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"I Didn't Do That!" Event Valence and Child Age Influence Adults' Discernment of Preschoolers' True and False Statements.

Justice can hinge on adults' abilities to distinguish accurate from inaccurate child testimony. Yet relatively little is known about factors that affect adults' abilities to determine the accuracy of children's eyewitness reports. In this study, adults (<i>N</i> = 108) viewed videoclips of 3- and 5-year-olds answering open-ended and leading questions about positive and negative actually experienced ("true") events or never experienced ("false") events that the children either affirmed or denied. Analyses revealed that adults were more accurate at determining the veracity of negative compared with positive incidents, particularly when children said that they had experienced the event. Moreover, adults' accuracy was at chance for older children's false denials. Psycholegal implications are discussed.

accuracy;adults;children;discernment;false memory;true memory;valence

pubmed

Role of Choline in the Modulation of Degenerative Processes: In Vivo and In Vitro Studies.

The purpose of the present study was to examine the nutraceutical potential of choline as an added value to its well-known brain nutrient role. Several toxicity, antitoxicity, genotoxicity, antigenotoxicity, and longevity endpoints were checked in the somatic mutation and recombination test in in vivo Drosophila animal model. Cytotoxicity in human leukemia-60 cell line (HL-60) promyelocytic and NIH3T3 mouse fibroblast cells, proapoptotic DNA fragmentation, comet assay, methylation status, and macroautophagy (MA) activity were tested in in vitro assays. Choline is not only safe but it is also able to protect against the DNA damage caused by an oxidative genotoxin. Moreover, it improves the life extension in the animal model. The in vitro results show that it is able to exhibit genetic damage against leukemia HL-60 cells. Single-strand breaks in DNA are observed at the molecular level in treatments with choline, although only a significant hypermethylation on the long interspersed elements-1 and a hypomethylation on the satellite-alpha DNA repetitive DNA sequences of HL-60 cells at the lowest concentration (0.447 mM) were observed. Besides, choline decreased MA at the lower assayed concentration and the MA response to topoisomerase inhibitor (etoposide) is maintained in the presence of treatment with 0.22 mM choline. Taking into account the hopeful results obtained in the in vivo and in vitro assays, choline could be proposed as a substance with an important nutraceutical value for different purposes.

DNA damage;Drosophila melanogaster;HL-60 and NIH3T3 cell lines;antigenotoxicity;antitoxicity;choline;cytotoxicity;longevity;macroautophagy;methylation status

pubmed

Regulation of systemic autoimmunity and CD11c⁺ Tbet⁺ B cells by SWEF proteins.

Recent studies have revealed the existence of a T-bet dependent subset of B cells, which expresses unique phenotypic and functional characteristics including high levels of CD11c and CD11b. In the murine system this B cell subset has been termed Age/autoimmune-associated B cells (ABCs) since it expands with age in non-autoimmune mice and it prematurely accumulates in autoimmune-prone strains. The molecular mechanisms that promote the expansion and function of ABCs are largely unknown. This review will focus on the SWEF proteins, a small family of Rho GEFs comprised of SWAP-70 and its homolog DEF6, a newly identified risk variant for human SLE. We will first provide an overview of the SWEF proteins and then discuss the complex array of biological processes that they control and the autoimmune phenotypes that spontaneously develop in their absence, highlighting the emerging involvement of these proteins in regulating ABCs. A better understanding of the pathways controlled by the SWEF proteins could help provide new insights into the mechanisms responsible for the expansion of ABCs in autoimmunity and potentially guide the design of novel therapeutic approaches.

Age-associated B cells;Autoimmunity;DEF6;SWAP-70

pubmed

Ultimate and proximate explanations of strong reciprocity.

Strong reciprocity (SR) has recently been subject to heated debate. In this debate, the "West camp" (West et al. in Evol Hum Behav 32(4):231-262, 2011), which is critical of the case for SR, and the "Laland camp" (Laland et al. in Science, 334(6062):1512-1516, 2011, Biol Philos 28(5):719-745, 2013), which is sympathetic to the case of SR, seem to take diametrically opposed positions. The West camp criticizes advocates of SR for conflating proximate and ultimate causation. SR is said to be a proximate mechanism that is put forward by its advocates as an ultimate explanation of human cooperation. The West camp thus accuses advocates of SR for not heeding Mayr's original distinction between ultimate and proximate causation. The Laland camp praises advocates of SR for revising Mayr's distinction. Advocates of SR are said to replace Mayr's uni-directional view on the relation between ultimate and proximate causes by the bi-directional one of reciprocal causation. The paper argues that both the West camp and the Laland camp misrepresent what advocates of SR are up to. The West camp is right that SR is a proximate cause of human cooperation. But rather than putting forward SR as an ultimate explanation, as the West camp argues, advocates of SR believe that SR itself is in need of ultimate explanation. Advocates of SR tend to take gene-culture co-evolutionary theory as the correct meta-theoretical framework for advancing ultimate explanations of SR. Appearances notwithstanding, gene-culture coevolutionary theory does not imply Laland et al.'s notion of reciprocal causation. "Reciprocal causation" suggests that proximate and ultimate causes interact simultaneously, while advocates of SR assume that they interact sequentially. I end by arguing that the best way to understand the debate is by disambiguating Mayr's ultimate-proximate distinction. I propose to reserve "ultimate" and "proximate" for different sorts of explanations, and to use other terms for distinguishing different kinds of causes and different parts of the total causal chain producing behavior.

Proximate explanation;Reciprocal causation;Strong reciprocity;Ultimate explanation

pubmed

Temporal variability of blood lead, mercury, and cadmium levels in elderly panel study (2008-2014).

Biological measurements have been employed as useful biomarkers for exposure. Because of its property of reflecting toxicokinetic differences, however, within-subject variability leads to biased results in epidemiologic studies. We examined the variability of lead (Pb), mercury (Hg), and cadmium (Cd) levels in blood samples from 1429 participants among 1677 elderly individuals aged over 60 years who lived in an urban area from August 2008 to April 2015. The geometric means of blood Pb, Hg, Cd were 1.92μg/dL, 2.48μg/L, and 1.33μg/L, and the intra-class correlations (ICCs) were 0.81, 0.71, and 0.83, respectively. The mean values of Pb and Hg levels in this study were lower than the results from single spot samples in other national biomonitoring surveys in Korea, with the exception of Cd was higher than those in other studies. Moreover, the predicted exceedances over the guidance levels for Pb, Hg, and Cd were 1.9%, 4.2%, and 0.3%, respectively. Korean elderly were exposed to high levels of Pb, Hg and Cd. Especially, those who had high levels of Cd were continuously exposed to Cd during study period with the 6 collection intervals. Therefore, factors affecting environmental Cd exposure should be further studied in the future.

Cadmium;Exceedance;Intra-class correlation (ICC);Lead;Mercury

pubmed

Inhibitory effects of fifteen phthalate esters in human cDNA-expressed UDP-glucuronosyltransferase supersomes.

Phthalate esters (PAEs) have been extensively used in industry as plasticizers and there remains concerns about their safety. The present study aimed to determine the inhibition of phthalate esters (PAEs) on the activity of the phase II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs). In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone was used to investigate the inhibition potentials of PAEs towards various s UGTs. PAEs exhibited no significant inhibition of UGT1A1, UGT1A3, UGT1A8, UGT1A10, UGT2B15, and UGT2B17, and limited inhibition of UGT1A6, UGT1A7 and UGT2B4. However, UGT1A9 was strongly inhibited by PAEs. In silico docking demonstrated a significant contribution of hydrogen bonds and hydrophobic interactions contributing to the inhibition of UGT by PAEs. The K_i values were 15.5, 52.3, 23.6, 12.2, 5.61, 2.79, 1.07, 22.8, 0.84, 73.7, 4.51, 1.74, 0.58, 6.79, 4.93, 6.73, and 7.23 μM for BBOP-UGT1A6, BBZP-UGT1A6, BBOP-UGT1A7, BBZP-UGT1A7, DiPP-UGT1A9, DiBP-UGT1A9, DCHP-UGT1A9, DBP-UGT1A9, BBZP-UGT1A9, BBOP-UGT1A9, DMEP-UGT1A9, DPP-UGT1A9, DHP-UGT1A9, DiBP-UGT2B4, DBP-UGT2B4, DAP-UGT2B4, and BBZP-UGT2B4, respectively. In conclusion, exposure to PAEs might influence the metabolic elimination of endogenous compounds and xenobiotics through inhibiting UGTs.

Kinetic parameters;Phthalate esters;Uridine diphosphate glucuronosyltransferases

pubmed

Radiographic Evidence of Sinonasal Inflammation in Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome: An Underrecognized Association.

Sinonasal inflammation on both clinical examinations and imaging significantly impacts both asthma and chronic obstructive pulmonary disease (COPD). The objective of this study was to examine the association between sinonasal inflammation and asthma-COPD overlap syndrome (ACOS). A total of 112 patients with a ratio of forced expiratory volume in 1 s to forced vital capacity of less than 70% were enrolled. COPD, asthma, and ACOS were clinically diagnosed according to the 2014 Global Initiative for Asthma and Global Initiative for Chronic Obstructive Lung Disease guidelines. Sinonasal inflammatory condition was evaluated using sinus computed tomography, and its severity was assessed according to the Lund-Mackay staging (LMS) system. Ethmoid sinus-dominant shadow was defined as the presence of greater LMS scores for the anterior and posterior ethmoid sinuses than for the maxillary sinus. COPD, asthma, and ACOS were diagnosed in 55 (49.1%), 39 (34.8%), and 18 patients (16.1%), respectively. The frequency of radiographic evidence of sinonasal inflammation in patients with COPD, asthma, ACOS was 60.0%, 94.9%, and 72.2%, respectively. Patients with ACOS and COPD had only mild radiographic evidence of sinonasal inflammation (LMS score, 1-7), whereas moderate (LMS score, 8-11) and severe (LMS score, ≥12) radiographic evidence of sinonasal inflammation were detected only in patients with asthma. Furthermore, the frequency of ethmoid sinus-dominant shadow was significantly higher in patients with asthma than in those with COPD and ACOS. Radiographic evidence of sinonasal inflammation was a common comorbidity in ACOS. Future studies are required to examine the role of sinonasal inflammation in ACOS.

Asthma-chronic obstructive pulmonary disease overlap syndrome;Lund-Mackay staging score;Sinonasal inflammation

pubmed

Chitosan as biomaterial in drug delivery and tissue engineering.

Chitin is one of the most abundant polysaccharide found on earth. The deacetylated form of chitin viz. chitosan has been reported for its various important pharmacological properties and its role in tissue engineering and regenerative medicine is also well documented. Chitosan based bone graft substitutes are biocompatible, biodegradable, osteoconductive, osteoinductive and structurally similar to bone, with excellent mechanical strength and cost effectiveness. Chitosan based hydrogels and wound healing bandages have also found a great market in the field of medicine. More recently, chitosan has gained popularity for its use as a matrix molecule for drug delivery and also finds an upcoming utility in the area of dentistry. The present article has tried to review the latest research on chitosan based tissue engineering constructs, drug delivery vehicles as well as dental care products. An attempt has also been made to discuss the various modifications of chitosan that enhance its use for a given set of applications which would pave a way for future applied research in the field of biomedical innovation and regenerative medicine.

Biomedicine;Chitosan;Denstistry;Drug delivery;Gene delivery;Tissue engineering

pubmed

Epidemiology of invasive pneumococcal and Haemophilus influenzae diseases in Northwestern Ontario, Canada, 2010-2015.

North American indigenous populations experience a high burden of invasive bacterial infections. Because Streptococcus pneumoniae and Haemophilus influenzae have multiple antigenic variants, the existing vaccines cannot prevent all cases. This study addresses the current epidemiology of invasive H. influenzae and pneumococcal disease (IPD) in a region of Northwestern Ontario, Canada with a relatively high (82%) indigenous population. Data were retrieved from a retrospective chart review at a hospital servicing a population of 29000 (82% indigenous), during January 2010-July 2015. Ten cases of invasive H. influenzae disease and 37 cases of IPD were identified. The incidence of both in the study population (6.3 and 23.1/100000/year, respectively) exceeded national rates (1.6 and 9.0/100000/year). H. influenzae serotype a (Hia) was the most common (50%), followed by non-typeable H. influenzae (20%). In adults, 77% of IPD cases were caused by serotypes included in the 23-valent pneumococcal polysaccharide vaccine. All paediatric IPD cases were caused by serotypes not included in the 13-valent pneumococcal conjugate vaccine. The case-fatality rate was 10% for invasive H. influenzae and 2.7% for IPD. Most cases exhibited substantial co-morbidity. In Northwestern Ontario, the incidence of invasive Hia disease exceeds that of H. influenzae type b (Hib) in the pre-Hib vaccine era. This provides strong support for the development of a new Hia vaccine. Improved pneumococcal vaccination of high-risk adults in the region is warranted.

Canada;Haemophilus influenzae;Indigenous;Invasive disease;Pneumococcal;Streptococcus pneumoniae

pubmed

Leaving no one behind: lessons on rebuilding health systems in conflict- and crisis-affected states.

Conflict and fragility are increasing in many areas of the world. This context has been referred to as the 'new normal' and affects a billion people. Fragile and conflict-affected states have the worst health indicators and the weakest health systems. This presents a major challenge to achieving universal health coverage. The evidence base for strengthening health systems in these contexts is very weak and hampered by limited research capacity, challenges relating to insecurity and apparent low prioritisation of this area of research by funders. This article reports on findings from a multicountry consortium examining health systems rebuilding post conflict/crisis in Sierra Leone, Zimbabwe, northern Uganda and Cambodia. Across the ReBUILD consortium's interdisciplinary research programme, three cross-cutting themes have emerged through our analytic process: communities, human resources for health and institutions. Understanding the impact of conflict/crisis on the intersecting inequalities faced by households and communities is essential for developing responsive health policies. Health workers demonstrate resilience in conflict/crisis, yet need to be supported post conflict/crisis with appropriate policies related to deployment and incentives that ensure a fair balance across sectors and geographical distribution. Postconflict/crisis contexts are characterised by an influx of multiple players and efforts to support coordination and build strong responsive national and local institutions are critical. The ReBUILD evidence base is starting to fill important knowledge gaps, but further research is needed to support policy makers and practitioners to develop sustainable health systems, without which disadvantaged communities in postconflict and postcrisis contexts will be left behind in efforts to promote universal health coverage.

gender;health economics;health policy;health systems;human resources for health

pubmed

The Impact of Health Information Technology on the Doctor-Patient Relationship in Child and Adolescent Psychiatry.

As health information technology continues to expand and permeate medicine, there is increasing concern for the effect on the therapeutic relationship between patient and psychiatrist. This article explores this impact, seeking wisdom from adult psychiatry and more broadly from general medical disciplines to draw conclusions regarding how the child psychiatry encounter may be affected. Several proposed strategies to mitigate potential negative impacts of health information technology on the therapeutic relationship across practice settings are offered.

Electronic health records;Health information technology;Patient-psychiatrist relationship

pubmed

Primary degradation of antidiabetic drugs.

Type 2 diabetes is a chronic disease affecting a large portion of the world population and is treated by orally administered drugs. Since these drugs are often taken in high doses and are excreted unchanged or partially metabolised many of them are nowadays detected in surface waters or wastewater treatment plants effluents. Unmetabolised antidiabetics or some of their transformation products retain their pharmacological activity, therefore their presence in the environment is highly undesired. One of the main routes of elimination from wastewaters or surface waters is biodegradation. Within this work we tested primary biodegradation of: metformin and its metabolite guanylurea, acarbose, glibenclamide, gliclazide and glimepiride. We also inspected what might be the extent of the degradation by examining the products formed during the degradation using liquid chromatography coupled to tandem mass spectrometry. Transformation of diabetes staple drug metformin to dead-end product guanylurea was generally confirmed. An alternative, though rather minor pathway leading to complete mineralisation was also found. Complete primary degradation was observed for acarbose, glibenclamide and glimepiride whereas gliclazide was shown to be resistant to biodegradation. These results allow a preliminary assessment of environmental persistency of a very important group of pharmaceuticals and show need for implementing monitoring programs.

Antidiabetic drugs;Environmental fate;Pharmaceuticals;Primary biodegradation;Sulphonamides

pubmed

Design and Validation of a Platform to Evaluate mHealth Apps.

Emerging technologies show great potential in the field of patient care. One such technology is mobile heath applications (mhealth apps), which have exploded in number and variety in recent years, and offer great promise in the ability to collect and monitor patient health data. Despite their apparent success in proliferation and user adoption, these applications struggle to integrate into the primary care system and there is scant information regarding their efficacy to effect patient behavior and consequently health outcomes. In this paper we investigate the potential of a promising clinical evaluation methodology, response adaptive randomized clinical trials, to rapidly and effectively evaluate the efficacy and effectiveness of mhealth apps and to personalize mhealth app selection to individualize patient benefit. Diabetes prevention provides the use case for evaluating the case for and against response-adaptive randomized trials.

Adaptive Clinical Trials;Diabetes Prevention;Mobile Health Applications;RCT;evaluation;mhealth apps;randomized controlled trials

pubmed

FAM3A mediates PPARγ's protection in liver ischemia-reperfusion injury by activating Akt survival pathway and repressing inflammation and oxidative stress.

FAM3A is a novel mitochondrial protein, and its biological function remains largely unknown. This study determined the role and mechanism of FAM3A in liver ischemia-reperfusion injury (IRI). In mouse liver after IRI, FAM3A expression was increased. FAM3A-deficient mice exhibited exaggerated liver damage with increased serum levels of AST, ALT, MPO, MDA and oxidative stress when compared with WT mice after liver IRI. FAM3A-deficient mouse livers had a decrease in ATP content, Akt activity and anti-apoptotic protein expression with an increase in apoptotic protein expression, inflammation and oxidative stress when compared WT mouse livers after IRI. Rosiglitazone pretreatment protected against liver IRI in wild type mice but not in FAM3A-deficient mice. In cultured hepatocytes, FAM3A overexpression protected against, whereas FAM3A deficiency exaggerated oxidative stress-induced cell death. FAM3A upregulation or FAM3A overexpression inhibited hypoxia/reoxygenation-induced activation of apoptotic gene and hepatocyte death in P2 receptor-dependent manner. FAM3A deficiency blunted rosiglitazone's beneficial effects on Akt activation and cell survival in cultured hepatocytes. Collectively, FAM3A protects against liver IRI by activating Akt survival pathways, repressing inflammation and attenuating oxidative stress. Moreover, the protective effects of PPARγ agonist(s) on liver IRI are dependent on FAM3A-ATP-Akt pathway.

Akt;FAM3A;FOXO1;PPARgamma;liver ischemia/reperfusion injury

pubmed

Untangling the most probable role for vitamin D₃ in autism.

Recent studies indicate an important role for vitamin D₃ in autism spectrum disorder (ASD), although its mechanism is not completely understood. The most puzzling aspect of ASD is that identical twins, who share identical DNA, do not have 100% concordance rates (∼88% for identical and ∼31% for fraternal twins). These findings provide major clues into the etiology: ASD must involve an environmental factor present in the prenatal milieu that both identical twins are not always exposed to because they do not always share it (i.e., placentas). Combined with the exponential increasing rates of ASD around the world, these observations suggest a contagious disease is probably transferred to the fetus via the placenta becoming infected by a cervical virus. Vitamin D₃ boosts immune responses clearing viral infections and increases serotonin and estrogen brain levels. Here we review the different roles and untangle the most probable one vitamin D₃ plays in ASD.

autism spectrum disorder;cerebral spinal fluids;cervix;choroid plexus;estrogen;human papillomavirus;learning disabilities;placenta;prenatal environment;serotonin;vitamin D3

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Evaluation of the Healing Potential of Demineralized Dentin Matrix Fixed with Recombinant Human Bone Morphogenetic Protein-2 in Bone Grafts.

We aimed to evaluate the efficacy of demineralized dentin matrix (DDM) fixed with recombinant human bone morphogenetic protein-2 (rhBMP-2) through an experimental and a clinical study. Unilateral upper second and third premolars of eight beagles were extracted. A mucoperiosteal flap was elevated around the extraction socket, and a bone defect was made using a surgical drill. Each DDM was fixed with rhBMP-2, and autogenous bone was grafted at the bone defect area with a collagenous membrane. The beagles were euthanized at two, four, eight, and 12 weeks after receiving the bone graft. Block specimens involving grafted bone and surrounding natural bone were extracted. A total of 23 patients who received bone grafts using human DDM fixed with rhBMP-2 (AutoBT BMP) with implant placements (36 implants; maxilla: 14, mandible: 22) were selected. The implant stability, marginal bone loss, and clinical outcome were evaluated. Three trephine cores were harvested fourmonths after bone grafting, and histologic examination was performed. In the histological evaluation performed four weeks after the bone graft, autogenous bone showed 52% new bone formation and DDM fixed with rhBMP-2 showed 33% new bone formation. Twelve weeks after the bone graft, autogenous bone showed 75% new bone formation and DDM fixed with rhBMP-2 showed 48% new bone formation. In the clinical study, favorable osseointegration was obtained in 35 out of 36 implant sites (one case of osseointegration failure). In all cases, severe complications were not observed. Histomorphometrically, new bone formation was observed in 14.98% of the cases. The residual DDM particles were 6.22%. AutoBT BMP provides good osteoinductive and osteoconductive potential and clinical efficacy.

demineralized dentin matrix;rhBMP-2

pubmed

Effect of landscape tree cover, sex and season on the bioaccumulation of persistent organochlorine pesticides in fruit bats of riparian corridors in eastern Mexico.

Riparian forests are recognized as important ecosystems for biodiversity conservation in transformed landscapes. Many animal species that use this type of vegetation facilitate its recovery through pollination and seed dispersal. In landscapes dominated by agrosystems and cattle ranching, persistent organochlorine pesticides (OCPs) in the riparian system may have an effect on the physiology and fitness of animals. In this study, we measured bioaccumulation of OCPs in the most abundant frugivorous bat, Sturnira hondurensis, from the upper part of La Antigua basin, Veracruz, Mexico and, from these data, estimated accumulation by the frugivorous bat community of riparian forests in contrasting, transformed (TL) and forested (FL) landscapes. Concentration of ΣDDT, Σdrines, Σclordano, ΣHCH, Σheptachlor and Σendosulfan was measured by gas-chromatography in 23 female and 33 male adult Sturnira captured during the dry and rainy seasons. Using censored data statistics, we found that the sex of the individual was significant for ΣHCH, and that interactions of landscape type (TL vs. FL) and season (dry vs. wet), and sex and season were significant for Σendosulfan and Σdrines, respectively. Mean ΣDDT (6.86 μg/g) and ΣHCH (28.22 μg/g) concentrations were lower than those reported for frugivorous bats in India but concentrations of Σdrines (13.86 μg/g) were higher than those reported in insectivorous bats. In our study sites, frugivorous bats are bioaccumulating higher amounts of OCPs in TL than in FL. We discuss the potential of this species as a bio-indicator of OCPs contamination in river basins.

Bio-indicator;Frugivorous;La Antigua;Organochlorine compounds;Phyllostomidae;Riparian corridor forests

pubmed

Targeting CXCR4 with [⁶⁸Ga]Pentixafor: a suitable theranostic approach in pleural mesothelioma?

C-X-C motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. This study investigated the feasibility of CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using [⁶⁸Ga]Pentixafor in malignant pleural mesothelioma. Six patients with pleural mesothelioma underwent [⁶⁸Ga]Pentixafor-PET/CT. 2'-[¹⁸F]fluoro-2'-deoxy-D-glucose ([¹⁸F]FDG)-PET/CT (4/6 patients) and immunohistochemistry obtained from biopsy or surgery (all) served as standards of reference. Additionally, 9 surgical mesothelioma samples were available for histological work-up. Whereas [¹⁸F]FDG-PET depicted active lesions in all patients, [⁶⁸Ga]Pentixafor-PET/CT recorded physiologic tracer distribution and none of the 6 patients presented [⁶⁸Ga]Pentixafor-positive lesions. This finding paralleled results of immunohistochemistry which also could not identify relevant CXCR4 surface expression in the samples analyzed. In contrast to past reports, our data suggest widely absence of CXCR4 expression in pleural mesothelioma. Hence, robust cell surface expression should be confirmed prior to targeting this chemokine receptor for diagnosis and/or therapy.

CXCR4;PET;[68Ga] pentixafor;pleural mesothelioma;theranostics

pubmed

A three-dimensional neural spheroid model for capillary-like network formation.

In vitro three-dimensional neural spheroid models have an in vivo-like cell density, and have the potential to reduce animal usage and increase experimental throughput. The aim of this study was to establish a spheroid model to study the formation of capillary-like networks in a three-dimensional environment that incorporates both neuronal and glial cell types, and does not require exogenous vasculogenic growth factors. We created self-assembled, scaffold-free cellular spheroids using primary-derived postnatal rodent cortex as a cell source. The interactions between relevant neural cell types, basement membrane proteins, and endothelial cells were characterized by immunohistochemistry. Transmission electron microscopy was used to determine if endothelial network structures had lumens. Endothelial cells within cortical spheroids assembled into capillary-like networks with lumens. Networks were surrounded by basement membrane proteins, including laminin, fibronectin and collagen IV, as well as key neurovascular cell types. Existing in vitro models of the cortical neurovascular environment study monolayers of endothelial cells, either on transwell inserts or coating cellular spheroids. These models are not well suited to study vasculogenesis, a process hallmarked by endothelial cell cord formation and subsequent lumenization. The neural spheroid is a new model to study the formation of endothelial cell capillary-like structures in vitro within a high cell density three-dimensional environment that contains both neuronal and glial populations. This model can be applied to investigate vascular assembly in healthy or disease states, such as stroke, traumatic brain injury, or neurodegenerative disorders.

Brain;Capillary-like network;Cellular self-assembly;Cortex;Endothelial cells;Neurovascular unit;Spheroid;Vasculogenesis;in vitro

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Fatalism and hypertension prevalence, awareness, treatment and control in US Hispanics/Latinos: results from HCHS/SOL Sociocultural Ancillary Study.

Compared with non-Hispanic whites, US Hispanics/Latinos display similar hypertension prevalence, but lower awareness, treatment, and control. Sociocultural factors may affect these patterns. Fatalism, the belief that health is predetermined by fate, relates to poorer adoption of risk reducing health behaviors. We examined the association of fatalism with hypertension prevalence, awareness, treatment, and control among 5313 Hispanics/Latinos, ages 18-74, who were enrolled from four US communities in the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study. After accounting for socioeconomic status and acculturation in logistic regression analyses, higher fatalism was associated with increased odds of hypertension (OR 1.14, 95 % CI 1.02, 1.28). This association was non-significant when diabetes and other health-related covariates were statistically adjusted. Fatalism was not associated with hypertension awareness, treatment, or control. Findings suggest that the association of fatalism with hypertension may be due largely to its association with SES, acculturation, or related health conditions.

Fatalism;Hispanic;Hypertension;Latino;Sociocultural

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Feeding a concentrate rich in rapeseed oil improves fatty acid composition and flavor in Norwegian goat milk.

Impaired quality due to a high content of free fatty acids (FFA) and off-flavors has caused challenges in the development of Norwegian goat milk products. The present study aimed to examine the effect of lipid-supplemented concentrates on milk fat content, fatty acid composition, FFA, lipoprotein lipase activity, sensory properties, and size of milk fat globules of goat milk. Thirty goats assigned to 3 experimental groups were fed different concentrates from 60 d in milk (DIM) until late lactation (230 DIM). The diets were (1) control concentrate (no added fat); (2) control concentrate with 8% (added on air-dry basis) hydrogenated palm oil enriched with palmitic acid (POFA); and (3) control concentrate with 8% (added on air-dry basis) rapeseed oil (RSO). The POFA group produced milk with the highest fat content, and fat content was positively correlated with the mean size of milk fat globules. Goats in the RSO group had a higher content of long-chain and unsaturated fatty acids, whereas milk from goats in the POFA group had a higher content of palmitic and palmitoleic acids (C16:0 and C16:1 cis). The control group produced milk with a higher content of short-, medium-, odd-, and branched-chain fatty acids compared with the 2 other groups. The content of FFA in milk was low in early and late lactation and peaked in mid lactation (90 DIM). A high content of FFA was correlated with poor sensory properties (tart/rancid flavor). The RSO group produced milk with lower content of FFA and off-flavors in mid lactation and a higher proportion of unsaturated fatty acids. Therefore, replacement of palm oil with rapeseed oil as a lipid source in dairy goat feed would be favorable.

fatty acid composition;free fatty acids;goat milk;palm oil;rapeseed oil

pubmed

Ellagic acid protects against neuron damage in ischemic stroke through regulating the ratio of Bcl-2/Bax expression.

An oxygen-glucose deprivation and reoxygenation model in primary cultured rat cortical neurons was developed for this study to investigate the effects of ellagic acid (EA), a low-molecular-weight polyphenol, on neuron cells and their function, and to evaluate whether EA can be safely utilized by humans as a functional food or therapeutic agent. Administration of EA significantly decreased the volume of cerebrum infarction and the neurological deficit scores of the rats; EA treatment also increased the number of Bcl-2-positive cells and the ratio of Bcl-2-positive to Bax-positive neurons in the semidarkness zone near the brain ischemic focus in the photothrombotic cerebral ischemia model. Treatment of EA resulted in increased neuron viability, cell nuclear integrity, and the ratio of Bcl-2/Bax expression in the primary cultured neuron model; EA treatment also lead to a decrease in the number of apoptotic cells. Our results therefore suggest a specific mechanism for the beneficial effects of EA, providing new insights into how it provides neuroprotection. To the best of our knowledge, these results represent new insights on the mechanisms of the brain cell protective activity of EA. Thus, EA may be used in functional foods or medicines to help treat nerve dysfunction, neurodegenerative disease, and aging.

AVC;Bax;Bcl-2;OGD/R;acide ellagique;ellagic acid;mort de cellule nerveuse;nerve cell death;neuron;neurone;stroke

pubmed

Arteriovenous malformation and thyroid metastasis from underlying renal cell carcinoma, an unusual presentation of malignancy: A case report.

Renal Clear Cell Carcinoma (RCC) comprises over 80% of renal malignancies in adults. Thyroid gland metastasis is rare in RCC. Few studies have described cases of RCC mistaken for benign arteriovenous malformation (AVM). To the best of our knowledge, an AVM arising from underlying RCC metastasis to the brain has not yet been reported. The current study presents a case of RCC metastasis to the thyroid gland, with an AVM identified to be a result of metastatic involvement in the brain. A 45-year-old African-American female presented with left-sided weakness, slurred speech, facial droop and seizure. The patient's medical history was notable for a diagnosis of RCC, 2010 American Joint Committee on Cancer Tumor-Node-Metastasis Stage 1B (T1B, N0, M0) grade III status post-right partial nephrectomy. Computed tomography (CT) imaging revealed a soft-tissue mass, suspected to be metastasis, in the left lobe of the thyroid, in addition to a 1.9 cm right intracranial mass in the parietal lobe. Positron emission tomography/computed tomography revealed a hypermetabolic area in the thyroid. Fine needle aspiration of the thyroid, and subsequent histopathological analysis, suggested a diagnosis of RCC metastasis. Subsequent immunohistochemical analysis of the thyroid tumor confirmed RCC metastasis. The patient also underwent a right partial craniotomy with resection of the intra-axial mass. Initial pathology was suggestive of an AVM. After several months, the patient was readmitted with headache, nausea and vomiting. Repeat imaging revealed recurrence of a 3.9 cm mass that was negative for AVM on biopsy; however, the immunostaining markers were positive for RCC. Recent literature suggests a link between AVMs and RCC as each exhibit highly vascular characteristics. RCC is a particularly vascular tumor that has been demonstrated to lead to the abnormal expression of various angiogenesis-promoting growth factors, including vascular endothelial growth factor. These angiogenic factors are vital to the pathophysiological pathway involved in the tumorigenesis and progression of RCC, and may explain the development of AVMs within these neoplasms, as demonstrated in the case presented in the current study.

arteriovenous malformation;presentation;renal cell cancer;thyroid metastasis;unusual

pubmed

Cervical En-Plaque Extradural Meningioma Involving Brachial Plexus.

Meningioma is one of the commonest spinal tumors, with a predilection for intradural occurrence. Its occurrence as an extradural, en plaque variety with extension into the brachial plexus is unusual. A 50-year-old male patient presented with progressive spastic quadriparesis. Magnetic resonance imaging showed an en plaque, epidural soft tissue tumor at C5-C7 levels on the right side with extraforaminal extension into the paraspinal region and the brachial plexus laterally. The patient underwent a C5-7 laminectomy and partial excision of the tumor. Histopathology was reported as psammomatous meningioma (World Health Organization grade I). An extradural spinal meningioma should be considered in the differential diagnosis of an exclusively extradural spinal tumor. Its occurrence as an en plaque variety is uncommon. We report an unusual case of the en plaque form of extradural cervical meningioma with diffuse involvement of the brachial plexus.

Brachial plexus;Cervical spine;Extradural tumor;Meningioma;Psammomatous

pubmed

Entire plastid phylogeny of the carrot genus (<i>Daucus</i>, Apiaceae): Concordance with nuclear data and mitochondrial and nuclear DNA insertions to the plastid.

We explored the phylogenetic utility of entire plastid DNA sequences in <i>Daucus</i> and compared the results with prior phylogenetic results using plastid and nuclear DNA sequences. We used Illumina sequencing to obtain full plastid sequences of 37 accessions of 20 <i>Daucus</i> taxa and outgroups, analyzed the data with phylogenetic methods, and examined evidence for mitochondrial DNA transfer to the plastid (<i>Dc</i>MP). Our phylogenetic trees of the entire data set were highly resolved, with 100% bootstrap support for most of the external and many of the internal clades, except for the clade of <i>D. carota</i> and its most closely related species <i>D. syrticus</i>. Subsets of the data, including regions traditionally used as phylogenetically informative regions, provide various degrees of soft congruence with the entire data set. There are areas of hard incongruence, however, with phylogenies using nuclear data. We extended knowledge of a mitochondrial to plastid DNA insertion sequence previously named <i>Dc</i>MP and identified the first instance in flowering plants of a sequence of potential nuclear genome origin inserted into the plastid genome. There is a relationship of inverted repeat junction classes and repeat DNA to phylogeny, but no such relationship with nonsynonymous mutations. Our data have allowed us to (1) produce a well-resolved plastid phylogeny of <i>Daucus</i>, (2) evaluate subsets of the entire plastid data for phylogeny, (3) examine evidence for plastid and nuclear DNA phylogenetic incongruence, and (4) examine mitochondrial and nuclear DNA insertion into the plastid.

Apiaceae;Daucus;DcMP;carrot;germplasm;mitochondria;next-generation sequencing;nuclear-to-plastid DNA transfer;plastid phylogeny

pubmed

Disentangling the effects of a multiple behaviour change intervention for diarrhoea control in Zambia: a theory-based process evaluation.

Diarrhoea is a leading cause of child death in Zambia. As elsewhere, the disease burden could be greatly reduced through caregiver uptake of existing prevention and treatment strategies. We recently reported the results of the Komboni Housewives intervention which tested a novel strategy employing motives including affiliation and disgust to improve caregiver practice of four diarrhoea control behaviours: exclusive breastfeeding; handwashing with soap; and correct preparation and use of oral rehydration salts (ORS) and zinc. The intervention was delivered via community events (women's forums and road shows), at health clinics (group session) and via radio. A cluster randomised trial revealed that the intervention resulted in a small improvement in exclusive breastfeeding practices, but was only associated with small changes in the other behaviours in areas with greater intervention exposure. This paper reports the findings of the process evaluation that was conducted alongside the trial to investigate how factors associated with intervention delivery and receipt influenced caregiver uptake of the target behaviours. Process data were collected from the eight peri-urban and rural intervention areas throughout the six-month implementation period and in all 16 clusters 4-6 weeks afterwards. Intervention implementation (fidelity, reach, dose delivered and recruitment strategies) and receipt (participant engagement and responses, and mediators) were explored through review of intervention activity logs, unannounced observation of intervention events, semi-structured interviews, focus groups with implementers and intervention recipients, and household surveys. Evaluation methods and analyses were guided by the intervention's theory of change and the evaluation framework of Linnan and Steckler. Intervention reach was lower than intended: 39% of the surveyed population reported attending one or more face-to-face intervention event, of whom only 11% attended two or more intervention events. The intervention was not equally feasible to deliver in all settings: fewer events took place in remote rural areas, and the intervention did not adequately penetrate communities in several peri-urban sites where the population density was high, the population was slightly higher socio-economic status, recruitment was challenging, and numerous alternative sources of entertainment existed. Adaptations made by the implementers affected the fidelity of implementation of messages for all target behaviours. Incorrect messages were consequently recalled by intervention recipients. Participants were most receptive to the novel disgust and skills-based interactive demonstrations targeting exclusive breastfeeding and ORS preparation respectively. However, initial disgust elicitation was not followed by a change in associated psychological mediators, and social norms were not measurably changed. The lack of measured behaviour change was likely due to issues with both the intervention's content and its delivery. Achieving high reach and intensity in community interventions delivered in diverse settings is challenging. Achieving high fidelity is also challenging when multiple behaviours are targeted for change. Further work using improved tools is needed to explore the use of subconscious motives in behaviour change interventions. To better uncover how and why interventions achieve their measured effects, process evaluations of complex interventions should develop and employ frameworks for investigation and interpretation that are structured around the intervention's theory of change and the local context. The study was registered as part of the larger trial on 5 March 2014 with ClinicalTrials.gov: NCT02081521 .

Behaviour change;Breastfeeding;Handwashing;Oral rehydration salts;Process evaluation;Theory of change;Zinc

pubmed

Prostaglandin E₂ Activates YAP and a Positive-Signaling Loop to Promote Colon Regeneration After Colitis but Also Carcinogenesis in Mice.

Prostaglandin E₂ (PGE₂) is mediator of inflammation that regulates tissue regeneration, but its continual activation has been associated with carcinogenesis. Little is known about factors in the PGE₂ signaling pathway that contribute to tumor formation. We investigated whether yes-associated protein 1 (YAP1), a transcriptional co-activator in the Hippo signaling pathway, mediates PGE₂ function. DLD-1 and SW480 colon cancer cell lines were transfected with vectors expressing transgenes or small hairpin RNAs and incubated with recombinant PGE₂, with or without pharmacologic inhibitors of signaling proteins, and analyzed by immunoblot, immunofluorescence, quantitative reverse-transcription polymerase chain reaction, transcriptional reporter, and proliferation assays. Dextran sodium sulfate (DSS) was given to induce colitis in C57/BL6 (control) mice, as well as in mice with disruption of the hydroxyprostaglandin dehydrogenase 15 gene (15-PGDH-knockout mice), Yap1 gene (YAP-knockout mice), and double-knockout mice. Some mice also were given indomethacin to block PGE₂ synthesis. 15-PGDH knockout mice were crossed with mice with intestine-specific disruption of the salvador family WW domain containing 1 gene (Sav1), which encodes an activator of Hippo signaling. We performed immunohistochemical analyses of colon biopsy samples from 26 patients with colitis-associated cancer and 51 age-and sex-matched patients with colorectal cancer (without colitis). Incubation of colon cancer cell lines with PGE₂ led to phosphorylation of cyclic adenosine monophosphate-responsive element binding protein 1 and increased levels of YAP1 messenger RNA, protein, and YAP1 transcriptional activity. This led to increased transcription of the prostaglandin-endoperoxide synthase 2 gene (PTGS2 or cyclooxygenase 2) and prostaglandin E-receptor 4 gene (PTGER4 or EP4). Incubation with PGE₂ promoted proliferation of colon cancer cell lines, but not cells with knockdown of YAP1. Control mice developed colitis after administration of DSS, but injection of PGE₂ led to colon regeneration in these mice. However, YAP-knockout mice did not regenerate colon tissues and died soon after administration of DSS. 15-PGDH-knockout mice regenerated colon tissues more rapidly than control mice after withdrawal of DSS, and had faster recovery of body weight, colon length, and colitis histology scores. These effects were reversed by injection of indomethacin. SAV1-knockout or 15-PGDH-knockout mice did not develop spontaneous tumors after colitis induction, but SAV1/15-PGDH double-knockout mice developed polyps that eventually progressed to carcinoma in situ. Administration of indomethacin to these mice prevented spontaneous tumor formation. Levels of PGE₂ correlated with those of YAP levels in human sporadic colorectal tumors and colitis-associated tumors. PGE₂ signaling increases the expression and transcriptional activities of YAP1, leading to increased expression of cyclooxygenase 2 and EP4 to activate a positive signaling loop. This pathway promotes proliferation of colon cancer cell lines and colon tissue regeneration in mice with colitis. Constitutive activation of this pathway led to formation of polyps and colon tumors in mice.

Inflammation;Mouse Model;Tumorigenesis;Villus Regeneration

pubmed

Imaging findings of Copa syndrome in a 12-year-old boy.

Copa syndrome is a newly described autosomal dominant autoinflammatory disease that presents as pulmonary hemosiderosis and polyarticular arthritis. Twenty-one cases from five families have been reported to date. We present chest computed tomography (CT) and temporomandibular joint magnetic resonance (MR) findings of a 12-year-old boy presenting with dyspnea on exertion, fatigue and clubbing. Additional findings included a restrictive pattern of pulmonary involvement and positive inflammatory markers and autoantibodies. Genetic testing revealed a p.W240R variant of the COPA gene confirming the diagnosis of Copa syndrome. CT of the chest showed a nonspecific interstitial pneumonia pattern distributed mainly in the lower lobes. MR of the temporomandibular joints and follow-up CT three years later are also described.

Autosomal dominant missense mutation;Child;Computed tomography;Copa syndrome;Nonspecific interstitial pneumonia;Pulmonary hemosiderosis;Temporomandibular joint arthritis

pubmed

Effect of Flavors and Modified Risk Messages on E-cigarette Abuse Liability.

To measure e-cigarettes' abuse liability compared to conventional tobacco cigarettes under flavor and message conditions amenable to regulation. Two studies used 2×2 within-subjects designs with factors of e-cigarette flavor (Study 1: tobacco vs. menthol; Study 2: cherry vs. unflavored) and message (Study 1: reduced harm vs. no message; Study 2: reduced exposure to carcinogens vs. no message) with cigarette smokers (N(total) = 36). Linear mixed effects models assessed abuse liability for tobacco products. Outcomes included the price after which consumption is zero (the maximum amount participants would pay for a tobacco product) from the multiple choice procedure (MCP) and cigarette purchase task (CPT) and demand elasticity (price sensitivity) from the CPT. In the MCP, the price where consumption reached zero was significantly lower in all e-cigarette conditions except tobacco flavor (message or no message) compared to cigarettes (p < .05 each). Demand elasticity was significantly higher for menthol/no message and unflavored/reduced exposure message conditions relative to cigarettes (p < .05 each). Flavors and modified risk messages included with e-cigarettes may affect e-cigarette abuse liability among smokers, suggesting regulatory pathways to influence demand for conventional and alternative tobacco products.

abuse liability;e-cigarette;flavor;risk messages

pubmed

Genotype-phenotype relationship of CCL5 in pulmonary tuberculosis infection in <i>Sahariya</i> tribe: A pilot study.

Sahariya, a primitive tribe of Central India, has shown significantly increased incidence of pulmonary tuberculosis (PTB). Our previous study on Sahariya showed a significant association of -403G>A single nucleotide polymorphism (SNP) of CCL5 with susceptibility to PTB. Hence, this study was aimed to analyze a genotype-phenotype relationship of this disease-associated SNP to develop a potential diagnostic marker for TB in this tribe. The present study was carried out on 70 plasma samples from Sahariya tribe, wherein the plasma CCL5 level was determined using a commercially available ELISA kit. The level of CCL5 decreased significantly in patients who were on therapy/completed their therapy [inactive TB patient/inactive PTB (IPTB)], particularly with AA genotype of -403G>A (P=0.046). The level, with AA genotype, was also found to gradually decrease in sputum 3+ and 1+/2+ than in sputum-negative samples. Similarly, the CCL5 level was found to be higher in sputum-positive/active TB patients than in IPTB group and healthy controls. Our results suggested that the CCL5 level was influenced collectively not only by the genotypes of -403G>A SNP and bacillary load but also by the treatment. Thus, CCL5 may be considered for the development of a diagnostic marker and also as an indicator of recovery.

CCL5 - resistance - Sahariya - susceptibility - tuberculosis

pubmed

Unintended consequences of machine learning in medicine?

Machine learning (ML) has the potential to significantly aid medical practice. However, a recent article highlighted some negative consequences that may arise from using ML decision support in medicine. We argue here that whilst the concerns raised by the authors may be appropriate, they are not specific to ML, and thus the article may lead to an adverse perception about this technique in particular. Whilst ML is not without its limitations like any methodology, a balanced view is needed in order to not hamper its use in potentially enabling better patient care.

artificial intelligence;healthcare;machine learning;medicine

pubmed

Utilization of Organs From Donors According to Hepatitis C Antibody and Nucleic Acid Testing Status: Time for Change.

Previous studies have grouped all donors positive for hepatitis C virus (HCV) antibody (Ab). Only recently has donor HCV nucleic acid testing (NAT) become routine, and the impact of Ab and NAT status on organ utilization is unknown. Using the United Network for Organ Sharing database, we identified 9290 donors from 2015 to 2016 for whom both HCV Ab and NAT data were available and compared organ utilization by HCV status. Overall, 93.8% of donors were Ab negative and NAT negative (Ab-NAT-), 0.15% were Ab negative and NAT positive, 1.8% were Ab positive and NAT negative (Ab+NAT-), and 4.2% were both Ab and NAT positive (Ab+NAT+). Ab-NAT- donors donated at the highest rate for all organs except livers, of which Ab+NAT- donors donated at a higher rate (81.2% vs 73.2%, p = 0.03). Livers were discarded for reasons related to abnormal biopsies in Ab+NAT+ donors, whereas kidneys from Ab- or NAT-positive donors were discarded for reasons related to HCV status. Using a propensity score-matched model, we estimated that using Ab+NAT- donors at the same rate as Ab-NAT- donors could result in 48 more kidney donors, 37 more heart donors, and 15 more lung donors annually. We urge the use of HCV Ab+NAT- donors for appropriately selected and consenting recipients.

United Network for Organ Sharing (UNOS);clinical research/practice;kidney transplantation/nephrology;liver transplantation/hepatology;organ acceptance;organ transplantation in general

pubmed

What does the character of medicine as a social practice imply for professional conscientious objection?

The dispute over professional conscientious objection presumes a picture of medicine as a practice governed by rules. This rule-based conception of medical practice is identifiable with John Rawls's conception of social practices. This conception does not capture the character of medical practice as experienced by practitioners, for whom it is a sensibility or "form of life" rather than rules. Moreover, the sensibility of medical practice as experienced by physicians is at best neutral, and at worst hostile, to the demands of those who would override physician conscientious objection to the provision of currently contested services. That being so, calls for overriding physician conscientious objection are much more demanding of the medical profession than they appear in light of Rawls's view. As such overriding may entail the forcible transformation of medicine's form of life, the author contends that it would be more prudent to provide contested services by circumventing the medical profession than by compelling it.

Conscientious objection;Medical professionalism;Social practice

pubmed

Contribution of CB1Rs in anxiety-related behaviors but not locomotor deficits induced by methamphetamine.

Several lines of evidence have indicated that Methamphetamine (METH) exposure leads to neurodegenerative changes in the dopaminergic neurons and subsequently may predispose users to motor deficit. On the other hand, there is a reciprocal regulation between the endocannabinoid and the dopaminergic systems. Previous studies also showed that the endocannabinoids are involved in the signaling mechanisms of various brain regions related to motor and cognitive functions. The cerebellum seems as a rational target to investigate the action of cannabinoids on motor coordination because of the high concentration of the cannabinoid receptor in the molecular layer of it and other regions involved in motor activity. The behavioral effects of systemic CBR agonist (3mg/kg/day WIN55,212-2) and antagonist (10mg/kg SR141716A) treatment on METH-induced motor deficits in rats were assessed using open field, rota-rod, and grip tests. Our results show that motor coordination and muscle strength significantly decreased in the animals received METH (5mg/kg, daily×3days) as compared to the saline groups. Pretreatment with neither WIN55,212-2 nor SR141716A had no effects on impairments induced by METH. Meanwhile, motor activity and anxiety-related behaviors significantly increased in the animals that received METH and pretreatment with SR141716A significantly attenuated anxiety-related behaviors induced by METH. In sum, our findings show that anxiety-related behaviors induced by METH can be affected by CB1R manipulation and provide evidence that antagonism of CB1R at high dose cannot reverse the deteriorative METH-induced locomotion changes.

CB receptors;Cerebellum;Endocannabinoids;Methamphetamine

pubmed

Towards a compact and precise sample holder for macromolecular crystallography.

Most of the sample holders currently used in macromolecular crystallography offer limited storage density and poor initial crystal-positioning precision upon mounting on a goniometer. This has now become a limiting factor at high-throughput beamlines, where data collection can be performed in a matter of seconds. Furthermore, this lack of precision limits the potential benefits emerging from automated harvesting systems that could provide crystal-position information which would further enhance alignment at beamlines. This situation provided the motivation for the development of a compact and precise sample holder with corresponding pucks, handling tools and robotic transfer protocols. The development process included four main phases: design, prototype manufacture, testing with a robotic sample changer and validation under real conditions on a beamline. Two sample-holder designs are proposed: NewPin and miniSPINE. They share the same robot gripper and allow the storage of 36 sample holders in uni-puck footprint-style pucks, which represents 252 samples in a dry-shipping dewar commonly used in the field. The pucks are identified with human- and machine-readable codes, as well as with radio-frequency identification (RFID) tags. NewPin offers a crystal-repositioning precision of up to 10 µm but requires a specific goniometer socket. The storage density could reach 64 samples using a special puck designed for fully robotic handling. miniSPINE is less precise but uses a goniometer mount compatible with the current SPINE standard. miniSPINE is proposed for the first implementation of the new standard, since it is easier to integrate at beamlines. An upgraded version of the SPINE sample holder with a corresponding puck named SPINEplus is also proposed in order to offer a homogenous and interoperable system. The project involved several European synchrotrons and industrial companies in the fields of consumables and sample-changer robotics. Manual handling of miniSPINE was tested at different institutes using evaluation kits, and pilot beamlines are being equipped with compatible robotics for large-scale evaluation. A companion paper describes a new sample changer FlexED8 (Papp et al., 2017, Acta Cryst., D73, 841-851).

NewPin;SPINEplus;SmartMagnet;high density;high precision;miniSPINE;sample holder

pubmed

T lymphocytes to predict radiation-induced late effects in normal tissues.

Radiotherapy is one of the main treatments for solid tumors. The total dose that can be delivered to the tumor is limited by the radiation amount received by the surrounding normal tissues, which are at risk of developing acute and late radiation-induced effects. Areas covered: Severe late radiation-induced toxicity occurs in 5% to 10% of patients following radiotherapy. However, the current radiotherapy and radiation protection protocols do not take into account the variations in radiosensitivity among individuals. This review will focus on late radiotherapy-induced side effects and on the different cellular assays (γ-H2AX/53BP1 focus formation, G2 metaphase, G0 micronucleus formation and radio-induced apoptosis in CD8⁺ T-lymphocytes: level I evidence) that have been developed to predict their occurrence in patients. Expert commentary: The routine prediction of late radiation-induced toxicity in normal tissues in the clinic will allow personalized radiotherapy with better outcome and less side effects. Patients at low risk of late toxicity could receive a higher total dose to the tumor. Conversely, patients at high risk of late toxicity should receive lower radiation doses per fraction, using state-of-the-art treatment techniques, or alternative therapies to avoid radiation-induced side effects.

Lymphocytes;apoptosis;fibroblasts;micronuclei;normal tissue late effects;phospho-H2AX;radiotherapy

pubmed

Effectiveness of the management of major depressive episodes/disorder in adults with comorbid chronic physical diseases: a protocol for a systematic review and meta-analysis.

Depression is a global-scale public health problem, and a significant association has been established between depression and chronic physical diseases. This growing comorbidity poses a challenge to healthcare systems. We aim to assess the effectiveness of the management of major depressive episodes/disorder in adults with comorbid chronic physical diseases. We will conduct a systematic review and meta-analysis of randomised clinical trials. Two databases MEDLINE and Cochrane Library (Cochrane Database for Systematic Reviews and CENTRAL), as well as the reference lists of the included articles, will be searched for studies either in English or Spanish with published results within the 2005-2015 period. Studies must fulfil the following conditions: (1) participants aged 18 years or older, diagnosed as having a major depressive episodes/disorder according to standardised criteria and chronic physical diseases; (2)interventions (be it pharmacological, psychological, psychosocial or a combination) must be compared with control conditions (other 'active' intervention, treatment as usual, waiting list or placebo); (3)and must report reduction in depressive symptoms after treatment, response to treatment, remission of major depressive episodes/disorder and significant improvement in quality of life. Data extraction, risk of bias evaluation, results summarisation and quality of the evidence (GRADE) will be performed as recommended by the Cochrane Collaboration. A qualitative synthesis and a random effects meta-analysis will be carried out. Effect sizes will be calculated (relative risk and Cohen's d), I² and Q statistics will be employed to study heterogeneity and publication bias analysis will be performed. Subgroup analyses and meta-regression will be carried out. Results are expected to be published in specialised peer-reviewed journals (preferred topics: Mental Health, Psychology, Psychiatry and/or Systematic Reviews) and dissemination activities will be targeted to all the healthcare providers. International Prospective Register of Systematic Reviews (CRD42016029166) submitted on 11 January 2016.

chronic disease;depressive disorder;disease management;study protocol;systematic review

pubmed

Artemisinin and its derivatives in treating protozoan infections beyond malaria.

Parasitic protozoan diseases continue to rank among the world's greatest global health problems, which are also common among poor populations. Currently available drugs for treatment present drawbacks, urging the need for more effective, safer, and cheaper drugs. Artemisinin (ART) and its derivatives are some of the most important classes of antimalarial agents originally derived from Artemisia annua L. However, besides the outstanding antimalarial and antischistosomal activities, ART and its derivatives also possess activities against other parasitic protozoa. In this paper we review the activities of ART and its derivatives against protozoan parasites in vitro and in vivo, including Leishmania spp., Trypanosoma spp., Toxoplasma gondii, Neospora caninum, Eimeria tenella, Acanthamoeba castellanii, Naegleria fowleri, Cryptosporidium parvum, Giardia lamblia, and Babesia spp. We conclude that ART and its derivatives may be good alternatives for treating other non-malarial protozoan infections in developing countries, although more studies are necessary before they can be applied clinically.

Antiprotozoan activity;Artemisinin;Leishmania spp;Neospora caninum;Toxoplasma gondii;Trypanosoma spp

pubmed

Small Antisense RNA RblR Positively Regulates RuBisCo in <i>Synechocystis</i> sp. PCC 6803.

Small regulatory RNAs (sRNAs) function as transcriptional and post-transcriptional regulators of gene expression in organisms from all domains of life. Cyanobacteria are thought to have developed a complex RNA-based regulatory mechanism. In the current study, by genome-wide analysis of differentially expressed small RNAs in <i>Synechocystis</i> sp. PCC 6803 under high light conditions, we discovered an asRNA (RblR) that is 113nt in length and completely complementary to its target gene <i>rbcL</i>, which encodes the large chain of RuBisCO, the enzyme that catalyzes carbon fixation. Further analysis of the RblR(+)/(-) mutants revealed that RblR acts as a positive regulator of <i>rbcL</i> under various stress conditions; Suppressing RblR adversely affects carbon assimilation and thus the yield, and those phenotypes of both the wild type and the overexpressor could be downgraded to the suppressor level by carbonate depletion, indicated a regulatory role of RblR in CO₂ assimilation. In addition, a real-time expression platform in <i>Escherichia coli</i> was setup and which confirmed that RblR promoted the translation of the <i>rbcL</i> mRNA into the RbcL protein. The present study is the first report of a regulatory RNA that targets RbcL in <i>Synechocystis</i> sp. PCC 6803, and provides strong evidence that RblR regulates photosynthesis by positively modulating <i>rbcL</i> expression in <i>Synechocystis</i>.

RblR;RuBisCo;Synechocystis sp. PCC 6803;rbcL;sRNA

pubmed

pH-sensitive inulin-based nanomicelles for intestinal site-specific and controlled release of celecoxib.

Aiming at a site-specific drug release in the lower intestinal tract, this paper deals with the synthesis and physicochemical/biological characterization of pH-sensitive nanomicelles from an inulin (INU) amphiphilic derivative. To allow an intestinal site specific release of the payload, INU-Vitamin E (INVITE) bioconjugates were functionalized with succinic anhydride to provide the system with pH-sensitive groups preventing a premature release of the payload into the stomach. The obtained INVITESA micelles resulted nanosized, with a low critical aggregation concentration and the release studies showed a marked pH-dependent release. The drug loading stabilized the micelles against the acidic hydrolysis. From transport studies on Caco-2 cells, resulted that INVITESA nanomicelles cross the cellular monolayer but are actively re-transported in the secretory (basolateral-apical) direction when loaded in apical side. It suggests that the entrapped drug could not be absorbed before the release from the micelles, enabling so a local release of the active.

Celecoxib;Celecoxib (PubMed CID: 2662);Controlled drug delivery;FITC (PubMed CID: 18730);Inulin;Inulin (PubMed CID: 16219508);Micelle;N-Hydroxysulfosuccinimide (PubMed CID: 133909);Vitamin E;Vitamin E (PubMed CID: 14985);Vitamin E succinate (PubMed CID: 20353);diciclohexylcarbodiimide (PubMed CID: 10868);pH sensitive

pubmed

Behavioural modification of personality traits: testing the effect of a trematode on nymphs of the red damselfly Xanthocnemis zealandica.

Research on animal personality is increasingly demonstrating that individuals in a population are characterised by distinct sets of behavioural traits that show consistency over time and across different situations. Parasites are known to alter the behaviour of their hosts, although their role in shaping host personality remains little studied. Here, we test the effect of trematode infection on two traits of their host's personality, activity and boldness, in nymphs of the red damselfly Xanthocnemis zealandica. Genetic analyses indicate that the undescribed trematode species falls within the superfamily Microphalloidea. Results of laboratory behavioural tests indicate that the two behavioural traits are related to each other: bolder individuals also show higher levels of spontaneous activity than shy ones. However, parasite infection had no effect on either of these behaviours or on their repeatability over three separate testing sessions. Although our findings suggest that this trematode does not influence personality traits of the damselfly host, it remains possible that other standard personality traits not tested here (exploratory tendency, aggressiveness) are affected by infection.

Animal personality;Behavioural modification;Host-parasite interactions;Repeatability;Trematodes

pubmed

Alterations in Mesoscopic Oscillations affecting Episodic Memory following Developmental Traumatic Brain Injury.

Certain deficits of episodic memory among young adults are the delayed consequences of an earlier mild or moderate Traumatic Brain Injury (mTBI). We examined alterations in hippocampal Local Field Oscillations (LFOs) of equivalently-impaired juvenile rodents to identify reliable functional markers of single-incidence mTBI. Two persistent, behavior-dependent, electrophysiological markers of injury were identified in the absence of external physiological symptoms by the analysis of wirelessly-transmitted hippocampal LFOs (3-80Hz) during repeat measures of the Novel Object Recognition (NOR) paradigm. Using a new method for detecting functional network activity at a single recording site, we correlated instantaneous increases in theta frequency and gamma magnitude with injury during periods of functional network organization and dissolution, presented here as Theta Epochs (TEs) and Theta Non-Epochs (TNEs), respectively. We estimated the efficacy of networks across pairs of such sites using new metrics such as the Coherence of Theta Phase (PCOH) and Inter-Epoch Intervals (IEIs) and demonstrated that behavioral deficits observed during the NOR testing stage correspond to electrophysiological deficits recorded during the preceding NOR familiarization stage. Increased theta frequency during TNEs and increased smoothness of PCOH during TEs were found to be robust markers of injury during memory-reliant behaviors.

Coherence of theta phase;Episodic memory;Functional network;Inter-epoch interval;Novel Object Recognition;Spectral specificity;Temporal synchrony;Theta Epoch;Theta Non-Epoch;Traumatic Brain Injury

pubmed

PCBs and OCPs in human milk in Eastern Siberia, Russia: Levels, temporal trends and infant exposure assessment.

The aim of our study is to investigate the spatial distribution of polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB), dichlorodiphenyltrichloroethane (p,p'-DDT) and its metabolites, α- and γ-isomers of hexachlorocyclohexane (HCH) in 155 samples of human milk (HM) from Eastern Siberia (six towns and seven villages in Irkutsk Region, one village of the Republic of Buryatia and one town in Zabaikal'sk Region, Russia), and to examine the dietary and social factors influencing the human exposure to the organochlorines. The median and range of the concentration of six indicator PCBs in HM in 14 localities in Eastern Siberia (114 (19-655) ng g^-1 lipids respectively) are similar to levels in the majority of European countries. However, in one village, Onguren, the median and range of levels of six indicator PCBs (1390 (300-3725) ng g^-1 lipids) were comparable to levels measured in highly contaminated populations. The Lake Baikal seals are highly exposed to persistent organic pollutants (POPs) and could be a potential source of PCB and DDT exposure in the Onguren cohort via the consumption of the Lake Baikal seal tissue. The location of food production in areas exposed to the emissions of local POP sources can also significantly influence POP levels in HM samples from industrialized areas. Estimated daily intakes (EDI) of HCH and HCB for infants are considerably lower or close to acceptable daily intake (ADI). The EDI of total DDTs and total PCBs are higher than ADI.

Diet;Human milk;Organochlorine pesticides;PCB

pubmed

Interaction of aqueous leaf extract of Aegle marmelos (L.) Corr. with cholinergic, serotonergic and adrenergic receptors: an ex vivo study.

The aim was to study interaction of aqueous leaf extract of Aegle marmelos (AM) with cholinergic, serotonergic, and adrenergic receptor systems using appropriate rat tissues-ileum, fundus and tracheal chain, respectively. Cumulative concentration-response curves (CRC) were constructed at various doses on each tissue for AM and respective standard agonist. The CRC was again plotted in presence and absence of respective standard antagonist to confirm the interaction of receptor system and AM. AM induced concentration-dependent contractions in isolated rat ileum (0.2-6.4 mg/ml) and fundus (0.2-3.2 mg/ml) that were inhibited significantly (P < 0.05) in the presence of atropine (10(-7) M) and ketanserin (10(-6) M), respectively. The relaxant effect, produced by AM (0.2 mg/ml) on carbachol (10(-5) M) precontracted rat tracheal chain, was also inhibited significantly (P < 0.05) by propranolol (1 ng/ml). It may be concluded that AM possesses agonistic activity on cholinergic, serotonergic and adrenergic receptors.

Aegle marmelos;fundus;ileum;single channel organ bath;tracheal chain

pubmed

Silver doped titanium oxide-PDMS hybrid coating inhibits Staphylococcus aureus and Staphylococcus epidermidis growth on PEEK.

Bacterial infection remains one of the most serious issues affecting the successful installation and retention of orthopedic implants. Many bacteria develop resistance to current antibiotics, which complicates or prevents traditional antibiotic-dependent eradication therapy. In this study, a hybrid coating of titanium dioxide and polydimethylsiloxane (PDMS) was synthesized to regulate the release of silver. The coatings were benefited from the antimicrobial activity of silver ion, the biocompatibility of titanium dioxide, and the flexibility of the polymer. Three studied silver doped coatings with different titanium dioxide-PDMS ratios effectively inhibited the attachment and growth of Staphylococcus aureus and Staphylococcus epidermidis in a dose-dependent manner. The coatings were successfully applied on the discs of polyether ether ketone (PEEK), a common spinal implant material and antibacterial property of these coatings was assessed via Kirby Bauer assay. More importantly, these selected coatings completely inhibited biofilm formation. The release study demonstrated that the release rate of silver from the coating depended on doping levels and also the ratios of titanium dioxide and PDMS. This result is crucial for designing coatings with desired silver release rate on PEEK materials for antimicrobial applications.

Antibacterial;Biofilm;Coating;PEEK;Silver

pubmed

Prognostic significance of lymphovascular space invasion in epithelial ovarian cancer.

To assess the effects of lymphovascular space invasion (LVSI) on cancer recurrence and survival in patients with primary epithelial ovarian cancer. A retrospective study was conducted of patients with stage I-IV primary epithelial ovarian cancer who underwent cytoreductive surgery. LVSI is defined as the presence of tumor cells within an endothelium-lined space, and the patients' pathologic slides were reevaluated by gynecological pathologists. Survival analysis was performed to compare risk factors. A total of 492 patients were included in the analysis. The incidence of LVSI was 58.5% in our cohort (288 cases), and it was significantly associated with advanced stage, high-grade serous histology, high grade, and lymph node metastasis (P<0.001). Kaplan-Meier analysis demonstrated that LVSI was only correlated with decreased PFS (5-year rate, 39% vs. 66%, P<0.001) and OS (5-year rate, 44% vs. 78%, P<0.001) in patients at early stage but not at advanced stage (5-year rate, PFS: 14% vs. 11%, P<0.001; OS: 29% vs. 29%, P=0.141). Multivariate analysis showed that LVSI remained a significant variable with PFS and OS in early-stage ovarian cancer (PFS: HR 2.29, 95% CI 1.45-3.57; OS: HR 2.20, 95% CI 1.59-3.44, both P<0.001). LVSI is an independent predictor of progression and survival in patients with primary epithelial ovarian cancer at early stage but not at advanced stage.

Lymphovascular space invasion;Ovarian carcinoma;Prognosis;Survival rate.

pubmed

Oleuropein aglycone in lipid bilayer membranes. A molecular dynamics study.

Olive oil has been recognized to possess many therapeutic applications. Its beneficial effects arise from many causes, but one of them lies on the presence of oleuropein aglycone (OA). OA presents a plethora of pharmacological beneficial properties. Although there is a great research going on the effect of polyphenols and their derivatives on different aspects of health, much less knowledge is available of the molecular basis of their beneficial effects. Due to the prominent hydrophobic character of OA and its high phospholipid/water partition coefficient, some of its possible effects on biological systems might be related to its capacity to interact with and locate into the membrane. In this work we have aimed to locate the molecule of OA in two membrane model systems, i.e., POPC/Chol and POPC/POPG/Chol. OA locates in between the hydrocarbon acyl chains of the phospholipids but its specific location and molecular interactions differ depending on the lipid system. OA is nearer to the membrane surface in the POPC/Chol system but it is located at a deeper position in the POPC/POPG/Chol system. Furthermore, OA seems to interact stronger with POPG than with POPC, implying the existence of specific interactions with negatively-charged phospholipids. Some of the biological effects of OA could be due to its preferential location in the membrane depending on the membrane lipid composition as well as the existence of specific interactions with specific phospholipids.

Membrane location;Molecular dynamics;Oleuropein

pubmed

Group prenatal care for women with gestational diabetes (.).

We aimed to determine if group prenatal care affects the progression to A2 gestational diabetes mellitus (GDM) when compared with conventional care for women with GDM. Prospective observational cohort of women diagnosed with GDM who attended group visits compared with a historical control group of women who received conventional obstetrical care in the year prior but would have met inclusion criteria for group care. The primary outcome was progression to A2 GDM. Secondary outcomes included antepartum, intrapartum and postpartum maternal outcomes and neonatal outcomes. A total of 165 subjects were included: 62 in group care and 103 in conventional care. Compared with patients with conventional care, group subjects were more likely to attend a postpartum visit (92% versus 66%; p = 0.002) and were almost 4 times more likely to receive recommended diabetes screening postpartum (OR 3.9, CI 1.8-8.6). Group subjects were much less likely to progress to A2 GDM (OR 0.15, CI 0.07-0.30). There were no differences in neonatal outcomes. Group prenatal care for women with diabetes is associated with decreased progression to A2 GDM and improved postpartum follow-up for appropriate diabetes screening without significantly affecting obstetrical or neonatal outcomes.

Diabetic prenatal care;gestational diabetes;group diabetic visits;group prenatal care

pubmed

Retrospective investigation of combination therapy with clarithromycin and levofloxacin for pulmonary Mycobacterium avium complex disease.

Fluoroquinolones are often used for the treatment of refractory Mycobacterium avium complex (MAC) disease when the clinical efficacy of the recommended regimen, which includes clarithromycin (CAM), rifampicin (RFP), and ethambutol (EB), is insufficient. However, recent in vitro and in vivo studies have suggested that fluoroquinolones decreased the antibacterial activity of CAM when they were administered in combination. In this study, we retrospectively investigated the influence of the combination of CAM and levofloxacin (LVFX) on clinical outcomes for pulmonary MAC disease patients. Pulmonary MAC disease patients from 2010 to 2012 were divided into two groups, those who received LVFX together with CAM (LVFX group) and those who received CAM without LVFX (control group). The number of patients who showed improvement was evaluated at 1, 3, 6 and 12 months after the start of therapy based on bacteriological examination (culture and smear examination) and the bacilli negative conversion rate. There were no significant differences between the LVFX group (n = 18, 64.5 ± 6.5 years old) and the control group (n = 57, 71.0 ± 7.0 years old) in terms of gender, age, etiologic agent, baseline culture examination score, concomitant medication, and dosage of each drug. The clinical outcomes in the LVFX group were inferior to those in the control group at all endpoints and observational periods, and we found a significant difference in the percent improvement of the smear examination by fluorescence microscopy method (38 % vs. 83 %) and the bacilli negative conversion rate (38 % vs. 79 %) at 3 months. Our study suggests that the combination of CAM and LVFX causes unfavorable clinical outcomes for pulmonary MAC disease treatment. There was no significant difference between both groups in terms of frequency of adverse events. The possibility that combined administration of CAM and LVFX causes unfavorable clinical outcomes for pulmonary MAC disease treatment was suggested.

Bacilli negative conversion rate;Clarithromycin;Clinical efficacy;Levofloxacin;Mycobacterium avium complex

pubmed

Acquired superoxide-scavenging ability of ceria nanoparticles.

Ceria nanoparticles (nanoceria) are well known as a superoxide scavenger. However, inherent superoxide-scavenging ability has only been found in the nanoceria with sizes of less than 5 nm and with very limited shape diversity. Reported herein is a strategy to significantly improve the superoxide-scavenging activity of nanoceria sized at greater than 5 nm. The nanoceria with sizes of greater than 5 nm, with different shapes, and with a negligible Ce(3+)/Ce(4+) ratio can acquire remarkable superoxide-scavenging abilities through electron transfer. This method will make it possible to develop nanoceria-based superoxide-scavengers with long-acting activity and tailorable characteristics.

cerium;electron transfer;nanoparticles;oxides;surface chemistry

pubmed

First effects of rising amyloid-β in transgenic mouse brain: synaptic transmission and gene expression.

Detecting and treating Alzheimer's disease, before cognitive deficits occur, has become the health challenge of our time. The earliest known event in Alzheimer's disease is rising amyloid-β. Previous studies have suggested that effects on synaptic transmission may precede plaque deposition. Here we report how relative levels of different soluble amyloid-β peptides in hippocampus, preceding plaque deposition, relate to synaptic and genomic changes. Immunoprecipitation-mass spectrometry was used to measure the early rise of different amyloid-β peptides in a mouse model of increasing amyloid-β ('TASTPM', transgenic for familial Alzheimer's disease genes APP/PSEN1). In the third postnatal week, several amyloid-β peptides were above the limit of detection, including amyloid-β40, amyloid-β38 and amyloid-β42 with an intensity ratio of 6:3:2, respectively. By 2 months amyloid-β levels had only increased by 50% and although the ratio of the different peptides remained constant, the first changes in synaptic currents, compared to wild-type mice could be detected with patch-clamp recordings. Between 2 and 4 months old, levels of amyloid-β40 rose by ∼7-fold, but amyloid-β42 rose by 25-fold, increasing the amyloid-β42:amyloid-β40 ratio to 1:1. Only at 4 months did plaque deposition become detectable and only in some mice; however, synaptic changes were evident in all hippocampal fields. These changes included increased glutamate release probability (P < 0.001, n = 7-9; consistent with the proposed physiological effect of amyloid-β) and loss of spontaneous action potential-mediated activity in the cornu ammonis 1 (CA1) and dentate gyrus regions of the hippocampus (P < 0.001, n = 7). Hence synaptic changes occur when the amyloid-β levels and amyloid-β42:amyloid-β40 ratio are still low compared to those necessary for plaque deposition. Genome-wide microarray analysis revealed changes in gene expression at 2-4 months including synaptic genes being strongly affected but often showing significant changes only by 4 months. We thus demonstrate that, in a mouse model of rising amyloid-β, the initial deposition of plaques does not occur until several months after the first amyloid-β becomes detectable but coincides with a rapid acceleration in the rise of amyloid-β levels and the amyloid-β42:amyloid-β40 ratio. Prior to acceleration, however, there is already a pronounced synaptic dysfunction, reflected as changes in synaptic transmission and altered gene expression, indicating that restoring synaptic function early in the disease progression may represent the earliest possible target for intervention in the onset of Alzheimer's disease.

Alzheimer’s disease;amyloid;gene expression;mouse;synaptic transmission

pubmed

The Comparison of R.E.N.A.L., PADUA and Centrality Index Score in Predicting Perioperative Outcomes and Complications after Laparoscopic Radio Frequency Ablation of Renal Tumors.

We assessed the association between the R.E.N.A.L., PADUA and centrality index scores and perioperative outcomes, and determined the efficacy of each scoring system over the simple parameter of tumor size. We conducted a retrospective review of the records of patients who underwent laparoscopic radio frequency ablation of renal tumors from February 2006 to April 2014 at our institution. Tumors were categorized using the R.E.N.A.L., PADUA and centrality index score, which were determined by analyzing preoperative imaging. The relationships between each variable and change in glomerular filtration rate, estimated blood loss, operative time and postoperative complications were examined. Laparoscopic radio frequency ablation was performed in 215 selected patients with preoperative imaging available. The interclass correlations coefficient of the 3 observers was 0.87, 0.84 and 0.82 for the C-Index, the R.E.N.A.L. and the PADUA scoring system, respectively. R.E.N.A.L. score, PADUA score and PADUA complexity were significantly associated with postoperative complications (p=0.040, 0.015 and 0.006, respectively). However, major complications were only associated with high PADUA complexity (chi-square 23.851, p <0.05). Each scoring system had a significant association with operative time and estimated blood loss (p <0.05), except that the C-index score had no relationship with estimated blood loss (p=0.083). The accuracy of each scoring system in predicting perioperative outcomes and postoperative complications was superior to that of tumor size. Each scoring system has an advantage over tumor size in describing tumor complexity and may help with surgical decision making. Further studies are required to validate their efficacy in evaluating the intraoperative and postoperative results after renal laparoscopic radio frequency ablation.

ablation techniques;kidney neoplasms;laparoscopy

pubmed

Optimisation of ultrasonic-assisted extraction of phenolic compounds, antioxidants, and anthocyanins from sugar beet molasses.

Response surface methodology was used to optimise experimental conditions for ultrasonic-assisted extraction (UAE) of functional components from sugar beet molasses. The central composite design (CCD) was used for the optimisation of extraction parameters in terms of total phenolic contents, antioxidant activities and anthocyanins. Result suggested the optimal conditions obtained by RSM for UAE from sugar beet molasses were as follows: HCl concentration 1.55-1.72 mol/L, ethanol concentration 57-63% (v/v), extraction temperature 41-48 °C, and extraction time 66-73 min. In the optimal conditions, the experimental total phenolic contents were 17.36 mg GAE/100mL, antioxidant activity was 16.66 mg TE/g, and total anthocyanins were 31.81 mg/100g of the sugar beet molasses extract, which were well matched the predicted values. Teen compounds, i.e. gallic acid, vanillin, hydroxybenzoic acid, syringic acid, cyanidin-3-O-rutinoside, cyanidin-3-O-glucoside, catechin, delphinidin-3-O-rutinoside, delphinidin-3-O-glucuronide and ferulic acid were determined by HPLC-DAD-MS/MS in sugar beet molasses.

Anthocyanins;Antioxidants;Phenolic compounds;Response surface methodology;Sugar beet molasses;Ultrasonic-assisted extraction

pubmed

Water quality monitoring using abnormal tail-beat frequency of crucian carp.

Fish are rapidly becoming favored as convenient sentinels for behavioral assays of toxic chemical exposure. Tail-beat frequency (TBF) of fish is highly correlated with swimming speed, which has been used to detect toxicants. Here we examined the effect on TBF of exposure to two chemicals, and evaluated the ability of this novel behavioral parameter to accurately monitor water quality. To further refine our approach, the Wall-hitting rate (WHR) was used to characterize behavioral avoidance after exposure. Overall, exposure to test chemicals at different levels induced significant increase in both behavioral parameters of the red crucian carp during 1-h exposure periods. Furthermore, the TBF achieved better performance as an indicator when it was calculated in cases where the fish hit the tank wall. Collectively, this study demonstrates the capacity of the TBF of fish to assess water quality in a reliable manner.

Behavior;Fish;Movement;Tail-beat frequency;Wall-hitting rate;Water toxicology

pubmed

Overcoming barriers to health-care access: A qualitative study among African migrants in Guangzhou, China.

Guangzhou is China's third most populous city, and the region's burgeoning manufacturing economy has attracted many young African businessmen and entrepreneurs to the city. The aims of this study were to examine strategies that African migrants in Guangzhou have adopted in response to health-care barriers, and explore their perceptions of how to address their needs. Twenty-five semi-structured interviews and two focus groups were conducted among African migrants residing in Guangzhou, China. Facing multiple barriers to care, African migrants have adopted a number of suboptimal and unsustainable approaches to access health care. These included: using their Chinese friends or partners as interpreters, self-medicating, using personal connections to medical doctors, and travelling to home countries or countries that offer English-speaking doctors for health care. Health-care providers and health organisations in Guangzhou have not yet acquired sufficient cultural competence to address the needs of African migrants residing in the city. Introducing linguistically and culturally competent health-care services in communities concentrated with African migrants may better serve the population. With the growing international migration to China, it is essential to develop sustainable approaches to improving health-care access for international migrants, particularly those who are marginalised.

Africa;China;access to care;health-care barriers;migrants

pubmed

Change in color of a maxillofacial prosthetic silicone elastomer, following investment in molds of different materials.

In the authors' experience, the color of silicone elastomer following polymerization in molds made of gypsum products is slightly different from the color that was matched in the presence of the patient, before the silicone is packed. It is hypothesized that the investing materials and separating media have an effect on the color during the polymerization process of the silicone. This study compares and evaluates the change in color of silicone elastomer packed in three commonly used investing materials - Dental stone (white color), dental stone (green color), and die stone (orange color); coated with three different separating media - Alginate-based medium, soap solution and a resin-based die hardening material. Pigmented silicone samples of dimensions 1.5 cm × 2 cm × 0.5 cm were made from the elastomer in the above-mentioned mold materials using combinations of the mentioned separating media. These served as test group samples. Control group samples were made by packing a mix of the same pigmented elastomer in stainless steel molds. The L*, a*, b* values of the test and control group samples were determined using a spectrophotometer. The change in color (Delta E) was calculated between the control and test groups. The mean L, a, b values for the control group were, 31.8, 26.2, and 36.3, respectively. Average values of change in color (Delta E) for samples packed utilizing alginate-based medium, die hardener, and soap solution, respectively in white dental stone (2.70, 2.74, and 2.88), green dental stone (2.19, 2.23, 2.42), and orange die stone (3.19, 2.72, 2.80) were tabulated. Among the investing materials studied, die stone showed the most color change (3.19), which was statistically significant. Among the separating media, die hardener showed the least color change (2.23). The best combination of an investing material and separating media as per this investigation is a dental stone (green) and alginate-based separating medium.

Color;investing materials;maxillofacial silicone;polymerization

pubmed

Prognostic impact of nomogram based on whole tumour size, tumour disappearance ratio on CT and SUVmax on PET in lung adenocarcinoma.

Lung adenocarcinoma frequently manifests as subsolid nodules, and the solid portion and ground-glass-opacity (GGO) portion on CT have different prognostic significance. Therefore, current T descriptor, defined as the whole tumour diameter without discrimination between solid and GGO, is insufficient. We aimed to determine the prognostic significance of solid tumour size and attempt to include prognostic factors such as tumour disappearance rate (TDR) on CT and SUVmax on PET/CT. Five hundred and ninety-five patients with completely resected lung adenocarcinoma were analyzed. We developed a nomogram using whole tumour size, TDR, and SUVmax. External validation was performed in another 102 patients. In patients with tumours measuring ≤2 cm and >2 to 3 cm, disease free survival (DFS) was significantly associated with solid tumour size (P < 0.001), but not with whole tumour size (P = 0.052). Developed nomogram was significantly superior to the conventional T stage (area under the curve of survival ROC; P = 0.013 by net reclassification improvement) in stratification of patient survival. In the external validation group, significant difference was noted in DFS according to proposed T stage (P = 0.009). Nomogram-based T descriptors provide better prediction of survival and assessment of individual risks than conventional T descriptors. • Current measurement of whole tumour diameter including ground-glass opacity is insufficient • TDR enables differentiation between invasive solid portion and non-invasive GGO portion • SUVmax demonstrates the biological aggressiveness of the tumour • We developed a nomogram using whole tumour size, TDR, and SUVmax • Nomogram-based clinical T descriptors provide better prediction of survival.

Adenocarcinoma;Lung neoplasm;Multidetector Computed Tomography;Positron-Emitted Tomography;Tumour staging

pubmed

The recruitment of chromatin modifiers by long noncoding RNAs: lessons from PRC2.

Polycomb repressive complex-2 (PRC2) is a histone methyltransferase required for epigenetic silencing during development and cancer. Among chromatin modifying factors shown to be recruited and regulated by long noncoding RNAs (lncRNAs), PRC2 is one of the most studied. Mammalian PRC2 binds thousands of RNAs in vivo, and it is becoming a model system for the recruitment of chromatin modifying factors by RNA. Yet, well-defined PRC2-binding motifs within target RNAs have been elusive. From the protein side, PRC2 RNA-binding subunits contain no known RNA-binding domains, complicating functional studies. Here we provide a critical review of existing models for the recruitment of PRC2 to chromatin by RNAs. This discussion may also serve researchers who are studying the recruitment of other chromatin modifiers by lncRNAs.

PRC2;RNA–protein interaction;epigenetic silencing;histone modification;long noncoding RNAs

pubmed

Direct Assessment of Plasma/Serum Sample Quality for Proteomics Biomarker Investigation.

Blood proteome analysis for biomarker discovery represents one of the most challenging tasks to be achieved through clinical proteomics due to the sample complexity, such as the extreme heterogeneity of proteins in very dynamic concentrations, and to the observation of proper sampling and storage conditions. Quantitative and qualitative proteomics profiling of plasma and serum could be useful both for the early detection of diseases and for the evaluation of pathological status. Two main sources of variability can affect the precision and accuracy of the quantitative experiments designed for biomarker discovery and validation. These sources are divided into two categories, pre-analytical and analytical, and are often ignored; however, they can contribute to consistent errors and misunderstanding in biomarker research. In this chapter, we review critical pre-analytical and analytical variables that can influence quantitative proteomics. According to guidelines accepted by proteomics community, we propose some recommendations and strategies for a proper proteomics analysis addressed to biomarker studies.

Biomarkers;Clinical proteomics;Mass spectrometry;Pre-analytical and analytical variables;Sample quality control

pubmed

Peripheral blood monocyte count reflecting tumor-infiltrating macrophages is a predictive factor of adverse pathology in radical prostatectomy specimens.

Tumor-infiltrating macrophages, which are thought to be derived from blood monocytes, interact with tumor cells to promote cancer progression. The aim of this study was to assess the association of peripheral blood monocyte count with pathological findings and local tumor-infiltrating macrophages in prostatectomy specimens. Preoperative peripheral blood monocyte counts were retrospectively assessed for their associations with pathological findings (pathological T stage, Gleason Score, extraprostatic extension, seminal vesicle invasion, and surgical margin) and biochemical recurrence of 248 patients who underwent radical prostatectomy. Local tumor-infiltrating macrophages were also evaluated immunohistochemically for their association with peripheral monocyte counts. The peripheral monocyte counts of the patients with extraprostatic extension, seminal vesicle invasion, or primary Gleason ≥4 were significantly higher than those of the patients without each of these pathological findings (P < 0.001, P = 0.034, and P = 0.004, respectively). Peripheral monocyte count was a significant predictor of adverse pathology and postoperative biochemical recurrence in localized prostate cancer by multivariate analysis (P = 0.001 and P = 0.041, respectively). Both the density and the count of tumor-infiltrating macrophages correlated significantly with the peripheral blood monocyte count (Spearman rank correlation coefficients were 0.463 and 0.649, respectively, P < 0.001). Peripheral blood monocyte count reflecting local tumor-infiltrating macrophages was a predictive factor for tumor progression and prognosis in patients with localized prostate cancer. Elucidating the mechanism of the interaction of peripheral monocytes with tumor-infiltrating macrophages is necessary.

adverse pathology;macrophage;monocyte;peripheral;prostate cancer

pubmed

Upper airway surgery for obstructive sleep apnea reduces blood pressure.

To evaluate if upper airway surgery reduces blood pressure in patients with obstructive sleep apnea (OSA). Prospective series. A prospective series of 112 consecutive OSA patients with hypertension (HTN). All patients were > 18 years old, respiratory disturbance index >5, all levels of apnea-hypopnea index (AHI), with a history of HTN treated with medication for at least 6 months. Surgical procedures included septoplasty, turbinate reduction, palate surgery, and tongue base reduction. There were 92 men and 20 women, with a mean age of 48.6 years, mean body mass index (BMI) was 27.5 (range, 19.7-34.7). Mean follow-up was 16.1 months. The mean preoperative AHI was 32.6 (range, 1.2-104), with the mean lowest oxygen saturation (LSAT) of 79.9% (range, 52%-93%). The mean adjusted preoperative and postoperative systolic blood pressure (SBP) was reduced from 146 ± 15.3 mm Hg to 122 ± 12.5 mm Hg (P < .001), and diastolic blood pressure (DBP) was reduced from 91 ± 10.2 mm Hg to 76 ± 7.8 mm Hg (P < .001). There was a decrease in overall BMI from 27.5 ± 3.6 to 25.5 ± 3.0 (P < .001); however, based on multivariate analysis, the reduction in SBP and DBP was not affected by this BMI reduction. Fifty-eight patients (51.8%) did not require their antihypertensive after surgery. There was poor correlation noted between HTN with AHI, LSAT, and oxygen duration <90%. Upper airway surgery does reduce SBP and DBP in patients with OSA. 4. Laryngoscope, 128:523-527, 2018.

Blood pressure;obstructive sleep apnea;upper airway surgery

pubmed

Magnetic nanoparticle incorporated oleogel as iontophoretic drug delivery system.

In this article, we validated the use of electric current as an external stimulus to induce an enhancement of drug release from magnetic nanoparticle (MNP) incorporated organogels (magnetogel) under iontophoretic conditions. For this purpose, we adopted a simple, two-step synthesis route to incorporate magnetic (Fe₃O₄) nanoparticles (MNP) and ciprofloxacin hydrochloride within the network of a soybean oil-based oleogel using stearic acid as gelator. We fabricated a series of MNP incorporated oleogels by varying the wt% of MNPs while keeping a constant weight ratio of soybean oil:stearic acid. The microstructures of the magnetogels were analyzed in MNP concentration-dependent manner by optical microscopy, powder X-ray diffraction, FTIR, mechanical, and electrical studies. Detailed analysis of the electrical properties revealed that the gel sample with a maximum proportion of MNP (S4) allowed the maximum passage of current through it among all the compositions. Under the iontophoretic environment of the active condition, we observed nearly 2.5 fold increase in cumulative drug release in case of sample S4 compared to the corresponding passive condition. These observations suggested that in future, our magnetogel formulation can be further developed as AC field induced 'remote controlled' agent for therapeutic application.

Drug delivery;Iontophoresis;Magnetic nanoparticles;Oleogels;Stimuli-responsive polymers

pubmed

Blood transfusion and coagulopathy in geriatric trauma patients.

Trauma resuscitation has undergone a paradigm shift with new emphasis on the early use of blood products and increased proportions of plasma and platelets. However, it is unclear how this strategy is applied or how effective it is in the elderly population. The study aim is to identify differences in transfusion practices and the coagulopathy of trauma in the elderly. Data was prospectively collected on all consecutive patients that met trauma activation criteria at a Level I trauma centre. Data fields included patient demographics, co-morbidities, injury and resuscitation data, laboratory values, thromboelastography (TEG) results, and outcome measures. Elderly patients were defined as those 55 and older. Propensity-score matched analysis was completed for patients receiving blood product transfusion. Patients were matched by gender, mechanism, injury severity score (ISS), head injury, and time from injury. Total of 628 patients were included, of which 142 (23%) were elderly. Elderly patients were more likely to be female (41% vs. 24%), suffer blunt mechanism of trauma (96% vs. 80%), have higher ISS scores (mean 25.4 vs. 21.6) and mortality (19% vs. 8%). Elderly patients were significantly more likely to receive a blood transfusion (42% vs. 30%), specifically for red cells and plasma. Propensity-matched analysis resulted in no difference in red cell transfusion or mortality. Despite the broad similarities between the matched cohorts, trauma coagulopathy as measured by TEG was less commonly observed in the elderly. Our results suggest that elderly trauma patients are more likely to receive blood products when admitted to a trauma centre, though this may be attributed to under-triage. The results also suggest an altered coagulopathic response to traumatic injury which is partially influenced by increased anticoagulant and antiplatelet medication use in the geriatric population. It is not clear whether the acute coagulopathy of trauma is equivalent in geriatric patients, and further study is therefore warranted.

Coagulopathy;Geriatric;Thromboelastography;Transfusion;Trauma

pubmed

The outcomes of radiotherapy and factors that predict overall survival in elderly patients with esophageal squamous cell carcinoma.

The aim of this study was to evaluate radiotherapy in terms of both feasibility and efficacy for the treatment of 206 elderly patients (≥70 years) with unresectable ESCC and to investigate the factors that predict overall survival in those patients. Totally, 206 elderly patients with esophageal cancer (≥70 years) treated with RT for ESCC in the Harbin Medical University Affiliated Tumor Hospital were retrospectively enrolled. Radiation treatment results and side effects were evaluated. Survival data were estimated using the Kaplan-Meier method, including OS, RFS and DDFS. A multivariate Cox regression analysis was performed to determine the relevant prognostic factors. The median OS and RFS were 20.68 and 24.19 months. Metastases before radiotherapy, having cervical or supraclavicular neoplasm, with lesion length >5 cm were the independent risk factors for OS. The total effective rate was 86.9% (179/206). Radiation therapy in elderly patients (≥70 years) can not only obtain good treatment result, but also make patients have better tolerance and reduce the risk of complications. Radiotherapy should be as a primary treatment option for elderly patients with inoperable ESCC.

Cox regression analysis;Esophageal squamous cell carcinoma;Prognostic factors;Radiotherapy

pubmed

Improved detection of congestive heart failure via probabilistic symbolic pattern recognition and heart rate variability metrics.

A timely diagnosis of congestive heart failure (CHF) is crucial to evade a life-threatening event. This paper presents a novel probabilistic symbol pattern recognition (PSPR) approach to detect CHF in subjects from their cardiac interbeat (R-R) intervals. PSPR discretizes each continuous R-R interval time series by mapping them onto an eight-symbol alphabet and then models the pattern transition behavior in the symbolic representation of the series. The PSPR-based analysis of the discretized series from 107 subjects (69 normal and 38 CHF subjects) yielded discernible features to distinguish normal subjects and subjects with CHF. In addition to PSPR features, we also extracted features using the time-domain heart rate variability measures such as average and standard deviation of R-R intervals. An ensemble of bagged decision trees was used to classify two groups resulting in a five-fold cross-validation accuracy, specificity, and sensitivity of 98.1%, 100%, and 94.7%, respectively. However, a 20% holdout validation yielded an accuracy, specificity, and sensitivity of 99.5%, 100%, and 98.57%, respectively. Results from this study suggest that features obtained with the combination of PSPR and long-term heart rate variability measures can be used in developing automated CHF diagnosis tools.

Congestive heart failure;Ensemble bagged trees;Heart rate variability;Probabilistic symbolic pattern recognition;RR intervals

pubmed

Combined effects of adsorption and photocatalysis by hybrid TiO₂/ZnO-calcium alginate beads for the removal of copper.

The use of nanosized titanium dioxide (TiO₂) and zinc oxide (ZnO) in the suspension form during treatment makes the recovering and recycling of photocatalysts difficult. Hence, supported photocatalysts are preferred for practical water treatment applications. This study was conducted to investigate the efficiency of calcium alginate (CaAlg) beads that were immobilized with hybrid photocatalysts, TiO₂/ZnO to form TiO₂/ZnO-CaAlg. These immobilized beads, with three different mass ratios of TiO₂:ZnO (1:1, 1:2, and 2:1) were used to remove Cu(II) in aqueous solutions in the presence of ultraviolet light. These beads were subjected to three cycles of photocatalytic treatment with different initial Cu(II) concentrations (10-80ppm). EDX spectra have confirmed the inclusion of Ti and Zn on the surface of the CaAlg beads. Meanwhile, the surface morphology of the beads as determined using SEM, has indicated differences of before and after the photocatalytic treatment of Cu(II). Among all three, the equivalent mass ratio TiO₂/ZnO-CaAlg beads have shown the best performance in removing Cu(II) during all three recycling experiments. Those TiO₂/ZnO-CaAlg beads have also shown consistent removal of Cu, ranging from 7.14-62.0ppm (first cycle) for initial concentrations of 10-80ppm. In comparison, bare CaAlg was only able to remove 6.9-48ppm of similar initial Cu concentrations. Thus, the potential use of TiO₂/ZnO-CaAlg beads as environmentally friendly composite material can be further extended for heavy metal removal from contaminated water.

Alginate;Heavy metals;Immobilization;Photocatalyst;Titanium dioxide;Zinc oxide

pubmed

Cancer of the Esophagus and Esophagogastric Junction: An Eighth Edition Staging Primer.

This primer for eighth edition staging of esophageal and esophagogastric epithelial cancers presents separate classifications for the clinical (cTNM), pathologic (pTNM), and postneoadjuvant pathologic (ypTNM) stage groups, which are no longer shared. For pTNM, pT1 has been subcategorized as pT1a and pT1b for the subgrouping pStage I adenocarcinoma and squamous cell carcinoma. A new, simplified esophagus-specific regional lymph node map has been introduced. Undifferentiated histologic grade (G4) has been eliminated; additional analysis is required to expose histopathologic cell type. Location has been removed as a category for pT2N0M0 squamous cell cancer. The definition of the esophagogastric junction has been revised. ypTNM stage groups are identical for both histopathologic cell types, unlike those for cTNM and pTNM.

AJCC/UICC eighth edition staging;Esophageal cancer;Esophagogastric cancer;Staging

pubmed

Tandem affinity purification of exosome and replication factor C complexes from the non-human infectious kinetoplastid parasite Crithidia fasciculata.

Kinetoplastid parasites are responsible for a range of diseases with significant global impact. Trypanosoma brucei and Trypanosoma cruzi cause human African trypanosomiasis and Chagas disease, respectively, while various Leishmania species are responsible for cutaneous, mucocutaneous and visceral leishmaniasis. Understanding the biology of these organisms is key for effective diagnosis, prophylaxis and treatment. The insect parasite Crithidia fasciculata offers a safe and low-cost alternative for studies of kinetoplastid biology. C. fasciculata does not infect humans, can be cultured to high yields in inexpensive serum-free medium in a standard laboratory, and has a completely sequenced publically available genome. Taking advantage of these features, however, requires the adaptation of existing methods of analysis to C. fasciculata. Tandem affinity purification is a widely used method that allows for the rapid purification of intact protein complexes under native conditions. Here we report the application of tandem affinity purification to C. fasciculata for the first time, demonstrating the effectiveness of the technique by purifying both the intact exosome and replication factor C complexes. Adding tandem affinity purification to the C. fasciculata toolbox significantly enhances the utility of this excellent model system.

Crithidia fasciculata;DNA replication;Exosome;Kinetoplastid;Tandem affinity purification

pubmed

Human aldehyde dehydrogenase 3A1 (ALDH3A1) exhibits chaperone-like function.

Aldehyde dehydrogenase 3A1 (ALDH3A1) is a metabolic enzyme that catalyzes the oxidation of various aldehydes. Certain types of epithelial tissues in mammals, especially those continually exposed to environmental stress (e.g., corneal epithelium), express ALDH3A1 at high levels and its abundance in such tissues is perceived to help to maintain cellular homeostasis under conditions of oxidative stress. Metabolic as well as non-metabolic roles for ALDH3A1 have been associated with its mediated resistance to cellular oxidative stress. In this study, we provide evidence that ALDH3A1 exhibits molecular chaperone-like activity further supporting its multifunctional role. Specifically, we expressed and purified the human ALDH3A1 in E. coli and used the recombinant protein to investigate its in vitro ability to protect SmaI and citrate synthase (from precipitation and/or deactivation) under thermal stress conditions. Our results indicate that recombinant ALDH3A1 exhibits significant chaperone function in vitro. Furthermore, over-expression of the fused histidine-tagged ALDH3A1 confers host E. coli cells with enhanced resistance to thermal shock, while ALDH3A1 over-expression in the human corneal cell line HCE-2 was sufficient for protecting them from the cytotoxic effects of both hydrogen peroxide and tert-butyl hydroperoxide. These results further support the chaperone-like function of human ALDH3A1. Taken together, ALDH3A1, in addition to its primary metabolic role in fundamental cellular detoxification processes, appears to play an essential role in protecting cellular proteins against aggregation under stress conditions.

Aldehyde dehydrogenase 3A1;Corneal crystallin;Molecular chaperone

pubmed

Synergistic apoptotic effects of apigenin TPGS liposomes and tyroservatide: implications for effective treatment of lung cancer.

To develop an alternative treatment for lung cancer, a combination of two potent chemotherapeutic agents - liposomal apigenin and tyroservatide - was developed. The therapeutic potential of this combination was investigated using A549 cells. Apigenin and tocopherol derivative-containing D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) liposomes might improve the delivery of apigenin to tumor cells, both in vitro and in vivo. Importantly, compared to either agent alone, the combination of apigenin TPGS liposomes and tyroservatide exhibited superior cytotoxicity, induced stronger G2 arrest, and suppressed A549 cancer cell invasion at a lower dose. The proapoptotic synergistic effects were also observed in A549 cells using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, flow cytometry, and Western blot analysis. More importantly, in vivo results showed that the combination of apigenin TPGS liposomes and tyroservatide exhibited tumor-growth inhibitory effects in A549 cell-bearing mice. In conclusion, our study showed that this combination therapy could serve as a promising synergistic therapeutic approach to improve outcomes in patients with lung cancer.

TPGS liposomes;apigenin;apoptosis;synergistic antitumor;tyroservatide

pubmed

Frameshift Mutations in the Mononucleotide Repeats of TAF1 and TAF1L Genes in Gastric and Colorectal Cancers with Regional Heterogeneity.

Initiation of transcription by RNA polymerase II requires TATA-box-binding protein (TBP)-associated factors (TAFs). TAF1 is a major scaffold by which TBP and TAFs interact in the basal transcription factor. TAF1L is a TAF1 homologue with 95 % amino acid identity with TAF1. TAF1 is involved in apoptosis induction and cell cycle regulation, but roles of TAF1 and TAF1L in tumorigenesis remain unknown. The aim of this study was to explore whether TAF1 and TAF1L genes were mutated in gastric (GC) and colorectal cancers (CRC). In a public database, we found that TAF1 and TAF1L genes had mononucleotide repeats in the coding sequences that might be mutation targets in the cancers with microsatellite instability (MSI). We analyzed the mutations in 79 GC and 124 CRC by single-strand conformation polymorphism analysis and DNA sequencing. In the present study, we found TAF1 frameshift mutations (3.8 % of CRC with MSI-H) and TAF1L frameshift mutations (2.9 % of GC and 3.8 % of CRC with MSI-H). These mutations were not found in stable MSI/low MSI (MSS/MSI-L) (0/90). In addition, we analyzed intratumoral heterogeneity (ITH) of TAF1 and TAF1L frameshift mutations in 16 CRC and found that two and one CRC harbored regional ITH of TAF1 and TAF1L frameshift mutations, respectively. Our data indicate that TAF1 and TAF1L genes harbored not only somatic mutations but also mutational ITH, which together might play a role in tumorigenesis of GC and CRC with MSI-H. Our results also suggest that ultra-regional mutation analysis is required for a comprehensive evaluation of mutation status in these tumors.

Basal transcription component;Cancers;Microsatellite instability;Mutation;TAF1;TAF1L

pubmed

Prevalence and risk factors of vitamin D insufficiency and deficiency among 6-24-month-old underweight and normal-weight children living in an urban slum of Bangladesh.

We quantified the prevalence of vitamin D status in 6-24-month-old underweight and normal-weight children and identified the socio-economic and dietary predictors for status. Cross-sectional, baseline data from a nutritional intervention study were analysed. Multinomial logistic regression was used to estimate the odds of being vitamin D deficient or insufficient with the reference being vitamin D sufficient. Urban slum area of Mirpur field site, Dhaka, Bangladesh. Underweight (weight-for-age Z-score <-2·00) and normal-weight (weight-for-age Z-score ≥-1·00) children aged 6-24 months. Among 468 underweight children, 23·1 % were sufficient, 42·3 % insufficient, 31·2 % deficient and 3·4 % severely vitamin D deficient. Among 445 normal-weight children, 14·8 % were sufficient, 39·6 % insufficient and 40·0 % deficient and 5·6 % severely deficient. With adjusted multinominal regression analysis, risk factors (OR (95 % CI)) for vitamin D deficiency in underweight children were: older age group (18-24 months old; 2·9 (1·5-5·7)); measurement of vitamin D status during winter (3·0 (1·4-6·4)) and spring (6·9 (3·0-16·1)); and maternal education (≥6 years of institutional education; 2·2 (1·0-4·9)). In normal-weight children, older age group (3·6 (1·2-10·6)) and living in the richest quintile (3·7 (1·1-12·5)) were found to be significantly associated with vitamin D insufficiency. The study demonstrates a significant burden of vitamin D insufficiency and deficiency in both underweight and normal-weight children <2 years of age from an urban slum of Bangladesh. Identification of risk factors may help in mitigating the important burden in such children.

Bangladesh;Children aged <2 years;Risk factors;Vitamin D

pubmed

First Indian report of IncX3 plasmid carrying <i>bla</i>_NDM-7 in <i>Escherichia coli</i> from bloodstream infection: potential for rapid dissemination.

<i>Enterobacteriaceae</i> with <i>bla</i>_NDM-7 is only infrequently observed. Self-transmissible plasmids carrying the <i>bla</i>_NDM gene increase the dissemination of carbapenem resistance in developing countries. This study investigates the whole genome sequence of a <i>bla</i>_NDM-7-positive <i>Escherichia coli</i>. The isolate was an extended-spectrum β-lactamase producer by combined disc diffusion test and carbapenemase producer by CarbaNP method. Sequencing results revealed the isolate as <i>E. coli</i> ST-167 with IncX3 plasmid carrying <i>bla</i>_NDM-7 in addition to <i>bla</i>_TEM-1 and <i>bla</i>_CMY-42 genes. The identification of IncX3-<i>bla</i>_NDM-7 combination is the first report in India where <i>bla</i>_NDM-7 is known to cause higher resistance to carbapenems compared to its variants.

IncX3;ST167 Escherichia coli;blaNDM-7;carbapenem resistance;whole genome sequencing

pubmed

Pathogenesis of systemic sclerosis-current concept and emerging treatments.

Systemic sclerosis (SSc) is an intractable multifaceted disease with high mortality. Although its pathogenesis is not fully understood, recent studies have advanced our knowledge on SSc. The cardinal pathological features of SSc are autoimmunity, vasculopathy, and fibrosis. The B cells in SSc are constitutively activated and lead to the production of a plethora of autoantibodies, such as anti-topoisomerase I and anti-centromere antibodies. In addition to these autoantibodies, which are valuable for diagnostic criteria or biomarkers, many other autoantibodies targeting endothelial cells, including endothelin type A receptor and angiotensin II type I receptor, are known to be functional and induce activation or apoptosis of endothelial cells. The autoantibody-mediated endothelial cell perturbation facilitates inflammatory cell infiltration, cytokine production, and myofibroblastic transformation of fibroblasts and endothelial cells. Profibrotic cytokines, such as transforming growth factor β, connective tissue growth factor, interleukin 4/interleukin 13, and interleukin 6, play a pivotal role in collagen production from myofibroblasts. Specific treatments targeting these causative molecules may improve the clinical outcomes of patients with SSc. In this review, we summarize recent topics on the pathogenesis (autoantibodies, vasculopathy, and fibrosis), animal models, and emerging treatments for SSc.

Autoantibodies;Fibrosis;Systemic sclerosis;Vasculopathy

pubmed

Automated retinal health diagnosis using pyramid histogram of visual words and Fisher vector techniques.

Untreated age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma may lead to irreversible vision loss. Hence, it is essential to have regular eye screening to detect these eye diseases at an early stage and to offer treatment where appropriate. One of the simplest, non-invasive and cost-effective techniques to screen the eyes is by using fundus photo imaging. But, the manual evaluation of fundus images is tedious and challenging. Further, the diagnosis made by ophthalmologists may be subjective. Therefore, an objective and novel algorithm using the pyramid histogram of visual words (PHOW) and Fisher vectors is proposed for the classification of fundus images into their respective eye conditions (normal, AMD, DR, and glaucoma). The proposed algorithm extracts features which are represented as words. These features are built and encoded into a Fisher vector for classification using random forest classifier. This proposed algorithm is validated with both blindfold and ten-fold cross-validation techniques. An accuracy of 90.06% is achieved with the blindfold method, and highest accuracy of 96.79% is obtained with ten-fold cross-validation. The highest classification performance of our system shows the potential of deploying it in polyclinics to assist healthcare professionals in their initial diagnosis of the eye. Our developed system can reduce the workload of ophthalmologists significantly.

Age-related macular degeneration;Bag-of-visual-words;Computer-aided diagnosis system;Diabetic retinopathy;Eye diseases;Fisher vector encoder;Fundus images;Glaucoma;Machine learning

pubmed

The needs of older people with mental health problems in a Portuguese psychiatric setting.

This study aims to identify met and unmet needs, according to the patient, the carer and the staff, and their relationship with socio-demographic and clinical characteristics in elderly people with mental health problems. A sample of 306 elderly patients ≥65 years, of both sexes, diagnosed with mental illness (ICD-10 criteria), was recruited from inpatient/outpatient settings in a Department of Psychiatry and Mental Health, in northern Portugal. Patients were assessed with the Camberwell Assessment of Need for the Elderly/CANE. The majority of diagnoses were depression (33.7%), dementia (24.5%), and schizophrenia (12.7%). The patients' main unmet needs found were psychological distress (15.0%), daytime activities (10.5%), and benefits (6.5%). Patients reported significantly lower unmet and global needs than carers and staff (Z = -8.58, p < 0.001; Z = -11.07, p < 0.001, respectively). A larger number of global needs (met and unmet) were associated with the diagnosis of dementia, followed by schizophrenia, bipolar, and depressive disorder (p < 0.001), with inpatients reporting more needs than outpatients. Mental disorders were associated with a greater number of needs in elderly patients, which makes this assessment important as it includes the patients' perspective, when they are the focus of intervention, in order to decrease distress and make more beneficial use of services, especially in inpatient settings. These different perspectives are crucial when assessing and planning psychiatric and mental health services.

CANE;elderly;geriatric psychiatry;mental health;needs assessment

pubmed

Step-Up Synthesis of Periodic Mesoporous Organosilicas with a Tyrosine Framework and Performance in Horseradish Peroxidase Immobilization.

New amino-acid-bridged periodic mesoporous organosilicas (PMOs) were constructed by hydrolysis and condensation reactions under acid conditions in the presence of a template. The tyrosine bissilylated organic precursor (TBOS) was first prepared through a multistep reaction by using tyrosine (a natural amino acid) as the starting material. PMOs with the tyrosine framework (Tyr-PMOs) were constructed by simultaneously using TBOS and tetraethoxysilane as complex silicon sources in the condensation process. All the Tyr-PMOs materials were characterized by XRD, FTIR spectroscopy, N₂ adsorption-desorption, TEM, SEM, and solid-state ²⁹ Si NMR spectroscopy to confirm the structure. The horseradish peroxidase (HRP) enzyme was first immobilized on these new Tyr-PMOs materials. Optimal conditions for enzyme adsorption included a temperature of 40 °C, a time of 8 h, and a pH value of 7. Furthermore, the novel Tyr-PMOs materials could store HRP for approximately 40 days and maintained the enzymatic activity, and the Tyr-PMOs-10 % HRP with the best immobilization effect could be reused at least eight times.

amino acids;immobilization;mesoporous materials;organosilicas;tyrosine-bridged organosilicas

pubmed

Binary combinations of organophosphorus and synthetic pyrethroids are more potent acetylcholinesterase inhibitors than organophosphorus and carbamate mixtures: An in vitro assessment.

Anticholinesterase insecticides such as organophosphorous (OP) and carbamates pesticides (CB); and synthetic pyrethroids (SP) pesticides commonly co-occur in the environment. This raises the possibility of antagonistic, additive, or synergistic neurotoxicity in exposed organisms. Acetylcholinesterase (AChE) inhibition has been demonstrated to be useful as a biomarker for exposure to OP and CBs in many environments. This study investigated the response of housefly (Musca domestica) head AChE (HF-AChE) exposed to five OPs; chlorpyrifos (CPF), malathion (MLT), triazophos (TRZ), monocrotophos (MCP) and profenofos (PRF) and two CBs; carbaryl (CRB) and carbofuran (CBF) as individual compounds and as binary mixtures of OPs and CBs under in vitro conditions. In addition, the selected OPs and CBs were evaluated for their toxicity in binary combinations with two SPs; deltamethrin (DLT) and cypermethrin (CYP) at fixed concentrations of 0.1 and 10μg/L. The toxicological interaction of five OPs with two CBs pesticides was evaluated under oxidised and un-oxidised conditions using a toxic unit (TU) approach and a concentration addition (CA) model. Pyrethroid combinations were assessed only under oxidised conditions. Since OPs and CBs act by a similar mechanism of inhibition of AChE, a dose additive effect was expected, but not conclusively found. TRZ with either CBF or CRB exhibited synergism under oxidised and un-oxidised conditions but the degree of synergism was stronger under un-oxidised conditions. Additivity was exhibited by CBF+MCP, CRB+MCP, CRB+MLT and CBF+MCP under un-oxidised conditions and CRB+MCP and CRB+CPF under oxidised conditions. Pyrethorids in combination with OPs (TRZ, MLT and CPF) were highly synergistic. In the present study, we used pure housefly head AChE without any interference of monooxygenase and/or esterase enzyme activities. Therefore these other enzymes were not producing the observed deviations from concentration-addition in the binary combinations between OPs, CBs and SPs. The mechanisms of OP, CB and SP interactions in pesticide mixtures requires further investigation.

Antagonism;Concentration addition model;Housefly acetylcholinesterase;Oxon analog;Synergism;Toxic unit model

pubmed

Bifidobacterium bifidum OLB6378 Simultaneously Enhances Systemic and Mucosal Humoral Immunity in Low Birth Weight Infants: A Non-Randomized Study.

Probiotic supplementation has been part of the discussion on methods to enhance humoral immunity. Administration of <i>Bifidobacterium bifidum</i> OLB6378 (OLB6378) reduced the incidence of late-onset sepsis in infants. In this non-randomized study, we aimed to determine the effect of administration of live OLB6378 on infants' humoral immunity. Secondly, we tried to elucidate whether similar effects would be observed with administration of non-live OLB6378. Low birth weight (LBW) infants weighing 1500-2500 g were divided into three groups: Group N (no intervention), Group L (administered live OLB6378 concentrate), and Group H (administered non-live OLB6378 concentrate). The interventions were started within 48 h after birth and continued until six months of age. Serum immunoglobulin G (IgG) levels (IgG at one month/IgG at birth) were significantly higher in Group L than in Group N (<i>p</i> < 0.01). Group H exhibited significantly higher serum IgG levels (<i>p</i> < 0.01) at one month of age and significantly higher intestinal secretory immunoglobulin A (SIgA) levels (<i>p</i> < 0.05) at one and two months of age than Group N. No difference was observed in the mortality or morbidity between groups. Thus, OLB6378 administration in LBW infants enhanced humoral immunity, and non-live OLB6378, which is more useful as a food ingredient, showed a more marked effect than the viable bacteria.

heat-treated;humoral immunity;non-live bacteria;probiotics;sepsis;serum IgG;stool secretory IgA

pubmed

Meaningful Use and Hospital Performance on Post-Acute Utilization Indicators.

To examine trends in hospital post-acute utilization indicators and to determine whether improvement in these indicators is associated with attesting to meaningful use (MU). Medicare claims-based, repeated measures on 30-day hospital-wide all-cause readmission and emergency department (ED) utilization rates for 160 short-stay hospitals (2009-2012); Medicare EHR Incentive Program Payments files (2011-2012); and other hospital and market data. Interrupted time series with concurrent comparison group. Propensity score-weighted multilevel models for change demonstrate that 30-day readmission rates (unadjusted) fell from 13.4 percent in 2009 to 12.1 percent in 2012. Similarly, 30-day ED utilization declined from 18.9 percent to 17.3 percent during the same period. However, MU and non-MU hospitals were indistinguishable vis-à-vis performance. Controlling for hospital and market characteristics, MU was unrelated to 30-day readmission. In contrast, 30-day ED utilization deteriorated. Hospitals with MU Stage 1 designation did not show significantly higher improvement on post-acute utilization compared to their counterparts without. To achieve gains in quality and safety, potentially associated with EHRs, and to advance care coordination and patient engagement, the regulators should strengthen accountability by linking comprehensive, outcomes-based performance measures to specific MU objectives.

30-day ED utilization;30-day readmission;EHRs;Meaningful use

pubmed

Crystal structure of the C-terminal domain of Bacillus subtilis GabR reveals a closed conformation by γ-aminobutyric acid binding, inducing transcriptional activation.

Bacillus subtilis GabR (BsGabR) is involved in the γ-aminobutyric acid (GABA) catabolism as a transcriptional regulator, consisting of an N-terminal helix-turn-helix DNA-binding domain and a C-terminal aminotransferase-like (AT-like) domain. Research on the C-terminal AT-like domain of BsGabR (BsGabR-CTD) has focused on the interaction with GABA as an effector, but most its functional details remain unclear. To understand the underlying mechanism, we report the crystal structure of BsGabR-CTD in complex with pyridoxal 5'-phosphate (PLP) and GABA at 2.0 Å resolution. The structure of ligand-bound BsGabR-CTD revealed two distinct monomeric states in a homodimer. One subunit is a closed-form containing the PLP-GABA adduct, and the other subunit is a PLP-bound open-form. Our structural studies provide a detailed mechanism indicating that the open-to-closed transition by the binding of GABA induces the conformational rearrangement of BsGabR-CTD, which may trigger the activation of transcription.

Aminotransferase-like domain;Bacillus subtilis GabR;External Schiff base;Transcriptional regulator;γ-Aminobutyric acid

pubmed

Neighborhood Predictors of Cognitive Training Outcomes and Trajectories in ACTIVE.

We examined the influence of neighborhood socioeconomic position (SEP), racial/ethnic composition, and living in a major city on cognitive trajectories and intervention outcomes. Data came from the Advanced Cognitive Training for Independent and Vital Elderly study ( N = 2,438). Mixed effects analyses examined the associations between neighborhood variables and memory, reasoning, speed of processing, and everyday cognition, estimating differences in initial gains (potentially related to practice) and long-term rate of change over 10 years. The effect of reasoning training on initial gain was weaker for individuals in a major city. For everyday cognition, there was a stronger initial gain for memory-trained and control participants in areas with more racial/ethnic minorities and for speed-trained and control individuals in higher SEP areas. The racial/ethnic minority effect was no longer significant after adjustment for multiple comparisons. Neighborhood factors may be more important in practice-related improvement than in long-term change.

cognition;cognitive training;neighborhood;plasticity;social determinants

pubmed

A new hypervolume approach for assessing environmental risks.

Assessing risks of uncertain but potentially damaging events, such as environmental disturbances, disease outbreaks and pest invasions, is a key analytical step that informs subsequent decisions about how to respond to these events. We present a continuous risk measure that can be used to assess and prioritize environmental risks from uncertain data in a geographical domain. The metric is influenced by both the expected magnitude of risk and its uncertainty. We demonstrate the approach by assessing risks of human-mediated spread of Asian longhorned beetle (ALB, Anoplophora glabripennis) in Greater Toronto (Ontario, Canada). Information about the human-mediated spread of ALB through this urban environment to individual geographical locations is uncertain, so each location was characterized by a set of probabilistic rates of spread, derived in this case using a network model. We represented the sets of spread rates for the locations by their cumulative distribution functions (CDFs) and then, using the first-order stochastic dominance rule, found ordered non-dominant subsets of these CDFs, which we then used to define different classes of risk across the geographical domain, from high to low. Because each non-dominant subset was estimated with respect to all elements of the distribution, the uncertainty in the underlying data was factored into the delineation of the risk classes; essentially, fewer non-dominant subsets can be defined in portions of the full set where information is sparse. We then depicted each non-dominant subset as a point cloud, where points represented the CDF values of each subset element at specific sampling intervals. For each subset, we then defined a hypervolume bounded by the outermost convex frontier of that point cloud. This resulted in a collection of hypervolumes for every non-dominant subset that together serve as a continuous measure of risk, which may be more practically useful than averaging metrics or ordinal rank measures. Overall, the approach offers a rigorous depiction of risk in a geographical domain when the underlying estimates of risk for individual locations are represented by sets or distributions of uncertain estimates. Our hypervolume-based approach can be used to compare assessments made with different datasets and assumptions.

Asian longhorned beetle;Environmental risks;Hypervolume;Invasive species;Non-dominant set;Stochastic dominance;Uncertainty

pubmed

Basic concepts in metal work failure after metastatic spine tumour surgery.

The development of spinal implants marks a watershed in the evolution of metastatic spine tumour surgery (MSTS), which has evolved from standalone decompressive laminectomy to instrumented stabilization and decompression with reconstruction when necessary. Fusion may not be feasible after MSTS due to poor quality of graft host bed along with adjunct chemotherapy and/or radiotherapy postoperatively. With an increase in the survival of patients with spinal tumours, there is a probability of an increase in the rate of implant failure. This review aims to help establish a clear understanding of implants/constructs used in MSTS and to highlight the fundamental biomechanics of implant/construct failures. Published literature on implant failure after spine surgery and MSTS has been reviewed. The evolution of spinal implants and their role in MSTS has been briefly described. The review defines implant/construct failures using radiological parameters that are practical, feasible, and derived from historical descriptions. We have discussed common modes of implant/construct failure after MSTS to allow further understanding, interception, and prevention of catastrophic failure. Implant failure rates in MSTS are in the range of 2-8%. Variability in patterns of failure has been observed based on anatomical region and the type of constructs used. Patients with construct/implant failures may or may not be symptomatic and present either as early (< 3months) or late failures (> 3months). It has been noted that not all the implant failures after MSTS result in revisions. Based on the observed radiological criteria and clinical presentations, we have proposed a clinico-radiological classification for implant/construct failure after MSTS.

Asymptomatic implant failure;Early failure;Late failure;Metastatic spine tumour surgery;Symptomatic implant failure

pubmed

"Even my sister says I'm acting like a crazy to get a check": Race, gender, and moral boundary-work in women's claims of disabling chronic pain.

Recent research examines how women claim chronic pain in response to gendered moral discourses. However, extant research does not explore how race shapes the moral boundary-work performed by women suffering from disabling chronic pain. Through the qualitative analysis of twenty-four semi-structured interviews with women fibromyalgia sufferers conducted between October 2014 and August 2016 in the U.S.A., I demonstrate how women with fibromyalgia claim chronic pain by doing moral boundary-work, referencing gendered and racialized moral discourses that structure how claims of chronic pain as disability are and are not read as legitimate by doctors, disability bureaucrats and personal networks. Extending Hansen et al.'s work on stigma and the "pathologization of poverty," I suggest that, per my sample, the different moral discourses deployed in white and Black women's claims of chronic pain can be explained by the racialized and gendered boundaries of citizenship that structure U.S. welfare and disability politics. Finally, I argue for intersectionality's relevance to research on moral boundary-work and the medicalization of poverty.

Chronic pain;Disability;Gender;Intersectionality;Morality;Race;U.S.A.;Welfare

pubmed

Amputations for extremity soft tissue sarcoma in an era of limb salvage treatment: Local control and survival.

Despite multimodality limb salvage treatment (LST) for locally advanced extremity soft tissue sarcoma (ESTS), some patients still need an amputation. Indications for amputation and oncological outcome for these patients are described. Between 1996 and 2016, all patients who underwent an amputation for ESTS were included. Patients who underwent an amputation as primary or as non-primary treatment formed Group I and II, respectively. Thirty-nine patients were included, 16 in Group I (41%) and 23 in Group II (59%). Tumor size or local recurrence which could not be treated with LST were the two main reasons for amputation. Local recurrence free survival (LRFS) (P = 0.396), distant metastases free survival (DMFS) (P = 0.965), disease-specific survival (DSS) (P = 0.745), and overall survival (OS) (P = 0.718) were comparable for both groups. Ten-year LRFS was 90.0% versus 83.7%; DMFS was 31.0% versus 42.2%; DSS was 52.2% versus 44.1%; and OS was 44.2% versus 41.6%, for group I and II respectively. Oncological outcome seems to be comparable between patients who underwent a primary or a non-primary amputation for ESTS. With the on-going possibilities concerning prosthesis and rehabilitation programs, it remains important to decide in a multidisciplinary sarcoma team meeting which treatment suits best for each individual patient.

amputation;soft tissue sarcoma;treatment

pubmed

Greater Omental Milky Spot Examination for Diagnosis of Peritoneal Metastasis in Gastric Cancer Patients.

To evaluate the diagnostic value of cytological greater omental milky spot examination for the diagnosis of peritoneal metastasis in gastric cancer patients. A total of 136 patients diagnosed with gastric cancer and without distant metastasis were enrolled in our study. All patients underwent laparoscopy and CH40 suspension liquid dye of peritoneal lymph nodes preoperatively as well as ascites or peritoneal lavage fluid collections and excisions of marked greater omental milky spot tissues perioperatively. According to the laparoscopic results, the patients were divided into T1-T2 stage (n = 56) without and into T3-T4 stage (n = 80) with tumor invasion into the serosal layer. Among the T1-T2-stage patients, tumor cells could be detected in peritoneal lavage fluids in 2 cases, whereas with greater omental milky spot examination, peritoneal metastasis was detected in 8 cases. Among the 80 cases in the T3-T4 stage, tumor cells could be detected in 28 cases via peritoneal lavage cytology and in 43 cases by greater omental milky spot examinations, and 4 cases had cancer cell infiltration also in nonmilky spot omental areas. The statistical analysis showed that the staging accuracy rate of exfoliative cytology examination was superior to that of the laparoscopic exploration (P < .05), but its sensitivity was significantly lower than that obtained with cytological greater omental milky spot examinations (P < .05). The laparoscopic exploration could make a preliminary diagnosis of peritoneal metastasis via serosal layer invasion detection. For further analyses, cytological examinations of greater omental milky spots were more sensitive than exfoliative cytology.

exfoliated cells;laparoscopic exploration;omental milky spot;peritoneal metastasis

pubmed

Novel microsatellite markers for the oriental fruit moth Grapholita molesta (Lepidoptera: Tortricidae) and effects of null alleles on population genetics analyses.

The oriental fruit moth (OFM) Grapholita molesta (Lepidoptera: Tortricidae) is an important economic pest of stone and pome fruits worldwide. We sequenced the OFM genome using next-generation sequencing and characterized the microsatellite distribution. In total, 56,674 microsatellites were identified, with 11,584 loci suitable for primer design. Twenty-seven polymorphic microsatellites, including 24 loci with trinucleotide repeat and three with pentanucleotide repeat, were validated in 95 individuals from four natural populations. The allele numbers ranged from 4 to 40, with an average value of 13.7 per locus. A high frequency of null alleles was observed in most loci developed for the OFM. Three marker panels, all of the loci, nine loci with the lowest null allele frequencies, and nine loci with the highest null allele frequencies, were established for population genetics analyses. The null allele influenced estimations of genetic diversity parameters but not the OFM's genetic structure. Both a STRUCTURE analysis and a discriminant analysis of principal components, using the three marker panels, divided the four natural populations into three groups. However, more individuals were incorrectly assigned by the STRUCTURE analysis when the marker panel with the highest null allele frequency was used compared with the other two panels. Our study provides empirical research on the effects of null alleles on population genetics analyses. The microsatellites developed will be valuable markers for genetic studies of the OFM.

Grapholita molesta ;SSR;next-generation sequencing;null allele;population genetic structure

pubmed

Essential oil diversity of Origanum vulgare L. populations from Southern Italy.

Essential oils (EOs) belonging to 25 wild populations of Origanum vulgare L. samples, growing wild in different locations of Calabria Region (Southern Italy), were analyzed using gas chromatography-mass spectrometry. The quantitative and qualitative data showed EO concentrations ranging from 0.96 to 5.10% and 37 compounds detected, representing more than 80% of the total composition of the oils. By applying hierarchical cluster analysis on the basis of the EO constituents, two main groups and three subgroups were found, reflecting the variation in the chemical composition of EOs from wild oregano populations. The first group consisted of acyclic (linalool/linalyl acetate) chemotypes with a predominant presence of linalyl acetate; the second was characterized by chemotypes rich in cymyl-compounds, mainly carvacrol, thymol and γ-terpinene. The data obtained contribute to broaden the inventory of wild oregano populations from Calabria to plan programs for the selection of chemotypes with new and specific uses.

Carvacrol (PubChem CID: 10364);Chemical composition;Essentials oils;GC/MS;Linalyl acetate (PubChem CID: 8294);Origanum vulgare L.;Thymol (PubChem CID: 6989);γ-Terpinene (PubChem CID: 7461)

pubmed

Postoperative myocardial infarction in acute type A aortic dissection: A report from the International Registry of Acute Aortic Dissection.

Postoperative myocardial infarction remains a serious complication in cardiac surgery. The incidence and impact of this condition in acute type A aortic dissection are poorly understood. A total of 1445 patients with acute type A aortic dissection who underwent surgery were enrolled in the International Registry of Acute Aortic Dissection from 1996 to 2013. Individuals with preoperative myocardial infarction at hospital presentation and a history of myocardial infarction were excluded. Patients with postoperative myocardial infarction (n = 38, 2.6%) were compared with those without postoperative myocardial infarction (n = 1407, 97.4%). The postoperative myocardial infarction group was more often of white race (100% vs 90%, P = .043) with bicuspid aortic valve (15.6% vs 4.5%, P = .015). Imaging demonstrated more aortic root involvement (75.8% vs 49.5%, P = .003), pericardial effusion (65.5% vs 44.1%, P = .022), and coronary artery compromise (27.3% vs 10.2%, P = .022). Patients with postoperative myocardial infarction were more frequently hypotensive or in shock during surgery (42.9% vs 25.5%, P = .021). Patients with postoperative myocardial infarction were more likely to have undergone root replacement (54.5% vs 33.3%, P = .011), coronary artery bypass grafting (28.6% vs 7.4%, P < .001), or aortic valve replacement (40.0% vs 23.8%, P = .027), and less likely to have had complete arch replacement (2.8% vs 14.0%, P = .050). Median circulatory arrest time was higher in postoperative myocardial infarction (60 vs 38 minutes, P = .024). In-hospital mortality (57.9% vs 16.3%, P < .001) and Kaplan-Meier estimates of 5-year mortality (P = .007) were distinctly higher in postoperative myocardial infarction. Postoperative myocardial infarction is a devastating complication of type A aortic dissection repair. It is associated with bicuspid aortic valve, root involvement, pericardial effusion, and extent of surgical repair. Patients with postoperative myocardial infarction have higher serious postoperative complications, in-hospital mortality, and 5-year mortality rates than those without postoperative myocardial infarction.

aortic dissection;myocardial infarction;type A dissection

pubmed

Emerging Insight into MAPK Inhibitors and Immunotherapy in Colorectal Cancer.

Our understanding of the genetic and non-genetic molecular alterations associated with colorectal cancer (CRC) progression and therapy resistance has markedly expanded in the recent years. In addition to their effects on tumor biology, targeted therapies can have effects on host immune responses. However, the mechanisms by which immune cells organize tumor microenvironments to regulate T-cell activity need to be comprehensively defined. There is good evidence in the literature that alterations in different members of the MAPK superfamily (mainly ERKs and p38 MAPKs) modify the inflammatory response and antitumor immunity, enhancing metastatic features of the tumors. In addition, a plethora of alterations that emerge at relapse often converge on the activation of MAPKs, particularly, ERKs, which act in concert with other oncogenic signals to modulate cellular homeostasis and clonal evolution during targeted therapies. Herein, we discuss how this knowledge can be translated into drug development strategies aimed at increasing tumor antigenicity and antitumor immune responses. Insights from these studies could provide a framework for considering additional combinations of targeted therapies and immunotherapies for the treatment of CRC.

ERKs;MAPKs;colorectal cancer;immune check point inhibitors;immune resistance;immunotherapy;p38 MAPKs

pubmed

Expectation and futurity: The remarkable success of genetic determinism.

Genetic determinism is nowadays largely questioned and widely criticized. However, if we look at the history of biology in the last one hundred years, we realize that genetic determinism has always been controversial. Why, then, did it acquire such relevance in the past despite facing longstanding criticism? Through the analysis of some of the ambitious expectations of future scientific applications, this article explores the possibility that part of the historical success of genetic determinism lies in the powerful rhetorical strategies that have connected the germinal matter with alluring bio-technological visions. Indeed, in drawing on the recent perspectives of "expectation studies" in science and technology, it will be shown that there has been an interesting historical relationship between reductionist notions of the gene as a hereditary unit, coded information or functional DNA segment, and startling prophecies of what controlling such an entity might achieve. It will also be suggested that the well-known promissory nature of genomics is far older than the emergence of biotechnology in the 1970s. At least from the time of the bio-utopias predicted by J.B.S. Haldane and J. S. Huxley, the gene has often been surrounded by what I call the "rhetoric of futurity": a promissory rhetoric that, despite momentous changes in the life sciences throughout the 20th century, has remained relatively consistent over time.

Genetic determinism;Genomics;Rhetoric of science

pubmed

Structure-biocompatibility and transfection activity relationships of cationic polyaspartamides with (dialkylamino)alkyl and alkyl or hydroxyalkyl side groups.

A series of 14 cationic derivatives of poly(aspartic acid) i.e. cationic polyaspartamides with different (dialkylamino)alkyl and alkyl or hydroxyalkyl side groups was synthesized by nucleophilic addition on polysuccinimide. The resulting polyaspartamides have moderate amphiphilic properties. Relationships between the structure and ratio of side groups and in vitro properties of polyaspartamides, including their cytotoxic and membrane-damaging activity towards human cell lines, primary skin fibroblasts and erythrocytes, were established and discussed. Cationic polyaspartamides vary in their DNA-binding, condensing and nuclease-protecting characteristics depending on the concentration ratio of (dialkylamino)alkyl and alkyl or hydroxyalkyl side groups. Effective cell transfection was achieved upon polyaspartamide-mediated plasmid DNA delivery in serum-free medium in the presence of chloroquine. Effect of serum proteins adsorption onto polyaspartamide based polyplexes, and the role of concentration of polyplexes in culture medium in their colloidal stability and transfection process were demonstrated. Synthesized polyaspartamides are biocompatible and long-acting gene carriers, which are applied to cells after dilution and without washing, thus providing transfection level comparable to that of commercial transfection reagent.

Cationic polyaspartamides;Dilution effect;Plasmid DNA delivery;Poly(aspartic acid);Serum proteins;Structure–activity relationship

pubmed

Tolerogenic dendritic cells generated with dexamethasone and vitamin D3 regulate rheumatoid arthritis CD4⁺ T cells partly via transforming growth factor-β1.

Tolerogenic dendritic cells (tolDC) are a new immunotherapeutic tool for the treatment of rheumatoid arthritis (RA) and other autoimmune disorders. We have established a method to generate stable tolDC by pharmacological modulation of human monocyte-derived DC. These tolDC exert potent pro-tolerogenic actions on CD4⁺ T cells. Lack of interleukin (IL)-12p70 production is a key immunoregulatory attribute of tolDC but does not explain their action fully. Here we show that tolDC express transforming growth factor (TGF)-β1 at both mRNA and protein levels, and that expression of this immunoregulatory cytokine is significantly higher in tolDC than in mature monocyte-derived DC. By inhibiting TGF-β1 signalling we demonstrate that tolDC regulate CD4⁺ T cell responses in a manner that is at least partly dependent upon this cytokine. Crucially, we also show that while there is no significant difference in expression of TGF-βRII on CD4⁺ T cells from RA patients and healthy controls, RA patient CD4⁺ T cells are measurably less responsive to TGF-β1 than healthy control CD4⁺ T cells [reduced TGF-β-induced mothers against decapentaplegic homologue (Smad)2/3 phosphorylation, forkhead box protein 3 (FoxP3) expression and suppression of (IFN)-γ secretion]. However, CD4⁺ T cells from RA patients can, nonetheless, be regulated efficiently by tolDC in a TGF-β1-dependent manner. This work is important for the design and development of future studies investigating the potential use of tolDC as a novel immunotherapy for the treatment of RA.

TGF-β1;regulation;rheumatoid arthritis;tolerogenic dendritic cells

pubmed

Bioinspired polymer microstructures for directional transport of oily liquids.

Nature has always served as an inspiration for scientists, helping them to solve a large diversity of technical problems. In our case, we are interested in the directional transport of oily liquids and as a model for this application we used the flat bug <i>Dysodius lunatus</i>. In this report, we present arrays of drops looking like polymer microstructures produced by the two-photon polymerization technique that mimic the micro-ornamentation from the bug's cuticle. A good directionality of oil transport was achieved, directly controlled by the direction of the pointed microstructures at the surface. If the tips of the drop-like microstructures are pointing towards the left side, the liquid front moves to the right and vice versa. Similar effects could be expected for the transport of oily lubricants. These results could, therefore, be interesting for applications in friction and wear reduction.

biomimetics;directional transport;two-photon lithography

pubmed

Sperm DNA methylation of H19 imprinted gene and male infertility.

Infertility affects up to 15% of reproductive-aged couples worldwide, with male factor being detected in 40%-50% of the cases. Proper sperm production is associated with the establishment of appropriate epigenetic marks in developing germ cells. Several studies have demonstrated the association between abnormal spermatogenesis and epigenetic disturbances with the major focus on DNA methylation. Imprinted genes are expressed in a parent-of-origin-specific manner, and the role of their DNA methylation in proper spermatogenesis has been documented recently. The existing evidence along with the absence of relevant data in south of Iran prompted us to study the methylation of H19 imprinted gene in spermatozoa of idiopathic infertile patients (males with abnormalities in sperm parameters) and healthy controls by Combined Bisulfite Restriction Analysis. According to our results, the lowest methylation percentage of H19 imprinted gene belongs to three cases with sperm characteristics under normal range (two cases Oligoasthenoteratozoospermia and one case Oligoteratozoospermia). However, our results show that the median of methylation percentage for H19 is not statistically significant between case and control groups. Our results and those of others introduce DNA methylation as a potential marker of fertility and should be investigated with more patients in future studies.

imprinted genes;infertility;sperm

pubmed

Semantic and phonological influences on visual word learning in a transparent language.

Orthographic representations of words are indispensable for reading fluency. The ways in which these representations are developed and their resistance to decay are hotly debated topics. The aim of this study was to investigate the influence of semantic and phonological representations on the formation of orthographic representations in a transparent orthography. In order to achieve this objective, an experiment with three conditions was carried out. In the first condition, a group of university students were asked to repeatedly read 10 new words after semantic and phonological training, in the second condition another group of participants read the new words after phonological training, and in the third condition participants read without previous training. Finally, a follow-up session was performed to test the resistance to decay of the orthographic representations. The results showed that participants who had received semantic training formed the representations faster than participants in the other conditions, as indicated by the decrease in length effect. These results indicate the important role of previous knowledge when people face new written words. A month later these orthographic representations still remained in the lexicon of the participants.

Adult readers;Orthographic learning;Reading;Semantic and phonological information;Transparent orthography

pubmed

Development of hydrophobicity and selective separation of hazardous chlorinated plastics by mild heat treatment after PAC coating and froth flotation.

Polyvinyl chloride (PVC) containing chlorine can release highly toxic materials and persistent organic pollutants if improperly disposed of. The combined technique of powder activated carbon (PAC) coating and mild heat treatment has been found to selectively change the surface hydrophobicity of PVC, enhancing its wettability and thereby promoting its separation from heavy plastic mixtures included polycarbonate (PC), polymethyl methacrylate (PMMA), polystyrene (PS) and acrylonitrile butadiene styrene (ABS) by means of froth flotation. The combined treatments helped to rearrange the surface components and make PVC more hydrophobic, while the remaining plastics became more hydrophilic. After the treatments at 150°C for 80s the contact angle of the PVC was greatly increased from 90.5 to 97.9°. The SEM and AFM reveal that the surface morphology and roughness changes on the PVC surface. XPS and FT-IR results further confirmed an increase of hydrophobic functional groups on the PVC surface. At the optimized froth flotation and subsequent mixing at 150rpm, 100% of PVC was recovered from the remaining plastic mixture with 93.8% purity. The combined technique can provide a simple and effective method for the selective separation of PVC from heavy plastics mixtures to facilitate easy industrial recycling.

Froth flotation;Mild heat treatment;PVC;Recycling;Surface modification

pubmed

Apathy: Risk Factor for Mortality in Nursing Home Patients.

To determine the prognostic value of apathy for mortality in patients of somatic (SC) and dementia special care (DSC) nursing home (NH) units. Longitudinal design, secondary analyses of a 2-year, cluster-randomized trial with six measurements, approximately 4 months in between. SC and DSC-units of Dutch NHs. NH-patients of seventeen SC-units (n = 342) and sixteen DCS-units (n = 371). Data were available for 713 NH-patients, 266 of whom died during the study. Apathy was assessed using the 10-item Apathy Evaluation Scale (AES-10) and applied as categorical variable using known cut-off scores as well as dimensional variable. Additionally, depressive symptoms were assessed using the Cornell Scale for Depression in Dementia. Mixed effects cox models using the coxme package in R revealed a higher risk of mortality between two measurements, if apathy was present (hazard ratio (HR) = 1.77; 95% confidence interval (CI] = 1.35-2.31, P < .001). Results remained significant (HR = 1.64; 95% CI = 1.23-2.19, P < .001) when controlled for depressive symptoms. DSC-units and SC-units did not differ (P > .05) in the effect of apathy on mortality. Male gender (HR = 1.67; 95% CI = 1.23-2.27, P < .001), and higher age in years (HR = 1.06; 95% CI = 1.04-1.08, P < .001) were also predictors of mortality. Regarding apathy as a dimensional construct, one standard deviation increase of AES-10 scores was associated with a 62% increase of mortality risk (HR = 1.62, 95% CI = 1.40-1.88, P < .001). Apathy was associated with mortality over a 4-month period in NH patients, even when controlling for depression. These data suggest that screening and treatment strategies for apathy should be developed for this patient population.

apathy;dementia care;depression;mortality;nursing home;risk factor;somatic

pubmed

Validation of a procedure to mix homogenous solutions in bags and syringes.

It is essential to obtain homogeneous drug mixtures, especially when only a fraction of the prepared dose is to be administered. This study aimed to validate a manual mixing method for guaranteeing homogeneity. One operator tested six standardised manual mixing techniques (one, five and 10 inversions, and one, five and 10 bottoms-up agitations) six times each for preparations in bags and syringes. The mixing step was reproduced experimentally by adding a small volume of analyte (0.8 mL for syringes and 6 mL for bags) to a large volume of matrix (50 mL for syringes and 300 mL for bags). Three analyte/matrix pairings were tested: water/water, water/glucose 20% and glucose 20%/water. The tracer (sodium chloride) was assayed using capillary electrophoresis. Volume measurement errors were corrected by weighing bags and syringes. In order to evaluate inter-individual variability, the 10 inversions technique was tested by 10 drug preparation technicians. Mixtures were considered acceptable if they were between 95% and 105% accurate and if the coefficient of variation was ≤5% of the average of the six repetitions. Both the 10 inversions and 10 bottoms-up agitations mixing techniques ensured acceptable mixtures by the principal technician in all tested conditions. When mixing using the 10 inversions method was tested by the 10 technicians, the mixture's mean acceptability could no longer be ensured. Use of a standardised mixing technique did not appear to be sufficient to obtain a homogeneous mixture across technicians. Standardised guidelines for needle position, needle rinsing and speed of addition should be implemented.

bags;drugs;mixtures;standardized manual mixing technique;syringes

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