Anticancer and superoxide scavenging activities of p-alkylaminophenols having various length alkyl chains.
A series of p-alkylaminophenols including 3, p-butylaminophenol; 4, p-hexylaminophenol; 5, p-octylaminophenol; and 6, N-(p-methoxybenzyl)aminophenol were synthesized based on the structure of fenretinide, N-(4-hydroxyphenyl)retinamide (1). This latter agent is a synthetic amide of all-trans-retinoic acid (RA), which is a cancer chemopreventive and antiproliferative agent. It was found that elongation of the alkyl chain length in these compounds increased antioxidative activity and inhibition of lipid peroxidation. These findings led us to investigate whether antiproliferative activity against cancer cells was effected by the length of alkyl chains linked to the aminophenol residue. All p-alkylaminophenols inhibited growth of HL60 and HL60R cells in a dose-dependent manners. The HL60R line is a resistant clone against RA. Growth of various cancer cell lines (HL60, HL60R, MCF-7, MCF-7/Adr(R), HepG2, and DU-145) was suppressed by p-alkylaminophenols in a fashion dependent on the aminophenol alkyl chain length (5>4>3>p-methylaminophenol (2)), with 5 being the most potent inhibitor of cell growth against HL60R, MCF-7/Adr(R), and DU-145 cells among p-alkylaminophenols tested, including 1. In particular, with the exception of compound 2, antiproliferative activity against DU-145 cells by these p-alkylaminophenols was greater than by 1. In HL60 cells, growth inhibition was associated with apoptosis. On the other hand, elongation of the alkyl chain length reduced superoxide trapping capability (2>3>4>5) in contrast to the effects on inhibition of lipid peroxidation. These results indicate that anticancer activity of p-alkylaminophenols correlated with the inhibitory activity of lipid peroxidation, but not with the superoxide scavenging activity.


Dietary consumption of meat, fat, animal products and advanced glycation end-products and the risk of Barrett's oesophagus.
Advanced glycation end-products (AGEs) are found in high quantity in high-fat foods and meat cooked at high temperature. AGEs have been shown to contribute to chronic inflammation and oxidative stress in humans. To investigate the associations between consumption of meat, fat and AGEs, and the risk of Barrett's oesophagus (BO). We conducted a case-control study using data from the patients who were scheduled for elective esophagogastroduodenoscopy (EGD) and from a random sample of patients who were identified at primary care clinics. Daily consumption of meat, fat and Nε-(carboxymethyl) lysine (CML), a major type of AGEs, was derived from the food frequency questionnaire (FFQ). Multivariate logistic regression models were used to estimate the odds ratio (OR) and its 95% confidence interval (CI) for BO. A total of 151 cases with BO and 777 controls without BO completed the FFQ. The multivariate OR (95% CI) for BO was 1.91 (1.07-3.38) for total meat, 1.80 (1.02-3.16) for saturated fat and 1.63 (0.96-2.76) for CML-AGE, when the highest tertile of intake was compared with the lowest. The association for total meat was attenuated to 1.61 (0.82-3.16), and that for saturated fat to 1.54 (0.81-2.94) after adjusting for CML-AGE. Higher consumption of total meat, saturated fat or possibly CML-AGE was associated with an increased risk of Barrett's oesophagus. CML-AGE may partly explain the association between total meat and saturated fat consumption and the risk of Barrett's oesophagus.


Human papilloma virus vaccine and cervical cancer screening acceptability among adults in Quebec, Canada.
The Pap test has been used for cervical cancer screening for more than four decades. A human papillomavirus (HPV) vaccine has been approved for use in Canada and is commercially available now. These two preventive interventions should be considered simultaneously. General population support is an important factor for the successful combination of these interventions. The study had two objectives: 1) To assess practices, beliefs, and attitudes regarding Pap test screening and HPV immunization; 2) To identify socio-demographic factors for Pap screening and vaccine acceptability. In 2006, 500 adults were invited to participate in a telephone survey in the region of Quebec City (urban and rural population, 600 000), Canada. Some neutral and standardized information on Pap test and HPV was provided before soliciting opinions. 471 adults (18-69 year-olds) answered the questionnaire, the mean age was 45 years, 67% were female, and 65% had college or university degree. Eighty-six percent of women had undergone at least one Pap-test in their life, 55% in the last year, and 15% from 1 to 3 years ago. Among screened women, the test had been performed in the last three years in 100% of 18-30 year-olds, but only in 67% of 60-69 year-olds (P < 0.0001). Only 15% of respondents had heard of HPV. Eighty-seven percent agreed that HPV vaccines could prevent cervical cancer, 73% that the vaccine has to be administered before the onset of sexual activity, 89% would recommend vaccination to their daughters and nieces. Among respondents < 25 years, 91% would agree to receive the vaccine if it is publicly funded, but only 72% would agree to pay $100/dose. There is an important heterogeneity in cervical cancer screening frequency and coverage. Despite low awareness of HPV infection, the majority of respondents would recommend or are ready to receive the HPV vaccine, but the cost could prevent its acceptability.


Omitting Ciprofloxacin Prophylaxis in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation and Its Impact on Clinical Outcomes and Microbiome Structure.
Fluoroquinolone prophylaxis during allogeneic hematopoietic stem cell transplantation (allo-HSCT) reduces bloodstream infections. However, this practice affects the gut microbiome and potentially increases dysbiosis, which is closely related to transplantation outcomes, and lower gastrointestinal (GI) tract acute graft-versus-host disease (GVHD). This study assessed the impact of omitting ciprofloxacin prophylaxis on GI GVHD, clinical outcomes, and microbiome composition in patients undergoing allo-HSCT. In this single-center, retrospective study comprising recipients of allo-HSCT performed between 2018 and 2020, routine ciprofloxacin prophylaxis (the exposure variable) was stopped in December 2018. The primary outcome was acute lower GI GVHD within 100 days post-transplantation; secondary outcomes were 1-year overall survival, nonrelapse mortality, relapse, and overall acute GVHD. Outcomes were compared using univariate and multivariate analyses and Kaplan-Meier/competing-risk analyses. Sequential stool samples were collected prospectively from a subpopulation of recipients, and the microbiome composition was analyzed. Seventy-five of the 129 patients (58.1%) received prophylactic ciprofloxacin treatment. Baseline characteristics did not differ between the 2 study groups: patients with ciprofloxacin prophylaxis and those without ciprofloxacin prophylaxis. The rate of lower GI GVHD also did not differ between the 2 groups (24% versus 18.5%; P = .597). None of the secondary outcomes was significantly different between the 2 groups in univariate, multivariate, and time-to-event analyses. In addition, microbiome analysis in a subpopulation of 22 patients did not reveal any significant between-group difference in alpha or beta diversity. Omitting prophylactic ciprofloxacin during allo-HSCT did not affect microbiome composition, lower GI-GVHD rate, or other significant clinical outcomes. The use of prophylactic antibiotics in this setting should be evaluated further.


Automated production of [68Ga]Ga-DOTA-exendin-4 via fractionated radionuclide generator elution on a cassette based synthesis module.
PET/CT imaging of glucagon-like peptide receptor 1 has recently filled a gap in reliably diagnosing insulinoma through non-invasive means. 68Ga-labelled derivatives of exendin-4 show high sensitivity as well as sufficient serum stability to enable routine clinical application. Here, we provide data for automated production of [68Ga][Nle14,Lys40(Ahx-DOTA-Ga)NH2]exendin-4 ([68Ga]Ga-DOTA-exendin-4) on a cassette based synthesis module (Modular-Lab PharmTracer, Eckert & Ziegler) using commercially available cassettes in combination with an approved 68Ge/68Ga generator (GalliaPharm, Eckert & Ziegler). This setup ensured high reproducibility as well as low radiation burden for the production team. Quality control including determination of radiochemical purity was performed by RP-HPLC using a water/0.1 % TFA/acetonitrile gradient on a C18 column. A modified TLC system with ammonium acetate & methanol as mobile phase and a novel limit test for determination of polysorbate 80 content in the final formulation are also described in this study. Reliable yields as well as high molar activity for patient use were only achieved using a fractionated elution approach. Batch data showed radiochemical purity of >93 % as determined by RP-HPLC and TLC as well as good stability over 2 h post production. Testing for polysorbate 80 confirmed a concentration <1 mg/mL in the final product solution. Specifications for routine production were established based on existing Pharmacopeia monographs for other radiopharmaceuticals and were validated with 5 master batches. The described synthesis method enables reproducible, automated in-house production of [68Ga]Ga-DOTA-exendin-4 for routine clinical application.


Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs).
Most gastrointestinal stromal tumors (GISTs) express constitutively activated forms of the KIT receptor tyrosine kinase protein, resulting from oncogenic mutations in the extracellular, juxtamembrane, or kinase domains. KIT oncoproteins are detected early in GIST tumorigenesis, and most GIST patients respond well to treatment with the KIT kinase inhibitor imatinib mesylate (STI571, Gleevec). However, GISTs can develop resistance to imatinib, and additional therapeutic strategies are needed. Little is known about oncogenic KIT signal transduction in GISTs, and whether the type of KIT mutation accounts for selective activation of downstream signaling intermediates. We therefore evaluated KIT downstream signaling profiles in 15 primary GISTs with mutations in KIT exons 9, 11, 13, and 17, and in two human GIST cell lines. All GISTs showed constitutive phosphorylation at KIT tyrosine residues Y703 and Y721. Additionally, most GISTs showed activation of MAPK p42/44, AKT, S6K, STAT1, and STAT3. STAT5 and JNK were not demonstrably activated in any GIST. Using GIST in vitro models, we showed that activation of MAPK p42/44, AKT, and S6K was KIT dependent, whereas STAT1 and STAT3 phosphorylation was only partially dependent on KIT activation. Correlation of activated signaling pathways with the type of KIT mutation revealed low levels of AKT phosphorylation in exon 9 mutant GISTs in contrast to a subset of GISTs with exon 11 mutations. However, additional factors are likely to modify the engagement of signaling pathways in GISTs as suggested by the fact that four GISTs with identical KIT exon 9 mutations had differential activation of MAPK p42/44 and STAT proteins. In summary, in this first report on KIT signal transduction in primary GISTs and GIST cell lines, we identified pathways that are constitutively activated in a KIT-dependent manner and therefore warrant further study as molecular targets in GISTs.


Piles of defeat. Napoleon at Waterloo.
Major events of history have frequently turned on seemingly trivial matters. One such situation involves Napoleon Bonaparte at Waterloo. Napoleon was not feeling well on the day of the battle of Waterloo, despite fighting well at Ligny, a few days before the last, dramatic June 18 battle. There is considerable indication that Napoleon was bothered by very painful thrombosed hemorrhoids. Did this affect his generalship that day? What is the evidence that Napoleon was afflicted with thrombosed hemorrhoids? What contribution could this factor have made to the French defeat at Waterloo?


Bioactive sterols from marine resources and their potential benefits for human health.
Bioactive agents from marine resources have shown their valuable health beneficial effects. Therefore, increase knowledge on novel functional ingredients with biological activities from marine animal and microbe has gained much attention. Sterols are recognized as potential in development functional food ingredients and pharmaceutical agents. Marine resources, with a great diversity, can be a very interesting natural resource of sterols. This chapter focuses on biological activities of marine animal and microbe sterols with potential health beneficial applications in functional foods and pharmaceuticals.


Exosomes derived from human adipose mesenchymal stem cells loaded bioengineered three-dimensional amniotic membrane-scaffold-accelerated diabetic wound healing.
The occurrence of wounds and defects in the healing process is one of the main challenges in diabetic patients. Herein, we investigated whether adipose-derived stem cells (ADSCs)-derived exosomes loaded bioengineered micro-porous three-dimensional amniotic membrane-scaffold (AMS) could promote healing in diabetic rats. Sixty diabetic rats were randomly allocated into the control group, exosome group, AMS group, and AMS + Exo group. On days 7, 14, and 21, five rats from each group were sampled for stereological, immunohistochemical, molecular, and tensiometrical assessments. Our results indicated that the wound closure rate, the total volumes of newly formed epidermis and dermis, the numerical densities of fibroblasts and proliferating cells, the length density blood vessels, collagen density as well as tensiometrical parameters of the healed wounds were considerably greater in the treated groups than in the control group, and these changes were more obvious in the AMS + Exo ones. Furthermore, the expression of TGF-β, bFGF, and VEGF genes was meaningfully upregulated in all treated groups compared to the control group and were greater in the AMS + Exo group. This is while expression of TNF-α and IL-1β, as well as cell numerical densities of neutrophils, M1 macrophages, and mast cells decreased more considerably in the AMS + Exo group in comparison with the other groups. Generally, it was found that using both AMS transplantation and ADSCs-derived exosomes has more effect on diabetic wound healing.


Functional diversity of family 3 β-glucosidases from thermophilic cellulolytic fungus Humicola insolens Y1.
The fungus Humicola insolens is one of the most powerful decomposers of crystalline cellulose. However, studies on the β-glucosidases from this fungus remain insufficient, especially on glycosyl hydrolase family 3 enzymes. In the present study, we analyzed the functional diversity of three distant family 3 β-glucosidases from Humicola insolens strain Y1, which belonged to different evolutionary clades, by heterogeneous expression in Pichia pastoris strain GS115. The recombinant enzymes shared similar enzymatic properties including thermophilic and neutral optima (50-60 °C and pH 5.5-6.0) and high glucose tolerance, but differed in substrate specificities and kinetics. HiBgl3B was solely active towards aryl β-glucosides while HiBgl3A and HiBgl3C showed broad substrate specificities including both disaccharides and aryl β-glucosides. Of the three enzymes, HiBgl3C exhibited the highest specific activity (158.8 U/mg on pNPG and 56.4 U/mg on cellobiose) and catalytic efficiency and had the capacity to promote cellulose degradation. Substitutions of three key residues Ile48, Ile278 and Thr484 of HiBgl3B to the corresponding residues of HiBgl3A conferred the enzyme activity towards sophorose, and vice versa. This study reveals the functional diversity of GH3 β-glucosidases as well as the key residues in recognizing +1 subsite of different substrates.


Nβ-methylation changes the recognition pattern of aza-β3-amino acid containing peptidomimetic substrates by protein kinase A.
The protein kinase A (PKA)-catalyzed phosphorylation of peptide substrate RRASVA analogs, containing Nβ-Me-aza-β3-amino acid residues in all subsequent positions, was studied. This work follows along the lines of our previous research of the phosphorylation of aza-β3-analogs of RRASVA (the shortest active substrate of PKA) and allows characterizing the influence of Nβ-methylation of aza-β3-amino acid residues on substrate recognition by PKA on substrate binding and phosphorylation steps. It was found that the effect of Nβ-methylation was dependent upon the position of the structure alteration. Moreover, the presence of a single Nβ-methylation site in the substrate changed the recognition pattern of this series of peptidomimetics, strongly affecting the phosphorylation step. Structure modeling of aza-β3- and Nβ-Me-aza-β3-containing substrates revealed that Nβ-methylation of aza-β3-moieties changed the peptide bond geometry from trans- to cis-configuration in -CO-NMe- fragments, with an exception for the N-terminally methylated Nβ-Me-aza-β3-RRRASVA (with the N-terminal amino group not participating in the peptide bond) and RRAS-Nβ-Me-aza-β3-VA. As has been shown in literature, this conformational preference of the backbone has a significant influence on the flexibility of the peptide substrate chain. Following our results, this property seems to have significant influence on the recognition of the amino acid side groups by the enzyme binding site, and in the case of PKA this structural modification was decisive for the phosphate transfer step of the catalytic process.


Effect of scanner in asymmetry studies using diffusion tensor imaging.
The purpose of this study was to evaluate the effects of longitudinal drift in scanner hardware, inter-scanner variability (bias) and scanner upgrade on asymmetries of diffusion properties using longitudinal data obtained on two scanners of the exact same model at one institution. A total of 224 normal subjects (63 females and 161 males) were included in this study. Each subject was scanned twice, at an interval of about 1 year (mean interval=1.0±0.11 years, range=0.6-1.3 years), using two 3.0-T scanners of the exact same model. Both scanners were simultaneously upgraded during the study period (159 subjects underwent a follow-up scan before upgrade, and the remaining 65 subjects underwent a follow-up scan after upgrade). The subjects were divided into 4 groups according to the combination of scanners used. With the use of tract-based spatial statistics (TBSS), we investigated the effects of scanner drift and inter-scanner variability (bias) on asymmetries of fractional anisotropy (FA) and mean diffusivity (MD). We also investigated the effect of scanner upgrade on FA and MD asymmetries. The voxel-wise analyses revealed a number of regions with significant longitudinal changes in FA and MD asymmetries in the groups where baseline and follow-up images were obtained on different scanners. Even with scanners of the exact same model, inter-scanner variability (bias) significantly affected FA and MD asymmetries, which were relatively stable within the same scanner. Scanner upgrade had a small effect on FA and MD asymmetries. The results indicate that the use of multiple scanners increases variability of DTI asymmetry measurements, and can affect the results of cross-sectional and especially longitudinal DTI asymmetry studies.


[Crisis management, highlighting new opportunities for organisation management in psychiatry].
The health crisis has radically changed psychiatric units. In order to react, a crisis unit was established, comprising the director, management team and medical staff. Its aim was to apply the necessary adaptation measures with regard to staff organisation and management. However, these measures have had a specifc and significant impact on patients' freedom to come and go, which must be medically justified. This crisis has highlighted more than ever the importance of coordination across the territory.


Designing photon upconversion nanoparticles capable of intense emission in whole human blood.
The properties of upconverting nanoparticles (UCNPs) are crucial for their applications in biomedicine. For studies of organisms and biological materials, the penetration depth of excitation light is also essential as the depth from which the luminescence can be detected. Currently, many researchers are trying to obtain UCNPs with intense emission under excitation wavelengths from the biological transparency windows to increase the penetration depth. However, studies comparing the properties of various types of UCNPs in real conditions are rare. This article shows how deep the 808, 975, 1208, and 1532 nm laser radiation penetrates human blood. Moreover, we determined how thick a layer of blood still permits for observation of the luminescence signal. The measured luminescence properties indicated that the near-infrared light could pass through the blood even to a depth of 7.5 mm. The determined properties of core/shell NaErF4/NaYF4 materials are the most advantageous, and their emission is detectable through 3.0 mm of blood layer using a 1532 nm laser. We prove that the NaErF4/NaYF4 UCNPs can be perfect alternatives for the most studied NaYF4:Yb3+,Er3+/NaYF4. Additionally, the setup proposed in this article can potentially decrease reliance on animal testing in initial biomedicine research.


Repair of the lacerated canaliculus.
There are various techniques used to repair a lacerated canaliculus. Successful functional results are obtained with the use of soft silicone tubing as a canalicular stent. One such technique used by the authors is described.


The CD40-TRAF6 axis controls affinity maturation and the generation of long-lived plasma cells.
Affinity maturation of the immune response and the generation of long-lived bone marrow (BM) plasma cells are hallmarks of CD40-dependent, thymus-dependent (TD) humoral immunity. Through disruption of the tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6)-binding site within the CD40 cytoplasmic domain, we selectively ablated affinity maturation and the generation of plasma cells after immunization. Mutagenesis of both the TRAF6 and TRAF2-TRAF3 sites was essential for arresting germinal center formation in response to immunization. CD40-induced B cell proliferation and early immunoglobulin production occurred even when all TRAF sites were ablated. These studies show that specific CD40-TRAF associations control well defined aspects of humoral immunity. In addition, they define the roles that TRAF-dependent and TRAF-independent pathways play in regulating antigen-driven B cell differentiation.


Bioinspired Synthesis of Platensimycin from Natural ent-Kaurenoic Acids.
The biomimetic formal synthesis of the antibiotic platensimycin for the treatment of infection by multidrug-resistant bacteria was accomplished starting from either ent-kaurenoic acid or grandiflorenic acid, each of which is a natural compound available in multigram scale from its natural source. Apart from the natural origin of the selected precursors, the keys of the described approach are the long-distance functionalization of ent-kaurenoic acid at C11 and the efficient protocol for the A-ring degradation of the diterpene framework.


5HT2 receptor changes in rat cortex and platelets following chronic ritanserin and clorgyline administration.
Chronic administration of clorgyline or ritanserin to adult rats for 28 days followed by a 3 day drug-free period results in a significant decrease in 5HT2 receptor number (Bmax) in rat frontal cortex from 315.23 +/- 10.72 fmol/mg protein to 249.63 +/- 13.99 fmol/mg protein and 222.55 +/- 17.17 fmol/mg protein, respectively. On rat blood platelets, ritanserin significantly increases recept number from 26.18 +/- 3.83 fmol/mg protein to 50.94 +/- 7.96 fmol bound/mg protein, whereas clorgyline has no significant effect (21.32 +/- 4.78 fmol/mg protein). Following both drug regimens, the affinity (Kd) of the respective ligands for the receptor is not significantly different from controls: the mean Kd value of the three groups for [3H]ketanserin is 1.57 +/- 0.05 nM in cortex and 0.83 +/- 0.25 nM for [125I]iodolysergic acid diethylamide (LSD) on platelets. Clorgyline increases serotonin (5HT) and noradrenaline (NA) levels in cerebellum, and decreases 5-hydroxyindole acetic acid (5HIAA) and homovanillic acid (HVA): ritanserin does not change the levels of the amines or their metabolites. The data shows that platelet and brain changes are not comparable after ritanserin administration. The receptor binding data demonstrates that curve fitting to two data points provides information which is comparable to and as statistically robust as that obtained from eight point saturation curves. Thus, if pilot studies show that the data follows a rectangular hyperbola, two point assays (optimal at 0.1 Kd and 3 Kd) can be used to obtain estimates of Bmax and Kd.


The present state of two-dimensional crystallization of membrane proteins.
This review summarizes the present literature on two-dimensional crystallization of membrane proteins, with emphasis on the technical aspects. It includes all the intrinsic membrane proteins that have been crystallized after solubilization. Four general ways of making crystals are described in detail. Furthermore, suggestions for improving crystallization conditions are presented.


Ultrasound estimated bladder weight and measurement of bladder wall thickness--useful noninvasive methods for assessing the lower urinary tract?
In the last decade interest has arisen in the use of ultrasound derived measurements of bladder wall thickness, detrusor wall thickness and ultrasound estimated bladder weight as potential diagnostic tools for conditions known to induce detrusor hypertrophy. However, to date such measurements have not been adopted into clinical practice. We performed a comprehensive review of the literature to assess the potential clinical usefulness of these measurements. A MEDLINE® search was conducted to identify all published literature up to June 2009, investigating measurements of bladder wall thickness, detrusor wall thickness and ultrasound estimated bladder weight. Measurements of bladder and detrusor wall thickness, and ultrasound estimated bladder weight have been studied in men, women and children. A convincing trend has been shown in the ability of these measurements to differentiate men with from those without bladder outlet obstruction. In addition, measurements of bladder wall thickness have revealed a considerable difference between detrusor overactivity and urodynamic stress incontinence. A number of confounding variables and a lack of standardized methodology has resulted in discrepancies among studies. Therefore, reproducible diagnostic ranges or cutoff values have not been established. Ultrasound derived measurements of bladder and detrusor wall thickness, and ultrasound estimated bladder weight are potential noninvasive clinical tools for assessing the lower urinary tract.


Immobilization of glucose oxidase and peroxidase and their application in flow-injection analysis for glucose in serum.
Glucose oxidase (GOD) and Horseradish peroxidase (HRP) were covalently coupled to alkylamine controlled pore glass by means of glutaraldehyde. About 700-800 U/g of immobilized GOD and 300-400 U/g of immobilized HRP were obtained. Some factors of affecting enzyme immobilization were discussed. The immobilized enzymes were packed into a plastic tube and used in flow-injection analysis (FIA) for glucose in serum. A good linearity range was observed for this immobilized enzyme system at 20 mg/mL to 1000 mg/dL D-glucose, the recovery was 95.4-103.5%, the within-batch imprecision was 0.8-2.2%, and the between-batch imprecision was 2.2-4.2%. More than 100 samples were measured within an hour. One enzyme column with five units of immobilized GOD and HRP, applied for 50 assays/d, has been used for more than 2 mo.


[Acute hydrocephalus in subarachnoid hemorrhage].
The AA. carry out a study on correlation among acute hydrocephalus, cerebral ischemia and hyponatremia in 70 patients with ESA.


Plasma brain natriuretic peptide--an independent predictor of cardiovascular mortality in acute heart failure.
To examine the prognostic importance of both plasma atrial natriuretic and B-(brain natriuretic peptide) following an episode of acute heart failure. A prospective cohort of 91 patients admitted into hospital with acute heart failure were recruited. After initial in-hospital management plasma ANP and BNP levels were measured by radioimmunoassay, and echocardiography was performed on the same day. Patients were followed up for 12 months and the main outcome measure was cardiovascular death. Plasma ANP and BNP levels were significantly higher in patients who died of a cardiovascular cause within 12 months (P<0.001 and P<0.0001, respectively) or at 1-month (P<0.05 and P<0.001) after recruitment. By Kaplan-Meier estimated life-table curves, patients with above median plasma ANP or BNP levels had significantly higher 1-year mortality (42.5% vs. 11.6%, both P<0.005). By multivariate Cox proportional hazard regression analysis, the plasma BNP level was the most important prognostic factor predicting mortality (chi2 = 18.3, P<0.0001), followed by age (chi2 = 11.5, P<0.001). Other factors including ANP, left ventricular ejection fraction by M-mode echocardiography, pulmonary arterial pressure, sex, cause of heart failure as well as New York Heart Association class were not significant. A plasma BNP level has independent and at least short-term prognostic significance in patients admitted with acute heart failure. This non-invasive and readily available blood test should be considered for risk stratification in patients with acute heart failure.


PET imaging of TSPO expression in immune cells can assess organ-level pathophysiology in high-consequence viral infections.
Ebola virus (EBOV) disease is characterized by lymphopenia, breach in vascular integrity, cytokine storm, and multiorgan failure. The pathophysiology of organ involvement, however, is incompletely understood. Using [18F]-DPA-714 positron emission tomography (PET) imaging targeting the translocator protein (TSPO), an immune cell marker, we sought to characterize the progression of EBOV-associated organ-level pathophysiology in the EBOV Rhesus macaque model. Dynamic [18F]-DPA-714 PET/computed tomography imaging was performed longitudinally at baseline and at multiple time points after EBOV inoculation, and distribution volumes (Vt) were calculated as a measure of peripheral TSPO binding. Using a mixed-effect linear regression model, spleen and lung Vt decreased, while the bone marrow Vt increased over time after infection. No clear trend was found for liver Vt. Multiple plasma cytokines correlated negatively with lung/spleen Vt and positively with bone marrow Vt. Multiplex immunofluorescence staining in spleen and lung sections confirmed organ-level lymphoid and monocytic loss/apoptosis, thus validating the imaging results. Our findings are consistent with EBOV-induced progressive monocytic and lymphocytic depletion in the spleen, rather than immune activation, as well as depletion of alveolar macrophages in the lungs, with inefficient reactive neutrophilic activation. Increased bone marrow Vt, on the other hand, suggests hematopoietic activation in response to systemic immune cell depletion and leukocytosis and could have prognostic relevance. In vivo PET imaging provided better understanding of organ-level pathophysiology during EBOV infection. A similar approach can be used to delineate the pathophysiology of other systemic infections and to evaluate the effectiveness of newly developed treatment and vaccine strategies.


Facilitation of beta-adrenoceptor-mediated slow channel responses by hypoxia in guinea pig ventricular myocardium.
The effects of hypoxia on the beta-adrenoceptor-mediated slow channel responses of guinea pig ventricular muscle in a potassium-rich (27 mM) solution containing Ba2+ were examined using microelectrode techniques. Isoproterenol produced a small depolarization of the resting membrane and also induced repetitive discharges of action potentials at higher concentrations, mainly due to a beta-adrenoceptor-mediated increase in the slow channel conductance. Two different threshold concentrations of isoproterenol, one for inducing depolarization and one for inducing automatic activity, were measured to assess myocardial responsiveness to catecholamines. During hypoxia, the electrically triggered slow upstroke action potentials of muscle were gradually depressed and catecholamine-induced membrane responses mediated by the beta-adrenoceptor/slow channel system were enhanced. The enhancement of the catecholamine effects was accelerated by acidosis and reversed by reoxygenation. Methyl xanthine-induced responses, similar to those induced by catecholamines, were also enhanced during hypoxia. It is suggested that not only changes of catecholamine-beta-adrenoceptor interaction, but also changes of intracellular metabolic processes, may be responsible, at least in part, for the enhancement of abnormal automatic activity mediated by the myocardial beta-adrenoceptor/slow channel system under hypoxic conditions.


Enzyme mimic nanomaterials as nanozymes with catalytic attributes.
Nanozymes are super-efficient nanomaterials with enzyme-like characteristics, as the name suggests. In the last decade, efforts have been made to develop "artificial enzymes," which are alternatives to natural enzymes. As nanoscience and nanotechnology advance, nanozymes, which are catalytic nanomaterials having enzyme-like properties, have fascinated researchers' attention. Nanozymes with unique physicochemical properties and nanomaterials that mimic catalytic activity have gained a special interest in the industrial sectors. However, several constraints have hampered their effective deployment in industrial processes, including denaturation, time-consuming manufacturing, overall high cost-ratio, and reutilization challenges. After a brief overview of nanozyme research, an analysis of the similarities and differences between nanozymes and natural and synthetic enzymes is presented. Because of their distinct properties, nanozymes stand out in this comparison. Nanozymes have exhibited a variety of applications leveraging the physiochemical properties of nanomaterials, ranging from in vitro detection to enzyme substitution in biological systems. In addition, nanozymes have introduced a new field called nanozymology, which blends nanotechnology with enzymology.


Is there any advantage in placing an additional calcar screw in locked nailing of proximal humeral fractures?
The objective of this study was to evaluate the biomechanical effect of an additional unlocked calcar screw compared to a standard setting with three proximal humeral head screws alone for fixation of an unstable 2-part fracture of the surgical neck. The additional calcar screw improves stiffness and failure load. Fourteen fresh frozen humeri were randomized into two equal sized groups. An unstable 2-part fracture of the surgical neck was simulated and all specimens were fixed with the MultiLoc(®)-nail. Group I represented a basic screw setup, with three locked head screws and two unlocked shaft screws. Group II was identical with a supplemental unlocked calcar screw (CS). Stiffness tests were performed in torsional loading, as well as in axial and in 20° abduction/20° adduction modes. Subsequently cyclic loading and load-to-failure tests were performed. Resulting stiffness, displacement under cyclic load and ultimate load were compared between groups using the t-test for independent variables (α=0.05). No significant differences were observed between the groups in any of the biomechanical parameters. Backing out of the CS was observed in three cases. The use of an additional unlocked calcar screw does not provide mechanical benefit in locked nailing of an unstable 2-part fracture of the surgical neck.


Endoscopic appearance of irradiated gastric mucosa.
Irradiation of the epigastric area for gastric cancer may induce actinic lesions of the stomach characterized on endoscopic examination by ulcerations, haemorrhagic gastritis, fragility of the mucosa, thickening and congestion of the gastric folds.


What are the best and worst things about having a father in UK Armed Forces? Analysis of free text responses.
This study aims to explore what adolescents report as the best and worst aspects of having a father in the UK military. Qualitative data were collected from 171 adolescents aged 11-16 years, via an online questionnaire exploring the impact of paternal military service on childhood well-being (response rate=70%). Questions about the best and worst aspects of their father's military role were examined. Content analysis has been used to code the qualitative data into themes. 85 girls and 86 boys were included with a mean age of 13 years (SD 1.92). The results showed lack of contact as the single most commonly reported negative factor of having a father in the military (61%). Positive aspects of their fathers' job most frequently reported included a sense of pride (25%) and financial benefits (25%). Adolescents take a great deal of pride in their father's jobs in the military, and they enjoy the financial benefits. A majority, however, feel a lack of contact with their father is the most negative factor.


Maternal chronic hypoxia increases expression of genes regulating lung liquid movement and surfactant maturation in male fetuses in late gestation.
Chronic fetal hypoxaemia is a common pregnancy complication associated with intrauterine growth restriction that may influence respiratory outcome at birth. We investigated the effect of maternal chronic hypoxia for a month in late gestation on signalling pathways regulating fetal lung maturation and the transition to air-breathing at birth using isobaric hypoxic chambers without alterations to maternal food intake. Maternal chronic hypoxia in late gestation increases fetal lung expression of genes regulating hypoxia signalling, lung liquid reabsorption and surfactant maturation, which may be an adaptive response in preparation for the successful transition to air-breathing at birth. In contrast to other models of chronic fetal hypoxaemia, late gestation onset fetal hypoxaemia promotes molecular regulation of fetal lung maturation. This suggests a differential effect of timing and duration of fetal chronic hypoxaemia on fetal lung maturation, which supports the heterogeneity observed in respiratory outcomes in newborns following exposure to chronic hypoxaemia in utero. Chronic fetal hypoxaemia is a common pregnancy complication that may arise from maternal, placental and/or fetal factors. Respiratory outcome of the infant at birth likely depends on the duration, timing and severity of the hypoxaemic insult. We have isolated the effect of maternal chronic hypoxia (MCH) for a month in late gestation on fetal lung development. Pregnant ewes were exposed to normoxia (21% O2 ) or hypoxia (10% O2 ) from 105 to 138 days of gestation (term ∼145 days). At 138 days, gene expression in fetal lung tissue was determined by quantitative RT-PCR. Cortisol concentrations were determined in fetal plasma and lung tissue. Numerical density of surfactant protein positive cells was determined by immunohistochemistry. MCH reduced maternal PaO2 (106 ± 2.9 vs. 47 ± 2.8 mmHg) and fetal body weight (4.0 ± 0.4 vs. 3.2 ± 0.9 kg). MCH increased fetal lung expression of the anti-oxidant marker CAT and decreased expression of the pro-oxidant marker NOX-4. MCH increased expression of genes regulating hypoxia signalling and feedback (HIF-3α, KDM3A, SLC2A1, EGLN-3). There was no effect of MCH on fetal plasma/lung tissue cortisol concentrations, nor genes regulating glucocorticoid signalling (HSD11B-1, HSD11B-2, NR3C1, NR3C2). MCH increased expression of genes regulating sodium (SCNN1-B, ATP1-A1, ATP1-B1) and water (AQP-4) movement in the fetal lung. MCH promoted surfactant maturation (SFTP-B, SFTP-D, ABCA3) at the molecular level, but did not alter the numerical density of surfactant positive cells in lung tissue. MCH in late gestation promotes molecular maturation of the fetal lung, which may be an adaptive response in preparation for the successful transition to air-breathing at birth.


DyScore: A Boosting Scoring Method with Dynamic Properties for Identifying True Binders and Nonbinders in Structure-Based Drug Discovery.
The accurate prediction of protein-ligand binding affinity is critical for the success of computer-aided drug discovery. However, the accuracy of current scoring functions is usually unsatisfactory due to their rough approximation or sometimes even omittance of many factors involved in protein-ligand binding. For instance, the intrinsic dynamics of the protein-ligand binding state is usually disregarded in scoring function because these rapid binding affinity prediction approaches are only based on a representative complex structure of the protein and ligand in the binding state. That is, the dynamic protein-ligand binding complex ensembles are simplified as a static snapshot in calculation. In this study, two novel features were proposed for characterizing the dynamic properties of protein-ligand binding based on the static structure of the complex, which is expected to be a valuable complement to the current scoring functions. The two features demonstrate the geometry-shape matching between a protein and a ligand as well as the dynamic stability of protein-ligand binding. We further combined these two novel features with several classical scoring functions to develop a binary classification model called DyScore that uses the Extreme Gradient Boosting algorithm to classify compound poses as binders or non-binders. We have found that DyScore achieves state-of-the-art performance in distinguishing active and decoy ligands on both enhanced DUD data set and external test sets with both proposed novel features showing significant contributions to the improved performance. Especially, DyScore exhibits superior performance on early recognition, a crucial requirement for success in virtual screening and de novo drug design. The standalone version of DyScore and Dyscore-MF are freely available to all at: https://github.com/YanjunLi-CS/dyscore.


Genotype-environment interaction in schizophrenia-spectrum disorder. Long-term follow-up study of Finnish adoptees.
Earlier adoption studies have convincingly confirmed the importance of a genetic contribution to schizophrenia. The designs, however, did not incorporate observations of the rearing-family environment. To test the hypothesis that genetic factors moderate susceptibility to environmentally mediated risks associated with rearing-family functioning. A Finnish national sample of adopted-away offspring of mothers with schizophrenia-spectrum disorders was compared blindly with adoptees without this genetic risk. Adoptive rearing was assessed using family rating scales based upon extended family observations at initial assessment. Adoptees were independently re-diagnosed after a median interval of 12 years, with register follow-up after 21 years. In adoptees at high genetic risk of schizophrenia, but not in those at low genetic risk, adoptive-family ratings were a significant predictor of schizophrenia-spectrum disorders in adoptees at long-term follow-up. Adoptees at high genetic risk are significantly more sensitive to adverse v. 'healthy' rearing patterns in adoptive families than are adoptees at low genetic risk.


Activation energy, relative substrate specificity and optimum pH of guanase from humanrat, mouse and guinea pig sera and tissues.
Some properties of serum and tissue guanase from man, rat, mouse and guinea pig have been studied. Serum guanase differs from tissue guanase in activation energy in the human species and in guinea pig. The mouse and rat brain enzyme differs from the liver and kidney enzyme. The guanase of each species differs from the enzyme of the other species in one or more properties.


Introduction to in vitro diagnostic device regulatory requirements.
A common application for microfluidics can be found in medical devices where the advantages of small volume measuring equipment can be exploited for In Vitro Diagnostics. This chapter focuses on the US and the EU regulations, explaining the broad landscape and regulatory pathways of each market.


Childhood ependymoma: a systematic review of treatment options and strategies.
Childhood intracranial ependymoma have a dismal prognosis, especially in young children and when a gross total resection cannot be performed. Even in the absence of a radiologically proven residuum, around two-thirds of these young children will have a recurrence. Adjuvant therapy is therefore necessary for most, if not all, patients. Despite some indication that benign ependymoma (WHO grade II) could show a better outcome, histology cannot be used at present to stratify treatment protocols.Craniospinal irradiation combined with posterior fossa boost has deleterious adverse effects on cognition. Consequently, pediatric oncology teams have, firstly, tried to use chemotherapy to delay or avoid irradiation, and secondly, progressively reduced irradiation fields to the tumor bed without altering the prognosis. Cisplatin, at a dose of 120 mg/m(2) (cumulated response rate of 34% [95% CI 19-54%]) is the only single agent that has reproducibly shown some efficacy in ependymoma. Despite some combinations showing efficacy in the adjuvant setting, childhood intracranial ependymomas can, in general, be considered as chemoresistant. The overexpression of the multidrug resistance-1 gene and the 06-methylguanine-DNA methyltransferase have been implicated as possible mechanisms for this phenomenon. As the use of chemotherapy with current agents is questionable, phase II studies with new agents and combinations are necessary. Since the main problem of this disease is local relapse, it may not be necessary to irradiate the whole posterior fossa. However, local control of the disease by irradiation has to be improved. In this respect, hyperfractionation or radiosensitizers may be valuable therapeutic options. The treatment of children with ependymoma is a challenge for all caregivers. There is no doubt that any possible improvement in the management of this rare tumor will only be the result of well designed cooperative trials.


1-Hydroxy-2(1H)-pyridinone-Based Chelators with Potential Catechol O-Methyl Transferase Inhibition and Neurorescue Dual Action against Parkinson's Disease.
Two analogues of tolcapone where the nitrocatechol group has been replaced by a 1-hydroxy-2(1H)-pyridinone have been designed and synthesised. These compounds are expected to have a dual mode of action both beneficial against Parkinson's disease: they are designed to be inhibitors of catechol O-methyl transferase, which contribute to the reduction of dopamine in the brain, and to protect neurons against oxidative damage. To assess whether these compounds are worthy of biological assessment to demonstrate these effects, measurement of their pKa and stability constants for Fe(III), in silico modelling of their potential to inhibit COMT and blood-brain barrier scoring were performed. These results demonstrate that the compounds may indeed have the desired properties, indicating they are indeed promising candidates for further evaluation.


A screen for constituents of motor control and decision making in Drosophila reveals visual distance-estimation neurons.
Climbing over chasms larger than step size is vital to fruit flies, since foraging and mating are achieved while walking. Flies avoid futile climbing attempts by processing parallax-motion vision to estimate gap width. To identify neuronal substrates of climbing control, we screened a large collection of fly lines with temporarily inactivated neuronal populations in a novel high-throughput assay described here. The observed climbing phenotypes were classified; lines in each group are reported. Selected lines were further analysed by high-resolution video cinematography. One striking class of flies attempts to climb chasms of unsurmountable width; expression analysis guided us to C2 optic-lobe interneurons. Inactivation of C2 or the closely related C3 neurons with highly specific intersectional driver lines consistently reproduced hyperactive climbing whereas strong or weak artificial depolarization of C2/C3 neurons strongly or mildly decreased climbing frequency. Contrast-manipulation experiments support our conclusion that C2/C3 neurons are part of the distance-evaluation system.


A 5-color flow cytometric method for extended 8-part leukocyte differential.
Microscopic leukocyte differentials display many drawbacks. Several single 5 to 8-color tubes using multiparameter flow cytometry (MFC) are able to provide extended differentials with sequential gating-based analysis strategies. We investigated a new 5-color MFC method to perform an extended 8-part differential with a simplified gating strategy. Whole blood was stained with a combination of antibodies including HLA-DR-FITC/CD19-PE/CD45-ECD/CD16-PC5 + CD71-PC5/CD5-PC7. An original approach was developed to exclude debris and straightforwardly gate the cells to identify sixteen populations. Strong correlations were obtained with the analyzer for neutrophils, lymphocytes, monocytes, and eosinophils (R2 >0.9). Abnormal cells, such as immature granulocytes and blast cells were identified with a good sensitivity and excellent correlation against cytomorphologic review (R2 =0.66 and 0.99, respectively). The choice of HLA-DR and CD5 improved specificity for the identification of activated T-lymphocytes and some lymphoid neoplastic cells, respectively. Here a new cytometric differential is proposed with a robust gating strategy which may be used even by unskilled cytometrists and can be easily automated. © 2017 International Clinical Cytometry Society.


A simple alternative confidence interval for the difference between two proportions.
The difference between two proportions is often the focus of interest in prospective comparative studies such as randomized controlled trials that have a binary outcome. Consequently, interval estimation for this parameter has received considerable attention in the literature. A hybrid procedure resulting from combining two sets of confidence limits for a single proportion as proposed by Newcombe has been previously recommended for this purpose because of its superior properties and relative simplicity. In this paper, we propose a simple alternative approach based on Fisher's z transformation. The results of an exact evaluation study show that this new procedure performs as well as Newcombe's procedure in terms of percent coverage and expected confidence interval width. Several examples are presented.


Dietary Carbohydrates Impair Healthspan and Promote Mortality.
The prospective cohort study, named PURE, found that in >135,000 participants from 18 countries, nutritive carbohydrates increase human mortality, whereas dietary fat reduces it, requesting a fundamental change of current nutritional guidelines. Experimental evidence from animal models provides synergizing mechanistic concepts as well as pharmacological options to mimic low-carb or ketogenic diets.


Systemic cytokine profiles of mice vaccinated with naked DNAs encoding six open reading frame antigens of porcine circovirus type 2 (PCV2).
The objective of this study was to characterize the murine immune response to vaccination with DNAs encoding each of six porcine circovirus type 2 (PCV2) open reading frames (ORFs). After intramuscular vaccination with the naked DNAs, blood was taken on days post-infection (DPI) 7 and 35 and subjected to Bio-Plex cytokine assays. ORF3 elicited high levels of the pro-inflammatory cytokine TNF-alpha (P<0.001) and decreased IL-12 levels (P<0.001) on DPI 7, and was lethal for nine of the 15 vaccinated mice, which died on DPIs 4, 6, 9, and 10. The remaining six mice showed general prostration but then recovered. The clinical signs correlated with the systemic TNF-alpha and IL-12 levels. ORF1 vaccination elevated T-helper (Th)1 (IFN-gamma; P<0.001) and Th2 (IL-13; P<0.05) cytokine levels on DPI 35, while ORF2 markedly elevated the expression of the humoral immunity- and Th-2-related cytokine IL-10 (P<0.001) on DPI 35. These observations provide insights into the immune responses generated by each PCV2 ORF.


Cell cycle-dependent DHFR and t-PA production in cotransfected, MTX-amplified CHO cells revealed by dual-laser flow cytometry.
The cell cycle-dependent regulation of the cellular dihydrofolate reductase content (DHFR) and tissue plasminogen activator (t-PA) production and secretion in plasmid-amplified cells was investigated in the DHFR-negative CHO cells transfected with the plasmid pSV-tPA.dhfr. This plasmid, carrying the dhfr and t-PA gene under control of different promotors, was amplified by serial passages in 5 microM methotrexate (MTX) for dhfr gene amplification. The intracellular amount of DHFR was quantitated in viable cells by MTX-FITC labeling and flow cytometric analysis of the FITC fluorescence. In comparison with the original CHO cells, the pSVtPA.dhfr-amplified cells showed a greater than 230-fold increase in MTX-FITC fluorescence. Using dual laser flow cytometry (uv: vital cell cycle with Hoechst 33342; 488 nm: DHFR with MTX-FITC), we show a maximum increase in the intracellular DHFR content during G1 and/or at G1/S transition (100 to 157%), followed by a continuous increase to 200% during S and G2/M. To determine t-PA production CHO cells were sorted from G1-, early/late S-, and G2/M-phase. After 1-, 2-, and 4-h incubation periods, t-PA production was quantitated using a sensitive t-PA ELISA technique. We found that t-PA production and secretion (2-h assay), unlike the expression of DHFR, increased continuously from relatively 100% in G1 to 127% in early S and reached its maximum of 159% in late S, whereas in G2/M-phase it decreased to 118%. Our results show that in pSVtPA.dhfr-coamplified CHO cells gene products DHFR and t-PA both exhibit different cell cycle-correlated accumulation and secretion, respectively, indicating that the brightest MTX-FITC-positive cells (G2/M) do not display the highest t-PA secretion rate.


Simultaneous dynamic proctography and peritoneography for pelvic floor disorders.
We sought to evaluate a new diagnostic technique for the identification of rectal and pelvic floor pathology in patients with obstructed defecation, pelvic fullness/prolapse, and/or chronic intermittent pelvic floor pain. Thirteen symptomatic women with either a nondiagnostic physical examination or nondiagnostic dynamic proctography (DPG) were studied. After placement of intraperitoneal and intrarectal contrast material, resting and straining pelvic x-rays were obtained in all patients, and defecation was videotaped using fluoroscopy. Simultaneous DPG and peritoneography identified clinically suspected and unsuspected enteroceles in 10 of the 13 patients studied. An enterocele or other pelvic floor hernia was ruled out by the technique in three of the women studied. Rectoceles and rectal prolapse that were identified during physical examination were confirmed by DPG with peritoneography. Simultaneous DPG and peritoneography also gave a qualitative assessment of the severity and clinical significance of the identified pelvic floor disorders. Results of simultaneous DPG and peritoneography affected operative treatment planning in 85 percent of patients studied. Simultaneous DPG and peritoneography identifies both rectal and pelvic floor pathology and provides a qualitative assessment of pelvic floor pathology severity, which allows for better treatment planning in selected patients with obstructed defecation and pelvic prolapse.


Association of sunbed use with skin cancer risk factors in Europe: an investigation within the Euromelanoma skin cancer prevention campaign.
Sunbed use has been significantly associated with increased risk of melanoma and non-melanoma skin cancer (NMSC), but its relationship with melanoma's risk factors such as high nevus count, atypical nevi and lentigines is poorly studied. Euromelanoma is a skin cancer prevention campaign conducted all over Europe. It offers a once-a-year screening during which participants' data, including sunbed use and phenotype, are collected via questionnaires. To investigate the association of sunbed use with nevus count, atypical nevi, lentigines and suspicion of skin cancer. To ensure reliability of the data, we defined inclusion and exclusion criteria for countries' eligibility for the risk analysis. Multivariate logistic regression models (including age, gender, education, skin type, family history of melanoma, personal history of skin cancer, any sun exposure and any sunscreen use) were used to calculate summary odds ratios (SORs) of each clinical endpoint for ever sunbed use. Overall, 227 888 individuals from 30 countries completed the Euromelanoma questionnaire. After the data quality check, 16 countries were eligible for the multivariate analysis, for a total of 145 980 participants (64.8% females; median age 43 years; 62.3% highly educated; 28.5% skin type I-II; 11.0% ever sunbed use). Ever sunbed use was independently associated with nevus count >50 [SOR = 1.05 (1.01-1.10)], atypical nevi [SOR = 1.04 (1.00-1.09)], lentigines [SOR = 1.16 (1.04-1.29)] and suspicion of melanoma [SOR = 1.13 (1.00-1.27)]. Conversely, no significant association was found between ever sunbed use and suspicion of NMSC [SOR = 1.00 (0.91-1.10)]. Indoor tanning is significantly associated with well-recognized risk factors for melanoma (including high nevus count, presence of atypical nevi and lentigines) as well as suspicion of melanoma within the Euromelanoma screenees. In order to reduce the prevalence of melanoma risk factors, avoidance/discontinuation of sunbed use should always be encouraged, especially but not exclusively for individuals with high-risk phenotypes.


Transition from traditional to modern forest management shaped the spatial extent of cattle pasturing in Białowieża Primeval Forest in the nineteenth and twentieth centuries.
Pasturing of livestock in forests has had profound consequences for Europe's landscapes. In Białowieża Primeval Forest (BPF), cattle pasturing was a part of traditional forest use that ceased only in the second half of the twentieth century. We collected information on the institutional changes governing forest cattle pasturing and the changes in spatial extent of cattle presence in BPF in last two centuries and information on cattle numbers and their impact on forest regeneration. The spatial extent of cattle pasturing was highly variable, with the distribution of grazing areas frequently changing. Forest near villages (constituting less than 10 % of the area) was most often used for cattle grazing during continued longer time periods. Historical data showed that cattle have had a clear impact on forest regeneration. However, the frequent changes that occurred in the extent of cattle grazing indicate that their impact occurred locally, was smaller in other less intensively used areas, and in the forest as a whole.


Inactivation of phagocytosis-stimulating activity of tuftsin by polymorphonuclear neutrophils. A possible role of leucine aminopeptidase as an ecto-enzyme.
The subcellular localization of the tuftsin-inactivating activity was studied using guinea-pig polymorphonuclear neutrophils and the following results were obtained. 1. The tuftsin-inactivating activity was present in the membrane fraction but not in the cytosol and the granular fractions. 2. Intact neutrophils inactivated tuftsin rapidly. However, when neutrophils were modified chemically by a poorly permeant reagent, diazotized sulfanilic acid, the tuftsin-inactivating activity decreased significantly without any inhibition of marker enzymes of cytosol, microsome, granules and mitochondria, suggesting that the tuftsin-inactivating activity is located on the plasma membrane as an ecto-enzyme. 3. When neutrophils were modified by diazotized sulfanilic acid at different concentrations, the tuftsin-inactivating activity of neutrophils was inhibited in proportion to the degree of inhibition of the activity of leucine aminopeptidase, an ecto-enzyme. 4, Hydrolysis of L-leucyl-beta-naphthylamide, a synthetic substrate of leucine aminopeptidase, was inhibited competitively by tuftsin. 5. Treatment of neutrophils with serine protease inhibitors affected neither tuftsin-inactivating nor leucine aminopeptidase activity at all, indicating no involvement of serine proteases, which is said to be located on the cell surface membrane, in the tuftsin-inactivation activity of neutrophils. The possibility was deduced from the above results that leucine aminopeptidase may act as a tuftsin-inactivating enzyme.


Horses (Equus caballus) use human local enhancement cues and adjust to human attention.
This study evaluates the horse (Equus caballus) use of human local enhancement cues and reaction to human attention when making feeding decisions. The superior performance of dogs in observing human states of attention suggests this ability evolved with domestication. However, some species show an improved ability to read human cues through socialization and training. We observed 60 horses approach a bucket with feed in a three-way object-choice task when confronted with (a) an unfamiliar or (b) a familiar person in 4 different situations: (1) squatting behind the bucket, facing the horse (2) standing behind the bucket, facing the horse (3) standing behind the bucket in a back-turned position, gazing away from the horse and (4) standing a few meters from the bucket in a distant, back-turned position, again gazing away from the horse. Additionally, postures 1 and 2 were tested both with the person looking permanently at the horse and with the person alternating their gaze between the horse and the bucket. When the person remained behind the correct bucket, it was chosen significantly above chance. However, when the test person was turned and distant from the buckets, the horses' performance deteriorated. In the turned person situations, the horses approached a familiar person and walked towards their focus of attention significantly more often than with an unfamiliar person. Additionally, in the squatting and standing person situations, some horses approached the person before approaching the correct bucket. This happened more with a familiar person. We therefore conclude that horses can use humans as a local enhancement cue independently of their body posture or gaze consistency when the persons remain close to the food source and that horses seem to orientate on the attention of familiar more than of unfamiliar persons. We suggest that socialization and training improve the ability of horses to read human cues.


Prevalence of latent structural heart disease in Nepali schoolchildren.
The present study aimed to quantify the burden of structural heart disease in Nepali children. We performed a school-based cross-sectional echocardiographic screening study with cluster random sampling among children 5-16 years of age. Between December 2012 and January 2019, 6573 children (mean age 10.6 ± 2.9 years) from 41 randomly selected schools underwent echocardiographic screening. Structural heart disease was detected in 14.0 per 1000 children (95% CI 11.3-17.1) and was congenital in 3.3 per 1000 (95% CI 2.1-5.1) and rheumatic in 10.6 per 1000 (95% CI 8.3-13.4). Rates of rheumatic heart disease were higher among children attending public as compared to private schools (OR 2.8, 95% CI 1.6-5.2, p = 0.0001). Rheumatic heart disease accounted for three out of four cases of structural heart disease and was more common among children attending public as compared to private schools.


Validating In Silico and In Vitro Patient-Specific Structural and Flow Models with Transcatheter Bicuspid Aortic Valve Replacement Procedure.
Bicuspid aortic valve (BAV) is the most common congenital cardiac malformation, which had been treated off-label by transcatheter aortic valve replacement (TAVR) procedure for several years, until its recent approval by the Food and Drug Administration (FDA) and Conformité Européenne (CE) to treat BAVs. Post-TAVR complications tend to get exacerbated in BAV patients due to their inherent aortic root pathologies. Globally, due to the paucity of randomized clinical trials, clinicians still favor surgical AVR as the primary treatment option for BAV patients. While this warrants longer term studies of TAVR outcomes in BAV patient cohorts, in vitro experiments and in silico computational modeling can be used to guide the surgical community in assessing the feasibility of TAVR in BAV patients. Our goal is to combine these techniques in order to create a modeling framework for optimizing pre-procedural planning and minimize post-procedural complications. Patient-specific in silico models and 3D printed replicas of 3 BAV patients with different degrees of post-TAVR paravalvular leakage (PVL) were created. Patient-specific TAVR device deployment was modeled in silico and in vitro-following the clinical procedures performed in these patients. Computational fluid dynamics simulations and in vitro flow studies were performed in order to obtain the degrees of PVL in these models. PVL degree and locations were consistent with the clinical data. Cross-validation comparing the stent deformation and the flow parameters between the in silico and the in vitro models demonstrated good agreement. The current framework illustrates the potential of using simulations and 3D printed models for pre-TAVR planning and assessing post-TAVR complications in BAV patients.


Als3-mediated attachment of enolase on the surface of Candida albicans cells regulates their interactions with host proteins.
The multifunctional protein enolase has repeatedly been identified on the surface of numerous cell types, including a variety of pathogenic microorganisms. In Candida albicans-one of the most common fungal pathogens in humans-a surface-exposed enolase form has been previously demonstrated to play an important role in candidal pathogenicity. In our current study, the presence of enolase at the fungal cell surface under different growth conditions was examined, and a higher abundance of enolase at the surface of C. albicans hyphal forms compared to yeast-like cells was found. Affinity chromatography and chemical cross-linking indicated a member of the agglutinin-like sequence protein family-Als3-as an important potential partner required for the surface display of enolase. Analysis of Saccharomyces cerevisiae cells overexpressing Als3 with site-specific deletions showed that the Ig-like N-terminal region of Als3 (aa 166-225; aa 218-285; aa 270-305; aa 277-286) and the central repeat domain (aa 434-830) are essential for the interaction of this adhesin with enolase. In addition, binding between enolase and Als3 influenced subsequent docking of host plasma proteins-high molecular mass kininogen and plasminogen-on the candidal cell surface, thus supporting the hypothesis that C. albicans can modulate plasma proteolytic cascades to affect homeostasis within the host and propagate inflammation during infection.


The GTPase CpgA is implicated in the deposition of the peptidoglycan sacculus in Bacillus subtilis.
Depletion of the Bacillus subtilis GTPase CpgA produces abnormal cell shapes, nonuniform deposition of cell wall, and five- to sixfold accumulation of peptidoglycan precursors. Nevertheless, the inherent structure of the cell wall appeared mostly unchanged. The results are consistent with CpgA being involved in coordinating normal peptidoglycan deposition.


Persisting changes in basolateral amygdala mRNAs after chronic ethanol consumption.
Adolescent alcohol use is common and evidence suggests that early use may lead to an increased risk of later dependence. Persisting neuroadaptions in the amygdala as a result of chronic alcohol use have been associated with negative emotional states that may lead to increased alcohol intake. This study assessed the long-term impact of ethanol consumption on levels of several basolateral amygdala mRNAs in rats that consumed ethanol in adolescence or adulthood. Male Long-Evans rats were allowed restricted access to ethanol or water during adolescence (P28, n=11, controls=11) or adulthood (P80, n=8, controls=10) for 18 days. After a sixty day abstinent period, the brain was removed and sections containing the basolateral amygdala were taken. In situ hybridization was performed for GABA(A) alpha(1), glutamic acid decarboxylase (GAD(67)), corticotropin releasing factor (CRF), and N-methyl-D-aspartate (NMDA) NR2A mRNAs. A significant decrease was observed in GABA(A) alpha(1), GAD(67), and CRF, but not NR2A, mRNAs in adult rats that consumed ethanol in comparison to controls. No significant changes were seen in adolescent consumers of ethanol for any of the probes tested. A separate analysis for each probe in the piriform cortex ascertained that the changes after ethanol consumption were specific to the basolateral amygdala. These results indicate that chronic ethanol consumption induces age-dependent alterations in basolateral amygdala neurochemistry.


The Influence of Patello-Femoral Overstuffing After Modular Unlinked Bicompartmental Knee Arthroplasty (BiKA) for Medial Tibio-Femoral and Patello-Femoral Osteoarthritis of the Knee.
The factors affecting results after bicompartmental knee arthroplasty (BiKA) have not been fully elucidated. This major ligament-preserving procedure may be more susceptible to overstuffing of the patello-femoral (PF) joint than the major ligament-sacrificing total knee arthroplasty. Currently, we investigated the effect of PF overstuffing after BiKA on its clinical outcome. There were 71 patients (74 knees) who underwent modular unlinked BiKA at our clinic who had a follow-up of 5 to 9 years. Final follow-up results were assessed by evaluating knee range of motion, the 2011 Knee Society Score (2011KSS), Japanese Knee Osteoarthritis Measure, and radiological findings. The degree of postoperative PF overstuffing was evaluated by computed tomography and magnetic resonance images for 55 knees, and the correlation between the degree of overstuffing and postoperative clinical results were examined. Overall clinical results improved significantly after surgery without any revision cases. The X-ray measurements showed the improved coronal alignments and the appropriate implant installation angles. Higher degree of postoperative PF overstuffing caused by insufficient amount of osteotomy on the anterior surface of the femur correlated with worse postoperative total 2011KSS at 2 years after surgery (Spearman's rank correlation coefficient (rs) = -0.387, P = .004), as opposed to no correlation at the time of the final follow-up (Spearman's rank correlation coefficient = 0.068, P = .623). Modular unlinked BiKA provided patients with a high level of satisfaction and functional improvement over 5 to 9 years postoperatively. However, because PF overstuffing affects initial patient satisfaction, the amount of osteotomy should be determined carefully during the surgery.


Site-specific reflex response of ubiquitin to loop insertions.
Predicting the structural effects of insertions in proteins by homology modeling remains a challenge. To investigate the molecular basis for conformational adaptations to insertions, ten mutants of ubiquitin were generated by introducing five different inserts, varying from five to 11 residues in size, at two different sites. Most insertion sequences were derived from homologous positions in structurally homologous ubiquitin-like proteins; to test sequence specificity, insertions were made into both homologous and non-homologous sites in ubiquitin. Structural inferences from NMR data suggest that each insertion site shows a reflex response to insertions: the sequence of the insertion has much less impact on structural adaptations than does the site of the insertion. Further, each site responds to insertions in a unique but consistent manner. For a given insertion site, different inserted sequences give rise to different stabilities, but the relationship between stability and sequence is not yet clear. However, the change in stability is similar for all insertions in a given site.


[Antileptospiral antibodies in the blood serum of donors].
The authors investigated the content of antileptospiral antibodies in 930 blood sera of nonimmunized blood donors. It was established that high titers of antileptospiral antibodies are contained in 5.2% of practically healthy persons.


Enzyme-inducing antiepileptic drugs and fractures in people with epilepsy: A systematic review.
People with epilepsy (PWE) have an increased fracture risk, independent of seizures. Antiepileptic drugs are thought to increase this risk, particularly those that induce the hepatic cytochrome P450 enzyme system. We aimed to determine whether PWE treated with enzyme-inducing antiepileptic drugs (EIAEDs) have decreased bone mineral density (BMD), or increased fracture incidence, versus those treated with non-EIAEDs. We searched MedLine, EMBase, CENTRAL, and CINAHL prior to November 2014 for all studies comparing fracture risk, or BMD change, in PWE treated for ≥ 1 year with EIAEDs versus non-EIAEDs. Thirteen observational studies met eligibility criteria. These studies, representing 68,973 adult PWE, were significantly heterogeneous, making meta-analysis impossible. Study results were split, with 5 studies showing decreased BMD in EIAED users, 5 studies showing no effect of EIAED on BMD, 2 studies showing increased fracture incidence in EIAED users, and 1 study showing no difference in fracture risk. The largest study (n = 63,259), which was also the most methodologically rigorous, showed an increased hazard ratio of 9-22% for any fracture, and 49-53% for hip fracture, in EIAED users. The literature is divided regarding the bone effects of EIAEDs; however, current best evidence supports an increased fracture risk in PWE treated with an EIAED compared to those treated with non-EIAEDs. A single article dominated our review, and other large methodologically rigorous studies are needed to confirm or refute its results. Further small studies, with limited power to control for multiple potentially confounding variables, are not likely to help.


Treatment of invasive candidiasis in the era of Candida resistance.
The increasing incidence of drug-resistant Candida brings a new challenge to the treatment of invasive candidiasis. Although cross-resistance among azoles and echinocandins was generally uncommon, reports of multidrug-resistant (MDR) Candida markedly increased in the last decade. The purpose of this review is to understand mechanisms and risk factors for resistance and how to tackle antifungal resistance. The paper describes the action of the three main classes of antifungals - azoles, echinocandins and polyenes - and Candida's mechanisms of resistance. The current evolution from cross-resistance to multiresistance among Candida explains the modern glossary - multidrug-resistant (MDR), extensively drug-resistant (XDR), and pandrug-resistant (PDR) - imported from bacteria. MDR Candida most commonly involves acquired resistance in species with intrinsic resistance, therefore it mostly involves C. glabrata, C. parapsilosis, C. krusei, C guilliermondii or C. auris , which is intrinsically multidrug resistant. Finally, strategies to tackle antifungal resistance became clearer, ideally implemented through antifungal stewardship. Avoiding antifungal's overuse and selecting the best drug, dose and duration, when they are needed, is fundamental. Knowledge of risk factors for resistance, microbiological diagnosis to the species, use of susceptibility test supported by antifungal stewardship programs help attaining effective therapy and sustaining the effectiveness of the current antifungal armamentarium.


Modulation of Asthma Pathogenesis by Nitric Oxide Pathways and Therapeutic Opportunities.
Asthma, a chronic airway inflammatory disease is typically associated with high levels of exhaled nitric oxide (NO). Over the past decades, extensive research has revealed that NO participates in a number of metabolic pathways that contribute to animal models of asthma and human asthma. In asthmatic airway, high levels of NO lead to greater formation of reactive nitrogen species (RNS), which modify proteins adversely affecting functional activities. In contrast, high levels of NO are associated with lower than normal levels of S-nitrosothiols, which serve a bronchodilator function in the airway. Detailed mechanistic studies have enabled the development of compounds that target NO metabolic pathways, and provide opportunities for novel asthma therapy. This review discusses the role of NO in asthma with the primary focus on therapeutic opportunities developed in recent years.


Taxonomic revision of the genus Benthana Budde-Lund, 1908 (Isopoda: Oniscidea: Philosciidae).
The neotropical genus Benthana (Philosciidae) is reviewed. Fourteen species are redescribed: Benthana picta, B. olfersii, B. longicornis, B. schubarti, B. albomarginata, B. werneri, B. santosi, B. longipenis, B. bocainensis, B. moreirai, B. dimorpha, B. iporangensis, B. sulcata, and B. longicaudata. Additional characters were proposed for B. convexa, B. taeniata, B. serrana, B. trinodulata, B. araucariana, and B. cairensis. New records are provided for 13 species, and four new species are described: Benthana aimores sp. nov., Benthana goitacas sp. nov., Benthana tupinamba sp. nov. and Benthana canastraensis sp. nov.. Two Chilean species are considered incertae sedis. A pictorial key and distribution maps for the species are provided.


Urgent training in domestic abuse is needed to open closed doors.
More than one quarter of nursing staff regularly encounter patients who have experienced domestic abuse, a Nursing Standard survey reveals.


A gene highly homologous to ACP1 encoding cysteine proteinase 3 in Entamoeba histolytica is present and expressed in E. dispar.
We have cloned the complete gene encoding cysteine proteinase 3 in E. histolytica as well as a cDNA encoding a highly homologous protein in E. dispar. In addition, we have demonstrated the presence and expression of the CP3 gene in various E. histolytica and E. dispar isolates. Since the expression of the gene is rather similar within both Entamoeba species, we assume that it does not constitute the proposed virulence factor of E. histolytica.


Frequency and predictors of post-traumatic stress disorder after stroke: a pilot study.
Few data exist about post-stroke symptoms of post-traumatic stress disorder (sPTSD) and none on DSM-IV formally diagnosed PTSD (fdPTSD). We investigated the frequency and predictors of sPTSD and fdPTSD 1-6 months after a nondisabling ischemic stroke (IS) or transient ischemic attack (TIA). Consecutive patients were assessed for sPTSD (Impact of Events Scale-Revised, IES-R, significant if >30) and fdPTSD (PTSD-Interview). We recorded sociodemographic factors, stroke features (including severity of the initial deficit, persistent disability, localization), associated mood changes, peritraumatic reactions during the stroke (Peritraumatic Distress Inventory (PDI) for fear and distress, Peritraumatic Dissociative Experience Questionnaire for cognitive appraisal), and psychiatric history. Patients with sPTSD and fdPTSD were compared to patients with IES-R<30. Among the 40 patients (65% male, mean age 52 years) studied post-IS (n=30; mean initial NIHSS 4) or TIA, 25% had sPTSD, including 10% with fdPTSD. sPTSD was more frequent in women (p=0.02), patients with intense peritraumatic reactions especially on PDI (p=0.001) or identified prior depression and anxiety (p=0.007). No other demographic factors or stroke characteristics were associated with sPTSD. Forty percent of sPTSD patients were depressed versus none of the controls (p<0.002). All fdPTSD patients had ≥ 3 prior psychiatric co-morbidities. After nondisabling IS or TIA, sPTSD is frequent, with fdPTSD for 10%. Patients with intense peritraumatic reactions, women, and those with prior psychiatric morbidity, require particular attention to detect sPTSD.


[Application of cell technologies for therapy of chronic renal insufficiency (experimental study)].
The experiments on 29 white non-inbred rats with chronic renal failure (CRF) induced by right-side nephrectomy and coagulation of 1/2-2/3 of parenchyma of the left kidney were made to study the trend in renal function after injection (into renal cortex or intravenously) of cultured stem or progenitor cells from human fetuses (total culture of fetal kidney or mesenchymal stem cells of the bone marrow). In control tests with salt solution functional indices reflected persistence of CRF. On day 4 after introduction of the fetal cells into renal parenchyma renal function improved and normalized in 2 weeks. After intravenous injection of fetal cells CRF reduced slowly, especially after injection of medullary mesenchymal cells with normalization in 1 month. 2.5-3.5 months after the injection test parameters in some rats deteriorated but remained close to normal values. Glomerular filtration after injection of stem and progenitor cells recovered better while canalicular sodium reabsorption underwent normalization but was followed by deterioration.


Radiofrequency catheter ablation of atypical atrioventricular nodal reentrant tachycardia.
Published reports of radiofrequency ablation of atypical atrioventricular nodal reentrant tachycardia (AVNRT) have been limited. We present our experience in 10 consecutive patients with atypical AVNRT who underwent radiofrequency ablation of the "slow" AV nodal pathway. There were 9 females and 1 male; their mean age was 44 +/- 19 years (+/- SD). The mean AVNRT cycle length and ventriculoatrial (VA) interval at the His position during AVNRT were 340 +/- 50 msec and 200 +/- 70 msec, respectively. The slow pathway was successfully ablated in all patients with a mean of 10 +/- 7 radiofrequency energy applications in the posteroseptal right atrium near the coronary sinus os. The mean procedure duration was 100 +/- 35 minutes. There were no complications. In 4 patients, target sites were identified during sinus rhythm by mapping for possible slow pathway potentials. In the other 6 patients, target sites were identified by mapping retrograde atrial activation during AVNRT or ventricular pacing. The VA times at successful target sites were a mean of 45 +/- 30 msec less than the VA time at the His catheter during AVNRT. There were no differences in success rate, number of radiofrequency energy applications, or procedure duration between patients in whom mapping was guided by possible slow pathway potentials or by retrograde atrial activation. During 6 +/- 3 months of follow-up, 1 patient had a recurrence of atypical AVNRT and underwent a second ablation procedure, which was successful. Radiofrequency ablation of atypical AVNRT can be safely and effectively accomplished when target sites are identified based either on possible slow pathway potentials during sinus rhythm or retrograde atrial activation times during tachycardia.


The involvement of smooth muscle P2X receptors in the prolonged vasorelaxation response to purine nucleotides in the rat mesenteric arterial bed.
1. ATP and adenine dinucleotides can elicit three different types of vasomotor response in the rat mesenteric arterial bed; vasocontraction, rapid relaxation (which may be masked by contraction) and slow and prolonged vasorelaxation. Contraction is mediated by smooth muscle P2X receptors and rapid relaxation by endothelial P2Y receptors. The mechanism of prolonged relaxation is, however, controversial. 2. In the present study, bolus injection of doses of alpha,beta-methylene ATP (alpha,beta-meATP; 5 pmol - 0.5 micromol; P2X receptor agonist) in methoxamine-preconstricted rat isolated mesenteric arterial beds, mimicked the action of ATP, causing contraction (R(max) 76+/-9 mmHg) followed by prolonged relaxation (78+/-11%; t(1/2) 14.6+/-1.5 min). KCl also elicited a biphasic response (R(max) contraction 73+/-8 mmHg; R(max) prolonged relaxation 70+/-6%; t(1/2) 7.7+/-1.9 min). 3. P2X receptor desensitization caused by perfusion with alpha,beta-meATP (10 microM) abolished contraction and prolonged relaxation to doses of alpha,beta-meATP (50 nmol). Rapid relaxation (32+/-7%; t(1/2) 32+/-2 s) was revealed, which was abolished by removal of the endothelium using distilled water. 4. Sodium deoxycholate treatment blocked contractile and prolonged relaxation responses to alpha,beta-meATP, ATP and KCl, whilst distilled water treatment had no significant effect on either phase of the biphasic responses. 5. These data indicate that smooth muscle P2X receptors are involved in both phases of the biphasic response (contraction followed by prolonged relaxation) to purine nucleotides in the rat isolated mesenteric arterial bed. Caution should be applied when using sodium deoxycholate to remove the endothelium because of possible damage caused by the detergent to receptors and/or the vascular smooth muscle.


Esthiomene resulting from cutaneous tuberculosis of external genitalia.
Tuberculosis of the external genitalia, which is rare, is usually secondary to pulmonary tuberculosis. Longstanding lupus vulgaris of the buttocks extending to the vulva and resulting in esthiomene is reported here. There was no evidence of tuberculosis of any other organ.


Walk the Talk: Characterizing Mobility in Older Adults Living on Low Income.
We provide an in-depth description of the mobility (capacity and enacted function, i.e., physical activity and travel behaviour) of community-dwelling older adults of low socioeconomic status. Participants [n = 161, mean age (range) = 74 (65-96) years] completed interviewer-administered questionnaires and objective measures of mobility. Our findings did not generally indicate that older adults of low socioeconomic status have a reduced capacity to be mobile. Participants presented with positive profiles across physical, psychosocial, and social environment domains that influence the capacity to be mobile. They also made a high proportion of trips by foot, although these did not together serve to meet physical activity guidelines for most. We challenge future researchers to focus on innovative strategies to recruit this difficult-to-access population, to consider the influence of socioeconomic status across the lifespan, and the role of behaviour-driven agency when investigating the association between the person, environment, and older adult mobility.


Tailor-Made Gives the Best Fits: Superior Na/K-Ion Storage Performance in Exclusively Confined Red Phosphorus System.
As the most promising anodic candidate for alkali ion batteries, red phosphorus (P) still faces big challenges, such as the poor rate and cycling performance, which are caused by the insulative nature and the large volume change throughout the alloy/dealloy process. To ameliorate above issues, the traditional way is confining P into the carbon host. However, investigations on maximizing P utilization are inadequate; in other words, how to achieve entire confinement with a high loading amount is still a problem. Additionally, the application of P in potassium-ion batteries (PIBs) is in its infant stage, and the corresponding potassiation product is controversial. Herein, a nitrogen-doped stripped-graphene CNT (N-SGCNT) as carbon framework is prepared to exclusively confine ultrafine P to construct P@N-SGCNT composites. Benefitting from the in situ cross-linked structure, N-SGCNT loaded with 41.2 wt % P (P2@N-SGCNT) shows outstanding Na+/K+ storage performance. For instance, P2@N-SGCNT exhibits high reversible capacities of 2480 mAh g-1 for sodium-ion batteries (SIBs) and 762 mAh g-1 for PIBs, excellent rate capabilities of 1770 mAh g-1 for SIBs and 354 mAh g-1 for PIBs at 2.0 A g-1, and long cycling stability (a capacity of 1936 mAh g-1 after 2000 cycles for SIBs and 319 mAh g-1 after 1000 cycles for PIBs). Furthermore, due to this exclusively confined P structure, the K+ storage mechanism with the end product of K4P3 has been identified by experimental and theoretical results.


Effect of phenformin on hepatic balances of gluconeogenic substrates in man.
The effect of a five day pretreatment with phenformin (3 X 50 mg daily) on hepatic metabolism was studied in six healthy volunteers. Arterial and hepatic venous concentrations of substrates and hepatic blood flow were estimated during a basal period and during a low-dose lactate infusion (0,03 mmol . kg-1 . min-1). The results have been compared with those obtained from untreated normal subjects in a previous study (16). During the baseline period arterial concentration of alanine and the hepatic venous concentration ratios of alanine: pyruvate and beta-hydroxybutyrate: acetoacetate were significantly increased with phenformin treatment, while the balances of carbon dioxide and glucose and the fractional extraction of alanine were decreased compared to the values obtained in untreated subjects. During lactate infusion mean arterial lactate concentration was significantly increased and hepatic lactate extraction was decreased compared to untreated persons under the same conditions. In the phenformin-treated group lactate infusion resulted in hepatic output of pyruvate and the hepatic glucose balance remained unchanged compared to baseline. Since the rate of hepatic blood flow was not increased during lactate infusion a significantly smaller glucose output and lactate uptake was obtained with phenformin. These findings support the present view that the hypoglycaemic effect of biguanides is due, at least in part, to inhibition of hepatic gluconeogenesis.


Admission blood pressure and clinical outcomes in patients with acute ischaemic stroke treated with intravenous alteplase and endovascular treatment versus endovascular treatment alone: A MR CLEAN-NO IV substudy.
High systolic blood pressure (SBP) is associated with poor functional outcome. We analysed whether the association of SBP with outcomes after endovascular treatment (EVT) is modified by prior intravenous thrombolysis (IVT). This was a post-hoc analysis of MR CLEAN-NO IV, a randomised trial of IVT with alteplase followed by EVT versus EVT alone, within 4.5 h from stroke onset. SBP was recorded on hospital admission. The primary outcome was 90-day modified Rankin Scale (mRS) score and secondary outcomes included symptomatic intracranial haemorrhage (sICH) and successful reperfusion (eTICI 2b-3), analysed with (ordinal) logistic regression. Estimates were calculated per 10 mmHg change in SBP. We assessed whether IVT modified the associations of SBP with these outcomes using multiplicative interaction terms. Of 539 randomised patients, 266 received IVT. The association of SBP with mRS score was J-shaped, with an inflection point at 150 mmHg. Using 150 mmHg as a reference point, SBPs higher than 150 mmHg were associated with poor functional outcome (acOR: 1.23, 95% CI: 1.09-1.38), but lower SBPs were not (acOR: 1.14, 95% CI: 0.99-1.30). Higher SBP was not associated with the risk of sICH (aOR: 1.09, 95% CI: 0.93-1.27) nor with the probability of successful reperfusion (aOR: 1.00, 95% CI: 0.91-1.10). Our main result was that we found no effect modification by IVT (p-values for interaction, mRS = 0.94; sICH = 0.26; successful reperfusion = 0.58). There was no effect modification of IVT with SBP for any of the clinical outcomes. Therefore, the level of SBP (if ⩽185/110 mmHg) should not guide IVT decisions in patients otherwise eligible for both IVT and EVT within the 4.5-h time window. ISRCTN80619088, https://www.isrctn.com/ISRCTN80619088.


Intravenous vs Topical Tranexamic Acid in Total Knee Arthroplasty Without Tourniquet Application: A Randomized Controlled Study.
Use of tranexamic acid (TXA) is effective and safe in reducing the blood loss in total knee arthroplasty (TKR) performed using a tourniquet, but, data in TKR performed without tourniquet are limited, and there is no study comparing the topical (T) with intravenous (IV) TXA administration. Our aim was to compare the topical (T) with intravenous (IV) TXA administration in TKR performed without tourniquet. A total of 120 patients undergoing unilateral TKR for knee osteoarthritis were included in a prospective randomized study. Operations were performed under spinal anesthesia, no tourniquet was used, and the postoperative regime was the same for all patients. Patients were divided into 3 groups; in group C (control), 40 patients received no TXA, in group IV, 40 patients received 1 g of TXA intravenously, and in group L, 1 g of TXA was applied locally to 40 patients. The primary outcome measures included the calculated blood loss, the transfusion rate, and quantity of allogeneic blood units, whereas secondary outcome measures were complications. There was no statistically significant difference in patient's demographics and perioperative results. Calculated blood loss, allogeneic blood transfusion rate, and quantity in group C were significantly higher compared with those of TXA groups (P < .001). There was no significant difference in complications rate between the 3 groups. According to the results of this study, IV or T administration of 1-g TXA significantly reduced the blood loss and the need for allogeneic blood transfusion in patients undergoing TKR without a tourniquet (with no significant difference between the 2 routes of administration).


Advances in mechanisms of atrial fibrillation: structural remodeling, high-frequency fractionated electrograms, and reentrant AF drivers.
The mechanisms to explain atrial fibrillation (AF) have been widely debated. Although contemporary experimental techniques have provided more insight, hypotheses regarding AF propagation conceived in the early half of the century remain minimally altered and relevant today. Modern mapping technologies have implicated multiwavelet reentry as the electrophysiologic basis to explain AF propagation within the atrial myocardium; however, reentry has also been observed within pulmonary veins and may behave as a focal trigger. The ability to terminate AF by catheter ablation has provided additional clues to explain AF induction and sustenance. The presence of complex fractionated electrograms (CFAE) and subsequent successful CFAE-directed ablation suggest that diseased atrial myocardium is a necessary substrate for AF maintenance. Atrial remodeling creates differential areas of refractory periods and conduction velocity, which, in turn, creates a suitable environment for AF. This review addresses the complex relationship between remodeled atrial myocardium and reentry and explores the role of CFAEs in AF maintenance.


Relative effectiveness of bivalent Original/Omicron BA.4-5 mRNA vaccine in preventing severe COVID-19 in persons 60 years and above during SARS-CoV-2 Omicron XBB.1.5 and other XBB sublineages circulation, Italy, April to June 2023.
During predominant circulation of SARS-CoV-2 Omicron XBB.1.5 and other XBB sublineages (April-June 2023), we found that a second or third booster of Comirnaty bivalent Original/Omicron BA.4-5 mRNA vaccine, versus a first booster received at least 120 days earlier, was effective in preventing severe COVID-19 for more than 6 months post-administration in persons 60 years and above. In view of autumn 2023 vaccination campaigns, use of bivalent Original/Omicron BA.4-5 mRNA vaccines might be warranted until monovalent COVID-19 vaccines targeting Omicron XBB.1 sublineages become available.


Capture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci.
Genome-wide association studies have been tremendously successful in identifying genetic variants associated with complex diseases. The majority of association signals are intergenic and evidence is accumulating that a high proportion of signals lie in enhancer regions. We use Capture Hi-C to investigate, for the first time, the interactions between associated variants for four autoimmune diseases and their functional targets in B- and T-cell lines. Here we report numerous looping interactions and provide evidence that only a minority of interactions are common to both B- and T-cell lines, suggesting interactions may be highly cell-type specific; some disease-associated SNPs do not interact with the nearest gene but with more compelling candidate genes (for example, FOXO1, AZI2) often situated several megabases away; and finally, regions associated with different autoimmune diseases interact with each other and the same promoter suggesting common autoimmune gene targets (for example, PTPRC, DEXI and ZFP36L1).


Functional Magnetic Resonance Imaging of Working Memory and Executive Dysfunction in Systemic Lupus Erythematosus and Antiphospholipid Antibody-Positive Patients.
Standardized cognitive tests and functional magnetic resonance imaging (fMRI) studies of systemic lupus erythematosus (SLE) patients demonstrate deficits in working memory and executive function. These neurobehavioral abnormalities are not well studied in antiphospholipid syndrome, which may occur independently of or together with SLE. This study compares an fMRI paradigm involving motor skills, working memory, and executive function in SLE patients without antiphospholipid antibody (aPL) (the SLE group), aPL-positive non-SLE patients (the aPL-positive group), and controls. Brain MRI, fMRI, and standardized cognitive assessment results were obtained from 20 SLE, 20 aPL-positive, and 10 healthy female subjects with no history of neuropsychiatric abnormality. Analysis of fMRI data showed no differences in performance across groups on bilateral motor tasks. When analysis of variance was used, significant group differences were found in 2 executive function tasks (word generation and word rhyming) and in a working memory task (N-Back). Patients positive for aPL demonstrated higher activation in bilateral frontal, temporal, and parietal cortices compared to controls during working memory and executive function tasks. SLE patients also demonstrated bilateral frontal and temporal activation during working memory and executive function tasks. Compared to controls, both aPL-positive and SLE patients had elevated cortical activation, primarily in the frontal lobes, during tasks involving working memory and executive function. These findings are consistent with cortical overactivation as a compensatory mechanism for early white matter neuropathology in these disorders.