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Evolutionary divergence in life history traits among populations of the Lake Malawi cichlid fish <i>Astatotilapia calliptera</i>.

During the early stages of adaptive radiation, populations diverge in life history traits such as egg size and growth rates, in addition to eco-morphological and behavioral characteristics. However, there are few studies of life history divergence within ongoing adaptive radiations. Here, we studied <i>Astatotilapia calliptera</i>, a maternal mouthbrooding cichlid fish within the Lake Malawi haplochromine radiation. This species occupies a rich diversity of habitats, including the main body of Lake Malawi, as well as peripheral rivers and shallow lakes. We used common garden experiments to test for life history divergence among populations, focussing on clutch size, duration of incubation, egg mass, offspring size, and growth rates. In a first experiment, we found significant differences among populations in average clutch size and egg mass, and larger clutches were associated with smaller eggs. In a second experiment, we found significant differences among populations in brood size, duration of incubation, juvenile length when released, and growth rates. Larger broods were associated with smaller juveniles when released and shorter incubation times. Although juvenile growth rates differed between populations, these were not strongly related to initial size on release. Overall, differences in life history characters among populations were not predicted by major habitat classifications (Lake Malawi or peripheral habitats) or population genetic divergence (microsatellite-based <i>F</i>_ST). We suggest that the observed patterns are consistent with local selective forces driving the observed patterns of trait divergence. The results provide strong evidence of evolutionary divergence and covariance of life history traits among populations within a radiating cichlid species, highlighting opportunities for further work to identify the processes driving the observed divergence.

FST‐QST;adaptive radiation;egg size;growth rate;phenotypic plasticity

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Remote sensing appraisal of Lake Chad shrinkage connotes severe impacts on green economics and socio-economics of the catchment area.

Lake Chad commonly serves as a major hub of fertile economic activities for the border communities and contributes immensely to the national growth of all the countries that form its boundaries. However, incessant and multi-decadal drying via climate change pose greater threats to this transnational water resource, and adverse effects on ecological sustainability and socio-economic status of the catchment area. Therefore, this study assessed the extent of shrinkage of Lake Chad using remote sensing. Landsat imageries of the lake and its surroundings between 1987 and 2005 were retrieved from Global Land Cover Facility website and analysed using Integrated Land and Water Information System version 3.3 (ILWIS 3.3). Supervised classification of area around the lake was performed into various land use/land cover classes, and the shrunk part of its environs was assessed based on the land cover changes. The shrinkage trend within the study period was also analysed. The lake water size reduced from 1339.018 to 130.686 km² (4.08-3.39%) in 1987-2005. The supervised classification of the Landsat imageries revealed an increase in portion of the lake covered by bare ground and sandy soil within the reference years (13 490.8-17 503.10 km²) with 4.98% total range of increase. The lake portion intersected with vegetated ground and soil also reduced within the period (11 046.44-10 078.82 km²) with 5.40% (967.62 km²) total decrease. The shrunk part of the lake covered singly with vegetation increased by 2.74% from 1987 to 2005. The shrunk part of the lake reduced to sand and turbid water showed 5.62% total decrease from 1987 to 2005 and a total decrease of 1805.942 km² in area. The study disclosed an appalling rate of shrinkage and damaging influences on the hydrologic potential, eco-sustainability and socio-economics of the drainage area as revealed using ILWIS 3.3.

climate change;ecological sustainability;land use;remote sensing;shrinkage;socio-economics

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Prospective economic evaluation of an electronic discharge communication tool: analysis of a randomised controlled trial.

To complete an economic evaluation within a randomised controlled trial (RCT) comparing the use of an electronic discharge communication tool (eDCT) compared with usual care. Patients being discharged from a single tertiary care centre's internal medicine Medical Teaching Units. Between January 2012 and December 2013, 1399 patients were randomised to a discharge mechanism. Forty-five patients were excluded from the economic evaluation as they did not have data for the index hospitalisation cost; 1354 patients contributed to the economic evaluation. eDCT generated at discharge containing structured content on reason for admission, details of the hospital stay, treatments received and follow-up care required. The control group was discharged via traditional dictation methods. The primary economic outcome was the cost per quality-adjusted life year (QALY) gained. Secondary outcomes included the cost per death avoided and the cost per readmission avoided. The average transcription cost was $C22.28 per patient, whereas the estimated cost of the eDCT was $C13.33 per patient. The cost per QALY gained was $C239 933 in the eDCT arm compared with usual care due to the very small gains in effectiveness and approximately $C800difference in resource utilisation costs. The bootstrap analyses resulted in eDCT being more effective and more costly in 29.2% of samples, less costly and more effective in 29.2% of samples, less effective and more costly in 23.9% of samples and finally, less costly and less effective in 17.7% of samples. The eDCT reduced per patient costs of the generation of discharge summaries. The bootstrap estimates demonstrate considerable uncertainty supporting the finding of neutrality reported in the clinical component of the RCT. The immediate transcription cost savings and previously documented provider and patient satisfaction may increase the impetus for organisations to invest in such systems, provided they have a foundation of eHealth infrastructure and readiness. NCT01402609.

health economics;health policy;organisation of health services;organisational development;quality in health care

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The efficacy of vestibular electrical stimulation on patients with unilateral vestibular pathologies.

This study aims to investigate the efficacy of vestibular electrical stimulation (VES) in unilateral vestibular lesions including benign paroxysmal positional vertigo (BPPV). Between June 2007 and August 2007, a total of 19 patients diagnosed with BPPV were included in this study and they were randomized into two groups using the 1:1 method. Ten patients were administered medical treatment plus VES (treatment group; 1 male, 9 females; mean age 55.8 years; range 27 to 74 years), whereas nine patients were only administered medicine (control group; 2 males, 6 females; mean age 54.9 years; range 34 to 73 years). Both groups received the same medical treatment throughout the study. Vestibular electrical stimulation was performed for 30 min long twice a day, three times a week; 12 sessions in total with 80 Hz high-frequency Transcutaneous Electrical Nerve Stimulation (TENS). Before and after the treatment, patients' severity of dizziness was assessed with Visual Analog Scale (VAS) and daily life activities with Dizziness Handicap Inventory (DHI), and their duration (sec) of single leg stance with eyes open and closed was recorded. Compared to prior to the treatment, VAS-dizziness and DHI scores, and the duration of single leg stance on one foot with eyes open and closed at the end of the treatment showed statistically significant improvement in both groups; however, although VES provided a positive contribution, we did not find a statistically significant difference between the two groups. It can be concluded that VES has positive contribution to medical treatment of patients with dizziness due to unilateral vestibular lesions; however the results of this study should be further investigated with larger groups of patients.

Unilateral vestibular pathology;vestibular electrical stimulation;vestibular rehabilitation

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Effects of point massage of liver and stomach channel combined with pith and trotter soup on postpartum lactation start time.

Delay in lactation initiation causes maternal anxiety and subsequent adverse impact on maternal exclusive breast feeding. It is important to explore a safe and convenient way to promote lactation initiation. The feasibility of point massage of liver and stomach channel combined with pith and trotter soup on prevention of delayed lactation initiation was investigated in the present study. 320 women were enrolled and randomly divided into four groups, control group (80 women), point massage group (80 women), pith and trotter soup group (80 women), and massage + soup group (80 women) to compare the lactation initiation time. We found that women in point massage group, pith and trotter soup group and massage + soup group had earlier initiation of lactation compared with control group. Women in massage + soup group had the earliest initiation time of lactation. There were significant differences between massage + soup group and pith and trotter soup group. But, there were no significant differences between massage + soup group and massage group. We conclude that point massage of the liver and stomach channel is easy to operate and has the preventive effect on delayed lactation initiation. Impact statement What is already known on this subject: Initiation of lactation is a critical period in postpartum milk secretion. Delays in lactation initiation lead to maternal anxiety and have an adverse impact on maternal exclusive breastfeeding. Sucking frequently by babies and mammary massage might be effective but insufficient for delayed lactation initiation. What the results of this study add: We found in the present study that lactation initiation is significantly earlier in women receiving routine nursing combined with point massage of liver and stomach channel, or pith trotters soup, or massage of liver and stomach channel with pith and trotters soup than in a control group receiving routine nursing. These three methods are all effective, while the most effective method is point massage combined with pith trotter soup. There was no maternal drug allergy, postpartum bleeding or other adverse reactions noted in all women. What the implications are of these findings for clinical practice and/or further research: The present study suggested that the application of point massage in clinic might be useful for preventing lack of milk postpartum by delayed lactation initiation and improving the exclusive breastfeeding rate. Further research might explore that molecular mechanism of lactation promotion by point massage using blood samples or animal models.

Delayed lactation initiation;lactation start time;liver and stomach channel;pith and trotter soup;point massage;postpartum

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Matrix Effects and Interferences of Different Citrus Fruit Coextractives in Pesticide Residue Analysis Using Ultrahigh-Performance Liquid Chromatography-High-Resolution Mass Spectrometry.

The matrix effects of ethyl acetate extracts from seven different citrus fruits on the determination of 80 pesticide residues using liquid chromatography coupled to high-resolution time-of-flight mass spectrometry (UHPLC-(ESI)-HR-TOF) at 4 GHz resolution mode were studied. Only 20% of the evaluated pesticides showed noticeable matrix effects (ME) due to coelution with natural products between t_R = 3 and 11 min. Principal component analysis (PCA) of the detected coextractives grouped the mandarins and the orange varieties, but separated lemon, oranges, and mandarins from each other. Matrix effects were different among species but similar between varieties, forcing the determination of pesticide residues through matrix-matched calibration curves with the same fruit. Twenty-three natural products (synephrine, naringin, poncirin, glycosides of hesperitin, limonin, nomilin, and a few fatty acids, among others) were identified in the analyzed extracts. Twelve of the identified compounds coeluted with 28 of the pesticides under study, causing different matrix effects.

Citrus sp.;high-resolution time-of-flight mass spectrometry;matrix effects;natural products;pesticide residues

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Retinoic Acid Signaling in P19 Stem Cell Differentiation.

Retinoic acid (RA), especially all-trans retinoic acid is the most potent natural metabolite of vitamin A. RA is involved in a variety of biological functions including embryogenesis, cell differentiation and apoptosis. RA acts through its nuclear receptors to induce transcription of specific target genes. Mouse P19 embryonic carcinoma (EC) stem cells (ES) are one of the most studied in vitro systems for RA-induced differentiation. P19 ES cells can differentiate to endodermal-like, mesodermal-like, and neuronal-like phenotypes in response to specific morphogens including RA and dimethyl sulfoxide (DMSO). At low concentrations, RA directs P19 ES cells to differentiate into cells displaying an endodermal phenotype, whereas at higher concentrations it induces differentiation to neuroectoderm. In the past, many RA---regulated genes have been discovered in EC and ES cells and efforts are ongoing to elucidate the exact mechanisms of RA-induced ES cell differentiation and apoptosis. In the RA-triggered differentiation process of the P19 ES cells, several proteins belonging to different families participate, some being obligatory while others, dispensable. Revealing the mechanisms behind RA-induced effects on ES cells has a bearing on understanding how cells proliferate, differentiate and undergo apoptosis that can provide greater insight into cancer biology and therapy. In addition to summarizing the reports on gene/protein targets of RA in stem cells, the signaling pathways driven by some of the specific class of proteins in the presence or absence of RA in P19 ES cell differentiation, especially to an endodermal phenotype, are the focus of this review.

G-proteins;JNK.;LIM-proteins;P19 ES cell;RAR;tumor suppressors

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Short Linear Sequence Motif LxxPTPh Targets Diverse Proteins to Growing Microtubule Ends.

Microtubule plus-end tracking proteins (+TIPs) are involved in virtually all microtubule-based processes. End-binding (EB) proteins are considered master regulators of +TIP interaction networks, since they autonomously track growing microtubule ends and recruit a plethora of proteins to this location. Two major EB-interacting elements have been described: CAP-Gly domains and linear SxIP sequence motifs. Here, we identified LxxPTPh as a third EB-binding motif that enables major +TIPs to interact with EBs at microtubule ends. In contrast to EB-SxIP and EB-CAP-Gly, the EB-LxxPTPh binding mode does not depend on the C-terminal tail region of EB. Our study reveals that +TIPs developed additional strategies besides CAP-Gly and SxIP to target EBs at growing microtubule ends. They further provide a unique basis to discover novel +TIPs, and to dissect the role of key interaction nodes and their differential regulation for hierarchical +TIP network organization and function in eukaryotic organisms.

X-ray crystallography;end-binding proteins;linear motif;microtubule plus-end tracking proteins;molecular mechanism;structure-function relationship

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Purification and analysis of the composition and antioxidant activity of polysaccharides from Helicteres angustifolia L.

The antioxidant activity of polysaccharides has attracted tremendous research interest in recent years. In this study, we aimed to investigate the antioxidant properties of Helicteres angustifolia L. polysaccharides (HALP) that was acquired by water extraction and alcohol precipitation using ultrasound-assisted method with decolorization and protein removal. The polysaccharides were then successively purified using chromatography on DEAE-cellulose and Sephadex S-300 columns with two major fractions: HALPs1-1 and HALPs2-1. The physicochemical properties, structural characterization, and antioxidant activities of these fractions were investigated. The results indicated that HALPs1-1 was a glucan with an average molecular weight of 151.70kDa, and HALPs2-1 was composed of glucuronic acid with an average molecular weight of 114.81kDa. Infrared spectroscopies and iodine potassium iodide tests showed that the HALP were acid α-pyranoses. The antioxidant activities of the polysaccharide fractions (HALP, HALPs1-1, and HALPs2-1) were evaluated in vitro. The results suggested that HALPs2-1 had the highest scavenging activities for ABTS, hydroxyl and DPPH radicals than other polysaccharides. Taken together, the results of this study suggested that polysaccharides from Helicteres angustifolia L. could be used as novel potential antioxidants.

Antioxidant activity;Helicteres angustifolia L.;Polysaccharides;Purification

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Clinical Features of 24 Patients With Rebound-Associated Vertebral Fractures After Denosumab Discontinuation: Systematic Review and Additional Cases.

We aimed to study the clinical and imaging characteristics of patients sustaining vertebral fractures after denosumab discontinuation. For this purpose, we conducted a computerized advanced literature search that identified 13 published cases, and we additionally included another 11 new cases from our centers. Twenty-four postmenopausal women with vertebral fracture(s) after denosumab discontinuation, experiencing 112 fractures in total, were analyzed. The mean number of fractures per patient was 4.7. The most commonly affected vertebrae were T12 and L1. All fractures occurred 8 to 16 months after the last denosumab injection. Eighty-three percent of the patients were treatment naïve, whereas 33% had prevalent vertebral fractures. Five (23%) patients were on concurrent aromatase inhibitor treatment. When patients were divided according to treatment duration with an arbitrary cut-off of 2 years, those with ≤2 years of denosumab treatment had fewer fractures compared with those with >2 years (mean ± SEM fractures 3.2 ± 0.7 versus 5.2 ± 1.4, p = 0.055). Vertebroplasty was used in 5 patients, resulting in additional clinical vertebral fractures in all cases. We conclude that vertebral fracture(s) after denosumab discontinuation are in the majority of patients multiples, and they occur a few months after the effect of the last dose is depleted. Therefore, patients should not delay or omit denosumab doses. Fractures are typically osteoporotic, located at the lower thoracic and the upper lumbar spine. Vertebroplasty is an unsuccessful treatment strategy for such patients. © 2017 American Society for Bone and Mineral Research.

DENOSUMAB;DISCONTINUATION;FRACTURE;OSTEOPOROSIS;VERTEBRAL

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erm gene distribution among Norwegian Bacteroides isolates and evaluation of phenotypic tests to detect inducible clindamycin resistance in Bacteroides species.

The aims of this study were to describe the distribution of the most common erm genes in a collection of Norwegian Bacteroides isolates and to investigate whether the phenotypic tests for determining inducible clindamycin resistance among Bacteroides species recommended by EUCAST, NordicAST and the manufacturer of E-test^®, are effective. We investigated 175 unique Bacteroides isolates for the presence of erm(B), erm(F) and erm(G) genes, determined their minimum inhibitory concentrations (MICs) to clindamycin and categorised their susceptibility according to EUCAST breakpoints. 27 isolates were resistant to clindamycin. Furthermore, we investigated whether these recommended methods could detect inducible resistance in the Bacteroides isolates: 1) EUCAST recommendation: Dissociated resistance to erythromycin (clindamycin susceptible with erythromycin MIC > 32 mg/L), 2) NordicAST recommendation: Double disk diffusion test (DDD) or 3) Manufacturer of E-test^®'s recommendation: prolonged incubation of clindamycin E-test^® for 48 h. erm genes were detected in 30 (17%, 95% CI 12%-23%) of 175 Bacteroides isolates with erm(F) as the dominating gene. There were six (4%, 95% CI 1%-7%) of 148 clindamycin susceptible isolates harbouring erm genes, they were considered inducibly resistant to clindamycin. None of the methods for phenotypic detection of inducible clindamycin resistance performed satisfactory with sensitivities of 33%, 17% and 0% and specificities of 90%, 99% and 97% for dissociated resistance, DDD and prolonged incubation of clindamycin E-test^®, respectively. In our view, the scientific basis for investigating every Bacteroides isolate for inducible resistance to clindamycin is weak. Molecular detection of erm genes may prove a better option than the phenotypic methods we evaluated.

Bacteroides species;Clindamycin resistance;Inducible resistance;Phenotypic detection;erm genes

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A randomized controlled study of intravenous fluid in acute ischemic stroke.

To compare the outcome of patients with acute ischemic stroke who received or did not receive intravenous fluid. This study was a prospective, multicenter, randomized, open-label trial with blinded outcome assessment. We enrolled acute ischemic stroke patients without dehydration aged between 18 and 85 years with NIH Stroke Scale score (NIHSS) score from 1 to 18 who presented within 72h after onset. Patients were randomly assigned to receive 0.9% NaCl solution 100ml/h for 3days or no intravenous fluid. On the interim unblinded analysis of the safety data, significant excess early neurological deterioration was observed among patients in the non-intravenous fluid group. Therefore, the study was prematurely discontinued after enrollment of 120 patients, mean age 60 years, 56.6% male. Early neurological deterioration (increased NIHSS ≥3 over 72h) not of metabolic or hemorrhagic origin was observed in 15% of the non-IV fluid group and 3.3% of the IV fluid group (p=0.02). Predictors of neurological deterioration were higher NIHSS score, higher plasma glucose, and increased pulse rate. There was no difference in the primary efficacy outcome, NIHSS≤4 at day 7, 83.3% vs 86.7%, p=0.61 or secondary efficacy outcomes. Administration of 0.9% NaCl 100ml/h for 72h in patients with acute ischemic stroke is safe and may be associated with a reduced risk of neurological deterioration. These study findings support the use of intravenous fluid in acute ischemic stroke patients with NIHSS less than 18 who have no contraindications.

Intravenous fluid;Ischemic stroke;Progressive stroke;Stroke in evolution

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An updated meta-analysis of the asporin gene D-repeat in knee osteoarthritis: effects of gender and ethnicity.

Knee osteoarthritis (KOA) is the most prevalent form of knee joint disease and characterized by the progressive degeneration of articular cartilage. Although pathology of KOA remains unknown, genetic factors are considered to be the major cause. Asporin is a group of biologically active components of extracellular matrix (ECM) in articular cartilage, and asporin gene (ASPN) D-repeat polymorphism was reported to be associated with KOA. Thus, our meta-analysis is aimed at investigation of the association between asporin D-repeat polymorphism and susceptibility of KOA. We gathered data from MEDLINE, Embase, OVID, and ScienceDirect to search relevant published epidemiological studies through April 2017. Compared with previous studies, our meta-analysis is the first study to investigate the association of ASPN D15, D16, and D17 alleles and KOA susceptibility by ethnic- and sex-stratified subgroup analysis. We found no significant association between D15 allele and susceptibility to KOA (OR = 1.05, 95% CI 0.95-1.17) in overall population. The same results were observed in the analysis of D16 (OR = 1.01, 95% CI 0.80-1.28) and D17 alleles (OR = 1.28, 95% CI 0.91-1.80). The ethnic- and sex-subgroup analyses did not alter the ORs. However, significant association was detected in the sensitivity analysis of D17 in overall population (OR = 1.05, 95% CI 0.95-1.17) and Asian population (OR = 1.78, 95% CI 1.02-3.11, P < 0.05). Our results indicated that D-repeat polymorphism of ASPN may not play a major role in susceptibility of KOA in ethnic- and sex-specific analysis. Because of the limitations of the present meta-analysis, firm conclusions could not be drawn based on the current evidence, and further studies are required to detect genuine role of ASPN.

Aspartic acid;Ethnicity;Gender;Knee;Meta-analysis;Osteoarthritis;Polymorphism

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Cloning and Characterization of Two Iridoid Synthase Homologs from Swertia Mussotii.

<i>Swertia mussotii</i> is an important medicinal plant found on the Qinghai Tibetan Plateau that has great economic and medicinal value. This plant has enjoyed a long history of use as a curative for hepatitis. The biological activity of secoiridoids, including gentiopicroside and swertiamarin, has been mainly tested for its anti-hepatitis effects. Here, we identify two candidate genes (<i>SmIS1</i> and <i>SmIS2</i>) that are homologues of iridoid synthase and that are components of the secoiridoid pathway in <i>S. mussotii</i>. Using sequencing and phylogenetic analyses, we confirm that SmIS1 and SmIS2 contain six conserved short-chain dehydrogenases/reductase (SDR) motifs and thus belong to the P5βRs group. The two purified <i>Escherichia coli</i>-expressed proteins reduced 8-oxogeranial to both nepetalactol and iridodials. A comparison of the kinetic parameters of SmIS1 and SmIS2 recombinant proteins revealed that SmIS2 has a lower affinity than SmIS1 for 8-oxogeranial. Transcript levels of the two genes were analysed in three different tissues of <i>S. mussotii</i> using semi-quantitative RT-PCR and RT-qPCR. SmIS1 and SmIS2 expression levels were more abundant in leaves and stems. This investigation adds to our knowledge of <i>P5βRs</i> genes in the secoiridoid synthesis pathway and provides candidate genes for genetically improving <i>S. mussotii</i> by enhancing secondary metabolite production.

Swertia mussotii;functional characterization;heterologous expression;iridoid synthase;medicinal plant;progesterone 5-β-reductase;secoiridoid biosynthesis

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Functional status mediates the association between peripheral neuropathy and health-related quality of life in individuals with diabetes.

To examine differences in health-related quality of life (HRQoL) between patients with and without diabetic peripheral neuropathy (DPN), and whether these differences can be explained by functional deficits. This was a cross-sectional study of 160 patients with type 2 diabetes mellitus, 80 with DPN and 80 without. Assessments included HRQoL (health utility score derived from EQ-5D-5L), functional status measurements [muscle strength, timed up and go (TUG), five times sit-to-stand (FTSTS), functional reach, body sway velocity] and self-reported balance confidence [Activities-specific Balance Confidence (ABC) scale]. Mean utility scores were 0.67 ± 0.14 and 0.77 ± 0.16 in patients with and without DPN, respectively (p < 0.001). Patients with DPN had lower great toe extensor strength (6.4 ± 1.8 vs 7.6 ± 2.8 lbs, p = 0.001), greater body sway velocity (2.40 ± 1.31 vs 1.90 ± 0.52 mm/s, p = 0.002), slower TUG (12.1 ± 4.6 vs 10.1 ± 2.3 s, p < 0.001) and FTSTS (15.8 ± 5.8 vs 13.9 ± 5.4 s, p = 0.03) scores, and lower ABC score (73.4 ± 21.3 vs 82.6 ± 16.9, p = 0.003), compared to those without DPN. On stepwise multiple regression, DPN status, FTSTS, body sway velocity, BMI, diabetes duration, pain, and gender explained 38% of HRQoL variance. Addition of ABC score into the model explained 45% of variance. Results from structural equation modelling showed that DPN had direct effects on HRQoL and indirect effects through FTSTS, body sway velocity, and ABC score, with χ ² = 8.075 (p = 0.044), root mean square error of approximation = 0.103 (lower bound 0.015, upper bound 0.191), Comparative Fit Index = 0.966, Tucker-Lewis Index = 0.887, and Standardized Root Mean Square Residual = 0.053. Patients with DPN have worse HRQoL compared to patients without DPN, partly mediated by functional status parameters. Effective interventions targeting functional status may be beneficial in improving HRQoL in these patients.

Diabetic polyneuropathy;Functional status;Health-related quality of life;Muscle strength;Postural balance;Range of motion;Type 2 diabetes mellitus

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Role of Trace Elements, Oxidative Stress and Immune System: a Triad in Premature Ovarian Failure.

The risk of premature ovarian failure (POF) increases in association with alteration in immunological parameters and oxidative stress (OS). Adequate intake of trace elements is required for antioxidant property and immune defense mechanism. The aim of this study was to explore the involvement of trace elements, OS, and immunological parameters in POF. This was a cross-sectional, case-control study, involving 65 participants divided into the POF (n = 35) and control (n = 30) groups. Serum levels of Se, Zn, and Cu were determined along with hormonal, OS, and immunological markers. POF group had significantly lower levels of Zn, Cu, Se, and Zn:Cu ratio. However, Se:Cu ratio was not significant between the groups. FSH and LH levels were negatively correlated with Zn and Cu levels and positively correlated with Se levels. Estrogen levels were negatively correlated with all the studied trace elements. Inter-element association between Zn and Se was significant in POF (r = - 0.39, p = 0.02) compared to control group (r = - 0.078, p = 0.65). In all the POF patients, SOD and GPx activities were significantly (p < 0.05) lower and MDA level was higher (p > 0.05) than control group. B cell marker CD19 was significantly (p < 0.0001) high in POF group. There are involvement of trace elements in hormonal regulation and antioxidant defense mechanism, which once gets altered leads to high ROS generation and affect functions of the immune system. Exaggereative immune system causing higher expression of B cell associated markers (CD19) leading to autoimmune condition in POF.

B cells;Plasma mass spectrometry;Premature ovarian failure;Reactive oxygen species;Trace elements

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Trade Policy and Health: Adding Retrospective Studies to the Research Agenda Comment on "The Trans-Pacific Partnership: Is It Everything We Feared for Health?"

Prospective studies of the potential health consequences of trade and investment treaties, such as the Trans-Pacific Partnership, are critical. These studies can make visible to trade policy-makers the potential negative impacts associated to such treaties and can influence the outcomes of such negotiations. However, few researchers have examined retrospectively the consequences of trade agreements. With more than 400 trade agreements and more than 2000 investment treaties currently in force, researchers have a large corpus of agreements to analyse in order to assess not only their potential impacts on health system and population health, but also their actual impacts. This comment suggests some research questions that would benefit from retrospective inquiry.

Population Health;Regulatory Chill;Social and Political Determinants of Health;Trade and Investment Policy

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Kyoto Congestive Heart Failure (KCHF) study: rationale and design.

Over the last decade, major developments in medicine have led to significant changes in the clinical management of heart failure patients. This study was designed to evaluate the recent trends in clinical characteristics, management, and short-term and long-term prognosis of patients with acute decompensated heart failure (ADHF) in Japan. The Kyoto Congestive Heart Failure study is a prospective, observational, multicentre cohort study, enrolling consecutive ADHF patients from 19 participating hospitals in Japan from November 2014 to March 2016. A total of 4000 patients will be enrolled into the study and patients' anthropometric, socio-economic, and clinical data from hospital admission to discharge will be collected. In addition, in a pre-determined subgroup of patients (n=1500), a longitudinal follow-up for 2 years is scheduled. The Kyoto Congestive Heart Failure study will provide valuable information regarding patients with ADHF in the real-world clinical practice of Japan and will be indispensable for future clinical and policy decision-making with respect to heart failure.

Cohort study;Decompensation;Heart failure;Prognosis

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Influence of ulceration etiology on the global quality of life and its specific dimensions, including the control of pain, in patients with lower limb vascular insufficiency.

The results of previous studies suggest that the quality of life in patients with lower limb ulcerations is markedly poorer than in the general population - with regard to physical, mental and social spheres. This complex character of that parameter necessitates comprehensive analyses of its specific aspects, including the level of the acceptance of illness and associated pain symptoms. To compare the quality of life and its specific dimensions in patients with lower limb ulcerations of various etiology. Patients with the ulcerations resulting from venous (<i>n</i> = 101) or arterial pathologies (<i>n</i> = 98), or having mixed etiology (<i>n</i> = 99) were examined with the: 1) Skindex-29 instrument, 2) Acceptance of Illness Scale, 3) Beliefs about Pain Control Questionnaire, and 4) Coping Strategy Questionnaire. The average quality of life related to physical symptoms was significantly higher in patients with venous ulcerations. Patients with ulcerations of arterial etiology more frequently used catastrophizing, and less often ignored pain sensations, used coping self-statements, and increased their activity levels; they were characterized by lower levels of control and poorer ability to decrease the pain. The internal locus of pain control increased proportionally to the global quality of life scores and levels of illness acceptance. Control over pain and ability to decrease the pain were more effective in individuals who used ignoring pain sensations, increasing the activity level, coping self-statements, and reinterpreting pain than in those using catastrophizing or praying and hoping strategies. Physical complaints seem to be the basic determinant of the quality of life in patients with the lower limb ulceration, irrespective of its etiology.

Skindex-29;pain control;quality of life;ulceration

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The Role of Robotics in the Invasive Management of Bladder Cancer.

Robot-assisted radical cystectomy (RARC) has been adopted widely in many centres, owed largely to the success of robot-assisted laparoscopic prostatectomy (RALP). It aims to replicate the oncological outcomes of open radical cystectomy (ORC), while providing a shorter recovery period. Despite this, previous RCTs have failed to show a benefit for RARC over ORC. These trials have compared extracorporeal RARC (eRARC) with ORC, which requires a further incision to mobilise the bowel for urinary reconstruction with an open technique. For intracorporeal RARC (iRARC), this urinary reconstruction is performed robotically without further incisions. There are theoretical benefits to this approach such as reduced recovery time for the bowel and reduced ileus rates, but no level 1 evidence currently exists to support this. While there has been an improvement in patient outcomes since the adoption of RARC, various other factors, such as enhanced recovery programmes and surgical learning curve, have made it difficult to attribute this solely to the robotic approach as many centres performing ORC have also shown similar improvements. In this review, we will discuss implementation of RARC as well as perioperative measures that have helped improve outcomes, offer a comparison of outcomes between ORC and RARC and highlight upcoming RCTs that may offer new evidence for or against a paradigm shift in the future of bladder cancer surgery.

Bladder cancer;Enhanced recovery;Extracorporeal;Intracorporeal;Robotic cystectomy

pubmed

Metabolic Syndrome in Psoriasis among Urban South Indians: A Case Control Study Using SAM-NCEP Criteria.

Psoriasis is a chronic inflammatory disease of the skin associated with increased cardiovascular morbidity. Metabolic syndrome is a significant forecaster of cardiovascular events. To assess the association of metabolic syndrome and its components in patients with psoriasis and to compare it with the age and sex matched control group. We conducted a hospital based case-control study on 156 adult patients with chronic plaque psoriasis and 156 patients with skin diseases other than psoriasis. Height, weight, BMI, blood pressure and waist circumference were documented in all the subjects. Fasting levels of serum glucose, serum triglycerides and serum HDL were estimated by automated clinical chemistry analyzer. The South Asian modified NCEP ATP criterion was used for the diagnosis of metabolic syndrome. Statistical analysis of the data was done using statistical processing software (SPSS-17). Metabolic syndrome was significantly more common in psoriatic patients than in controls (28.8% vs 16.7%, p=0.01). Hypertriglyceridemia was significantly more prevalent in cases than in controls (34% vs 20.5%, p=0.008). The reduced HDL levels also showed a significantly high occurrence among cases (27.6% vs 13.5%, p=0.002). Moderate increase of blood pressure was seen among cases as compared to controls but the difference was not statistically significant (p=0.1). Impaired blood glucose and abdominal obesity were similar in both groups. Smoking and alcoholism did not influence the association of metabolic syndrome with psoriasis. There was no correlation of metabolic syndrome with severity and duration of psoriasis. Our findings suggest that metabolic syndrome as well as dyslipidemia is common in psoriasis patients among urban South Indians. This study highlights the need for screening at diagnosis and regular follow up of the metabolic aspects of the disease along with the skin lesions.

High density lipid;Smoking;Triglycerides

pubmed

β Cell Aging Markers Have Heterogeneous Distribution and Are Induced by Insulin Resistance.

We hypothesized that the known heterogeneity of pancreatic β cells was due to subpopulations of β cells at different stages of their life cycle with different functional capacities and that further changes occur with metabolic stress and aging. We identified new markers of aging in β cells, including IGF1R. In β cells IGF1R expression correlated with age, dysfunction, and expression of known age markers p16^ink4a, p53BP1, and senescence-associated β-galactosidase. The new markers showed striking heterogeneity both within and between islets in both mouse and human pancreas. Acute induction of insulin resistance with an insulin receptor antagonist or chronic ER stress resulted in increased expression of aging markers, providing insight into how metabolic stress might accelerate dysfunction and decline of β cells. These novel findings about β cell and islet heterogeneity, and how they change with age, open up an entirely new set of questions about the pathogenesis of type 2 diabetes.

aging markers;beta-cell heterogeneity;islets

pubmed

Fishing-induced changes in adult length are mediated by skipped-spawning.

Elucidating fishing effects on fish population dynamics is a critical step toward sustainable fisheries management. Despite previous studies that have suggested age or size truncation in exploited fish populations, other aspects of fishing effects on population demography, e.g., via altering life histories and density, have received less attention. Here, we investigated the fishing effects altering adult demography via shifting reproductive trade-offs in the iconic, overexploited, Pacific bluefin tuna Thunnus orientalis. We found that, contrary to our expectation, mean lengths of catch increased over time in longline fisheries. On the other hand, mean catch lengths for purse seine fisheries did not show such increasing trends. We hypothesized that the size-dependent energetic cost of the spawning migration and elevated fishing mortality on the spawning grounds potentially drive size-dependent skipped spawning for adult tuna, mediating the observed changes in the catch lengths. Using eco-genetic individual-based modeling, we demonstrated that fishing-induced evolution of skipped spawning and size truncation interacted to shape the observed temporal changes in mean catch lengths for tuna. Skipped spawning of the small adults led to increased mean catch lengths for the longline fisheries, while truncation of small adults by the purse seines could offset such a pattern. Our results highlight the eco-evolutionary dynamics of fishing effects on population demography and caution against using demographic traits as a basis for fisheries management of the Pacific bluefin tuna as well as other migratory species.

Pacific bluefin tuna, Thunnus orientalis;adult demography;eco-genetic individual-based modeling;fisheries selectivity;fishing-induced evolution;life history trade-offs

pubmed

Perceptions and Expected Immediate Reactions to Severe Storm Displays.

The National Weather Service has adopted warning polygons that more specifically indicate the risk area than its previous county-wide warnings. However, these polygons are not defined in terms of numerical strike probabilities (p_s ). To better understand people's interpretations of warning polygons, 167 participants were shown 23 hypothetical scenarios in one of three information conditions-polygon-only (Condition A), polygon + tornadic storm cell (Condition B), and polygon + tornadic storm cell + flanking nontornadic storm cells (Condition C). Participants judged each polygon's p_s and reported the likelihood of taking nine different response actions. The polygon-only condition replicated the results of previous studies; p_s was highest at the polygon's centroid and declined in all directions from there. The two conditions displaying storm cells differed from the polygon-only condition only in having p_s just as high at the polygon's edge nearest the storm cell as at its centroid. Overall, p_s values were positively correlated with expectations of continuing normal activities, seeking information from social sources, seeking shelter, and evacuating by car. These results indicate that participants make more appropriate p_s judgments when polygons are presented in their natural context of radar displays than when they are presented in isolation. However, the fact that p_s judgments had moderately positive correlations with both sheltering (a generally appropriate response) and evacuation (a generally inappropriate response) suggests that experiment participants experience the same ambivalence about these two protective actions as people threatened by actual tornadoes.

Protective actions;risk perceptions;tornado warning polygons

pubmed

The design and SAR of a novel series of 2-aminopyridine based LRRK2 inhibitors.

Leucine-rich repeat kinase 2 (LRRK2) has attracted considerable interest as a therapeutic target for the treatment of Parkinson's disease. Compounds derived from a 2-aminopyridine screening hit were optimised using a LRRK2 homology model based on mixed lineage kinase 1 (MLK1), such that a 2-aminopyridine-based lead molecule 45, with in vivo activity, was identified.

2-Aminopyridines;Homology model;Kinativ;LRRK2;Parkinson’s

pubmed

All trans retinoic acid depresses the content and activity of the mitochondrial ATP synthase in human keratinocytes.

Proteomic analysis shows that treatment of keratinocytes cultures with all trans retinoic acid (ATRA), under condition in which it inhibits cell growth, results in marked decrease of the level of the F1-β subunit of the catalytic sector of the mitochondrial FoF1 ATP synthase complex. Enzymatic analysis shows in ATRA-treated keratinocytes a consistent depression of the ATPase activity, with decreased olygomycin sensitivity, indicating an overall alteration of the ATP synthase complex. These findings, together with the previously reported inhibition of respiratory complex I, show that depression of the activity of oxidative phosphorylation enzymes is involved in the cell growth inhibitory action of ATRA.

ATP synthase;All-trans retinoic acid;Human keratinocytes;Mass spectrometry;Proteomics

pubmed

Chemical characterization of Myrciaria floribunda (H. West ex Willd) fruit.

M. floribunda fruit was studied to characterize its chemical composition. The chemical composition, bioactive compounds, antioxidant activity and volatiles of the fruit were determined. The chemical composition was determined according to AOAC and AOCS, the bioactive compounds by HPLC, the volatiles by GCMS and the antioxidant activity by ABTS⁺ and DPPH methods. The chemical composition of the freeze-dried fruit was 1.89 g·100 g^-1, 2.43 g·100 g^-1, 4.78 g·100 g^-1 and 90.89 g·100 g^-1 of ashes, lipids, proteins and total carbohydrates on a dry base, respectively. The concentration of the carotenoids was 52.22 mg·100 g^-1 and for the flavonoid rutin was 78.56 mg·100 g^-1. The gallic and ellagic acid contents were 5.45 mg·g^-1 and 2.21 mg·g^-1, respectively. The cis-β-ocimene corresponded to 50.90% of the volatiles. The antioxidant activity by ABTS⁺ method was 550.14 µmol Trolox·g^-1 and by the DPPH method the EC₅₀ was 85.68 g·g^-1. The fruits presented relevant antioxidant activity, a high concentration of carotenoids and of rutin.

Carotenoids;Myrtaceae;Phenolic acids

pubmed

Differential effect of Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) on leukocyte infiltration during contact hypersensitivity responses.

2'-4' Dinitrofluorobenzene (DNFB) induced contact hypersensitivity is an established model of contact sensitivity and leukocyte migration. Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) deficient mice were used to examine the role of PECAM-1 in the migration capacity of several different leukocyte populations after primary and secondary application. γδ T lymphocytes, granulocytes, and Natural Killer cells were most affected by PECAM-1 deficiency at the primary site of application. γδ T lymphocytes, granulocytes, DX5+ Natural Killer cells, and, interestingly, effector CD4+ T lymphocytes were most affected by the loss of PECAM-1 at the secondary site of application. PECAM-1 is used by many leukocyte populations for migration, but there are clearly differential effects on the usage by each subset. Further, the overall kinetics of each population varied between primary and secondary application, with large relative increases in γδ T lymphocytes during the secondary response.

CD4+ T lymphocytes;Contact Hypersensitivity;Emigration;Granulocytes;Leukocyte;Monocytes;Natural Killer Lymphocytes;Platelet Endothelial Cell Adhesion Molecule-1;γδT lymphocytes

pubmed

Simultaneous use of caustic and oxygen for efficient sulfide control in sewers.

Periodic caustic shock-loading is a commonly used method for sulfide control in sewers. Caustic shock-loading relies on the elevation of the sewage pH to ≥10.5 for several hours, thereby removing sewer pipe biofilms as well as deactivating SRB activity in the remaining biofilm. Although a widely used method, SRB activity is often not completely inhibited, and as such sulfide is still being generated. Here, we propose and experimentally demonstrate an innovative approach which combines caustic with oxygen, another commonly used method, as a dosing strategy for overcoming the drawbacks of caustic shock-loading. Six laboratory-scale rising main reactors were subjected to three dosing schemes over a period of three months, namely (i) simultaneous caustic and oxygen addition, (ii) caustic addition and (iii) no chemical addition. Our results showed that the combination of caustic and oxygen achieved efficient sulfide control, leading to a prolonged biofilm recovery period in between caustic shocks. In addition, methane emissions were reduced to a negligible level compared to caustic treatment only. To translate the findings to real-life application, the key parameters obtained during the long-term lab-scale experiments were subjected to extensive simulation studies using the SeweX model under a wide range of conditions commonly found in sewers. Overall, this study highlights the potential of periodic shock-loading and intermittent oxygen injection as combined dosing strategy for efficient sulfide control in sewers.

Caustic shock-loading;Dynamic modelling;Oxygen;Sewer corrosion;Sulfate reducing bacteria;Sulfide abatement

pubmed

The immunological personality of close relatives of SLE patients.

Immunological abnormalities seen in relatives of patients with autoimmune disorders can be useful in understanding the pathogenesis of the disease since, unlike in patients, they cannot result from the disease process or drug treatment. In this article we present a brief overview of our studies of the basic immunological status of close relatives of SLE patients. We looked at blood levels of IgG, IgM and antibodies to double-stranded DNA, as well as at NK cell numbers and cytotoxic activity and the levels of NKT, B and T cells. As many as 60% of relatives showed one or more abnormalities in these assays. Most notably there were increased levels of IgG in male and female relatives and a reduction of IgM in females. IgG correlated inversely with NKT cell numbers adding strength to the concept that the presence of IgG autoantibodies in patients is due to impaired regulation by NKT cells. IgM, on the other hand, correlated inversely with NK cells which may thus have a role in bringing about the reduced IgM seen in some patients. Immunological abnormalities were found to be more often associated with parents and offspring of patients than with their siblings, pointing to the involvement of environmental or epigenetic influences in lupus pathogenesis.

NK and NKT cells;Relatives of lupus patients;immunoglobulin regulation;immunological abnormalities;lupus pathogenesis

pubmed

Toll-Like Receptor Ligands and Interferon-γ Synergize for Induction of Antitumor M1 Macrophages.

Tumor-associated macrophages may either promote or suppress tumor growth depending on their activation status. Interferon-γ (IFN-γ) has been identified as a key factor for inducing tumoricidal M1 phenotype in macrophages. However, it remains unclear whether IFN-γ is sufficient or if additional stimuli are required. Here, we tested IFN-γ and a panel of toll-like receptor (TLR) agonists for the ability to activate murine macrophages toward a tumoricidal M1 phenotype. The following TLR ligands were used: TLR1/TLR2 agonist Pam3CSK4, TLR2/TLR6 agonist lipotechoic acid, TLR3 agonist poly(I:C), TLR4 agonist lipopolysaccharide (LPS), TLR5 agonist flagellin, TLR7 agonist CL264, and TLR9 agonist CpG. We used an <i>in vitro</i> growth inhibition assay to measure both cytotoxic and cytostatic activity of mouse macrophages against Lewis lung carcinoma (LLC) and MOPC315 plasmacytoma tumor cells. Production of nitric oxide (NO) and cytokines by activated macrophages was quantified. We found that IFN-γ alone was not able to render macrophages tumoricidal. Similarly, macrophage activation with single TLR agonists was inefficient. In sharp contrast, IFN-γ was shown to synergize with TLR agonists for induction of macrophage tumoricidal activity and production of both NO and pro-inflammatory cytokines (TNF-α, IL-12p40, and IL-12p70). Furthermore, IFN-γ was shown to suppress macrophage IL-10 secretion induced by TLR agonists. NO production was necessary for macrophage tumoricidal activity. We conclude that two signals from the microenvironment are required for optimal induction of antitumor M1 macrophage phenotype. Combination treatment with IFN-γ and TLR agonists may offer new avenues for macrophage-based cancer immunotherapy.

cancer;immunotherapy;interferon-γ;macrophages;nitric oxide;toll-like receptors;tumoricidal

pubmed

A Microarray Immunoassay for Serum Thyrotropin and Thyroglobulin Using Antibodies Immobilized on Track-Etched Membranes.

Serum thyroglobulin (Tg) and thyroid stimulating hormone (TSH) measurements have evolved as important analytes for monitoring the prognosis of patients with differentiated thyroid cancer, post-thyroidectomy. Individual analyte immunoassay is the current practice in clinical pathology, but the simultaneous assay for all relevant analytes for a given disease, can reduce assay costs, improve patient compliance and give the clinician more information for an unequivocal diagnosis. Microarray immunoassay (MI) can achieve this goal and, hence, we have developed and validated a immuno-radiometric MI for quantitation of serum TSH and Tg by using highly micro-porous polycarbonate (PC) track-etched membranes (TEM) to immobilize the monoclonal anti-TSH and polyclonal anti-Tg antibodies in ~1 mm diameter spots. Non-competitive immunoassays were performed using mixture of ¹²⁵I labeled monoclonal anti-TSH and anti-Tg antibodies. Phosphorimager was used to quantify the bound radioactivity. TSH and Tg were detected with detection limit of 0.07 µIU/ml and 0.13 ng/ml respectively, which is lower than the clinically required cut-off level. The assay showed: acceptable intra-assay precision within 20 % and recovery in the range of 76-111.2 %. MI compared well with the established immunoradiometric assay (IRMA) with r = 0.98, <i>p</i> < 0.01 (n = 41). No cross-reactivity was seen between the immobilized antibodies. Although two hormones are addressed in this report, MI using PC TEM and isotopic/non-isotopic tracers has the potential for highly automated multiplexed analysis.

Antibody chip;Microarray immunoassay;Thyroglobulin;Thyroid stimulating hormone;Track-etched membranes

pubmed

Nuclear localization and transactivation by Vitis CBF transcription factors are regulated by combinations of conserved amino acid domains.

The highly conserved CBF pathway is crucial in the regulation of plant responses to low temperatures. Extensive analysis of Arabidopsis CBF proteins revealed that their functions rely on several conserved amino acid domains although the exact function of each domain is disputed. The question was what functions similar domains have in CBFs from other, overwintering woody plants such as Vitis, which likely have a more involved regulation than the model plant Arabidopsis. A total of seven CBF genes were cloned and sequenced from V. riparia and the less frost tolerant V. vinifera. The deduced species-specific amino acid sequences differ in only a few amino acids, mostly in non-conserved regions. Amino acid sequence comparison and phylogenetic analysis showed two distinct groups of Vitis CBFs. One group contains CBF1, CBF2, CBF3 and CBF8 and the other group contains CBF4, CBF5 and CBF6. Transient transactivation assays showed that all Vitis CBFs except CBF5 activate via a CRT or DRE promoter element, whereby Vitis CBF3 and 4 prefer a CRT element. The hydrophobic domains in the C-terminal end of VrCBF6 were shown to be important for how well it activates. The putative nuclear localization domain of Vitis CBF1 was shown to be sufficient for nuclear localization, in contrast to previous reports for AtCBF1, and also important for transactivation. The latter highlights the value of careful analysis of domain functions instead of reliance on computer predictions and published data for other related proteins.

CBF pathway;Nuclear localization signal;Transactivation;Vitis species

pubmed

A Survey on Mental Health Status of Adult Population Aged 15 and above in the Province of Ardebil, Iran.

The main objective of this study was to determine the mental health status of population aged 15 and over in the province of Ardebil in 2015. The statistical population of this cross-sectional field survey consisted of residents of urban and rural areas of Ardebil province in Iran. An estimated sample size of 1200 people were chosen using systematic random cluster sampling. Access was provided by the contribution of Geographical Post Office of Ardebil, Pars abad and Germi cities. The General Health Questionnaire-28 (GHQ-28) was used as the screening tool for mental disorders. Data analysis in the current study was carried out using the SPSS-18 software. Using GHQ traditional scoring method, the results showed that 21.4% of individuals (26.3% of females and 16.5% of males) were suspected of mental disorders. The prevalence of suspected cases of mental disorders was 20.8% in urban and 22.8% in rural areas. The results also showed that somatization and anxiety symptoms were more prevalent than social dysfunction and depression symptoms, and were more common in women than men. The results of this research also showed that the prevalence of suspected cases of mental disorders increased with aging. Such disorders were more common in females, age group of 65 and above, people living in rural areas, divorced and widowed, illiterate and unemployed individuals compared with other groups. The results of this study showed that about one fifth of people in the province were suspected of mental disorders. Therefore, it is mandatory for the provincial public health authorities to take the needed steps to ensure that necessary requirements encompassing prevention and promotion of mental health are implemented.

Adult population;Ardebil province;general health questionnaire (GHQ-28);mental health status

pubmed

Extended locoregional use of intercostal artery perforator propeller flaps.

Besides conventional flaps, intercostal artery perforator flaps have been reported to cover trunk defects. In this report the use of anterior intercostal artery perforator (AICAP) flap, lateral intercostal artery perforator (LICAP) flap and dorsal intercostal artery perforator (DICAP) flap for thoracic, abdominal, cervical, lumbar and sacral defects with larger dimensions and extended indications beyond the reported literature were reevaluated. Thirty-nine patients underwent surgery between August 2012 and August 2014. The age of the patients ranged between 16 and 79 with a mean of 49 years. The distribution of defects were as follows; 12 thoracic, 8 parascapular, 3 cervical, 8 abdominal, 4 sacral and 4 lumbar. AICAP, LICAP and DICAP flaps were used for reconstruction. Fifty-two ICAP flaps were performed on 39 patients. Flap dimensions ranged between 6 × 9 cm and 14 × 35 cm. Twenty-six patients had single flap coverage and 13 patients had double flap coverage. Forty-six flaps have been transferred as propeller flaps and 6 flaps have been transferred as perforator plus flap. Forty flaps (75%) went through transient venous congestion. In one DICAP flap, 30% of flap was lost. No infection, hematoma or seroma were observed in any patient. Follow-up period ranged between 3 and 32 months with a mean of 9 months. The ICAP flaps provide reliable and versatile options in reconstructive surgery and can be used for challenging defects in trunk.

intercostal artery perforator flaps;propeller flaps;trunk reconstruction

pubmed

HCV-Related Rheumatic Manifestations and Therapeutic Strategies.

A number of hepatic and extra-hepatic autoimmune disorders may complicate a percentage of patients with hepatitis C virus (HCV) infection that is both hepatotropic and lymphotropic agent; the resulting clinical phenotypes can be grouped into the so-called HCV syndrome. This latter includes various rheumatic disorders that are frequently characterized by clinical or serological overlap; thus, a correct patients' classification is necessary prior to decide the therapy. The management of these conditions is particularly difficult, given the coexistence of viral infection and immunological alterations. In this scenario, cryoglobulinemic vasculitis represents the prototype of HCV-related rheumatic disorders that can be treated at different levels by means of etiological (antivirals) and/or pathogenetic and/or symptomatic treatments (rituximab, cyclophosphamide, steroids, plasmapheresis, etc). In clinical practice, the therapeutic strategy should take into account the specific symptoms combination and the severity/activity of the disease, according to each patient's conditions. This review focuses on the clinico-diagnostic assessments and therapeutical approaches of some rheumatic disorders complicating HCV infection, mainly arthritis, sicca syndrome, and osteosclerosis; while, cryoglobulinemic vasculitis is comprehensively examined in another article of the present issue.

HCV;Hepatitis C virus;Sjögren's syndrome;antiviral;arthritis;lymphoma;mixed cryoglobulinemia;ostesclerosis;rituximab;vasculitis

pubmed

Sphingolipid-Enriched Extracellular Vesicles and Alzheimer's Disease: A Decade of Research.

Extracellular vesicles (EVs), particularly exosomes, have emerged in the last 10 years as a new player in the progression of Alzheimer's disease (AD) with high potential for being useful as a diagnostic and treatment tool. Exosomes and other EVs are enriched with the sphingolipid ceramide as well as other more complex glycosphingolipids such as gangliosides. At least a subpopulation of exosomes requires neutral sphingomyelinase activity for their biogenesis and secretion. As ceramide is often elevated in AD, exosome secretion may be affected as well. Here, we review the available data showing that exosomes regulate the aggregation and clearance of amyloid-beta (Aβ) and discuss the differences in data from laboratories regarding Aβ binding, induction of aggregation, and glial clearance. We also summarize available data on the role of exosomes in extracellular tau propagation, AD-related exosomal mRNA/miRNA cargo, and the use of exosomes as biomarker and gene therapy vehicles for diagnosis and potential treatment.

Alzheimer’s disease;amyloid;biomarker;ceramide;exosome;miRNA;sphingomyelinase;tau;vesicle

pubmed

Which blood pressure measurement, systolic or diastolic, better predicts future hypertension in normotensive young adults?

The impact of age-related differences in blood pressure (BP) components on new-onset hypertension is not known. A follow-up examination of 93 303 normotensive individuals (mean age 41.1 years) who underwent a health checkup in 2005 was conducted every year for 8 years. The primary end point was new-onset hypertension (systolic BP [SBP]/diastolic BP [DBP] ≥140/90 mm Hg and/or the initiation of antihypertensive medications with self-reported hypertension). During the mean 4.9 years of follow-up, 14 590 subjects developed hypertension. The impact of DBP on the risk of developing hypertension compared with optimal BP (SBP <120 mm Hg and DBP <80 mm Hg) was significantly greater than that of SBP in subjects younger than 50 years (hazard ratios, 17.5 for isolated diastolic high-normal vs 10.5 for isolated systolic high-normal [P<.001]; 8.0 for isolated diastolic normal vs 4.1 for isolated systolic normal [P<.001]). Among the subjects 50 years and older, the corresponding effects of DBP and SBP were similar. Regarding the risk of new-onset hypertension, high DBP is more important than SBP in younger adults (<50 years) with normal or high-normal BP.

blood pressure;diastolic blood pressure;follow-up study;hypertension;prehypertension

pubmed

In Situ Single-Molecule RNA Genotyping Using Padlock Probes and Rolling Circle Amplification.

Present-day techniques allow for massively parallel and high-throughput characterization of the somatic mutation status of samples. Most of these assays rely on whole specimen extracts, where heterogeneous spatial context of the specimen is lost. This chapter describes an up-to-date protocol for multiplexed, in situ genotyping of RNA in preserved tissue and cell lines, using padlock probes and rolling circle amplification. The presented approach allows for automated quantification of mRNA expression and mutation status, in single cells or in designated specimen areas. Briefly, mRNA is first reverse-transcribed to cDNA. Padlock probes specifically hybridize to the cDNA copy of the allele and become circularized and thereby physically linked to their targets. Following this conversion, padlock probes are copied in situ by rolling circle amplification and labeled with flourophore-conjugated probes, allowing for their detection with conventional fluorescence microscopy.

In situ;Padlock probe;Single cell;mRNA genotyping

pubmed

Long-term postpartum effect of severe maternal morbidity on sexual function.

There was limited knowledge on the sexual function in women who have survived severe obstetric complications. The aim of this study was to compare the level of sexual functioning among women with and without severe morbidity at six months postpartum and to identify the factors associated with sexual function scores of women. A prospective double-cohort study design was applied at two tertiary hospitals over a six-month period. Postpartum women with and without severe maternal morbidity were selected as the exposed and the non-exposed group, respectively. The study included 145 exposed and 187 non-exposed women. Those with severe maternal morbidity were significantly ( P < 0.001) older (mean (SD): 31.6 years (6.26) vs. 29.2 years (5.65)) and had longer hospital stays (mean (SD): 5.9 days (3.79) vs. 3.6 days (2.23)). They were also more likely to have delivered preterm (75.9 vs. 93.0) and to have had a caesarean section (80.7 vs. 67.9) than those without severe maternal morbidity. After adjusting for age and mental health, there was no significant difference in Female Sexual Function Index scores ( P = 0.895) between the two groups. Both groups showed the highest sexual dysfunction in pain and the lowest dysfunction in orgasm. Linear regression analyses showed no association between Female Sexual Function Index scores and sociodemographic characteristics, reproductive history, or quality of life. Sexual function in women with severe maternal morbidity did not differ from that in women without severe maternal morbidity. In-depth qualitative studies of women who have experienced potentially life-threatening conditions may improve the understanding of their sexual function.

Female Sexual Function Index;prospective double cohort;severe maternal morbidity;severe obstetric complications;sexual function

pubmed

External Validity: The Next Step for Systematic Reviews?

Systematic reviews-which identify, assess, and summarize existing research-are usually designed to determine whether research shows that an intervention has evidence of effectiveness, rather than whether an intervention will work under different circumstances. The reviews typically focus on the internal validity of the research and do not consistently incorporate information on external validity into their conclusions. In this article, we focus on how systematic reviews address external validity. We conducted a brief scan of 19 systematic reviews and a more in-depth examination of information presented in a systematic review of home visiting research. We found that many reviews do not provide information on generalizability, such as statistical representativeness, but focus on factors likely to increase heterogeneity (e.g., numbers of studies or settings) and report on context. The latter may help users decide whether the research characteristics-such as sample demographics or settings-are similar to their own. However, we found that differences in reporting, such as which variables are included and how they are measured, make it difficult to summarize across studies or make basic determinations of sample characteristics, such as whether the majority of a sample was unemployed or married. Evaluation research and systematic reviews would benefit from reporting guidelines for external validity to ensure that key information is reported across studies.

external validity;systematic reviews

pubmed

Controlled burn and immediate mobilization of potentially toxic elements in soil, from a legacy mine site in Central Victoria, Australia.

Conducting controlled burns in fire prone areas is an efficient and economic method for forest management, and provides relief from the incidence of high severity wild fires and the consequent damage to human property and ecosystems. However, similar to wild fires, controlled burns also affect many of the physical and biogeochemical properties of the forest soil and may facilitate remobilization of potentially toxic elements (PTEs) sequestered in vegetation and soil organic matter. The objective of the current study is to investigate the mobilization of PTEs, in Central Victorian forest soils in Australia after a controlled burn. Surface soil samples were collected two days before and after the controlled burn to determine the concentration of PTEs and to examine the physicochemical properties. Results show that As, Cd, Mn, Ni and Zn concentrations increased 1.1, 1.6, 1.7, 1.1 and 1.9 times respectively in the post-burn environment, whereas the concentrations of Hg, Cr and Pb decreased to 0.7, 0.9 and 0.9 times respectively, highlighting considerable PTE mobility during and after a controlled burn. Whilst these results do not identify very strong correlations between physicochemical properties of soil and PTEs in the pre- and post-burn environments, PTEs themselves demonstrated very strong and significant correlations. The mobilization of As, Hg and other toxic elements raise potential health concerns as the number of controlled burns are projected to increase in response to climate change. Due to this increased level of PTE release and remobilization, the use of any kinds of controlled burn must be carefully considered before being used as a forest management strategy in mining-affected landscapes which include areas with high PTE concentrations.

Arsenic and metals;Environmental pollution;Forest fire;Historical mining;Prescribed fire;Soil and water pollution

pubmed

Tetanus, diphtheria, and acellular pertussis vaccination during pregnancy and reduced risk of infant acute respiratory infections.

To protect infants from pertussis infection, the Advisory Committee on Immunization Practices (ACIP) recommends women receive the tetanus toxoid, reduced diphtheria toxoid, acellular pertussis (Tdap) vaccine between 27 and 36weeks of pregnancy. Here, we assessed the association between timing of maternal Tdap vaccination during pregnancy and acute respiratory infection (ARI) in infants <2months of age. This retrospective cohort study included 99,434 infants born to active duty military women in the Department of Defense Birth and Infant Health Registry from 2006 through 2013. Multivariable log-binomial regression was used to calculate relative risks (RRs) and 95% confidence intervals (CIs) for the association between maternal Tdap vaccination during pregnancy and infant ARI at <2months of age. Infants of mothers who received Tdap vaccination during pregnancy vs those who did not were 9% less likely to be diagnosed with an ARI at <2months of age (RR, 0.91; 95% CI, 0.84-0.99), and the risk was 17% lower if vaccination was received between 27 and 36weeks of pregnancy (RR, 0.83; 95% CI, 0.74-0.93). Similar results were observed when comparing mothers who received Tdap vaccination prior to pregnancy in addition to Tdap vaccination between 27 and 36weeks of pregnancy versus mothers who only received vaccination prior to pregnancy (RR, 0.85; 95% CI, 0.74-0.98). Maternal Tdap vaccination between 27 and 36weeks of pregnancy was consistently protective against infant ARI in the first 2months of life vs no vaccination during pregnancy, regardless of Tdap vaccination prior to pregnancy. Our findings strongly support current ACIP guidelines recommending Tdap vaccination in late pregnancy for every pregnancy.

Infant acute respiratory infection;Pertussis;Tdap vaccination;Tetanus toxoid, reduced diphtheria toxoid, acellular pertussis;Timing of Tdap vaccination;Vaccinations in pregnancy

pubmed

Interarticulator coordination in children with and without cerebral palsy.

The current study investigates how interarticulator coordination changes across speaking tasks varying in articulatory and linguistic demands for children with CP and their typically-developing peers. Articulatory movements from 12 children with spastic CP (7M, 5F, 4-15 years of age) and 12 typically-developing age- and sex-matched peers were cross-correlated to determine the degree of spatial and temporal coupling between the upper lip and jaw, lower lip and jaw, and upper and lower lips. Spatial and temporal coupling were also correlated with intelligibility. Results indicated that children with CP have reduced spatial coupling between the upper and lower lips and reduced temporal coupling between all articulators as compared to their typically-developing peers. For all participants, sentences were produced with the greatest degree of interarticulator coordination when compared to the diadochokinetic and syllable repetition tasks. Measures of interarticulator coordination were correlated with intelligibility for the speakers with CP.

Cerebral palsy;dysarthria;intelligibility;speech motor control

pubmed

MiR-570 inhibits cell proliferation and glucose metabolism by targeting IRS1 and IRS2 in human chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML) is a chronic myeloproliferative disorder characterized by the accumulation of myeloid cells with a chromosomal translocation known as the Philadelphia chromosome. In this study, we investigated the roles of miR-570 in CML development. Expression of miR-570 in CML samples and cell lines was determined by qRT-PCR. Glucose uptake and ATP concentration detection assays were used to analyze cell glucose metabolism. MTT and western blot assays were performed for cell proliferation and apoptosis, respectively. The targets of miR-570 were predicted by bioinformatics and confirmed using luciferase activity, qRT-PCR and western blot assays. The expression levels of miR-570 were significantly reduced in CML clinical samples and cells. Overexpression of miR-570 inhibited cell proliferation, promoted apoptosis, and suppressed glucose metabolism in CML cells. Insulin receptor substrates (IRS) 1 and IRS2 were identified as direct targets of miR-570. IRS1 or IRS2 were knocked down in K562 cells. Loss of IRS1/2 expression led to suppressed cell proliferation, elevated apoptosis, and decreased glucose metabolism in CML cells, which is consistent with their roles as miR-570 targets. MiR-570 directly targeted IRS1 and IRS2 in CML, suppressing cell proliferation and glucose metabolism. MiR-570 may provide a strategy for CML therapy.

Chronic Myelogenous Leukemia;IRS1;IRS2;miR-570

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Anthelmintic Flubendazole and Its Potential Use in Anticancer Therapy.

Flubendazole is a widely used anthelmintic drug belonging to benzimidazole group. The molecular mechanism of action of flubendazole is based on its specific binding to tubulin, which results in disruption of microtubule structure and function, and in the interference with the microtubule-mediated transport of secretory vesicles in absorptive tissues of helminths. The microtubule-disrupting properties of benzimidazole derivatives raised recently interest in these compounds as possible anti-cancer agents. In this minireview flubendazole effects towards selected human malignant cells including myeloma, leukemia, neuroblastoma, breast cancer, colorectal cancer and melanoma are discussed along with basic data on its pharmacokinetics, metabolism and toxicity.

anti-cancer treatment;benzimidazole carbamate;flubendazole;melanoma;microtubules;mitotic catastrophe

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Prognostic Value of Hyperlactatemia and Lactate Clearance After Mitral Valve Surgery.

Blood lactate is frequently used to guide management in critically ill patients. In patients undergoing mitral valve surgery, an elevated lactate level is frequently observed; however, overall mortality is low. The authors hypothesized that hyperlactemia is not a useful predictor of poor outcomes in this patient population. The main aim of this study was to explore how blood lactate level and lactate clearance are associated with 30-day mortality and major adverse events in patients undergoing mitral valve surgery. This was a retrospective database review. Logistic regression analysis was performed to assess the associations of perioperative factors with blood lactate in the intensive care unit (ICU). Tertiary-care teaching hospital. The study comprised 917 patients undergoing mitral valve surgery. None. The majority of patients (71.8%) had elevated blood lactate ≥2 mmol/L on ICU admission; however, within 24 hours, 85.1% of all patients had normal lactate values. Overall 30-day mortality was 2.29% (n = 21). The combination of lactate ≥7 mmol/L on ICU admission and a persistent elevated blood lactate level 24 hours after ICU admission provides an excellent prediction of 30-day mortality (C statistic = 0.85). However, even a significantly elevated lactate level on ICU admission was well-tolerated in the majority of patients as long as lactate values normalized within 24 hours. Male sex, longer cardiopulmonary bypass time, blood transfusion in the ICU, and an elevated blood lactate level on ICU admission and 12 hours after ICU admission all were independent risk factors of clearance failure. An elevated blood lactate level is common after mitral valve surgery and is well-tolerated in the majority of patients. Adding lactate clearance improved the predictive value of the blood lactate level.

blood lactate;cardiopulmonary bypass;critically ill;heart surgery;lactate clearance;postoperative care

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Joint Symposium of Korean Cancer Association & UICC-ARO-Cross-boundary cancer studies: cancer and Universal Health Coverage (UHC) in Asia.

On 16 June 2016, the Korean Cancer Association (KCA) and Union for International Cancer Control-Asia Regional Office (UICC-ARO) organized a joint symposium as part of the official program of the 42nd Annual Meeting of the Korean Cancer Association to discuss the topic 'Cross-boundary Cancer Studies: Cancer and Universal Health Coverage (UHC) in Asia.' Universal Health Coverage is included in the Sustainable Development Goals adopted by the United Nations as part of the 2030 Agenda for Sustainable Development. The objectives of UHC are to ensure that all people can receive high-quality medical services, are protected from public health risks, and are prevented from falling into poverty due to medical costs or loss of income arising from illness. The participants discussed the growing cost of cancer in the Asian region and the challenges that this poses to the establishment and deployment of UHC in the countries of Asia, all of which face budgetary and other systemic constraints in controlling cancer in the region. Representatives from Korea, Japan and Indonesia reported on the status of UHC in their countries and the challenges that are being faced, many of which are common to other countries in Asia. In addition to country-specific presentations about the progress of and challenges facing UHC, there were also presentations from WHO Kobe Centre concerning advancing UHC in non-communicable diseases and prospects for further collaboration and research on UHC. A presentation from the University of Tokyo also highlighted the need to focus on multidisciplinary studies in an age of globalization and digitization.

UICC-ARO;Universal Health Coverage (UHC);WHO Kobe Centre;cross-boundary cancer studies;sustainable development

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Beneficial Effects of Yogasanas and Pranayama in limiting the Cognitive decline in Type 2 Diabetes.

Out of many complications that were observed in type 2 diabetes, cognitive impairment is the most neglected. The aim of the present study is to assess the cognitive decline in type 2 diabetes and to observe the role of yogasanas and pranayama in ameliorating the cognitive decline. Sixty eight type 2 diabetic subjects were recruited in the study, 34 of them did specific yogasanas and pranayama (test group) for six months and the remaining age and sex matched 34 subjects were recruited as (control group) who were not on any specific exercise regimen. Glycaemic index was estimated by measuring the glycosylated haemoglobin (HbA_1c) concentration with Bio-Rad apparatus and cognition was assessed by using Addenbrook's Cognitive Examination-Revised (ACE-R), which is a neuropsychological battery. Data was analysed with unpaired student t test. P value<0.05 is considered as statistically significant. Validity was assessed by receiver operating characteristics. Analysis of data indicated more cognitive scores in the test group when compared with the control group. In test group six months practice of yogasanas and pranayama has also significantly brought down the high glycaemic values which were observed in the control group. These findings allow the study to conclude that regular practice of yogasanas and pranayama has a beneficial effect on cognitive performance in type 2 diabetic subjects by stabilizing blood glucose.

Addenbrook’s Cognitive Examination-Revised;Cognition;HbA1c;Type 2 diabetes;Yogasanas and pranayama

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Subareolar Sclerosing Ductal Hyperplasia.

Subareolar sclerosing duct hyperplasia (SSDH) remains to be fully characterized nearly 20 years after initial description. Thirty-five SSDH cases diagnosed over a 16-year period (January 2000 to December 2015) were reviewed. All patients were female (mean age = 59 years, range = 18-80) who had presented with a unilateral solitary lesion (left 22, right 13) with a mean size of 1.3 cm (range = 0.4-3.0 cm), and showed florid and papillary epithelial hyperplasia with dense sclerosis without involvement of nipple or areolar epidermis. Significant lesions concurrent within SSDH included low-grade adenosquamous carcinoma (n = 1), ductal carcinoma in situ (DCIS; n = 1), lobular carcinoma in situ (LCIS; n = 1), and atypical ductal hyperplasia (ADH; n = 13). No case of SSDH recurred in a mean follow-up of 44 months (range = 6-189). Subsequent significant lesions occurred in 6 patients: DCIS (n = 3; ipsilateral 2, contralateral 1), ipsilateral ADH (n = 2), and ipsilateral atypical lobular hyperplasia (n = 1). Long-term follow-up for patients with SSDH is indicated as DCIS can occur subsequently in either breast.

breast;epithelial hyperplasia;nipple;radial scar;subareolar

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A synthetic peptide blocking TRPV1 activation inhibits UV-induced skin responses.

Transient receptor potential type 1 (TRPV1) can be activated by ultraviolet (UV) irradiation, and mediates UV-induced matrix metalloproteinase (MMP)-1 and proinflammatory cytokines in keratinocytes. Various chemicals and compounds targeting TRPV1 activation have been developed, but are not in clinical use mostly due to their safety issues. We aimed to develop a novel TRPV1-targeting peptide to inhibit UV-induced responses in human skin. We designed and generated a novel TRPV1 inhibitory peptide (TIP) which mimics the specific site in TRPV1 (aa 701-709: Gln-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr, QRAITILDT), Thr⁷⁰⁵, and tested its efficacy of blocking UV-induced responses in HaCaT, mouse, and human skin. TIP effectively inhibited capsaicin-induced calcium influx and TRPV1 activation. Treatment of HaCaT with TIP prevented UV-induced increases of MMP-1 and pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor-α. In mouse skin in vivo, TIP inhibited UV-induced skin thickening and prevented UV-induced expression of MMP-13 and MMP-9. Moreover, TIP attenuated UV-induced erythema and the expression of MMP-1, MMP-2, IL-6, and IL-8 in human skin in vivo. The novel synthetic peptide targeting TRPV1 can ameliorate UV-induced skin responses in vitro and in vivo, providing a promising therapeutic approach against UV-induced inflammation and photoaging.

Matrix metalloproteinases;Pro-inflammatory cytokines;Transient receptor potential vanilloid 1;Ultraviolet

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SmLEA2, a gene for late embryogenesis abundant protein isolated from Salvia miltiorrhiza, confers tolerance to drought and salt stress in Escherichia coli and S. miltiorrhiza.

Abiotic stresses, such as drought and high salinity, are major factors that limit plant growth and productivity. Late embryogenesis abundant (LEA) proteins are members of a diverse, multigene family closely associated with tolerance to abiotic stresses in numerous organisms. We examined the function of SmLEA2, previously isolated from Salvia miltiorrhiza, in defense responses to drought and high salinity. Phylogenetic analysis indicated that SmLEA2 belongs to the LEA_2 subfamily. Its overexpression in Escherichia coli improved growth performance when compared with the control under salt and drought stresses. We further characterized its roles in S. miltiorrhiza through overexpression and RNAi-mediated silencing. In response to drought and salinity treatments, transgenic plants overexpressing SmLEA2 exhibited significantly increased superoxide dismutase activity, reduced levels of lipid peroxidation, and more vigorous growth than empty-vector control plants did. However, transgenic lines in which expression was suppressed showed the opposite results. Our data demonstrate that SmLEA2 plays an important role in the abiotic stress response and its overexpression in transgenic S. miltiorrhiza improves tolerance to excess salt and drought conditions.

Abiotic stress;Escherichia coli;LEA;Salvia miltiorrhiza

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Trapping and proliferation of target cells on C₆₀ fullerene nano fibres.

The ratio of the surface area to the volume of materials increases in inverse proportion to their size and therefore the surface area of nanostructures and nanomaterials is extremely large compared to that of macroscopic materials of the same volume, thanks to which it is supposed that chemical and biochemical reactions may be greatly enhanced and target molecules and cells may be efficiently trapped on the surface of nanomaterials. It is well known that C₆₀ molecules are stable both physically and chemically and the affinity of C₆₀ molecules with biomolecules is rather high. Here, we synthesise fibres composed of C₆₀ and sulphur and immobilise the surface of the fibres with the primary antibody; i.e., epithelial cell adhesion molecules (anti-EpCAM), to trap target cells. The primary antibody is evenly immobilised on the fibres confirmed by a fluorescent secondary antibody attached to the primary one and then TE2 esophageal and DLD-1 colon cancer cells are successfully trapped by the primary antibody immobilised on the fibres thanks to its high affinity with TE2 and DLD-1 cells, whereas few IM9 B lymphoblast cells are captured on the fibres since the affinity of the primary antibody with IM9 cells is extremely low. Furthermore, those cells trapped by the primary antibody immobilised on the fibres proliferate faster than native cells thanks to the primary antibody acting as a growth factor. The present result suggests that different types of cells can be trapped and grown on nano fibres by immobilising appropriate antibody molecules on the surface of the fibres. Even an extremely small number of cells in sample fluids may be analysed and characterised for the detection of diseases such as cancer in the early stage by trapping and proliferating target cells on the fibres.

Biotechnology;Materials science;Nanotechnology

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Supporting the role of community members employed as research staff: Perspectives of community researchers working in addiction research.

Community researchers are laypersons who conduct research activities in their own communities. In addiction and HIV research, community researchers are valued for their insider status and knowledge. At the same time, their presence on the research team raises concerns about coercion and confidentiality when community researchers and participants know each other personally, and the work of navigating between the worlds of research and community leads to moral distress and burnout for some community researchers. In this paper, we draw upon the concept of 'moral experience' to explore the local moral worlds of community researchers in the context of addiction research. In February and March 2010, we conducted focus groups with 36 community researchers employed on community-based addiction studies in the United States to elicit perspectives on ethical and moral challenges they face in their work and insights on best practices to support their role in research. Community researchers described how their values were realized or thwarted in the context of research, and their strategies for coping with shifting identities and competing priorities. They delineated how their knowledge could be used to inform development of research protocols and help principal investigators build and maintain trust with the community researchers on their teams. Our findings contribute to current understandings of the moral experiences of community members employed in research, and inform policies and practices for the growing field of community-engaged research. Funders, research organizations, and research ethics boards should develop guidelines and standards to ensure studies have key resources in place to support community researchers and ensure quality and integrity of community-engaged work. Investigators who work with community researchers should ensure channels for frontline staff to provide input on research protocols and to create an atmosphere where challenges and concerns can be openly and safely discussed.

Addiction research;Community based research;Community engaged research;Community researchers;HIV/AIDS research;Moral experience;Research ethics;United States

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High resolution measurement of DUF1220 domain copy number from whole genome sequence data.

DUF1220 protein domains found primarily in Neuroblastoma BreakPoint Family (NBPF) genes show the greatest human lineage-specific increase in copy number of any coding region in the genome. There are 302 haploid copies of DUF1220 in hg38 (~160 of which are human-specific) and the majority of these can be divided into 6 different subtypes (referred to as clades). Copy number changes of specific DUF1220 clades have been associated in a dose-dependent manner with brain size variation (both evolutionarily and within the human population), cognitive aptitude, autism severity, and schizophrenia severity. However, no published methods can directly measure copies of DUF1220 with high accuracy and no method can distinguish between domains within a clade. Here we describe a novel method for measuring copies of DUF1220 domains and the NBPF genes in which they are found from whole genome sequence data. We have characterized the effect that various sequencing and alignment parameters and strategies have on the accuracy and precision of the method and defined the parameters that lead to optimal DUF1220 copy number measurement and resolution. We show that copy number estimates obtained using our read depth approach are highly correlated with those generated by ddPCR for three representative DUF1220 clades. By simulation, we demonstrate that our method provides sufficient resolution to analyze DUF1220 copy number variation at three levels: (1) DUF1220 clade copy number within individual genes and groups of genes (gene-specific clade groups) (2) genome wide DUF1220 clade copies and (3) gene copy number for DUF1220-encoding genes. To our knowledge, this is the first method to accurately measure copies of all six DUF1220 clades and the first method to provide gene specific resolution of these clades. This allows one to discriminate among the ~300 haploid human DUF1220 copies to an extent not possible with any other method. The result is a greatly enhanced capability to analyze the role that these sequences play in human variation and disease.

Bioinformatics;CNV;Copy number variation;DUF1220;Genome informatics;Next-generation sequencing

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Cognitive functioning in the general population: Factor structure and association with mental disorders-The neuropsychological test battery of the mental health module of the German Health Interview and Examination Survey for Adults (DEGS1-MH).

The objective of this study is to obtain population level data about cognitive functions and their association with mental disorders. We here report factor analytic and psychometric findings of a neuropsychological test battery and examine the association of current and past mental disorders with cognitive function in a large nationwide population-based sample of 18- to 79-year-old adults in Germany (n = 3,667) participating in the mental health module of the German Health Interview and Examination Survey for Adults 2008-2011. Confirmatory factor analysis confirmed verbal memory and executive function factors. Older age was strongly associated with lower verbal memory and executive function and with higher vocabulary scores. After adjustment for age, sex, and education, rather modest decrements were found for verbal memory (β = -.118, p = .002) and executive functions (β = -.191, p < .001) in participants with any current mental disorder (n = 442) compared to those without (n = 3,201). Small decrements in memory (β = -.064, p = .031) and executive function (β = -.111, p < .001) were found in participants with any mental disorder in the last 12 months but not in those with past (fully or partially remitted) mental disorders, compared to participants without a history of mental disorder. More fine-grained analyses of these data will investigate the complex interplay between cognition, health behaviors, and specific mental and somatic diseases.

cognition;epidemiology;neuropsychology;psychometrics

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Low Density Lipoproteins Amplify Cytokine-signaling in Chronic Lymphocytic Leukemia Cells.

Recent studies suggest there is a high incidence of elevated low-density lipoprotein (LDL) levels in Chronic Lymphocytic Leukemia (CLL) patients and a survival benefit from cholesterol-lowering statin drugs. The mechanisms of these observations and the kinds of patients they apply to are unclear. Using an in vitro model of the pseudofollicles where CLL cells originate, LDLs were found to increase plasma membrane cholesterol, signaling molecules such as tyrosine-phosphorylated STAT3, and activated CLL cell numbers. The signaling effects of LDLs were not seen in normal lymphocytes or glycolytic lymphoma cell-lines but were restored by transduction with the nuclear receptor PPARδ, which mediates metabolic activity in CLL cells. Breakdown of LDLs in lysosomes was required for the amplification effect, which correlated with down-regulation of HMGCR expression and long lymphocyte doubling times (LDTs) of 53.6±10.4months. Cholesterol content of circulating CLL cells correlated directly with blood LDL levels in a subgroup of patients. These observations suggest LDLs may enhance proliferative responses of CLL cells to inflammatory signals. Prospective clinical trials are needed to confirm the therapeutic potential of lowering LDL concentrations in CLL, particularly in patients with indolent disease in the "watch-and-wait" phase of management.

Cholesterol;Chronic lymphocytic leukemia;HMGCR;Janus kinases;Lipoproteins;Lysosomal lipase;Nuclear receptors;Ruxolitinib;STAT3

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Addition of bioactive glass to glass ionomer cements: Effect on the physico-chemical properties and biocompatibility.

Glass ionomer cements (GICs) are a subject of research because of their inferior mechanical properties, despite their advantages such as fluoride release and direct bonding to bone and teeth. Recent research aims to improve the bioactivity of the GICs and thereby improve mechanical properties on the long term. In this study, two types of bioactive glasses (BAG) (45S5F and CF9) are combined with GICs to evaluate the physico-chemical properties and biocompatibility of the BAG-GIC combinations. The effect of the addition of Al³⁺ to the BAG composition and the use of smaller BAG particles on the BAG-GIC properties was also investigated. Conventional aluminosilicate glass (ASG) and (modified) BAG were synthesized by the melt method. BAG-GIC were investigated on setting time, compressive strength and bioactivity. Surface changes were evaluated by Fourier transform infrared (FT-IR), scanning electron microscopy (SEM), EDS and PO₄^3- -and Ca²⁺ uptake in SBF. Biocompatibility of selected BAG-GICs was determined by a direct toxicity assay. The addition of BAG improves the bioactivity of the GIC, which can be observed by the formation of an apatite (Ap) layer, especially in CF9-containing GICs. More BAG leads to more bioactivity but decreases strength. The addition of Al³⁺ to the BAG composition improves strength, but decreases bioactivity. BAGs with smaller particle sizes have no effect on bioactivity and decrease strength. The formation of an Ap layer seems beneficial to the biocompatibility of the BAG-GICs. Bioactive GICs may have several advantages over conventional GICs, such as remineralization of demineralized tissue, adhesion and proliferation of bone- and dental cells, allowing integration in surrounding tissue. CF9 BAG-GIC combinations containing maximum 10mol% Al³⁺ are most promising, when added in ≤20wt% to a GIC.

Apatite;Bioactive glass;Bioactivity;Biocompatibility;Fluoride;Glass ionomer

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Designing Safer Analgesics via μ-Opioid Receptor Pathways.

Pain is both a major clinical and economic problem, affecting more people than diabetes, heart disease, and cancer combined. While a variety of prescribed or over-the-counter (OTC) medications are available for pain management, opioid medications, especially those acting on the μ-opioid receptor (μOR) and related pathways, have proven to be the most effective, despite some serious side effects including respiration depression, pruritus, dependence, and constipation. It is therefore imperative that both academia and industry develop novel μOR analgesics which retain their opioid analgesic properties but with fewer or no adverse effects. In this review we outline recent progress towards the discovery of safer opioid analgesics.

GPCR;computational biology;drug discovery;opioid receptor;safer painkiller

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Endoscopic management of complications of self-expandable metal stents for treatment of malignant esophageal stenosis and tracheoesophageal fistulas.

Self-expandable metal stent (SEMS) implantation may rapidly improve the symptoms of malignant esophageal stenosis and tracheoesophageal fistulas (TEF). However, dysphagia often returns subsequently and repeated endoscopic intervention may be necessary. The aims of the study were to identify the risk factors of complications, and the frequency and efficacy of repeated endoscopic interventions; and to provide technical recommendations on appropriate stent selection. We analyzed retrospectively the clinical data of 212 patients with locally advanced esophageal cancer who underwent SEMS implantation. A total of 238 SEMS implantations were performed with 99.06% technical success and 1.26% procedure-related deaths in the enrolled 212 cases. Complications occurred in 84 patients (39.62%) and in 55 cases (25.94%) repeated endoscopic procedures were required. Early reintervention 24-48 h after the stent implantations was necessary due to stent migration (12 cases), arrhythmia (2 cases), intolerable retrosternal pain (1 case) and dyspnea (1 case). An average of 1.98 repeated gastroscopies (range 1-6; median 2), 13.58 weeks (range 1.5-48; median 11) after the stent implantation were performed during the follow-up period: 37 stent repositions, 23 restent implantations, 15 endoscopic esophageal dilations and 7 stent removals. In 48 cases (87.3%) oral feeding of patients was made possible by endoscopic interventions. In a quarter of SEMS implantations, complications occur that can be successfully managed by endoscopic interventions. Our experiences have shown that individualized stent choice may substantially reduce the complications rate and make repeated endoscopic interventions easier.

esophageal cancer;esophageal obstruction;self-expandable metal stent

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Fluctuating residual limb volume accommodated with an adjustable, modular socket design: A novel case report.

This novel case report describes the problems of prescribing a prosthetic socket in a left transfemoral amputee secondary to chronic patellofemoral instability compounded by complex regional pain syndrome. Case Description and Methods: Following the amputation, complex regional pain syndrome symptoms recurred in the residual limb, presenting mainly with oedema. Due to extreme daily volume fluctuations of the residual limb, a conventional, laminated thermoplastic socket fitting was not feasible. Findings and Outcomes: An adjustable, modular socket design was trialled. The residual limb volume fluctuations were accommodated within the socket. Amputee rehabilitation could be continued, and the rehabilitation goals were achieved. The patient was able to wear the prosthesis for 8 h daily and to walk unaided indoors and outdoors. An adjustable, modular socket design accommodated the daily residual limb volume fluctuations and provided a successful outcome in this case. It demonstrates the complexities of socket fitting and design with volume fluctuations. Clinical relevance Ongoing complex regional pain syndrome symptoms within the residual limb can lead to fitting difficulties in a conventional, laminated thermoplastic socket due to volume fluctuations. An adjustable, modular socket design can accommodate this and provide a successful outcome.

Prosthetic design;complex regional pain syndrome;prosthetics;rehabilitation;rehabilitation of amputees

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The BMP4-Smad signaling pathway regulates hyperandrogenism development in a female mouse model.

Polycystic ovary syndrome is a common endocrine disorder and a major cause of anovulatory sterility in women at reproductive age. Most patients with polycystic ovary syndrome have hyperandrogenism, caused by excess androgen synthesis. Bone morphogenetic protein 4 (BMP4) is an essential regulator of embryonic development and organ formation, and recent studies have also shown that BMP4 may be involved in female steroidogenesis process. However, the effect of BMP4 on hyperandrogenism remains unknown. Here, using a female mouse model of hyperandrogenism, we found that ovarian BMP4 levels were significantly decreased in hyperandrogenism. Elevated androgens inhibited BMP4 expression via activation of androgen receptors. Moreover, BMP4 treatment suppressed androgen synthesis in theca cells and promoted estrogen production in granulosa cells by regulating the expression of steroidogenic enzymes, including <i>CYP11A</i>, <i>HSD3B2</i>, <i>CYP17A1</i>, and <i>CYP19A1</i> Consistently, knockdown of BMP4 augmented androgen levels and inhibited estrogen levels. Mechanistically, Smad signaling rather than the p38 MAPK pathway regulated androgen and estrogen formation, thereby mediating the effect of BMP4. Of note, BMP4-transgenic mice were protected against hyperandrogenism. Our observations clarify a vital role of BMP4 in controlling sex hormone levels and offer new insights into intervention for managing hyperandrogenism by targeting the BMP4-Smad signaling pathway.

SMAD transcription factor;androgen;bone morphogenetic protein (BMP);cytochrome P450;endocrinology;hyperandrogenism;polycystic ovary syndrome

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Two isoforms of hormone-sensitive lipase b are generated by alternative exons usage and transcriptional regulation by insulin in grass carp (Ctenopharyngodon idella).

The aim of this study was to investigate the gene structure of two hormone-sensitive lipase b (HSLb) isoforms and their transcriptional regulation by insulin in grass carp (Ctenopharyngodon idella). HSL is an important lipolytic enzyme responsible for the hydrolysis of triacylglycerols (TAGs). Two isoforms (HSLa and HSLb) have been cloned in fish, but information about their gene structure and function is very few. In this study, a novel grass carp HSLb isoform (HSLb2) were firstly isolated and characterized from grass carp, encoding peptides of 848 amino acid residues. HSLb2 comprises 13 coding exons and contains a different exon encoding six amino acids in the 5'-region compared to previous reported HSLb (HSLb1), revealing that alternative multiple exons usage (Exon b1 and Exon b2) results in a significant variation in the 5'-region of HSLb transcripts. Exon b2 is located close to the 3' end of exon b1. Both HSLb2 and HSLb1 mRNAs were expressed in a wide range of tissues, but the abundance of each HSLb messenger RNA (mRNA) showed the tissue-dependent expression patterns. Incubation of hepatocytes with insulin in vitro reduced the mRNA levels of HSLb2 rather than HSLb1, suggesting two HSLb forms may serve somewhat different roles in the regulation of lipogenesis by insulin. To our knowledge, for the first time, the present study provides evidence that HSLb1 and HSLb2 are differentially expressed among tissues and also differentially regulated by insulin in vitro, which provide the groundwork to elucidate the gene structure and physiological function of HSL in fish.

Alternative exons usage;Ctenopharyngodon idella;Gene expression;Hormone-sensitive lipase;Insulin

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The effect of disc-shaped gastric resection of anastomosis site on reducing postoperative dysphagia and stricture after esophagogastric anastomosis in patients with esophageal cancer.

Esophagectomy remains the most reliable technique for managing esophageal cancer, but anastomotic complications including postoperative leak, ischemia and stricture negatively affect outcomes of this specific surgery. The aim of this study was to evaluate the effects of a novel method of esophagogastric anastomosis for reducing postoperative dysphagia and stricture formation. Eighty patients who were scheduled for esophagectomy due to esophageal cancer were randomly assigned into two groups: intervention and control (40 each). In the control group, the esophagogastric anastomosis was performed with a linear gastric incision, whilst in the intervention group a new method of disc-shaped gastric resection for anastomosis was applied. Postoperative outcomes were compared between the two groups. The incidence of postoperative dysphagia and anastomotic stricture was significantly lower in the disc-shaped resection group (dysphagia 45% vs 75%, P = 0.02; stricture 12.5% vs 32.5%, P = 0.03), whilst the length of stay in an intensive care unit (ICU), anastomotic leakage and other complications were not significantly different between the two groups (all P > 0.05). Anastomotic complications can be reduced by improving surgical techniques. The decreased incidence of postoperative dysphagia and anastomotic stricture in our study may be partly due to providing the proper diameter for the site of anastomosis when using the disc-shaped gastric resection method. Hence, this new method can improve the clinical outcomes of patients who undergo esophagectomy with esophagogastric anastomosis.

esophageal cancer;esophagectomy;esophagogastic anastomosis;postoperative complications

pubmed

Impact of thrombelastography in paediatric intensive care.

We assessed the clinical impact of thrombelastography (TEG®) results (TEG® 5000, Haemonetics Corporation, Braintree, MA, USA) by measuring their ability to cause changes in a theoretical treatment plan and contribute to the understanding of haemostasis. We prospectively included paediatric intensive care unit (PICU) patients who had standard tests of haemostasis and TEG ordered and had an arterial catheter or extracorporeal access port in situ. Blood for standard tests and TEG was taken simultaneously. Independent of patient care, general patient information and results of standard laboratory tests were presented to five clinicians who were asked to document their theoretical treatment plan. Clinicians were then shown TEG results and asked if they caused a change in their plan, if they confirmed initial standard laboratory test results, if they enabled a better understanding of haemostasis and if they provided additional information. Inter-rater agreement between the clinicians was determined. Forty-two TEG results were obtained from 34 patients. Overall, the inclusion of TEG results led to a change in treatment plan in 97 of 207 occasions (47%), confirmed standard laboratory test results in 177 of 204 occasions (87%), enabled a better understanding of haemostasis in 140 of 204 occasions (69%) and provided additional information in 131 of 204 occasions (64%). Variation existed between clinicians, seemingly due to individual differences, with poor inter-rater agreement. We conclude that TEG results led to changes in treatment plans almost half the time, confirmed findings of standard tests and provided a better understanding of haemostasis, but randomised controlled trials are required to determine the role and influence of TEG results on patient outcome.

thrombelastography, paediatric intensive care unit, haemostasis, observer variation

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Wrongness, Responsibility, and Conscientious Refusals in Health Care.

In this article, I address what kinds of claims are of the right kind to ground conscientious refusals. Specifically, I investigate what conceptions of moral responsibility and moral wrongness can be permissibly presumed by conscientious objectors. I argue that we must permit HCPs to come to their own subjective conclusions about what they take to be morally wrong and what they take themselves to be morally responsible for. However, these subjective assessments of wrongness and responsibility must be constrained in several important ways: they cannot involve empirical falsehoods, objectionably discriminatory attitudes, or unreasonable normative beliefs. I argue that the sources of these constraints are the basic epistemic, relational, and normative competencies needed to function as a minimally decent health-care professional. Finally, I consider practical implications for my framework, and argue that it shows us that the objection raised by the plaintiffs in Zubik v. Burwell is of the wrong sort.

Zubik v. Burwell;conscientious objection;conscientious refusal;moral wrongness;professional competency;responsibility;subjective

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Developmental mechanisms of longitudinal stripes in the Japanese four-lined snake.

The developmental mechanisms of color patterns formation and its evolution remain unclear in reptilian sauropsids. We, therefore, studied the pigment cell mechanisms of stripe pattern formation during embryonic development of the snake Elaphe quadrivirgata. We identified 10 post-ovipositional embryonic developmental stages based on external morphological characteristics. Examination for the temporal changes in differentiation, distribution, and density of pigment cells during embryonic development revealed that melanophores first appeared in myotome and body cavity but not in skin surface at Stage 5. Epidermal melanophores were first recognized at Stage 7, and dermal melanophores and iridophores appeared in Stage 9. Stripe pattern first appeared to establish at Stage 8 as a spatial density gradient of epidermal melanophores between the regions of future dark brown longitudinal stripes and light colored background. Our study, thus, provides a comprehensive pigment-cell-based understanding of stripe pattern formation during embryonic development. We briefly discuss the importance of the gene expression studies by considering the biologically relevant theoretical models with standard developmental staging for understanding reptilian color pattern evolution.

embryo;iridophore;melanophore;snake;stripe pattern formation

pubmed

Reporting medical device safety incidents to regulatory authorities: An analysis and classification of technology-induced errors.

The European Union Medical Device Directive 2007/47/EC1 defines software with a medical purpose as a medical device. The implementation of health information technology suffers from patient safety problems that require effective post-market surveillance. The purpose of this study was to review, classify and discuss the incident data submitted to a nationwide database of the Finnish National Competent Authority with other forms of data. We analysed incident reports submitted to the authority database by users of electronic health records from 2010 to 2015. We identified 138 valid reports. Adverse events associated with electronic health record vulnerabilities, clustered around certain error types, cause serious harm and occur in all types of healthcare settings. The low rate of reported incidents raises questions about not only the challenges associated with medical software oversight but also the obstacles for reporting.

adverse event;electronic health record;medical software;oversight;patient safety

pubmed

Osteobastoma of the Talus: A case report and review of the literature.

Osteoblastoma is benign bone forming tumour with rare malignant transformation. The common locations include spine, proximal humerus and hip. It rarely affects the talus. A case of osteoblastoma of the talus in a 33-years old healthy male who presented to the foot and ankle clinic in October 2015 complaining of pain of the right ankle for 12 months following football injury is discussed.

Osteoblastoma;Talus tumour

pubmed

Efficient generation of receiver operating characteristics for the evaluation of damage detection in practical structural health monitoring applications.

Permanently installed guided wave monitoring systems are attractive for monitoring large structures. By frequently interrogating the test structure over a long period of time, such systems have the potential to detect defects much earlier than with conventional one-off inspection, and reduce the time and labour cost involved. However, for the systems to be accepted under real operational conditions, their damage detection performance needs to be evaluated in these practical settings. The receiver operating characteristic (ROC) is an established performance metric for one-off inspections, but the generation of the ROC requires many test structures with realistic damage growth at different locations and different environmental conditions, and this is often impractical. In this paper, we propose an evaluation framework using experimental data collected over multiple environmental cycles on an undamaged structure with synthetic damage signatures added by superposition. Recent advances in computation power enable examples covering a wide range of practical scenarios to be generated, and for multiple cases of each scenario to be tested so that the statistics of the performance can be evaluated. The proposed methodology has been demonstrated using data collected from a laboratory pipe specimen over many temperature cycles, superposed with damage signatures predicted for a flat-bottom hole growing at different rates at various locations. Three damage detection schemes, conventional baseline subtraction, singular value decomposition (SVD) and independent component analysis (ICA), have been evaluated. It has been shown that in all cases, the component methods perform significantly better than the residual method, with ICA generally the better of the two. The results have been validated using experimental data monitoring a pipe in which a flat-bottom hole was drilled and enlarged over successive temperature cycles. The methodology can be used to evaluate the performance of an installed monitoring system and to show whether it is capable of detecting particular damage growth at any given location. It will enable monitoring results to be evaluated rigorously and will be valuable in the development of safety cases.

component analysis;damage detection;guided wave ultrasonics;pipe monitoring;receiver operating characteristic;structural health monitoring

pubmed

The impact of drugs for multiple sclerosis on sleep.

Although there is a growing literature on the presence of sleep disorders in multiple sclerosis (MS), few studies have specifically addressed the impact of drugs on sleep of these patients. Moreover, even when sleep is considered, quantitative assessment by standardized questionnaires or polysomnography is lacking. The studies that have been done highlight that interferon-beta and some symptomatic medications may affect sleep, thus contributing to fatigue, depression, and poor quality of life; conversely, natalizumab and cannabinoids may improve sleep. Common limitations of the literature reviewed here are small sample size, selection bias, and often a lack of objective outcome measures. Clinicians need to remember to ask about sleep in all MS patients and intervene when appropriate. A systematic approach that takes sleep into account is recommended to enhance recognition and appropriate management of sleep disruption, including disorders related to medication. Consideration of the impact on sleep should also be part of the design of trials of new therapies.

Multiple sclerosis;disease-modifying drugs;neuroinflammation;quality of life;sleep disorders

pubmed

Secondary gastric cancer malignancies following a breast cancer diagnosis: A population-based analysis.

To quantify the population-risk of developing gastric cancer (GC) following breast cancer (BC). GC incidence following a ductal or lobular BC were separately compared to incidence in the general United States population using SEER data. GC rates were similar to the general population for ductal BC. Women aged 35-75 with lobular BC had a significantly higher incidence of GC; women aged 40-44 had the highest risk. The risk of secondary GC is high among young women diagnosed with lobular BC. More studies investigating the etiology and prevalence of familial GC syndromes at the population-level are needed.

Gastric cancer;Hereditary cancer syndromes

pubmed

Advanced Imaging Techniques of the Skull Base.

Although conventional imaging can depict the anatomy of the head and neck with exquisite detail, it often falls short in its ability to characterize tissue physiology and abnormality; this is especially seen in the posttherapy setting where benign posttreatment changes and recurrent tumors can show intense postcontrast enhancement and similar features on conventional imaging. Advanced imaging can evaluate tissue physiology and, along with conventional imaging, provide a more accurate assessment of the skull base. This article describes the technical details and clinical applications of different advanced imaging techniques with a primary focus on diffusion-weighted imaging.

CT perfusion;Diffusion-weighted imaging;Head and neck imaging;Head and neck squamous cell carcinoma;MR perfusion

pubmed

Recent Advances in Comprehending the Signaling Pathways Involved in the Progression of Breast Cancer.

This review describes recent advances in the comprehension of signaling pathways involved in breast cancer progression. Calcium sensing receptor (CaSR), caveolae signaling, signaling referred to hypoxia-inducing factors and disturbances in the apoptotic machinery are related to more general biological mechanisms and are considered first. The others refer to signaling pathways of more specific biological mechanisms, namely the heparin/heparin-sulfate interactome, over-expression of miRNA-378a-5p, restriction of luminal and basal epithelial cells, fatty-acid synthesis, molecular pathways related to epithelial to mesenchimal transition (EMT), HER-2/neu gene amplification and protein expression, and the expression of other members of the epithelial growth factor receptor family. This progress in basic research is fundamental to foster the ongoing efforts that use the new genotyping technologies, and aim at defining new prognostic and predictive biomarkers for a better personalized management of breast cancer disease.

breast cancer;calcium sensing receptor;cancer progression;caveolae;hypoxia inducing factors;personalized medicine;signaling pathways

pubmed

CMG-Pol epsilon dynamics suggests a mechanism for the establishment of leading-strand synthesis in the eukaryotic replisome.

The replisome unwinds and synthesizes DNA for genome duplication. In eukaryotes, the Cdc45-MCM-GINS (CMG) helicase and the leading-strand polymerase, Pol epsilon, form a stable assembly. The mechanism for coupling DNA unwinding with synthesis is starting to be elucidated, however the architecture and dynamics of the replication fork remain only partially understood, preventing a molecular understanding of chromosome replication. To address this issue, we conducted a systematic single-particle EM study on multiple permutations of the reconstituted CMG-Pol epsilon assembly. Pol epsilon contains two flexibly tethered lobes. The noncatalytic lobe is anchored to the motor of the helicase, whereas the polymerization domain extends toward the side of the helicase. We observe two alternate configurations of the DNA synthesis domain in the CMG-bound Pol epsilon. We propose that this conformational switch might control DNA template engagement and release, modulating replisome progression.

CMG helicase;DNA polymerase;DNA replication;single-particle electron microscopy

pubmed

Microbiota and metabolome during controlled and spontaneous fermentation of Nocellara Etnea table olives.

This study is aimed to investigate bacterial community and its dynamics during the fermentation of Nocellara Etnea table olives and to study its effect on metabolome formation. Six different combination of bacterial cultures (BC1-BC6) were used as starters for table olive fermentation and one additional process, conducted without addition of any starters, was used as control (C). The processes were conducted in triplicate and, overall, 21 vessels were performed at industrial scale. The fermentation was monitored for 120 days through culture-dependent and -independent approaches. Microbial counts of the main microbial groups revealed slight differences among brine samples, with the exception of LAB counts and Enterobacteriaceae, which were higher and lower, respectively, in most of the inoculated samples than the control ones. In addition, results demonstrated that the use of bacterial cultures (except the BC1), singly or in different combinations, clearly influenced the fermentation process reducing the final pH value below 4.50. When microbiota was investigated through sequencing analysis, data revealed the presence of halophilic bacteria and, among lactobacilli, the dominance of Lactobacillus plantarum group at the initial stage of fermentation, in all brine samples, except in the BC5 in which dominated Lactobacillus casei group. At 60 and 120 days of fermentation, an overturned bacterial ecology and an increase of biodiversity was observed in all samples, with the occurrence of Lactobacillus paracollinoides, Lactobacillus acidipiscis and Pediococcus parvulus. Correlation between bacterial OTU and volatile organic compounds (VOCs) revealed that, aldehydes and alcohol compounds exhibited a positive correlation with Proteobacteria, while several esters with LAB and Hafnia. In particular, esters, associated with fruity and floral notes, were positively correlated to L. paracollinoides, L. acidipiscis, and P. parvulus species. Although the VOCs amounts were sample-specific, overall aldehydes were mostly produced at the beginning of the fermentation, while acids, alcohols and esters at the end of the process.

LAB;Starter cultures;Table olives;VOCs

pubmed

Intra-abdominal Pressure Monitoring in Open Abdomen Management with Dynamic Abdominal Closure.

The importance of elevated intra-abdominal pressure (IAP) and abdominal compartment syndrome (ACS) have been recognized in critical care for its potential damaging effects. But, quantification of IAP values may be useful as a clinical tool for determining efficacy of coughing and straining for functional recovery of OA patients. We would like to evaluate IAP generated in an OA patient and the effect of negative pressure therapy (NPT) and dynamic abdominal closure systems (ABRA) on the IAP values at rest and during coughing and straining and compare those with IAP measurements of closed abdomen after standard open elective colorectal surgery (non-OA). Eight OA and eight non-OA patients were included in this study. OA patient with NPT and ABRA (OA + NA), OA patient without NPT and ABRA completely unbraced (OA-NA) (NA stands for NPT and ABRA), and non-OA patients underwent IAP measurements at rest, during coughing, and during straining via transurethral catheter. There was no difference in the mean of IAP measurement at rest in OA-NA (6.1 mmHg), OA + NA (6.5 mmHg), and non-OA (6.0 mmHg) patients. During coughing, IAP of OA-NA, OA + NA, and non-OA patients were 11.5, 19.1, and 22.0 mmHg and during straining, IAP of OA-NA, OA + NA, and non-OA patients were 11.5, 17.5, and 23.5 mmHg, respectively. Application of NPT in conjunction with ABRA did not increase IAP at rest but provided significant IAP increase in OA + NA patients, when compared to OA-NA patients during coughing and straining. NPT in conjunction with ABRA offers the advantage of increase of IAP during coughing and straining.

Coughing;Dynamic abdominal closure;Intra-abdominal pressure;Negative pressure system;Open abdomen;Straining

pubmed

In Situ Growth of Mesoporous Silica with Drugs on Titanium Surface and Its Biomedical Applications.

Mesoporous silica has been developed for the modification of titanium surfaces that are used as implant materials. Yet, the traditional modification methods failed to effectively construct mesoporous silica on the titanium surface evenly and firmly, in which the interaction between mesoporous silica and titanium was mainly physical. Here, in situ growth of mesoporous silica on a titanium surface was performed using a simple evaporation-induced self-assembly strategy. Meantime, in situ introduction of drugs (heparin and vancomycin) to mesoporous silica was also adopted to improve the drug-loading amount. Both the above-mentioned processes were completed at the same time. Transmission electron microscopy, N₂ adsorption-desorption isotherms, Fourier transform infrared spectroscopy, scanning electron microscopy, and water contact angle measurements were used to characterize the structure of the mesoporous silica film. Results indicated that the mesoporous silica film that in situ grew on the titanium surface was smooth, thin, transparent, and stable. Cytotoxicity, proliferation performance of osteoblast cells, and in vitro and in vivo studies of the antibacterial activity of the coating were tested. This is the first study to modify the titanium surface by the in situ growth of a mesoporous silica coating with two kinds of drugs. The stability of the mesoporous silica coating can be attributed to the chemical bonding between dopamine and silicon hydroxyl of the mesoporous silica coating, and the smooth surface of mesoporous silica is a result of the method of in situ growth. The large amount of drug-loading also could be ascribed to the in situ introduction of drugs during the synthetic process. The strategy proposed in this work will bring more possibilities for the preparation of advanced functional materials based on the combination of mesoporous structure and metallic materials.

biomedical applications;drug delivery;in situ growth;mesoporous silica coatings;titanium surface

pubmed

Neural Biomarker and Early Temperament Predict Increased Internalizing Symptoms After a Natural Disaster.

Although most people will experience a traumatic event at some point in their life, only some will develop significant psychological symptoms in the aftermath. In the current study, we use a preexisting longitudinal study located in Long Island to examine the impact of Hurricane Sandy on internalizing symptoms in a large sample of children. We focused on temperamental fear and a biomarker of risk for anxiety, the error-related negativity (ERN). The ERN is a negative deflection in the event-related potential (ERP) occurring when individuals make mistakes and is increased in anxious individuals. The final sample consisted of 223 children who had undergone an observational assessment of fear at age 3 years and an electroencephalogram assessment of the ERN at age 6 years. At the age 9 year assessment, internalizing symptoms were assessed, and then again after the hurricane (∼65 weeks later). A significant three-way interaction among fearfulness, hurricane stressors, and the ERN in predicting posthurricane increases in internalizing symptoms suggested that children who were high in fear at age 3 years and experienced elevated hurricane stressors were characterized by subsequent increases in internalizing symptoms, but only when they were also characterized by an increased ERN at age 6 years. These findings support a diathesis-stress model, suggesting that early temperament and prestressor biological markers confer risk for increased psychological symptoms following environmental stressors.

anxiety;biomarker;developmental psychopathology;error-related negativity;trauma

pubmed

A new aerobic chemolithoautotrophic arsenic oxidizing microorganism isolated from a high Andean watershed.

Biological arsenic oxidation has been suggested as a key biogeochemical process that controls the mobilization and fate of this metalloid in aqueous environments. To the best of our knowledge, only four aerobic chemolithoautotrophic arsenite-oxidizing (CAO) bacteria have been shown to grow via direct arsenic oxidation and to have the essential genes for chemolithoautotrophic arsenite oxidation. In this study, a new CAO bacterium was isolated from a high Andean watershed evidencing natural dissolved arsenic attenuation. The bacterial isolate, designated TS-1, is closely related to the Ancylobacter genus, in the Alphaproteobacteria class. Results showed that TS-1 has genes for arsenite oxidation and carbon fixation. The dependence of bacterial growth from arsenite oxidation was demonstrated. In addition, a mathematical model was suggested and the kinetic parameters were obtained by simultaneously fitting the biomass growth, arsenite depletion curves, and arsenate production. This research increases the knowledge of chemolithoautotrophic arsenic oxidizing microorganisms and its potential role as a driver for natural arsenic attenuation.

Arsenic;Biogeochemistry;Biotransformation;Chemolithoautotrophic arsenite-oxidizing (CAO) bacteria

pubmed

Alcohol screening among young people: a prospective study from the Swiss Sentinel Surveillance System (Sentinella) of physicians' a priori opinions.

Systematic screening for excessive alcohol use among young people is recommended but rarely implemented. Family practitioners tend to select patients for screening, based on their preliminary subjective opinions, which may be biased. To evaluate the ability of family practitioners to identify excessive alcohol use among young people prior to screening them. This prospective study was conducted through Sentinella, an epidemiological network involving 150 family practitioners across Switzerland. All patients aged 10-24 years old, consulting participating physicians between January 1 and December 31, 2014 were eligible. First, physicians were asked to give their a priori opinion about patients' potential alcohol use. Subsequently, they asked two screening questions: (i) 'Do you drink alcohol?' and (ii) 'How many times have you had 5 (4 for girls) or more standard drinks in one day over the past year?'. Excessive alcohol use was defined as ≥1 episode of binge drinking a month. Physicians' a priori opinions were regarded as a screening test and were compared with patients' answers. 7723 patients were eligible for analysis. Their mean age (SD) was 17.3(4.0) years. The two screening questions identified 3559 (46.1%) and 509 (6.6%) patients who consumed alcohol occasionally and regularly, respectively. 406 patients (5.3%) reported excessive alcohol use. Physicians' a priori opinions had a sensitivity of 26.4% and a positive predictive value of 35.5% for the identification of excessive alcohol use. The systematic use of a screening tool should be preferred over family practitioners' subjective opinions to identify excessive alcohol use in young people.

Adolescent;alcohol drinking;binge drinking;epidemiological monitoring;general practitioners;paediatrics

pubmed

Structure, Immunogenicity, and Protective Mechanism of an Engineered Enterovirus 71-Like Particle Vaccine Mimicking 80S Empty Capsid.

Enterovirus 71 (EV71) is the major causative agent of severe hand, foot, and mouth disease, which affects millions of young children in the Asia-Pacific region annually. In this study, we engineered a novel EV71 virus-like particle (VLP) that lacks VP4 (therefore designated VLP_ΔVP4) and investigated its structure, antigenicity, and vaccine potential. The cryo-electron microscopy (cryo-EM) structure of VLP_ΔVP4 was reconstructed to 3.71-Å resolution. Results from structural and biochemical analyses revealed that VLP_ΔVP4 resembles the end product of the viral uncoating process, the 80S empty capsid. VLP_ΔVP4 is able to elicit high-titer neutralizing antibodies and to fully protect mice against lethal viral challenge. Mechanistic studies showed that, at the cellular level, the anti-VLP_ΔVP4 sera exert neutralization effects at both pre- and postattachment stages by inhibiting both virus attachment and internalization, and at the molecular level, the antisera can block multiple interactions between EV71 and its key receptors. Our study gives a better understanding of EV71 capsid assembly and provides important information for the design and development of new-generation vaccines for EV71, and perhaps for other enteroviruses, as well.<b>IMPORTANCE</b> Enterovirus 71 (EV71) infection may lead to severe hand, foot, and mouth disease, with significant morbidity and mortality. Knowledge regarding EV71 particle assembly remains limited. Here, we report the generation and characterization of a novel EV71 virus-like particle that lacks the VP4 capsid subunit protein. This particle, termed VLP_ΔVP4, structurally mimics the 80S empty capsid, which is the end stage of EV71 uncoating. We further show that VLP_ΔVP4 exhibits desirable immunogenicity and protective efficacy in proof-of-concept studies. In addition, the inhibitory mechanisms of the VLP_ΔVP4-induced antibodies are unraveled at both the cellular and molecular levels. Our work provides the first evidence of picornaviral particle assembly in the complete absence of VP4 and identifies VLP_ΔVP4 as an improved EV71 vaccine candidate with desirable traits. These findings not only enhance our understanding of particle assembly and uncoating of picornaviruses, but also provide important information for structure-guided vaccine design for EV71 and other enteroviruses.

cryo-EM;enterovirus 71;structure;uncoating;vaccine;virus-like particle

pubmed

Volatile Metabolomic Composition of <i>Vitex</i> Species: Chemodiversity Insights and Acaricidal Activity.

The <i>Vitex</i> genus (Lamiaceae) produces a plethora of metabolites that include ecdysteroids and terpenoids, some of which have demonstrated insect repellent properties. The volatile composition of several members of this genus has not been chemically defined, as many taxa are endemic to remote ecosystems. In this study, leaves were collected from the northeast of Brazil from <i>Vitex capitata, V. megapotamica, V. gardneriana</i>, and <i>V. rufescens</i> plants and examined for their chemical profile via GC-MS/FID of essential oil extracts. The analyses showed a diversity of terpenoids. Of particular note were seven-member ring sesquiterpenes which were present in great abundance; a dendrogram showed clades separating by the production of bicyclogermacrene, aromadendrane and 5,10-cycloaromadendrane sesquiterpenoids for the four species. Comparison of volatile metabolite profiles to 13 other <i>Vitex</i> species showed strong similarities in the production of some monoterpenes, but varied by their production of larger terpenes, especially those with gem-dimethylcyclopropyl subunits on seven-member ring compounds. From this work, we suggest that the sesquiterpene skeleton with seven member rings is a good chemosystematic biomarker candidate for the <i>Vitex</i> genus. Separation using this biomarker was then validated using Inter-Simple Sequence Repeat profiling. Lastly, experiments examining the toxicity of these four oils against the coconut mite <i>Aceria guerreronis</i> showed that only the oil of <i>V. gardneriana</i> had strong acaricidal activity, with an LC₅₀ of 0.85 mg/mL, thus demonstrating its potential for use as a natural pesticide.

Vitex capitata;Vitex gardneriana;Vitex megapotamica;Vitex rufescens;chemodiversity

pubmed

What next after basal insulin? Treatment intensification with lixisenatide in Asian patients with type 2 diabetes mellitus.

There is increasing evidence that the pathophysiology of type 2 diabetes mellitus (T2DM) in Asian patients differs from that in Western patients, with early phase insulin deficiencies, increased postprandial glucose excursions, and increased sensitivity to insulin. Asian patients may also experience higher rates of gastrointestinal adverse events associated with glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as nausea and vomiting, compared with their Western counterparts. These factors should be taken into consideration when selecting therapy for basal insulin treatment intensification in Asian patients. However, the majority of studies to establish various agents for treatment intensification in T2DM have been conducted in predominantly Western populations, and the levels of evidence available in Chinese or Asian patients are limited. This review discusses the different mechanisms of action of short-acting, prandial, and long-acting GLP-1RAs in addressing hyperglycemia, and describes the rationale and available clinical data for basal insulin in combination with the short-acting prandial GLP-1RA lixisenatide, with a focus on treatment of Asian patients with T2DM.

2型糖尿病;insulin;lixisenatide;type 2 diabetes mellitus;利西那肽;胰岛素

pubmed

TGF-β1/p53 signaling in renal fibrogenesis.

Fibrotic disorders of the renal, pulmonary, cardiac, and hepatic systems are associated with significant morbidity and mortality. Effective therapies to prevent or curtail the advancement to organ failure, however, remain a major clinical challenge. Chronic kidney disease, in particular, constitutes an increasing medical burden affecting >15% of the US population. Regardless of etiology (diabetes, hypertension, ischemia, acute injury, urologic obstruction), persistently elevated TGF-β1 levels are causatively linked to the activation of profibrotic signaling networks and disease progression. TGF-β1 is the principal driver of renal fibrogenesis, a dynamic pathophysiologic process that involves tubular cell injury/apoptosis, infiltration of inflammatory cells, interstitial fibroblast activation and excess extracellular matrix synthesis/deposition leading to impaired kidney function and, eventually, to chronic and end-stage disease. TGF-β1 activates the ALK5 type I receptor (which phosphorylates SMAD2/3) as well as non-canonical (e.g., src kinase, EGFR, JAK/STAT, p53) pathways that collectively drive the fibrotic genomic program. Such multiplexed signal integration has pathophysiological consequences. Indeed, TGF-β1 stimulates the activation and assembly of p53-SMAD3 complexes required for transcription of the renal fibrotic genes plasminogen activator inhibitor-1, connective tissue growth factor and TGF-β1. Tubular-specific ablation of p53 in mice or pifithrin-α-mediated inactivation of p53 prevents epithelial G₂/M arrest, reduces the secretion of fibrotic effectors and attenuates the transition from acute to chronic renal injury, further supporting the involvement of p53 in disease progression. This review focuses on the pathophysiology of TGF-β1-initiated renal fibrogenesis and the role of p53 as a regulator of profibrotic gene expression.

Fibrosis;Kidney;Plasminogen activator Inhibitor-1;TGF-β1;p53

pubmed

Willingness to Pay for Complementary Health Care Insurance in Iran.

Complementary health insurance is increasingly used to remedy the limitations and shortcomings of the basic health insurance benefit packages. Hence, it is essential to gather reliable information about the amount of Willingness to Pay (WTP) for health insurance. We assessed the WTP for health insurance in Iran in order to suggest an affordable complementary health insurance. The study sample consisted of 300 household heads all over provinces of Iran in 2013. The method applied was double bounded dichotomous choice and open-ended question approach of contingent valuation. The average WTP for complementary health insurance per person per month by double bounded dichotomous choice and open-ended question method respectively was 199000 and 115300 Rials (8 and 4.6 USD, respectively). Household's heads with higher levels of income and those who worked had more WTP for the health insurance. Besides, the WTP increased in direct proportion to the number of insured members of each household and in inverse proportion to the family size. The WTP value can be used as a premium in a society. As an important finding, the study indicated that the households were willing to pay higher premiums than currently collected for the complementary health insurance coverage in Iran. This offers the policy makers the opportunity to increase the premium and provide good benefits package for insured people of country then better risk pooling.

Contingent valuation method;Health insurance;Iran;Willingness to pay

pubmed

Care management process of breast cancer in primary health-care system, Golestan Province, Iran, 2013-2014.

Health-care service processes need to be assessed over time. We aimed to assess the breast cancer care process in primary health system of Golestan Province, North Iran. To perform a descriptive cross-sectional study, information on breast cancer care processes in primary health-care system was collected using a "collecting form" from 234 health houses, 29 health posts, 44 urban health centers, and 80 rural health centers in Golestan Province. Registered data in the centers and patients' journal were used in data collection. Moreover, we collected data on all women who were diagnosed with breast cancer in 2014 to know the characteristics of the patients. Around 50% of health workers at rural or urban area were trained on breast cancer. Moreover, 2% of women from general population in rural area and around 6% of them in urban area have been trained on breast cancer. Mean age of women diagnosed with breast cancer was 48 ± 10 years and 40.2% of them were affected at age between 43 and 52 years. The results showed that 18.9% of women have received their information through self-study before the diagnosis of breast cancer while 53.8% of them received their information from the private clinics after diagnosis of breast cancer. The process of breast cancer care in Golestan Province needs to be improved in the primary health-care level. Both inter- and multi-disciplinary activities are needed.

Breast cancer;care process;health service management;primary health care

pubmed

Considerations on the harvesting site and donor derivation for mesenchymal stem cells-based strategies for diabetes.

Mesenchymal Stem Cells (MSCs) possess important characteristics that could be exploited in therapeutic strategies for Type 1 Diabetes (T1D) and for certain complications of Type 2 Diabetes (T2D). MSCs can inhibit autoimmune, alloimmune and inflammatory processes. Moreover, they can promote the function of endogenous and transplanted pancreatic islets. Furthermore, they can stimulate angiogenesis. MSC functions are largely mediated by their secretome, which includes growth factors, exosomes, and other extracellular vesicles. MSCs have shown a good safety profile in clinical trials. MSC-derived exosomes are emerging as an alternative to the transplantation of live MSCs. MSCs harvested from different anatomical locations (e.g. bone marrow, umbilical cord, placenta, adipose tissue, and pancreas) have shown differences in gene expression profiles and function. Data from clinical trials suggest that umbilical cord-derived MSCs could be superior to bone marrow-derived MSCs for the treatment of T1D. Autologous MSCs from diabetic patients may present abnormal functions. BM-MSCs from T1D patients exhibit gene expression differences that may impact in vivo function. BM-MSCs from T2D patients seem to be significantly impaired due to the T2D diabetic milieu. In this review, we highlight how the harvesting site and donor derivation can affect the efficacy of MSC-based treatments for T1D and T2D.

Islet transplantation;beta cell replacement;cell therapy;stem cells;type 1 diabetes;xenotransplantation

pubmed

Constraint-Induced Aphasia Therapy in the Acute Stage: What Is the Key Factor for Efficacy? A Randomized Controlled Study.

Constraint-induced aphasia therapy (CIAT) has proven effective in patients with subacute and chronic forms of aphasia. It has remained unclear, however, whether intensity of therapy or constraint is the relevant factor. Data about intensive speech and language therapy (SLT) are conflicting. To identify the effective component of CIAT and assess the feasibility of SLT in the acute stage after stroke. A total of 60 patients with aphasia (68.2 ± 11.7 years) were enrolled 18.9 days after first-ever stroke. They were randomly distributed into 3 groups: (1) CIAT group receiving therapy for 3 hours per day (10 workdays, total 30 hours); (2) conventional communication treatment group, with same intensity without constraints; and (3) control group receiving individual therapy twice a day as well as group therapy (total 14 hours). Patients were assessed pretreatment and posttreatment using the Aachener Aphasia Test (primary end point: token test) and the Communicative Activity Log (CAL). Pretreatment, there were no between-group differences. Posttreatment, all groups showed significant improvements without between-group differences. It was found that 14 hours of aphasia therapy administered within 2 weeks as individual therapy, focusing on individual deficits, combined with group sessions has proven to be most efficient. This approach yielded the same outcome as 30 hours of group therapy, either in the form of CIAT or group therapy without constraints. SLT in an intensive treatment schedule is feasible and was well tolerated in the acute stage after stroke.

communication disorders;language and speech disorder rehabilitation;stroke

pubmed

Interventions for the prevention and treatment of disability due to acquired joint contractures in older people: a systematic review.

acquired joint contractures have significant effects on quality of life and functioning. to determine the effects of interventions to prevent and treat disabilities in older people with acquired joint contractures. systematic search (last 8/2016) via Cochrane Library, PubMed, EMBASE, PEDro, CINAHL, trial registries, reference lists of retrieved articles and scientific congress pamphlets. Controlled and randomised controlled trials in English or German comparing an intervention with another intervention or standard care were included. Two independent researchers performed the selection of publications, data extraction and critical appraisal. seventeen studies with 992 participants met the inclusion criteria: 16 randomised controlled trials and 1 controlled trial (nursing homes = 4, community settings = 13). The methodological quality of the studies varied. Splints were examined in four studies, stretching exercises in nine studies, and ultrasound, passive movement therapy, bed-positioning and group exercise were each examined in one study. Studies on splints revealed inconclusive results regarding joint mobility or spasticity. Five of seven studies that assessed active stretching programmes for healthy older people reported statistically significant effects on joint mobility in favour of the intervention. Pain, quality of life, activity limitations and participation restrictions were rarely assessed. the evidence for the effectiveness of interventions to prevent and treat disability due to joint contractures is weak, particularly for established nursing interventions such as positioning and passive movement. Better understanding is required regarding the delivery of interventions, such as their intensity and duration. In addition to functional issues, activities and social participation should also be studied as outcomes.

contracture;older people;systematic review

pubmed

Nutrition Counselling Practices among General Practitioners in Croatia.

Chronic non-communicable diseases are a significant public health problem and imbalanced nutrition is one of the most significant risk factor for them. The objective of this study was to examine Croatia's general practitioners' nutrition counselling practice and determine the factors that influence such practice. A cross-sectional study was conducted among 444 (17.0%) randomly selected general practitioners (GPs) in Croatia from May to July 2013 via a 32-item anonymous questionnaire. Study showed that 77.0% of participants had provided nutrition counselling exclusively to patients with specific health risks; 18.7% participants had provided nutrition counselling for all patients, regardless of their individual risks, while 4.3% had not provide nutrition counselling. As the most significant stimulating factor for implementing nutrition counselling in their daily work with patients, 55.6% of the participants identified personal interest regarding nutrition and the effects it has on health. The latter factor was more frequently emphasized among female general practitioners (<i>p</i> < 0.001) and general practitioners without chronic diseases (<i>p</i> < 0.001). The most significant barrier for nutrition counselling was lack of time (81.6%). It is necessary to make additional efforts to increase the frequency of nutrition counselling provided by general practitioners in Croatia. The majority of Croatian general practitioners could increase their nutrition counselling practice in order to promote balanced nutrition and improve the overall health status of their patients.

Croatia;counselling;general practitioners;nutrition;primary health care

pubmed

Compensation mechanisms that improve distractor filtering are short-lived.

We investigated possible compensation mechanisms for improving filtering of distractors from entering visual Working Memory (WM). Participants preformed a change-detection task in which three targets, six targets, or three targets along with three distractors (the filtering trial) were randomly presented. In six experiments, we tried to reduce the filtering cost, calculated as the difference in accuracy between the three targets and the filtering condition, by either cueing the possible locations of the distractors using placeholders (that could be either fixed throughout the experiment or change every trial; i.e., location cue), or by providing the location cue coupled with a warning cue singling the upcoming filtering trial. Results revealed that the filtering cost was not reduced by a fixed location cue (Experiment 1 and Experiment 5). However, the fixed location cue coupled with a warning cue (Experiment 2 and Experiment 5) or a location cue that changed positions every trial (Experiment 6), were sufficient to reduce the filtering cost. Additionally, longer preparation interval for filtering trials did not further reduce the filtering cost (Experiment 3). We argue these findings support that in the context of visual WM, spatial filtering settings can only be held for a limited amount of time. Thus, these filtering settings must be reactivated in order to be effective and to reduce the filtering cost.

Distractor suppression;Filtering ability;Spatial attention;Visual working memory

pubmed

Recent advances in the chemical synthesis of sugar-nucleotides.

Diphosphate;Nucleoside;Pyrophosphorylation;Sugar-1-phosphate;Sugar-nucleotide

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CRMP1 and CRMP4 are required for proper orientation of dendrites of cerebral pyramidal neurons in the developing mouse brain.

Neural circuit formation is a critical process in brain development. Axon guidance molecules, their receptors, and intracellular mediators are important to establish neural circuits. Collapsin response mediator proteins (CRMPs) are known intercellular mediators of a number of repulsive guidance molecules. Studies of mutant mice suggest roles of CRMPs in dendrite development. However, molecular mechanisms of CRMP-mediated dendritic development remain to elucidate. In this study, we show abnormal orientation of basal dendrites (extension to deeper side) of layer V pyramidal neurons in the cerebral cortex of CRMP4-/- mice. Moreover, we observed severe abnormality in orientation of the basal dendrites of these neurons in double knockout of CRMP1 and 4, suggesting redundant functions of these two genes. Redundant gene functions were also observed in proximal bifurcation phenotype in apical dendrites of hippocampal CA1 pyramidal neurons. These results indicate that CRMP1 and CRMP4 regulate proper orientation of the basal dendrites of layer V neurons in the cerebral cortex.

CRMP;Dendrite;Development;Guidance

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Extracts of black and brown rice powders improve hepatic lipid accumulation via the activation of PPARα in obese and diabetic model mice.

Rice powder extract (RPE) from black and brown rice (Oryza sativa L. indica) improves hepatic lipid accumulation in obese and diabetic model mice via peroxisomal fatty acid oxidation. RPE showed PPARα agonistic activity which did not differ between black and brown RPE despite a higher anthocyanin content in black RPE.

PPAR;fatty acid oxidation;lipid metabolism;liver;rice powder

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Nonstrangulating intestinal infarctions associated with Strongylus vulgaris: Clinical presentation and treatment outcomes of 30 horses (2008-2016).

Strongylus vulgaris is re-emerging in horses kept under surveillance-based parasite control regimens. Information on nonstrangulating intestinal infarction associated with S. vulgaris is needed to improve recognition of the condition. To describe the typical clinical presentation, laboratory findings, gross pathology, treatment and outcome of horses with nonstrangulating intestinal infarction. Retrospective case series. Nonstrangluating intestinal infarction was diagnosed in 30 horses with a localised intestinal infarction with concurrent signs of S. vulgaris migration and no signs of intestinal strangulation or enterocolitis. Data were obtained from medical records in the period 2008-2016. Long-term follow-up information was obtained by telephonic interviews. Levels of S. vulgaris-specific antibodies were retrospectively assessed. Associations between nonstrangulating intestinal infarction and selected variables were evaluated using Fisher's exact and Mann-Whitney U tests. The most consistent findings at admission were mild colic of >24 h duration without signs of shock or strangulated intestine, increased peritoneal fluid WBC (>5 × 10⁹ /L), increased serum amyloid A (SAA) concentration and a positive S. vulgaris-specific antibody titre. Medical treatment was attempted in nine horses with none surviving. Exploratory laparotomy was performed in 21 horses. Eleven horses were subjected to euthanasia intraoperatively due to the presumed poor prognosis. Of the nine horses, three (33%) undergoing intestinal resection survived to discharge. The surviving horses were alive and returned to athletic function for at least 2 years following discharge. Only nine of the 30 horses underwent resection of the infarcted intestine, and the prognosis for surgical intervention in nonstrangulating intestinal infarction is, therefore, difficult to estimate. In areas where S. vulgaris is prevalent, nonstrangulating intestinal infarction should be considered as a differential diagnosis in horses presenting with mild colic and peritonitis. Survival of nonstrangulating intestinal infarction is possible in cases where surgical intervention with resection of the infarcted intestine is feasible. The summary is available in Spanish - see Supporting Information.

colic;horse;large strongyle;thromboembolic

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Adverse Childhood Experiences Are Linked to Age of Onset and Reading Recognition in Multiple Sclerosis.

Adverse childhood experiences (ACEs) exert a psychological and physiological toll that increases risk of chronic conditions, poorer social functioning, and cognitive impairment in adulthood. To investigate the relationship between childhood adversity and clinical disease features in multiple sclerosis (MS). Sixty-seven participants with MS completed the ACE assessment and neuropsychological assessments as part of a larger clinical trial of cognitive remediation. Adverse childhood experience scores, a measure of exposure to adverse events in childhood, significantly predicted age of MS onset (<i>r</i> = -0.30, <i>p</i> = 0.04). ACEs were also linked to reading recognition (a proxy for premorbid IQ) (<i>r</i> = -0.25, <i>p</i> = 0.04). ACE scores were not related to age, current disability, or current level of cognitive impairment measured by the Symbol Digit Modalities Test (SDMT). Childhood adversity may increase the likelihood of earlier age of onset and poorer estimated premorbid IQ in MS.

adverse childhood experiences;age of onset;childhood abuse;multiple sclerosis;premorbid IQ

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Chemogenetic inhibition reveals midline thalamic nuclei and thalamo-accumbens projections mediate cocaine-seeking in rats.

Drug addiction is a chronic disease that is shaped by alterations in neuronal function within the cortical-basal ganglia-thalamic circuit. However, our understanding of how this circuit regulates drug-seeking remains incomplete, and relapse rates remain high. The midline thalamic nuclei are an integral component of the cortical-basal ganglia-thalamic circuit and are poised to mediate addiction behaviors, including relapse. It is surprising that little research has examined the contribution of midline thalamic nuclei and their efferent projections in relapse. To address this, we expressed inhibitory, G_i/o -coupled DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) in a subset of the midline thalamic nuclei or in midline thalamic nuclei neurons projecting to either the nucleus accumbens or the amygdala. We examined the effect of transiently decreasing activity of these neuronal populations on cue-induced and cocaine-primed reinstatement of cocaine-seeking. Reducing activity of midline thalamic nuclei neurons attenuated both cue-induced and cocaine-primed reinstatement, but had no effect on cue-induced reinstatement of sucrose-seeking or locomotor activity. Interestingly, attenuating activity of efferent projections from the anterior portion of midline thalamic nuclei to the nucleus accumbens blocked cocaine-primed reinstatement but enhanced cue-induced reinstatement. Decreasing activity of efferent projections from either the posterior midline thalamic nuclei to the nucleus accumbens or the midline thalamic nuclei to amygdala had no effect. These results reveal a novel contribution of subsets of midline thalamic nuclei neurons in drug-seeking behaviors and suggest that modulation of midline thalamic nuclei activity may be a promising therapeutic target for preventing relapse.

DREADDs;addiction;cocaine;neural circuits;rat

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Autologous Cord Blood Infusions Are Safe and Feasible in Young Children with Autism Spectrum Disorder: Results of a Single-Center Phase I Open-Label Trial.

Despite advances in early diagnosis and behavioral therapies, more effective treatments for children with autism spectrum disorder (ASD) are needed. We hypothesized that umbilical cord blood-derived cell therapies may have potential in alleviating ASD symptoms by modulating inflammatory processes in the brain. Accordingly, we conducted a phase I, open-label trial to assess the safety and feasibility of a single intravenous infusion of autologous umbilical cord blood, as well as sensitivity to change in several ASD assessment tools, to determine suitable endpoints for future trials. Twenty-five children, median age 4.6 years (range 2.26-5.97), with a confirmed diagnosis of ASD and a qualified banked autologous umbilical cord blood unit, were enrolled. Children were evaluated with a battery of behavioral and functional tests immediately prior to cord blood infusion (baseline) and 6 and 12 months later. Assessment of adverse events across the 12-month period indicated that the treatment was safe and well tolerated. Significant improvements in children's behavior were observed on parent-report measures of social communication skills and autism symptoms, clinician ratings of overall autism symptom severity and degree of improvement, standardized measures of expressive vocabulary, and objective eye-tracking measures of children's attention to social stimuli, indicating that these measures may be useful endpoints in future studies. Behavioral improvements were observed during the first 6 months after infusion and were greater in children with higher baseline nonverbal intelligence quotients. These data will serve as the basis for future studies to determine the efficacy of umbilical cord blood infusions in children with ASD. Stem Cells Translational Medicine 2017;6:1332-1339.

Autism spectrum disorder;Autologous umbilical cord blood;Cell therapy

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Integrative overview of the herpetofauna from Serra da Mocidade, a granitic mountain range in northern Brazil.

The Brazilian mountain ranges from the Guiana Shield highlands are largely unexplored, with an understudied herpetofauna. Here the amphibian and reptile species diversity of the remote Serra da Mocidade mountain range, located in extreme northern Brazil, is reported upon, and biogeographical affinities and taxonomic highlights are discussed. A 22-days expedition to this mountain range was undertaken during which specimens were sampled at four distinct altitudinal levels (600, 960, 1,060 and 1,365 m above sea level) using six complementary methods. Specimens were identified through an integrated approach that considered morphological, bioacoustical, and molecular analyses. Fifty-one species (23 amphibians and 28 reptiles) were found, a comparable richness to other mountain ranges in the region. The recorded assemblage showed a mixed compositional influence from assemblages typical of other mountain ranges and lowland forest habitats in the region. Most of the taxa occupying the Serra da Mocidade mountain range are typical of the Guiana Shield or widely distributed in the Amazon. Extensions of known distribution ranges and candidate undescribed taxa are also recorded. This is the first herpetofaunal expedition that accessed the higher altitudinal levels of this mountain range, contributing to the basic knowledge of these groups in remote areas.

Amazonia;Pantepui;bioacoustics;biogeography;lowland forest;morphology;mountain;mtDNA;phylogenetic relationships

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