Tuning the Thickness of Ba-Containing "Functional" Layer toward High-Performance Ceria-Based Solid Oxide Fuel Cells.
Developing highly efficient ceria-based solid oxide fuel cells with high power density is still a big concern for commercial applications. In this work, a novel structured Ce0.8Sm0.2O2-δ (SDC)-based fuel cell with a bilayered anode consisting of Ni-SDC and Ni-BaZr0.1Ce0.7Y0.2O3-δ (Ni-BZCY) was designed. In addition to the catalysis function, the Ni-BZCY anode "functional" layer also provides Ba source for generating an electron-blocking layer in situ at the anode/electrolyte interface during sintering. The Ni-BZCY thickness significantly influences the quality of the electron-blocking layer and electrochemical performances of the cell. The cell with a 50 μm thick Ni-BZCY layer exhibits the best performance in terms of open circuit voltage (OCV) and peak power density (1068 mW cm(-2) at 650 °C). The results demonstrate that this cell with an optimal structure has a distinct advantage of delivering high power performance with a high efficiency at reduced temperatures.


Preoperative cardiac evaluation: mechanisms, assessment, and reduction of risk.
The changing paradigm in cardiovascular disease in which atherosclerotic lesions exist in a spectrum of stable to unstable, the lack of a perfect prediction tool, and the paucity of randomized controlled data on appropriate intervention make protection of cardiac patients undergoing thoracic surgery challenging. Nociception-related sympathetic drive combines with inflammatory stimuli and the cardiodepressant effects of anesthesia to create a window of maximum risk in the early postoperative period (8-24 hours), and although multivariate models have shown that a combination of surgery-specific risk, patient-specific cardiovascular history, and estimated functional capacity best determine the need for further investigation, the optimal choice of investigation is unclear. Exercise or dobutamine stress echocardiography provide the best validated investigations, and in the case of poor images, dobutamine MR imaging is increasingly used. When disease is found, medical and interventional options are available. PCI is often used, but the risk of converting a stable flow-limiting lesion into a less stable non-flow-limiting lesion must be considered, along with a delay for anti-platelet therapy and endothelialization of the stent. Alternatively, medical protection with acute beta-blockade or alpha2-agonists reduces risk (although beta-blockade often is avoided in chronic lung disease, even nonselective agents are safe in patients with non-airways reactive COPD). In addition, it is likely that statin use reduces risk, probably by stabilizing plaques, but patients with cardiac risk are increasingly likely to be taking this medication already. The assessment and management of cardiac risk in the perioperative thoracic surgery patient is challenging. With focused, rational, and individually tailored management; tight monitoring of postoperative pain; and a close working relationship between the surgeon, anesthesiologist, and cardiologist, patient care can be optimized, and risk can be effectively controlled.


Identification of Waitea circinata as a Pathogen of the Moss Bryum argenteum var. argenteum on a Golf Course Fairway.
Waitea circinata Warcup and Talbot (also referred to as W. circinata var. circinata) is an important fungal pathogen of amenity turfgrasses and is especially problematic on Poa annua in putting greens in the late spring or early summer. The pathogen was first identified in 2005 from Japan and has since been seen widely throughout the United States (1,2). On occasion, the pathogen has been observed attacking creeping bentgrass (Agrostis stolonifera) but is typically less virulent. Disease symptoms include prominent yellow rings appearing throughout established turf and moderate leaf necrosis. In the summer of 2012, moss from a section of fairway on a golf course in Edwards, CO was observed to be rapidly killed by a fungal pathogen producing copious amounts of aerial mycelium and appearing similar to Waitea microscopically. Aerial mycelium was transferred to acidified potato dextrose agar (PDA) (1 ml lactic/L). After 1 day at 25°C, mycelia were transferred to PDA. After 2 weeks, plates were covered with white aerial mycelium and separate, spherical, 0.5-mm diameter, salmon-colored sclerotia, which turned dark brown within a few days and were produced submerged throughout the media. Spores were never produced and right-angled branching of mycelia, characteristic of Waitea, was observed in mature cultures. Mycelial plugs were incubated in nutrient broth and DNA was extracted using a MoBio Power Plant DNA extraction kit. Amplification of ribosomal ITS sequences with ITS4 and ITS5 resulted in a 100% identity match with GenBank sequence HM807352, W. circinata var. circinta (3). To demonstrate pathogenicity on Bryum argenteum, unaffected moss from the submitted sample (identified as B. argenteum var. argenteum via 100% sequence identity with the published GenBank sequence GU907062) was removed from the originally submitted sample and placed in separate growth chambers at 95% humidity and 21, 26, and 31°C. An additional experiment employed local B. agenteum plants collected from the URI Kingston, RI campus. Agar plugs from the isolated W. circinata were placed on top of the moss and within 2 days the fungus had caused complete mortality at all three temperatures. The experiment was also undertaken using the same environmental conditions with 5-week-old annual bluegrass (P. annua) and creeping bentgrass cv. A4 grown from seed. Plants were inoculated with infected rye grains at 31, 26, and 21°C. After 1 week, the P. annua plants showed significant mortality at 26 and 31°C with little infection at 21°C and the A. stolonifera plants showed moderate mortality at 26°C and little infection at the other two temperatures. All experiments utilized an additional uninoculated control treatment that showed no moss/turf necrosis or mortality. Experiments were all repeated once and used three replicates per experiment. While moss is not intentionally cultivated on golf courses, it does occur with regularity and often presents itself as a difficult pest to manage. This particular isolate of W. circinata has identical ribosomal and physiological characteristics of the reported P. annua pathogen but can attack one moss species and may be a possible candidate for selective biological control of moss in golf course settings. It is unclear how widespread moss pathogenicity is within W. circinata. References: (1) E. N. Njambere et al. Plant Dis. 95:78 2011. (2) T. Toda et al. Plant Dis. 89:536, 2005. (3) T. J. White et al. Page 315 in: PCR Protocols: A Guide to Methods and Applications, 1990.


Network-level allosteric effects are elucidated by detailing how ligand-binding events modulate utilization of catalytic potentials.
Allosteric regulation has traditionally been described by mathematically-complex allosteric rate laws in the form of ratios of polynomials derived from the application of simplifying kinetic assumptions. Alternatively, an approach that explicitly describes all known ligand-binding events requires no simplifying assumptions while allowing for the computation of enzymatic states. Here, we employ such a modeling approach to examine the "catalytic potential" of an enzyme-an enzyme's capacity to catalyze a biochemical reaction. The catalytic potential is the fundamental result of multiple ligand-binding events that represents a "tug of war" among the various regulators and substrates within the network. This formalism allows for the assessment of interacting allosteric enzymes and development of a network-level understanding of regulation. We first define the catalytic potential and use it to characterize the response of three key kinases (hexokinase, phosphofructokinase, and pyruvate kinase) in human red blood cell glycolysis to perturbations in ATP utilization. Next, we examine the sensitivity of the catalytic potential by using existing personalized models, finding that the catalytic potential allows for the identification of subtle but important differences in how individuals respond to such perturbations. Finally, we explore how the catalytic potential can help to elucidate how enzymes work in tandem to maintain a homeostatic state. Taken together, this work provides an interpretation and visualization of the dynamic interactions and network-level effects of interacting allosteric enzymes.


Bacterial sensing via neuronal Nod2 regulates appetite and body temperature.
Gut bacteria influence brain functions and metabolism. We investigated whether this influence can be mediated by direct sensing of bacterial cell wall components by brain neurons. In mice, we found that bacterial peptidoglycan plays a major role in mediating gut-brain communication via the Nod2 receptor. Peptidoglycan-derived muropeptides reach the brain and alter the activity of a subset of brain neurons that express Nod2. Activation of Nod2 in hypothalamic inhibitory neurons is essential for proper appetite and body temperature control, primarily in females. This study identifies a microbe-sensing mechanism that regulates feeding behavior and host metabolism.


Enhanced selectivity and capacity of clinoptilolite for Cd2+ removal from aqueous solutions by incorporation of magnetite nanoparticles and surface modification with cysteine.
In this study, magnetic zeolite (MZ) nanocomposite modified with cysteine was developed in order to enhance selectivity and capacity of clinoptilolite for cadmium ion. The prepared MZ nanocomposite is containing clinoptilolite and magnetite nanoparticles with weight ratio of 3:1. The synthesized nanocomposite was characterized by transmission electron microscopy, X-ray diffraction and vibrating sample magnetometer. Surface modification was confirmed by Fourier transform infrared spectrometer. Experiments were carried out to find the optimum conditions for modification of clinoptilolite and to investigate the effective parameters (pH, adsorbent dosage, contact time, and temperature) on the adsorption of Cd(2+) ion by modified clinoptilolite. The results showed enhanced selectivity of modified MZ in the presence of other naturally occurring cations (Na(+), K(+), Ca(2+) and Mg(2+)) and ammonium. Kinetic and equilibrium data were well fitted by a pseudo second-order and Langmuir model, respectively, with high correlation coefficients. The maximum adsorption capacities of the modified and non-modified clinoptilolite were found to be 20.0 mg/g and 5.2 mg/g, respectively. Thermodynamic parameters revealed that the adsorption process is spontaneous and endothermic under studied conditions.


Identifying armed respondents to domestic violence restraining orders and recovering their firearms: process evaluation of an initiative in California.
We evaluated a law enforcement initiative to screen respondents to domestic violence restraining orders for firearm ownership or possession and recover their firearms. The initiative was implemented in San Mateo and Butte counties in California from 2007 through 2010. We used descriptive methods to evaluate the screening process and recovery effort in each county, relying on records for individual cases. Screening relied on an archive of firearm transactions, court records, and petitioner interviews; no single source was adequate. Screening linked 525 respondents (17.7%) in San Mateo County to firearms; 405 firearms were recovered from 119 (22.7%) of them. In Butte County, 88 (31.1%) respondents were linked to firearms; 260 firearms were recovered from 45 (51.1%) of them. Nonrecovery occurred most often when orders were never served or respondents denied having firearms. There were no reports of serious violence or injury. Recovering firearms from persons subject to domestic violence restraining orders is possible. We have identified design and implementation changes that may improve the screening process and the yield from recovery efforts. Larger implementation trials are needed.


Proteomics of follicular fluid from women with polycystic ovary syndrome suggests molecular defects in follicular development.
Polycystic ovary syndrome (PCOS), a major cause of anovulatory infertility, is characterized by arrested follicular growth. Altered protein levels in the follicular fluid surrounding the ovum may reflect the molecular defects of folliculogenesis in these women. To identify differentially regulated proteins in PCOS by comparing the follicular fluid protein repertoire of PCOS with healthy women. The follicular fluid samples were collected from PCOS and normo-ovulatory women undergoing in vitro fertilization. Follicular fluid proteins were subjected to digestion using trypsin, and resultant peptides were labeled with isobaric tags for relative and absolute quantification reagents and analyzed by liquid chromatography tandem mass spectrometry. Differential abundance of selected proteins was confirmed by ELISA. A total of 770 proteins were identified, of which 186 showed differential abundance between controls and women with PCOS. Proteins involved in various processes of follicular development including amphiregulin; heparan sulfate proteoglycan 2; tumor necrosis factor, α-induced protein 6; plasminogen; and lymphatic vessel endothelial hyaluronan receptor 1 were found to be deregulated in PCOS. We also identified a number of new proteins from follicular fluid, whose function in the ovary is not yet clearly established. These include suprabasin; S100 calcium binding protein A7; and helicase with zinc finger 2, transcriptional coactivator. Proteins indispensable for follicular growth were found to be differentially expressed in follicular fluid of women with PCOS, which may in part explain the aberrant folliculogenesis observed in these women.


Performance of an electronic health record-based phenotype algorithm to identify community associated methicillin-resistant Staphylococcus aureus cases and controls for genetic association studies.
Community associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is one of the most common causes of skin and soft tissue infections in the United States, and a variety of genetic host factors are suspected to be risk factors for recurrent infection. Based on the CDC definition, we have developed and validated an electronic health record (EHR) based CA-MRSA phenotype algorithm utilizing both structured and unstructured data. The algorithm was validated at three eMERGE consortium sites, and positive predictive value, negative predictive value and sensitivity, were calculated. The algorithm was then run and data collected across seven total sites. The resulting data was used in GWAS analysis. Across seven sites, the CA-MRSA phenotype algorithm identified a total of 349 cases and 7761 controls among the genotyped European and African American biobank populations. PPV ranged from 68 to 100% for cases and 96 to 100% for controls; sensitivity ranged from 94 to 100% for cases and 75 to 100% for controls. Frequency of cases in the populations varied widely by site. There were no plausible GWAS-significant (p < 5 E -8) findings. Differences in EHR data representation and screening patterns across sites may have affected identification of cases and controls and accounted for varying frequencies across sites. Future work identifying these patterns is necessary.


The effect of different forms of dysglycemia during pregnancy on maternal and fetal outcomes in treated women and comparison with large cohort studies.
We describe the impact of different forms of dysglycemia on maternal and neonatal health. This research is a part of the PEARL-Peristat Maternal and newborn registry, funded by Qatar National Research Fund (QNRF) Doha, Qatar. A population-based retrospective data analysis of 12,255 women with singleton pregnancies screened during the year 2016-2017, of which 3,027 women were identified with gestation diabetes mellitus (GDM) during pregnancy and 233 were diabetic before pregnancy. Data on maternal outcome was collected from the PEARL-Peristat Maternal and newborn registry. The prevalence of GDM and diabetes mellitus (DM) was 24.7 % and 1.9%, respectively. 55% of DM, 38% of GDM and 25.6% of controls were obese (p<0.001). 71% of pregnant women with DM and 57.8% of those with GDM were older than 30 years versus 44.2% of controls. Pregnant women with DM or GDM had higher prevalence of hypertension versus normal controls (9.9%, 5.5% and 3.5%, respectively; p<0.001). Among women with vaginal deliveries, the proportion of women with induction of labor was significantly higher in the DM and GDM compared to control subjects (33.9%, 26.5% and 12.4%, respectively; p<0.001). The number of women who underwent Cesarean section was significantly higher in the DM and GDM groups versus normal controls (51.9%, 36.8%, and 28.5%, respectively; p<0.001). Preterm delivery was significantly higher in women with DM and GDM (13.7% and 9%, respectively versus normal women (6.4%); p<0.001). Babies of DM and GDM had significantly higher occurrence of respiratory distress (RDS) or transient tachypnea (TTS): 9% and 5.8 % versus normal controls (4.8%). Macrosomia was more prevalent in babies of DM (6.4%) and GDM (6.8%) compared to controls (5%) (p: <0.001). Significant hypoglycemic episodes occurred more frequently in babies of DM and GDM women (11.2% and 3%, respectively) versus controls (0.6%) (p: <0.001. Infants of DM and GDM mothers required more treatments of phototherapy (9.4% and 8.9%, respectively) versus those born to normal women (7.2%) (p: 0.006). The prevalence of congenital anomalies and neonatal death did not differ between the groups. Despite the improvement in the prenatal diagnosis and management of dysglycemia, there is still a higher prevalence of prematurity, macrosomia, and hypoglycemia in infants of mothers with DM and GDM. Measurements to reduce obesity and control dysglycemia in women during the childbearing period are highly required to prevent the still higher morbidity during pregnancy.


Diamond micro-optics: microlenses and antireflection structured surfaces for the infrared spectral region.
Fabrication and evaluation of a subwavelength grating in diamond, designed to reduce the Fresnel reflection, is demonstrated. The antireflection (AR) structures are designed to reduce the surface reflection at an illuminating wavelength of 10.6 microm. With this AR-treatment, where no other material is introduced (i.e., no thin film coating), the unique properties of diamond can be fully used. The fabricated AR structures were optically evaluated with a spectrophotometer. The transmission through a diamond substrate with AR structures on both sides was increased from 71% to 97%, with a theoretical value of 99%. Microlenses in diamond are also demonstrated. The lenses are evaluated with interferometers and show good performance. The micro-optical structures were fabricated by electron-beam lithography or photolithographic methods followed by plasma etching.


Radionuclide imaging with human polyclonal immunoglobulin (Tc-HIG) and bone scan in patients with rheumatoid arthritis and serum-negative polyarthritis.
Rheumatoid arthritis (RA) is a chronic polyarthritic syndrome in which actively inflamed joints coexist with others being in remission. Compatible bone scan (BS) reveals joints with increased activity due to degenerative alterations, whilst scanning with human polyclonal immunoglobulin (HIG) is capable to show which of the joints present active inflammation of the synovial membrane. The aim of the study is to investigate the utility of molecular imaging with HIG in patients suffering from RA. Forty patients (9 males plus 31 females), suffering from painful polyarthritic syndrome, with a mean age 45.3±7 years and a duration of disease 18.3±4.2 months were enrolled in the study. Twenty-six of the patients were serum positive to RA factor, considered as suffering from RA, whilst fourteen of them were RA factor negatives and they were considered as patients with serum-negative polyarthritis. All patients were submitted to x-rays and ultrasound examination (US) in joints of interest, plus whole body BS with (99m)Tc-MDP and finally scan with (99m)Tc-HIG. A total of 1680 joints have been evaluated. In 6 of the patients-two with serum negative RA (252 joints), radionuclide imaging with HIG was within normal limits, despite the fact that in compatible bone scan degenerative alterations have been mentioned in 30 joints. In all these patients disease was evaluated as inactive ("arthrotic changes"). In the remaining 34 patients-12 with serum negative RA (1428 joints), increased accumulation of HIG, concerning serum positive patients, has been mentioned to 163 joints ("arthritic changes"), whilst in the same group, BS revealed degenerative changes to 265 joints. Concerning serum negative patients, the respective results were 64 versus 190 joints. Increased uptake of HIG has been found in 189/226 swollen and painful joints (overall sensitivity according to clinical criteria 83.3%) and in 38 joints without any clinical evidence of inflammation, with clinical active inflammation presented after follow-up to 35 of them, yielding thus specificity at the level of 92%. Matched findings between these two methods have been mentioned to 185 out of 227 joints with an abnormal scan with HIG. Abnormal x-rays and US findings have been mentioned in 67 of the joints. According to the above mentioned, BS in RA reveals joints being actively inflamed or not, whilst radionuclide study with HIG is capable to distinguish actively inflamed joints, even in patients with serum negative RA, in a greater extent than anatomical imaging modalities.


Gender, ethnicity and graduate status, and junior doctors' self-reported preparedness for clinical practice: national questionnaire surveys.
Medical schools need to ensure that graduates feel well prepared for their first medical job. Our objective was to report on differences in junior doctors' self-reported preparedness for work according to gender, ethnicity and graduate status. Postal and electronic questionnaires. UK. Medical graduates of 2008 and 2009, from all UK medical schools, one year after graduation. The main outcome measure was the doctors' level of agreement with the statement that 'My experience at medical school prepared me well for the jobs I have undertaken so far', to which respondents were asked to reply on a scale from 'strongly agree' to 'strongly disagree'. Women were slightly less likely than men to agree that they felt well prepared for work (50% of women agreed or strongly agreed vs. 54% of men), independently of medical school, ethnicity, graduate entry status and intercalated degree status, although they were no more likely than men to regard lack of preparedness as having been a problem for them. Adjusting for the other subgroup differences, non-white respondents were less likely to report feeling well prepared than white (44% vs. 54%), and were more likely to indicate that lack of preparedness was a problem (30% non-white vs. 24% white). There were also some gender and ethnic differences in preparedness for specific areas of work. The identified gender and ethnic differences need to be further explored to determine whether they are due to differences in self-confidence or in actual preparedness.


Could azathioprine be considered as a therapeutic alternative in the treatment of alopecia areata? A pilot study.
Alopecia areata is an autoimmune disease resulting in partial or total nonscarring hair loss and the treatment of severe alopecia areata is difficult. The aim of this study was to evaluate the efficacy and safety of azathioprine as a systemic monotherapy for moderate to severe alopecia areata. A total of 20 patients [14 men (70%) and six women (30%)] with minimum 6 months history of alopecia areata were included. The extent of scalp hair regrowth during and after the completion of the 6 months treatment was evaluated by the Severity of Alopecia Tool (the SALT score). The daily drug intake was calculated as 2 mg/kg of body weight. Mean duration of current episode of scalp hair loss was 26.4 (26.4 ± 17) months. Mean regrowth percentage was 52.3% (52.3 ± 38.4). Mean hair loss percentage before treatment was 72.7% (72.7 ± 28.3) compared with 33.5% (33.5 ± 30.7) after 6 months of azathioprine treatment. This showed a highly significant statistical difference (Paired t-test, CI 95% =21.5-54.1). Mean hair loss score (S(0) -S(5) ) before treatment was 3.9 (3.9 ± 1.6) and after 6 months of azathioprine treatment was 1.8 (1.8 ± 1.3). Assessment showed significant difference from baseline score (sign test, P < 0.0001). No significant statistical difference was observed with respect to gender before and after azathioprine treatment. Treatment with azathioprine as a systemic monotherapy clinically produces relevant improvement in moderate-to-severe alopecia areata. Generally azathioprine is a low-cost and well-tolerated drug and with controlled studies on larger number of patients, long-term efficacy and safety of this treatment should be investigated.


The long-term effects of naprapathic manual therapy on back and neck pain - results from a pragmatic randomized controlled trial.
Back and neck pain are very common, disabling and recurrent disorders in the general population and the knowledge of long-term effect of treatments are sparse. The aim of this study was to compare the long-term effects (up to one year) of naprapathic manual therapy and evidence-based advice on staying active regarding non-specific back and/or neck pain. Naprapathy, a health profession mainly practiced in Sweden, Finland, Norway and in the USA, is characterized by a combination of manual musculoskeletal manipulations, aiming to decrease pain and disability in the neuromusculoskeletal system. Subjects with non-specific pain/disability in the back and/or neck lasting for at least two weeks (n = 409), recruited at public companies in Sweden, were included in this pragmatic randomized controlled trial. The two interventions compared were naprapathic manual therapy such as spinal manipulation/mobilization, massage and stretching, (Index Group), and advice to stay active and on how to cope with pain, provided by a physician (Control Group). Pain intensity, disability and health status were measured by questionnaires. 89% completed the 26-week follow-up and 85% the 52-week follow-up. A higher proportion in the Index Group had a clinically important decrease in pain (risk difference (RD) = 21%, 95% CI: 10-30) and disability (RD = 11%, 95% CI: 4-22) at 26-week, as well as at 52-week follow-ups (pain: RD = 17%, 95% CI: 7-27 and disability: RD = 17%, 95% CI: 5-28). The differences between the groups in pain and disability considered over one year were statistically significant favoring naprapathy (p < or = 0.005). There were also significant differences in improvement in bodily pain and social function (subscales of SF-36 health status) favoring the Index Group. Combined manual therapy, like naprapathy, is effective in the short and in the long term, and might be considered for patients with non-specific back and/or neck pain. Current Controlled Trials ISRCTN56954776.


Maternal smoking cessation and reduced academic and behavioral problems in offspring.
There is some debate whether smoking during pregnancy causes or is only a risk factor for negative academic outcomes and increased risk of psychopathology in offspring. This study evaluated whether maternal smoking cessation would reduce the risk of adverse outcomes in school-aged children. Women completed an online survey that included items about child scholastic performance and the Child Behavior Checklist (CBCL). Mothers were divided based on pre-pregnancy and pregnancy smoking status into: (1) Nonsmokers (N=320); (2) Women that smoked in the 3 months preceding and throughout pregnancy (Smokers, N=83); and (3) Smoking before, but not during pregnancy (Quitters, N=72). The Smokers and Quitters groups each had lower education and incomes compared to Nonsmokers but were indistinguishable from each other on these measures. The offspring of Smokers were more likely (p<.05) to be behind their peers on standardized tests in math (27.8%) relative to both Nonsmokers (17.4%) and Quitters (13.0%) with similar findings for reading. Smokers reported more behavioral problems by their children in several areas including Hyperactivity and Impulsivity, Social problems, and Externalizing problems including Aggression and Rule-Breaking. Further, the children of Quitters had significantly fewer Attention and Externalizing problems than Smokers. These outcomes were observed even after accounting for the variance attributable to maternal education and several other potential confounds. Together, these findings indicate that smoking cessation is associated with reduced risk of having children with academic and neuropsychological difficulties. These outcomes are discussed within the framework that nicotine may be a neurobehavioral teratogen.


Modelling of light pollution in suburban areas using remotely sensed imagery and GIS.
This paper describes a methodology for modelling light pollution using geographical information systems (GIS) and remote sensing (RS) technology. The proposed approach attempts to address the issue of environmental assessment in sensitive suburban areas. The modern way of life in developing countries is conductive to environmental degradation in urban and suburban areas. One specific parameter for this degradation is light pollution due to intense artificial night lighting. This paper aims to assess this parameter for the Athens metropolitan area, using modern analytical and data capturing technologies. For this purpose, night-time satellite images and analogue maps have been used in order to create the spatial database of the GIS for the study area. Using GIS advanced analytical functionality, visibility analysis was implemented. The outputs for this analysis are a series of maps reflecting direct and indirect light pollution around the city of Athens. Direct light pollution corresponds to optical contact with artificial night light sources, while indirect light pollution corresponds to optical contact with the sky glow above the city. Additionally, the assessment of light pollution in different periods allows for dynamic evaluation of the phenomenon. The case study demonstrates high levels of light pollution in Athens suburban areas and its increase over the last decade.


Cysteine and glutathione deficiency in AIDS patients: a rationale for the treatment with N-acetyl-cysteine.
A series of clinical studies and laboratory investigations suggests that the acquired immunodeficiency syndrome (AIDS) may be the consequence of a virus-induced cysteine deficiency. HIV-infected persons at all stages of the disease were found to have decreased plasma cystine and cysteine concentrations and decreased intracellular glutathione levels. In rhesus macaques, cysteine levels decrease already within 1-2 weeks after infection with the closely related virus SIVmac. HIV-infected persons and SIV-infected rhesus macaques have also, on the average, substantially increased plasma glutamate levels. Increased glutamate levels aggravate the cysteine deficiency by inhibiting the membrane transport of cystine. Even moderately elevated extracellular glutamate levels as they occur in HIV-infected persons cause a substantial decrease of intracellular cysteine levels. Clinical studies revealed that individual cystine and glutamate levels are correlated with the individual lymphocyte reactivity and T4+ cell counts but not T8+ cell counts. This phenomenon was demonstrated not only in HIV-infected persons but also in healthy human individuals. The cellular cysteine supply affects amongst others the intracellular glutathione level and IL-2-dependent proliferation of T cells and (inversely) also the activation of the transcription factor NF-kappa B. The cysteine deficiency of HIV-infected persons is, therefore, possibly responsible not only for the cellular dysfunction but also for the overexpression of tumor necrosis factor-alpha (TNF-alpha), interleukin-2 receptor alpha-chain, and and beta 2-microglobulin. All the corresponding genes are associated with kappa-like enhancer sequences.(ABSTRACT TRUNCATED AT 250 WORDS)


Barriers to the development of palliative care in Western Europe.
The Eurobarometer Survey of the EAPC Task Force on the Development of Palliative Care in Europe is part of a programme of work to produce comprehensive information on the provision of palliative care across Europe. To identify barriers to the development of palliative care in Western Europe. A qualitative survey was undertaken amongst boards of national associations, eliciting opinions on opportunities for, and barriers to, palliative care development. By July 2006, 44/52 (85%) European countries had responded to the survey; we report here on the results from 22/25 (88%) countries in Western Europe. Data from the Eurobarometer Survey were analysed thematically by geographical region and by the degree of development of palliative care in each country. From the data contained within the Eurobarometer, we identified six significant barriers to the development of palliative care in Western Europe: (i) lack of palliative care education and training programmes; (ii) lack of awareness and recognition of palliative care; (iii) limited availability of/knowledge about opioid analgesics; (iv) limited funding; (v) lack of coordination amongst services; and (vi) uneven palliative care coverage. Findings from the EAPC Eurobarometer Survey suggest that barriers to the development of palliative care in Western Europe may differ substantially from each other in both their scope and context and that some may be considered to be of greater significance than others. A number of common barriers to the development of the discipline do exist and much work still remains to be done in the identified areas. This paper provides a road map of which barriers need to be addressed.


Psychosocial resources and barriers to self-management in African American adolescents with type 2 diabetes: a qualitative analysis.
The purpose of this qualitative study was to identify psychosocial resources and barriers to self-management among African American adolescents with type 2 diabetes and their mothers. African American adolescents (n = 10) aged 14 to 19 years old with type 2 diabetes for >1 year and their mothers (n = 10) were recruited from the pediatric diabetes clinic of a large medical center practice. Participants were independently interviewed and responded to a series of open-ended questions concerning illness experiences and resources and barriers to diabetes self-management. This study used a modified grounded theory approach to data coding and analysis. Adolescents and mothers shared similar perceptions of resources and barriers to self-management. Resources included mother's role as the primary support person, emergence of greater self-efficacy and coping over time, family recognition of the seriousness of diabetes, and the presence of supportive peers. Barriers included comorbidity, dietary and other regimen challenges, negative peer influences, and financial problems. Resources and barriers identified in this study represent the multiple contexts that influence type 2 diabetes (eg, individual, family, peer, economic, and cultural).


Inducible repair and intrinsic radiosensitivity: a complex but predictable relationship?
Two groups have proposed a simple linear relationship between inducible radioresistance in a variety of mammalian cells and their intrinsic radiosensitivity at 2 Gy (Lambin et al., Int.J. Radiat. Biol. 69, 279-290, 1996; Alsbeih and Raaphorst, unpublished results, 1997). The inducible repair response (IRR) is quantified as a ratio, alpha(S)/alpha(R), i.e. the slope in the hypersensitive low-dose region, alpha(S), relative to the alpha(R) term of the classical linear-quadratic formula. These proposals imply that the intrinsic radiosensitivity at clinically relevant doses is directly linked to the cell's ability to mount an adaptive response as a result of exposure to very low doses of radiation. We have re-examined this correlation and found that the more extensive data set now available in the literature does not support the contention of a simple linear relationship. The two parameters are correlated, but by a much more complex relationship. A more logical fit is obtained with a log-linear equation. A series of log-linear curves are needed to describe the correlation between IRR and SF2, because of the spectrum of alpha/beta ratios among the cell lines and hence the confounding effect of the beta term at a dose of 2 Gy. The degree of repair competence before irradiation starts could also be a major factor in the apparent magnitude of the amount of repair induced. There appears to be a systematic difference in the data sets from different series of cell lines that have been obtained using flow cytometry techniques in the laboratory in Vancouver and using dynamic microscope imaging at the Gray Laboratory. We suggest that the use of a brief exposure to a laser beam in flow cytometry before the cells are irradiated might itself partially induce a stress response and change the DNA repair capacity of the cells. The clinical consequences of the relationship for predicting the benefits of altered fractionation schedules are discussed. [ru5]


Controlled study of the effect of angiotensin converting enzyme inhibition versus calcium-entry blockade on insulin sensitivity in overweight hypertensive patients: Trandolapril Italian Study (TRIS).
The aim of this study was to evaluate the effect of trandolapril, an angiotensin converting enzyme inhibitor, on blood pressure, forearm blood flow and insulin sensitivity in comparison with nifedipine gastrointestinal therapeutic system. This is a multicentre, two-way parallel-group, open-label comparative study in 90 overweight hypertensive patients, who were randomly assigned to treatment for 8 weeks with either trandolapril or nifedipine. At baseline and after treatment, all patients underwent an oral glucose tolerance test, an evaluation of their metabolic profiles and a euglycaemic hyperinsulinaemic clamp test. In a subgroup of 18 patients, a forearm study was carried out. Blood pressure fell by the second week of treatment and remained significantly reduced compared with baseline in both treatment groups. Plasma triglyceride levels were also significantly reduced after trandolapril therapy, but no significant changes occurred in the other metabolic parameters during treatment with either drug. During the euglycaemic hyperinsulinaemic clamp, whole-body glucose use was similar in the two treatment groups at baseline, and a moderate but statistically significant increase in insulin sensitivity was observed after trandolapril treatment (trandolapril: 5.0 +/- 0.2 versus 4.5 +/- 0.2 mg/kg per min; nifedipine: 4.1 +/- 0.3 versus 4.2 +/- 0.3 mg/kg per min; P < 0.05, versus baseline and trandolapril versus nifedipine treatment). Skeletal muscle glucose uptake was significantly higher after trandolapril than after nifedipine therapy (5.0 +/- 0.7 and 3.0 +/- 0.4 mg/min, respectively; P < 0.01). As forearm blood flow was similar in the two treatment groups at baseline and was unchanged after 8 weeks of therapy, skeletal muscle glucose extraction was significantly greater in the ACE inhibitor treated-group than in the nifedipine comparative group (trandolapril: baseline 21 +/- 2, treatment 24 +/- 3 mg/dl; nifedipine: baseline 18 +/- 3, treatment 16 +/- 2 mg/dl; P < 0.05, trandolapril versus nifedipine treatment). During short-term treatment, ACE inhibition with trandolapril was able to moderately improve insulin sensitivity, in comparison with calcium blockade, and this effect appeared to be independent of the haemodynamic action of the drug.


Oral microbial community composition is associated with pancreatic cancer: A case-control study in Iran.
Oral microbiota may be related to pancreatic cancer risk because periodontal disease, a condition linked to multiple specific microbes, has been associated with increased risk of pancreatic cancer. We evaluated the association between oral microbiota and pancreatic cancer in Iran. A total of 273 pancreatic adenocarcinoma cases and 285 controls recruited from tertiary hospitals and a specialty clinic in Tehran, Iran provided saliva samples and filled out a questionnaire regarding demographics and lifestyle characteristics. DNA was extracted from saliva and the V4 region of the 16S rRNA gene was PCR amplified and sequenced on the MiSeq. The sequencing data were processed using the DADA2 plugin in QIIME 2 and taxonomy was assigned against the Human Oral Microbiome Database. Logistic regression and MiRKAT models were calculated with adjustment for potential confounders. No association was observed for alpha diversity with an average of 91.11 (standard deviation [SD] 2.59) sequence variants for cases and 89.42 (SD 2.58) for controls. However, there was evidence for an association between beta diversity and case status. The association between the Bray-Curtis dissimilarity and pancreatic cancer was particularly strong with a MiRKAT P-value of .000142 and specific principal coordinate vectors had strong associations with cancer risk. Several specific taxa were also associated with case status after adjustment for multiple comparisons. The overall microbial community appeared to differ between pancreatic cancer cases and controls. Whether these reflect differences evident before development of pancreatic cancer will need to be evaluated in prospective studies.


One-Level Versus 2-Level Treatment With Cervical Disc Arthroplasty or Fusion: Outcomes Up to 7 Years.
Anterior cervical discectomy and fusion (ACDF) and cervical disc arthroplasty (CDA) have been used to treat degenerative disc disease at single as well as multiple cervical levels. This study compares the safety and efficacy of 1-level versus 2-level CDA and ACDF. In total, 545 and 397 patients with degenerative disc disease were studied in 1-level and 2-level Food and Drug Administration (FDA)-approved clinical trials, respectively: CDA (n = 280 and 209), ACDF (n = 265 and 188). Data from these studies were used to compare 1- versus 2-level procedures: the propensity score method was used to adjust for potential confounding effects, and adjusted mean outcome safety and efficacy scores at 2 and 7 years postsurgery were compared between 1-level and 2-level procedures within treatment type. One-level and 2-level procedures had similar rates of improvement in overall success and patient-reported outcomes scores for both CDA and ACDF. There were no statistical differences in rates of implant-related adverse events (AEs) or serious implant-related AEs between 1-level and 2-level CDA. The 7-year rate of implant-related AEs was higher for 2-level than 1-level ACDF (27.7% vs 18.9%, P ≤ .036), though the rates of serious implant-related AEs between ACDF groups did not differ significantly. Secondary surgery rates were not statistically different between 1-level and 2-level procedures (CDA or ACDF) at the index or adjacent levels at 2 or 7 years. Grade IV heterotopic ossification at 7 years was reported in 4.6% of 1-level CDA patients and 8.6%/7.3% at the superior/inferior levels, respectively, of 2-level CDA patients. One- and 2-level CDA appear equally safe and effective in the treatment of cervical degenerative disc disease. Two-level ACDF appears to be as effective as 1-level ACDF but with a higher rate of some AEs at long-term follow-up. 2. clinicaltrials.gov: NCT00667459, NCT00642876, and NCT00637156.


Frequency distribution of temporomandibular disorders according to occlusal factors: A cross-sectional study.
Temporomandibular disorder (TMD) is a common condition affecting the temporomandibular joint and causes pain and discomfort. However, the role of factors contributing to this problem is still controversial. The purpose of this cross-sectional study was to determine the correlation of occlusal factors and parafunctional habits with TMD and The determination of TMD prevalence among patients referring to Isfahan Dental School in 2017. In this cross-sectional study, A total of 200 patients between 20 and 50 years were examined and questioned based on the Research Diagnostic Criteria for Temporomandibular Disorders assessment instrument. The association of occlusal factors (dental relationship, lateral occlusal scheme, horizontal differences between centric occlusion and Maximum intercuspation (MI), difference between MI and mandibular resting position) and parafunctional habits (bruxism/clenching and habits) with TMD was analyzed using Chi-square tests and independent sample t-test (α = 0.05). Binomial logistic regression analysis was performed with respect to confounding variables. The prevalence of TMD in the studied sample was 58.9%. Only bruxism showed a significant difference between TMD and non-TMD groups (P < 0.05). Other parafunctional and occlusal factors did not act as influential factors for TMD. Parafunction may play an important role in the initiation of TMD, although other habits and occlusal factors are considered as noninfluential factors. However, larger sample size and multicenter sampling are recommended for the future studies.


Secure and Trustable Electronic Medical Records Sharing using Blockchain.
Electronic medical records (EMRs) are critical, highly sensitive private information in healthcare, and need to be frequently shared among peers. Blockchain provides a shared, immutable and transparent history of all the transactions to build applications with trust, accountability and transparency. This provides a unique opportunity to develop a secure and trustable EMR data management and sharing system using blockchain. In this paper, we present our perspectives on blockchain based healthcare data management, in particular, for EMR data sharing between healthcare providers and for research studies. We propose a framework on managing and sharing EMR data for cancer patient care. In collaboration with Stony Brook University Hospital, we implemented our framework in a prototype that ensures privacy, security, availability, and fine-grained access control over EMR data. The proposed work can significantly reduce the turnaround time for EMR sharing, improve decision making for medical care, and reduce the overall cost.


Microtensile Bond Strength Between Glass Ionomer Cement and Silver Diamine Fluoride-Treated Carious Primary Dentin.
Purpose: The study objectives were to investigate the effect of silver diamine fluoride (SDF) on the microtensile bond strength between glass ionomer cement and carious primary dentin and evaluate the mode of restoration failure. Methods: Forty carious primary molars were sectioned in half through the middle of the carious lesion and randomly allocated to test and control groups. The test specimens were treated with 38 percent SDF, and the control, deionized water. The samples were stored in artificial saliva for 14 days at 37 degrees Celsius, and the dentin surfaces were conditioned and restored with Fuji IX GP Extra. After 24 hours in artificial saliva, the specimens were prepared for microtensile bond strength testing and stressed in tension at one mm per minute until failure. Mean bond strengths were compared using the paired t test. The failure mode was assessed with a stereomicroscope under 40X magnification. Results: The mean microtensile strength for the test group was 7.4 MPa (SD=±5.1) and 6.3 (±4.6) for the control group (P>0.05). Most common failure mode was the mixed failure mode in both groups. Conclusion: Silver diamine fluoride does not adversely affect the bond strength between glass ionomer cement and carious primary dentin in vitro.


Concanavalin A and wheat germ agglutinin receptors on Dictyostelium discoideum. Their visualization by scanning electron microscopy with microspheres.
The cellular slime mold, Dictyostelium discoideum, is a convenient model for studying cellular interactions during development. Evidence that specific cell surface components are involved in cellular interactions during its development has been obtained by Gerisch and co-workers (1, 2) using immunological techniques. Smart and Hynes (3) have shown that a cell surface protein can be iodinated on cells in aggregation phase, but not in vegetative phase, by the lactoperoxidase procedure. Recently, McMahon et al. (4), and Hoffman and McMahon have demonstrated, by SDS gel electrophoresis, considerable differences in cell surface proteins and glycoproteins of plasma membranes isolated from cells at different stages of development. Plant lectins have also been used to monitor changes in cell surface properties of D. discoideum cells during development. Weeks and co-workers (5, 6) have detected differences in the binding and agglutination of cells by concanavalin A (Con A). Gillette and Filosa (7) have shown that Con A inhibits cell aggregation and prematurely induces cyclic AMP phosphodiesterase. Capping of Con A receptors has also been reported (8). Reitherman et al. (9) have recently reported that agglutination of cells by several plant lectins and the slime mold agglutination, discoidin, changes during development. Such studies indicate that differences in surface properties exist for cells at various stages of development. However, owing to the uncertainties in the factors which contribute to lectin-induced cell agglutination (10), the molecular basis for these observations remain to be determined. In this study, we have used microspheres (11-14) coupled to either Con A or wheat germ agglutinin (WGA) as visual markers to study by scanning electron microscopy the topographical distribution of lectin receptors on D. discoideum cells fixed at different stages of development. We also describe the effect of labeling on the distribution of lectin receptors and on the morphology of the cell surface.


A case control study on the effectiveness of breast cancer screening by clinical breast examination in Japan.
A case-control study was conducted in Miyagi and Gunma prefectures, Japan, to evaluate the effectiveness of breast cancer screening by clinical breast examination (CBE) alone in reducing breast cancer mortality. Case subjects, who were female and had died of breast cancer, were collected from residential registry files and medical records. Control subjects matched in sex, age and residence were randomly selected from residential registry files. The screening histories during 5 years prior to the cases having been diagnosed as breast cancer were surveyed using the examinee files of the screening facilities. Finally, the data of 93 cases and 375 controls were analyzed. The odds ratio (OR) of breast cancer death for participating in screening at least once during 5 years was 0.93 (95% confidence interval (95% CI) 0.48-1.79). The cases were more symptomatic than the controls when screened. If the participants who had had symptoms in their breasts were classified as not screened, the OR decreased to 0.56 (95% CI 0.27-1.18). The case control study suggests that the current screening modality (CBE) lacks effectiveness (OR = 0.93), although it might be effective for an asymptomatic population (OR = 0.56). The number of cases was small, and a larger case-control study is desirable to define whether CBE is effective or not. However, it is necessary to consider the introduction of mammographic screening to reduce breast cancer mortality in Japan.


The Protozoan Trichomonas vaginalis Targets Bacteria with Laterally Acquired NlpC/P60 Peptidoglycan Hydrolases.
The human eukaryotic pathogen Trichomonas vaginalis causes trichomoniasis, a prevalent sexually transmitted infection. This extracellular protozoan is intimately associated with the human vaginal mucosa and microbiota, but key aspects of the complex interactions between the parasite and the vaginal bacteria remain elusive. We report that T. vaginalis has acquired, by lateral gene transfer from bacteria, genes encoding peptidoglycan hydrolases of the NlpC/P60 family. Two of the T. vaginalis enzymes were active against bacterial peptidoglycan, retaining the active-site fold and specificity as dl-endopeptidases. The endogenous NlpC/P60 genes are transcriptionally upregulated in T. vaginalis in the presence of bacteria. The overexpression of an exogenous copy enables the parasite to outcompete bacteria from mixed cultures, consistent with the biochemical activity of the enzyme. Our study results highlight the relevance of the interactions of this eukaryotic pathogen with bacteria, a poorly understood aspect of the biology of this important human parasite.IMPORTANCETrichomonas vaginalis is a parasitic protozoan of the human urogenital tract that causes trichomoniasis, a very common sexually transmitted disease. Despite residing extracellularly and in close association with the vaginal bacteria (i.e., the microbiota), very little is known about the nature of the parasite-bacterium interactions. Our study showed that this parasite had acquired genes from bacteria which retained their original function. They produce active enzymes capable of degrading peptidoglycan, a unique polymer of the bacterial cell envelope, helping the parasite to outcompete bacteria in mixed cultures. This study was the first to show that a laterally acquired group of genes enables a eukaryotic mucosal pathogen to control bacterial population. We highlight the importance of understanding the interactions between pathogens and microbiota, as the outcomes of these interactions are increasingly understood to have important implications on health and disease.


Two in One: Light as a Tool for 3D Printing and Erasing at the Microscale.
The ability to selectively remove sections from 3D-printed structures with high resolution remains a current challenge in 3D laser lithography. A novel photoresist is introduced to enable the additive fabrication of 3D microstructures at one wavelength and subsequent spatially controlled cleavage of the printed resist at another wavelength. The photoresist is composed of a difunctional acrylate cross-linker containing a photolabile o-nitrobenzyl ether moiety. 3D microstructures are written by photoinduced radical polymerization of acrylates using Ivocerin as photoinitiator upon exposure to 900 nm laser light. Subsequent scanning using a laser at 700 nm wavelength allows for the selective removal of the resist by photocleaving the o-nitrobenzyl group. Both steps rely on two-photon absorption. The fabricated and erased features are imaged using scanning electron microscopy (SEM) and laser scanning microscopy (LSM). In addition, a single wire bond is successfully eliminated from an array, proving the possibility of complete or partial removal of structures on demand.


Shorter dialysis session length was not associated with lower mental health and physical functioning in elderly hemodialysis patients: Results from the Japan Dialysis Outcome and Practice Patterns Study (J-DOPPS).
Health-related quality of life (HRQOL) is often prioritized over long-term survival in elderly patients. Although a longer dialysis session length (DSL) has been shown to reduce mortality, its effects on improving the HRQOL are unknown. Using data from the Japan Dialysis Outcomes and Practice Patterns Study (J-DOPPS), patients aged ≥ 65 years on maintenance hemodialysis were enrolled. DSL was categorized as short (<210 minutes), medium (210-240 minutes), or long (>240 minutes). The primary outcomes were changes in mental health (ΔMH) and physical functioning (ΔPF) scores assessed using the Japanese version of SF-12, in one year. The differences in the ΔMH and ΔPF among the three groups were assessed via regression (beta) coefficients derived using a linear regression model. Of 1,187 patients at baseline, 319 (26.9%) had a short length, 686 (57.8%) a medium length, and 182 (15.3%) a long length. We assessed the ΔMH data from 793 patients and the ΔPF data from 738. No significant differences in the ΔMH were noted for the short or long groups compared with the medium group (score difference: 0.26, 95% confidence interval [CI]: -4.17 to 4.69 for short; score difference: -1.15, 95% CI: -6.17 to 3.86 for long). Similarly, no significant differences were noted for these groups versus the medium group in ΔPF either (score difference: -1.43, 95% CI: -6.73 to 3.87 for short; score difference: -1.71, 95% CI: -7.63 to 4.22 for long). A shorter DSL might have no adverse effects on MH or PF for elderly patients.


Selective activation of the SK1 subtype of human small-conductance Ca2+-activated K+ channels by 4-(2-methoxyphenylcarbamoyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (GW542573X) is dependent on serine 293 in the S5 segment.
A new small molecule, 4-(2-methoxy-phenylcarbamoyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (GW542573X), is presented as an activator of small-conductance Ca(2+)-activated K(+) (SK, K(Ca)2) channels and distinguished from previously published positive modulators of SK channels, such as 1-ethyl-2-benzimidazolinone (1-EBIO) and cyclohexyl-[2-(3,5-dimethylpyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA), in several aspects. GW542573X is the first SK1-selective compound described: an EC(50) value of 8.2 +/- 0.8 microM (n = 6, [Ca(2+)](i) = 200 nM) was obtained from inside-out patches excised from hSK1-expressing HEK293 cells. Whole-cell experiments showed that hSK2 and hSK3 channels were more than 10 times, and hIK channels even more than 100 times, less sensitive to GW542573X. The Ca(2+)-response curve of hSK1 was left-shifted from an EC(50)(Ca(2+)) value of 410 +/- 20 nM (n = 9) to 240 +/- 10 nM (n = 5) in the presence of 10 microM GW542573X. In addition to this positive modulation, GW542573X activated SK1 in the absence of Ca(2+) and furthermore induced a 15% increase in the maximal current at saturating Ca(2+). Thus, GW542573X also acts as a genuine opener of the hSK1 channels, a mechanism of action (MOA) not previously obtained with SK channels. The differential potency on hSK1 and hSK3 enabled a chimera approach to elucidate site(s) important for this new MOA and selectivity property. A single amino acid (Ser293) located in S5 of hSK1 was essential, and substituting the corresponding Leu476 in hSK3 with serine conferred hSK1-like potency (EC(50) = 9.3 +/- 1.4 microM, n = 5). GW542573X may activate SK channels via interaction with "deep-pore" gating structures at the inner pore vestibule or the selectivity filter in contrast to 1-EBIO and CyPPA that exert positive modulation via the intracellular calmodulin binding domain.


Predicting outcomes in critically ill patients with acute kidney injury undergoing intermittent hemodialysis--a retrospective cohort analysis.
Despite advances in the management of critically ill patients with acute kidney injury (AKI), the prognosis is poor. The evidence base on risk factors for poor outcomes in these patients is scarce. Our aim was to identify predictors of outcome in AKI patients undergoing intermittent hemodialysis (IHD). We retrospectively analyzed patient records from consecutive, critically ill patients with AKI treated with IHD in one teaching secondary care hospital from 2002 to 2006. We used multivariate Cox proportional hazard regression analysis to identify predictors of mortality, hemodynamical instability during hemodialysis and failing renal recovery. Totally, we included 39 patients with a mean APACHE II score of 20.1 (SD 7.5) who had an average of 5.1 +/- 4.8 hemodialysis sessions. All-cause mortality was 35.9% (14/39 patients). In multivariate analysis, pre-existing cardiac co-morbidity (HR 1.92 [0.58-6.47]), metabolic acidosis (2.40 [0-74-7.74]) and presence of ARDS (1.83 [0.52-6.46]) were the strongest predictors. 7 patients (18%) sustained new hemodynamic instability during hemodialysis, for which ARDS (6.42 [0.64-64.03]) was a strong predictor. Among survivors, 20 patients (80%) had partial or complete renal recovery. Preexisting renal insufficiency (3.13 [0.34-29.13]) and high net ultrafiltration quantities (3.30 [0.40-26.90]) were the strongest predictors for failing renal recovery. As a consequence of the small samples size none of the associations was statistically significant. Presence of ARDS and high net ultrafiltration rates seem to represent key factors affecting prognosis in patients with AKI undergoing IHD. Targeting these risk factors may improve the poor prognosis of these patients.


Historical aspects of propolis research in modern times.
Propolis (bee glue) has been known for centuries. The ancient Greeks, Romans, and Egyptians were aware of the healing properties of propolis and made extensive use of it as a medicine. In the middle ages propolis was not a very popular topic and its use in mainstream medicine disappeared. However, the knowledge of medicinal properties of propolis survived in traditional folk medicine. The interest in propolis returned in Europe together with the renaissance theory of ad fontes. It has only been in the last century that scientists have been able to prove that propolis is as active and important as our forefathers thought. Research on chemical composition of propolis started at the beginning of the twentieth century and was continued after WW II. Advances in chromatographic analytical methods enabled separation and extraction of several components from propolis. At least 180 different compounds have been identified so far. Its antibacterial, antiseptic, anti-inflammatory, antifungal, anesthetic, and healing properties have been confirmed. Propolis has been effectively used in treatment of dermatological, laryngological, and gynecological problems, neurodegenerative diseases, in wound healing, and in treatment of burns and ulcers. However, it requires further research that may lead to new discoveries of its composition and possible applications.


Gastrin receptors on isolated canine parietal cells.
The receptors in the fundic mucosa that mediate gastrin stimulation of acid secretion have been studied. Synthetic human gastrin-17-I (G17) with a leucine substitution in the 15th position ( [Leu15]-G17) was iodinated by chloramine T; high saturable binding was found to enzyme-dispersed canine fundic mucosal cells. 127I-[Leu15]-G17, but not 127I-G17, retained binding potency and biological activity comparable with uniodinated G17. Fundic mucosal cells were separated by size by using an elutriator rotor, and specific 125I-[Leu-15]-G17 binding in the larger cell fractions was highly correlated with the distribution of parietal cells. There was, however, specific gastrin binding in the small cell fractions, not accounted for by parietal cells. Using sequential elutriation and stepwise density gradients, highly enriched parietal and chief cell fractions were prepared; 125I-[Leu15]-G17 binding correlated positively with the parietal cell (r = 0.98) and negatively with chief cell content (r = -0.96). In fractions enriched to 45-65% parietal cells, specific 125I-[Leu15]-G17 binding was rapid, reaching a steady state at 37 degrees C within 30 min. Dissociation was also rapid, with the rate similar after 100-fold dilution or dilution plus excess pentagastrin. At a tracer concentration from 10 to 30 pM, saturable binding was 7.8 +/- 0.8% per 10(6) cells (mean +/- SE) and binding in the presence of excess pentagastrin accounted for 11% of total binding. G17 and carboxyl terminal octapeptide of cholecystokinin (26-33) were equipotent in displacing tracer binding and in stimulating parietal cell function ( [14C]aminopyrine accumulation), whereas the tetrapeptide of gastrin (14-17) had a much lower potency. Proglumide inhibited gastrin binding and selectively inhibited gastrin stimulation of parietal cell function. Canine parietal cells have specific receptors for gastrin that mediate stimulation of parietal cell function. Gastrin receptors were undetectable on chief cells, and yet present on another smaller mucosal cell(s).


Stromelysin-1 (MMP-3) in synovial fluid of patients with rheumatoid arthritis has potential to cleave membrane bound Fas ligand.
To investigate the relationship between matrix metalloproteinases (MMP) and the soluble form of Fas ligand (sFasL) in the synovial fluid (SF) of patients with rheumatoid arthritis (RA), and to determine which MMP have a major role in cleaving FasL. The concentrations of sFas and sFasL in SF from 48 patients with RA and 43 patients with osteoarthritis (OA) were measured using specific ELISA. The levels of different MMP (MMP-1, 2, 3, 7, 9) in SF were also measured by ELISA. The active forms of gelatinases were detected by gelatin zymogram. Human FasL-expressing transfected cells (hFasL/L5178Y) were used to investigate whether FasL is cleaved from membrane bound FasL. Significantly higher levels of MMP-1, 3, and 9 were found in SF from RA patients compared to OA patients, but MMP-7 was not detectable in either group. The concentrations of sFas and sFasL in SF were also higher in RA than in OA patients. However, there was no relationship between the concentration of sFas and sFasL. Among MMP, MMP-3 concentrations in SF were closely correlated with the level of sFasL and with disease activity of RA. Enzymatic cleavage assay indicated that MMP-3 has potential to cleave the FasL expressed on hFasL/L5178Y cells and to produce sFasL. There was significant correlation between the concentration of sFasL and MMP-3 in SF of patients with RA. In addition, our data indicate that the shedding of FasL may be regulated by MMP-3 in the joint of patients with RA.


ERN1 knockdown modifies the hypoxic regulation of TP53, MDM2, USP7 and PERP gene expressions in U87 glioma cells.
Endoplasmic reticulum stress and hypoxia are necessary components of malignant tumors growth and suppression of ERN1 (from endoplasmic reticulum to nuclei-1) signalling pathway, which is linked to the apoptosis and cell death processes, significantly decreases proliferative processes. Glioma cells with ERN1 knockdown were used in order to investigate the effect of ERNI blockade on the expression of TP53, MDM2, PERP, and USP7 genes and its hypoxic regulation. We have studied the expression of TP53 (tumor protein 53), MDM2 (TP53 E3 ubiquitin protein ligase homolog), PERP (TP53 apoptosis effector), and USP7 (ubiquitin specific peptidase 7) genes, which are related to cell proliferation and apoptosis, in glioma cells with ERN1 knockdown under hypoxic condition. It was shown that blockade of ERNI gene function in U87 glioma cells intensified the expression of TP53 and USP7 genes, but decreased the expression ofMDM2 and PERP genes. Thus, an enhanced expression of TP53 gene in ERN1 knockdown glioma cells correlates with the decreased level of ubiquitin ligase MDM2 and increased expression level of USP7 which deubiquitinates TP53 and MDM2 and induces TP53-dependent cell growth repression and apoptosis. At the same time, the expression levels of TP53, MDM2, and USP7 genes do not change significantly in glioma cells with suppression of endoribonuclease activity only, but PERP gene expression is strongly increased. Moreover, the expression of TP53 and UPS7 genes is decreased in hypoxic conditions in control glioma cells only; however, MDM2 and PERP gene expressions are increased in both cell types, being more significant in ERN1 knockdown cells. Thus, the expression of genes encoding TP53 and related to TP53 factors depends upon the endoplasmic reticulum stress signaling as well as on hypoxia, and correlates with suppression of glioma growth under ERN1 knockdown.


Dissociating preview validity and preview difficulty in parafoveal processing of word n + 1 during reading.
Many studies have shown that previewing the next word n + 1 during reading leads to substantial processing benefit (e.g., shorter word viewing times) when this word is eventually fixated. However, evidence of such preprocessing in fixations on the preceding word n when in fact the information about the preview is acquired is far less consistent. A recent study suggested that such effects may be delayed into fixations on the next word n + 1 (Risse & Kliegl, 2012). To investigate the time course of parafoveal information-acquisition on the control of eye movements during reading, we conducted 2 gaze-contingent display-change experiments and orthogonally manipulated the processing difficulty (i.e., word frequency) of an n + 1 preview word and its validity relative to the target word. Preview difficulty did not affect fixation durations on the pretarget word n but on the target word n + 1. In fact, the delayed preview-difficulty effect was almost of the same size as the preview benefit associated with the n + 1 preview validity. Based on additional results from quantile-regression analyses on the time course of the 2 preview effects, we discuss consequences as to the integration of foveal and parafoveal information and potential implications for computational models of eye guidance in reading.


Regional differences in mortality from conditions amenable to medical intervention in The Netherlands: a comparison of four time periods.
In The Netherlands, as in many other countries, important geographical variation in mortality from conditions amenable to medical intervention exists. Associations with a number of simple medical care supply characteristics (general practitioner density, hospital bed density, and percentage of regional hospital beds located in university and small hospitals) are generally weak and inconsistent, both before and after controlling for possible confounding factors. We explored one of the possible reasons for this lack of consistency, which is the time dependency of the relationship between medical care supply and avoidable mortality. A comparison of associations in four time periods (1950-54, 1960-64, 1970-74 and 1980-84) shows that the percentage of variance in regional mortality levels which can be "explained" by the medical care supply variables has changed over time. Although the patterns of change differ little from what one would expect on the basis of the time of introduction of medical care innovations, the exact nature of the associations is puzzling. Apart from some expected negative associations between mortality and the presence of university hospitals, we also found a few unexpected positive associations with general practitioner density. Possible explanations for these findings are discussed, and it is concluded that further study is necessary to reveal the causes of a higher or lower mortality level for conditions considered to be amenable to medical intervention.


In vivo Distribution and Clearance of Purified Capsular Polysaccharide from Burkholderia pseudomallei in a Murine Model.
Burkholderia pseudomallei is the causative agent of melioidosis, a severe infection prominent in northern Australia and Southeast Asia. The "gold standard" for melioidosis diagnosis is bacterial isolation, which takes several days to complete. The resulting delay in diagnosis leads to delayed treatments, which could result in death. In an attempt to develop better methods for early diagnosis of melioidosis, B. pseudomallei capsular polysaccharide (CPS) was identified as an important diagnostic biomarker. A rapid lateral flow immunoassay utilizing CPS-specific monoclonal antibody was developed and tested in endemic regions worldwide. However, the in vivo fate and clearance of CPS has never been thoroughly investigated. Here, we injected mice with purified CPS intravenously and determined CPS concentrations in serum, urine, and major organs at various intervals. The results indicate that CPS is predominantly eliminated through urine and no CPS accumulation occurs in the major organs. Immunoblot analysis demonstrated that intact CPS was excreted through urine. To understand how a large molecule like CPS was eliminated without degradation, a 3-dimenational structure of CPS was modeled. The predicted CPS structure has a rod-like shape with a small diameter that could allow it to flow through the glomerulus of the kidney. CPS clearance was determined using exponential decay models and the corrected Akaike Information Criterion. The results show that CPS has a relatively short serum half-life of 2.9 to 4.4 hours. Therefore, the presence of CPS in the serum and/or urine suggests active melioidosis infection and provides a marker to monitor treatment of melioidosis.


A perfusion procedure for imaging of the mouse cerebral vasculature by X-ray micro-CT.
Micro-CT is a novel X-ray imaging modality which can provide 3D high resolution images of the vascular network filled with contrast agent. The cerebrovascular system is a complex anatomical structure that can be imaged with contrast enhanced micro-CT. However, the morphology of the cerebrovasculature and many circulatory anastomosis in the brain result in high variations in the extent of contrast agent filling in the blood vessels and as a result, the vasculature of different subjects appear differently in the acquired images. Specifically, the posterior circulation is not consistently perfused with the contrast agent in many brain specimens and thus, many major vessels that perfuse blood to the midbrain and hindbrain are not visible in the micro-CT images acquired from these samples. In this paper, we present a modified surgical procedure of cerebral vasculature perfusion through the left ventricle with Microfil contrast agent, in order to achieve a more uniform perfusion of blood vessels throughout the brain and as a result, more consistent images of the cerebrovasculature. Our method consists of filling the posterior cerebral circulation with contrast agent, followed by the perfusion of the whole cerebrovasculature. Our histological results show that over 90% of the vessels in the entire brain, including the cerebellum, were filled with contrast agent. Our results show that the new technique of sample perfusion decreases the variability of the posterior circulation in the cerebellum in micro-CT images by 6.9%. This new technique of sample preparation improves the quality of cerebrovascular images.


Whole Genome Sequencing of Extended Spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae Isolated from Hospitalized Patients in KwaZulu-Natal, South Africa.
Extended spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae remain a critical clinical concern worldwide. The aim of this study was to characterize ESBL-producing K. pneumoniae detected within and between two hospitals in uMgungundlovu district, South Africa, using whole genome sequencing (WGS). An observational period prevalence study on antibiotic-resistant ESKAPE (i.e. Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp.) bacteria was carried out in hospitalized patients during a two-month period in 2017. Rectal swabs and clinical specimens were collected from patients hospitalized and were screened for ESBL-producing, Gram-negative ESKAPE bacteria using cefotaxime-containing MacConkey agar and ESBL combination disk tests. Nine confirmed ESBL-K. pneumoniae isolated from six patients and two hospitals were whole genome sequenced using an Illumina MiSeq platform. Genome sequences were screened for presence of integrons, insertion sequences, plasmid replicons, CRISPR regions, resistance genes and virulence genes using different software tools. Of the 159 resistant Gram-negative isolates collected, 31 (19.50%) were ESBL-producers, of which, nine (29.03%) were ESBL-K. pneumoniae. The nine K. pneumoniae isolates harboured several β-lactamase genes, including blaCTX-M-15, blaTEM-1b, blaSHV-1, blaOXA-1 concomitantly with many other resistance genes e.g. acc(6')-lb-cr, aadAI6, oqxA and oqxB that confer resistance to aminoglycosides and/or fluoroquinolones, respectively. Three replicon plasmid types were detected in both clinical and carriage isolates, namely ColRNAI, IncFIB(K), IncF(II). Sequence type ST152 was confirmed in two patients (one carriage isolate detected on admission and one isolate implicated in infection) in one hospital. In contrast, ST983 was confirmed in a clinical and a carriage isolate of two patients in two different hospitals. Our data indicate introduction of ESBL-producing K. pneumoniae isolates into hospitals from the community. We also found evidence of nosocomial transmission within a hospital and transmission between different hospitals. The Clustered Regularly Interspaced Palindromic Repeats (CRISPR)-associated cas3 genes were further detected in two of the nine ESBL-KP isolates. This study showed that both district and tertiary hospital in uMgungundlovu District were reservoirs for several resistance determinants and highlighted the necessity to efficiently and routinely screen patients, particularly those receiving extensive antibiotic treatment and long-term hospitalization stay. It also reinforced the importance of infection, prevention and control measures to reduce the dissemination of antibiotic resistance within the hospital referral system in this district.


Responses by four Local Research Ethics Committees to submitted proposals.
There is relatively little research concerning the processes whereby Local Research Ethics Committees discharge their responsibilities towards society, potential participants and investigators. To examine the criteria used by LRECs in arriving at their decisions concerning approval of research protocols through an analysis of letters sent to investigators. Four LRECs each provided copies of 50 letters sent to investigators after their submitted proposals had been considered by the committees. These letters were subjected to a content analysis, in which specific comments and requests for additional information and changes in the protocols were recorded and compared. Overall 24% of proposals were approved without request for changes or clarifications, but this varied by committee: one committee approved only 6% of proposals without change or clarification while the others ranged from 26% to 32%. The content analyses of responses indicated that they could be placed into four categories: (i) further information for the committee to aid in their deliberations; (ii) requests for changes to the design or justification for the design used; (iii) changes to the information sheets provided to potential participants; and (iv) changes to consent procedures. Of these, alterations to information sheets were the most common type of request. These four types of response could be seen as safeguarding the wellbeing of potential participants (the principle of non-maleficence), of promoting the scientific validity of the research (the principle of beneficence), and of enhancing the rights of potential participants (the principle of autonomy). The committees were consistent in the types of requests they made of investigators, which can be seen as attempts to protect participants' rights and ensure the scientific validity of studies. Without an analysis of the proposals sent to the committees, however, it is difficult to account for the variation in the requirements set by the committees before approval was given.


An in vitro assay to study chikungunya virus RNA synthesis and the mode of action of inhibitors.
Chikungunya virus (CHIKV) is a re-emerging mosquito-borne alphavirus that causes severe persistent arthralgia. To better understand the molecular details of CHIKV RNA synthesis and the mode of action of inhibitors, we have developed an in vitro assay to study CHIKV replication/transcription complexes isolated from infected cells. In this assay (32)P-CTP was incorporated into the CHIKV genome, subgenomic (sg) RNA and into a ~7.5 kb positive-stranded RNA, termed RNA II. We mapped RNA II, which was also found in CHIKV-infected cells, to the 5' end of the genome up to the start of the sgRNA promoter region. Most of the RNA-synthesizing activity, negative-stranded RNA and a relatively large proportion of nsP1 and nsP4 were recovered from a crude membrane fraction obtained by pelleting at 15,000 G: . Positive-stranded RNA was mainly found in the cytosolic S15 fraction, suggesting it was released from the membrane-associated replication/transcription complexes (RTCs). The newly synthesized RNA was relatively stable and remained protected from cellular nucleases, possibly by encapsidation. A set of compounds that inhibit CHIKV replication in cell culture was tested in the in vitro RTC assay. In contrast to 3'dNTPs, chain terminators that acted as potent inhibitors of RTC activity, ribavirin triphosphate and 6-aza-UTP did not affect the RNA-synthesizing activity in vitro. In conclusion, this in vitro assay for CHIKV RNA synthesis is a useful tool for mechanistic studies on the RTC and mode of action studies on compounds with anti-CHIKV activity.


The Manila Declaration on Migration and Health: commentary of the Association of Pacific Rim Universities Global Health Program.
Migration has played, and continues to play, an important role in shaping our global economy. As of 2017, there were 258 million international migrants worldwide, over 100 million of whom came from the Asia-Pacific region. Migration is increasingly recognized as a social determinant of health, as migrants often experience vulnerabilities that make them susceptible to a range of negative health outcomes. Addressing the health and human rights concerns of migrants requires concerted and global efforts from many stakeholders, including universities. The Global Health Program of the Association of Pacific Rim Universities (APRU), a non-profit network of more than 50 universities in the region, is an example of an avenue to foster research, innovation, collaborative engagement, and large-scale advocacy around migration and health. In 2017, a special half-day workshop was held in Manila, convening 167 participants from 10 economies and 21 disciplines. The goal of the workshop was to delineate the role of universities in promoting migrant health and well-being. The global health experts from a diverse set of backgrounds collaboratively developed a policy statement to be used to better address migrant health and human rights. The objective of this paper is to disseminate the policy statement, highlighted specific action items that universities can take to protect and promote migrant health. The Manila Declaration on Migration and Health highlights that universities must ensure that their campuses are safe, supportive, and empowering environments for all migrants and their families. Universities are also urged to capitalize on their educational and research expertise to generate data on migrant experiences and communicate this research to policymakers. This commentary highlights how institutions of higher education can serve as powerful avenues for promoting migrant health and human rights. Universities can play a vital role in building awareness and sensitivity to migrant challenges and needs, as well as helping to develop policy frameworks appropriate to their diverse contexts to guide, promote, and reinforce commitment to migrant rights and health. Universities should also ensure that their campuses are safe, supportive, and empowering environments for all migrants and their families.


The Relationships between Development and Low Temperature Tolerance in Barley Near Isogenic Lines Differing for Flowering Behavior.
Flowering time, vernalization requirement, photoperiod sensitivity and low temperature tolerance are key traits in the Triticeae. We characterized a set of isogenic genetic stocks-representing single and pairwise substitutions of spring alleles at the VRN-H1, VRN-H2 and VRN-H3 loci in a winter barley background-at the structural, functional and phenotypic levels. High density mapping with reference to the barley genome sequence confirmed that in all cases target VRN alleles were present in the near isogenic lines (NILs) and allowed estimates of introgression size (at the genetic and physical levels) and gene content. Expression data corroborated the structural and phenotypic results. The latter confirmed that substitution of a spring allele at any of the VRN loci is sufficient to eliminate vernalization requirement. There was no significant change in low temperature tolerance with substitution of a spring allele at VRN-H2, but there were significant losses in cold tolerance with substitutions at VRN-H1 and VRN-H3. Reductions in cold tolerance are ascribed to an accelerated transition from the vegetative to reproductive state. The set of NILs will be a rich resource for understanding the genetics of vernalization, low temperature tolerance and other traits encoded/regulated by genes within the introgressed intervals.


Minimum formalin fixation time for consistent estrogen receptor immunohistochemical staining of invasive breast carcinoma.
To identify the minimum time necessary for consistent immunohistochemical estrogen receptor (ER) results in our laboratory, we evaluated results in timed fixation blocks and cases with disparate and similar needle core biopsy and partial mastectomy specimens. Tissue sections of 24 ER-positive, invasive breast carcinomas were fixed for 3, 6, 8, and 12 hours and 1, 2, and 7 days. ER values were quantified using the Q score (0-7). In timed fixation blocks, the mean Q score per block was 2.46 for blocks fixed for 3 hours, 5.75 for blocks fixed for 6 hours, and 6.70 for blocks fixed for 8 hours (P < .001). The difference between the case maximum and mean block Q scores was a plateau of almost 0 at 6 to 8 hours of formalin fixation. For needle core biopsy specimen fixation times, the means for specimens with ER-disparate and ER-similar results were 1.2 and 6.3 hours, respectively (P = .01). The minimum formalin fixation time for reliable immunohistochemical ER results is 6 to 8 hours in our laboratory, regardless of the type or size of specimen.


Angiotensin II induces fibronectin expression associated with cardiac fibrosis in the rat.
Fibronectin expression was studied in the heart of rats given a continuous infusion of angiotensin II (Ang II). Northern blot analysis showed that left ventricular fibronectin steady-state mRNA increased fivefold to eightfold in response to pressor doses of Ang II after 24 hours. Accumulation of immunodetectable fibronectin in the ventricles occurred after the mRNA levels increased. The changes in fibronectin expression were reversible when Ang II treatment was withdrawn. The Ang II-induced increase in fibronectin mRNA accompanied similar increases for collagen type I, collagen type IV, and atrial natriuretic factor steady-state mRNA. Interstitial and perivascular fibrosis was identified in both ventricles of angiotensin-treated rats within 3 days. In situ hybridization identified cells associated with areas of fibrosis as the principal site of fibronectin mRNA accumulation in treated animals. By comparison, normal hearts showed fibronectin expression primarily within ventricular vascular tissue and the atrial endocardium. A dose-dependent reduction of fibronectin expression followed treatment with losartan, indicating an Ang II type 1 receptor-mediated effect. Normalization of blood pressure during Ang II infusion by either hydralazine or prazosin had different effects on the level of fibronectin steady-state mRNA, indicating that blood pressure elevation was not the principal factor responsible for fibronectin induction. Concurrent administration of angiotensin-converting enzyme inhibitors with Ang II attenuated the increased fibronectin expression. Our data indicate that Ang II induces an acute fibrotic response within the heart and suggests that Ang II stimulates fibronectin expression within nonmyocytic cardiac cells by a direct action.


A study of photoluminescence properties and performance improvement of Cd-doped ZnO quantum dots prepared by the sol-gel method.
In the present work, ZnO quantum dots (QDs) have been prepared by the sol-gel method, and the performance of the QDs has been improved. The effect of Cd concentration on the structural and luminescent properties of the QDs, as well as the effect of the mass ratio of trioctylphosphine oxide (TOPO)/octadecylamine (ODA), has been investigated. The ZnO and Cd-doped ZnO QDs have hexagonal wurtzite structures and are 3 to 6 nm in diameter. When the Cd content was increased, the QD particle size was reduced; this effect was confirmed in the corresponding ultraviolet-visible spectra. The fluorescence intensity was simultaneously enhanced significantly. Both the UV and fluorescence spectra were blue-shifted. The luminous intensity was further enhanced when the QDs were modified with TOPO/ODA. Fourier transform infrared and X-ray diffraction techniques proved that the polymer successfully coated the surfaces of the QDs. A TOPO/ODA mass ratio of 1:2 was determined to result in the best optical performance among the different ratios examined. The results showed that the described synthetic method is appropriate for the preparation of doped QDs with high-fluorescence quantum efficiency.


Asymptomatic carotid artery stenosis: who should be screened, who should be treated and how should we treat them?
Although stopping smoking, lowering blood pressure and reducing lipid levels will reduce global stroke risk and cardiovascular mortality, these remain leading causes of death and disability especially in ageing populations. Further prevention strategies are needed and, in the first part of this review, we explore the potential benefits of appropriate screening for carotid artery disease to reduce stroke and identify those who may have related cardiac disease. Although whole-population carotid screening is an inefficient and costly means of identifying candidates with tight carotid stenosis who might warrant intervention, it can identify many people with lower levels of stenosis who may benefit from cardiovascular risk-reducing medications. Longer-term benefits and cost-effectiveness of any targeted screening program needs further evaluation. Patients with carotid stenosis are known to be at increased risk of stroke and vascular death. Whilst randomized clinical trials and guidelines have reported stroke hazards and benefits of interventional treatment for carotid stenosis, uncertainty remains about their optimal medical management. In the second part of this review we discuss Level I evidence for medical and surgical treatment of asymptomatic carotid stenosis, reasons for the current lack of consensus on interventional management of these patients and future studies which may help to clarify which groups will (and which will likely not) benefit from interventions.


A mutation in SLC22A4 encoding an organic cation transporter expressed in the cochlea strial endothelium causes human recessive non-syndromic hearing loss DFNB60.
The high prevalence/incidence of hearing loss (HL) in humans makes it the most common sensory defect. The majority of the cases are of genetic origin. Non-syndromic hereditary HL is extremely heterogeneous. Genetic approaches have been instrumental in deciphering genes that are crucial for auditory function. In this study, we first used NADf chip to exclude the implication of known North-African mutations in HL in a large consanguineous Tunisian family (FT13) affected by autosomal recessive non-syndromic HL (ARNSHL). We then performed genome-wide linkage analysis and assigned the deafness gene locus to ch:5q23.2-31.1, corresponding to the DFNB60 ARNSHL locus. Moreover, we performed whole exome sequencing on FT13 patient DNA and uncovered amino acid substitution p.Cys113Tyr in SLC22A4, a transporter of organic cations, cosegregating with HL in FT13 and therefore the cause of ARNSHL DFNB60. We also screened a cohort of small Tunisian HL families and uncovered an additional deaf proband of consanguineous parents that is homozygous for p.Cys113Tyr carried by the same microsatellite marker haplotype as in FT13, indicating that this mutation is ancestral. Using immunofluorescence, we found that Slc22a4 is expressed in stria vascularis (SV) endothelial cells of rodent cochlea and targets their apical plasma membrane. We also found Slc22a4 transcripts in our RNA-seq library from purified primary culture of mouse SV endothelial cells. Interestingly, p.Cys113Tyr mutation affects the trafficking of the transporter and severely alters ergothioneine uptake. We conclude that SLC22A4 is an organic cation transporter of the SV endothelium that is essential for hearing, and its mutation causes DFNB60 form of HL.


Alcohol demand, delayed reward discounting, and craving in relation to drinking and alcohol use disorders.
A behavioral economic approach to alcohol use disorders (AUDs) emphasizes both individual and environmental determinants of alcohol use. The current study examined individual differences in alcohol demand (i.e., motivation for alcohol under escalating conditions of price) and delayed reward discounting (i.e., preference for immediate small rewards compared to delayed larger rewards) in 61 heavy drinkers (62% with an AUD). In addition, based on theoretical accounts that emphasize the role of craving in reward valuation and preferences for immediate rewards, craving for alcohol was also examined in relation to these behavioral economic variables and the alcohol-related variables. Intensity of alcohol demand and delayed reward discounting were significantly associated with AUD symptoms, but not with quantitative measures of alcohol use, and were also moderately correlated with each other. Likewise, craving was significantly associated with AUD symptoms, but not with alcohol use, and was also significantly correlated with both intensity of demand and delayed reward discounting. These findings further emphasize the relevance of behavioral economic indices of motivation to AUDs and the potential importance of craving for alcohol in this relationship.


p120catenin alteration in cancer and its role in tumour invasion.
Since its discovery in 1989 as a substrate of the Src oncogene, p120catenin has been revealed as an important player in cancer initiation and tumour dissemination. p120catenin regulates a wide range of cellular processes such as cell-cell adhesion, cell polarity and cell proliferation and plays a pivotal role in morphogenesis, inflammation and innate immunity. The pleiotropic effects of p120catenin rely on its interactions with numerous partners such as classical cadherins at the plasma membrane, Rho-GTPases and microtubules in the cytosol and transcriptional modulators in the nucleus. Alterations of p120catenin in cancer not only concern its expression level but also its intracellular localization and can lead to both pro-invasive and anti-invasive effects. This review focuses on the p120catenin-mediated pathways involved in cell migration and invasion and discusses the potential consequences of major cancer-related p120catenin alterations with respect to tumour spread.


Assessment of zero-valent iron-based nanotherapeutics for ferroptosis induction and resensitization strategy in cancer cells.
Addressing nanomedicine resistance is critical for its ultimate clinical success; despite this, advancing the therapeutic designs for cancer therapy are rarely discussed in the literature. In this study, we discovered that ferroptosis is the central mechanism governing the therapeutic efficacy and resistance of treatment with zero-valent iron nanoparticles (ZVI NPs). In ZVI-sensitive oral cancer cells, ZVI NPs-induced ferroptosis was characterized by mitochondrial lipid peroxidation and reduced levels of glutathione peroxidases (GPx) in subcellular organelles. However, resistant cells could attenuate ZVI-induced oxidative stress and GPx reduction. They also showed stronger mitochondrial respiration ability, thus resisting ZVI NPs-induced mitochondrial membrane potential loss. Transcriptome comparison and quantitative polymerase chain reaction (qPCR) analysis revealed that ZVI-resistant cancer cells expressed a gene set related to enhanced NADPH supply, higher detoxification capacity of reactive oxygen species, and decreased sensitivity to ferroptosis inducers (FINs). Finally, we discovered that certain FINs were able to sensitize ZVI-resistant cancer cells to become treatable without compromising healthy non-malignant cells. These findings suggest that ferroptosis can serve as a druggable target for anti-cancer nanomedicine and therapeutic resistance modulation using ZVI NPs.


Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers.
Mitochondria are key players in aging and in the pathogenesis of age-related diseases. Recent mitochondrial transcriptome analyses revealed the existence of multiple small mRNAs transcribed from mitochondrial DNA (mtDNA). Humanin (HN), a peptide encoded in the mtDNA 16S ribosomal RNA region, is a neuroprotective factor. An in silico search revealed six additional peptides in the same region of mtDNA as humanin; we named these peptides small humanin-like peptides (SHLPs). We identified the functional roles for these peptides and the potential mechanisms of action. The SHLPs differed in their ability to regulate cell viability in vitro. We focused on SHLP2 and SHLP3 because they shared similar protective effects with HN. Specifically, they significantly reduced apoptosis and the generation of reactive oxygen species, and improved mitochondrial metabolism in vitro. SHLP2 and SHLP3 also enhanced 3T3-L1 pre-adipocyte differentiation. Systemic hyperinsulinemic-euglycemic clamp studies showed that intracerebrally infused SHLP2 increased glucose uptake and suppressed hepatic glucose production, suggesting that it functions as an insulin sensitizer both peripherally and centrally. Similar to HN, the levels of circulating SHLP2 were found to decrease with age. These results suggest that mitochondria play critical roles in metabolism and survival through the synthesis of mitochondrial peptides, and provide new insights into mitochondrial biology with relevance to aging and human biology.