in schizophrenia, in part, via increasing cortical dopamine release. 5-HT(1A) agonism has been also suggested to contribute to the ability to increase cortical dopamine release. The present study tested the hypothesis that clozapine, olanzapine, risperidone, and perhaps other atypical APDs, increase dopamine release in rat medial prefrontal cortex (mPFC) via 5-HT(1A) receptor activation, as a result of the blockade of 5-HT(2A) and D(2) receptors. M100907 (0.1 mg/kg), a 5-HT(2A) antagonist, significantly increased the ability of both S:(-)-sulpiride (10 mg/kg), a D(2) antagonist devoid of 5-HT(1A) affinity, and R:(+)-8-OH-DPAT (0.05 mg/kg), a 5-HT(1A) agonist, to increase mPFC dopamine release. These effects of M100907 were abolished by WAY100635 (0.05 mg/kg), a 5-HT(1A) antagonist, which by itself has no effect on mPFC dopamine release. WAY100635 (0.2 mg/kg) also reversed the ability of clozapine (20 mg/kg), olanzapine (1 mg/kg), risperidone (1 mg/kg), and the R:(+)-8-OH-DPAT (0.2 mg/kg) to increase mPFC dopamine release. Clozapine is a direct acting 5-HT(1A) partial agonist, whereas olanzapine and risperidone are not. These results suggest that the atypical APDs via 5-HT(2A) and D(2) receptor blockade, regardless of intrinsic 5-HT(1A) affinity, may promote the ability of 5-HT(1A) receptor stimulation to increase mPFC DA release, and provide additional evidence that coadministration of 5-HT(2A) antagonists and typical APDs, which are D(2) antagonists, may facilitate 5-HT(1A) agonist activity.


Erythropoietin receptor contributes to melanoma cell survival in vivo.
Erythropoietin (Epo) is widely used clinically to treat anemia associated with various clinical conditions including cancer. Data from several clinical trials suggest significant adverse effect of Epo treatment on cancer patient survival. However, controversy exists whether Epo receptor (EpoR) is functional in cancer cells. In this study, we demonstrated that EpoR mRNA expression was detectable in 90.1% of 65 melanoma cell lines, and increased copy number of the Epo and EpoR loci occurred in 30 and 24.6% of 130 primary melanomas, respectively. EpoR knockdown in melanoma cells resulted in diminished ERK phosphorylation in response to Epo stimulation, decreased cell proliferation and increased response to the inhibitory effect of hypoxia and cisplatin in vitro. EpoR knockdown significantly decreased melanoma xenograft size and tumor invasion in vivo. On the contrary, constitutive activation of EpoR activated cell proliferation pathways in melanoma cells and resulted in increased cell proliferation and resistance to hypoxia and cisplatin treatment in vitro. EpoR activation resulted in significantly larger xenografts with increased tumor invasion of surrounding tissue in vivo. Daily administration of recombinant Epo fails to stimulate melanoma growth in vivo, but the treatment increased vascular size in the xenografts. Increased local recurrence after excision of the primary tumors was observed after Epo treatment. Epo induced angiogenesis in Matrigel plug assays, and neutralization of Epo secreted by melanoma cells results in decreased angiogenesis. These data support that EpoR is functional in melanoma and EpoR activation may promote melanoma progression, and suggest that Epo may stimulate angiogenesis and increase survival of melanoma cells under hypoxic condition in vivo.


Direct and Auger Electron-Induced, Single- and Double-Strand Breaks on Plasmid DNA Caused by 99mTc-Labeled Pyrene Derivatives and the Effect of Bonding Distance.
It is evident that 99mTc causes radical-mediated DNA damage due to Auger electrons, which were emitted simultaneously with the known γ-emission of 99mTc. We have synthesized a series of new 99mTc-labeled pyrene derivatives with varied distances between the pyrene moiety and the radionuclide. The pyrene motif is a common DNA intercalator and allowed us to test the influence of the radionuclide distance on damages of the DNA helix. In general, pUC 19 plasmid DNA enables the investigation of the unprotected interactions between the radiotracers and DNA that results in single-strand breaks (SSB) or double-strand breaks (DSB). The resulting DNA fragments were separated by gel electrophoresis and quantified by fluorescent staining. Direct DNA damage and radical-induced indirect DNA damage by radiolysis products of water were evaluated in the presence or absence of the radical scavenger DMSO. We demonstrated that Auger electrons directly induced both SSB and DSB in high efficiency when 99mTc was tightly bound to the plasmid DNA and this damage could not be completely prevented by DMSO, a free radical scavenger. For the first time, we were able to minimize this effect by increasing the carbon chain lengths between the pyrene moiety and the 99mTc nuclide. However, a critical distance between the 99mTc atom and the DNA helix could not be determined due to the significantly lowered DSB generation resulting from the interaction which is dependent on the type of the 99mTc binding motif. The effect of variable DNA damage caused by the different chain length between the pyrene residue and the Tc-core as well as the possible conformations of the applied Tc-complexes was supplemented with molecular dynamics (MD) calculations. The effectiveness of the DNA-binding 99mTc-labeled pyrene derivatives was demonstrated by comparison to non-DNA-binding 99mTcO4-, since nearly all DNA damage caused by 99mTcO4- was prevented by incubating with DMSO.


Targeted gene panel sequencing in early infantile onset developmental and epileptic encephalopathy.
Early-onset developmental and epileptic encephalopathy (DEE) is characterized by repeated seizures beginning within 3 months of birth and severe interictal epileptiform discharge, including burst suppression. This study assessed the utility of targeted gene panel sequencing in the genetic diagnosis of this disease. Targeted gene panel sequencing was performed in 150 early infantile-onset DEE patients (≤3 months of age), and we extensively reviewed their clinical characteristics, including therapeutic efficacy, according to genotype. Of the early infantile-onset DEE patients, 70 were neonatal-onset DEE and the other 80 patients began experiencing seizures from 1 to 3 months after birth. There were 11 different pathogenic or likely pathogenic variants among 34.7% (52/150) of patients with early infantile-onset DEE, in whom KCNQ2, STXBP1, CDKL5, and SCN1A were the major pathogenic variants. Among the neonatal-onset DEE patients, pathological genes were identified in 42.9% (30/70), indicating a significantly higher diagnostic yield than in 27.5% (22/80) of patients who experienced seizure onset 1 to 3 months after birth (p = 0.048). Among the neonatal-onset DEE group, variants in KCNQ2, STXBP1, and CDKL5 were detected at high frequencies, accounting for 66.7% (20/30) of the pathogenic or likely pathogenic variants found in this study. Targeted gene panel sequencing demonstrated a high yield of pathogenic variants in the diagnosis of early-onset epileptic encephalopathy, especially in those with neonatal-onset DEE. Early diagnosis of early-onset epileptic encephalopathy may improve the prognosis of patients by earlier selection of appropriate treatment based on pathogenic variant.


[Some aspects of rhinoseptoplasty].
The article contents analysis of preoperative preparation of 34 patients for rhinoseptoplasty, points out most frequent short- and long-term complications, methods of complications prevention and management. It is recommended to use computed imaging and endoscopy for examination of patients with nasal deformation. Psychological status of the patient should be examined not only by the surgeon but also by the psychologist and psychiatrist.


Weight Stigmatization among Physical Therapy Students and Registered Physical Therapists.
Weight stigmatization is reflected in anti-fat attitudes and stereotypical perceptions of people who are overweight; it has been demonstrated to be prevalent in many segments of society across multiple countries. Studies examining the prevalence of weight stigmatization use different research tools, which can hinder inter-study comparisons. There is also evidence indicating weight stigmatization among registered physical therapists, although its magnitude differs between studies. Limited information exists regarding the attitudes and beliefs of physical therapy (PT) students toward individuals with obesity. Examining weight stigmatization among PT students is particularly important for developing appropriate educational interventions that may influence the professional lives of future physical therapists. This study aims to characterize and compare the stigmatizing attitudes and beliefs of PT students and certified physical therapists regarding people with obesity in Israel. Its secondary objective is to translate three weight stigmatization questionnaires into Hebrew and determine their psychometric properties. A cross-sectional, anonymous, and computerized self-report survey was completed by 285 certified physical therapists (average age 39.6 ± 10.1 years) and 115 PT students (average age 26.4 ± 4.9 years). The study used three validated weight stigma questionnaires employed in earlier studies to determine different aspects of weight stigmatization: the Fat Phobia Scale (short form; FPS), Anti-Fat Attitudes (AFA) questionnaire, and Beliefs about Obese People (BAOP). These questionnaires were translated into Hebrew and their psychometric properties ascertained. Similar to the original English versions, the translated versions of the three questionnaires demonstrated good internal consistency (Cronbach's α values of FPS = 0.77; AFA = 0.75; BOAP = 0.59). The three questionnaires showed a low correlation. No significant difference was noted in the FPS and AFA scores between groups, reflecting that both demonstrated average weight stigmatization (FBS in both groups: average score of 3.6 out of 5; AFA therapists: 3.3 ± 1.2, students: 3.0 ± 1.2 out of 9). However, significant between-group differences were observed for BOAP, which examines beliefs regarding individuals' control over their weight (therapists: 16.4 ± 5.6, students: 18.0 ± 5.7 out of 48; p < 0.01). Student and certified physical therapists demonstrate average levels of weight stigmatization, as reflected in the FPS and AFA scores. Nevertheless, compared to certified physical therapists, physical therapist students believe more strongly that obesity cannot be controlled by the individual. The students' beliefs could affect their clinical judgment and behavior as health care professionals in the future. Therefore, anti-fat attitudes and stereotypical perceptions should be addressed and remediated early using educational interventions during the study period.


Breast deformities and mastopexy.
LEARNING OBJECTIONS: After reviewing this article, the participant should be able to: 1. Appreciate the diversity of approaches for the correction of breast deformities and mastopexy. 2. Review the salient literature. 3. Understand patient selection criteria and indications. Breast deformities and mastopexy continue to challenge plastic surgeons. Deformities such as Poland syndrome, tuberous breast, gynecomastia, and other congenital conditions are uncommon; therefore, management experience is often limited. Various techniques have been described, with no general consensus regarding optimal management. Mastopexy has become more common and is performed both with and without augmentation mammaplasty. However, a variety of techniques are available, and a thorough understanding of the indications, patient selection criteria, and techniques is important to optimize outcomes. This article will review these and other conditions to provide a better understanding of the current available data and evidence for these operations.


The impact of sodium aescinate on acute lung injury induced by oleic acid in rats.
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with high rates of morbidity and mortality. Currently, several surfactant or anti-inflammatory drugs are under test as treatments for ALI. Sodium aescinate (SA) has been shown to exert anti-inflammatory and antiedematous effects. In the present work, the authors explored the effects of SA and the possible mechanisms of SA action in rats with ALI induced by oleic acid (OA) administration. Eight groups of rats received infusions of normal saline (NS) or OA. Rats exposed to OA were pretreated with 1 mg/kg of SA, or posttreated with SA at low (1 mg/kg), medium (2 mg/kg), or high (6 mg/kg) dose; a positive-control group received methylprednisolone. The pressure of oxygen in arterial blood (P(O(2))) levels, the pulmonary wet/dry weight (W/D) ratios, and indices of quantitative assessment (IQA) of histological lung injury were obtained 2 or 6 hours after OA injection (0.1 mL/kg, intravenously). The levels of superoxide dismutase (SOD), malondialdehyde (MDA), matrix metalloproteinase gelatinase B (MMP-9), and tissue inhibitor of metalloproteinase (TIMP-1) in both plasma and lung tissue were also determined. Both pre- and posttreatment with SA improved OA-induced pulmonary injury, increased P(O(2)) and SOD values, lowered IQA scores, and decreased the lung W/D ratio and MDA and MMP-9 levels in plasma and lung tissue. SA appeared to abrogate OA-induced ALI by modulating the levels of SOD, MDA, and MMP-9 in plasma and lung tissue.


Xenobiotic-induced activation of human aryl hydrocarbon receptor target genes in Drosophila is mediated by the epigenetic chromatin modifiers.
Aryl hydrocarbon receptor (AHR) is the key transcription factor that controls animal development and various adaptive processes. The AHR's target genes are involved in biodegradation of endogenous and exogenous toxins, regulation of immune response, organogenesis, and neurogenesis. Ligand binding is important for the activation of the AHR signaling pathway. Invertebrate AHR homologs are activated by endogenous ligands whereas vertebrate AHR can be activated by both endogenous and exogenous ligands (xenobiotics). Several studies using mammalian cultured cells have demonstrated that transcription of the AHR target genes can be activated by exogenous AHR ligands, but little is known about the effects of AHR in a living organism. Here, we examined the effects of human AHR and its ligands using transgenic Drosophila lines with an inducible human AhR gene. We found that exogenous AHR ligands can increase as well as decrease the transcription levels of the AHR target genes, including genes that control proliferation, motility, polarization, and programmed cell death. This suggests that AHR activation may affect the expression of gene networks that could be critical for cancer progression and metastasis. Importantly, we found that AHR target genes are also controlled by the enzymes that modify chromatin structure, in particular components of the epigenetic Polycomb Repressive complexes 1 and 2. Since exogenous AHR ligands (alternatively - xenobiotics) and small molecule inhibitors of epigenetic modifiers are often used as pharmaceutical anticancer drugs, our findings may have significant implications in designing new combinations of therapeutic treatments for oncological diseases.


Panchromatic photoproduction of H2 with surface plasmons.
The optical resonances of plasmonic nanostructures depend critically on the geometrical details of the absorber. We show that this unique property of plasmons can potentially be used to create panchromatic absorbers covering most of the useful solar spectrum, by measuring the light-to-hydrogen conversion capabilities of a series multielectrode photocatalytic devices, based on functionalized gold nanorods of appropriately chosen aspect ratios. Judiciously combining nanorods of various aspect ratios almost doubles the H2 production of the device over what is optimally possible with a device using gold nanorods of a single aspect ratio (all other key parameters being equal). The estimated quantum efficiency (absorbed photons-to-hydrogen) averaged over the entire solar spectrum of the best performing plasmonic multielectrode array was approximately 0.1%, and the measured H2 production rate for all of the devices was found to be approximately proportional to the hot electron generation. The device was monitored continuously for over 200 hr of operation without measurable diminution in the rate.


Media Coverage of Pedophilia and Its Impact on Help-Seeking Persons with Pedophilia in Germany-A Focus Group Study.
The public stigma associated with pedophilia, the sexual attraction to prepubescent children, is tremendous. Previous research indicates that undifferentiated media coverage plays an essential role in perpetuating the public stigma by falsely equating pedophilia and child sexual abuse (CSA) and thus may stop persons suffering from a pedophilic disorder from seeking professional help. Until now, a comprehensive examination of positive as well as negative media effects on affected individuals is missing. Therefore, the present study explores if and how media coverage impacts the lives of help-seeking persons with pedophilia by conducting four qualitative focus group discussions with a clinical sample (N = 20) from the German Prevention Network "Kein Täter werden". Present results demonstrate that media coverage of pedophilia was perceived as mostly undifferentiated, even though participants observed an increase in fact-based reporting over the years. Moreover, it seems that media coverage has strong emotional and behavioral consequences for patients (e.g., negative reporting reduced self-esteem). In sum, our results highlight that differentiated media coverage could play a key role in supporting help-seeking persons with pedophilic disorder, while the impact of undifferentiated media coverage appears to be mostly negative. Therefore, our results point to the need to reframe pedophilia using differentiated media coverage to help affected persons receive treatment efficiently and thereby prevent CSA.


Interference of Pteridium arachnoideum (Kaulf.) Maxon. (Dennstaedtiaceae) on the establishment of rainforest trees.
In order to identify the effect of P. arachnoideum, we studied 11 native tree species commonly used in reforestation projects. Bioassays were conducted in laboratory to evaluate the effect of bracken leachate on the germination and morphology of seedlings. Juveniles of some of these species were planted in two adjacent but contrasting areas in relation to the dominance of P. arachnoideum. The evaluation of growth and survivorship was performed after six and twelve months. This study reveals that for some pioneer and secondary trees P. arachnoideum leachate exerted an inhibitory effect on seed germination and seedling morphology. Field experiments revealed that pioneers are apparently more resistant to P. arachnoideum leachate than secondary species.


Numerical investigation of a typhoid disease model in fuzzy environment.
Salmonella Typhi, a bacteria, is responsible for typhoid fever, a potentially dangerous infection. Typhoid fever affects a large number of people each year, estimated to be between 11 and 20 million, resulting in a high mortality rate of 128,000 to 161,000 deaths. This research investigates a robust numerical analytic strategy for typhoid fever that takes infection protection into consideration and incorporates fuzzy parameters. The use of fuzzy parameters acknowledges the variation in parameter values among individuals in the population, which leads to uncertainties. Because of their diverse histories, different age groups within this community may exhibit distinct customs, habits, and levels of resistance. Fuzzy theory appears as the most appropriate instrument for dealing with these uncertainty. With this in mind, a model of typhoid fever featuring fuzzy parameters is thoroughly examined. Two numerical techniques are developed within a fuzzy framework to address this model. We employ the non-standard finite difference (NSFD) scheme, which ensures the preservation of essential properties like dynamic consistency and positivity. Additionally, we conduct numerical simulations to illustrate the practical applicability of the developed technique. In contrast to many classical methods commonly found in the literature, the proposed approach exhibits unconditional convergence, solidifying its status as a dependable tool for investigating the dynamics of typhoid disease.


Intramuscular metastatic squamous cell carcinoma of the cervix: autopsy case report.
Cancer of the uterine cervix is the fourth leading cause of death in women in Brazil, accounting for 4800 fatal cases per year. The histology of this neoplasia is mainly represented by squamous cell carcinoma (80-85%), adenocarcinomas (10-15%), and, more rarely, mixed carcinomas. The Papanicolaou (Pap) smear test is the method of excellence in detecting incipient or pre-malignant lesions. Since its implementation, the Pap test has been reducing the incidence of this neoplasia worldwide, despite its lack of high sensitivity and specificity. Both incidence and mortality from cervical cancer have sharply decreased following the introduction of well-run screening programs. The cervical cancer typically spreads to adjacent structures by contiguity; pelvic and para-aortic lymph nodes are involved by lymphatic dissemination. Less frequently, hematogenic spread is observed, and when it occurs, the brain, breast, and skeletal muscle are rarely involved. The authors report a case of a young woman who underwent periodical gynecological examination with negative Pap tests and presented to the hospital with an advanced cervical metastatic disease involving thyroid, muscles, lymph nodes, and breast (among others sites). The diagnosis of the primary site was not elucidated during life. The patient died, and at autopsy an endophytic squamous cell carcinoma of the cervix was diagnosed.


A Comparison of Nonoperative and Operative Treatment of Type 2 Tibial Spine Fractures.
Tibial spine fractures (TSFs) are typically treated nonoperatively when nondisplaced and operatively when completely displaced. However, it is unclear whether displaced but hinged (type 2) TSFs should be treated operatively or nonoperatively. To compare operative versus nonoperative treatment of type 2 TSFs in terms of overall complication rate, ligamentous laxity, knee range of motion, and rate of subsequent operation. Cohort study; Level of evidence, 3. We reviewed 164 type 2 TSFs in patients aged 6 to 16 years treated between January 1, 2000, and January 31, 2019. Excluded were patients with previous TSFs, anterior cruciate ligament (ACL) injury, femoral or tibial fractures, or grade 2 or 3 injury of the collateral ligaments or posterior cruciate ligament. Patients were placed according to treatment into the operative group (n = 123) or nonoperative group (n = 41). The only patient characteristic that differed between groups was body mass index (22 [nonoperative] vs 20 [operative]; P = .02). Duration of follow-up was longer in the operative versus the nonoperative group (11 vs 6.9 months). At final follow-up, 74% of all patients had recorded laxity examinations. At final follow-up, the nonoperative group had more ACL laxity than did the operative group (P < .01). Groups did not differ significantly in overall complication rate, reoperation rate, or total range of motion (all, P > .05). The nonoperative group had a higher rate of subsequent new TSFs and ACL injuries requiring surgery (4.9%) when compared with the operative group (0%; P = .01). The operative group had a higher rate of arthrofibrosis (8.9%) than did the nonoperative group (0%; P = .047). Reoperation was most common for hardware removal (14%), lysis of adhesions (6.5%), and manipulation under anesthesia (6.5%). Although complication rates were similar between nonoperatively and operatively treated type 2 TSFs, patients treated nonoperatively had higher rates of residual laxity and subsequent tibial spine and ACL surgery, whereas patients treated operatively had a higher rate of arthrofibrosis. These findings should be considered when treating patients with type 2 TSF.


Methyl-CpG binding domain protein 1 regulates localization and activity of Tet1 in a CXXC3 domain-dependent manner.
Cytosine modifications diversify and structure the genome thereby controlling proper development and differentiation. Here, we focus on the interplay of the 5-methylcytosine reader Mbd1 and modifier Tet1 by analyzing their dynamic subcellular localization and the formation of the Tet oxidation product 5-hydroxymethylcytosine in mammalian cells. Our results demonstrate that Mbd1 enhances Tet1-mediated 5-methylcytosine oxidation. We show that this is due to enhancing the localization of Tet1, but not of Tet2 and Tet3 at heterochromatic DNA. We find that the recruitment of Tet1 and concomitantly its catalytic activity eventually leads to the displacement of Mbd1 from methylated DNA. Finally, we demonstrate that increased Tet1 heterochromatin localization and 5-methylcytosine oxidation are dependent on the CXXC3 domain of Mbd1, which recognizes unmethylated CpG dinucleotides. The Mbd1 CXXC3 domain deletion isoform, which retains only binding to methylated CpGs, on the other hand, blocks Tet1-mediated 5-methylcytosine to 5-hydroxymethylcytosine conversion, indicating opposite biological effects of Mbd1 isoforms. Our study provides new insights on how cytosine modifications, their modifiers and readers cross-regulate themselves.


A broad-taxa approach as an important concept in ecotoxicological studies and pollution monitoring.
Aquatic invertebrates play a pivotal role in (eco)toxicological assessments because they offer ethical, cost-effective and repeatable testing options. Additionally, their significance in the food chain and their ability to represent diverse aquatic ecosystems make them valuable subjects for (eco)toxicological studies. To ensure consistency and comparability across studies, international (eco)toxicology guidelines have been used to establish standardised methods and protocols for data collection, analysis and interpretation. However, the current standardised protocols primarily focus on a limited number of aquatic invertebrate species, mainly from Arthropoda, Mollusca and Annelida. These protocols are suitable for basic toxicity screening, effectively assessing the immediate and severe effects of toxic substances on organisms. For more comprehensive and ecologically relevant assessments, particularly those addressing long-term effects and ecosystem-wide impacts, we recommended the use of a broader diversity of species, since the present choice of taxa exacerbates the limited scope of basic ecotoxicological studies. This review provides a comprehensive overview of (eco)toxicological studies, focusing on major aquatic invertebrate taxa and how they are used to assess the impact of chemicals in diverse aquatic environments. The present work supports the use of a broad-taxa approach in basic environmental assessments, as it better represents the natural populations inhabiting various ecosystems. Advances in omics and other biochemical and computational techniques make the broad-taxa approach more feasible, enabling mechanistic studies on non-model organisms. By combining these approaches with in vitro techniques together with the broad-taxa approach, researchers can gain insights into less-explored impacts of pollution, such as changes in population diversity, the development of tolerance and transgenerational inheritance of pollution responses, the impact on organism phenotypic plasticity, biological invasion outcomes, social behaviour changes, metabolome changes, regeneration phenomena, disease susceptibility and tissue pathologies. This review also emphasises the need for harmonised data-reporting standards and minimum annotation checklists to ensure that research results are findable, accessible, interoperable and reusable (FAIR), maximising the use and reusability of data. The ultimate goal is to encourage integrated and holistic problem-focused collaboration between diverse scientific disciplines, international standardisation organisations and decision-making bodies, with a focus on transdisciplinary knowledge co-production for the One-Health approach.


Change in the positional specificity of lipoxygenase 1 due to insertion of fatty acids into phosphatidylcholine deoxycholate mixed micelles.
Linoleic and arachidonic acids were inserted into phosphatidylcholine deoxycholate mixed micelles (PDM-micelles) with their tail groups buried inside and carboxylic groups exposed outside. The fatty acid hydrophobic tail had a high affinity for the hydrophobic region of phosphatidylcholine micelles. The fatty acids inserted into phosphatidylcholine micelles were better substrates for soybean lipoxygenase 1 (LOX1) with two distinct pH optima at 7.0 and 10.0. With Tween 20-solubilized linoleic acid, the enzyme had a pH optimum at 9.0, exclusively forming 13-hydroperoxides. However, with linoleic and arachidonic acids inserted into PDM-micelles, LOX1 synthesized exclusively 9- and 5-hydroperoxides, respectively. The enzyme brought about the transformation of the substrate either at pH 7.4 or at 10.0, less efficiently at pH 10.0. However, the regioselectivity of the enzyme was not altered by increasing the pH from 7.4 to 10.0. Thus, LOX1 could utilize fatty acids bound to membranes as physiological substrates. The enzyme utilized the carboxylic group of linoleic and arachidonic acids inserted into the PDM-micelles as a recognition site to convert the compounds into 9- and 5-hydroperoxides, respectively. This was confirmed by activity measurements using methyl linoleate as the substrate. Circular dichroism measurement of LOX1 with PDM-micelles suggested that while there was a small change in the tertiary structure of LOX1, the secondary structure was unaffected. Soybean LOX1, which is arachidonate 15-LOX, acted as "5-LOX", thus making it possible to change the regiospecificity of the LOX1-catalyzed reaction by altering the physical state of the substrate.


Rosenthal fiber-rich glioblastoma: a case report.
Rosenthal fibers (RFs) are thick, elongated, brightly eosinophilic structures occurring within astrocytic processes. Although the presence of abundant RFs within brain tumors is most closely associated with a low-grade astrocytoma, particularly pilocytic astrocytoma (PA), a few RFs are recognized to occur, although rarely, in glioblastoma (GBM). We report a very rare case of GBM with abundant RFs. A 60-year-old woman presented with a 6-month history of difficulty coordinating her right hand, occasional intermittent diplopia, and occasional dizzy spells. An MRI showed a heterogeneously enhancing, infiltrating mass lesion with a cystic component involving the left midbrain, thalamus, and posterior basal ganglia. Biopsy was performed. Cytologic touch imprints revealed fibrillary astrocytic cells possessing oval nuclei and long delicate processes with abundant RFs. Histologic sections showed diffusely infiltrating astrocytoma with prominent RFs diffusely distributed throughout the tumor, brisk mitotic activity, vascular proliferation, and small areas of necrosis, as seen in a GBM. The Ki-67 (MIB-1) labeling index was 7.1%. P53 immunoreactivity was not seen. A follow-up MRI study performed 3 months after the biopsy showed a considerable tumor progression with extension into the left superior cerebellar peduncle and progressive hydrocephalus. This is a case of RF-rich GBM (primary or de novo type). The differential diagnosis includes PA and anaplastic PA. For the histological diagnosis, infiltrating astrocytoma with abundant RFs should be carefully examined in light of clinical information (e.g., patient age, evolution of the symptoms) and neuroimaging studies.


[Correlation between basal concentration of C-reactive protein in the blood, levels of serum antiendotoxin antibodies and endotoxin-binding capacity of monocytes and granulocytes in healthy people].
The associative links between base concentration of C-reactive protein (hsCRP), levels of serum antiendotoxin antibodies of different classes and endotoxin-binding capacity of monocytes and granulocytes of healthy volunteers were investigated by cluster analysis. In the group of healthy volunteers with increased base concentration of hsCRP in blood the levels of serum antiendotoxin antibodies of different classes and endotoxin-binding capacity of monocytes and granulocytes were reduced. Thus, the disbalance of detoxification and clearance of endotoxin by humoral and cellular mechanisms can be one of the possible causes of development of low intensity inflammation and increase of hsCRP concentration in blood.


Exploring Plants with Flowers: From Therapeutic Nutritional Benefits to Innovative Sustainable Uses.
Flowers have played a significant role in society, focusing on their aesthetic value rather than their food potential. This study's goal was to look into flowering plants for everything from health benefits to other possible applications. This review presents detailed information on 119 species of flowers with agri-food and health relevance. Data were collected on their family, species, common name, commonly used plant part, bioremediation applications, main chemical compounds, medicinal and gastronomic uses, and concentration of bioactive compounds such as carotenoids and phenolic compounds. In this respect, 87% of the floral species studied contain some toxic compounds, sometimes making them inedible, but specific molecules from these species have been used in medicine. Seventy-six percent can be consumed in low doses by infusion. In addition, 97% of the species studied are reported to have medicinal uses (32% immune system), and 63% could be used in the bioremediation of contaminated environments. Significantly, more than 50% of the species were only analysed for total concentrations of carotenoids and phenolic compounds, indicating a significant gap in identifying specific molecules of these bioactive compounds. These potential sources of bioactive compounds could transform the health and nutraceutical industries, offering innovative approaches to combat oxidative stress and promote optimal well-being.


Molecular variation of Trypanosoma brucei subspecies as revealed by AFLP fingerprinting.
Genetic analysis of Trypanosoma spp. depends on the detection of variation between strains. We have used the amplified fragment length polymorphism (AFLP) technique to develop a convenient and reliable method for genetic characterization of Trypanosome (sub)species. AFLP accesses multiple independent sites within the genome and would allow a better definition of the relatedness of different Trypanosome (sub)species. Nine isolates (3 from each T. brucei subspecies) were tested with 40 AFLP primer combinations to identify the most appropriate pairs of restriction endonucleases and selective primers. Primers based on the recognition sequences of EcoRI and BglII were chosen and used to analyse 31 T. brucei isolates. Similarity levels calculated with the Pearson correlation coefficient ranged from 15 to 98%, and clusters were determined using the unweighted pair-group method using arithmetic averages (UPGMA). At the intraspecific level, AFLP fingerprints were grouped by numerical analysis in 2 main clusters, allowing a clear separation of T. b. gambiense (cluster I) from T. b. brucei and T. b. rhodesiense isolates (cluster II). Interspecies evaluation of this customized approach produced heterogeneous AFLP patterns, with unique genetic markers, except for T. evansi and T. equiperdum, which showed identical patterns and clustered together.


Self-reported physical and mental health of Australian carers: a cross-sectional study.
To report on self-reported physical and mental health of informal carers in rural regions of New South Wales, Australia. A cross-sectional community-based sample (n=222) of carers completed a questionnaire incorporating self-reported measures of health from validated international instruments including Medical Outcomes Study Scale (SF-36), the Centre for Epidemiology-Depression (CES-D) and Kessler-10 (K-10) Psychological Distress Scales, along with information on participant demographics and other key caregiving characteristics such as health condition of care recipient. Rural carers' self-reported health was poor as evident on the SF-36 Physical and Mental Health component scores as well as each individual domain of the SF-36. Results from the CES-D and K-10 scores indicated very high rates of depressive symptoms and psychological distress. Over 70% of carers within the current study had CES-D scores indicative of depressive symptoms. Scores on the K-10 indicate almost half the carers were experiencing high levels of psychological distress, which is over 4 times the rate reported in the general Australian population. Results from this study were compared to Australian population normative data and were found to be significantly below Australian age-matched population norms for SF-36, CES-D and K-10. These findings illustrate the poor health profile of informal carers relative to the general Australian population, especially in terms of depressive symptoms and psychological distress. This highlights the need for additional support for rural carers in order to ease the accumulated mental and physical health burdens of this group.


Fluorescence assay for the determination of glutathione based on a ring-fused 2-pyridone derivative in dietary supplements.
Herein, a novel fluorescent method for the determination of GSH levels in aqueous solutions involving the utilization of citric acid as a derivatization reagent was developed. Therefore, the crucial parameters of the derivatization process were established from what has resulted in the development of a sensitive, reproducible, and accurate GSH assay. The method was validated, and its applicability in the characterization of the GSH concentration in dietary supplements concerning the selectivity in the determination of GSH over GSSG was both confirmed. The chemical structure of the new fluorophore 3-[(carboxymethyl)carbamoyl]-5-oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-7-carboxylic acid - CTPC was elucidated using detailed NMR: one-dimensional (1H, 13C), as well as two-dimensional NMR spectra (1H-1H COSY, 1H-13C HSQC, 1H-13C HMBC, 1H-15N HSQC, 1H-15N HMBC) experiments. Besides, the essential optical, biological and antioxidative properties of CTPC were investigated.


Development and Verification of a Linked Δ 9-THC/11-OH-THC Physiologically Based Pharmacokinetic Model in Healthy, Nonpregnant Population and Extrapolation to Pregnant Women.
Conducting clinical trials to understand the exposure risk/benefit relationship of cannabis use is not always feasible. Alternatively, physiologically based pharmacokinetic (PBPK) models can be used to predict exposure of the psychoactive cannabinoid (-)-Δ9-tetrahydrocannabinol (THC) and its active metabolite 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC). Here, we first extrapolated in vitro mechanistic pharmacokinetic information previously quantified to build a linked THC/11-OH-THC PBPK model and verified the model with observed data after intravenous and inhalation administration of THC in a healthy, nonpregnant population. The in vitro to in vivo extrapolation of both THC and 11-OH-THC disposition was successful. The inhalation bioavailability (Finh) of THC after inhalation was higher in chronic versus casual cannabis users (Finh = 0.35 and 0.19, respectively). Sensitivity analysis demonstrated that 11-OH-THC but not THC exposure was sensitive to alterations in hepatic intrinsic clearance of the respective compound. Next, we extrapolated the linked THC/11-OH-THC PBPK model to pregnant women. Simulations showed that THC plasma area under the curve (AUC) does not change during pregnancy, but 11-OH-THC plasma AUC decreases by up to 41%. Using a maternal-fetal PBPK model, maternal and fetal THC serum concentrations were simulated and compared with the observed THC serum concentrations in pregnant women at term. To recapitulate the observed THC fetal serum concentrations, active placental efflux of THC needed to be invoked. In conclusion, we built and verified a linked THC/11-OH-THC PBPK model in healthy nonpregnant population and demonstrated how this mechanistic physiologic and pharmacokinetic platform can be extrapolated to a special population, such as pregnant women. SIGNIFICANCE STATEMENT: Although the pharmacokinetics of cannabinoids have been extensively studied clinically, limited mechanistic pharmacokinetic models exist. Here, we developed and verified a physiologically based pharmacokinetic (PBPK) model for (-)-Δ9-tetrahydrocannabinol (THC) and its active metabolite, 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC). The PBPK model was verified in healthy, nonpregnant population after intravenous and inhalation administration of THC, and then extrapolated to pregnant women. The THC/11-OH-THC PBPK model can be used to predict exposure in special populations, predict drug-drug interactions, or impact of genetic polymorphism.


[Vulnerability and health problems while traveling: the viewpoint of the tourist in the city of Rio de Janeiro].
This article examines how a group of tourists perceives health issues related to safety, prevention and health care during their travels. Interviews were conducted with Brazilian tourists visiting the city of Rio de Janeiro, as well as local residents leaving the city on trips. The interviews were analyzed in accordance with the dimensions of vulnerability, information, prevention and health care, from which vulnerability emerged as a category of analysis. The reports of the trajectory of the tourists made it possible to identify problems and opportunities that could be used by the health sector for actions of prevention and promotion. The means of transport determines the trajectory of tourists and their security alternatives. Traveling in groups and visiting tourist attractions are seen as protective factors, which reinforces the role of information and social support networks as resources used by tourists in the absence of specific policies geared to this highly mobile and vulnerable population group.