Rediscovery and redefinition of Malcolm Smith's Trimeresurus kanburiensis in Thailand, with a report of envenoming.
Three specimens of an apparently rare pit viper, Trimeresurus kanburiensis, previously known only from the holotype collected in 1928, were found near Kanchanaburi in western Thailand. One of the snakes had bitten a young woman on the foot. She experienced severe local pain, swelling that involved the whole of the bitten limb and beyond, local bruising, recurrent shock, peripheral leucocytosis and a mild coagulopathy, but she recovered despite the lack of specific treatment. The severity of envenoming augurs ill for a young or debilitated patient bitten by this species. During the last 20 years, the name T. kanburiensis has been used incorrectly for the medically more important species, T. purpureomaculatus. Conversely, the name T. purpureomaculatus has been misapplied to specimens of a species of viper from southern Thailand which we consider very similar to T. kanburiensis, but for which a new specific name, 'T. venustus', has been suggested recently. The rediscovery and redefinition of T. kanburiensis should prevent further confusion.


The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts.
Epidermal growth factor receptor (EGFR) inhibitors such as gefitinib show antitumor activity in a subset of non-small cell lung cancer (NSCLC) patients having mutated EGFR. Recent work shows that phosphatidylinositol-3-kinase (PI3-K) is coupled to the EGFR only in NSCLC cell lines expressing ErbB-3 and that EGFR inhibitors do not inhibit PI3-K signaling in these cells. The central role PI3-K plays in cell survival suggests that a PI3-K inhibitor offers a strategy to increase the antitumor activity of EGFR inhibitors in resistant NSCL tumors that do not express ErbB-3. We show that PX-866, a PI3-K inhibitor with selectivity for p110alpha, potentiates the antitumor activity of gefitinib against even large A-549 NSCL xenografts giving complete tumor growth control in the early stages of treatment. A-549 xenograft phospho-Akt was inhibited by PX-866 but not by gefitinib. A major toxicity of PX-866 administration was hyperglycemia with decreased glucose tolerance, which was reversed upon cessation of treatment. The decreased glucose tolerance caused by PX-866 was insensitive to the AMP-activated protein kinase inhibitor metformin but reversed by insulin and by the peroxisome proliferator-activated receptor-gamma activator pioglitazone. Prolonged PX-866 administration also caused increased neutrophil counts. Thus, PX-866, by inhibiting PI3-K signaling, may have clinical use in increasing the response to EGFR inhibitors such as gefitinib in patients with NSCLC and possibly in other cancers who do not respond to EGFR inhibition.


Diet and pregnancy status in Australian women.
To investigate and report the diet quality of young Australian women by pregnancy status. Pregnancy status was defined as pregnant (n 606), trying to conceive (n 454), had a baby in the last 12 months (n 829) and other (n 5597). The Dietary Questionnaire for Epidemiological Studies was used to calculate diet quality using the Australian Recommended Food Score (ARFS) methodology. Nutrient intakes were compared with the Nutrient Reference Values for Australia and New Zealand. A population-based cohort participating in the Australian Longitudinal Study on Women's Health (ALSWH). A nationally representative sample of Australian women, aged 25 to 30 years, who completed Survey 3 of the ALSWH. The 7486 women with biologically plausible energy intake estimates, defined as >4.5 but <20.0 MJ/d, were included in the analyses. Pregnancy status was not significantly predictive of diet quality, before or after adjusting for area of residence and socio-economic status. Pregnant women and those who had given birth in the previous 12 months had marginally higher ARFS (mean (se): 30.2 (0.4) and 30.2 (0.3), respectively) than 'other' women (29.1 (0.1)). No single food group accounted for this small difference. Across all pregnancy categories there were important nutrients that did not meet the current nationally recommended levels of intake, including dietary folate and fibre. Women do not appear to consume a wider variety of nutritious foods when planning to become pregnant or during pregnancy. Many young Australian women are failing to meet key nutrient targets as nationally recommended.


Damage and recovery of the bone marrow microenvironment induced by cancer chemotherapy - potential regulatory role of chemokine CXCL12/receptor CXCR4 signalling.
The bone marrow microenvironment houses haematopoietic stem cells (HSC), mesenchymal stem cells (MSC) and their progeny, supports haematopoiesis, osteogenesis, osteoclastogenesis, and adipogenesis. It plays a key role in maintaining homeostatic production of erythroid, myeloid or lymphoid cells, appropriate bone mass and bone health throughout life. Through cell-cell adhesion and chemotactic axes, a reciprocal inter-dependent relationship exists between these two cell lineages. Following chemotherapy-induced myelosuppression observed in cancer patients, HSCs are induced to enter into the cell cycle in order to re-establish the damaged microenvironment. These cells not only have the capacity to mobilize to the peripheral blood, but the ability to repopulate the marrow cavity as required. However, depending on the dosage and length of chemotherapy treatment, complications in bone and bone marrow recovery occur. This may manifest as marrow haematopoietic depletion, high marrow fat content, reduced bone formation and aggravated osteoclastic bone resorption. Although the molecular and cellular mechanisms governing injured states of the marrow microenvironment are yet to be fully elucidated, many reports have demonstrated the CXCL12/CXCR4 axis plays an important role in regulating the two cell lineages. Their interaction maintains bone marrow homeostasis and orchestrates its regeneration following chemotherapy. This review explores movement of MSC and HSC, haematopoiesis, commitment of osteoblasts, osteoclasts, and adipocytes, as well as the major signalling pathways that regulate these cellular processes under chemotherapy-treated conditions. This review also discusses molecular targets that are being used clinically or are currently under investigation for preserving the bone marrow microenvironment during or enhancing recovery after chemotherapy.


Agoraphobic avoidance in patients with psychosis: Severity and response to automated VR therapy in a secondary analysis of a randomised controlled clinical trial.
The social withdrawal of many patients with psychosis can be conceptualised as agoraphobic avoidance due to a range of long-standing fears. We hypothesised that greater severity of agoraphobic avoidance is associated with higher levels of psychiatric symptoms and lower levels of quality of life. We also hypothesised that patients with severe agoraphobic avoidance would experience a range of benefits from an automated virtual reality (VR) therapy that allows them to practise everyday anxiety-provoking situations in simulated environments. 345 patients with psychosis in a randomised controlled trial were categorised into average, moderate, high, and severe avoidance groups using the Oxford Agoraphobic Avoidance Scale. Associations of agoraphobia severity with symptom and functioning variables, and response over six months to brief automated VR therapy (gameChange), were tested. Greater severity of agoraphobic avoidance was associated with higher levels of persecutory ideation, auditory hallucinations, depression, hopelessness, and threat cognitions, and lower levels of meaningful activity, quality of life, and perceptions of recovery. Patients with severe agoraphobia showed the greatest benefits with gameChange VR therapy, with significant improvements at end of treatment in agoraphobic avoidance, agoraphobic distress, ideas of reference, persecutory ideation, paranoia worries, recovering quality of life, and perceived recovery, but no significant improvements in depression, suicidal ideation, or health-related quality of life. Patients with psychosis with severe agoraphobic avoidance, such as being unable to leave the home, have high clinical need. Automated VR therapy can deliver clinical improvement in agoraphobia for these patients, leading to a number of wider benefits.


Factors Influencing Discharge Disposition After Ankle Arthrodesis.
Although functional and morbidity outcomes following ankle arthrodesis have been widely studied, patterns of health care resource utilization remain unclear. The purpose of this study was to identify preoperative and postoperative risk factors for nonroutine discharge following ankle arthrodesis. A secondary study aim was to determine risk factors associated with prolonged hospital stay. Using the National Health Discharge Survey (NHDS) database for the years 2001 through 2007, an estimated 40 941 patients having undergone ankle arthrodesis were identified and separated into those who were discharged to home (routine discharge) and those who were discharged to rehabilitation facilities (nonroutine discharge). Factors influencing discharge disposition and hospital length of stay were determined using multivariable binary logistic regression analysis. Risk factors for nonroutine discharge were increasing age, male sex, diabetes mellitus, atrial fibrillation, more than 1 general or surgery-related complication, additional days of care, and the 2005 to 2007 time period. Risk factors associated with prolonged hospital stay were advanced age, female sex, diabetes mellitus, more than 1 general or surgery-related complication, and the 2001 to 2004 time period. Early identification of these factors might prove useful for better allocation of resources and implementation of effective strategies aimed at preventing longer hospitalizations and nonroutine discharges in selected patients at risk. Level II, prognostic study.


Novel anterior segment phenotypes resulting from forkhead gene alterations: evidence for cross-species conservation of function.
Mutations in murine and human versions of an ancestrally related gene usually result in similar phenotypes. However, interspecies differences exist, and in the case of two forkhead transcription factor genes (FOXC1 and FOXC2), these differences include corneal or anterior segment phenotypes, respectively. This study was undertaken to determine whether such discrepancies provide an opportunity for identifying novel human-murine ocular phenotypes. Four pedigrees with early-onset glaucoma phenotypes secondary to segmental chromosomal duplications or deletions encompassing FOXC1 and 18 individuals from 9 FOXC2 mutation pedigrees underwent detailed ocular phenotyping. Subsequently, mice with mutations in Foxc1 or a related forkhead gene, Foxe3, were assessed for features of the human phenotypes. A significant increase in central corneal thickness was present in affected individuals from the segmental duplication pedigrees compared with their unaffected relatives (mean increase 13%, maximum 35%, P < 0.05). Alterations in corneal thickness were present in mice heterozygous and homozygous for Foxe3 mutations but neither in Foxc1 heterozygotes nor the small human segmental deletion pedigree. Mutations in FOXC2 resulted in ocular anterior segment anomalies. These were more severe and prevalent with mutations involving the forkhead domain. Normal corneal development is dependent on the precise dose and levels of activity of certain forkhead transcription factors. The altered corneal thickness attributable to increased forkhead gene dosage is particularly important, because it may affect the clinical management of certain glaucoma subtypes and lead to excessive treatment. The FOXC1 and Foxe3 data, taken together with the novel ocular phenotypes of FOXC2 mutations, highlight the remarkable cross-species conservation of function among forkhead genes.


Assessment of pfmdr 1 gene copy number by tandem competitive polymerase chain reaction.
The pfmdr 1 gene encodes a Plasmodium falciparum homologue of the human P-glycoprotein expressed on the surface of the parasite food vacuole. Variation in copy number and specific codon mutations of pfmdr 1 have been implicated in the development of parasite resistance to antimalarial drugs. We describe here the technique of Tandem-Competitive Polymerase Chain Reaction (TC-PCR), which allows accurate measurement of pfmdr 1 copy number in parasite DNA obtained directly from small quantities (100 microliters) of red blood cells. We reliably quantified pfmdr1 in previously well characterised strains of Plasmodium falciparum with differing pfmdr1 gene copy numbers using starting amounts of between 3,000 and 40,000 gene copies. We then used TC-PCR to determine pfmdr1 gene copy number in field specimens of venous blood taken from 10 patients with malaria contracted along the Thai-Burmese border. In this region of high grade parasite resistance to mefloquine greater than 70% of samples had a copy number greater than 1 of pfmdr1 determined with a repeatability coefficient of 0.58.


High dose transdermal nicotine for fast metabolizers of nicotine: a proof of concept placebo-controlled trial.
Smokers with a faster rate of nicotine metabolism, estimated using the ratio of 3'-hydroxycotinine (3-HC) to cotinine, have lower plasma nicotine levels and are more likely to relapse with 21 mg nicotine patch therapy, than smokers with slower rates of nicotine metabolism. Thus, faster metabolizers of nicotine may require a higher nicotine patch dose to achieve cessation. This proof of concept randomized placebo-controlled trial evaluated the efficacy and safety of 8 weeks of 42 mg transdermal nicotine versus 21 mg, among 87 fast metabolizers of nicotine (3-HC/cotinine ≥ 0.18). After 1 week of treatment, an intent-to-treat (ITT) analysis showed that participants treated with 42 mg nicotine had significantly higher expired-air carbon monoxide (CO)-confirmed 24-hr abstinence (75% vs. 58.1%; OR = 3.21; 95% CI: 1.12-9.24, p = .03) but not 7-day abstinence (50% vs. 34.9%; OR = 2.02; 95% CI: 0.82-4.94, p = .13). After 8 weeks of treatment, ITT analysis showed that participants treated with 42 mg nicotine had marginally higher rates of CO-confirmed 24-hr abstinence (45.5% vs. 30.2%; OR = 2.32; 95% CI: 0.92-5.92, p = .08) but not 7-day abstinence (29.6% vs. 23.3%; OR = 1.52, 95% CI: 0.57-4.07, p = .41). Percent nicotine and cotinine replacement were significantly greater for 42 mg nicotine versus 21 mg (p < .005). There were no significant differences between treatment arms in the frequency of severe side effects and serious adverse events or blood pressure during treatment (p > .10). Further examination of the efficacy of 42 mg nicotine patch therapy for fast metabolizers of nicotine is warranted.


Experimental demonstration of a flexible and stable semiconductor laser linewidth emulator.
We propose and demonstrate experimentally a laser source whose linewidth is adjustable independently of its other characteristics. This source can be used to test whether a particular laser would be suitable in a system, without the need to purchase several different lasers. It also has the advantage that the linewidth is generated digitally so it is extremely stable over time. We demonstrate a dialed-linewidth emulator between 256 kHz to 150 MHz. The narrowest linewidth shown by this technique is the original linewidth of the semiconductor laser source used in the setup. We also investigate the effect of driving our modulator into its nonlinear range.


Early Neolithic Horsebean from Yiftah'el, Israel.
Charred seeds of horsebean (Vicia faba L.) from the seventh millennium B.C. that were found at Yiftah'el, Israel, push back the known use of this vetch by about 2000 years. Horsebean should be included in the ensemble of legumes grown by some early Neolithic people. The site, situated near the southwest outlet of Biq'at Bet Netofa, lies in a valley with heavy soil suitable for growing contemporary cultivars of horsebean. The still unknown wild ancestor of the horsebean may have originated in similar habitats in the Levant.


Effect of phototherapy on delayed onset muscle soreness.
The purpose of this study was to investigate the effects of phototherapy on delayed onset muscle soreness (DOMS) as measured using the Visual Analog Scale (VAS), McGill Pain Questionnaire, Resting Angle (RANG), and girth measurements. Previous research has failed to prove the beneficial effects of phototherapy on DOMS. This was a randomized double-blind controlled study with 27 subjects (18-35 years) assigned to one of three groups. The experimental group received 8 J/cm2 of phototherapy each day for five consecutive days using super luminous diodes with wavelengths of 880 and visible diodes of 660 nm at three standardized sites over the musculotendinous junction of the bicep. The sham group received identical treatment from a dummy cluster. The controls did not receive treatment. The study was completed over five consecutive days: on day one baseline measurements of RANG and upper arm girths were recorded prior to DOMS induction. On days 2-5, RANG, girth, and pain were assessed using VAS and the McGill Pain Questionnaire. The experimental group exhibited a significant decrease in pain associated with DOMS compared to the control (p=0.01) and sham groups (p=0.03) based upon the VAS at the 48-h period. The McGill Pain Questionnaire showed a significant difference in pain scores at the 48-h period between the experimental and the sham groups (p=0.01). There were no significant differences day to day and between the groups with respect to girth and RANG. The results of this study provide scientific evidence that phototherapy as used in this study provides a beneficial effect to patients who may experience DOMS after a novel exercise session.


Transthoracic lung aspiration for the aetiological diagnosis of pneumonia: 25 years of experience from The Gambia.
Pneumonia remains the leading cause of death in young children worldwide. Global pneumonia control depends on a good understanding of the aetiology of pneumonia. Percutaneous transthoracic aspiration culture is much more sensitive than blood culture in identifying the aetiological agents of pneumonia. However, the procedure is not widely practised because of lack of familiarity with it and concerns about potential adverse events. We review the diagnostic usefulness and safety of this procedure over 25 years of its use in research and routine practice at the UK Medical Research Council (MRC), The Gambia, and give a detailed description of the procedure itself. Published materials were identified from the MRC's publication database and systematic searches using the PubMed/Medline and Google search engines. Data from a current pneumonia aetiology study in the unit are included together with clinical experience of staff practising at the unit over the period covered in this review. A minimum of 500 lung aspirates were performed over the period of review. Lung aspiration produces a greater yield of diagnostic bacterial isolates than blood culture. It is especially valuable clinically when pathogens not covered by standard empirical antibiotic treatment, such as Mycobacterium tuberculosis and Staphylococcus aureus, are identified. There have been no deaths following the procedure in our setting and a low rate of other complications, all transient. Lung aspiration is currently the most sensitive method for diagnosing pneumonia in children. With appropriate training and precautions it can be safely used for routine diagnosis in suitable referral hospitals.


Long-term tensile bond strength of differently cemented nanocomposite CAD/CAM crowns on dentin abutment.
To test the tensile bond strength of luted composite computer aided design/computer aided manufacturing (CAD/CAM) crowns after use of different adhesive systems combined with different resin composite cements on dentin abutments. Human molars (n=200) were embedded in acrylic resin, prepared in a standardized manner and divided into 20 groups (n=10). The crowns were treated as follows: (i) Monobond Plus/Heliobond (MH), (ii) Ambarino P60 (AM), (iii) Visio.link (VL), (iv) VP connect (VP), and (v) non-treated as control groups (CG) and luted with Variolink II (VAR) or Clearfil SA Cement (CSA). Tensile bond strength (TBS) was measured initially (24h water, 37°C) and after aging (5000 thermal cycles, 5/55°C). The failure types were evaluated after debonding. TBS values were analyzed using three-way and one-way ANOVA, followed by post hoc Scheffé-test, and two-sample Student's t-tests. Among VAR and after aging, CG presented significantly higher TBS (p=0.007) than groups treated with MH, AM and VP. Other groups showed no impact of pre-treatment. A decrease of TBS values after thermal aging was observed within CSA: CG (p=0.002), MH (p<0.001), VL (p<0.001), AM (p=0.002), VP (p<0.001) and within VAR: MH (p=0.002) and AM (p=0.014). Groups cemented with VAR showed significantly higher TBS then groups cemented with CSA: non-aged groups: CG (p<0.001), and after thermal aging: CG (p=0.003), MH (p<0.001), VL (p=0.005), VP (p=0.010). According to the study results nano-composite CAD/CAM crowns should be cemented with VAR. Pre-treatment is not necessary if the tested resin composite cements are used.


Quantitative surface radiance mapping using multiview images of light-emitting turbid media.
A novel method is presented for accurately reconstructing a spatially resolved map of diffuse light flux on a surface using images of the surface and a model of the imaging system. This is achieved by applying a model-based reconstruction algorithm with an existing forward model of light propagation through free space that accounts for the effects of perspective, focus, and imaging geometry. It is shown that flux can be mapped reliably and quantitatively accurately with very low error, <3% with modest signal-to-noise ratio. Simulation shows that the method is generalizable to the case in which mirrors are used in the system and therefore multiple views can be combined in reconstruction. Validation experiments show that physical diffuse phantom surface fluxes can also be reconstructed accurately with variability <3% for a range of object positions, variable states of focus, and different orientations. The method provides a new way of making quantitatively accurate noncontact measurements of the amount of light leaving a diffusive medium, such as a small animal containing fluorescent or bioluminescent markers, that is independent of the imaging system configuration and surface position.


Impact of cyanotic heart disease on school performance.
Surgical correction greatly decreases the mortality and cardiac morbidity of cyanotic congenital heart disease, but children remain at risk of long term difficulties in other areas. A historical cohort study was conducted to determine the relation between heart disease and school performance in 29 children aged 7 to 12 years old with simple transposition of the great arteries or tetralogy of Fallot. All children had surgical correction of their lesion before 2.5 years of age. Those at greater risk of school difficulties because of recognised complications of their heart disease or for reasons other than directly attributable to the heart disease were excluded. Comparison was made with 36 children who had presented with cardiac murmurs at a similar age, but who did not require treatment. Children with cyanotic disease showed significantly poorer performance in all academic areas assessed by the Wide Range Achievement Test-Revised; the difference in group mean score (adjusted for differences in maternal education, sex, and parental occupational prestige) for reading was 10.3 points (confidence interval (CI) 1.25 to 19.34), for spelling 7.8 (CI 1.11 to 14.52), and for arithmetic 6.8 (CI 0.19 to 13.39). The differences in adjusted group means for the Wechsler Intelligence Scale for Children-Revised full scale, performance and verbal IQs were significant, particularly the later at 10.1 points (CI 2.59 to 17.61). Teacher reports indicated significant differences in arithmetic when outcome was dichotomised to 'below grade' or 'not below grade'. There were no significant associations between outcome measures and the medical or perioperative parameters, however, including those related to hypoxia. It is concluded that the increased incidence of academic problems and the nature of the cognitive difficulties in children with uncomplicated corrective cardiac surgery for cyanotic heart disease are not fully explained by chronic hypoxia, or by other factors related to the cardiac surgery.


IL (interleukin)-1alpha promotes nuclear factor-kappaB and AP-1-induced IL-8 expression, cell survival, and proliferation in head and neck squamous cell carcinomas.
Interleukin 1alpha (IL-1alpha) is an important regulatory cytokine, the release of which after an injury can induce activation of transcription factors nuclear factor (NF)kappaB and activator protein (AP-1), which promote expression of genes involved in cell survival, proliferation, and angiogenesis. IL-1alpha is expressed autonomously by head and neck squamous cell carcinomas (HNSCCs) and a variety of other cancers, raising the possibility that IL-1alpha may serve as an autocrine factor that stimulates the activation of prosurvival transcription factors and target genes in cancer. In this study, we examined the role of IL-1alpha in the activation of NFkappaB and AP-1, the expression of proangiogenic cytokine IL-8, and in the survival and proliferation of HNSCC cell lines. HNSCCs were found to secrete and respond to functional IL-1alpha, in that culture supernatant from a high IL-1alpha-secreting line, UM-SCC-11B, could induce secretion of cytokine IL-8 by a low IL-1alpha-secreting line, UM-SCC-9; and the induction of IL-8 secretion could be blocked by the anti-IL-1alpha-neutralizing antibody or the IL-1 receptor antagonist (IL-1RA). Furthermore, IL-1alpha could induce the expression of IL-8 through an autocrine mechanism, in that transfection of UM-SCC-9 cells with a plasmid encoding IL-1alpha resulted in the increased coexpression of IL-1alpha and IL-8; whereas transfection with a plasmid encoding IL-1RA lacking the secretory leader sequence led to the decreased coexpression of IL-1alpha and IL-8. IL-1alpha was found to induce coexpression of IL-8 through the activation of NFkappaB and AP-1, in that mutation of the NFkappaB site within the IL-8 promoter abolished autocrine- and recombinant IL-1alpha-induced IL-8 reporter gene activity, whereas mutation in AP-1 partially decreased IL-8 reporter gene activity in UM-SCC-9 cells. Intracellular expression of IL-1RA decreased NFkappaB reporter gene activity, indicating that endogenously expressed IL-1alpha contributes to constitutive NFkappaB activation in this HNSCC line. Expression of IL-1alpha affected survival of UM-SCC-9, inasmuch as transfection of cells with plasmid encoding IL-1alpha or IL-1RA led to the increased or decreased survival of cells cotransfected with a beta-galactosidase reporter gene, respectively. IL-1alpha was also found to promote the increased growth of UM-SCC-9 cells in vitro. We demonstrate that exogenous and endogenous IL-1alpha contributes to the transcriptional activation of NFkappaB and AP-1, to the expression of IL-8, and to cell survival and the growth of HNSCC in vitro.


Size-Resolved Source Emission Rates of Indoor Ultrafine Particles Considering Coagulation.
Indoor ultrafine particles (UFP, <100 nm) released from combustion and consumer products lead to elevated human exposure to UFP. UFP emitted from the sources undergo aerosol transformation processes such as coagulation and deposition. The coagulation effect can be significant during the source emission due to high concentration and high mobility of nanosize particles. However, few studies have estimated size-resolved UFP source emission strengths while considering coagulation in their theoretical and experimental research work. The primary objective of this study is to characterize UFP source strength by considering coagulation in addition to other indoor processes (i.e., deposition and ventilation) in a realistic setting. A secondary objective is to test a hypothesis that size-resolved UFP source emission rates are unimodal and log-normally distributed for three common indoor UFP sources: an electric stove, a natural gas burner, and a paraffin wax candle. Experimental investigations were performed in a full-scale test building. Size- and time-resolved concentrations of UFP ranging from 2 to 100 nm were monitored using a scanning mobility particle sizer (SMPS). Based on the temporal evolution of the particle size distribution during the source emission period, the size-dependent source emission rate was determined using a material-balance modeling approach. The results indicate that, for a given UFP source, the source strength varies with particle size and source type. The analytical model assuming a log-normally distributed source emission rate could predict the temporal evolution of the particle size distribution with reasonable accuracy for the gas stove and the candle. Including the effect of coagulation was found to increase the estimates of source strengths by up to a factor of 8. This result implies that previous studies on indoor UFP source strengths considering only deposition and ventilation might have largely underestimated the true values of UFP source strengths, especially for combustion due to the natural gas stove and the candle.


Synthesis of stable polymetalated aromatic complexes through metal-macrocycle capsule-triggered cyclization.
Polymetalated aromatic compounds are of great interest because of their intermediate roles in many organic transformations. However, they are elusive and synthetically challenging. In this study, a dynamic coordination capsule constructed by a flexible macrocycle and silver(i) ions is applied to trigger one-step or cascade cyclization reactions for various alkyne substrates, finally leading to five unprecedented polysilver heteroaromatic intermediates (including indole, quinoline, benzocarbazole and 2,2'-biindole). The acquired heteroaromatic species is doubly charged, particularly at vicinal positions, and each is surrounded by a tetrasilver aggregate. The metal-macrocycle capsule holds a great potential of flexibly adjusting its conformation to adapt different polysilver heteroaromatic species. DFT calculations further reveal that metal-perturbed aromaticity and multi-centered bonding both contribute to stabilization of the polysilver heteroaromatic complexes.


Incorporating radiomics into clinical trials: expert consensus endorsed by the European Society of Radiology on considerations for data-driven compared to biologically driven quantitative biomarkers.
Existing quantitative imaging biomarkers (QIBs) are associated with known biological tissue characteristics and follow a well-understood path of technical, biological and clinical validation before incorporation into clinical trials. In radiomics, novel data-driven processes extract numerous visually imperceptible statistical features from the imaging data with no a priori assumptions on their correlation with biological processes. The selection of relevant features (radiomic signature) and incorporation into clinical trials therefore requires additional considerations to ensure meaningful imaging endpoints. Also, the number of radiomic features tested means that power calculations would result in sample sizes impossible to achieve within clinical trials. This article examines how the process of standardising and validating data-driven imaging biomarkers differs from those based on biological associations. Radiomic signatures are best developed initially on datasets that represent diversity of acquisition protocols as well as diversity of disease and of normal findings, rather than within clinical trials with standardised and optimised protocols as this would risk the selection of radiomic features being linked to the imaging process rather than the pathology. Normalisation through discretisation and feature harmonisation are essential pre-processing steps. Biological correlation may be performed after the technical and clinical validity of a radiomic signature is established, but is not mandatory. Feature selection may be part of discovery within a radiomics-specific trial or represent exploratory endpoints within an established trial; a previously validated radiomic signature may even be used as a primary/secondary endpoint, particularly if associations are demonstrated with specific biological processes and pathways being targeted within clinical trials. KEY POINTS: • Data-driven processes like radiomics risk false discoveries due to high-dimensionality of the dataset compared to sample size, making adequate diversity of the data, cross-validation and external validation essential to mitigate the risks of spurious associations and overfitting. • Use of radiomic signatures within clinical trials requires multistep standardisation of image acquisition, image analysis and data mining processes. • Biological correlation may be established after clinical validation but is not mandatory.


Properties of Fe-organic matter associations via coprecipitation versus adsorption.
The association of organic matter (OM) with minerals is recognized as the most important stabilization mechanism for soil organic matter. This study compared the properties of Fe-OM complexes formed from adsorption (reaction of OM to postsynthesis ferrihydrite) versus coprecipitation (formation of Fe solids in the presence of OM). Coprecipitates and adsorption complexes were synthesized using dissolved organic matter (DOM) extracts from a forest little layer at varying molar C/Fe ratios of 0.3-25.0. Sample properties were studied by N2 gas adsorption, XRD, FTIR, Fe EXAFS, and STXM-NEXAFS techniques. Coprecipitation resulted in much higher maximum C contents (∼130 mg g(-1) C difference) in the solid products than adsorption, which may be related to the formation of precipitated insoluble Fe(III)-organic complexes at high C/Fe ratios in the coprecipitates as revealed by Fe EXAFS analysis. Coprecipitation led to a complete blockage of mineral surface sites and pores with ≥177 mg g(-1) C and molar C/Fe ratios ≥2.8 in the solid products. FTIR and STXM-NEXAFS showed that the coprecipitated OM was similar in composition to the adsorbed OM. An enrichment of aromatic C was observed at low C/Fe ratios. Association of carboxyl functional groups with Fe was shown with FTIR and STXM-NEXAFS analysis. STXM-NEXAFS analysis showed a continuous C distribution on minerals. Desorption of the coprecipitated OM was less than that of the adsorbed OM at comparable C/Fe ratios. These results are helpful to understand C and Fe cycling in the natural environments with periodically fluctuating redox conditions, where coprecipitation can occur.


Crystal Structures Adopted by Black Phosphorus at High Pressures.
Black phosphorus undergoes two reversible structural transitions at high pressures. The first is to a structure of the type arsenic A7. This structure is transformed to a simple cubic structure at higher pressures. The reversibility between the A7 and simple cubic structures at 111 kilobars indicates that the transition obtainable at this pressure provides a good calibration point by which high-pressure x-ray data may be united with volumetric or resistance measurements, or both.


The potential role of sediment organic phosphorus in algal growth in a low nutrient lake.
The role of sediment-bound organic phosphorus (Po) as an additional nutrient source is a component of internal P budgets in lake system that is usually neglected. Here we examined the relative importance of sediment Po to internal P load and the role of bioavailable Po in algal growth in Lake Erhai, China. Lake Erhai sediment extractable Po accounted for 11-43% (27% average) of extractable total P, and bioavailable Po accounted for 21-66% (40%) of Po. The massive storage of bioavailable Po represents an important form of available P, essential to internal loads. The bioavailable Po includes mainnly labile monoester P and diester P was identified in the sequential extractions by H2O, NaHCO3, NaOH, and HCl. 40% of H2O-Po, 39% of NaHCO3-Po, 43% of NaOH-Po, and 56% of HCl-Po can be hydrolyzed to labile monoester and diester P, suggesting that the bioavailability of Po fractions was in decreasing order as follows: HCl-Po > NaOH-Po > H2O-Po > NaHCO3-Po. It is implied that traditional sequential fractionation of Po might overestimate the availability of labile Po in sediments. Furthermore, analysis of the environmental processes of bioavailable Po showed that the stabler structure of dissloved organic matter (DOM) alleviated the degradation and release of diester P, abundant alkaline phosphatase due to higher algal biomass promoted the degradation of diester P. The stability of DOM structure and the degradation of diester P might responsible for the spatial differences of labile monoester P. The biogeochemical cycle of bioavailable Po replenishs available P pools in overlying water and further facilitate algal growth during the algal blooms. Therefore, to control the algal blooms in Lake Erhai, an effective action is urgently required to reduce the accumulation of Po in sediments and interrupt the supply cycle of bioavailable Po to algal growth.


Coordination and artifacts in joint activity: the case of tagging in high-risk industries.
The social, organizational, and technological complexity of high-risk organizations creates a strong need for coordination. Joint activity in such systems thus relies both on formal coordination and on a set of informal coordinative practices. Coordinated joint activity is documented in this paper from two perspectives: the development of coordinative practices to overcome the limitations of formal coordination, and the use of artifacts for coordinative purposes. The empirical material is provided by a workplace study undertaken according to theoretical conceptions of situated action and cognition. It was undertaken in the context of a design project that aims at improving the tagout process in a high-risk industry. Findings first describe and analyze situations in which formal coordination turned out to be more of a constraint than a resource for effective action. They then illustrate the role played by artifacts in coordinated activity, focusing on the use of a particular artifact, the tagout tag, in different situations.


Retention of Moisture-tolerant and Conventional Resin-based Sealant in Six- to Nine-year-old Children.
The purpose of this study was to evaluate and compare the retention rates and development of caries in permanent molars in children sealed with moisture-tolerant, resin-based (Embrace WetBond), and conventional resin-based (Helioseal) sealant over a period of one year. This was a double blind, split-mouth, randomized controlled trial among six- to nine-year-olds. Sixty-eight permanent mandibular first molars in 34 children were randomly assigned to be sealed with Embrace WetBond or Helioseal sealant. The final sample was 32 children with 64 teeth. At 12 months, 23 of 32 (72 percent) sealants were completely retained in Embrace WetBond, whereas only 16 of 32 (50 percent) were retained in the Helioseal group. There was a statistically significant difference in retention rates of Embrace WetBond and Helioseal sealants at 12 months (P<.05). At 12 months follow-up, only two teeth developed caries in Embrace WetBond; in the Helioseal group, five teeth developed caries (two initial and three enamel caries). Embrace WetBond was superior to Helioseal sealant, as Embrace exhibited higher retention and lower caries scores. Embrace WetBond can be preferred over conventional resin-based sealants for community and outreach sealant programs where use of rubber dam for moisture control is difficult to practice.


Transcriptional profiling reveals molecular basis and novel genetic targets for improved resistance to multiple fermentation inhibitors in Saccharomyces cerevisiae.
Lignocellulosic biomass is a promising source of renewable biofuels. However, pretreatment of lignocellulosic biomass generates fermentation inhibitors that adversely affect the growth of industrial microorganisms such as Saccharomyces cerevisiae and prevent economic production of lignocellulosic biofuels. A critical challenge on developing S. cerevisiae with improved inhibitor resistance lies in incomplete understanding of molecular basis for inhibitor stress response and limited information on effective genetic targets for increasing yeast resistance to mixed fermentation inhibitors. In this study, we applied comparative transcriptomic analysis to determine the molecular basis for acetic acid and/or furfural resistance in S. cerevisiae. We recently developed a yeast strain YC1 with superior resistance to acetic acid, furfural, and their mixture through inverse metabolic engineering. In this study, we first determined transcriptional changes through RNA sequencing in YC1 versus the wild-type strain S-C1 under three different inhibitor conditions, including acetic acid alone, furfural alone, and mixture of acetic acid and furfural. The genes associated with stress responses of S. cerevisiae to single and mixed inhibitors were revealed. Specifically, we identified 184 consensus genes that were differentially regulated in response to the distinct inhibitor resistance between YC1 and S-C1. Bioinformatic analysis next revealed key transcription factors (TFs) that regulate these consensus genes. The top TFs identified, Sfp1p and Ace2p, were experimentally tested as overexpression targets for strain optimization. Overexpression of the SFP1 gene improved specific ethanol productivity by nearly four times, while overexpression of the ACE2 gene enhanced the rate by three times in the presence of acetic acid and furfural. Overexpression of SFP1 gene in the resistant strain YC1 further resulted in 42 % increase in ethanol productivity in the presence of acetic acid and furfural, suggesting the effect of Sfp1p in optimizing the yeast strain for improved tolerance to mixed fermentation inhibitor. Transcriptional regulation underlying yeast resistance to acetic acid and furfural was determined. Two transcription factors, Sfp1p and Ace2p, were uncovered for the first time for their functions in improving yeast resistance to mixed fermentation inhibitors. The study demonstrated an omics-guided metabolic engineering framework, which could be developed as a promising strategy to improve complex microbial phenotypes.


The burden of mild asthma: Clinical burden and healthcare resource utilisation in the NOVELTY study.
Patients with mild asthma represent a substantial proportion of the population with asthma, yet there are limited data on their true burden of disease. We aimed to describe the clinical and healthcare resource utilisation (HCRU) burden of physician-assessed mild asthma. Patients with mild asthma were included from the NOVEL observational longiTudinal studY (NOVELTY; NCT02760329), a global, 3-year, real-world prospective study of patients with asthma and/or chronic obstructive pulmonary disease from community practice (specialised and primary care). Diagnosis and severity were based on physician discretion. Clinical burden included physician-reported exacerbations and patient-reported measures. HCRU included inpatient and outpatient visits. Overall, 2004 patients with mild asthma were included; 22.8% experienced ≥1 exacerbation in the previous 12 months, of whom 72.3% experienced ≥1 severe exacerbation. Of 625 exacerbations reported, 48.0% lasted >1 week, 27.7% were preceded by symptomatic worsening lasting >3 days, and 50.1% required oral corticosteroid treatment. Health status was moderately impacted (St George's Respiratory Questionnaire score: 23.5 [standard deviation ± 17.9]). At baseline, 29.7% of patients had asthma symptoms that were not well controlled or very poorly controlled (Asthma Control Test score <20), increasing to 55.6% for those with ≥2 exacerbations in the previous year. In terms of HCRU, at least one unscheduled ambulatory visit for exacerbations was required by 9.5% of patients, including 9.2% requiring ≥1 emergency department visit and 1.1% requiring ≥1 hospital admission. In this global sample representing community practice, a significant proportion of patients with physician-assessed mild asthma had considerable clinical burden and HCRU.


GPU-accelerated atom and dynamic bond visualization using hyperballs: a unified algorithm for balls, sticks, and hyperboloids.
Ray casting on graphics processing units (GPUs) opens new possibilities for molecular visualization. We describe the implementation and calculation of diverse molecular representations such as licorice, ball-and-stick, space-filling van der Waals spheres, and approximated solvent-accessible surfaces using GPUs. We introduce HyperBalls, an improved ball-and-stick representation replacing tubes, linking the atom spheres by hyperboloids that can smoothly connect them. This type of depiction is particularly useful to represent dynamic phenomena, such as the evolution of noncovalent bonds. It is furthermore well suited to represent coarse-grained models and spring networks. All these representations can be defined by a single general algebraic equation that is adapted for the ray-casting technique and is well suited for execution on the GPU. Using GPU capabilities, this implementation can routinely, accurately, and interactively render molecules ranging from a few atoms up to huge macromolecular assemblies with more than 500,000 particles. In simple cases, based only on spheres, we have been able to display up to two million atoms smoothly.


Meiotic recombination-deficient mutants of Schizosaccharomyces pombe.
A mutant screen employing the ade6-M26 recombination hotspot was developed and used to isolate Schizosaccharomyces pombe mutants deficient in meiotic recombination. Nine rec mutations were recessive, defining six complementation groups, and reduced ade6 meiotic recombination 3-fold to greater than or equal to 300-fold when homozygous. Three recessive rec mutations analyzed further also reduced meiotic intragenic recombination at ura4 on chromosome III and intergenic recombination between pro2 and arg3 on chromosome I. The observed non-co-ordinate reductions of the recombinant frequencies in the three test intervals suggest a degree of locus (or intragenic vs. intergenic) specificity of the corresponding rec+ gene products. None of the mutations specifically inactivated the ade6-M26 hotspot. Additional rec genes may be identified with these methods.


Posterior tibial tendon dysfunction in rheumatoid arthritis.
Although hindfoot pathology in rheumatoid arthritis is a significant cause of disability for patients, the etiology of the planovalgus deformity is controversial. The present study surveys 99 patients with clinically proven rheumatoid arthritis for the presence and severity of hindfoot pathology. Specific attention was directed at the function of the posterior tibial tendon, as disruption of this structure has been implicated by some investigators as a cause of hindfoot deformity in rheumatoid arthritis. Assessment of posterior tibial function was by manual testing using two different grading scales, as well as by examination for several signs associated with posterior tibial tendon dysfunction. Between 13% and 64% of the study population could be considered to have posterior tibial tendon dysfunction, depending upon the specific diagnostic criteria used. Using the presence of all three of the most stringent criteria for diagnosis, 11% of patients were believed to have posterior tibial tendon dysfunction. These criteria were loss of the longitudinal arch, inability to perform a heel-rise, and lack of a palpable posterior tibial tendon. This study demonstrates that planovalgus deformity in rheumatoid arthritis can be due to clinically evident dysfunction of the posterior tibial muscle-tendon unit. There is a complex interplay between hindfoot joint disruption due to the inflammatory process and deformity due to tendinous dysfunction. If there is primary subtalar joint instability secondary to the inflammatory process, the posterior tibial tendon is rendered dysfunctional due to deranged hindfoot mechanics, as with primary posterior tibial tendon rupture. Since treatment of either condition (i.e., primary hindfoot instability or primary posterior tibial tendon rupture) is similar, the distinction is not important clinically.(ABSTRACT TRUNCATED AT 250 WORDS)


Separation of DNA replication from the assembly of break-competent meiotic chromosomes.
The meiotic cell division reduces the chromosome number from diploid to haploid to form gametes for sexual reproduction. Although much progress has been made in understanding meiotic recombination and the two meiotic divisions, the processes leading up to recombination, including the prolonged pre-meiotic S phase (meiS) and the assembly of meiotic chromosome axes, remain poorly defined. We have used genome-wide approaches in Saccharomyces cerevisiae to measure the kinetics of pre-meiotic DNA replication and to investigate the interdependencies between replication and axis formation. We found that replication initiation was delayed for a large number of origins in meiS compared to mitosis and that meiotic cells were far more sensitive to replication inhibition, most likely due to the starvation conditions required for meiotic induction. Moreover, replication initiation was delayed even in the absence of chromosome axes, indicating replication timing is independent of the process of axis assembly. Finally, we found that cells were able to install axis components and initiate recombination on unreplicated DNA. Thus, although pre-meiotic DNA replication and meiotic chromosome axis formation occur concurrently, they are not strictly coupled. The functional separation of these processes reveals a modular method of building meiotic chromosomes and predicts that any crosstalk between these modules must occur through superimposed regulatory mechanisms.


NEW MOLECULES IN THE TUMOR NECROSIS FACTOR LIGAND AND RECEPTOR SUPERFAMILIES WITH IMPORTANCE FOR PHYSIOLOGICAL AND PATHOLOGICAL BONE RESORPTION.
Osteoclasts are tissue-specific polykaryon bone-resorbing cells derived from the monocyte/macrophage hematopoietic lineage with specialized functions required for the adhesion of the cells to bone and the subsequent polarization of the cell membrane, secretion of acid to dissolve mineral crystals, and release of proteolytic enzymes to degrade the extracellular matrix proteins. Most pathological conditions in the skeleton lead to loss of bone due to excess osteoclastic bone resorption, including periodontal disease, rheumatoid arthritis, and osteoporosis. In rare cases, most of them genetic, patients with osteopetrosis exhibit sclerotic bone due either to a lack of osteoclasts or to non-functional osteoclasts. Mainly because of phenotypic findings in genetically manipulated mice or due to spontaneous mutations in humans, mice, and rats, several genes have been discovered as being crucial for osteoclast formation and activation. Recent breakthroughs in our understanding of osteoclast biology have revealed the critical roles in osteoclast differentiation played by RANKL, RANK, and OPG, three novel members of the tumor necrosis factor ligand and receptor superfamilies. The further study of these molecules and downstream signaling events are likely to provide a molecular basis for the development of new drugs for the treatment of diseases with excess or deficient osteoclastic bone resorption.


Comparison of health care expenditures among insured users and nonusers of complementary and alternative medicine in Washington State: a cost minimization analysis.
The purpose of this analysis was to compare health care expenditures between insured patients with back pain, fibromyalgia syndrome, or menopause symptoms who used complementary and alternative medical (CAM) providers for some of their care to a matched group of patients who did not use any CAM care. Insurance coverage was equivalent for both conventional and CAM providers. Insurance claims data for 2000-2003 from Washington State, which mandates coverage of CAM providers, were analyzed. CAM-using patients were matched to CAM-nonusing patients based on age group, gender, index medical condition, overall disease burden, and prior-year expenditures. Both unadjusted tests and linear regression models indicated that CAM users had lower average expenditures than nonusers. (Unadjusted: $3,797 versus $4,153, p = 0.0001; beta from linear regression -$367 for CAM users.) CAM users had higher outpatient expenditures that which were offset by lower inpatient and imaging expenditures. The largest difference was seen in the patients with the heaviest disease burdens among whom CAM users averaged $1,420 less than nonusers, p < 0.0001, which more than offset slightly higher average expenditures of $158 among CAM users with lower disease burdens. This analysis indicates that among insured patients with back pain, fibromyalgia, and menopause symptoms, after minimizing selection bias by matching patients who use CAM providers to those who do not, those who use CAM will have lower insurance expenditures than those who do not use CAM.


Healthy living in hard times.
Using microdata for adults from 1987 to 2000 years of the Behavioral Risk Factor Surveillance System (BRFSS), I show that smoking and excess weight decline during temporary economic downturns while leisure-time physical activity rises. The drop in tobacco use occurs disproportionately among heavy smokers, the fall in body weight among the severely obese and the increase in exercise among those who were completely inactive. Declining work hours may provide one reason why behaviors become healthier, possibly by increasing the non-market time available for lifestyle investments. Conversely, there is little evidence of an important role for income reductions. The overall conclusion is that changes in behaviors supply one mechanism for the procyclical variation in mortality and morbidity observed in recent research.


Using Evidence to Design Cancer Care Facilities.
The nuts and bolts of planning and designing cancer care facilities-the physical space, the social systems, the clinical and nonclinical workflows, and all of the patient-facing services-directly influence the quality of clinical care and the overall patient experience. Cancer facilities should be conceived and constructed on the basis of evidence-based design thinking and implementation, complemented by input from key stakeholders such as patients, families, and clinicians. Specifically, facilities should be designed to improve the patient experience, offer options for urgent care, maximize infection control, support and streamline the work of multidisciplinary teams, integrate research and teaching, incorporate palliative care, and look beyond mere diagnosis and treatment to patient wellness-all tailored to each cancer center's patient population and logistical and financial constraints. From conception to completion to iterative reevaluation, motivated institutions can learn to make their own facilities reflect the excellence in cancer care that they aim to deliver to patients.


Emotional Reactions to Cybersecurity Breach Situations: Scenario-Based Survey Study.
With the ever-expanding interconnectedness of the internet and especially with the recent development of the Internet of Things, people are increasingly at risk for cybersecurity breaches that can have far-reaching consequences for their personal and professional lives, with psychological and mental health ramifications. We aimed to identify the dimensional structure of emotion processes triggered by one of the most emblematic scenarios of cybersecurity breach, the hacking of one's smart security camera, and explore which personality characteristics systematically relate to these emotion dimensions. A total of 902 participants from the United Kingdom and the Netherlands reported their emotion processes triggered by a cybersecurity breach scenario. Moreover, they reported on their Big Five personality traits, as well as on key indicators for resilient, overcontrolling (internalizing problems), and undercontrolling (aggression) personality types. Principal component analyses revealed a clear 3-dimensional structure of emotion processes: emotional intensity, proactive versus fight/flight reactions, and affective versus cognitive/motivational reactions. Regression analyses revealed that more internalizing problems (β=.33, P<.001), resilience (β=.22, P<.001), and agreeableness (β=.12, P<.001) and less emotional stability (β=-.25, P<.001) have significant predictive value for higher emotional intensity. More internalizing problems (β=.26, P<.001), aggression (β=.25, P<.001), and extraversion (β=.07, P=.01) and less resilience (β=-.19, P<.001), agreeableness (β=-.34, P<.001), consciousness (β=-.19, P<.001), and openness (β=-.22, P<.001) have significant predictive value for comparatively more fight/flight than proactive reactions. Less internalizing problems (β=-.32, P<.001) and more emotional stability (β=.14, P<.001) and aggression (β=.13, P<.001) have significant predictive value for a comparatively higher salience for cognitive/motivational than affective reactions. To adequately describe the emotion processes triggered by a cybersecurity breach, two more dimensions are needed over and above the general negative affectivity dimension. This multidimensional structure is further supported by the differential relationships of the emotion dimensions with personality characteristics. The discovered emotion structure could be used for consistent predictions about who is at risk to develop long-term mental well-being issues due to a cybersecurity breach experience.


PRE-WORKOUT SUPPLEMENT INDUCED CARDIAC ISCHAEMIA IN A YOUNG FEMALE.
The popularity of pre-workout supplements is rising amongst professional athletes and fitness enthusiasts. Despite increased usage, the safety profile of pre-workout supplements is likely to be not well understood. Additionally, many different brands use various undisclosed proprietary blends of active ingredients creating safety regulation difficulties. This lack of oversight could prove unsafe for certain patients. This patient MK is a 33-year-old healthy housewife who presented with central chest tightness, pre-syncope and mild dyspnoea to the emergency department via ambulance. The presentation was in the context of recent strenuous exercise and ingestion of a pre-workout supplement (Alpha Lean-7). Most striking in her presentation was a troponin rise of 50 ng/L, while not very high it is unusual given her lack of cardiac risk factors. She had a 3-day uneventful admission with a downtrending troponin prior to discharge. This case highlights the possible dangers of pharmacologically active ingredients in pre-workout supplements.


Inhibition of collagen synthesis by select calcium and sodium channel blockers can be mitigated by ascorbic acid and ascorbyl palmitate.
Calcium, sodium and potassium channel blockers are widely prescribed medications for a variety of health problems, most frequently for cardiac arrhythmias, hypertension, angina pectoris and other disorders. However, chronic application of channel blockers is associated with numerous side effects, including worsening cardiac pathology. For example, nifedipine, a calcium-channel blocker was found to be associated with increased mortality and increased risk for myocardial infarction. In addition to the side effects mentioned above by different channel blockers, these drugs can cause arterial wall damage, thereby contributing to vascular wall structure destabilization and promoting events facilitating rupture of plaques. Collagen synthesis is regulated by ascorbic acid, which is also essential for its optimum structure as a cofactor in lysine and proline hydroxylation, a precondition for optimum crosslinking of collagen and elastin. Therefore, the main objective in this study was to evaluate effects of various types of channel blockers on intracellular accumulation and cellular functions of ascorbate, specifically in relation to formation and extracellular deposition of major collagen types relevant for vascular function. Effects of select Na- and Ca- channel blockers on collagen synthesis and deposition were evaluated in cultured human dermal fibroblasts and aortic smooth muscle cells by immunoassay. All channel blockers tested demonstrated inhibitory effects on collagen type I deposition to the ECM by fibroblasts, each to a different degree. Ascorbic acid significantly increased collagen I ECM deposition. Nifedipine (50 µM), a representative of channel blockers tested, significantly reduced ascorbic acid and ascorbyl palmitate-dependent ECM deposition of collagen type l and collagen type lV by cultured aortic smooth muscle cells. In addition, nifedipine (50 µM) significantly reduced ascorbate-dependent collagen type l and type lV synthesis by cultured aortic smooth muscle cells, assayed by measuring intracellular collagen content. We observed increased intracellular levels of ascorbate under supplementation with elevated doses of ascorbic acid, as well as its lipid soluble derivative ascorbyl palmitate. Nifedipine reduced ascorbic acid intracellular influx in cultured aortic smooth muscle cells with nifedipine (50 µM) compared to control. Adverse effects of nifedipine were neutralized either by an increased level of cell supplementation with ascorbic acid or by substituting it with ascorbyl palmitate. These studies suggest that adverse effects of channel blockers could be caused by their weakening the arterial wall integrity by interfering with proper extracellular matrix formation. In conclusion, these studies confirm the adverse effects of channel blockers on collagen type l and lV deposition, the key ECM components essential for maintaining optimal structural integrity of the arterial walls. Ascorbate supplementation reversed channel blocker inhibition of these collagen types synthesis and deposition. The results of this study imply the benefits of ascorbate and ascorbate palmitate supplementation in medical management of cardiovascular disease in order to compensate for adverse effects of channel blockers.


Do simple cells in primary visual cortex form a tight frame?
Sets of neuronal tuning curves, which describe the responses of neurons as functions of a stimulus, can serve as a basis for approximating other functions of stimulus parameters. In a function-approximating network, synaptic weights determined by a correlation-based Hebbian rule are closely related to the coefficients that result when a function is expanded in an orthogonal basis. Although neuronal tuning curves typically are not orthogonal functions, the relationship between function approximation and correlation-based synaptic weights can be retained if the tuning curves satisfy the conditions of a tight frame. We examine whether the spatial receptive fields of simple cells in cat and monkey primary visual cortex (V1) form a tight frame, allowing them to serve as a basis for constructing more complicated extrastriate receptive fields using correlation-based synaptic weights. Our calculations show that the set of V1 simple cell receptive fields is not tight enough to account for the acuity observed psychophysically.


Mechanics of load-drag-unload contact cleaning of gecko-inspired fibrillar adhesives.
Contact self-cleaning of gecko-inspired synthetic adhesives with mushroom-shaped tips has been demonstrated recently using load-drag-unload cleaning procedures similar to that of the natural animal. However, the underlying mechanics of contact cleaning has yet to be fully understood. In this work, we present a detailed experiment of contact self-cleaning that shows that rolling is the dominant mechanism of cleaning for spherical microparticle contaminants, during the load-drag-unload procedure. We also study the effect of dragging rate and normal load on the particle rolling friction. A model of spherical particle rolling on an elastomer fibrillar adhesive interface is developed and agrees well with the experimental results. This study takes us closer to determining design parameters for achieving self-cleaning fibrillar adhesives.


Autologous cord blood harvesting in North Eastern Italy: ethical questions and emerging hopes for curing diabetes and celiac disease.
The Friuli Venezia Giulia (FVG), a region of North Eastern Italy, has passed legislation (Decree No 2324/2010) to regulate the banking of umbilical cord blood samples for personal, autologous, or family-directed use, and to implement the Agreement of the State-Regions Permanent Conference (Decree No 62/CSR/2010). This paper aims to identify the formalities and the reasons why families collect and bank their cord blood in foreign banks for both personal and private use. To this end, at the Institute for Maternal and Child Health of Trieste (the regional capital city of the FVG), Italy, which assists about 1800 pregnant women a year, 129 questionnaires, drafted from January 2010 to December 2011 and concerning the granting of authorization to export samples, were examined. The collected data showed that 75% of involved families had resorted to anonymous public collection, which is available to anyone with therapeutic needs, and provided compatibility and hematologic protocols recognized by the scientific and international community (main indications: leukemia, hemoglobinopaties, and inherited hematologic and immunologic disorders). Conversely, 25.0% requested private storage at a foreign bank for personal or family-dedicated use. The principal motivation by disease was for treatment for diabetes (22.4%) and celiac disease (19.7%) (a multiorgan disease for which the FVG region has provided safeguards by approving a specific law granting support to families; Decree No 561/2007). For these two types of disease we found that information was received from the internet and not from general medical physicians, with a significant difference found using the χ(2) test (P < 0.01). The indication of treating these diseases with cord blood stem cell transplantation appears to be well grounded and encouraging, and has recently been corroborated by the international literature; however, the economic and social motivations promoting cord blood storage, for a fee, in the event of diseases that are still under study, require accurate information through general medical physicians on the actual possibilities of treatment.


Cell-to-cell movement of plastids in plants.
Our objective was to test whether or not plastids and mitochondria, the two DNA-containing organelles, move between cells in plants. As our experimental approach, we grafted two different species of tobacco, Nicotiana tabacum and Nicotiana sylvestris. Grafting triggers formation of new cell-to-cell contacts, creating an opportunity to detect cell-to-cell organelle movement between the genetically distinct plants. We initiated tissue culture from sliced graft junctions and selected for clonal lines in which gentamycin resistance encoded in the N. tabacum nucleus was combined with spectinomycin resistance encoded in N. sylvestris plastids. Here, we present evidence for cell-to-cell movement of the entire 161-kb plastid genome in these plants, most likely in intact plastids. We also found that the related mitochondria were absent, suggesting independent movement of the two DNA-containing organelles. Acquisition of plastids from neighboring cells provides a mechanism by which cells may be repopulated with functioning organelles. Our finding supports the universality of intercellular organelle trafficking and may enable development of future biotechnological applications.


Differences in fruit and vegetable intake among Hispanic subgroups in California: results from the 2005 California Health Interview Survey.
To compare total fruit and vegetable intake in cup equivalents and its individual components among Hispanic subgroups in California. Data are from the adult portion of the 2005 California Health Interview Survey. Hispanic/Latino subjects (n=7,954) were grouped into six subcategories (Mexican, Central American, Caribbean, Spanish American, South American, and >1 group). Total fruit and vegetable intake in cup equivalents was estimated from frequency responses about seven food categories. Both t test and chi(2) test were used to assess differences in sociodemographic characteristics across Hispanic subgroups. Multivariate linear regressions using SUDAAN software (Survey Data Analysis, version 9.0.1, 2005, Research Triangle Institute, Research Triangle Park, NC) were conducted to obtain means of total fruit and vegetable intake in cup equivalents and its components by Hispanic subgroups controlling for confounders. Hispanic subgroups did not differ in their intake of total fruit and vegetable intake in cup equivalents (mean 3.4 c and 2.9 c for men and women, respectively). Small but significant differences (P<0.01) were found across Hispanic subgroups in individual fruit and vegetable components (green salad [women only], cooked dried beans and nonfried white potatoes) after adjusting for potential sociodemographic and acculturation confounders. Fruit and vegetable intake by Hispanic respondents did not meet the national recommendation, although their reported intake is higher compared to other race/ethnicity groups. The public health message remains the same: Increase fruit and vegetable intake. Examination of intake for subgroups of Hispanics may enhance the utility of dietary information for surveillance, program and message design, and intervention and evaluation.


Screening trauma patients for alcohol problems: are insurance companies barriers?
Impairment caused by alcohol is the leading risk factor for trauma. However, many physicians do not screen for alcohol use because of concerns about confidentiality and denial of insurance coverage. The purpose of this study was to examine objectively the confidentiality issues and insurance statutes affecting alcohol screening in trauma centers. We conducted a survey of insurance commissioners in all 50 states to determine the prevalence of statutes allowing denial of coverage for injuries sustained while impaired due to alcohol, reviewed state insurance laws, and reviewed federal regulations protecting the confidentiality of alcohol information in patients seeking alcohol treatment. Special federal regulations protecting confidentiality of alcohol screening data depend on how such information is acquired and do not routinely cover trauma patients. Concerns about screening on insurance coverage are valid in 38 states. Segregating information about alcohol use in the medical record and assigning designated chemical dependency counselors to screen all trauma patients would provide confidentiality of alcohol information under current federal regulations, allowing denial of release of such information, except under subpoena.


Development and validation of a prognostic model predicting symptomatic hemorrhagic transformation in acute ischemic stroke at scale in the OHDSI network.
Hemorrhagic transformation (HT) after cerebral infarction is a complex and multifactorial phenomenon in the acute stage of ischemic stroke, and often results in a poor prognosis. Thus, identifying risk factors and making an early prediction of HT in acute cerebral infarction contributes not only to the selections of therapeutic regimen but also, more importantly, to the improvement of prognosis of acute cerebral infarction. The purpose of this study was to develop and validate a model to predict a patient's risk of HT within 30 days of initial ischemic stroke. We utilized a retrospective multicenter observational cohort study design to develop a Lasso Logistic Regression prediction model with a large, US Electronic Health Record dataset which structured to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). To examine clinical transportability, the model was externally validated across 10 additional real-world healthcare datasets include EHR records for patients from America, Europe and Asia. In the database the model was developed, the target population cohort contained 621,178 patients with ischemic stroke, of which 5,624 patients had HT within 30 days following initial ischemic stroke. 612 risk predictors, including the distance a patient travels in an ambulance to get to care for a HT, were identified. An area under the receiver operating characteristic curve (AUC) of 0.75 was achieved in the internal validation of the risk model. External validation was performed across 10 databases totaling 5,515,508 patients with ischemic stroke, of which 86,401 patients had HT within 30 days following initial ischemic stroke. The mean external AUC was 0.71 and ranged between 0.60-0.78. A HT prognostic predict model was developed with Lasso Logistic Regression based on routinely collected EMR data. This model can identify patients who have a higher risk of HT than the population average with an AUC of 0.78. It shows the OMOP CDM is an appropriate data standard for EMR secondary use in clinical multicenter research for prognostic prediction model development and validation. In the future, combining this model with clinical information systems will assist clinicians to make the right therapy decision for patients with acute ischemic stroke.


Derivative analysis of absorption features in hyperspectral remote sensing data of carbonate sediments.
This study uses derivative spectroscopy to assess qualitative and quantitative information regarding seafloor types that can be extracted from hyperspectral remote sensing reflectance signals. Carbonate sediments with variable concentrations of microbial pigments were used as a model system. Reflectance signals measured directly over sediment bottoms were compared with remotely sensed data from the same sites collected using an airborne sensor. Absorption features associated with accessory pigments in the sediments were lost to the water column. However major sediment pigments, chlorophyll a and fucoxanthin, were identified in the remote sensing spectra and showed quantitative correlation with sediment pigment concentrations. Derivative spectra were also used to create a simple bathymetric algorithm.


Impact of febrile neutropenia on R-CHOP chemotherapy delivery and hospitalizations among patients with diffuse large B-cell lymphoma.
This analysis from an observational study of clinical practice describes the impact of febrile neutropenia (FN) on chemotherapy delivery and hospitalizations. Adults with diffuse large B-cell lymphoma (DLBCL) scheduled to receive ≥ 3 cycles of 2- or 3-weekly CHOP with rituximab (R-CHOP-14/21) were eligible. Primary outcome was incidence of FN. FN data were available for 409 patients receiving R-CHOP-14 and 702 patients receiving R-CHOP-21. FN incidence was R-CHOP-14, 20% (81/409) and R-CHOP-21, 19% (133/702). Rates of primary prophylaxis with granulocyte-colony stimulating factor were R-CHOP-14, 84% (345/409) and R-CHOP-21, 36% (252/702). A large number of patients experienced their first FN episode in cycle 1 (R-CHOP-14, 24/81 [30%]; R-CHOP-21, 63/133 [47%]). Multiple risk factors (≥ 2) for FN were more frequent in patients experiencing FN than in patients not experiencing FN (R-CHOP-14, 60/81 [74%] versus 179/328 [55%]; R-CHOP-21, 98/133 [74%] versus 339/569 [60%]). A similar trend was observed for unplanned hospitalizations (R-CHOP-14, 63/81 [78%] versus 68/328 [21%]; R-CHOP-21, 105/133 [79%] versus 100/569 [18%]). Achievement of chemotherapy relative dose intensity ≥ 90% was lower among patients experiencing FN than in patients not experiencing FN (R-CHOP-14, 30/81 [37%] versus 234/328 [71%]; R-CHOP-21, 83/133 [62%] versus 434/569 [76%]). In patients with DLBCL treated with R-CHOP-14 or R-CHOP-21, patients with an event of FN were more likely to experience suboptimal chemotherapy delivery and increased incidence of unplanned hospitalizations than those without FN. FN-related hospitalizations are likely to impact chemotherapy delivery and to incur substantial costs.


Molecular characteristics and clinical outcomes of patients with Neurofibromin 1-altered metastatic colorectal cancer.
Loss-of-function alterations of Neurofibromin 1 (NF1) activate RAS, a driver of colorectal cancer. However, the clinical implications of NF1 alterations are largely unknown. We performed a comprehensive molecular profiling of NF1-mutant colorectal cancer using data from 8150 patients included in a dataset of commercial CLIA-certified laboratory (Caris Life Sciences). In addition, NF1 expression levels were tested for associations with clinical outcomes using data from 431 patients in the CALGB/SWOG 80405 trial. In the Caris dataset, 2.2% of patients had pathogenic or presumed pathogenic NF1 mutations. NF1-mutant tumors more frequently harbored PIK3CA (25.0% vs. 16.7%) and PTEN mutations (24.0% vs. 4.2%) than wild type tumors. Gene set enrichment analysis revealed that MAPK and PI3K pathway signatures were enriched in NF1-mutant tumors. In the CALGB/SWOG 80405 cohort, low NF1 expression was associated with poor prognosis, and high NF1 expression was associated with better efficacy of cetuximab than bevacizumab. Together, we revealed concurrent genetic alterations in the PI3K pathways in NF1-mutant tumors, suggesting the need to simultaneously block MAPK and PI3K pathways in treatment. The potential of NF1 alteration as a novel biomarker for targeted therapy was highlighted, warranting further investigations in clinical settings.


CADD: predicting the deleteriousness of variants throughout the human genome.
Combined Annotation-Dependent Depletion (CADD) is a widely used measure of variant deleteriousness that can effectively prioritize causal variants in genetic analyses, particularly highly penetrant contributors to severe Mendelian disorders. CADD is an integrative annotation built from more than 60 genomic features, and can score human single nucleotide variants and short insertion and deletions anywhere in the reference assembly. CADD uses a machine learning model trained on a binary distinction between simulated de novo variants and variants that have arisen and become fixed in human populations since the split between humans and chimpanzees; the former are free of selective pressure and may thus include both neutral and deleterious alleles, while the latter are overwhelmingly neutral (or, at most, weakly deleterious) by virtue of having survived millions of years of purifying selection. Here we review the latest updates to CADD, including the most recent version, 1.4, which supports the human genome build GRCh38. We also present updates to our website that include simplified variant lookup, extended documentation, an Application Program Interface and improved mechanisms for integrating CADD scores into other tools or applications. CADD scores, software and documentation are available at https://cadd.gs.washington.edu.


Improved physiological noise regression in fNIRS: A multimodal extension of the General Linear Model using temporally embedded Canonical Correlation Analysis.
For the robust estimation of evoked brain activity from functional Near-Infrared Spectroscopy (fNIRS) signals, it is crucial to reduce nuisance signals from systemic physiology and motion. The current best practice incorporates short-separation (SS) fNIRS measurements as regressors in a General Linear Model (GLM). However, several challenging signal characteristics such as non-instantaneous and non-constant coupling are not yet addressed by this approach and additional auxiliary signals are not optimally exploited. We have recently introduced a new methodological framework for the unsupervised multivariate analysis of fNIRS signals using Blind Source Separation (BSS) methods. Building onto the framework, in this manuscript we show how to incorporate the advantages of regularized temporally embedded Canonical Correlation Analysis (tCCA) into the supervised GLM. This approach allows flexible integration of any number of auxiliary modalities and signals. We provide guidance for the selection of optimal parameters and auxiliary signals for the proposed GLM extension. Its performance in the recovery of evoked HRFs is then evaluated using both simulated ground truth data and real experimental data and compared with the GLM with short-separation regression. Our results show that the GLM with tCCA significantly improves upon the current best practice, yielding significantly better results across all applied metrics: Correlation (HbO max. +45%), Root Mean Squared Error (HbO max. -55%), F-Score (HbO up to 3.25-fold) and p-value as well as power spectral density of the noise floor. The proposed method can be incorporated into the GLM in an easily applicable way that flexibly combines any available auxiliary signals into optimal nuisance regressors. This work has potential significance both for conventional neuroscientific fNIRS experiments as well as for emerging applications of fNIRS in everyday environments, medicine and BCI, where high Contrast to Noise Ratio is of importance for single trial analysis.


3D modeling to characterize lamina cribrosa surface and pore geometries using in vivo images from normal and glaucomatous eyes.
En face adaptive optics scanning laser ophthalmoscope (AOSLO) images of the anterior lamina cribrosa surface (ALCS) represent a 2D projected view of a 3D laminar surface. Using spectral domain optical coherence tomography images acquired in living monkey eyes, a thin plate spline was used to model the ALCS in 3D. The 2D AOSLO images were registered and projected onto the 3D surface that was then tessellated into a triangular mesh to characterize differences in pore geometry between 2D and 3D images. Following 3D transformation of the anterior laminar surface in 11 normal eyes, mean pore area increased by 5.1 ± 2.0% with a minimal change in pore elongation (mean change = 0.0 ± 0.2%). These small changes were due to the relatively flat laminar surfaces inherent in normal eyes (mean radius of curvature = 3.0 ± 0.5 mm). The mean increase in pore area was larger following 3D transformation in 4 glaucomatous eyes (16.2 ± 6.0%) due to their more steeply curved laminar surfaces (mean radius of curvature = 1.3 ± 0.1 mm), while the change in pore elongation was comparable to that in normal eyes (-0.2 ± 2.0%). This 3D transformation and tessellation method can be used to better characterize and track 3D changes in laminar pore and surface geometries in glaucoma.


Triage, treatment and transfer of patients with stroke in emergency department trial (the T3 Trial): a cluster randomised trial protocol.
Internationally recognised evidence-based guidelines recommend appropriate triage of patients with stroke in emergency departments (EDs), administration of tissue plasminogen activator (tPA), and proactive management of fever, hyperglycaemia and swallowing before prompt transfer to a stroke unit to maximise outcomes. We aim to evaluate the effectiveness in EDs of a theory-informed, nurse-initiated, intervention to improve multidisciplinary triage, treatment and transfer (T3) of patients with acute stroke to improve 90-day death and dependency. Organisational and contextual factors associated with intervention uptake also will be evaluated. This prospective, multicentre, parallel group, cluster randomised trial with blinded outcome assessment will be conducted in EDs of hospitals with stroke units in three Australian states and one territory. EDs will be randomised 1:1 within strata defined by state and tPA volume to receive either the T3 intervention or no additional support (control EDs). Our T3 intervention comprises an evidence-based care bundle targeting: (1) triage: routine assignment of patients with suspected stroke to Australian Triage Scale category 1 or 2; (2) treatment: screening for tPA eligibility and administration of tPA where applicable; instigation of protocols for management of fever, hyperglycaemia and swallowing; and (3) transfer: prompt admission to the stroke unit. We will use implementation science behaviour change methods informed by the Theoretical Domains Framework [1, 2] consisting of (i) workshops to determine barriers and local solutions; (ii) mixed interactive and didactic education; (iii) local clinical opinion leaders; and (iv) reminders in the form of email, telephone and site visits. Our primary outcome measure is 90 days post-admission death or dependency (modified Rankin Scale >2). Secondary outcomes are health status (SF-36), functional dependency (Barthel Index), quality of life (EQ-5D); and quality of care outcomes, namely, monitoring and management practices for thrombolysis, fever, hyperglycaemia, swallowing and prompt transfer. Outcomes will be assessed at the patient level. A separate process evaluation will examine contextual factors to successful intervention uptake. At the time of publication, EDs have been randomised and the intervention is being implemented. This theoretically informed intervention is aimed at addressing important gaps in care to maximise 90-day health outcomes for patients with stroke. Australian and New Zealand Clinical Trials Registry ACTRN12614000939695 . Registered 2 September 2014.


Sodium ascorbate induces apoptosis in neuroblastoma cell lines by interfering with iron uptake.
Neuroblastoma (NB) is an extra-cranial solid tumour of childhood. In spite of the good clinical response to first-line therapy, complete eradication of NB cells is rarely achieved. Thus, new therapeutic strategies are needed to eradicate surviving NB cells and prevent relapse. Sodium ascorbate has been recently reported to induce apoptosis of B16 melanoma cells through down-regulation of the transferrin receptor, CD71. Since NB and melanoma share the same embryologic neuroectodermal origin, we used different human NB cell lines to assess whether the same findings occurred. We could observe dose- and time-dependent induction of apoptosis in all NB cell lines. Sodium ascorbate decreased the expression of CD71 and caused cell death within 24 h. An increase in the global and specific caspase activity took place, as well as an early loss of the mitochondrial transmembrane potential. Moreover, intracellular iron was significantly decreased after exposure to sodium ascorbate. Apoptotic markers were reverted when the cells were pretreated with the iron donor ferric ammonium citrate (FAC), further confirming that iron depletion is responsible for the ascorbate-induced cell death in NB cells. Sodium ascorbate is highly toxic to neuroblastoma cell lines and the specific mechanism of vitamin C-induced apoptosis is due to a perturbation of intracellular iron levels ensuing TfR-downregulation.


[Characterization of class 1 and class 2 integron gene cassettes in Escherichia coli strains isolated from urine cultures: a multicenter study].
Escherichia coli is the most common pathogen isolated from both nosocomial and community acquired urinary tract infections. Although there are many studies from different centers concerning the antibiotic susceptibility of E.coli isolates in Turkey, the studies are quite few about class 1 and class 2 integron cassettes in clinical E.coli isolates from urinary samples. The aim of the study was to investigate the antibiotic susceptibility and the carriage of integron gene cassettes in E.coli strains isolated from urinary samples. A total of 626 E.coli strains isolated from urine cultures in microbiology laboratories located at 10 provinces from different regions of Turkey (Denizli, Ankara, Kayseri, Niğde, Şanlıurfa, Kahramanmaras, Tokat, Malatya, Konya and Trabzon) between June 2011-June 2012 were included in the study. The identification and antibiotic susceptibility testing of the isolates were studied by conventional methods as well as Vitek® 2 Compact (bioMérieux, France) and BD Phoenix™ 100 (Becton Dickinson, USA) systems. The antibiotic susceptibilities of all the isolates were retested by Kirby-Bauer disk diffusion method according to CLSI recommendations in the main center of the study in order to achive the standardization. The presence of integrons was detected with polymerase chain reaction (PCR) method by using specific primers targeting class 1 (intI1) and class 2 (intI2) integrase gene regions. After integron amplification the samples were cloned and subjected to DNA sequencing. When the antibiotic susceptibility of the isolates were evaluated, the highest resistance was observed against most commonly used empirical antibiotics namely ampicillin and trimethoprim-sulfamethoxazole (SXT) with the mean rate of 58.6% (range: 43.8%-73.2%) and 41.2% (range: 35.4%-45.8%), respectively. The most effective antibiotics detected against the isolates were imipenem and amikacin with the lowest resistance rates of 0.2% (range: 0%-1.1%) and 0.6% (range: 0%-3.2%), respectively. The frequency of positive IntI1 gene and class 1 integron gene cassettes were found as 25.8% (162/626) and 16.6% (104/626), respectively, whereas the frequency of positive intI2 gene II and class 2 integron gene cassettes were 5.1% (32/626) and 3% (19/626), respectively. The lowest intI1 gene frequency was detected in the isolates from Kayseri (16.6%) and the highest in the isolates from Kahramanmaraş (35.4%) provinces. While there was no intI2 gene in the isolates from Denizli and Kayseri, the highest frequency was 12.1% in the isolates from Şanlıurfa province. dfrA1 gene, the most frequent gene among integron gene cassettes was positive in 31 class 1 integron gene cassette alone, and positive with aadA1 gene in 18 class 1 integron gene cassettes. dfrA1 gene was positive with aadA1a just in one isolate. dfrA17 allele was positive in one isolate alone, in 28 isolates with aadA1, and in 15 isolates with aadA5. aadA1 gene was detected in four isolates. dfrA17-sat-aadA5 co-existence was detected among class 2 integron gene cassette in isolates from six provinces. dfrA1-sat-aadA1 was detected in one isolate from Ankara province and dfrA1 was detected in one isolate in Niğde province only. As a result, dfrA1 and aadA1 genes are the most common types of genes among class 1 and class 2 integron gene cassettes in E.coli isolated from urine cultures. It was concluded that high resistance against streptomycin (31.2%) and SXT (41.2%) supported the dissemination of integron-mediated genes dfr, sul1 and aad in the isolates.


Therapeutic Effects of Ziziphus jujuba Mill. Fruit in Traditional and Modern Medicine: A Review.
Ziziphus jujuba Mill. belonging to the Rhamnaceae family, has been consumed since ancient times as a medicine and food. In the different traditional medical schools, Z. jujuba has been used to treat various diseases such as respiratory system diseases (asthma, cough, and laryngitis), gastrointestinal problems (constipation, colitis and liver diseases), as well as cardiovascular and genitourinary system diseases. From the perspective of Islamic traditional medicine (ITM), Z. jujuba fruit is an emollient, laxative, and maturative, it can purify blood and improve blood circulation, relieve internal heat and reduce inflammation. Some therapeutic uses of Z. jujuba such as antibacterial, antioxidant, sedative, hepato-protective, anti-hyperglycemic, and anti-hyperlipidemic activities have been shown in modern pharmacological studies. In the current study, traditional and ethno-medicinal uses, botany, phytochemistry and pharmacological activities of Z. jujuba were reviewed.


AMF responsive DOX-loaded magnetic microspheres: transmembrane drug release mechanism and multimodality postsurgical treatment of breast cancer.
DOX-loaded magnetic alginate-chitosan microspheres (DM-ACMSs) were developed as a model system to evaluate alternating magnetic field (AMF)-responsive, chemo-thermal synergistic therapy for multimodality postsurgical treatment of breast cancer. This multimodality function can be achieved by the combination of DOX for chemotherapy, with superparamagnetic iron oxide nanoparticles (SPIONs) as magnetic hyperthermia agents and drug release trigger. Both moieties are encapsulated in ACMSs which also allow on-demand drug release. It is demonstrated that the optimized SPION content in DM-ACMSs is about 0.29 mg Fe, at which DM-ACMSs could exhibit the best hyperthermia performance. Under a remote AMF, DM-ACMs can quickly reach a 22.5% cumulative drug release in the tumor site within 10 min upon exposure under AMF, whereas only 0.2% DOX is released in the absence of AMF. Furthermore, a comparison study of AMF and water bath as heating source indicates that the cumulative drug release amount upon AMF exposure is twice that by water bath heating. Further analysis revealed that the AMF stimulated drug release is driven by both thermal and concentration gradient from inside to outside, which can be well-described by the coupling mechanism of mass and heat transfer using the Soret diffusion model. In vitro cytotoxicity tests on MCF-7 breast cancer cells show that the combined therapy based on DM-ACMSs leads to 95.5% cell death, about 1.5-fold and 1.1-fold higher than that of single magnetic hyperthermia or chemotherapy, respectively. The in vivo anti-tumor effect on tumor-bearing mice demonstrates that the residual tumor disappears in 12 days after chemo-thermal synergistic treatment using DM-ACMSs, and there is no recurrence in the entire experiment period (40 days) as compared to 25 days recurrence for single-modality treatment. Our results not only provide an innovative DM-ACMSs system as a stimuli-responsive, synergistic chemo-thermal therapy platform for efficient reduction in the recurrence of breast cancer, but also provide insight into the intricate interplay of the functional components in magnetic hydrogel microspheres.


Impact of the interval between coronary angiography and off-pump coronary bypass surgery on postoperative renal function.
Postoperative acute kidney injury (AKI) is a significant complication after coronary artery bypass surgery. Prior coronary angiography increases the likelihood of AKI due to the use of a radiocontrast dye. This study examined the effect of coronary angiography on the postoperative renal function after off-pump coronary artery bypass surgery (OPCAB). The records of 110 patients who required OPCAB were reviewed. These patients also had at least two of the following conditions: chronic kidney disease, hypertension, diabetes mellitus, emergency surgery, congestive heart failure, age >75 years, hematocrit <30%, a left ventricular ejection fraction <40%, or the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The patients were divided into two groups; coronary angiography performed within two days of OPCAB (Control group, n = 55), and coronary angiography performed more than two days before OPCAB (Angio group, n = 55). The serum creatinine (SCr) and serum cystatin C levels were measured on the day before surgery, as well as on postoperative days 1, 2, 3 and 7. The estimated glomerular filtration rate (eGFR) was also obtained on those days. AKI was defined as an increase in Cr >/=50% or >/=0.3 mg/dl within 48 hours. The postoperative changes in the SCr, cystatin C and eGFR were similar in the two groups. The incidence of AKI and renal replacement therapy were similar in the two groups. Coronary angiography performed within two days of OPCAB does not affect the postoperative renal function.


Red blood cell sorbitol as an indicator of polyol pathway activity. Inhibition by sorbinil in insulin-dependent diabetic subjects.
In a double-blind crossover study of 15 diabetic patients, elevated red blood cell (RBC) sorbitol levels were reduced by oral doses of the potent aldose reductase inhibitor, sorbinil (250 mg o.d.), to near-normal ranges. In diabetic rats with severe hyperglycemia, oral sorbinil (5 mg/kg) dramatically reduced (80-90%) sorbitol levels in tissues without affecting blood glucose; the RBC dose-response curve was similar to that in lens and sciatic nerve. In streptozotocin-treated rats with varying degrees of diabetes sorbitol levels in the lens, sciatic nerve, and RBC were elevated in proportion to the degree of hyperglycemia. RBC sorbitol levels in these animals were positively correlated with the levels in lens and sciatic nerve. These results establish that orally administered sorbinil is effective in lowering elevated sorbitol levels, and strongly suggest that the reduction seen in RBC sorbitol levels in human diabetic subjects is likely to reflect comparable effects of the drug in less accessible tissues associated with the long-term complications of diabetes.


The General Factor of Personality as Ego-Resiliency.
It was originally hypothesized by Block that what has come to be known as the General Factor of Personality (GFP) reflects ego-resiliency. We test Block's hypothesis in two studies. In Study 1 a meta-analysis (N = 15,609) examining the relationship between the GFP and ego-resiliency/resilience was conducted. In Study 2 (N = 157) archival data from Block and Block was used to examine the association between rater judged ego-resiliency across childhood, adolescence, and into early adulthood and the GFP based on self-report in early adulthood. Using structural equation modeling for the meta-analytic data, the correlation between the GFP and ego-resiliency/resilience was estimated at r = 0.93. Using a trait-state occasion model to test the hypothesis in Study 2, the correlation between the GFP and rated ego-resiliency was estimated at r = 0.85. The results of the two studies offer substantial support for Block's original hypothesis. Given the strength of the associations between the GFP and ego-resiliency/resilience one may conclude that the two constructs largely reflect the same underlying phenomenon.