Lateral dimension and amino-functionalization on the balance to assess the single-cell toxicity of graphene on fifteen immune cell types.
Given the wide variety of potential applications of graphene oxide (GO), its consequent release into the environment poses serious concerns on its safety. The future production and exploitation of graphene in the years to come should be guided by its specific chemical-physical characteristics. The unparalleled potential of single-cell mass cytometry (CyTOF) to dissect by high-dimensionality the specific immunological effects of nanomaterials, represents a turning point in nanotoxicology. It helps us to identify the safe graphene in terms of physical-chemical properties and therefore to direct its future safe production. Here we present a high-dimensional study to evaluate two historically indicated as key parameters for the safe exploitation: functionalization and dimension. The role of lateral dimension and the amino-functionalization of GO on their immune impact were here evaluated as synergistic players. To this end, we dissected the effects of GO, characterized by a large or small lateral size (GO 1.32 μm and GO 0.13 μm, respectively), and its amino-functionalized counterpart (GONH2 1.32 μm and GONH2 0.13 μm, respectively) on fifteen cell types of human primary peripheral blood mononuclear cells (PBMCs). We describe how the smallest later size not only evokes pronounced toxicity on the pool of PBMCs compared to larger GOs but also towards the distinct immune cell subpopulations, in particular on non-classical monocytes, plasmacytoid dendritic cells (pDCs), natural killer cells (NKs) and B cells. The amino-functionalization was able to improve the biocompatibility of classical and non-classical monocytes, pDCs, NKs, and B cells. Detailed single-cell analysis further revealed a complex interaction of all GOs with the immune cells, and in particular monocyte subpopulations, with different potency depending on their physicochemical properties. Overall, by high-dimensional profiling, our study demonstrates that the lateral dimension is an important factor modulating immune cells and specifically monocyte activation, but a proper surface functionalization is the dominant characteristic in its immune effects. In particular, the amino-functionalization can critically modify graphene impact dampening the immune cell activation. Our study can serve as a guide for the future broad production and use of graphene in our everyday life.


Regression analyses of prognostic factors in metastatic malignant melanoma.
Patients entered into phase II trials in metastatic malignant melanoma should be carefully selected in order to ensure that they live long enough to permit a meaningful evaluation of the efficacy of a given drug. In this selection emphasis has been put on performance status. However, also for patients with a good performance status, survival is often short. The purpose of this study has been to identify supplementary prognostic factors as these could be of help in the design of phase II trials. From 1978-1986, 177 consecutive patients were given various chemotherapy regimens for metastatic malignant melanoma in the Norwegian Radium Hospital. About 92% had a performance status of ECOG 0-2. Median survival was 4.0 months (0-30 months). Multivariate survival analysis selected lactate dehydrogenase (LDH) greater than 450 U/l, presence of brain metastases, leukocyte count greater than 10 x 10(9)/l, and erythrocyte sedimentation rate (ESR) greater than 15 mm/h as significant prognostic factors indicating short survival with low probability of surviving 3 months. Patients with normal values of LDH, leukocyte count, and ESR had a median survival of 11.5 months with 94% surviving 3 months. We conclude that this information could have an impact on the design of phase II trials.


Modeling the dynamic features of the electrogenic Na,K pump of cardiac cells.
The purpose of this paper is to examine the dynamic features of the electrogenic Na,K pump of cardiac cells, based on a comparative analysis of a mechanistic model and an ad hoc mathematical description of the Na,K pump. Both representations are incorporated into a modified version of the Beeler-Reuter model for the ventricular membrane, and the resulting action potential models are studied under conditions of repetitive stimulation at steady rates between 0 and 3 Hz. The two Na,K pump representations have nearly identical steady-state characteristics of sensitivity to internal Na+ concentration, external K+ concentration, and membrane potential. Rapid voltage-dependent transient pump currents are present in the mechanistic model, while they are absent in the ad hoc mathematical description we used. The stimulation results show that a sizable peak of pump current caused by the action potential upstroke in the mechanistic model affects phase 1 repolarization, and that this effect is relatively independent of the stimulation rate. The pump current generated by our ad hoc mathematical description is constant during the action potential and does not affect directly the repolarization time course. While the two Na,K pump models show similar pumping efficiency at low stimulation rates, the mechanistic pump is more efficient at high rates of activity. In essence, the distinctive features of the mechanistic model are due to an energy barrier expressing the voltage dependence of the translocation step of the mechanism, and to the redistribution of the intermediates of the biochemical reactions during activity. In comparison, the ad hoc mathematical description exhibits a fixed dependence of the pump current on voltage and ionic concentrations.


Nurse education in competitive markets: the case for relationship marketing.
Since the National Health Service reforms of the late 1980s, nurse education has been increasingly subject to market forces. This new competitive environment presents not only threat, but also challenge and opportunity. Providers of nurse education who recognize the need for market orientation and develop responsive marketing strategies will maximize their potential for market retention and growth. Traditional marketing strategies have considerable limitations for public sector services. The new and growing field of relationship marketing offers nurse education an opportunity to retain and develop profitable relationships with both internal and external markets. This paper reviews the marketing arena in nurse education and proposes context-based qualitative research to ascertain definitive constructs of service quality. Such constructs might then be rooted in a theoretical framework of service quality measurement, and be measured within the disconfirmation paradigm of relationship marketing.


Conflict detection and base-rate extremity.
People tend to ignore the probabilistic rules cued by the base-rate information and rely on the heuristic intuition cued by the descriptive information to make "stereotypical" responses in base-rate problems. Conflict detection studies have shown that reasoners can detect conflicts between heuristic intuition and probabilistic considerations despite ultimately stereotypical responses. However, these studies primarily used extreme base-rate tasks. A critical open question is the extent to which successful conflict detection relies on an extreme base rate. The present study explores this issue by manipulating the base-rate extremity of problems in which the descriptive information and the base-rate information conflict or not. As a result, when reasoners made stereotypical responses in the conflict version of the moderate base-rate task, they took longer to respond, had lower confidence in their responses, and were slower to evaluate their confidence than in the no-conflict version of the task. All three measures indicate that stereotypical reasoners can stably detect conflict in moderate base-rate tasks, which expands the scope of successful conflict detection. Moreover, our response confidence data found a larger detection effect size in the extreme base-rate condition than in the moderate base-rate condition. This suggests that conflict detection is more efficient as the base-rate extremity increases. Implications for the boundary conditions of conflict detection are discussed.


Fever-Inducible Lipid Nanocomposite for Boosting Cancer Therapy through Synergistic Engineering of a Tumor Microenvironment.
A fever-mimic response capable of recruiting reprogrammed macrophages holds great potential in the engineering of the tumor microenvironment (TME). Low-temperature photothermal therapy (LT-PTT) can maintain tumors at a fever-like temperature (<45 °C) temporarily; however, it still faces several challenges in efficient regulation of TME because of reciprocal cross-talk between the bypass pathways. Here, we report a synergistic engineering of TME through an enhanced activation of a fever-mimic response based on both LT-PTT and tumor vascular normalization. Such engineering is achieved by a fever-inducible lipid nanocomposite (GNR-T/CM-L), which produces mild heat (∼43 °C) and sequentially releases multicomponents to cooperatively upregulate interferon-gamma under NIR irradiation, forming a bidirectionally closed loop for downstream M1 tumor-associated macrophage polarization and promoting the inhibition of the tumor growth. In proof-of-concept studies, GNR-T/CM-L demonstrated efficient tumor ablation in breast tumor xenograft-bearing mice and significantly prolonged their survival period. It paves an avenue to precisely reprogram TME for efficient cancer therapy through synergistic pathways of creating fever-like responses in the tumor.


Camptothecin analogs with enhanced activity against human breast cancer cells. I. Correlation of potency with lipophilicity and persistence in the cleavage complex.
The effect of 7-alkyl substitutions on growth inhibition in seven Camptothecin (CPT) ring systems with various groups at the ten position was evaluated in three human breast cancer cell lines that model (1) hormone-sensitive (MCF-7/wt), (2) hormone insensitive (MDA-MB-231), or (3) alkylator-resistant (MCF-7/4-hc) forms of disease. To assess the impact of persistence of cleavage complexes on antiproliferative activity, a post-exposure recovery period in drug-free medium was incorporated into the growth inhibition assay. This modification produced on average a twofold reduction in the growth inhibition endpoint (the IC50), suggesting a greater apoptotic response. The results further revealed a three log range in potency from a mean IC50 of 2 nM (7-butyl-10,11-methylenedioxy-CPT) to 2.5 microM (7-bromomethyl-10-hydryoxy-CPT). Increasing 7-alkyl chain length in six of the ten-substituted CPTs enhanced potency, which was directly correlated with persistence of topoisomerase I-induced DNA cleavage complexes in 10-hydroxy, 10-methoxy, and 10,11-methylenedioxy substituted CPTs. Modeling of the binding mode of 7-butyl-10-amino-CPT revealed a direct hydrogen bond contact for the 10-amino to the side chain of Glu-356 of Core Subdomain I of top1 in addition to known contacts found for other camptothecins. More important, residues 350-356 and 425-431 of Core Subdomain I may provide induced fit stabilization to the lipophilic alkyl moiety at the seven position.


Patient with intractable nausea and vomiting.
A chest x-ray--followed by further questioning about the patient's medical history--revealed the cause of this woman's symptoms.


Study between anb angle and Wits appraisal in cone beam computed tomography (CBCT).
To analyse the ANB and Wits values and to study correlations between those two measurements and other measurements in diagnosing the anteroposterior maxilo-mandibular relationship with CBCT. Ninety patients who had previously a CBCT (i-CAT®) as a diagnostic register were selected. A 3D cephalometry was designed using one software package, InVivo5®. This cephalometry included 3 planes of reference, 3 angle measurements and 1 linear measurement. The means and standard deviations of the mean of each measurement were assessed. After that, a Pearson's correlation coefficient has been performed to analyse the significance of each relationship. When classifying the sample according to the anteroposterior relationship, the values obtained of ANB (Class I: 53%; Class II: 37%; Class III: 10%) and Wits (Class I: 35%; Class II: 56%; Class III: 9%) did not coincide, except for the Class III group. However, of the patients classified differently (Class I and Class II patients) by ANB and Wits, a high percentage of individuals (n=22; 49%), had a mesofacial pattern with a mandibular plane angle within normal values. A correlation has been found between ANB and Wits (r=0,262), occlusal plane angle and ANB (r=0,426), and mandibular plane angle and Wits (r=0,242). No correlation was found between either Wits or ANB in relation with the age of the individuals. ANB and Wits must be included in 3D cephalometric analyses as both are necessary to undertake a more accurate diagnosis of the maxillo-mandibular relationship of the patients.


Muscarinic transmission in the basolateral amygdala is necessary for the acquisition of socially transmitted food preferences in rats.
We examined the involvement of muscarinic receptors in the basolateral amygdala (BLA) in the social transmission of food preference (STFP) learning by assessing the effects of scopolamine (20 microg/side), injected prior to social training, on a 24-h food-choice test. Muscarinic receptor blockade in the BLA significantly impaired STFP, as shown by the rats' chance preference for the odorized trained food. The present results are consistent with the suggestion that intact cholinergic transmission in the BLA is necessary for acquisition and/or initial consolidation and provide evidence that BLA integrity is part of the underlying circuit of STFP learning.


Matrix-isolation vibrational circular dichroism (VCD) spectroscopy of chiral 1-phenyl-1-propanol.
Matrix Isolation IR and VCD spectroscopy is used to characterize the self-aggregation of the title compound. It is shown that only the IR spectral region of the OH-/CH-stretching modes is sensitive to hydrogen bonding interactions and that the fingerprint region is not notably affected. In contrast, some characteristic VCD spectral features can be identified in the fingerprint region.


Air quality monitoring in NIS (SERBIA) and health impact assessment.
The aim of this study is to indicate the significance of air quality monitoring and to determine the air quality fields for the assessment of air pollution health effects, with special attention to risk population. Radial basis function network was used for air quality index mapping. Between 1991 and 2005, on the territory of Nis, several epidemiological studies were performed on risk groups (pre-school children, school children, pregnant women and persons older than 65). The total number of subjects was 5837. The exposed group comprised individuals living in the areas with unhealthy AQI, while the control group comprised individuals living in city areas with good or moderate AQI. It was determined that even relatively low levels of air pollution had impact on respiratory system and the occurrence of anaemia, allergy and skin symptoms.


Macrophage Migration Inhibitor Factor Upregulates MCP-1 Expression in an Autocrine Manner in Hepatocytes during Acute Mouse Liver Injury.
Macrophage migration inhibitor factor (MIF), a multipotent innate immune mediator, is an upstream component of the inflammatory cascade in diseases such as liver disease. Monocyte chemoattractant protein-1 (MCP-1), a highly representative chemokine, is critical in liver disease pathogenesis. We investigated the role of MIF in regulating hepatocytic MCP-1 expression. MIF and MCP-1 expression were characterized by immunochemistry, RT-PCR, ELISA, and immunoblotting in CCl4-treated mouse liver and isolated hepatocytes. MIF was primarily distributed in hepatocytes, and its expression increased upon acute liver injury. Its expression was also increased in injured hepatocytes, induced by LPS or CCl4, which mimic liver injury in vitro. MIF was expressed earlier than MCP-1, strongly inducing hepatocytic MCP-1 expression. Moreover, the increase in MCP-1 expression induced by MIF was inhibited by CD74- or CD44-specific siRNAs and SB203580, a p38 MAPK inhibitor. Further, CD74 or CD44 deficiency effectively inhibited MIF-induced p38 activation. MIF inhibitor ISO-1 reduced MCP-1 expression and p38 phosphorylation in CCl4-treated mouse liver. Our results showed that MIF regulates MCP-1 expression in hepatocytes of injured liver via CD74, CD44, and p38 MAPK in an autocrine manner, providing compelling information on the role of MIF in liver injury, and implying a new regulatory mechanism for liver inflammation.


A narrative review of evidence to support increased domestic resource mobilization for family planning in Nigeria.
Family planning (FP) is an important public health intervention that is proven to reduce unplanned pregnancies, unsafe abortions, and maternal mortality. Increasing investments in FP would ensure stability and better maternal health outcomes in Nigeria. However, evidence is needed to make a case for more domestic investment in family planning in Nigeria. We undertook a literature review to highlight the unmet needs for family planning and the situation of its funding landscape in Nigeria. A total of 30 documents were reviewed, including research papers, reports of national surveys, programme reports, and academic/research blogs. The search for documents was performed on Google Scholar and organizational websites using predetermined keywords. Data were objectively extracted using a uniform template. Descriptive analysis was performed for quantitative data, and qualitative data were summarized using narratives. Frequencies, proportions, line graphs and illustrative chart were used to present the quantitative data. Although total fertility rate declined over time from 6.0 children per woman in 1990 to 5.3 in 2018, the gap between wanted fertility and actual fertility increased from 0.2 in 1990 to 0.5 in 2018. This is because wanted fertility rate decreased from 5.8 children per woman in 1990 to 4.8 per woman in 2018. Similarly, modern contraceptive prevalence rate (mCPR) decreased by 0.6% from 2013 to 2018, and unmet need for family planning increased by 2.5% in the same period. Funding for family planning services in Nigeria comes from both external and internal sources in the form of cash or commodities. The nature of external assistance for family planning services depends on the preferences of funders, although there are some similarities across funders. Irrespective of the type of funder and the length of funding, donations/funds are renewed on annual basis. Procurement of commodities receives most attention for funding whereas, commodities distribution which is critical for service delivery receives poor attention. Nigeria has made slow progress in achieving its family planning targets. The heavy reliance on external donors makes funding for family planning services to be unpredictable and imbalanced. Hence, the need for more domestic resource mobilization through government funding.


Post-mortem genetic analysis of sudden unexplained death in a young cohort: a whole-exome sequencing study.
Sudden unexplained death (SUD) constitutes a considerable portion of unexpected sudden death in the young. Molecular autopsy has proved to be an efficient diagnostic tool in the multidisciplinary management of SUD. Yet, many cases remain undiagnosed using the widely adopted targeted genetic screening strategies. Here, we investigated the genetic substrates of a young SUD cohort (18-40 years old) from China using whole-exome sequencing (WES), with the primary aim to identify novel SUD susceptibility genes. Within 255 previously acknowledged SUD-associated genes, 21 variants with likely functional effects (pathogenic/likely pathogenic) were identified in 51.9% of the SUD cases. More importantly, a set of 33 candidate genes associated with myopathy were identified to be novel susceptibility genes for SUD. Comparative analysis of the cumulative PHRED-scaled CADD score and polygenetic burden score showed that the amount and deleteriousness of variants in the 255 SUD-associated genes and the 33 candidate genes identified by this study were significantly higher compared with 289 randomly selected genes. A significantly higher genetic burden of rare variants (MAF < 0.1%) in the 33 candidate genes also highlighted putative roles of these genes in SUD. After incorporating these novel genes, the genetic testing yields of the current SUD cohort elevated from 51.9 to 66.7%. Our study expands understanding of the genetic variants underlying SUD and presents insights that improve the utility of genetic screenings.


Mechanical versus biological heart valves: a ten-year comparison in a single centre.
Between January 1977 and December 1986, 1606 Bjørk-Shiley tilting disc prostheses (BS) and 1346 Carpentier Edwards porcine prostheses (CE) were implanted in 1300 and 1156 patients, respectively, at the same institution. During the time of implantation, both valves have developed: the BS through standard disc and convexo-concave to monostrut, and the CE valves from standard to supra-annular. Newer valve types were used where applicable as they became available. Preoperative status in respect of age and cardiac rhythm were similar. There were significantly more females (64% BS: 54% CE, P less than 0.001); worse NYHA grade (74% Grade 111 and IV-BS: 56% 111 and IV-CE, P less than 0.001) more closed heart surgery (26% BS: 18% CE, P less than 0.001) and more previous open heart surgery (11.6% BS: 8.9% CE, P less than 0.001) in the BS group. All BS patients were anticoagulated and 49% of mitral CE patients and 7% of aortic CE patients were anticoagulated. There was no significant difference between the two groups in hospital mortality (BS 7.2%: CE 6.3%), late mortality (BS 2.5%/patient year: CE 3.2%/patient year) overall incidence of systemic embolism (BS 1.3%/patient year: CE 1.4/patient year), prosthetic valve endocarditis (BS 0.7%/patient year: CE 0.9%/patient year), valve failure (BS 0.5%/patient year: CE 0.9%/patient year) or peri-prosthetic leak (BS 1.2%/patient year: CE 1.3%/patient year). The incidence of systemic embolism in the aortic position was lower with the BS prosthesis (BS 0.2%/patient year: CE 1.2%/patient year, P less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)


Benzo(A)Pyrene-Induced Lung Cancer: Chemo Protective Effect of Coronarin D in Swiss Albino Mice.
Lung cancer is considered one of the most prevalent cancers worldwide and also has a high death rate. The prevalence of lung cancer is high in developed countries than in developing countries due to the lifestyle changes and quality of air. Coronarin D is a diterpene, which is isolated from the Hedychium coronarium. It demonstrated several pharmacological properties such as anti-allergic, anti-inflammatory, antimicrobial, and anticancer activities. In the current investigation, the potential of Coronarin D on the B(a)P-induced lung cancer was studied in the experimental mice model. The B(a)P-administrated animals exhibited a reduced level of immune cells, IgG, IgM, immune complexes, SOD, and CAT. The B(a)P-administrated animals expressed high levels of IgA, LPO, xenobiotic markers, tissue marker, tumor marker, and proinflammatory cytokines. On treatment with Coronarin D, the level of neutrophils, lymphocytes, leucocytes, and absolute neutrophils was elevated in the B(a)P-administered mice. The immune complex was augmented in the Coronarin D-treated animals in comparison with B(a)P-treated mice. The level of IgG and IgM was increased, whereas the level of IgA was reduced in the Coronarin D-treated animals. The level of LPO was downregulated, whereas the level of SOD and CAT was upregulated in Coronarin D-treated animals. The expression level of xenobiotic markers, tissue marker, tumor marker, and proinflammatory cytokines was reduced in the Coronarin D-treated animals. The histopathological results revealed that lung tissues of Coronarin D-treated animals had less alveolar damage with decreased hyperplasia. These findings suggest that the Coronarin D can be utilized as a potent chemopreventive agent for treating lung cancer in the future.


Spatial response surface modelling in the presence of data paucity for the evaluation of potential human health risk due to the contamination of potable water resources.
Potential human health risk from waterborne diseases arising from unsatisfactory performance of on-site wastewater treatment systems is driven by landscape factors such as topography, soil characteristics, depth to water table, drainage characteristics and the presence of surface water bodies. These factors are present as random variables which are spatially distributed across a region. A methodological framework is presented that can be applied to model and evaluate the influence of various factors on waterborne disease potential. This framework is informed by spatial data and expert knowledge. For prediction at unsampled sites, interpolation methods were used to derive a spatially smoothed surface of disease potential which takes into account the uncertainty due to spatial variation at any pre-determined level of significance. This surface was constructed by accounting for the influence of multiple variables which appear to contribute to disease potential. The framework developed in this work strengthens the understanding of the characteristics of disease potential and provides predictions of this potential across a region. The study outcomes presented constitutes an innovative approach to environmental monitoring and management in the face of data paucity.


Expression of erythroid differentiation factor (EDF) in Chinese hamster ovary cells.
Plasmid DNA containing EDF subunit cDNA and mouse dihydrofolate reductase (DHFR) cDNA was transfected into CHO DHFR- cells by the calcium-phosphate method. DHFR positive transformants secreted recombinant EDF (r-EDF) constitutively in an active form and accumulated it in the conditioned medium. Furthermore, cells which were resistant to methotrexate (MTX : 0.5 microM) secreted r-EDF up to 1 microgram/ml. r-EDF was identical to natural EDF (n-EDF) produced by human acute monocytic leukemia cell line, THP-1, as regards its dimeric structure and a biological activity.


Reactions to, and trial intentions for, three dissuasive cigarette designs: a cross-sectional survey of adolescents in Scotland.
There has been growing academic and policy interest in opportunities to decrease the appeal of cigarette sticks, such as making them an unattractive colour or requiring them to display a health warning. We therefore explored reactions to, and trial intentions for, three 'dissuasive' cigarette designs among adolescents in Scotland. A cross-sectional survey with 12-17 year olds in Scotland (n=594) was conducted between November 2017 and November 2018. Participants were shown one 'standard' cigarette (imitation cork filter with white paper casing) and three dissuasive cigarettes: (1) a cigarette with the warning 'smoking kills'; (2) a cigarette with the warning 'toxic' and a skull and cross-bones image and (3) a dark green cigarette. Participants rated each cigarette on nine five-point reaction measures (eg, appealing/unappealing or attractive/unattractive). A composite reaction score was computed for each cigarette, which was binary coded (overall negative reactions vs neutral/positive reactions). Participants also indicated whether they would try each cigarette (coded: Yes/No). Demographics, smoking status and smoking susceptibility were also measured. More participants had negative reactions to the dark green (93% of adolescents), 'smoking kills' (94%) and 'toxic' (96%) cigarettes, compared with the standard cigarette (85%). For all three dissuasive designs, Chi-square tests found that negative reactions were more likely among younger adolescents (vs older adolescents), never-smokers (vs ever smokers) and non-susceptible never-smokers (vs susceptible never-smokers). Most participants indicated that they would not try any of the cigarettes (range: 84%-91%). Dissuasive cigarettes present an opportunity to further reduce the appeal of smoking among adolescents.


TCF-based fluorescent probe for monitoring superoxide anion produced in bacteria under chloramphenicol- and heat-induced stress.
We report on a superoxide anion (O2˙-) responsive fluorescent probe called TCF-OTf. TCF-OTf is able to monitor O2˙- production when the bacterial species Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and Enterococcus faecalis are exposed to chloramphenicol and heat shock at 50 and 58 °C.


Endothelin B receptor-mediated vasoconstriction induced by endothelin A receptor antagonist.
The vasoconstrictor effect of endothelins (ET) is mediated by endothelin A (ETA) and endothelin B (ETB) receptors. Furthermore, ETB receptor stimulation results in release of vasodilators. Hence, ETA receptor antagonists should attenuate ET-mediated vasoconstriction. The aim of the present study was to evaluate and compare the effects of BQ-123, an ETA receptor antagonist, and bosentan, an ETA and ETB receptor antagonist, on coronary vasomotor tone, left ventricular systolic function and ET-1 efflux in the presence or absence of myocardial ischaemia/reperfusion. Isolated rat hearts were perfused using a Langendorff preparation. Global ischaemia was induced on average by 68 +/- 2% (+/- standard error of the mean) reduction of a baseline perfusion flow-rate 10 min after introduction of ET antagonists. Thirty minutes of ischaemia was followed by 30 min reperfusion. ET-1 efflux in coronary perfusate was measured by radioimmunoassay. In non-ischaemic hearts (n = 7), BQ-123 (10(-6) M) perfusion induced a progressive decrease in coronary flow-rate compared with control group. This flow reduction persisted after wash-out of BQ-123. In contrast, bosentan (10(-5) M, n = 7) induced no change in perfusion rate. In the absence of ET antagonists (n = 16), there was a 22 +/- 6% post-ischaemic increase in perfusion flow-rate. BQ-123 (n = 5) but not bosentan (n = 12) abolished this post-ischaemic increase in flow-rate. Neither BQ-123 nor bosentan induced significant variation in force of contraction. In ischaemic hearts, ischaemia per se induced a transient decrease in force of contraction. Bosentan significantly (P < 0.05) accentuated and BQ-123 tended to accentuate (P = 0.06) this decrease in force of contraction during ischaemia. Bosentan but not BQ-123 significantly impaired the recovery of systolic function during reperfusion (P < 0.05). Both BQ-123 and bosentan perfusion increased ET-1 efflux rate to 730 +/- 188% and 315 +/- 81% respectively. This effect was abolished during ischaemia for BQ-123, but not for bosentan. In isolated perfused rat hearts, both BQ-123 and bosentan increased ET-1 efflux, but only BQ-123 exerted vasoconstrictor effects. These results thus generated the hypothesis that: (1) ET-1 release within the coronary vascular bed may be physiologically subject to negative feedback regulation mediated via ETA receptors; (2) ETA receptor antagonists increase ET-1 efflux, which may lead to net vasoconstriction via unopposed ETB stimulation. Furthermore, the negative inotropic effects observed during ischaemia suggest that ET is critical to the maintenance of systolic function during ischaemia.


The leucine-rich repeat (LRR) domain of NLRP3 is required for NLRP3 inflammasome activation in macrophages.
The NLRP3 inflammasome is a critical component of innate immunity that defends the host from microbial infections. However, its aberrant activation contributes to the pathogenesis of several inflammatory diseases. Activation of the NLRP3 inflammasome induces the secretion of proinflammatory cytokines IL-1β and IL-18 and pyroptotic cell death. NLRP3 contains a leucine-rich repeat (LRR) domain at its C terminus. Although posttranslational modifications in this LRR domain have been shown to regulate NLRP3 inflammasome activation, the role of the entire LRR domain in NLRP3 inflammasome activation remains controversial. Here, we generated mouse macrophages that express an endogenous NLRP3 mutant lacking the LRR domain. Deletion of the LRR domain diminished NLRP3 inflammasome activation in macrophages. Furthermore, using NLRP3-deficient macrophages that are reconstituted with NLRP3 mutants lacking the LRR domain, we found that deletion of the LRR domain inhibited NLRP3 inflammasome activation. Mechanistically, deletion of the LRR domain inhibited NLRP3 self-association, oligomerization, and interaction with the essential regulator NEK7. Our results demonstrate a critical role for the LRR domain in NLRP3 inflammasome activation.


Progress in opioid reward research: From a canonical two-neuron hypothesis to two neural circuits.
Opioid abuse and related overdose deaths continue to rise in the United States, contributing to the national opioid crisis in the USA. The neural mechanisms underlying opioid abuse and addiction are still not fully understood. This review discusses recent progress in basic research dissecting receptor mechanisms and circuitries underlying opioid reward and addiction. We first review the canonical GABA-dopamine neuron hypothesis that was upheld for half a century, followed by major findings challenging this hypothesis. We then focus on recent progress in research evaluating the role of the mesolimbic and nigrostriatal dopamine circuitries in opioid reward and relapse. Based on recent findings that activation of dopamine neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) is equally rewarding and that GABA neurons in the rostromedial tegmental nucleus (RMTg) and the substantia nigra pars reticula (SNr) are rich in mu opioid receptors and directly synapse onto midbrain DA neurons, we proposed that the RTMg→VTA → ventrostriatal and SNr → SNc → dorsostriatal pathways may act as the two major neural substrates underlying opioid reward and abuse. Lastly, we discuss possible integrations of these two pathways during initial opioid use, development of opioid abuse and maintenance of compulsive opioid seeking.


[Clinicopathologic study of 11 patients with Paget's disease of scrotum].
To probe the relationship of clinicopathologic presentations and prognosis of Paget's disease primarily involving the scrotum. 11 cases of scrotal Paget's disease were studied retrospectively from 1984 to 1997. PAS was stained and EMA, S-100, HMB45, CEA and CA15-3 were immunostained in all cases for the differential diagnosis from Bowen's disease and malignant melanoma. Six of 11 cases involved hair follicle and/or sweat glands, and 3 cases involved dermis (one had metastasis of left superficial and deep inguinal lymph nodes, and left internal iliac lymph nodes). Paget's cells were positive for PAS (11/11), EMA (11/11), CEA (6/11), CA15-3 (11/11), and negative for S-100, HMB45. Wide local excision of the lesions was performed in 10 of 11 patients both for primary disease and recurrent disease. 3 of the 10 patients underwent lymph nodes resection and metastasis was found in 1 case pathologically. One patient accepted chemotherapy and died, from respiratory insufficiency after one month. The other 10 patients were followed up for 6 to 127 months and no patient died of Paget's disease. Involvement of hair follicles and sweat glands by Paget's cell does not influence the prognosis.However, invasion of dermis by Paget's cells may suggest possible metastasis.


Raman spectroscopy of the multianion mineral gartrellite-PbCu(Fe3+,Cu)(AsO4)2(OH,H2O)2.
The multianion mineral gartrellite PbCu(Fe3+,Cu)(AsO4)2(OH,H2O)2 has been studied by a combination of Raman and infrared spectroscopy. The vibrational spectra of two gartrellite samples from Durango and Ashburton Downs were compared. Gartrellite is one of the tsumcorite mineral group based upon arsenate and sulphate anions. Crystal symmetry is either triclinic in the case of an ordered occupation of two cationic sites, triclinic due to ordering of the H bonds in the case of species with 2 water molecules per formula unit, or monoclinic in the other cases. Characteristic Raman spectra of the minerals enable the assignment of the bands to specific vibrational modes. These spectra are related to the structure of gartrellite. The position of the hydroxyl and water stretching vibrations are related to the strength of the hydrogen bond formed between the OH unit and the AsO4 anion.


Forensic Identification from Three-Dimensional Sphenoid Sinus Images Using the Iterative Closest Point Algorithm.
Forensic identification of human remains is crucial for legal, humanitarian, and civil reasons. Wide heterogeneity in sphenoid sinus morphology can be used for personal identification. This study aimed to propose a new protocol for personal identification based on three-dimensional (3D) reconstruction of sphenoid sinus CT images using Iterative Closest Point (ICP) algorithm. Seven hundred thirty-two patients which consisted of 348 females and 384 males were retrospectively included. The study sample includes 732 previous images as a source point set and 743 later ones as a scene target set. The sphenoid sinus computed tomography (CT) images were processed on a workstation (Dolphin imaging) to obtain 3D images and stored as a file format of Stereo lithography (.STL). Then, a Python library vtkplotter was used to transform the STL format to PLY format, which was adapted to Point Cloud Library (PCL). The ICP algorithm was used for point clouds matching. The metric Rank-N recognition rate was used for evaluation. The scene target set of 743 individuals was compared with the source point set of 732 individual models and achieved Rank-1 accuracy of 96.24%, Rank-2 accuracy of 99.73%, and Rank-3 accuracy of 100%. Our results indicated that the 3D point cloud registration of sphenoid sinuses was useful for assessing personal identification in forensic contexts.


Experience with dalbavancin for long-term antimicrobial suppression of left ventricular assist device infections.
Left ventricular assist devices (LVAD) are a common strategy for management of end-stage heart failure. LVADs carry a risk of infection of the implanted device components, and skin flora are commonly implicated. Long-term antibiotics may be needed for management of deep device infection or recurrent superficial infections. In appropriately selected patients, dalbavancin can be a feasible option given its extended dosing interval. This is a retrospective, single-center review of patients presenting with an LVAD infection between January 2011 and November 2022, where management included the use of dalbavancin. Data regarding LVAD placement, details of index infection, dalbavancin use and outcomes was obtained from chart review, and documented in a RedCap database. The mean time from LVAD placement to index infection was 131.6 weeks (standard deviation 87.2 weeks). The most common targeted organism was Corynebacterium striatum in six of 10 patients. Index infection presented as deep driveline infection in four patients and recurrent superficial driveline infection in three patients. Five patients had a concurrent bloodstream infection. Dalbavancin was discontinued in two patients due to breakthrough infection, with one patient requiring surgical intervention. No drug-related adverse events were noted. Dalbavancin is an attractive option in the management of long-term LVAD infection in patients for whom alternative oral or parenteral antibiotics are not a feasible option. Additional studies are needed to determine the optimal dosing of dalbavancin in this setting, and to study adverse events and long-term outcomes of dalbavancin.


Metabolomics profiling in acute liver transplant rejection in a pediatric population.
Pediatric liver transplantation rejection affects 20% of children. Currently, liver biopsy, expensive and invasive, is the best method of diagnosis. Discovery and validation of clinical biomarkers from blood or other biospecimens would improve clinical care. For this study, stored plasma samples were utilized from two cross-sectional cohorts of liver transplant patients at Children's Healthcare of Atlanta. High resolution metabolic profiling was completed using established methods. Children with (n = 18) or without (n = 25) acute cellular rejection were included in the analysis (n = 43 total). The mean age of these racially diverse cohorts ranged from 12.6 years in the rejection group and 13.6 years in the no rejection group. Linear regression provided 510 significantly differentiating metabolites between groups, and OPLS-DA showed 145 metabolites with VIP > 2. A total of 95 overlapping significant metabolites between OPLS-DA and linear regression analyses were detected. Pathway analysis (p < 0.05) showed bile acid biosynthesis and tryptophan metabolism as the top two differentiating pathways. Network analysis also identified tryptophan and clustered with liver enzymes and steroid use. We conclude metabolic profiling of plasma from children with acute liver transplant rejection demonstrates > 500 significant metabolites. This result suggests that development of a non-invasive biomarker-based test is possible for rejection screening.


Selective accumulation of PpIX and photodynamic effect after aminolevulinic acid treatment of human adenomyosis xenografts in nude mice.
To evaluate the effect of photodynamic therapy with aminolevulinic acid (ALA) on human adenomyosis xenografts in a mouse model. Human adenomyosis tissues were implanted SC into nude mice. We measured 5-aminolevulinic acid pharmacokinetics in these mice by analyzing tissue sections 1 to 6 hours after intraperitoneal administration. Twenty-four hours after photodynamic therapy, we evaluated tissue morphologic features. Department of obstetrics and gynecology at a university hospital in Japan. Immunodeficient mice. Tissue grafts were taken from women with adenomyosis attending a university hospital. Photodynamic treatment. Peak fluorescence after intraperitoneal ALA administration and tissue histological changes 24 hours after photodynamic therapy. Peak fluorescence was observed 3 hours after intraperitoneal administration. Histological studies revealed decreased numbers of epithelial and stromal cells in adenomyosis models after therapy. Photodynamic therapy with ALA caused extensive cell death in human adenomyosis tissues implanted into nude mice. Photodynamic treatment using ALA is a potential treatment for patients with adenomyosis uteri.


The use of the inferior epigastric artery for accessory lower polar artery revascularization in live donor renal transplantation.
This study describes the surgical technique and outcomes of live donor renal allografts with multiple arteries in which the lower polar artery was anastomosed to the inferior epigastric artery after declamping. Between 1988 and 2004, 477 consecutive live donor renal transplants were performed, including 429 with single and 48 with multiple arteries. Anastomosis of the lower polar artery to the inferior epigastric artery was used for 15 grafts with multiple arteries. Successful revascularization of all areas of the transplanted graft was confirmed by Doppler ultrasonography in most patients and radionuclide renal scanning +/- MRA in some patients. In live donor renal transplantation with multiple arteries, the anastomosis of the lower polar artery to the inferior epigastric artery after declamping avoids prolongation of the ischemia time that occurs with other surgical and microsurgical techniques of intracorporeal and ex vivo surgeries.


Perceived oral health status, oral function and related behaviour among the patients of Behçet's disease.
The majority of patients with Behçet's disease (BD) suffers from oral ulcers. The aim of the present study was to survey self-rated oral health status, oral function, and oral health behaviour of patients with BD in eastern Japan. Subjects were 33 BD patients and 101 healthy individuals ranging in age from 20 to 59 years. The survey was conducted using a self-administered questionnaire. The items of oral health in the questionnaire included subjective symptoms, self-rated dental problems and oral health behaviour. We found that compared to the healthy subjects, BD patients experienced more severe physical limitations, mainly involving difficulty in pronouncing words (p < 0.01) and the pain of oral mucosa and gingival tissue caused by oral ulcers (p < 0.01). Based on the results of oral health behaviour, BD patients did not behave positively with regard to maintaining oral health including regular tooth brushing despite relatively higher risk of dental diseases that they face. The present results suggest that oral ulcers due to BD induced dental disorder such as the pain of gingiva, oral mucosa, and difficulty in the pronouncing of words. In spite of this, their oral health behaviour is not positive compared to the healthy subjects. Thus, the need to develop a more active pragramme for oral health education for patients with BD is indicated.


Addition of large amount of municipal sewage sludge as raw material in cement clinker production.
Two addition modes were used to explore the maximum addition of municipal sewage sludge as a raw material in cement clinker production. The clinker and cement product quality were determined by chemical analysis, cement quality testing, characterization of the clinker crystalline phases, and leaching tests. Municipal sewage sludge addition in the raw mix could be up to 30% based on the cement clinker moduli, and the cement quality met the P.O 42.5 cement standard (GB 175-2007). The amount of municipal sewage sludge added based on the direct addition mode should be less than 15% because of an insufficient early-term cement strength (third day). The leaching concentrations of heavy metals in all cements were below the threshold (GB 30760-2014) using the latest leaching procedure (GB 30810-2014). The municipal sewage sludge could be used with a high addition (30%) in the raw mix as a raw material in cement clinker production.


Surgical treatment of bone metastasis from osteophilic cancer. Results in 401 peripheral and spinal locations.
Peripheral and spinal bone metastases arise mainly from 5 osteophilic cancers: lung, prostate, kidney, breast and thyroid. Few studies combined results for the two types metastatic location (peripheral and spinal). Therefore we performed a multicenter retrospective study of surgically managed peripheral and spinal bone metastases to assess: (1) global function at a minimum 1 year's follow-up and; (2) factors affecting survival. Global function is improved by surgery, with acceptable survival. Between 2015 and 2016, 386 patients were operated on in 11 centers for 401 metastases: 231 peripheral, and 170 spinal. Mean age was 62.6±12.5 years in the 212 female patients (54%) versus 66.4±11.5 years in the 174 males (46%) (p=0.001). Pre- to postoperative comparison was made on pain on VAS (visual analog scale), WHO (World Health Organization) score, Karnofsky score, walking and global upper-limb function. Survival was estimated at 4 years' follow-up. The most frequent locations were in the femur (n=146, 36%) and thoracic spine (n=107, 27%). The primary cancer was revealed by the metastasis in 82 patients (21%). There were 55 general complications (14%) and 48 local complications (12%). Twenty-one patients (5.4%) died during the first month. VAS and Karnofsky sores improved: respectively, 6.6±2.3 vs. 3.4±2.1 (p<0.001) and 65±14 vs. 72±20 (p=0.01). Walking, upper-limb function and Frankel grade improved in respectively 49/86 (57%), 19/29 (66%) and 31/84 (37%) patients. Median survival was 13.3 months (95% CI: 10.8-17.1), and was related to the primary (log-rank, p<0.001): lung 6.5 months (95% CI: 5.2-8.9), prostate 11.1 months (95% CI: 5.3-43.6), kidney 12.9 months (95% CI: 8.4-22.6), breast 26.5 months (95% CI: 19.0-34.0), and thyroid 49.0 months (95% CI: 12.2-NA). On multivariate analysis, independent factors for death comprised internal fixation rather than prosthesis (OR=2.20; 95% CI: 1.59-3.04 (p<0.001)), high preoperative ASA score (OR=1.78; 95% CI: 1.40-2.28 (p<0.001)), preoperative chemotherapy (OR=1.26; 95% CI: 1.13-1.41 (p<0.001)) and major visceral metastasis (lung, brain, liver) (OR=11.80; 95% CI: 5.21-26.71 (p<0.001)). Although function improved only slightly, pain relief and maintained autonomy suggest enhanced comfort in life, confirming the study hypothesis only partially. Factors affecting survival and clinical results argue for preventive surgery when possible, before general health status deteriorates. IV; retrospective observational.


Efficacy and safety of mildronate for acute ischemic stroke: a randomized, double-blind, active-controlled phase II multicenter trial.
Mildronate, an inhibitor of carnitine-dependent metabolism, is considered to be an anti-ischemic drug. This study is designed to evaluate the efficacy and safety of mildronate injection in treating acute ischemic stroke. We performed a randomized, double-blind, multicenter clinical study of mildronate injection for treating acute cerebral infarction. 113 patients in the experimental group received mildronate injection, and 114 patients in the active-control group received cinepazide injection. In addition, both groups were given aspirin as a basic treatment. Modified Rankin Scale (mRS) score was performed at 2 weeks and 3 months after treatment. National Institutes of Health Stroke Scale (NIHSS) score and Barthel Index (BI) score were performed at 2 weeks after treatment, and then vital signs and adverse events were evaluated. A total of 227 patients were randomized to treatment (n = 113, mildronate; n = 114, active-control). After 3 months, there was no significant difference for the primary endpoint between groups categorized in terms of mRS scores of 0-1 and 0-2 (p = 0.52 and p = 0.07, respectively). There were also no significant differences for the secondary endpoint between groups categorized in terms of NIHSS scores of >5 and >8 (p = 0.98 and p = 0.97, respectively) or BI scores of >75 and >95 (p = 0.49 and p = 0.47, respectively) at 15 days. The incidence of serious adverse events was similar between the two groups. Mildronate injection is as effective and safe as cinepazide injection in treating acute cerebral infarction.


Descriptive analysis of patients with community-onset and hospital-onset methicillin-resistant Staphylococcus aureus infections.
Three hundred sixty-seven hospital- and community-onset methicillin-resistant Staphylococcus aureus (MRSA) infections diagnosed in a Dallas-Fort Worth Metroplex community hospital are described. Differences in age, gender, ethnicity, and susceptibility to four antibiotics between the two groups of patients are explored.


Cellular Migration Assay: An In Vitro Technique to Simulate the Wound Repair Mechanism.
Wound regeneration is a complex process, which necessitates proper coordination among the inflammatory response, vascularization, matrix formation, and reformation of epithelial tissue. It is a unique process, where healing and regeneration take place simultaneously. Matrix formation is the first critical stage that starts the communication between the keratinocytes, fibroblasts, and integrins. This, in turn, stimulates the differentiation of monocytes into macrophages, to produce cytokines for fibroblasts. This phenomenon is the crucial part for the keratinocyte migration and epithelialization to fill the wound. To understand the complex procedure of wound regeneration, there is a need for easy, convenient, and low-cost approaches that will simulate the wound-repairing process. Scratch assay or cellular migration assay is one of the most convenient and affordable approaches, commonly used by the scientific community. In this chapter, we present the fundamental principles of the experimental procedures required for the Scratch assay.


Hybrid liquid chromatography high resolution and accuracy mass spectrometry approach for quantification of antibody-drug conjugates at the intact protein level in biological samples.
Preclinical in vivo and in vitro characterization of Antibody-Drug Conjugates (ADCs) involves the development of several bioanalytical methods to address many drug exposure questions. The current pharma industry approach requires at least three different assays that must be run, i.e., total antibody (mAb), conjugated payload or conjugated mAb, and free payload assays. Herein we present analytical performances of a quantitative hybrid Ligand Binding/Liquid Chromatography High Resolution and Accuracy Mass Spectrometry (LB/LCHRAM) method that can condense much of the necessary bioanalytical information in one method. The method includes an immuno-capture step, and it detects whole ADC molecules. It was applied to plasma mouse samples and showed reliable bioanalytical performance according to full method validation standards. Quantitation using extracted ion chromatograms and deconvoluted mass peaks was evaluated. The limit of quantitation resulted in 0.5ng of protein on column with a linear dynamic range spanning from 0.5 to 10μg/mL. Moreover, lower drug-to-antibody ratio (DAR) ADC species can be simultaneously detected, also enabling qualitative characterization of in vivo ADC conjugation.


Intravenous leiomyomatosis of the uterus: Preoperative and intraoperative assessment.
To assess factors influencing preoperative diagnosis and hemorrhage during surgery with uterine intravenous leiomyomatosis. This retrospective single-institution study used univariate analysis and multivariate models to investigate potential factors contributing to preoperative diagnosis and hemorrhage during surgery associated with intravenous leiomyomatosis in 135 patients from January 2012 to April 2022. Risk factors for disease recurrence were also investigated. The SPSS statistical analysis package was used for data analysis. Previous myomectomy or fibroid ablation and tumor location on color Doppler were related to preoperative diagnosis (P = 0.031 and P = 0.003, respectively). Multivariate regression analysis demonstrated that lesions extending to the broad ligament were the only factors affecting preoperative diagnosis (odds ratio [OR] 5.383, 95% confidence interval [CI] 1.49-19.47). Univariate analysis showed that previous myomectomy or fibroid ablation (P = 0.017), tumor location (P = 0.027), and parauterine involvement (P = 0.014) were associated with intraoperative hemorrhage. Parauterine involvement was an independent risk factor for increased bleeding (OR 1.36, 95% CI 1.14-3.92). Six patients (4.4%) relapsed. The present study demonstrated that age (P = 0.031) and surgical type (P < 0.001) might be associated with disease recurrence. Treatment emphasis should focus on lesions extending to the broad ligament. Intraoperative bleeding associated with parauterine involvement should be stopped as effectively as possible.


Properties of anti-Lyb-2-mediated B-cell activation and the relationship between Lyb-2 molecules and receptors for B-cell stimulatory factor-1 on murine B lymphocytes.
The murine B-cell differentiation antigen Lyb-2 has been shown to be involved in B-lymphocyte activation and has been postulated by some to be related to a receptor for B-cell stimulatory factor I (BSF-1) (H. Yakura et al., J. Immunol. 137, 1475, 1986). Here we have demonstrated that monoclonal antibody (mAB) to Lyb-2 resembles BSF-1 in its ability to activate small resting B cells and enhancement of surface Ia. Anti-Lyb-2 antibodies bound B cells with very high avidity and were able to induce mobilization of cytosolic-free calcium. Anti-Lyb-2 mAB differs from BSF-1 in that BSF-1 but not anti-Lyb-2 is able to synergize with anti-mu in induction of B-cell proliferation. The relation between Lyb-2 molecules and BSF-1 receptors was tested in assays that measure binding of anti-Lyb-2 or BSF-1 in B cells and were found not to compete with each other. It appears that the two B-cell agonists anti-Lyb-2 and BSF-1 may exert their effects on B cells through different cell surface moieties as well as different intracellular pathways.


Influence of lower limb torque, range of motion, and foot alignment in patellar rotation (Arno angle) in athletes.
Alterations of frontal plane patellar alignment could be related to lower limb disorders. Clinical assessment must be able to identify the influence of non-local factors in patellar alignment. To identify the influence of lower limb torque, range of motion (ROM), and foot alignment on patellar rotation in healthy athletes. This cross-sectional study was performed with 232 healthy basketball and volleyball elite athletes. Participants were assessed in preseason for: patellar medial and lateral rotation (Arno angle), passive hip internal rotation (IR) ROM, iliotibial band flexibility, hip abductors and external rotators (ER) torque, shank-forefoot alignment (SFA), and ankle dorsiflexion ROM. Hierarchical multiple linear regression was performed to identify if these variables and sex, age, and body mass could be associated with patellar rotation in a standing position. Hip ER isometric torque explained a small part (10%) of the variance of the Arno angle in healthy athletes (R² change=0.10; unstandardized ß=11.74 (95% CI 6.82, 16.65); Standardized Coefficient Beta=0.32) and sex explained 2% of its variance (R² change=0.02; unstandardized ß= 2.42 (95% CI 0.32, 4.52); Standardized Coefficient Beta=0.15). After controlling for sex, hip ER torque explained 9% of Arno angle variance (R² change=0.09; unstandardized ß= 11.09 (95% CI 6.43, 15.76; Standardized Coefficient Beta=0.31). The other variables were not associated with patellar rotation. Hip ER torque may influence patellar rotation in different directions (medial or lateral rotation). Possible mechanisms that explain the contribution of higher and lower hip ER torque in lateral and medial patellar rotation, respectively, are discussed.


vhMentor: An Ontology Supported Mobile Agent System for Pervasive Health Care Monitoring.
Healthcare provision is a set of activities that demands the collaboration of several stakeholders (e.g. physicians, nurses, managers, patients etc.) who hold distinct expertise and responsibilities. In addition, medical knowledge is diversely located and often shared under no central coordination and supervision authority, while medical data flows remain mostly passive regarding the way data is delivered to both clinicians and patients. In this paper, we propose the implementation of a virtual health Mentor (vhMentor) which stands as a dedicated ontology schema and FIPA compliant agent system. Agent technology proves to be ideal for developing healthcare applications due to its distributed operation over systems and data sources of high heterogeneity. Agents are able to perform their tasks by acting pro-actively in order to assist individuals to overcome limitations posed during accessing medical data and executing non-automatic error-prone processes. vhMentor further comprises the Jess rules engine in order to implement reasoning logic. Thus, on the one hand vhMentor is a prototype that fills the gap between healthcare systems and the care provision community, while on the other hand allows the blending of next generation distributed services in healthcare domain.


Simple sensitive microbioassay for adenine arabinoside and hypoxanthine arabinoside in human plasma.
Previous methods using low- or high-pressure liquid chromatography and UV absorbance for quantitation of arabinosides in plasma can practically detect only >/=200 ng of adenine arabinoside and >/=100 ng of hypoxanthine arabinoside per ml, and they require expensive equipment and expert technical assistance. We describe in this report a simple quantitative microbioassay for arabinosides in human plasma based on their ability to inhibit the cytopathic effect of vaccinia virus in an adenosine deaminase-free cell culture system. Using prior separation of nucleosides in plasma by thin-layer chromatography, followed by the microbioassay, we quantitated adenine arabinoside with a sensitivity of approximately 4 ng/ml and hypoxanthine arabinoside at approximately 625 ng/ml. This assay method is simple, sensitive, and reproducible, requires small plasma samples, measures biological activity, and is adaptable to routine use. It is an important tool for evaluating the pharmacology of adenine arabinoside and Ara-AMP in patients in current clinical trials.


Dietary advice with or without oral nutritional supplements for disease-related malnutrition in adults.
Disease-related malnutrition has been reported in 10% to 55% of people in hospital and the community. Dietary advice encouraging the use of energy- and nutrient-rich foods rather than oral nutritional supplements has been suggested as the initial approach for managing disease-related malnutrition. To examine evidence that dietary advice in adults with disease-related malnutrition improves survival, weight and anthropometry; to estimate the size of any additional effect of nutritional supplements combined with dietary advice and to compare the effects of dietary advice with oral nutritional supplements. Relevant publications were identified from comprehensive electronic database searches and handsearching.Last search: 14 February 2010. Randomised controlled trials of dietary advice with or without oral nutritional supplements in people with disease-related malnutrition in any health-care setting compared with no advice, oral nutritional supplements or dietary advice given alone. Two authors independently assessed trial eligibility, risk of bias and extracted data. Forty-five studies (3186 participants) met the inclusion criteria; (dietary advice compared with: no advice (1053 participants); with oral nutritional supplements (332 participants); with dietary advice and oral nutritional supplements (731 participants); and dietary advice plus oral nutritional supplements compared with no additional intervention (1070 participants). Follow-up ranged from 18 days to 24 months. No comparison showed a significant difference between groups for mortality or morbidity. There was a significant change in weight found between groups when comparing dietary advice to no advice for interventions lasting greater than 12 months, mean difference 3.75 kg (95% confidence interval 0.97 to 6.53), and when all studies were combined, mean difference 1.47 kg (95% confidence interval 0.32 to 2.61) although there was significant heterogeneity in the combined analysis (I(2) = 90%). Similar improvements in weight were found for the comparison of dietary advice with nutritional supplements if required versus no advice, mean difference 2.20 kg (95% confidence interval 1.16 to 3.25). Dietary advice compared with no advice was also associated with significantly improved mid-arm muscle circumference when all studies were combined, but with moderate heterogeneity, mean difference 0.81 mm (95% confidence interval 0.31 to 1.31). Dietary advice given with nutritional supplements compared with dietary advice alone resulted in improvements in: mid-arm muscle circumference, mean difference -0.89 mm (95% confidence interval -1.35 to -0.43); triceps skinfold thickness, mean difference -1.22 mm (95% confidence interval -2.34 to -0.09); and grip strength, mean difference -1.67 kg (95% confidence interval -2.96 to -0.37), although the effects on triceps skinfold thickness and grip strength were heterogeneous. Dietary advice with supplements if required resulted in a significant increase in triceps skinfold thickness compared with no advice, mean difference 0.40 mm (95% confidence interval 0.10 to 0.70), although these results are from a single trial with only 29 participants. Evidence of variable quality suggests that dietary advice with or without oral nutritional supplements may improve weight, body composition and grip strength. We found no evidence of benefit of dietary advice or oral nutritional supplements given alone or in combination on survival. Studies addressing the impact of nutritional interventions on nutritional, functional and patient-centred outcomes are needed.


Safety regulation in professional football: Empirical evidence of intended and unintended consequences.
In response to increasing public awareness and negative long-term health effects of concussions, the National Football League implemented the "Crown-of-the-Helmet Rule" (CHR). The CHR imposes penalties on players who initiate contact using the top of the helmet. This paper examines the intended effect of this policy and its potential for unintended consequences. We find evidence supporting the intended effect of the policy- a reduction in weekly concussion reports among defensive players by as much as 32% (34% for all head and neck injuries), but also evidence of an increase in weekly lower extremity injury reports for offensive players by as much as 34%.


Quality assessment of prostate MRI by PI-QUAL score: Inter-reader agreement and impact on prostate cancer local staging at 3 Tesla.
To evaluate whether the Prostate Imaging Quality (PI-QUAL) score impacts prostate cancer (PCa) staging on MRI. The secondary goal was to test inter-reader agreement among radiologists experienced in prostate imaging. A retrospective, single-center study with patients who underwent 3 Tesla prostate MRI scans and were submitted to radical prostatectomy (RP) between January 2018 and November 2021 and were eligible for our study. Extraprostatic extension (EPE) data were collected from original MR reports (EPEm) and pathological reports of RP specimens (EPEp). Three expert prostate radiologists (ESUR/ESUI criteria R1, R2, R3) independently evaluated all MRI exams according to PI-QUAL score for image quality (1 to 5; 1: poor, 5: excellent), blinded to original imaging reports and clinical data. We studied the diagnostic performance of MRI using pooled data from PI-QUAL scores (≤3 vs. ≥4). We also performed univariate and multivariate analyses to assess the PI-QUAL score impact on local PCa staging. Cohen's K and Tau-b Kendall tests were used to assess the inter-reader agreement for PI-QUAL score, T2WI, DWI, and DCE. Our final cohort included 146 patients, of which 27.4% presented EPE on pathology. We observed no impact of imaging quality on accuracy for EPE prediction: AUC of 0.750 (95% CI 0.26-1) for PI-QUAL ≤ 3 and 0.705 (95% CI 0.618-0.793) for PI-QUAL ≥ 4. The multivariate analysis demonstrated a correlation of EPEm (OR 3.25, p 0.001) and ISUP grade group (OR 1.89, p 0.012) to predict EPEp. The inter-reader agreement was moderate to substantial (0.539 for R1-R2, 0.522 for R2-R3, and 0.694 for R1-R3). Our clinical impact evaluation showed no direct correlation between MRI quality by PI-QUAL score and accuracy in detecting EPE in patients undergoing RP. Additionally, we had moderate to a substantial inter-reader agreement for the PI-QUAL score.


Acute myeloblastic leukaemia without Philadelphia chromosome developing after interferon therapy for chronic myelocytic leukaemia with Philadelphia chromosome.
We report a patient who developed Philadelphia chromosome negative acute myeloblastic leukaemia with trisomy 8 and trisomy 11 after receiving treatment with alkylating agents and interferon for chronic myelocytic leukaemia positive for Philadelphia chromosome. Leukaemic cells were positive for myeloperoxidase and expressed CD13, CD33 and DR; some expressed CD2, CD4 and CD34. The fluorescence in situ hybridization method revealed that bcr-abl fusion genes were absent from > 90% of the bone marrow cells. The major bcr rearrangement was not detected by Southern blot analysis. We conclude that the leukaemic cells negative for Philadelphia chromosome may have developed as a result of treatment with alkylating agents and interferon in the present case.


A prospective analysis of intraoperative electromyographic monitoring of pedicle screw placement with computed tomographic scan confirmation.
In a prospective study of 90 patients undergoing lumbar pedicle screw instrumentation, 512 screws were tested intraoperatively using electrical stimulation. The accuracy of this technique was verified after surgery by computed tomography. Computed tomographic scans taken after surgery were used to evaluate the efficacy of intraoperative screw stimulation and electromyographic monitoring of pedicle screw placement. Previous cadaveric and clinical studies showed the risk of pedicle screw malposition and the inadequate reliability of intraoperative radiographs to identify misplaced screws. Screws (total, 512) in 90 patients were stimulated intraoperatively, and stimulation threshold was recorded. Computed tomographic scans were taken after surgery to document pedicle screw position. Electromyographic thresholds and computed tomographic data were evaluated independently and compared to assess the accuracy of the electromyographic screw stimulation technique. Intraoperative screw stimulation was extremely accurate in confirming the adequacy of screw position. A stimulation threshold greater than 15 mA provided a 98% confidence that the screw was within the pedicle. In eight of 90 patients (9%), electromyographic monitoring detected a screw malposition that was not identified on lateral radiograph. Screw stimulation monitoring is a valuable and efficacious adjunct to lumbar pedicle screw instrumentation. A stimulation threshold greater than 15 mA reliably indicates adequate screw position. A stimulation threshold between 10 and 15 mA was generally associated with adequate screw position, although exploration of the pedicle is recommended. A stimulation threshold less than 10 mA was associated with a significant cortical perforation in most instances.


Obturator hernia: A case report and review of the literature.
An obturator hernia is a rare condition but is associated with the highest mortality of all abdominal wall hernias. Early surgical intervention is often hindered by clinical and radiological diagnostic difficulty. The following case report highlights these diagnostic difficulties, and reviews the current literature on management of such cases. We present the case of an 86-year-old lady who presented with intermittent small bowel obstruction, clear hernial orifices, and right medial thigh pain. Pre-operative CT imaging was suggestive of an obstructed right femoral hernia. However, intra-operatively the femoral canal was clear and an obstructed hernia was found passing through the obturator foramen lying between the pectineus and obturator muscles in the obturator canal. Obturator hernias are notorious for diagnostic difficulty. Patients often present with intermittent bowel obstruction symptoms due to a high proportion exhibiting Richter's herniation of the bowel. Hernial sacs can irritate the obturator nerve within the canal, manifesting as medial thigh pain, and often no hernial masses can be detected on clinical examination. Increasing speed of diagnosis through early CT imaging has been shown to reduce the morbidity and mortality associated with obturator hernias. However, over-reliance on CT findings should be cautioned, as imaging and operative findings may not always correlate. A high suspicion for obturator hernia should be maintained when assessing a patient presenting with bowel obstruction particularly where intermittent symptoms or medial thigh pain are present. Rapid clinical and appropriate radiological assessment, followed by early surgery is critical to successful treatment.


Muscarinic toxins.
Muscarinic toxins isolated from the venom of Dendroaspis snakes may interact with a high affinity, large selectivity and various functional properties with muscarinic receptors. Therefore, these toxins are invaluable tools for studying the physiological role, molecular functioning and structural organization of the five subtypes of these G-Protein Coupled Receptors. We review the data on the most relevant results dealing with the isolation/identification, mode of action, structure/function and exploitation of these toxins and finally highlight the unresolved issues related to their pharmacological studies.


Marine sponges as bioindicators of pollution by synthetic microfibers in Antarctica.
Different marine sponge species from Tethys Bay, Antarctica, were analyzed for contamination by polyester and polyamide microplastics (MPs). The PISA (Polymer Identification and Specific Analysis) procedure was adopted as it provides, through depolymerization and HPLC analysis, highly sensitive mass-based quantitative data. The study focused on three analytes resulting from the hydrolytic depolymerization of polyesters and polyamides: terephthalic acid (TPA), 6-aminohexanoic acid (AHA), and 1-6-hexanediamine (HMDA). TPA is a comonomer found in the polyesters poly(ethylene terephthalate) (PET) and poly(butylene adipate co terephthalate) (PBAT), and in polyamides such as poly(1,4-p-phenylene terephthalamide) (Kevlar™ and Twaron™ fibers) and poly(hexamethylene terephthalamide) (nylon 6 T). AHA is the monomer of nylon 6. HMDA is a comonomer of the aliphatic nylon 6,6 (HMDA-co-adipic acid) and of semi-aromatic polyamides such as, again, nylon 6 T (HMDA-co-TPA). Except for the biodegradable PBAT, these polymers exhibit high to extreme mechanical, thermal and chemical resistance. Indeed, they are used as technofibers in protective clothing able to withstand extreme conditions as those typical of Antarctica. Of the two amine monomers, only HMDA was found above the limit of quantification, and only in specimens of Haliclona (Rhizoniera) scotti, at a concentration equivalent to 27 μg/kg of nylon 6,6 in the fresh sponge. Comparatively higher concentrations, corresponding to 2.5-4.1 mg/kg of either PBAT or PPTA, were calculated from the concentration of TPA detected in all sponge species. Unexpectedly, TPA did not originate from PET (the most common textile fiber) as it was detected in the acid hydrolysate, whereas the PISA procedure results in effective PET depolymerization only under alkaline conditions. The obtained results showed that sponges, by capturing and concentrating MPs from large volumes of filtered marine waters, may be considered as effective indicators of the level and type of pollution by MPs and provide early warnings of increasing levels of pollution even in remote areas.


Hypogammaglobulinemia in newly diagnosed chronic lymphocytic leukemia: Natural history, clinical correlates, and outcomes.
Although hypogammaglobulinemia is a well recognized complication in patients with chronic lymphocytic leukemia (CLL), its prevalence at the time of CLL diagnosis, and association with novel prognostic markers and clinical outcome is not well understood. All patients at the Mayo Clinic between January 1999 and July 2013 who had newly diagnosed CLL and had a baseline assessment of serum immunoglobulin G (IgG) were included. The relation between hypogammaglobulinemia at diagnosis and the novel prognostic parameters time to first treatment (TFT) and overall survival (OS) were evaluated. Of 1485 patients who met the eligibility criteria, 382 (26%) had hypogammaglobulinemia (median IgG, 624 mg/dL), whereas the remaining 1103 patients (74%) had normal serum IgG levels (median IgG, 1040 mg/dL). Patients who had hypogammaglobulinemia at diagnosis were more likely to have advanced Rai stage (III-IV; P = .001) and higher expression of CD49d (P < .001) compared with patients who had normal IgG levels. Although the median TFT for patients who had hypogammaglobulinemia was shorter compared with that for patients who had normal IgG levels (3.8 years vs 7.4 years; P < .001), on multivariable analysis, there was no difference in OS between these 2 groups (12.8 years vs 11.3 years, respectively; P = .73). Of 1103 patients who had CLL with normal IgG levels at diagnosis and who did not receive CLL therapy, the risk of acquired hypogammaglobulinemia was 11% at 5 years and 23% at 10 years. Hypogammaglobulinemia is present in 25% of patients with newly diagnosed CLL. Approximately 25% of patients who have CLL with normal IgG levels at diagnosis will subsequently develop hypogammaglobulinemia on long-term follow-up. The presence of hypogammaglobulinemia does not appear to impact overall survival.


The draft genome sequence of Meyerozyma guilliermondii strain YLG18, a yeast capable of producing and tolerating high concentration of 2-phenylethanol.
The draft genome of a wild-type Meyerozyma guilliermondii strain YLG18, which could convert l-phenylalanine (l-phe) to 2-phenylethanol (2-PE) and tolerate high concentration of 2-PE was sequenced and analyzed. 18S rDNA analysis indicated that strain YLG18 is closely related to M. guilliermondii. The assembled draft genome of strain YLG18 is 12.8 Mb, containing 5275 encoded protein sequences with G + C content of 43.75%. Among these annotated genes, two aminotransferases, one phenylpyruvate decarboxylase and two bifunctional alcohol dehydrogenases (adh) play key roles in the achievement of 2-PE production from l-phe via Ehrlich pathway. In addition, membrane protein insertase (YidC), heat shock protein (Hsp90) and chaperons (SGT1) were identified, which may contribute to the increased tolerance to 2-PE.


Isotopically non-stationary metabolic flux analysis: complex yet highly informative.
Metabolic flux analysis (MFA) using isotopic tracers aims at the experimental determination of in vivo reaction rates (fluxes). In recent years, the well-established 13C-MFA method based on metabolic and isotopic steady state was extended to INST-MFA (isotopically non-stationary MFA), which is performed in a transient labeling state. INST-MFA offers short-time experiments with a maximal information gain, and can moreover be applied to a wider range of growth conditions or organisms. Some of these conditions are not accessible by conventional methods. This comes at the price of significant methodological complexity involving high-frequency sampling and quenching, precise analysis of many samples and an extraordinary computational effort. This review gives a brief overview of basic principles, experimental workflows, and recent progress in this field. Special emphasis is laid on the trade-off between total effort and information gain, particularly on the suitability of INST-MFA for certain types of biological questions. In order to integrate INST-MFA as a viable method into the toolbox of MFA, some major challenges must be addressed in the coming years. These are discussed in the outlook.


Functionally generated paths for ceramometal restorations.
This article describes a procedure to generate functional path occlusion for ceramometal restorations. With this procedure, the metal framework is formed conventionally, full contour inlay wax is added to the metal framework, and the patient carves functional paths into the wax. These paths are registered with a stone matrix that the ceramist uses as a guide. Advantages over conventional techniques include increased accuracy and simplification of procedures.


Preparation of Dawson heteropolyacid-embedded silver nanoparticles/graphene oxide nanocomposite thin film used to modify pencil graphite electrode as a sensor for trace electrochemical sensing of levodopa.
Measurement of levodopa (LD) as the most efficient treatment accessible for controlling the symptoms of Parkinson's disease was investigated. The electrocatalytic measurement of LD was performed at the surface of pencil graphite electrode (PGE) modified with graphene oxide (GO) and silver nanoparticle@Dawson heteropolyacid (AgNPs@DHPA). For this purpose, GO and the intermediate (AgNPs@DHPA) were first synthesized using a simple, cost-effective and straightforward method. The synthetic compounds, morphology, and surface characteristics of the modified sensor were evaluated. The results demonstrated that AgNPs@DHPA well-dispersed on the GO/PGE surface with a mean size of 6.27 nm and thickness of 42 nm. The electrochemical behavior of the modified PGE was also investigated. The heterogeneous charge transfer rate constant (ks) and transfer coefficient (α) for the electron transfer between AgNPs@DHPA/GO and PGE were obtained as 16.44 s-1 and 0.59, respectively. Also, the diffusion coefficient of LD for AgNPs@DHPA/GO/PGE thin film was calculated using chronoamperometric experiments (D = 9.05 × 10-6 cm2 s-1). Optimal parameters were obtained to access the best response for the measurement of LD. The results revealed that the modified PGE was able to measure the trace amounts of LD in phosphate buffer solution (pH = 6.0) in the concentration ranges from 3.0 × 10-9 to 1.0 × 10-7 M and 1.0 × 10-7 to 1.0 × 10-5 M. The calculated limit of detection was obtained 7.6 × 10-10 M which was much better than the previously reported electrochemical sensors. The modified electrode was used to measure LD in tablet, blood serum and urine.


Acidification of Escherichia coli and Salmonella typhimurium cytoplasm reduces the mutagenic effect of N-methyl-N'-nitro-N-nitrosoguanidine.
Preliminary acidification of the cytoplasm of E. coli cells growing at pH 6.9 by adding to the medium 50 mM of sodium acetate or propionate reduced the mutagenic effect of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) to almost the spontaneous level. In experiments with S. typhimurium the protective effects of cytoplasm acidification against the mutagenic effect of MNNG was observed at pH 5.5 and was absent at a medium pH of 6.9. Alkalinization of the cytoplasm by adding 80 mM of methylamine to the growth medium at pH 8.1 did not modify the effect of MNNG on the cells of E. coli and S. typhimurium. Alkalinization of the cytoplasm of E. coli B/r and K12 was followed by a reduction of the intracellular non-protein SH group level by 25 and 50%, respectively. It is supposed that the protective effect of acidification may be due to a decline in the productivity of mutagenically more active intermediates of MNNG when the pH is reduced and the associated fall of the level of intracellular non-protein thiols occurs. The above situation may serve as a model for studying the effects of MNNG and other alkylating agents on cells differing in physiological status.


Reproduction in Polemonium: factors influencing outbreeding potential.
Three measures of potential outbreeding efficiency were quantified throughout two flowering seasons in a population of the mass-flowering Polemonium foliosissimum: 1) the distances flown between plants by bumblebee pollinators; 2) the proximity of visited plants; and 3) the diversity of individuals visited. Results were consistent between years. Individual plants did not function differentially with respect to female (i.e., pollen receipt) and male (i.e., pollen donation) function. Both female and male components of outbreeding, as estimated by all three measures, were positively correlated with the number of flowers per plant. Significantly more outbreeding could occur during the final phase of flowering when most individuals had relatively few blossoms. Although the potential for outbreeding was the same at any time through an individual's blooming regime, individuals for which the peak of blooming occurred after the peak for the population as a whole have significantly more outbreeding potential via both female and male function. These factors may combine such that any pressure to increase outbreeding in this self-incompatible species manifests itself in directional selection for delayed flowering time.


Surgery and adjuvant therapies in the treatment of stage IV melanoma: our experience in 84 patients.
Survival rates of patients with stage IV melanoma are poor: Median survival is 7-8 months and 5-year survival rates about 5%. There is no agreement on the role of surgery at this stage. Most patients with metastatic melanoma are not able to undergo resection and usually are sent to systemic chemo- and immunotherapy. Eighty-four patients operated on for stage IV melanoma were evaluated. Of them, 61.9% were submitted to reiterative surgery with 168 operations and 182 surgical procedures overall. A total of 90.5% was submitted to adjuvant therapies according to aggressive and reiterated schedules: chemotherapy, immunotherapy, dendritic cells vaccine, infusion of tumor infiltrating lymphocytes, local therapies as electrochemotherapy. The mean overall survival (Kaplan-Meier) was 56.7 months (1 year: 72.1%, 3 years: 46.5%, 5 years: 23.16%). The survival of reiterative surgery was significatively longer than single surgery (62.7 vs 42.4 months, median 50.9 vs 16.0), p = 0.03. Multivariated Cox analysis was performed for disease-free interval, repeated surgery, adjuvant therapies, and site of metastasis according to the American Joint Committee on Cancer: Reiterative surgery was shown as an independent prognostic factor (p < 0.05). Metastatic resection associated with adjuvant therapy may improve overall survival and, in some instances, can provide long-term survival, whatever site and numbers of metastasis. In our series, reiterative surgery was more significatively efficient in improving survival than single-time surgery.


[Subacute sclerosing panencephalitis. Van Bogaert's disease. Apropos of a case].
Presentation of a case of Van Bogaert, and discussion telling about clinical aspect and ocular complications.


Characteristics of urban streets in relation to perceived restorativeness.
The research on the restorative capacity of various environments has been growing exponentially in recent years. However, previous researchers mainly focus on urban green spaces, natural environments or urban landscapes. The streetscapes which have a close tie with residents' daily life and may have an essential effect on people's psychological wellbeing have not attracted extensive attention from academic research, failing to provide a cohesive guideline for streetscape design. To address this gap, this paper conducted an experiment to explore the relationship between restorative quality and streetscape characteristics, in which 30 photographs representing the various streetscapes in Xuzhou in eastern China, were used as stimuli, and the restorative qualities of these photographs were measured through online surveys. The results indicated that: (1) the streetscape with higher rate of plants in the view and diverse species of plants implied a high restorative capacity; (2) less non-motor vehicles and clear traffic signs painted on the streets are the other promoters of the restorative capacity of streetscapes. These findings contribute new knowledge about the role of streetscape characteristics to enhance the restorative potential and have applications for designers and urban managers.


Intracranial aneurysms--a survey of the results of surgical treatment at the Prince Henry Hospital, Sydney, 1972-1976.
In this paper, 124 intracranial aneurysms in 114 patients operated on during a five-year period, are reviewed, and the mortality is analysed in respect to factors of age, sex, duration of preoperative interval, site, and type of operation. A comparison with an earlier comprehensive ten-year cooperative study is attempted.


Conformational properties and biological activities of α-D-mannan from Sanghuangporus sanghuang in liquid culture.
Sanghuang is a well-known edible and medicinal fungus consumed in Asia for centuries. In the present study, a novel exopolysaccharide named as mannan (SSEPS2) was isolated from the liquid culture broth of Sanghuangporus sanghuang by using ethanol precipitation, anion-exchange chromatography, and size-exclusion chromatography, which was exclusively composed of D-mannose with the molecular weight 9.43 × 104 g/mol. The structural analysis suggested that SSEPS2 consisted of 1,3-linked and 1,2-linked α-D-mannopyranose (Manp), with substitution at O-6 of 1,2-linked α-D-Manp by 1,6-linked α-D-Manp residues and terminal α-D-Manp residues. The exponent of α (0.58) indicated that SSEPS2 existed in a flexible chain conformation, with a coil-like structure in 0.1 M NaNO3 at 25 °C, which was further confirmed by the atomic force microscopy images and a three-dimensional molecular model. It exhibited potential antitumor activity against the growth of HepG2 (human hepatoma) and MCF-7 cell lines in vitro. The IC50 values for inhibiting HepG-2 cells and MCF-7 cells proliferation were 365 and 340 μg/mL, which showed its potential application in the development of anticancer therapeutics.


Is there a casual relation between air pollution and dementia?
Dementia has been cited as a critical public health risk in the contemporary world, while few empirical researchers try to reveal the casual relationship between air pollutant concentrations (APCs) and dementia, especially given the increasing prevalence of air pollution on a global scale. Accordingly, this paper tries to infer the causal relationship between APCs and dementia. The 59,605 valid data was compiled through a combination of the statistic from the China Family Panel Study, China Environmental Statistics Yearbook, World Meteorological Association and China National Bureau of Statistics. The RD design of this study utilizes the discontinuous variation in APCs and dementia as one crosses the Huai River boundary, which is an arbitrary heating policy that causes the significant difference in APCs between the north and south of China. We used stata17.0 to analyze the data. The results of the RD regression indicated that a 100 μ g/m3 rise in APCs led to an increase of 42.4% in the hazard ratio of suffering dementia (Coeff=-0.58, SD= 0.23, P < 0.05). Meanwhile, heterogeneous models revealed that the hazard ratio of suffering dementia by APCs was more significant in the older compared to younger (coeff= 1.35 vs coeff= 1.55, P < 0.05), male compared to female (coeff= 1.62 vs coeff= 0.71, P < 0.05), smoking compared to non-smoke (coeff= 2.12 vs coeff= 0.93, P < 0.05), and thin groups compared to medium and obesity (coeff= 2.05 vs coeff= 1.22, coeff= 1.28, P < 0.05). In addition, the O3 and SO2 were the air pollutants with the highest (coeff= 1.54, P < 0.05) and lowest effects (coeff= 0.81, P < 0.05) on the hazard ratio of suffering dementia among the five APCs, respectively. And the robustness of the results was ensured by changing the RD bandwidth, polynomial order. The results indicated that APCs significantly induced the hazard ratio of suffering dementia of Chinese residents, which provides empirical evidence in supporting the Chinese government to invest more in combating air pollution and ensure the public health of Chinese residents.


Hypomagnesemia and concurrent acid-base and electrolyte abnormalities in patients with congestive heart failure.
Patients with severe decompensated congestive heart failure (CHF) commonly exhibit acid-base and electrolyte disturbances mainly due to the activation of several neurohumoral mechanisms as well as to drugs regularly used in this population. Magnesium deficit is not infrequently observed in CHF patients but its pathophysiology remains less well-studied as compared with other electrolyte alterations, such as hypokalemia. However, there is evidence that early detection and correction of magnesium abnormalities could obviate potentially deleterious arrhythmogenic effects. To assess the incidence of magnesium level disorders and analyze the underlying pathophysiological mechanisms in patients with CHF. Eighty-six consecutive CHF patients (NYHA class III or IV) admitted to our hospital over a period of 5 years were studied. Patients with diabetes mellitus, liver or renal failure, and chronic obstructive lung disease were excluded. All patients received conventional treatment with digoxin, diuretic agents and an angiotensin converting enzyme inhibitor. On admission, blood and urine electrolytes and renal function parameters were determined. Arterial blood gases and serum anion gap determinations were also performed. Hypomagnesemia was found in 15 [n=15 (17.4%)] CHF patients. The majority of these patients also exhibited other electrolyte abnormalities, such as hypokalemia, hypocalcemia and hypophosphatemia. Inappropriate magnesiuria (fractional excretion of magnesium >4%) was evident in eight hypomagnesemic patients. A variety of associated conditions, including poor dietary intake, also favored magnesium depletion. Magnesium deficit is a common electrolyte disorder in CHF (NYHA class III/IV) patients and several interrelated mechanisms are implicated in its pathogenesis. Clinicians' awareness of the incidence of hypomagnesemia in this population as well as its related pathophysiology could be useful for the early detection and appropriate treatment to inhibit its arrhythmogenic potential.


Parent ratings of ADHD symptoms: differential symptom functioning across Malaysian Malay and Chinese children.
This study examined differential symptom functioning (DSF) in ADHD symptoms across Malay and Chinese children in Malaysia. Malay (N=571) and Chinese (N=254) parents completed the Disruptive Behavior Rating Scale, which lists the DSM-IV ADHD symptoms. DSF was examined using the multiple indicators multiple causes (MIMIC) structural equation modeling procedure. Although DSF was found for a single inattention (IA) symptom and three hyperactivity-impulsivity (HI) symptoms, all these differences had low effect sizes. Controlling for these DSF, Chinese children had higher IA and HI latent factor scores. However the effect sizes were small. Together, these findings suggest adequate support for invariance of the ADHD symptoms across these ethno-cultural groups. The implications of the findings for cross-cultural invariance of the ADHD symptoms are discussed.


[Surveillance of schistosomiasis after its transmission being interrupted in Huangshan City, 1994-2010].
In Huangshan City, schistosomiasis surveillance from 1994 to 2010 showed that there were no patients and livestock newly infected with schistosome, no infected Oncomelania snails, but the snail status was stable. It is suggested that the schistosomiasis control strategy with emphasis on snail surveillance is effective, and snail surveillance is still a key measure of schistosomiasis surveillance in the future.


Mesenchymal stem cells: amazing remedies for bone and cartilage defects.
Skeletal disorders are among the leading debilitating factors affecting millions of people worldwide. The use of stem cells for tissue repair has raised many promises in various medical fields, including skeletal disorders. Mesenchymal stem cells (MSCs) are multipotent stromal cells with mesodermal and neural crest origin. These cells are one of the most attractive candidates in regenerative medicine, and their use could be helpful in repairing and regeneration of skeletal disorders through several mechanisms including homing, angiogenesis, differentiation, and response to inflammatory condition. The most widely studied sources of MSCs are bone marrow (BM), adipose tissue, muscle, umbilical cord (UC), umbilical cord blood (UCB), placenta (PL), Wharton's jelly (WJ), and amniotic fluid. These cells are capable of differentiating into osteoblasts, chondrocytes, adipocytes, and myocytes in vitro. MSCs obtained from various sources have diverse capabilities of secreting many different cytokines, growth factors, and chemokines. It is believed that the salutary effects of MSCs from different sources are not alike in terms of repairing or reformation of injured skeletal tissues. Accordingly, differential identification of MSCs' secretome enables us to make optimal choices in skeletal disorders considering various sources. This review discusses and compares the therapeutic abilities of MSCs from different sources for bone and cartilage diseases.


Response to ibutilide and the long-term outcome after catheter ablation for non-paroxysmal atrial fibrillation.
This study aimed to assess the relationship between the cardiac rhythm response to ibutilide infusion after pulmonary vein isolation and the recurrence of long-term atrial arrhythmias. One hundred and thirty-eight patients with non-paroxysmal atrial fibrillation who had had their first catheter ablation were retrospectively included. All patients whose atrial fibrillation did not terminate after pulmonary vein isolation were administered intravenous ibutilide (1.0 mg). Those with termination of atrial fibrillation after ibutilide administration were defined as responders (n = 86); those without termination of atrial fibrillation, as non-responders ( n = 52). The primary endpoint was any documented recurrence of atrial arrhythmia lasting more than 30 seconds after the initial catheter ablation. Conversion of atrial fibrillation to sinus rhythm, directly or via atrial flutter, with ibutilide administration was achieved in 62.3% of patients. A longer duration of atrial fibrillation was associated with failed termination of atrial fibrillation (odds ratio 1.009, 95% confidence interval 1.002-1.017, p = 0.011). During a median follow-up period of 610 days (interquartile range 475-1 106) post ablation, non-responders (n = 24, 46.2%) had a higher recurrence rate of atrial arrhythmia than the responders (n = 26, 30.2%; log-rank, p = 0.011) after the initial catheter ablation. Multivariate Cox regression analysis revealed that non-responders (hazard ratio 1.994, 95% confidence interval 1.117-3.561, p = 0.020) was significantly correlated with recurrence of atrial arrhythmias. In patients whose atrial fibrillation persisted after pulmonary vein isolation, the response to ibutilide administration could predict the recurrence of atrial arrhythmias after catheter ablation, which may be useful for risk stratification for recurrence of atrial fibrillation and individualised management of atrial fibrillation.


Phototoxic effects of nonlinear optical microscopy on cell cycle, oxidative states, and gene expression.
Nonlinear optical imaging modalities, such as stimulated Raman scattering (SRS) microscopy, use pulsed-laser excitation with high peak intensity that can perturb the native state of cells. In this study, we used bulk RNA sequencing, quantitative measurement of cell proliferation, and fluorescent measurement of the generation of reactive oxygen species to assess phototoxic effects of near-IR pulsed laser radiation, at different time scales, for laser excitation settings relevant to SRS imaging. We define a range of laser excitation settings for which there was no significant change in mouse Neuro2A cells after laser exposure. This study provides guidance for imaging parameters that minimize photo-induced perturbations in SRS microscopy to ensure accurate interpretation of experiments with time-lapse imaging or with paired measurements of imaging and sequencing on the same cells.