Sensitivities of in vivo markers of arterial organ damage in patients with peripheral atherosclerosis.
Biomarkers of vascular diseases such as ankle-brachial index (ABI), peripheral pulse pressure (pPP), central pulse pressure (cPP), and pulse wave velocity (PWV) allow assessment of arterial organ damage (AOD). However, the utility of markers other than ABI in patients with peripheral arterial disease (PAD), which are also associated with a significant increase of cardiovascular events, remains unclear. Asymptomatic (n = 21) and symptomatic patients (n = 46) with a positive sonography for PAD or history of lower limb revascularization were included. ABI, pPP, cPP, and PWV were assessed. PWV were performed using a brachial cuff-based method (aortic PWV (aPWV)) and oscillography (carotid-femoral pulse wave velocity (cfPWV)), respectively. The two methods for PWV were compared using Bland Altman analysis. Sensitivities of ABI, pPP, cPP, cfPWV, and aPWV for AOD were calculated. Sixty-seven patients (35.8 % female, mean age 69, range 39-91 years) had a significantly higher aPWV than cfPWV (median 10.5 m/s (IQR: 8.8-12.65 m/s) vs. median 9.0 m/s (IQR: 7.57-10.55 m/s), p = 0.0013). There was no correlation between cfPWV and age (r = 0.311, p = 0.116). Bland Altman analysis revealed a mean difference of -1.04 (-2SD; -6.38 to + 2SD; 4.31). The sensitivities for AOD were 68.7 % for ABI, 61.2 % for aPWV, 40.3 % for cfPWV, 31.3 % for peripheral PP, and 10.4 % for central aortic PP (p < 0.001). Brachial-derived aPWV differs from the gold standard assessment (cfPWV), which may be underestimated in PAD due to atherosclerotic obstructions along the aorto-iliac segment. The sensitivities of noninvasive in vivo markers of AOD vary widely and tend to underestimate the actual presence of AOD.


An iron-based thin film as a highly efficient catalyst for electrochemical water oxidation in a carbonate electrolyte.
A highly active iron-based water-oxidation catalyst was electrodeposited from a CO2 saturated bicarbonate solution containing Fe(2+). This catalyst (Fe-Ci) produces a current density of 10 mA cm(-2) at an overpotential of 560 mV and the activity remains constant over 18 h in the environmentally benign HCO3(-)/CO3(2-) buffer (pH 9.75). A Tafel slope of 34 mV dec(-1) was obtained for Fe-Ci, which is lower than other reported values for iron-based catalysts.


Topologically linked protein rings in the bacteriophage HK97 capsid.
The crystal structure of the double-stranded DNA bacteriophage HK97 mature empty capsid was determined at 3.6 angstrom resolution. The 660 angstrom diameter icosahedral particle contains 420 subunits with a new fold. The final capsid maturation step is an autocatalytic reaction that creates 420 isopeptide bonds between proteins. Each subunit is joined to two of its neighbors by ligation of the side-chain lysine 169 to asparagine 356. This generates 12 pentameric and 60 hexameric rings of covalently joined subunits that loop through each other, creating protein chainmail: topologically linked protein catenanes arranged with icosahedral symmetry. Catenanes have not been previously observed in proteins and provide a stabilization mechanism for the very thin HK97 capsid.


Prostatic Artery Embolization versus Standard Surgical Treatment for Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia: A Systematic Review and Meta-analysis.
Prostatic artery embolization (PAE) has been introduced into clinical practice for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH-LUTS) despite a lack of high-level evidence. To perform a systematic review and meta-analysis of clinical trials comparing efficacy and safety of PAE versus established surgical therapies. Medline, Embase, and York CRD were searched up to June 23, 2018. Only comparative studies were included. The risk of bias was assessed by the Cochrane Collaboration tool. Meta-analyses were performed using RevMan 5.3. Five studies including 708 patients met the selection criteria. Risk of bias was rated high for most of the studies. Mean reduction in the International Prostate Symptom Score was lower after PAE compared with standard surgical therapies (mean difference 3.80 points [95% confidence interval: 2.77-4.83]; p<0.001). PAE was less efficient regarding improvements in all functional parameters assessed including maximum urinary flow, post void residual, and reduction of prostate volume. In contrast, patient-reported erectile function (International Index of Erectile Function 5) was better after PAE and significantly fewer adverse events occurred after PAE. Moderately strong evidence confirms efficacy and safety of PAE in the treatment of BPH-LUTS in the short term. Significant advantages regarding safety and sexual function, but clear disadvantages regarding all other patient-reported and functional outcomes were found for PAE. Large-scale randomized controlled trials including longer follow-up periods are mandatory before PAE can be considered as a standard therapy and to define the ideal indication for PAE in the management of BPH-LUTS. We reviewed the role of prostatic artery embolization (PAE) in the treatment of symptoms associated with benign overgrowth of the prostate. The results suggest that PAE is not as effective as established surgical therapies but has fewer side effects. Further research is required to determine whether PAE is the best treatment for certain types of patients. PAE should, therefore, not yet be considered a standard treatment.


Regulation of cGMP-induced relaxation and cGMP-dependent protein kinase in rat myometrium during pregnancy.
Increases in guanosine 3',5'-cyclic monophosphate (cGMP) induced by nitric oxide (NO), nitrovasodilators, and atrial peptides correlate with relaxation of vascular smooth muscle. Relaxation of myometrial smooth muscle by increases in cGMP, however, has required unusually high concentrations of the cyclic nucleotide. We tested the hypothesis that the sensitivity of myometrium to relaxation by cGMP is increased during pregnancy. Aortic smooth muscle was more sensitive to relaxation by cGMP than myometrial tissues, and, contrary to our hypothesis, myometrium from pregnant rats was least sensitive. Although levels of cGMP were elevated after treatment with the NO donor, S-nitroso-N-acetylpenicillamine, relaxation of myometrial tissues obtained from pregnant rats occurred only at extraordinarily high concentrations. The levels of cGMP-dependent protein kinase (PKG) were significantly decreased in myometrium from pregnant rats compared with myometrium from nonpregnant cycling animals or aortic smooth muscle. Administration of estradiol to ovariectomized rats increased myometrial PKG expression, and progesterone antagonized this response. We conclude that 1) myometrial tissues from pregnant rats are not sensitive to relaxation by cGMP and 2) this insensitivity to cGMP is accompanied by progesterone-mediated decreases in the level of PKG expression.


A computer model analysis of the active-site coupling mechanism in the pyruvate dehydrogenase multienzyme complex of Escherichia coli.
A computer modeling system developed to analyze experimental data for inactivation of the Escherichia coli alpha-ketoglutarate dehydrogenase complex (KGDC) accompanying release of lipoyl moieties by lipoamidase and by trypsin [Hackert, M.L., Oliver, R.M. & Reed, L.J. (1983) Proc. Natl. Acad. Sci. USA 80, 2226-2230] was used to analyze analogous data for the E. coli pyruvate dehydrogenase complex (PDC). The model studies indicate that the activity of PDC, as found for KGDC, is influenced by redundancies and random processes, which we describe as a multiple random coupling mechanism. In both complexes more than one lipoyl moiety services each pyruvate dehydrogenase (EC 18.104.22.168) or alpha-ketoglutarate dehydrogenase (EC 126.96.36.199) (E1) subunit, and an extensive lipoyl-lipoyl interaction network for exchange of electrons and possibly acyl groups must also be present. The best fit between computed and experimental data for PDC was obtained with a model that has four lipoyl domains with four or, more probably, eight lipoyl moieties servicing each E1 subunit. The lipoyl-lipoyl interaction network for PDC has lipoyl domain interactions similar to those found for KGDC plus the additional possibility of interaction of a lipoyl moiety and its paired mate on each dihydrolipoamide acetyltransferase (EC 18.104.22.168) (E2) subunit. The two lipoyl moieties on an E2 subunit in PDC appear to be functionally indistinguishable, each servicing the acetyltransferase site of that E2 subunit and a dihydrolipoamide dehydrogenase (EC 22.214.171.124) (E3) subunit if the latter is bound to that particular E2 subunit. The observed difference between inactivation of PDC by lipoamidase and by trypsin appears to be due to dead-end competitive inhibition by lipoyl domains that have been modified by excision of lipoyl moieties by lipoamidase.


Sexually dimorphic effects of catechol-O-methyltransferase (COMT) inhibition on dopamine metabolism in multiple brain regions.
The catechol-O-methyltransferase (COMT) enzyme metabolises catecholamines. COMT inhibitors are licensed for the adjunctive treatment of Parkinson's disease and are attractive therapeutic candidates for other neuropsychiatric conditions. COMT regulates dopamine levels in the prefrontal cortex (PFC) but plays a lesser role in the striatum. However, its significance in other brain regions is largely unknown, despite its links with a broad range of behavioural phenotypes hinting at more widespread effects. Here, we investigated the effect of acute systemic administration of the brain-penetrant COMT inhibitor tolcapone on tissue levels of dopamine, noradrenaline, and the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). We examined PFC, striatum, hippocampus and cerebellum in the rat. We studied both males and females, given sexual dimorphisms in several aspects of COMT's function. Compared with vehicle, tolcapone significantly increased dopamine levels in the ventral hippocampus, but did not affect dopamine in other regions, nor noradrenaline in any region investigated. Tolcapone increased DOPAC and/or decreased HVA in all brain regions studied. Notably, several of the changes in DOPAC and HVA, particularly those in PFC, were more prominent in females than males. These data demonstrate that COMT alters ventral hippocampal dopamine levels, as well as regulating dopamine metabolism in all brain regions studied. They demonstrate that COMT is of significance beyond the PFC, consistent with its links with a broad range of behavioural phenotypes. Furthermore, they suggest that the impact of tolcapone may be greater in females than males, a finding which may be of clinical significance in terms of the efficacy and dosing of COMT inhibitors.


Laboratory values for children with newly diagnosed inflammatory bowel disease.
The goal was to determine how often common laboratory tests yield normal results at the time of diagnosis for children with inflammatory bowel disease. Data were obtained from a registry of children with newly diagnosed inflammatory bowel disease who were enrolled prospectively in 18 US/Canadian centers. Laboratory values investigated included hemoglobin level, platelet count, albumin level, and erythrocyte sedimentation rate. Disease severity was categorized by physician global assessment. A total of 526 children (mean age: 11.6 years; 58% male; 392 with Crohn disease and 134 with ulcerative colitis) were studied. All 4 values were normal for 21% of patients with mild Crohn disease and 54% with mild ulcerative colitis. In contrast, only 3.8% of children with moderate/severe Crohn disease and 4.3% with moderate/severe ulcerative colitis had normal results for all 4 tests. The erythrocyte sedimentation rate was least likely to be normal; overall, 26% of patients with inflammatory bowel disease had a normal erythrocyte sedimentation rate, including 18% with moderate/severe disease. Hemoglobin levels were normal for 32%, platelet counts for 50%, and albumin levels for 60%. There was no clear association between Crohn disease location and either severity or number of normal laboratory values. In contrast, there were direct correlations between ulcerative colitis disease severity and both the extent of bowel inflammation and the number of abnormal laboratory tests. The presence of normal screening laboratory studies should not dissuade clinicians from considering a diagnosis of inflammatory bowel disease.


Consistency of response to sumatriptan/naproxen sodium in a placebo-controlled, crossover study.
Two identical randomized, placebo-controlled, crossover studies were conducted to evaluate consistency of response to sumatriptan/naproxen sodium 85/500 mg (S/NS) over four attacks in adults with migraine. Patients were instructed to treat within 1 h of pain onset while pain was mild. Co-primary end-points were pain-free response at 2 h (2hPF) and 24-h sustained pain-free response (24hSPF) calculated as percentages of all attacks. In Study 1, 570 patients treated 1693 attacks with S/NS and 424 with placebo. In Study 2, 565 patients treated 1678 attacks with S/NS and 422 with placebo. Compared with placebo, S/NS conferred higher 2hPF rates (Study 1: S/NS 52%, placebo 25%; Study 2: S/NS 50%, placebo 20%; both P < 0.001) and higher 24hSPF rates (Study 1: S/NS 37%, placebo 17%; Study 2: S/NS 34%, placebo 12%; both P < 0.001). 2hPF was reported in at least two of the first three S/NS-treated attacks in 55.0% of patients in Study 1 and 52.1% of patients in Study 2. 24hSPF was reported in at least two of the first three S/NS-treated attacks in 35.7% of patients in Study 1 and 32.6% of patients in Study 2. The incidences of any adverse event and of specific adverse events were low and generally similar between S/NS and placebo.


Predicting Attrition in a Text-Based Nutrition Education Program: Survival Analysis of Text2BHealthy.
Text-based programs have been shown to effectively address a wide variety of health issues. Although little research examines short message service (SMS) text messaging program characteristics that predict participant retention and attrition, features of SMS text message programs, such as program duration and intensity, message content, and the participants' context, may have an impact. The impact of stop messages-messages with instructions for how to drop out of an SMS text message program-may be particularly important to investigate. The aim of this study was to describe attrition from Text2BHealthy, a text-based nutrition and physical activity promotion program for parents of low-income elementary school children, and to determine the impact of message content and number of stop messages received on attrition. Using data from 972 parents enrolled in Text2BHealthy, we created Kaplan-Meier curves to estimate differences in program duration for different SMS text message types, including nutrition, physical activity, stop, and other messages. Covariates, including rurality and number of stop messages received, were included. Retention rates by school ranged from 74% (60/81) to 95.0% (132/139), with an average retention rate of 85.7% (833/972) across all schools. Program duration ranged from 7 to 282 days, with a median program duration of 233 days and an average program duration of 211.7 days. Among those who dropped out, program duration ranged from 7 to 247 days, with a median program duration of 102.5 days. Receiving a stop message increased the probability of attrition compared with receiving messages about nutrition, physical activity, or other topics (hazard ratio=51.5, 95% CI 32.46-81.7; P<.001). Furthermore, each additional stop message received increased the probability of attrition (hazard ratio=10.36, 95% CI 6.14-17.46; P<.001). The degree of rurality also had a significant effect on the probability of attrition, with metropolitan county participants more likely to drop out of the program than rural county participants. The interaction between SMS text message type and total number of stop messages received had a significant effect on attrition, with the effect of the number of stop messages received dependent on the SMS text message type. This study demonstrates the potential of SMS text message programs to retain participants over time. Furthermore, this study suggests that the probability of attrition increases substantially when participants receive messages with instructions for dropping out of the program. Program planners should carefully consider the impact of stop messages and other program content and characteristics on program retention. Additional research is needed to identify participant, programmatic, and contextual predictors of program duration and to explicate the relationship between program duration and program efficacy.


The structural basis for the regulation of tissue transglutaminase by calcium ions.
The role of calcium ions in the regulation of tissue transglutaminase is investigated by experimental approaches and computer modeling. A three-dimensional model of the transglutaminase is computed by homology building on crystallized human factor XIII and is used to interpret structural and functional results. The molecule is a prolate ellipsoid (6.2 x 4.2 x 11 nm) and comprises four domains, assembled pairwise into N-terminal and C-terminal regions. The active site is hidden in a cleft between these regions and is inaccessible to macromolecular substrates in the calcium-free form. Protein dynamics simulation indicates that these regions move apart upon addition of calcium ions, revealing the active site for catalysis. The protein dimensions are consistent with results obtained with small-angle neutron and X-ray scattering. The gyration radius of the protein (3 nm) increases in the presence of calcium ions (3.9 nm), but it is virtually unaffected in the presence of GTP, suggesting that only calcium ions can promote major structural changes in the native protein. Proteolysis of an exposed loop connecting the N-terminal and C-terminal regions is linearly correlated with enzyme inactivation and prevents the calcium-induced conformational changes.


Anticancer and Antibacterial Activity Studies of Gold(I)-Alkynyl Chromones.
Three gold(I) complexes of alkynyl chromones were synthesized and characterized. The single-crystal X-ray structure analysis of a dinuclear compound and of a flavone derivative exhibit a typical d10 gold(I)-alkynyl linear arrangement. All complexes were evaluated as anticancer and antibacterial agents against four human cancer cell lines and four pathogenic bacterial strains. All compounds show antiproliferative activity at lower micromolar range concentrations. Complex 4 showed a broad activity profile, being more active than the reference drug auranofin against HepG2, MCF-7 and CCRF-CEM cancer cells. The cellular uptake into MCF-7 cells of the investigated complexes was measured by atomic absorption spectroscopy (AAS). These measurements showed a positive correlation between an increased cellular gold content and the incubation time of the complexes. Unexpectedly an opposite effect was observed for the most active compound. Biological assays revealed various molecular mechanisms for these compounds, comprising: (i) thioredoxin reductase (TrxR) inhibition, (ii) caspases-9 and -3 activation; (iii) DNA damaging activity and (iv) cell cycle disturbance. The gold(I) complexes were also bactericidal against Gram-positive methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) bacterial strains, while showing no activity against the Gram-negative Escherichia coli bacterial strain.


Making a Sustainable Diet Acceptable: An Emerging Programming Model With Applications to Schools and Nursing Homes Menus.
Background: Food consumption is one of the most important drivers of the relation between human well-being and Earth's ecosystems. The current production level is difficult to sustain without compromising environmental integrity or public health. This calls for a decisive change in food consumption patterns in order to improve nutrition quality while respecting biodiversity and ecosystems. This change will produce some effect only if it is also culturally acceptable, accessible, economically fair and affordable. The design of food plans is traditionally carried out using mathematical optimization models, such as linear programming. This method has proved to be successful in providing nutritionally adequate diets while minimizing their economic and environmental impact. Nevertheless, cultural habits as well as attractiveness and variety of meals is very difficult to deal with, and no fully satisfactory way to include these issues in linear programming has been found. Objective: The aim of this paper is to move from traditional linear programming to a new programming methodology in order to cope also with acceptability in the design of meal plans. Method: Binary integer linear programming is the new modeling paradigm. In the proposed model, meal plans consist of providing the sequence and composition of daily meals over a given period of time and each meal can be composed using dishes from a given set. Therefore, instead of defining just a level of consumption of food groups or food items, the proposed model provides a realistic menu. To cope with sustainability, the energy and nutritional content of each dish is calculated together with its price and environmental impact. Furthermore, acceptability can be explicitly taken into account in a very natural way, that is bounding the daily, weekly, or total repetitions of single dishes and of dishes in the same food groups. Results: The paper reviews three successful studies with increasing complexity considering lunch plans for schools and full-board menus for nursing homes. The case studies show a great reduction of the environmental impact of the meal plans while ensuring an adequate nutritional intake, affordable prices and most importantly the plans are varied and culturally acceptable.


Prevalence and progression of internal carotid artery stenosis in patients with peripheral arterial occlusive disease.
The purpose of this study was to determine the prevalence of significant carotid stenosis, to identify risk factors increasing this prevalence, and to determine the risk of progression of stenosis, in patients with peripheral arterial occlusive disease who are neurologically asymptomatic. Consecutive patients who underwent evaluation in a vascular laboratory for peripheral arterial occlusive disease, who had no recent neurologic symptoms, were investigated. From July 1999 to December 2000, 620 patients underwent duplex scanning on one occasion, and 417 on two occasions. The average age was 72 +/- 10 years, and 61% were men. An occluded internal carotid artery was found in 4.8% of patients. The prevalence of a carotid stenosis >50% was 33% on the initial evaluation. Age of more than 70 years (P =.007), diabetes mellitus (P =.042), history of stroke (P =.011), and ankle/brachial index of less than 0.8 (P =.0006), were independently associated with carotid stenosis >50%. The odds ratio associated with each of these risk factors was similar. The prevalence of carotid stenosis >50% was 16%, 21%, 38%, 47%, and 44% for patients with no, one, two, three, and four risk factors, respectively. The highest prevalence of carotid stenosis >50% was identified in patients with ankle/brachial indices of less than 0.4 (59%). During the follow-up period, no patient had a cerebrovascular event. In 15% of carotid arteries, progression from one class of stenosis to a more severe class was observed, and 6.5% of patients progressed from a lower degree to 50% to 99% stenosis. No differences in progression of disease were identified when the variables of age, diabetes, previous stroke, and ankle/brachial index of less than 0.8 were studied or when patients with zero to two of these putative risk factors were compared with patients with three or four. Screening for carotid stenosis in asymptomatic patients with peripheral vascular disease is justifiable, but not mandatory, when two or more risk factors are present or when the ankle/brachial index is less than 0.4. Rates of progression to clinically significant stenosis are low and do not justify reevaluation every 6 months. Further research to identify the optimal interval for reevaluation is needed.


Neonatal Venous Thromboembolism.
Neonates are the pediatric population at highest risk for development of venous thromboembolism (VTE), and the incidence of VTE in the neonatal population is increasing. This is especially true in the critically ill population. Several large studies indicate that the incidence of neonatal VTE is up almost threefold in the last two decades. Central lines, fluid fluctuations, sepsis, liver dysfunction, and inflammation contribute to the risk profile for VTE development in ill neonates. In addition, the neonatal hemostatic system is different from that of older children and adults. Platelet function, pro- and anticoagulant proteins concentrations, and fibrinolytic pathway protein concentrations are developmentally regulated and generate a hemostatic homeostasis that is unique to the neonatal time period. The clinical picture of a critically ill neonate combined with the physiologically distinct neonatal hemostatic system easily fulfills the criteria for Virchow's triad with venous stasis, hypercoagulability, and endothelial injury and puts the neonatal patient at risk for VTE development. The presentation of a VTE in a neonate is similar to that of older children or adults and is dependent upon location of the VTE. Ultrasound is the most common diagnostic tool employed in identifying neonatal VTE, but relatively small vessels of the neonate as well as frequent low pulse pressure can make ultrasound less reliable. The diagnosis of a thrombophilic disorder in the neonatal population is unlikely to change management or outcome, and the role of thrombophilia testing in this population requires further study. Treatment of neonatal VTE is aimed at reducing VTE-associated morbidity and mortality. Recommendations for treating, though, cannot be extrapolated from guidelines for older children or adults. Neonates are at risk for bleeding complications, particularly younger neonates with more fragile intracranial vessels. Developmental alterations in the coagulation proteins as well as unique pharmacokinetics must also be taken into consideration when recommending VTE treatment. In this review, epidemiology of neonatal VTE, pathophysiology of neonatal VTE with particular attention to the developmental hemostatic system, diagnostic evaluations of neonatal VTE, and treatment guidelines for neonatal VTE will be reviewed.


Select Food Group Intake of US Children Aged 2 to 4 Years by WIC Participation Status and Income.
Food group and nutrient priorities for Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) Food Package IV for children aged 2 to 4 years were described in the 2017 review of the WIC Food Package. Research has evaluated priority nutrient intake, but priority food group intake remains unknown. To compare mean intake of priority food groups/subgroups of WIC children to WIC-eligible nonparticipants and higher income children. Further, we hoped to assess differences in percent contribution of food subgroups to total food group intake by WIC participation status and income. Cross-sectional study conducted using data from the 2011-14 National Health and Nutrition Examination Survey. One thousand forty-seven children aged 2 to 4 years. Mean intake reported in cup equivalents and ounce equivalents. We also looked at mean percent that food subgroups contributed to total intake within a food group. Analyses were performed for high and low priority food groups/subgroups: high = seafood, total vegetables, dark green vegetables, red/orange vegetables, whole grains, and nuts/seeds/soy; low = total starchy vegetables, other vegetables, legumes computed as vegetables, total dairy, and total protein foods. Multivariable linear regression analysis was used evaluate the relationship between income/WIC participation and mean intake/percent food subgroups contributed to total food group intake. Among low-income WIC-eligible children, participation in WIC was associated with greater mean intake of red/orange vegetables (0.18 ± 0.03 vs 0.01 ± 0.06 c equivalents; P < 0.05) and legumes (0.07 ± 0.01 vs 0.01 ± 0.02 c equivalents; P < 0.01). No differences in mean intake were observed between WIC children and higher income children. Grain intake of WIC children was composed of a higher percentage of whole grains (19.1% ± 1.6% vs 13.2% ± 1.5%; P < 0.01) compared with higher income children. The percent vegetable subgroups contributed to total vegetable intake varied by income; no differences were observed for dairy or protein subgroups. Among low-income children, participation in WIC was associated with greater intake of certain vegetables. Participation in WIC may also help close the diet quality gap between low-income and higher income children for priority foods targeted by the WIC food package. Future research should explore socioeconomic disparities in intake of nutrient-poor foods.


Nanometer-resolved radio-frequency absorption and heating in biomembrane hydration layers.
Radio-frequency (RF) electromagnetic fields are readily absorbed in biological matter and lead to dielectric heating. To understand how RF radiation interacts with macromolecular structures and possibly influences biological function, a quantitative description of dielectric absorption and heating at nanometer resolution beyond the usual effective medium approach is crucial. We report an exemplary multiscale theoretical study for biomembranes that combines (i) atomistic simulations for the spatially resolved absorption spectrum at a single planar DPPC lipid bilayer immersed in water, (ii) calculation of the electric field distribution in planar and spherical cell models, and (iii) prediction of the nanometer resolved temperature profiles under steady RF radiation. Our atomistic simulations show that the only 2 nm thick lipid hydration layer strongly absorbs in a wide RF range between 10 MHz and 100 GHz. The absorption strength, however, strongly depends on the direction of the incident wave. This requires modeling of the electric field distribution using tensorial dielectric spectral functions. For a spherical cell model, we find a strongly enhanced RF absorption on an equatorial ring, which gives rise to temperature gradients inside a single cell under radiation. Although absolute temperature elevation is small under conditions of typical telecommunication usage, our study points to hitherto neglected temperature gradient effects and allows thermal RF effects to be predicted on an atomistically resolved level. In addition to a refined physiological risk assessment of RF fields, technological applications for controlling temperature profiles in nanodevices are possible.


Glucocorticoids mediate stress-induced priming of microglial pro-inflammatory responses.
Acute and chronic stress sensitizes or "primes" the neuroinflammatory response to a subsequent pro-inflammatory challenge. While prior evidence shows that glucocorticoids (GCs) play a pivotal role in stress-induced potentiation of neuroinflammatory responses, it remains unclear whether stress-induced GCs sensitize the response of key CNS immune substrates (i.e. microglia) to pro-inflammatory stimuli. An ex vivo approach was used to address this question. Here, stress-induced GC signaling was manipulated in vivo and hippocampal microglia challenged with the pro-inflammatory stimulus LPS ex vivo. Male Sprague-Dawley rats were either pretreated in vivo with the GC receptor antagonist RU486 or adrenalectomized (ADX). Animals were then exposed to an acute stressor (inescapable tailshock; IS) and 24 h later hippocampal microglia were isolated and challenged with LPS to probe for stress-induced sensitization of pro-inflammatory responses. Prior exposure to IS resulted in a potentiated pro-inflammatory cytokine response (e.g. IL-1β gene expression) to LPS in isolated microglia. Treatment in vivo with RU486 and ADX inhibited or completely blocked this IS-induced sensitization of the microglial pro-inflammatory response. The present results suggest that stress-induced GCs function to sensitize the microglial pro-inflammatory response (IL-1β, IL-6, NFκBIα) to immunologic challenges.


Axitinib (AG-013736), an oral specific VEGFR TKI, shows potential therapeutic utility against cholangiocarcinoma.
Cholangiocarcinoma is a refractory cancer whose incidence has been increasing worldwide in recent years. Neoangiogenesis plays an important role in the growth of various solid cancers, including cholangiocarcinoma. Vascular endothelial growth factor plays an important role in tumor-induced angiogenesis and its expression is associated with the progression and prognosis of cholangiocarcinoma. This study examined whether axitinib (AG-013736, INLYTA(®)), a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3, could be a potentially useful therapeutic agent for cholangiocarcinoma. We performed expression profiling of angiogenesis-related molecules in eight cholangiocarcinoma cell lines and found that three of them showed high vascular endothelial growth factor expression. Among them, we examined the in vivo anti-tumor effect of axitinib on NCC-BD1 (a gemcitabine-sensitive extra-hepatic cholangiocarcinoma cell line) and TKKK (a gemcitabine-resistant intra-hepatic cholangiocarcinoma cell line) using subcutaneous xenograft models. Oral administration of axitinib significantly inhibited the growth of TKKK xenografts at a dose of 6 mg kg(-1) day(-1) (P<0.05), and the growth of NCC-BD1 xenografts at 30 mg kg(-1)day(-1) (P<0.05). Treated tumors showed a significant decrease of microvessel density and the tumor cell proliferation index and a mild but significant increase of the apoptotic index in comparison with untreated tumors. Our results suggest that axitinib should be a promising therapy for vascular endothelial growth factor-expressing cholangiocarcinoma, irrespective of tumor origin and gemcitabine sensitivity.


Regional and global impacts of Criegee intermediates on atmospheric sulphuric acid concentrations and first steps of aerosol formation.
Carbonyl oxides ("Criegee intermediates"), formed in the ozonolysis of alkenes, are key species in tropospheric oxidation of organic molecules and their decomposition provides a non-photolytic source of OH in the atmosphere (Johnson and Marston, Chem. Soc. Rev., 2008, 37, 699, Harrison et al, Sci, Total Environ., 2006, 360, 5, Gäb et al., Nature, 1985, 316, 535, ref. 1-3). Recently it was shown that small Criegee intermediates, C.I.'s, react far more rapidly with SO2 than typically represented in tropospheric models, (Welz, Science, 2012, 335, 204, ref. 4) which suggested that carbonyl oxides could have a substantial influence on the atmospheric oxidation of SO2. Oxidation of 502 is the main atmospheric source of sulphuric acid (H2SO4), which is a critical contributor to aerosol formation, although questions remain about the fundamental nucleation mechanism (Sipilä et al., Science, 2010, 327, 1243, Metzger et al., Proc. Natl. Acad. Sci. U. S. A., 2010 107, 6646, Kirkby et al., Nature, 2011, 476, 429, ref. 5-7). Non-absorbing atmospheric aerosols, by scattering incoming solar radiation and acting as cloud condensation nuclei, have a cooling effect on climate (Intergovernmental Panel on Climate Change (IPCC), Climate Change 2007: The Physical Science Basis, Cambridge University Press, 2007, ref. 8). Here we explore the effect of the Criegees on atmospheric chemistry, and demonstrate that ozonolysis of alkenes via the reaction of Criegee intermediates potentially has a large impact on atmospheric sulphuric acid concentrations and consequently the first steps in aerosol production. Reactions of Criegee intermediates with SO2 will compete with and in places dominate over the reaction of OH with SO2 (the only other known gas-phase source of H2SO4) in many areas of the Earth's surface. In the case that the products of Criegee intermediate reactions predominantly result in H2SO4 formation, modelled particle nucleation rates can be substantially increased by the improved experimentally obtained estimates of the rate coefficients of Criegee intermediate reactions. Using both regional and global scale modelling, we show that this enhancement is likely to be highly variable spatially with local hot-spots in e.g. urban outflows. This conclusion is however contingent on a number of remaining uncertainties in Criegee intermediate chemistry.


Effect of gamma-irradiation on some chemical characteristics and volatile content of linseed.
The effect of irradiation (2.5, 4.0, 5.5, and 7.0 kGy) on chemical properties and volatile contents of linseed was investigated. Consistent decreases were observed in both protein and oil content of the irradiated linseed samples with increasing irradiation doses. The ash content of the irradiated linseed samples increased significantly (P<.05) with increasing irradiation doses except for 5.5 kGy. Irradiation treatment caused irregular changes in palmitic and stearic acid content. Although styrene and p-xylene content decreased as a result of irradiation, 1-hexanol content only decreased at 7.0 kGy. Benzaldehyde, p-cymene, and nonanol were not determined at irradiation doses above 4.0 kGy.


The efficacy of breast augmentation: breast size increase, patient satisfaction, and psychological effects.
In this study designed to quantify the degree of breast enlargement produced by augmentation mammaplasty, 112 women who underwent breast augmentation were interviewed. The size increase that typically resulted from various implant volumes was measured by comparing preoperative and postoperative bra sizes. For the study group as a whole, the average increase was two bra sizes (either increased cup size or a combination of increased cup size and chest circumference), regardless of the implant volume inserted. Patients also were asked a series of questions to evaluate the impact of the surgery on various psychological parameters, including body image, feelings of self-confidence, and interpersonal relationships. Along with having a very positive body image, the group reported decreased self-consciousness (86 percent) and heightened self-confidence (88 percent); in addition, 95 percent said they felt better about themselves after surgery. The women's satisfaction with the results of augmentation and the success of surgery in meeting their expectations also were measured. Eighty-six percent reported being completely or mostly satisfied with the postoperative results, 86 percent felt the operation was a complete success, and 95 percent said that augmentation met their expectations.


The genetic basis of murine and human sex determination: a review.
Determination of mammalian sex depends on the presence or absence of a functional testis. Testes are determined by the activity of the testis determining factor encoded by the sex determining gene, Y (SRY) located on the Y chromosome. Considerable evidence suggests that the SRY gene is the only gene on the Y chromosome that is both necessary and sufficient to initiate testis determination. Other steps in the mammalian sex determining pathway are unknown, although recent advances have shown that mutations in X chromosome and autosomal loci are also associated with sex reversal, suggesting the presence of at least one other sex determining gene. Duplications of sequences on the short arm of the human X chromosome, including the DAX-1 (DSS-AHC critical region on the X chromosome, gene 1) gene, are occasionally associated with XY male-to-female sex reversal. In addition, mutations in the SRY-related gene SOX9 (SRY-related box) are associated with a failure of human testicular determination. Furthermore, the occurrence of inherited sex reversed conditions in both mice and men indicate the presence of at least one other sex determining gene. Breeding the Y chromosome from certain Mus musculus domesticus strains into the laboratory mouse strain C57BL/6J results in XY male-to-female sex reversal. This suggests both allelic variation of the Sry gene and the presence of autosomal sex determining genes. In humans, familial cases of SRY-negative XX males occur. Analysis of the transmission of the trait indicates the segregation of an autosomal or X-linked recessive mutation. The mutation may be in a gene whose wild-type function is to inhibit male sex determination. SRY may trigger male sex determination by repressing or functionally antagonizing the product of this gene.


The health and health behaviours of Australian metropolitan nurses: an exploratory study.
Nurses make up the largest component of the health workforce and provide the majority of patient care. Most health education is delivered by nurses, who also serve as healthy living and behavioural role models. Anything that diminishes their health status can impact their credibility as role models, their availability and ability to deliver quality care, and is potentially disadvantageous for the health of the population. Study aims were to investigate nurses' overall health and the presence of chronic disease; to describe nurses' health-related behaviours and to compare them to those of the general population, with both groups matched by age and gender. Cross-sectional descriptive paper-based survey of nurses from two Sydney metropolitan hospitals using established instruments and questions and measurements taken with standardised methods. This nursing sample (n = 381) had a mean age of 39.9 (SD 11.7, range 20-67) years, Most (n = 315; 82.7 %) were female, worked full-time (80.0 %), and were shift workers (93.0 %). The majority (94.0 %) indicated good, very good or excellent health, despite 42.8 % indicating they had chronic disease. The most common risk factors for chronic disease were inadequate vegetable (92.6 %) and fruit intake (80.1 %), overweight and obesity (44.0 %) and risky alcohol intake (34.7 %); health screening behaviours were not ideal. Aside from overweight and obesity, these risk factors were more prevalent in nurses than the equivalent group of the New South Wales population, particularly for risky alcohol intake which was much more common in female nurses and most marked in those aged under 35 years. However, 80 % met the guidelines for physical activity, more than the equivalent group of the New South Wales population. There are early 'warning signs' concerning the health status of nurses. Despite perceiving current good health, support is required for nurses to prevent future chronic disease, particularly in the areas of nutrition and alcohol intake. With these concerns, the nursing workforce ageing and demands for care increasing, it is now time to implement health enhancing strategies for nurses.


Effect of functional knee brace use on acceleration, agility, leg power and speed performance in healthy athletes.
To investigate performance levels and accommodation period to functional knee brace (FKB) use in non-injured braced subjects while completing acceleration, agility, lower extremity power and speed tasks. A 2 (non-braced and braced conditions) × 5 (testing sessions) repeated-measures design. 27 healthy male athletes were provided a custom fitted FKB. Each subject performed acceleration, agility, leg power and speed tests over 6 days; five non-braced testing sessions over 3 days followed by five braced testing sessions also over 3 days. Each subject performed two testing sessions (3.5 h per session) each day. Performance levels for each test were recorded during each non-braced and braced trial. Repeated measures analysis of variance, with a post hoc Tukey's test for any test found to be significant, were used to determine if accommodation to FKB was possible in healthy braced subjects. Initial performance levels were lower for braced than non-braced for all tests (acceleration p=0.106; agility p=0.520; leg power p=0.001 and speed p=0.001). However, after using the FKB for approximately 14.0 h, no significant performance differences were noted between the two testing conditions (acceleration non-braced, 0.53±0.04 s; braced, 0.53±0.04 s, p=0.163, agility non-braced, 9.80±0.74 s; braced, 9.80±0.85 s, p=0.151, lower extremity power non-braced, 58±7.4 cm; braced, 57±8.1 cm, p=0.163 and speed non-braced, 1.86±0.11 s; braced, 1.89±0.11 s, p=0.460). An initial decrement in performance levels was recorded when a FKB is used during an alactic performance task. After 12.0-14.0 h of FKB use, performance measures were similar between the two testing conditions.


Clouds of different colors: A prospective look at head and neck surgical resident call experience.
Graduate medical education programs typically set up call under the assumption that residents will have similar experiences. The terms black cloud and white cloud have frequently been used to describe residents with more difficult (black) or less difficult (white) call experiences. This study followed residents in the department of head and neck surgery during call to determine whether certain residents have a significantly different call experience than the norm. It is a prospective observational study conducted over 16 months in a tertiary care center with a resident training program in otolaryngology. Resident call data on total pages, consults, and operative interventions were examined, as well as subjective survey data about sleep and perceived difficulty of resident call. Analysis showed no significant difference in call activity (pages, consults, operative interventions) among residents. However, data from the resident call surveys revealed perceived disparities in call difficulty that were significant. Two residents were clearly labeled as black clouds compared to the rest. These residents did not have the highest average number of pages, consults, or operative interventions. This study suggests that factors affecting call perception are outside the objective, absolute workload. These results may be used to improve resident education on sleep training and nighttime patient management in the field of otolaryngology and may influence otolaryngology residency programs.


Palliative Care, End-of-Life Care, and Advance Care Planning in Neuro-oncology.
Despite new therapeutic approaches, most patients with high-grade glioma face limited overall survival and have a high symptom burden throughout their disease trajectory, especially in the end-of-life phase. This article provides an overview of the role of palliative care in neuro-oncology. Management recommendations are made for neurologic symptoms in patients with advanced brain tumors, including headaches, nausea, and fatigue. Special attention is given to how and when to involve subspecialty palliative care and hospice services to improve symptom management during active tumor treatment and in the end-of-life phase of patients with brain tumors. Advance care planning and end-of-life goals should be addressed early in the disease trajectory; this article provides a road map for these discussions. The high symptom burden of patients with brain tumors affects their quality of life as well as their ability to make treatment decisions. It is therefore warranted to involve patients with high-grade glioma in treatment decision making early in the disease course, with a focus on end-of-life care and advance care planning. Research in other World Health Organization grade IV cancers has shown that the early involvement of specialty palliative care improves quality of life and caregiver satisfaction. Patients with brain tumors should be actively screened for fatigue, and underlying factors such as hormone deficiencies, low blood counts, and sleep issues should be addressed before focusing interventions for tumor- and treatment-related fatigue. Palliative care can address typical symptoms, such as fatigue, nausea, and headaches that have the potential to severely disable patients with brain tumors. Advance care planning should be introduced proactively and early in the disease trajectory to ensure a dignified death and improved caregiver bereavement.


Autoadjusted versus fixed CPAP for obstructive sleep apnoea: a multicentre, randomised equivalence trial.
The obstructive sleep apnoea syndrome (OSAS) is conventionally treated by continuous positive airway pressure set at a fixed level (fCPAP). Automatic mask pressure adjustment (autoCPAP) is increasingly used during home therapy. We investigated whether autoCPAP is equivalent to fCPAP in improving sleepiness in patients with OSAS in the long-term. In this multicentre equivalence trial, 208 patients with OSAS, with median Epworth sleepiness score (ESS) 13, apnoea/hypopnoea index 48.4/hour, were randomised to treatment with autoCPAP (5-15 mbar) or fCPAP (pressure set at the 90th percentile applied by autoCPAP during 2-4 weeks adaptation). Coprimary outcomes were changes in subjective and objective sleepiness from baseline to 2 years after treatment. Equivalence ranges were ±2 points in ESS and ±3 min sleep resistance time evaluated by recording responses to light signals. At 2 years, in the intention to treat analysis, the reduction in sleepiness versus pretreatment baseline was similar in patients using autoCPAP (n=113, mean ESS-change -6.3, 95% CI -7.1 to -5.5; sleep resistance time +8.3 min, +6.9 to +9.7) and fCPAP (n=95, mean ESS-change -6.2, 95% CI -7.0 to -5.3; sleep resistance time +6.3 min, +4.7 to +7.8). The 95% CI of difference in ESS-reduction between autoCPAP and fCPAP was -0.9 to +1.4 and the 95% CI of difference in increase in sleep resistance time was -2.6 to +1.0 min. Blood pressure reduction and OSAS-related costs were similar between groups. AutoCPAP and fCPAP are equivalent within prespecified ranges in improving subjective and objective sleepiness in patients with OSAS over the course of 2 years. Costs of these treatments are similar. ClinicalTrials.gov NCT00280800.


Predicting and communicating flood risk of transport infrastructure based on watershed characteristics.
This research aims to identify and communicate water-related vulnerabilities in transport infrastructure, specifically flood risk of road/rail-stream intersections, based on watershed characteristics. This was done using flooding in Värmland and Västra Götaland, Sweden in August 2014 as case studies on which risk models are built. Three different statistical modelling approaches were considered: a partial least square regression, a binomial logistic regression, and artificial neural networks. Using the results of the different modelling approaches together in an ensemble makes it possible to cross-validate their results. To help visualize this and provide a tool for communication with stakeholders (e.g., the Swedish Transport Administration - Trafikverket), a flood 'thermometer' indicating the level of flooding risk at a given point was developed. This tool improved stakeholder interaction and helped highlight the need for better data collection in order to increase the accuracy and generalizability of modelling approaches.


Enhanced interfacial activity of multi-arm poly(ethylene oxide) star polymers relative to linear poly(ethylene oxide) at fluid interfaces.
Interfacial tension reduction, dynamic dilatational elasticity and extent of adsorption were investigated for linear poly(ethylene oxide) (PEO) chains of varying molecular weight and for PEO star polymers with an average of 64 arms per star at air/water, xylene/water, and cyclohexane/water interfaces. Adsorption on planar interfaces was monitored by ellipsometry, while interfacial tension and dilatational elasticity were measured separately by pendant drop tensiometry. Previously reported to be efficient emulsifiers, PEO stars are shown here to also be more effective foaming agents than linear PEO. Accordingly, PEO stars adsorb to a greater extent and produce larger interfacial tension reduction and greater dynamic dilatational moduli than linear PEO. The more extensive adsorption and greater interfacial tension reduction for PEO stars are attributed to their compactness. More mass is introduced per unit area of interface, and more interfacial penetration is achieved, upon their adsorption than for adsorption of linear polymers that adopt the conformation of loops, trains and tails. Whereas cyclohexane is a non-solvent for PEO, xylene is a good solvent. Dispersing PEO stars in the xylene phase yields greater interfacial tension reduction at the xylene/water interface than occurs when initially dispersing PEO stars in the aqueous phase. In contrast, the interfacial tension for linear PEO shows no dependence on the phase from which it adsorbs. Ellipsometry confirms the path-dependent extent of adsorption to the xylene/water interface, but also reveals additional complexity. When adsorbing from xylene, thick interfacial films result that likely contain dispersed water, as suggested by the observation of spontaneous water-in-xylene emulsification when PEO stars are initially dispersed in xylene. This is tentatively attributed to shear provided by Marangoni flow. Spontaneous emulsification occurs only when PEO stars are initially dispersed in the xylene phase. Linear PEO produces neither thick interfacial films nor spontaneous emulsification.


Staffing in cardiology in the United Kingdom 1990. Sixth biennial survey: with data on facilities in cardiology in England and Wales 1989.
The Sixth Biennial Survey of Staffing in Cardiology was conducted in July 1990. This report summarises the data that were collected, together with the results of a survey of facilities in cardiology made in 1989. The total number of cardiologists in the United Kingdom, defined as individuals trained in the specialty and spending at least 40% of their time working in it, is now 323. Six individuals work part time only, making 320 whole time posts. This number has increased over the two years from 1988 to 1990 by 32, of which 23 work only in the specialty and nine as general physicians with a major interest in cardiology. The rate of increase in numbers over the past decade has been reasonably consistent with an average of approximately 4.4% per year. Thirty one districts in England and Wales still have no cardiologist and 13 other districts have little provision with an average of three (visiting) sessions each per week. The population in these 44 districts is 8.3 million. Scotland also has an inadequate distribution of service in the specialty. If recommendations for cardiac surgery and angioplasty made in the Fourth Report of a Joint Cardiology Committee of the Royal College of Physicians of London and the Royal College of Surgeons of England are to be met, we calculate that we need 63 more cardiologists in our major centres. To provide one cardiologist in every district hospital and two for larger districts would require 94 more specialists, making a total shortfall of 157 individuals. We have no excess of senior registrars to provide for a major expansion at consultant level. Time spent within the senior registrar (or academic equivalent) grade has tended steadily to decline and very few now reach the end of their contracts. The need for more individuals to pass through the senior registrar grade will be met in part by a planned reduction in the training period to three years. This will be inadequate, however, because projected retirements show that the number of consultant vacancies will increase sharply from 1997. We believe that additional senior registrar posts must be created if a serious shortfall in service provision by consultants is to be avoided. The provision of non-invasive facilities in cardiology is reasonable. The need for additional equipment for invasive cardiology has not been assessed. The number of physiological measurement technicians varies considerably between regions and is generally inadequate.


Constitutive material modeling of cell: a micromechanics approach.
The variations in mechanical properties of cells obtained from experimental and theoretical studies can be overcome only through the development of a sound mathematical framework correlating the derived mechanical property with the cellular structure. Such a formulation accounting for the inhomogeneity of the cytoplasm due to stress fibers and actin cortex is developed in this work. The proposed model is developed using the Mori-Tanaka method of homogenization by treating the cell as a fiber-reinforced composite medium satisfying the continuum hypothesis. The validation of the constitutive model using finite element analysis on atomic force microscopy (AFM) and magnetic twisting cytometry (MTC) has been carried out and is found to yield good correlation with reported experimental results. It is observed from the study that as the volume fraction of the stress fiber increases, the stiffness of the cell increases and it alters the force displacement behavior for the AFM and MTC experiments. Through this model, we have also been able to find the stress fiber as a likely cause of the differences in the derived mechanical property from the AFM and MTC experiments. The correlation of the mechanical behavior of the cell with the cell composition, as obtained through this study, is an important observation in cell mechanics.


The readiness of SNOMED problem list concepts for meaningful use of electronic health records.
By 2015, SNOMED CT (SCT) will become the USA's standard for encoding diagnoses and problem lists in electronic health records (EHRs). To facilitate this effort, the National Library of Medicine has published the "SCT Clinical Observations Recording and Encoding" and the "Veterans Health Administration and Kaiser Permanente" problem lists (collectively, the "PL"). The PL is studied in regard to its readiness to support meaningful use of EHRs. In particular, we wish to determine if inconsistencies appearing in SCT, in general, occur as frequently in the PL, and whether further quality-assurance (QA) efforts on the PL are required. A study is conducted where two random samples of SCT concepts are compared. The first consists of concepts strictly from the PL and the second contains general SCT concepts distributed proportionally to the PL's in terms of their hierarchies. Each sample is analyzed for its percentage of primitive concepts and for frequency of modeling errors of various severity levels as quality measures. A simple structural indicator, namely, the number of parents, is suggested to locate high likelihood inconsistencies in hierarchical relationships. The effectiveness of this indicator is evaluated. PL concepts are found to be slightly better than other concepts in the respective SCT hierarchies with regards to the quality measure of the percentage of primitive concepts and the frequency of modeling errors. There were 58% primitive concepts in the PL sample versus 62% in the control sample. The structural indicator of number of parents is shown to be statistically significant in its ability to identify concepts having a higher likelihood of inconsistencies in their hierarchical relationships. The absolute number of errors in the group of concepts having 1-3 parents was shown to be significantly lower than that for concepts with 4-6 parents and those with 7 or more parents based on Chi-squared analyses. PL concepts suffer from the same issues as general SCT concepts, although to a slightly lesser extent, and do require further QA efforts to promote meaningful use of EHRs. To support such efforts, a structural indicator is shown to effectively ferret out potentially problematic concepts where those QA efforts should be focused.


Xiao-Ai-Ping, a TCM Injection, Enhances the Antigrowth Effects of Cisplatin on Lewis Lung Cancer Cells through Promoting the Infiltration and Function of CD8(+) T Lymphocytes.
Objectives. To investigate how Xiao-Ai-Ping injection, a traditional Chinese medicine and an ancillary drug in tumor treatment, enhances the antitumor effects of cisplatin on Lewis lung cancer (LLC) cells. Methods. LLC-bearing mice were daily intraperitoneally injected with various doses of cisplatin, Xiao-Ai-Ping, or cisplatin plus Xiao-Ai-Ping, respectively. Body weight and tumor volumes were measured every three days. Results. Combination of Xiao-Ai-Ping and cisplatin yielded significantly better antigrowth and proapoptotic effects on LLC xenografts than sole drug treatment did. In addition, we found that Xiao-Ai-Ping triggered the infiltration of CD8(+) T cells, a group of cytotoxic T cells, to LLC xenografts. Furthermore, the mRNA levels of interferon- γ (ifn- γ ), perforin-1 (prf-1), and granzyme B (gzmb) in CD8(+) T cells were significantly increased after combination treatment of Xiao-Ai-Ping and cisplatin. In vitro studies showed that Xiao-Ai-Ping markedly upregulated the mRNA levels of ifn- γ , prf-1, and gzmb in CD8(+) T cells in a concentration-dependent manner, suggesting that Xiao-Ai-Ping augments the function of CD8(+) T cells. Conclusions. Xiao-Ai-Ping promotes the infiltration and function of CD8(+) T cells and thus enhances the antigrowth effects of cisplatin on LLC xenografts, which provides new evidence for the combination of Xiao-Ai-Ping and cisplatin in clinic in China.


Nuclear pore complexes. Elimination and reconstruction during mitosis.
Nuclear structures similar to those of the nuclear pore complex were found on chromosomes. This finding indicates that part of the pore complex is retained by the chromosomes through mitosis in the absence of the nuclear membrane. The formation of approximately the same number of pore complexes in the presence and absence of protein synthesis during the first 4 h after mitosis proves the reassembly rather than new synthesis of the pore complex. The structure of pore complexes reconstructed in the absence of protein synthesis cannot be distinguished from the structure of those of control cells.


A paradigm for commensalism: the role of a specific microbial polysaccharide in health and disease.
The human gastrointestinal tract is colonized by 100 trillion microorganisms, including both beneficial and potentially pathogenic species. A zwitterionic polysaccharide (PSA) from the gastrointestinal microorganism Bacteroides fragilis has been shown to be the archetypal molecule of commensal bacteria that mediates development of the host immune system. PSA stimulates the normal balance of Th1 and Th2 CD4+ T cells and can correct histologic defects in the spleen and thymus of germ-free mice. PSA stimulates the innate immune system as a ligand for Toll-like receptor 2 and thereby promotes interactions with the adaptive immune system that are required for T-cell activation. PSA protects animals from colitis induced by Helicobacter hepaticus, a commensal with pathogenic potential. In animals harboring a B. fragilis mutant that does not express PSA, H. hepaticus colonization leads to disease and proinflammatory cytokine production in colonic tissues. Purified PSA administered to animals suppresses the production of the proinflammatory cytokine interleukin-17 by intestinal immune cells. PSA protects animals from inflammatory disease through a functional requirement for interleukin-10-producing CD4+ T cells. Thus polysaccharides of the bacterial microbiota can mediate the critical balance between health and disease in the host. As evidence accumulates, this concept is being accepted as an important feature of the immune repertoire.


Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC.
Inactivation of the adenomatous polyposis coli (APC) tumor suppressor gene initiates colorectal neoplasia. One of the biochemical activities associated with the APC protein is down-regulation of transcriptional activation mediated by beta-catenin and T cell transcription factor 4 (Tcf-4). The protein products of mutant APC genes present in colorectal tumors were found to be defective in this activity. Furthermore, colorectal tumors with intact APC genes were found to contain activating mutations of beta-catenin that altered functionally significant phosphorylation sites. These results indicate that regulation of beta-catenin is critical to APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or beta-catenin.


GateCT™ surface tracking system for respiratory signal reconstruction in 4DCT imaging.
To assess the temporal and spatial accuracy of the GateCT™ system (VisionRT, London, UK), a recently released respiratory tracking system for 4DCT, under both ideal and nonideal respiratory conditions. Three experiments were performed by benchmarking and comparing its results with the ground-truth input data and those generated by the widely used Varian RPM™ system (Real-time Position Management, Varian, Palo Alto, CA). The first experiment used 10 sinusoidal breathing patterns (constant amplitude and frequency using sin(6)ωt), 10 "consistent" patient breathing patterns, and 10 "sporadic" patient breathing patterns. Motion was simulated with the quasar™ Programmable Respiratory Motion Platform (MODUS, London, Canada) as the surrogate. The GateCT™ and RPM™ systems were used to track the breathing patterns. The data from both systems were then analyzed in the Fourier domain, to evaluate temporal/phase accuracy, using the Pearson's correlation coefficient (PCC). The analysis correlated the ground-truth input data against the GateCT™ and RPM™ tracking results, respectively. The second experiment used 10 ideal sinusoidal breathing patterns, five of period 2.0 s, and five of period 5.0 s, with varying abdominal amplitudes found in clinical cases (peak-to-peak range: 1.67-10 mm) to test the sensitivity of the system to reconstruct various range of motion. And, the third experiment used 12 consecutive clinical patients to track the abdominal motion simultaneously by the GateCT™ and RPM™ systems. The baseline of the tracking results from both the two systems was analyzed via the mean-position-estimate (MPE) calculations. All experiments were tracked for at least 120 s. In the first experiment, the average PCC values (±SD) of all thirty breathing patterns were 0.9995 ± 0.00035 and 0.9994 ± 0.00041 for the GateCT™ and the RPM™ system, respectively. These nearly identical results demonstrated similar temporal/phase tracking accuracy for the two systems. The results in the second experiment, however, revealed a pattern for the GateCT™ system in which the uncertainty of its mean-position tracking increased as the amplitude of the breathing pattern decreased. For example, a non-negligible baseline drift of up to 29.3% with respect to the peak-to-peak amplitude of 1.67-mm was observed. On the contrary, the RPM™ system displayed a more consistent recording of amplitudes over time with the greatest drift being <7.7%. The third experiment confirmed these findings in the clinical setting. Consistent decrease in PCC values due to the increase in artificial amplitude drifts, as the breathing amplitude decreased, was found. The lowest PCC value was 0.7239 for a patient with 1.57-mm peak-to-peak amplitude. The GateCT™ system revealed its consistency in temporal/phase tracking but had limitations in accurately tracking the absolute abdominal positions, thus suggesting its appropriateness for phase-sorting of 4DCT rather than amplitude-sorting. In contrast, the RPM™ system demonstrated stable respiratory signal tracking in all ranges and accurately both in phase and amplitude, and is a robust system to use for both phase-sorting and amplitude-sorting techniques. The impact of the observed mean-position drift in the GateCT™ system on the resulting 4DCT image quality, in amplitude-sorting, needs further investigation.


Suicidal Behavior in the Mediterranean Countries.
Suicidal behavior is a serious public health problem worldwide and shows large intersocietal variation. This study aimed at comparatively investigating the aspects of suicidal behavior in 22 countries surrounding the Mediterranean Sea. The study was conducted with official data retrieved from several sources. The suicidal mortality data were collected from World Health Organization's data repository. Descriptive statistics, group comparison, correlational and regression statistical analyses were used to summarize the data. The average age standardized suicide rates in the Mediterranean countries are lower than the world average. Except in Morocco, more men kill themselves than women. Suicide rates are lower in Mediterranean Muslim than in Mediterranean Christian countries. Slovenia, France and Croatia have the highest suicide mortality rates. Greatest percentages of suicidal ideation are seen in Croatia, Turkey and Slovenia and the greatest percentages of suicidal attempts are seen in Palestine, Cyprus, Greece and Slovenia. According to the results of the multiple regression analyses, the coefficient of human inequality index was associated with lower both-sex and male suicide rates. Greater percentages of people saying religion is unimportant in daily life in a country were found to be related to higher female suicide rates. The findings from the study have shown that the prevalence of suicidal deaths, thoughts and attempts vary between the Mediterranean countries. Lower suicide rates are observed in the Muslim Mediterranean nations than in the Judeo-Christian ones. However, the rates of suicide mortality in non-Arab Muslim nations being comparable to the rates in non-Muslim countries confirm the concerns over mis/underreporting of suicidal behavior in Arab Muslim countries due to religio-cultural stigma attached to suicide. The average suicidal mortality rates are lower in Mediterranean countries than the world average. Generally, more men than women kill themselves. Results from the multivariate analysis revealed that as the level of human inequality increases the rates for both-sex and male suicidal mortality decreases. Religion seem to be protective against female suicides. The study has also shown that more research is needed about suicidal behavior in the Mediterranean countries.


A Longitudinal Analysis of Contextual Exposure to Peers with College Educated Parents and Students' College Enrollment.
Students with college educated parents are more likely to attain higher levels of education than students of parents with lower levels of education. Past research has explained this favorable outcome as the result of advantageous placement and greater availability of educational resources. Using data from Add Health and AHAA, we find evidence that exposure to students of college educated parents at the school level and within courses increase the likelihood of four year college enrollment even after controlling for family background, achievement, and placement. We also found that exposure to students of college educated parents has especially strong positive effects on college enrollment for students whose own parents do not have a college degree. These findings suggest that greater exposure to students of highly educated parents at the school level and within courses partially explains the favorable educational attainment of students with college educated parents.


A task-specific analysis of the benefit of haptic shared control during telemanipulation.
Telemanipulation allows human to perform operations in a remote environment, but performance and required time of tasks is negatively influenced when (haptic) feedback is limited. Improvement of transparency (reflected forces) is an important focus in literature, but despite significant progress, it is still imperfect, with many unresolved issues. An alternative approach to improve teleoperated tasks is presented in this study: Offering haptic shared control in which the operator is assisted by guiding forces applied at the master device. It is hypothesized that continuous intuitive interaction between operator and support system will improve required time and accuracy with less control effort, even for imperfect transparency. An experimental study was performed in a hard-contact task environment. The subjects were aided by the designed shared control to perform a simple bolt-spanner task using a planar three degree of freedom (DOF) teleoperator. Haptic shared control was compared to normal operation for three levels of transparency. The experimental results showed that haptic shared control improves task performance, control effort and operator cognitive workload for the overall bolt-spanner task, for all three transparency levels. Analyses per subtask showed that free air movement (FAM) benefits most from shared control in terms of time performance, and also shows improved accuracy.


Escalators, rubber clogs, and severe foot injuries in children.
Reports in the media suggest that escalator-related foot injuries are on the rise. Trendy, bright-colored rubber clogs have been implicated in a significant number of these incidents involving children. We review the children who sustained severe foot injuries on escalators, were wearing rubber clogs at the time of injury, and who were admitted to hospital for emergency surgery. A list of children who sustained foot injuries on escalators was generated from the hospital database and included for study. From clinical chart review, demographic data, footwear type, and injuries sustained were recorded. Inpatient or outpatient treatment rendered was also recorded for each patient. Between September 2006 and September 2008, we treated 17 children for escalator-related foot injuries. There were 10 boys and 7 girls who were between 2 and 9 years of age (mean: 5.5). Thirteen children (76.5%) from this group were wearing rubber clogs at the time of injury. Nine of these 13 (69.2%) children sustained severe foot injuries that required admission to hospital for emergency surgery and are the focus of this study. One child had an unsalvageable traumatic amputation of the great toe at the level of the interphalangeal joint. Two children sustained crush injuries to the great toe: 1 with severe degloving and the other with an open fracture of the proximal phalanx. One child had an open fracture-dislocation of the second metatarsophalangeal joint with a comminuted fracture of the second metatarsal. Five children sustained multiple deep lacerations in the foot and 2 of them had associated cut tendons that required repair. In the group not wearing rubber clogs, 3 of 4 children had severe foot injuries. In this series, 4 children with rubber clogs and another child with a different footwear sustained minor injuries; they were treated as outpatients. Escalator-related foot injuries involving rubber clogs can result in severe crushing of the foot and even traumatic amputation. The broad toe-box design may give a false perception of the distance between the foot and the side of the escalator, whereas the 'softness' of these rubber clogs makes them vulnerable to crush by moving escalator steps. This is the first report in the literature describing escalator-related severe foot injuries in children who were wearing rubber clogs. Injuries sustained can be significant and permanent. The potential dangers of escalators and rubber clogs must not be underestimated. Level IV, Case Series.


Photochemotherapy of Cutaneous Graft-versus-Host Disease May Reduce Concomitant Visceral Disease.
Photochemotherapy may be used to treat cutaneous graft-versus-host disease (GvHD). Animal models show that in the days after photochemotherapy and antigen provocation, cells with an antigen-specific suppressive phenotype are elicited in the lymphoid organs. In GvHD, host antigens are present not only in the skin treated by photochemotherapy but also in the visceral tissues. The aim of this paper was to evaluate the effect on visceral acute GvHD (aGvHD) of photochemotherapy of the skin. We retrospectively evaluated 33 patients with aGvHD of the skin, the liver, and/or the gastrointestinal tract treated with photochemotherapy for their aGvHD of the skin and did a long-term follow-up of 10 years on survival. The complete response (CR) to photochemotherapy was 39%, the complete and partial response was 64% and the 6-month survival was 64%. Total body irradiation (TBI) before hematopoietic stem cell transplantation predisposed for CR of aGvHD of the liver and the gastrointestinal tract (p = 0.045). In the TBI group, the accumulated dose (numbers of treatments) for CR of visceral aGvHD increased with the body surface area affected by disease, from 8 (min-max: 5-14) for skin disease stage 1 to 10.5 (6-33) for stage 2 and 13 (11-21) for stage 3 (p = 0.04). Skin disease stage 1 showed a trend to be associated with CR in visceral disease at 28, 56, and 100 days (p = 0.07). Overall CR in visceral disease predicted a better 10-year overall survival (p = 0.0036). Finally, after TBI aGvHD of the gastrointestinal tract without anti-thymocyte globulin (ATG), clearance of T cells and dendritic cells responded better than aGvHD of the liver and aGvHD of the gastrointestinal tract with ATG (p = 0.01). Photochemotherapy after ionizing irradiation regulates the cell-mediated immunity in the viscera, and the systemic efficacy increases when the skin itself is less affected by disease. ATG modulates the regulatory effect of the gastrointestinal tract.


An interactive internet-based continuing education course on sexually transmitted diseases for physicians and midwives in Peru.
Clinicians in developing countries have had limited access to continuing education (CE) outside major cities, and CE strategies have had limited impact on sustainable change in performance. New educational tools could improve CE accessibility and effectiveness. The objective of this study was to evaluate an interactive Internet-based CE course on Sexually Transmitted Diseases (STDs) management for clinicians in Peru. Participants included physicians and midwives in private practice drawn from a census of 10 Peruvian cities. The CE included a three-hour workshop for improving Internet skills, followed by a 22-hour online course on STD-syndrome-management, with subsequent educational support. The course used case-based clinical vignettes tailored to local STD problems. Knowledge and reported practices on STD management were assessed before, immediately after and at four months after completion of the course. Statistical analysis included parametric tests-linear regression multivariate analysis, paired t-test and repeated measures ANOVA using SPSS 14.0. Of 1,071 eligible clinicians, 510 agreed to participate, as did an additional 132 public sector clinicians. Of these 642 participants, 619 (96.4%) completed the course, and 596 (96.3%) took the four-month follow-up evaluation. Physician and midwife scores improved from 64.2% correct answers on the pre-test to 77.9% correct on the four-month follow-up test (p<0.001). Most participants (95%) found the online course useful for their work needs. Self reported STD management practices did not change. Among physicians and midwives in Peru, an Internet-based CE course was feasible, acceptable with high participation rates, and led to sustained improvement in knowledge at four months. Further studies are needed to test it as a model for improving the training of physicians, midwives, and other health care providers.


Monitoring fluoride exposure with fingernail clippings.
The purpose of this review is to discuss new information regarding the relationship between the level of fluoride exposure and the corresponding fluoride concentrations in fingernail clippings. While there are several techniques available to extract fluoride from fingernails prior to analysis with the electrode, the HMDS-facilitated diffusion method is the most popular. Fluoride enters fingernails at the growth end and reaches the distal end approximately three months later. The fluoride concentration in the clipping reflects the average fluoride intake and plasma concentration during the period when the clipping was formed. Therefore, the concentration in the clipping is directly related to the average fluoride exposure that occurred during a 1-2 week period (depending on the length of the clipping) about three months ago and not to recent and possibly variable exposures that occur during the day. Published studies have demonstrated that fingernail fluoride concentrations reflect fluoride exposures from drinking water, toothpaste and the work environment and can be expected to do so for any source of intake including salt.


Mild cognitive impairment is associated with subclinical diastolic dysfunction in patients with chronic heart disease.
To examine mild cognitive impairment and its associations with subclinical cardiac dysfunction in patients with chronic heart disease yet to develop the clinical syndrome of chronic heart failure (CHF). Patients from the Nurse-led Intervention for Less Chronic Heart Failure Study (n = 373 with chronic heart disease other than CHF; 64 ± 11 years, 69% men) were screened for mild cognitive impairment [Montreal cognitive assessment (MoCA) score <26] and underwent echocardiographic/clinical profiling. We investigated associations of mild cognitive impairment and MoCA cognitive domain subscores with global cardiac status ('normal' vs. 'diastolic dysfunction' vs. 'other cardiac abnormality') and individual echocardiographic parameters. Patients with mild cognitive impairment (n = 161; 43%) demonstrated a higher age-adjusted prevalence of diastolic dysfunction (37% vs. 24%; P < 0.05). Multivariate logistic regression (adjusted for age, sex, and other relevant clinical factors) indicated that the odds of mild cognitive impairment were two-times higher with diastolic dysfunction (P = 0.030) and 1.7-times higher with 'other cardiac abnormalities' (P = 0.082) vs. normal cardiac status. In turn, mild cognitive impairment was predicted by left-ventricular (LV) filling pressure (based on the ratio of early diastolic filling and annular velocities; adjusted odds ratio 1.07 per unit increase, P = 0.022), but not LV structural parameters. Specific deficits in the cognitive domains of executive functioning and visuo-constructional abilities were also independently predicted by diastolic dysfunction (P < 0.05). Mild cognitive impairment is prevalent in patients with subclinical chronic heart disease at high-risk of CHF. Independent associations with LV diastolic dysfunction suggest a link between cardiac and cognitive functioning beyond shared risk factors.


The Interplay between the Endocannabinoid System, Epilepsy and Cannabinoids.
Epilepsy is a neurological disorder that affects approximately 50 million people worldwide. There is currently no definitive epilepsy cure. However, in recent years, medicinal cannabis has been successfully trialed as an effective treatment for managing epileptic symptoms, but whose mechanisms of action are largely unknown. Lately, there has been a focus on neuroinflammation as an important factor in the pathology of many epileptic disorders. In this literature review, we consider the links that have been identified between epilepsy, neuroinflammation, the endocannabinoid system (ECS), and how cannabinoids may be potent alternatives to more conventional pharmacological therapies. We review the research that demonstrates how the ECS can contribute to neuroinflammation, and could therefore be modulated by cannabinoids to potentially reduce the incidence and severity of seizures. In particular, the cannabinoid cannabidiol has been reported to have anti-convulsant and anti-inflammatory properties, and it shows promise for epilepsy treatment. There are a multitude of signaling pathways that involve endocannabinoids, eicosanoids, and associated receptors by which cannabinoids could potentially exert their therapeutic effects. Further research is needed to better characterize these pathways, and consequently improve the application and regulation of medicinal cannabis.


Subjective Needs and Thoughts for the Treatment of Patients with Inflammatory Bowel Disease: Applying Q Methodology.
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract that requires lifetime management. Many studies have attempted to establish questionnaires and/or parameters to assess the quality of care for IBD patients. However, no study to date has investigated patients using the Q-methodology, which is subjective and has been studied systematically, to identify and categorize their opinions and subjective thinking about their disease and treatment. We have therefore aimed here to conduct a preliminary study of the Q-methodology to investigate the subjective thinking of IBD patients in Korea. Q-methodology, a method of analyzing the subjectivity of questionnaire items, was examined in this study. Inputs from 50 IBD patients were classified into 34 normalized statements using a 9-point scale with a normal distribution. The collected data were analyzed using the QUANL PC program. Using the Q-methodology, IBD patients were classified into type I, II, III, and IV treatment needs: medical staff-dependent, relationship-oriented, information-driven, and social awareness, respectively. The subjective needs of IBD patients and their thoughts about the treatment can be classified into four types. Our findings suggest that we can establish a systematic strategy for personalized care according to patient type.


Myofascial trigger points.
Painful conditions of the musculoskeletal system, including myofascial pain syndrome, constitute some of the most important chronic problems encountered in a clinical practice. A myofascial trigger points is a hyperirritable spot, usually within a taut band of skeletal muscle, which is painful on compression and can give rise to characteristic referred pain, motor dysfunction, and autonomic phenomena. Trigger points may be relieved through noninvasive measures, such as spray and stretch, transcutaneous electrical stimulation, physical therapy, and massage. Invasive treatments for myofascial trigger points include injections with local anesthetics, corticosteroids, or botulism toxin or dry needling. The etiology, pathophysiology, and treatment of myofascial trigger points are addressed in this article.


Sharing hard labour: developing a standard template for data summaries in guideline development.
A key objective of the Guidelines International Network (GIN) is to reduce duplication of effort. To address this objective, a working group was established to define a minimum dataset for inclusion in all evidence tables. A literature review was conducted to identify existing evidence tables, and GIN member organisations were asked to provide the tables they use. The results were used to develop a minimum dataset (template) for studies addressing intervention questions. The template was pilot-tested by a group of guideline developers and reviewed at GIN conferences. RESULTS The literature search yielded 65 articles. These dealt with reporting standards and trial quality (eg, CONSORT statement) rather than which data should be extracted from studies. However, the checklist items given were considered useful. Nineteen GIN members provided evidence tables; 17 tables were used for analysis. The number of items included in the tables ranged from 8 to 19, with several items common to all tables. Within individual items, the level of detail varied widely. The draught template included a majority of items relating to objective data. Pilot testing revealed that the median time to read a paper and complete the template was 2 h for a randomised controlled trial and 2½ h for a non-randomised, controlled intervention study. The median rating for both relevance and clarity of items was high. CONCLUSION The template listing the items needed to summarise an interventional study is now available for large-scale testing by all organisations.


Insulin resistance and impaired baroreflex gain during pregnancy.
Pregnancy decreases baroreflex gain, but the underlying mechanism is unclear. Insulin resistance, which has been associated with reduced transport of insulin into the brain, is a consistent feature of many conditions exhibiting impaired baroreflex gain, including pregnancy. Therefore, using conscious pregnant and nonpregnant rabbits, we tested the novel hypothesis that the pregnancy-induced impairment in baroreflex gain is due to insulin resistance and reduced brain insulin. Baroreflex gain was determined by quantifying changes in heart rate in response to stepwise steady-state changes in arterial pressure, secondary to infusion of nitroprusside and phenylephrine. We found that insulin sensitivity and baroreflex gain were strongly correlated in nonpregnant and term pregnant rabbits (r2 = 0.59). The decrease in insulin sensitivity and in baroreflex gain exhibited similar time courses throughout pregnancy, reaching significantly lower levels at 3 wk of gestation and remaining reduced at 4 wk (term is 31 days). Treatment of rabbits with the insulin-sensitizing drug rosiglitazone during pregnancy almost completely normalized baroreflex gain. Finally, pregnancy significantly lowered cerebrospinal fluid insulin concentrations. These data identify insulin resistance as a mechanism underlying pregnancy-induced baroreflex impairment and suggest, for the first time in any condition, that decreased brain insulin concentrations may be the link between reductions in peripheral insulin sensitivity and baroreflex gain.


An increased fluid intake leads to feet swelling in 100-km ultra-marathoners - an observational field study.
An association between fluid intake and changes in volumes of the upper and lower limb has been described in 100-km ultra-marathoners. The purpose of the present study was (i) to investigate the association between fluid intake and a potential development of peripheral oedemas leading to an increase of the feet volume in 100-km ultra-marathoners and (ii) to evaluate a possible association between the changes in plasma sodium concentration ([Na+]) and changes in feet volume. In seventy-six 100-km ultra-marathoners, body mass, plasma [Na+], haematocrit and urine specific gravity were determined pre- and post-race. Fluid intake and the changes of volume of the feet were measured where the changes of volume of the feet were estimated using plethysmography. Body mass decreased by 1.8 kg (2.4%) (p < 0.0001); plasma [Na+] increased by 1.2% (p < 0.0001). Haematocrit decreased (p = 0.0005). The volume of the feet remained unchanged (p > 0.05). Plasma volume and urine specific gravity increased (p < 0.0001). Fluid intake was positively related to the change in the volume of the feet (r = 0.54, p < 0.0001) and negatively to post-race plasma [Na+] (r = -0.28, p = 0.0142). Running speed was negatively related to both fluid intake (r = -0.33, p = 0.0036) and the change in feet volume (r = -0.23, p = 0.0236). The change in the volume of the feet was negatively related to the change in plasma [Na+] (r = -0.26, p = 0.0227). The change in body mass was negatively related to both post-race plasma [Na+] (r = -0.28, p = 0.0129) and running speed (r = -0.34, p = 0.0028). An increase in feet volume after a 100-km ultra-marathon was due to an increased fluid intake.


Cardiovascular disease and risk factors in patients with psoriasis and psoriatic arthritis.
Patients with psoriasis and psoriatic arthritis (PsA) have an increased incidence of cardiovascular disease (CVD) and cardiovascular risk factors such as smoking, hypertension, and metabolic syndrome compared to the normal population. Patients with psoriasis and PsA may also have increased risk from nonconventional risk factors such as raised levels of homocysteine and excessive alcohol consumption. We conducted a comprehensive review of the literature on CVD and all cardiovascular risk factors in patients with psoriasis and PsA. All studies identified from a Medline (www.ncbi.nlm.nih.gov) search pertaining to CVD, individual risk factors in psoriasis, and PsA were included. Studies included a healthy reference population, were published between 1975 and 2009, and were written in English. Our search yielded 14 studies that documented rates of CVD in patients with psoriasis and PsA compared to controls. Substantial evidence points to elevated risk of CVD in patients with psoriasis and PsA. It remains difficult to conclude if risk factors are caused by psoriasis or share a common pathogenesis. Physicians treating patients with psoriasis and PsA must be aware of all potential cardiovascular risk factors in their patients.


Perceptions of hyperbaric oxygen therapy among podiatrists practicing in high-risk foot clinics.
Foot ulceration is a devastating and costly consequence of diabetes. Hyperbaric oxygen therapy is recognised as an adjunctive therapy to treat diabetes-related foot ulceration, yet uptake is low. Semi-structured interviews were conducted with 16 podiatrists who manage patients with foot ulcers related to diabetes to explore their perceptions of, and the barriers/facilitators to, referral for hyperbaric oxygen. Podiatrists cited logistical issues such as location of facilities as well as poor communication pathways, lack of delegation and lack of follow up when patients presented for hyperbaric treatment. In general, podiatrists had an understanding of the premise of hyperbaric oxygen therapy and evidence to support its use but could only provide very limited citations of key papers and guidelines to support their position. Podiatrists stated that they felt a patient was lost from their care when referred for hyperbaric oxygen and that aftercare might not be adequate. Improved referral and delegation pathways for patients presenting for hyperbaric oxygen, as well as the provision of easily accessible evidence to support this therapy, could help to increase podiatrists' confidence in deciding whether or not to recommend their patients for hyperbaric oxygen therapy.


Ursolic acid derivatives for pharmaceutical use: a patent review (2012-2016).
Ursolic acid (UA), belongs to a group of pentacyclic triterpenoids and is known to possess some very interesting biological properties. Protocols have been developed in order to synthesize bioactive UA analogs which have resulted in numerous ursolic acid analogs being synthesized during the period 2012-2016. Ursolic acid and its analogues can be employed to treat various cancers, inflammatory diseases, diabetes, Parkinson's disease, Alzheimer's disease, hepatitis B, hepatitis C and AIDS to mention but a few. Areas covered: This review covers patents on therapeutic activities of ursolic acid (UA) and its synthetic derivatives published during the four year period 2012-2016. A discussion about structure-activity relationships (SAR) of these analogs is also included. Expert opinion: Ursolic acid and its synthetic derivatives demonstrated excellent anticancer, antidiabetic, antiarrhythmic, anti-hyperlipidemic, antimicrobial, anti-hypercholesterolemic, and anti-cardiovascular properties. Additionally, various ursolic acid analogues have been synthesized through modification at positions C2-OH, C3-OH and C17-CO2H. It is noteworthy that the C-17 amide and amino analogs of UA possessed better anticancer activity compared to the parent compound (UA). Most importantly, UA has the potential to conjugate with other anticancer drugs or be transformed into its halo derivatives since this will greatly facilitate scientists to get lead compounds in cancer drug discovery.


PCSK9 Variants, Low-Density Lipoprotein Cholesterol, and Neurocognitive Impairment: Reasons for Geographic and Racial Differences in Stroke Study (REGARDS).
Despite concerns about adverse neurocognitive events raised by prior trials, pharmacological PCSK9 (proprotein convertase subtilisin/kexin type-9) inhibition was not associated with neurocognitive effects in a recent phase 3 randomized trial. PCSK9 loss-of-function (LOF) variants that result in lifelong exposure to lower levels of low-density lipoprotein cholesterol can provide information on the potential long-term effects of lower low-density lipoprotein cholesterol on neurocognitive impairment and decline. We investigated the association between PCSK9 LOF variants and neurocognitive impairment and decline among black REGARDS study (Reasons for Geographic and Racial Differences in Stroke) participants with (n=241) and without (n=10 454) C697X or Y142X LOF variants. Neurocognitive tests included the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery (Word List Learning, World List Delayed Recall, Semantic Animal Fluency) and Six-Item Screener (SIS) assessments, administered longitudinally during follow-up. Neurocognitive impairment was defined as a score ≥1.5 SD below age, sex, and education-based stratum-specific means on 2 or 3 CERAD assessments or, separately, a score <5 on any SIS assessment at baseline or during follow-up. Neurocognitive decline was assessed using standardized continuous scores on individual neurocognitive tests. The mean sample age was 64 years (SD, 9), 62% were women, and the prevalence of neurocognitive impairment at any assessment was 6.3% by CERAD and 15.4% by SIS definitions. Adjusted odds ratios for neurocognitive impairment for participants with versus without PCSK9 LOF variants were 1.11 (95% confidence interval [CI], 0.58-2.13) using the CERAD battery and 0.89 (95% CI, 0.61-1.30) using the SIS assessment. Standardized average differences in individual neurocognitive assessment scores over the 5.6-year (range, 0.1-9.1) study period ranged between 0.07 (95% CI, -0.06 to 0.20) and -0.07 (95% CI, -0.18 to 0.05) among participants with versus without PCSK9 LOF variants. Patterns of neurocognitive decline were similar between participants with and without PCSK9 LOF variants (all P>0.10). Odds ratios for neurocognitive impairment per 20 mg/dL low-density lipoprotein cholesterol decrements were 1.02 (95% CI, 0.96-1.08) and 0.99 (95% CI, 0.95-1.02) for the CERAD and SIS definitions of impairment, respectively. These results suggest that lifelong exposure to low PCSK9 levels and cumulative exposure to lower levels of low-density lipoprotein cholesterol are not associated with neurocognitive effects in blacks.