Pathways into treatment for eating disorders: A quantitative examination of treatment barriers and treatment attitudes.
Most individuals with eating disorders do not receive treatment for their eating disorder. Closing this "treatment gap" requires a quantitative examination of individuals' attitudes towards accessing various types of treatment and of individuals' perceived barriers to seeking treatment. Thus, we recruited a sample of 425 individuals with either diagnosed or undiagnosed eating disorders and asked them to complete a survey assessing treatment attitudes, treatment barriers, and eating disorder symptom severity. Undiagnosed individuals reported more positive attitudes towards novel Internet- and smartphone-delivered treatments, and stronger barriers relating to eating disorders mental health literacy, than diagnosed individuals. Nevertheless, both diagnosed and undiagnosed individuals were broadly more positive towards established (i.e., non-novel) treatments than novel treatments. The strongest barriers to seeking treatment were fear of losing control, fear of change, and finding motivation to change. Eating disorder symptoms were positively associated with the strength of most treatment barriers. Results were broadly unchanged after adjusting for individuals' past experiences of treatment. In conclusion, the development and dissemination of novel treatments and the provision of eating disorders mental health literacy may offer promising potential pathways into treatment for individuals with undiagnosed eating disorders. Nevertheless, researchers must pay attention to and improve, individuals' attitudes towards accessing these novel treatments. The positive correlations of symptom severity with treatment barrier strength highlights the importance of early intervention for individuals with eating disorders. Finally, the fear of losing control may be a uniquely salient treatment barrier for individuals with eating disorders that requires greater attention in future research on eating disorder treatment seeking.


Meta-analysis of selective serotonin reuptake inhibitors in patients with depression and coronary heart disease.
The occurrence of depression in patients with coronary heart disease (CHD) substantially increases the likelihood of a poorer cardiovascular prognosis. Although antidepressants are generally effective in decreasing depression, their use in patients with CHD is controversial. We carried out a meta-analysis to evaluate the health effects of selective serotonin reuptake inhibitors (SSRIs) versus placebo or no antidepressants in patients with CHD and depression. Observational studies and randomized controlled trials (RCTs) were searched in MEDLINE, EMBASE, PsycINFO, Cochrane Controlled Clinical Trial Register and other trial registries, and references of relevant articles. Primary outcomes were readmission for CHD (including myocardial infarction, unstable angina, and stroke) and all-cause mortality; the secondary outcome was severity of depression symptoms. Seven articles on 6 RCTs involving 2,461 participants were included. One study incorrectly randomized participants, and another was a reanalysis of RCT data. These were considered observational and analyzed separately. When only properly randomized trials were considered (n = 734 patients), patients on SSRIs showed no significant differences in mortality (risk ratio 0.39, 95% confidence interval 0.08 to 2.01) or CHD readmission rates (0.74, 0.44 to 1.23) compared to controls. Conversely, when all studies were included, SSRI use was associated with a significant decrease in CHD readmission (0.63, 0.46 to 0.86) and mortality rates (0.56, 0.35 to 0.88). A significantly greater improvement in depression symptoms was always apparent in patients on SSRIs with all selected indicators. In conclusion, in patients with CHD and depression, SSRI medication decreases depression symptoms and may improve CHD prognosis.


Incidence and management of complications after neoadjuvant chemotherapy followed by extrapleural pneumonectomy for malignant pleural mesothelioma.
To investigate the incidence and management of postoperative complications after neoadjuvant chemotherapy followed by extrapleural pneumonectomy for malignant pleural mesothelioma. Patients with histologically proven mesothelioma of clinical stages T1-3, N0-2, M0 and considered to be completely resectable received neoadjuvant chemotherapy (cisplatin+gemcitabine or cisplatin+pemetrexed) followed by extrapleural pneumonectomy and postoperative radiotherapy. The incidence and management of postoperative complications in general and of bronchopleural fistula and postpneumonectomy-empyema in particular were analyzed. Univariate analysis was performed to identify prognostic factors [sex, age, side of operation, weight loss, smoking, chemotherapy, EORTC-score (European Organization for Research and Treatment of Cancer-classification) and duration of operation]. Between 1st May 1999 and 15th August 2005, 63 patients underwent complete extrapleural pneumonectomy after neoadjuvant chemotherapy. Postoperative complications were observed in 39 cases (62%) and 2 patients died within 30 days (3.2%). Postpneumonectomy-empyema occurred in 15.8% of the patients (n=10), six with a bronchopleural fistula on the right side. All empyemas were treated successfully. Five patients developed chylothorax (7.9%) and four patients had complications due to a patch failure: cardiac herniation (n=2), restriction of cardiac output (n=1) or gastric herniation (n=1). Patients with higher EORTC-score presented significantly more postoperative complications (p=0.03). A longer duration of surgery tended to be associated with a higher incidence of postoperative complications, especially of empyemas. Extrapleural pneumonectomy after neoadjuvant chemotherapy can be performed with mortality rates comparable to standard pneumonectomies. Complications are frequent but can be successfully managed; the EORTC-score seems to be a predictor for postoperative complications.


Regulation of the mucosal immune response.
Infectious diseases continue to exact an extensive toll on populations living closest to the equatorial regions of the globe. A substantial proportion of these infections gain access to the host via the mucosal tissues. Thus, the development of new vaccines that enhance mucosal immunity is considered to be of paramount importance in order to prevent or limit the impact of these infections. Mucosal immune responses must discriminate between commensal flora within the lumen and potential pathogens. These responses are highly adapted to induce protection without excessive amounts of inflammation. The balances that regulate mucosal immune and inflammatory responses have to be understood if effective mucosal immunity is to be induced through local immunization. This review will summarize some of the unique properties of mucosal immune responses and focus on recent advances that have significantly influenced our understanding of the regulation of immune and inflammatory responses following infection.


Exploiting AR-Regulated Drug Transport to Induce Sensitivity to the Survivin Inhibitor YM155.
Androgen receptor (AR) signaling is fundamental to prostate cancer and is the dominant therapeutic target in metastatic disease. However, stringent androgen deprivation therapy regimens decrease quality of life and have been largely unsuccessful in curtailing mortality. Recent clinical and preclinical studies have taken advantage of the dichotomous ability of AR signaling to elicit growth-suppressive and differentiating effects by administering hyperphysiologic levels of testosterone. In this study, high-throughput drug screening identified a potent synergy between high-androgen therapy and YM155, a transcriptional inhibitor of survivin (BIRC5). This interaction was mediated by the direct transcriptional upregulation of the YM155 transporter SLC35F2 by the AR. Androgen-mediated YM155-induced cell death was completely blocked by the overexpression of multidrug resistance transporter ABCB1. SLC35F2 expression was significantly correlated with intratumor androgen levels in four distinct patient-derived xenograft models, and with AR activity score in a large gene expression dataset of castration-resistant metastases. A subset of tumors had significantly elevated SLC35F2 expression and, therefore, may identify patients who are highly responsive to YM155 treatment. The combination of androgen therapy with YM155 represents a novel drug synergy, and SLC35F2 may serve as a clinical biomarker of response to YM155.


Synthesis and evaluation of the functional oligonucleotides-PEG conjugates.
We have previously demonstrated that the phenylsulfide and phenylsulfoxide derivatives of 2-amino-6-vinylpurine exhibit efficient cross-linking with high selectivity towards cytidine through synchronous activation within duplex. In this study, we synthesized their conjugates with PEG for possible application to in vitro as well as in vivo antisense agents. Thus, the ODN (2) with the antisense sequence toward luciferase was synthesized, having the 2-amino-6-vinylpurine nucleoside analog at the reactive site for targeting C and the amino linker at the 3' terminal. The vinyl group was transformed to the corresponding substituted phenylsulfide derivatives (3), and then the amino group of the 3' end was converted to the thiopropionyl group (4). The thiol nucleophile of 4 was reacted to the acid-responsive PEG2 in good isolated yields (55-62%).


Mesenchymal stem cells as a treatment for peripheral arterial disease: current status and potential impact of type II diabetes on their therapeutic efficacy.
Mesenchymal stem cells (MSCs), due to their paracrine, transdifferentiation, and immunosuppressive effects, hold great promise as a therapy for peripheral arterial disease. Diabetes is an important risk factor for peripheral arterial disease; however, little is known of how type II diabetes affects the therapeutic function of MSCs. This review summarizes the current status of preclinical and clinical studies that have been performed to determine the efficacy of MSCs in the treatment of peripheral arterial disease. We also present findings from our laboratory regarding the impact of type II diabetes on the therapeutic efficacy of MSCs neovascularization after the induction of hindlimb ischemia. In our studies, we documented that experimental type II diabetes in db/db mice impaired MSCs' therapeutic function by favoring their differentiation towards adipocytes, while limiting their differentiation towards endothelial cells. Moreover, type II diabetes impaired the capacity of MSCs to promote neovascularization in the ischemic hindlimb. We further showed that these impairments of MSC function and multipotency were secondary to hyperinsulinemia-induced, Nox4-dependent oxidant stress in db/db MSCs. Should human MSCs display similar oxidant stress-induced impairment of function, these findings might permit greater leverage of the potential of MSC transplantation, particularly in the setting of diabetes or other cardiovascular risk factors, as well as provide a therapeutic approach by reversing the oxidant stress of MSCs prior to transplantation.


Triggering ubiquitination of a CDK inhibitor at origins of DNA replication.
To ensure proper timing of the G1-S transition in the cell cycle, the cyclin E-Cdk2 complex, which is responsible for the initiation of DNA replication, is restrained by the p21(Cip1)/p27(Kip1)/p57(Kip2) family of CDK (cyclin-dependent kinase) inhibitors in humans and by the related p27(Xic1) protein in Xenopus. Activation of cyclin E-Cdk2 is linked to the ubiquitination of human p27(Kip1) or Xenopus p27(Xic1) by SCF (for Skp1-Cullin-F-box protein) ubiquitin ligases. For human p27(Kip1), ubiquitination requires direct phosphorylation by cyclin E-Cdk2. We show here that Xic1 ubiquitination does not require phosphorylation by cyclin E-Cdk2, but it does require nuclear accumulation of the Xic1-cyclin E-Cdk2 complex and recruitment of this complex to chromatin by the origin-recognition complex together with Cdc6 replication preinitiation factors; it also requires an activation step necessitating cyclin E-Cdk2-kinase and SCF ubiquitin-ligase activity, and additional factors associated with mini-chromosome maintenance proteins, including the inactivation of geminin. Components of the SCF ubiquitin-ligase complex, including Skp1 and Cul1, are also recruited to chromatin through cyclin E-Cdk2 and the preinitiation complex. Thus, activation of the cyclin E-Cdk2 kinase and ubiquitin-dependent destruction of its inhibitor are spatially constrained to the site of a properly assembled preinitiation complex.


First translational 'Think Tank' on cerebrovascular disease, cognitive impairment and dementia.
As the human population continues to age, an increasing number of people will exhibit significant deficits in cognitive function and dementia. It is now recognized that cerebrovascular, metabolic and neurodegenerative diseases all play major roles in the evolution of cognitive impairment and dementia. Thus with our more recent recognition of these relationships and our need to understand and more positively impact on this world health problem, "The Leo and Anne Albert Charitable Trust" (Gene Pranzo, Trustee with significant support from Susan Brogan, Meeting Planner) provided generous support for this inaugural international workshop that was held from April 13-16, 2015 at the beautiful Ritz Carlton Golf Resort in North Naples, Florida. Researchers from SUNY Downstate Medical Center, Brooklyn, NY organized the event by selecting the present group of translationally inclined preclinical, clinical and population scientists focused on cerebrovascular disease (CVD) risk and its progression to vascular cognitive impairment (VCI) and dementia. Participants at the workshop addressed important issues related to aging, cognition and dementia by: (1) sharing new data, information and perspectives that intersect vascular, metabolic and neurodegenerative diseases, (2) discussing gaps in translating population risk, clinical and preclinical information to the progression of cognitive loss, and (3) debating new approaches and methods to fill these gaps that can translate into future therapeutic interventions. Participants agreed on topics for group discussion prior to the meeting and focused on specific translational goals that included promoting better understanding of dementia mechanisms, the identification of potential therapeutic targets for intervention, and discussed/debated the potential utility of diagnostic/prognostic markers. Below summarizes the new data-presentations, concepts, novel directions and specific discussion topics addressed by this international translational team at our "First Leo and Anne Albert Charitable Trust 'Think Tank' VCI workshop".


The differential contributions of visual imagery constructs on autobiographical thinking.
There is a growing theoretical and empirical consensus on the central role of visual imagery in autobiographical memory. However, findings from studies that explore how individual differences in visual imagery are reflected on autobiographical thinking do not present a coherent story. One reason for the mixed findings was suggested to be the treatment of visual imagery as an undifferentiated construct while evidence shows that there is more than one type of visual imagery. The present study investigates the relative contributions of different imagery constructs; namely, object and spatial imagery, on autobiographical memory processes. Additionally, it explores whether a similar relation extends to imagining the future. The results indicate that while object imagery was significantly correlated with several phenomenological characteristics, such as the level of sensory and perceptual details for past events - but not for future events - spatial imagery predicted the level of episodic specificity for both past and future events. We interpret these findings as object imagery being recruited in tasks of autobiographical memory that employ reflective processes while spatial imagery is engaged during direct retrieval of event details. Implications for the role of visual imagery in autobiographical thinking processes are discussed.


Limb muscle dysfunction in COPD: effects of muscle wasting and exercise training.
Lower-limb muscle weakness has often been reported in COPD, and contributes to exercise intolerance. Controversial information is available regarding upper-limb muscle adaptations and the influence of muscle wasting on muscle weakness. We investigated leg and arm muscle function in 59 stable COPD patients (GOLD stage III) with preserved fat-free mass (FFM) and in 28 patients with reduced FFM relative to age- and sex-matched healthy control subjects and studied the effects of 8 wk of whole-body exercise training. FFM was measured with bioelectrical impedance analysis. Isokinetic quadriceps (F-leg) and biceps strength (F-arm), as well as quadriceps (E-leg) and biceps endurance (E-arm) were determined with a Biodex dynamometer. Exercise training consisted of cycle ergometry, treadmill walking, weight training, and gymnastics during 5 d.wk. F-leg (76.2 +/- 3.6 vs 118.2 +/- 6.3 N.m, P < 0.001) and F-arm (25.6 +/- 1.3 vs 38.1 +/- 2.1 N.m, P < 0.001) were significantly and similarly reduced in the COPD patient group compared with controls. Also, E-leg (-2.13 +/- 0.12 vs -1.61 +/- 0.11, P < 0.01), but not E-arm (-2.72 +/- 0.11 and -2.47 +/- 0.13 NS), was decreased in patients. F-leg (62.4 +/- 4.3 vs 82.8 +/- 4.7 N.m, P < 0.01), but not F-arm or muscle endurance, was reduced in FFM-depleted compared with non-FFM-depleted patients. Whereas after training F-leg and E-leg significantly increased by 20% in the whole COPD group, biceps muscle function remained unchanged. Lower- and upper-limb muscle dysfunction was observed in COPD patients, irrespective of the presence of FFM depletion. Generalized muscle weakness suggests systemic muscular involvement, although the preserved arm endurance and the poor response of arm performance to exercise training is indicative for intrinsic differences in muscular adaptations between leg and arm muscles.


High-resolution broadband spectroscopy with a resonator-based phase modulator.
A method for significant enhancement of the spectral resolution of a Fabry-Perot resonator in transmission and absorption measurements is proposed. In the method, a laser with ultrashort pulses is used as the optical source. A dispersive element is placed in front of the Fabry-Perot resonator and a phase modulator is incorporated into the resonator. The spectrum of the laser pulse transmitted through the system is approximately periodic with ultranarrow peaks. The sample transmission spectrum is measured by scanning the output pulse spectrum. It is demonstrated, in numerical simulations, that for realistic parameters of the phase modulator, the finesse of the Fabry-Perot resonator is increased from 72 to 1900 and a resolution of 1 MHz is achieved. A method for increasing the spectral range of measurements with scanning the periodic spectra is also proposed. The method is based on the use of a waveguide array of Mach-Zehnder interferometers or a single discretely tunable interferometer. The measurement of the sample transmission spectrum within 33 free spectral ranges of the resonator is numerically demonstrated. The spectral range of the measurement can be increased up to 10 THz resulting in the equivalent finesse of the system of 10(7) for a 100 fs laser pulse.


Interactions of calmodulin and alpha-actinin with the NR1 subunit modulate Ca2+-dependent inactivation of NMDA receptors.
Glutamate receptors are associated with various regulatory and cytoskeletal proteins. However, an understanding of the functional significance of these interactions is still rudimentary. Studies in hippocampal neurons suggest that such interactions may be involved in calcium-induced reduction in the open probability of NMDA receptors (inactivation). Thus we examined the role of the intracellular domains of the NR1 subunit and two of its binding partners, calmodulin and alpha-actinin, on this process using NR1/NR2A heteromers expressed in human embryonic kidney (HEK) 293 cells. The presence of the first 30 residues of the intracellular C terminus of NR1 (C0 domain) was required for inactivation. Mutations in the last five residues of C0 reduced inactivation and produced parallel shifts in binding of alpha-actinin and Ca2+/calmodulin to the respective C0-derived peptides. Although calmodulin reduced channel activity in excised patches, calmodulin inhibitors did not block inactivation in whole-cell recording, suggesting that inactivation in the intact cell is more complex than binding of calmodulin to C0. Overexpression of putative Ca2+-insensitive, but not Ca2+-sensitive, forms of alpha-actinin reduced inactivation, an effect that was overcome by inclusion of calmodulin in the whole-cell pipette. The C0 domain also directly affects channel gating because NR1 subunits with truncated C0 domains that lacked calmodulin or alpha-actinin binding sites had a low open probability. We propose that inactivation can occur after C0 dissociates from alpha-actinin by two distinct but converging calcium-dependent processes: competitive displacement of alpha-actinin by calmodulin and reduction in the affinity of alpha-actinin for C0 after binding of calcium to alpha-actinin.


The anti-inflammatory and antioxidant effects of acute consumption of pigmented rice in humans.
The pathogenesis of lifestyle diseases has been significantly correlated to high levels of oxidative stress and pro-inflammation. The antioxidant and anti-inflammatory properties of polyphenols in coloured rice varieties could have potential to neutralize oxidative stress and modulate inflammatory responses. A cross-over design, randomised, dietary intervention human clinical trial was conducted on a pre-screened healthy population (n = 24) investigating the antioxidant and anti-inflammatory potential of pigmented rice (purple, red and brown) varieties. Post baseline blood samples collection volunteers consumed a serve of cooked pigmented rice. Blood samples were collected at 30-minutes, 1, 2 and 4-hours post rice consumption. A one-week wash-out period between each supplementation bout (rice variety) was conducted. Blood and biochemical parameters were analysed on baseline blood samples. Antioxidant activity, malondialdehyde (MDA) and a pro-inflammatory cytokine panel were analysed on the blood samples collected. Post purple rice consumption, antioxidant activity increased (p < 0.0001) by 70.5% and maintained elevated for all time points. The red rice variety Yunlu29, significantly (p < 0.005) reduced MDA levels by 9.2% at the 30-minute time point. Purple rice demonstrated a significant (p < 0.05) decrease by 4.0% at the 30-minute time point only. Purple rice significantly decreased TNF-α levels at the 1-hour (p < 0.05) and 4-hour (p < 0.005) time points by 21.9% and 25.4% respectively. IL-6 concentrations were significantly reduced at 1 and 2-hour post Purple (p < 0.05; 11.7%) and Yunlu29 (red) (p < 0.01; 14.1%) consumption respectively. The brown rice variety did not affect any parameters tested. The outcomes of this study, highlight that polyphenols found in pigmented rice may play a key role in targeting specific oxidative stress and inflammatory therapeutic pathways. Pigmented rice varieties may serve as a potential functional food in reducing risk factors associated with lifestyle diseases.


Total liquid ventilation provides superior respiratory support to conventional mechanical ventilation in a large animal model of severe respiratory failure.
Total liquid ventilation (TLV) has the potential to provide respiratory support superior to conventional mechanical ventilation (CMV) in the acute respiratory distress syndrome (ARDS). However, laboratory studies are limited to trials in small animals for no longer than 4 hours. The objective of this study was to compare TLV and CMV in a large animal model of ARDS for 24 hours. Ten sheep weighing 53 ± 4 (SD) kg were anesthetized and ventilated with 100% oxygen. Oleic acid was injected into the pulmonary circulation until PaO2:FiO2 ≤ 60 mm Hg, followed by transition to a protective CMV protocol (n = 5) or TLV (n = 5) for 24 hours. Pathophysiology was recorded, and the lungs were harvested for histological analysis. Animals treated with CMV became progressively hypoxic and hypercarbic despite maximum ventilatory support. Sheep treated with TLV maintained normal blood gases with statistically greater PO2 (p < 10(-9)) and lower PCO2 (p < 10(-3)) than the CMV group. Survival at 24 hours in the TLV and CMV groups were 100% and 40%, respectively (p < 0.05). Thus, TLV provided gas exchange superior to CMV in this laboratory model of severe ARDS.


Adolescents with cancer: how can we meet their specific needs in developing countries?
Cancer occurring in adolescents (10 to 19 years) is more than twice as common as cancer in children but has received less attention in South Africa. In the process of becoming adults, adolescents undergo major physical, psychological, and social changes. They manifest specific behaviors and have special emotional needs. Malignant disease and its treatment have the potential to disrupt seriously the processes of adolescence, whereas the emotional instability and the risk-prone behavior characteristic to this age may jeopardize the success of the treatment. A further disruption in the management of these patients, in South Africa, is the need to refer children over the age of 13 to the adult medicine service. Research done worldwide on transferring of adolescents with cancer and other chronic diseases to adult health care underscores the need for a structured and individualized transition. Whilst, in some developed countries, adolescent cancer units already function for years, the extent of the problem has not yet been evaluated in most developing countries, where cancer registers do not even exist. A few simple measures might improve substantially the outcome of cancer in adolescents in the developing world.


Upstream use of small-molecule glycoprotein iib/iiia inhibitors in patients with non-ST-segment elevation acute coronary syndromes: a systematic overview of randomized clinical trials.
The use of upstream small-molecule glycoprotein (GP) IIb/IIIa inhibitors in non-ST-segment elevation acute coronary syndromes (NSTE ACS) has been studied in multiple randomized clinical trials. We systematically reviewed the effect of upstream GP IIb/IIIa inhibitor use in NSTE ACS as reported in published clinical trials. Randomized clinical trials of upstream small-molecule GP IIb/IIIa inhibitors in NSTE ACS were identified through a PubMed and EMBASE search and were included if they contained 30-day outcome data. Odds ratios were generated from the published data and pooled by means of random effects modeling. The primary outcome measures were 30-day death and 30-day death or myocardial infarction. Primary safety measures were major bleeding and transfusion during the index hospitalization. Twelve clinical trials were included, evaluating tirofiban, eptifibatide, and lamifiban. Of these, 7 evaluated upstream GP IIb/IIIa inhibitors versus placebo (n=24 031) and 5 evaluated a strategy of upstream GP IIb/IIIa inhibitors versus upstream placebo with later provisional use at the time of percutaneous coronary intervention (n=19 643). Overall, upstream GP IIb/IIIa inhibitor use was associated with an 11% reduction in 30-day death/myocardial infarction (odds ratio [OR], 0.89; 95% confidence interval [CI], 0.83 to 0.95) but no significant mortality effect (OR, 0.93; 95% CI, 0.83 to 1.05). The risk of major bleeding was 23% higher in patients treated with upstream GP IIb/IIIa inhibitors (OR, 1.23; 95% CI, 1.02 to 1.48). Results were similar when only trials comparing upstream GP IIb/IIIa inhibitors versus placebo were considered: 30-day death/myocardial infarction (OR, 0.88; 95% CI, 0.81 to 0.95); 30-day death (OR, 0.89; 95% CI, 0.76 to 1.03); and major bleeding (OR, 1.17; 95% CI, 0.88 to 1.54). Upstream versus selective use at percutaneous coronary intervention trended toward lower 30-day death/myocardial infarction (OR, 0.91; 95% CI, 0.82 to 1.01) but had no effect on mortality (OR, 1.00; 95% CI, 0.81 to 1.23) and increased major bleeding risk by 34% (OR, 1.34; 95% CI, 1.10 to 1.63). In NSTE ACS, treatment with upstream small-molecule GP IIb/IIIa inhibitors provides a significant but modest ischemic benefit when compared with initial placebo. Compared with delayed, selective use at percutaneous coronary intervention, early upstream use is associated with a trend toward fewer ischemic events. However, these modest benefits are associated with an increased risk of bleeding.


Chronic placental ischemia alters amniotic fluid milieu and results in impaired glucose tolerance, insulin resistance and hyperleptinemia in young rats.
Although small size at birth is associated with hypertension and associated co-morbidities such as insulin resistance and type II diabetes mellitus, many of the animal models employed to simulate this phenomenon do not closely mimic the ontogeny of growth restriction observed clinically. While intrauterine growth restriction (IUGR) is often detected near mid-pregnancy in women and persists until term, most rodent models of IUGR employ ligation of uterine arteries for a brief period during late gestation (days 19-21 of pregnancy). We hypothesized that IUGR associated with chronic reduction in uteroplacental perfusion (RUPP) and placental ischemia during the third trimester of pregnancy in the rat alters the amniotic fluid (AF) environment and results in hypertensive offspring presenting with metabolic abnormalities such as glucose intolerance and insulin resistance. Insulin-like growth factor-1 (IGF-1), IGF-2, Na(+) concentration and oxidative stress in the AF were increased, while K(+) concentration was decreased in the RUPP compared with normal pregnant (NP) fetuses. RUPP-offspring (RUPP-O) were smaller (6.1 +/- 0.2 versus 6.7 +/- 0.2 g; P < 0.05) at birth compared with NP-offspring (NP-O) groups. At nine weeks of age, mean arterial pressure (121 +/- 3 versus 107 +/- 5 mmHg; P < 0.05), fasting insulin (0.71 +/- 0.014 versus 0.30 +/- 0.08 ng/mL; P < 0.05), glucose (4.4 +/- 0.2 versus 3.1 +/- 0.3 mmol/L; P < 0.05), leptin (3.8 +/- 0.5 versus 2.3 +/- 0.3 ng/mL; P < 0.05) and the homeostasis model assessment of insulin resistance index was greater (2.9 +/- 0.6 versus 1.0 +/- 0.3; P < 0.05) in the RUPP-O compared with the NP-O rats. These data indicate that chronic placental ischemia results in numerous alterations to the fetal environment that contributes to the development of impaired glucose metabolism, insulin resistance and hyperleptinemia in young offspring.


Bond strength of dental adhesive systems irradiated with ionizing radiation.
The aim of the present paper was to determine the effect of different types of ionizing radiation on the bond strength of three different dentin adhesive systems. One hundred twenty specimens of 60 human teeth (protocol number: 032/2007) sectioned mesiodistally were divided into 3 groups according to the adhesives systems used: SB (Adper Single Bond Plus), CB (Clearfil SE Bond) and AP (Adper Prompt Self-Etch). The adhesives were applied on dentin and photo-activated using LED (Lec 1000, MMoptics, 1000 mW/cm2). Customized elastomer molds (0.5 mm thickness) with three orifices of 1.2 mm diameter were placed onto the bonding areas and filled with composite resin (Filtek Z-250), which was photo-activated for 20 s. Each group was subdivided into 4 subgroups for application of the different types of ionizing radiation: ultraviolet radiation (UV), diagnostic x-ray radiation (DX), therapeutic x-ray radiation (TX) and without irradiation (control group, CG). Microshear tests were carried out (Instron, model 4411), and afterwards the modes of failure were evaluated by optical and scanning electron microscope and classified using 5 scores: adhesive failure, mixed failures with 3 significance levels, and cohesive failure. The results of the shear bond strength test were submitted to ANOVA with Tukey's test and Dunnett's test, and the data from the failure pattern evaluation were analyzed with the Mann Whitney test (p = 0.05). No change in bond strength of CB and AP was observed after application of the different radiation types, only SB showed increase in bond strength after UV (p = 0.0267) irradiation. The UV also changed the failure patterns of SB (p = 0.0001). The radio-induced changes did not cause degradation of the restorations, which means that they can be exposed to these types of ionizing radiation without weakening the bond strength.


Superoxide dismutase activity and expression in human venous and arterial bypass graft vessels.
Venous bypass grafts are more prone to accelerated atherosclerosis than arterial grafts, which is partly related to increased oxidative stress and diminished nitric oxide bioavailability. In veins superoxide production is dependent primarily on nox2 NAD(P)H oxidase expression, while in arteries nox4 appears to play an important role. This may in part explain differences in susceptibility to graft failure. Net levels of oxidative stress are however determined in parallel by the production as well as by degradation of free radicals (eg. by superoxide dismutases, catalases, thioredoxins etc). The differences in superoxide dismutase (SOD) expression and activity in human bypass conduit vessels remain unclear. Accordingly, we aimed to compare SOD activity and protein levels as well as its functional effects on superoxide production in segments of human internal mammary arteries (IMA) and saphenous veins (HSV) from patients undergoing bypass graft surgery (n=24). SOD activity was assessed by inhibition of pyrogallol autoxidation, Cu-Zn SOD and Mn SOD protein levels were studied by immunoblotting. Basal superoxide release was detected by lucigenin (5 microM) enhanced chemiluminescence. Total SOD activity did not differ significantly between HSV and IMA. Similarly, no difference was observed in SOD activity in the presence of KCN (Mn-SOD). Human bypass conduit vessels show amounts of Cu-Zn SOD or Mn-SOD protein levels. In both HSV and IMA segments superoxide production was more than doubled in the presence of SOD inhibitor-DETC. These studies suggest that the differences in oxidative stress between human arteries and veins are unlikely to be caused by SOD activity. However SOD plays and important role in amelioration of oxidative stress in both types of vessels.


Risk Factors for Gambling Problems: An Analysis by Gender.
Differences in problem gambling rates between males and females suggest that associated risk factors vary by gender. Previous combined analyses of male and female gambling may have obscured these distinctions. This study aimed to develop separate risk factor models for gambling problems for males and for females, and identify gender-based similarities and differences. It analysed data from the largest prevalence study in Victoria Australia (N = 15,000). Analyses determined factors differentiating non-problem from at-risk gamblers separately for women and men, then compared genders using interaction terms. Separate multivariate analyses determined significant results when controlling for all others. Variables included demographics, gambling behaviour, gambling motivations, money management, and mental and physical health. Significant predictors of at-risk status amongst female gamblers included: 18-24 years old, not speaking English at home, living in a group household, unemployed or not in the workforce, gambling on private betting, electronic gaming machines (EGMs), scratch tickets or bingo, and gambling for reasons other than social reasons, to win money or for general entertainment. For males, risk factors included: 18-24 years old, not speaking English at home, low education, living in a group household, unemployed or not in the workforce, gambling on EGMs, table games, races, sports or lotteries, and gambling for reasons other than social reasons, to win money or for general entertainment. High risk groups requiring appropriate interventions comprise young adults, especially males; middle-aged female EGM gamblers; non-English speaking populations; frequent EGM, table games, race and sports gamblers; and gamblers motivated by escape.


Fragmented life courses: the changing profile of Britain's ethnic populations.
This article describes the potential of the Longitudinal Study to analyse different ethnic groups by broad period of entry. This is illustrated with the use of one variable (childlessness), but could be the basis for further analytical work on other variables. Each group has a unique demographic profile, which is largely explained by its migration history. Migration influences important life course transitions. Differences between more established residents (present in 1981 and 1991) and less established residents (present in 1991 only) imply that generalisations for the entire ethnic group or future generations should not be made.


Animated pose templates for modeling and detecting human actions.
This paper presents animated pose templates (APTs) for detecting short-term, long-term, and contextual actions from cluttered scenes in videos. Each pose template consists of two components: 1) a shape template with deformable parts represented in an And-node whose appearances are represented by the Histogram of Oriented Gradient (HOG) features, and 2) a motion template specifying the motion of the parts by the Histogram of Optical-Flows (HOF) features. A shape template may have more than one motion template represented by an Or-node. Therefore, each action is defined as a mixture (Or-node) of pose templates in an And-Or tree structure. While this pose template is suitable for detecting short-term action snippets in two to five frames, we extend it in two ways: 1) For long-term actions, we animate the pose templates by adding temporal constraints in a Hidden Markov Model (HMM), and 2) for contextual actions, we treat contextual objects as additional parts of the pose templates and add constraints that encode spatial correlations between parts. To train the model, we manually annotate part locations on several keyframes of each video and cluster them into pose templates using EM. This leaves the unknown parameters for our learning algorithm in two groups: 1) latent variables for the unannotated frames including pose-IDs and part locations, 2) model parameters shared by all training samples such as weights for HOG and HOF features, canonical part locations of each pose, coefficients penalizing pose-transition and part-deformation. To learn these parameters, we introduce a semi-supervised structural SVM algorithm that iterates between two steps: 1) learning (updating) model parameters using labeled data by solving a structural SVM optimization, and 2) imputing missing variables (i.e., detecting actions on unlabeled frames) with parameters learned from the previous step and progressively accepting high-score frames as newly labeled examples. This algorithm belongs to a family of optimization methods known as the Concave-Convex Procedure (CCCP) that converge to a local optimal solution. The inference algorithm consists of two components: 1) Detecting top candidates for the pose templates, and 2) computing the sequence of pose templates. Both are done by dynamic programming or, more precisely, beam search. In experiments, we demonstrate that this method is capable of discovering salient poses of actions as well as interactions with contextual objects. We test our method on several public action data sets and a challenging outdoor contextual action data set collected by ourselves. The results show that our model achieves comparable or better performance compared to state-of-the-art methods.


Source of cannabinoids: what is available, what is used, and where does it come from?
Cannabis sativa L. is an ancient medicinal plant wherefrom over 120 cannabinoids are extracted. In the past two decades, there has been increasing interest in the therapeutic potential of cannabis-based treatments for neurological disorders such as epilepsy, and there is now evidence for the medical use of cannabis and its effectiveness for a wide range of diseases. Cannabinoid treatments for pain and spasticity in patients with multiple sclerosis (Nabiximols) have been approved in several countries. Cannabidiol (CBD), in contrast to tetra-hydro-cannabidiol (THC), is not a controlled substance in the European Union, and over the years there has been increasing use of CBD-enriched extracts and pure CBD for seizure disorders, particularly in children. No analytical controls are mandatory for CBD-based products and a pronounced variability in CBD concentrations in commercialized CBD oil preparations has been identified. Randomized controlled trials of plant-derived CBD for treatment of Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) have provided evidence of anti-seizure effects, and in June 2018, CBD was approved by the Food and Drug Administration as an add-on antiepileptic drug for patients two years of age and older with LGS or DS. Medical cannabis, with various ratios of CBD and THC and in different galenic preparations, is licensed in many European countries for several indications, and in July 2019, the European Medicines Agency also granted marketing authorisation for CBD in association with clobazam, for the treatment of seizures associated with LGS or DS. The purpose of this article is to review the availability of cannabis-based products and cannabinoid-based medicines, together with current regulations regarding indications in Europe (as of July 2019). The lack of approval by the central agencies, as well as social and political influences, have led to significant variation in usage between countries.


Quorum sensing by farnesol revisited.
Quorum sensing, a form of molecular communication in microbial communities, is relatively well studied in bacterial species, but poorly understood in fungi. Farnesol, a quorum sensing molecule secreted by the opportunistic human pathogenic fungus Candida albicans, was the first quorum sensing molecule described in a eukaryotic organism. However, despite considerable research efforts and advances in recent years, the mechanisms behind its action remain largely elusive. Only recently, we showed that deletion of the C. albicans gene EED1 (eed1Δ), which is essential for hyphal maintenance, resulted in both increased farnesol production and hypersensitivity to farnesol, providing a link between farnesol signaling and elongated hyphal growth. This finding raised several questions concerning farnesol signaling. In this short review we use the unique phenotype of the eed1Δ mutant to summarize current hypotheses and to speculate on possible mechanisms of quorum sensing in C. albicans and its implication in fungus-host interaction, by drawing comparisons to comparatively well-studied quorum sensing systems in bacteria.


[Neutropenia in a patient treated with clozapine in combination with other psychotropic drugs].
Clozapine is an atypical antipsychotic known for its efficacy in refractory schizophrenia. However, according to different epidemiological studies clozapine can induce neutropenia in less than 3% of patients and may represent a major problem for the management of treatment-resistant patients not responding to conventional or other atypical antipsychotics. Recently, a few case of neutropenia have been reported following the addition of other medications to clozapine, notably paroxetine, risperidone, trimethoprim-sulfamethoxazole and erythromycin. In our report we present the case of Mr A., a 40-year-old Caucasian patient with a 20-year history of paranoid schizophrenia. After numerous trials with conventional antipsychotics, partial remission of psychotic symptoms was obtained with clozapine. Over the past eight years during his treatment with clozapine, the patient presented 2 episodes of neutropenia. The first episode came five years after starting clozapine and was attributed to the addition 6 weeks earlier of haloperidol (2 mg/day) to clozapine (250 mg/day) and divalproex (1,500 mg/day). Recently, one week after the addition of risperidone (2 mg/day) to clozapine (550 mg/day), leukocytes count dropped from 12 100/mm(3) to 5 700/mm(3) and neutrophils from 7 400/mm(3) to 900/mm(3). The patient was also taking haloperidol (4 mg/day), methotrimeprazine (35 mg/day), procyclidine (5 mg/day) and valproic acid (1,500 mg/day). Twelve days after discontinuation of risperidone, leukocytes and neutrophils count increased to 11,100/mm(3) and 6,300/mm(3) respectively while the treatment with clozapine was continued. The first eighteen weeks of treatment represent the period where the risk of neutropenia is the highest. In our patient neutropenia occurred 5 and 7 years after starting clozapine. It is proposed that the two neutropenic episode were precipitated by adding respectively haloperidol and risperidone to clozapine. Also, divalproex can potentially cause a decrease in white blood cell count and may have contributed to the two neutropenic episode. It is suggested that drug interactions may be responsible for neutropenia in clozapine treated patients and that clozapine should not necessarily be discontinued in the presence of neutropenia. Also we propose that hematological surveillance should be done on a weekly basis for 4 to 6 weeks following the addition of psychotropic drugs known for their potential to cause neutropenia when associated with clozapine. Therefore polypharmacy may contribute to cause neutropenia in clozapine treated patients and that discontinuation of an antipsychotic should be done before introducing another one.


Interaction of multi-functional silver nanoparticles with living cells.
Silver nanoparticles (AgNPs) are widely used in household products and in medicine due to their antibacterial and to wound healing properties. In recent years, there is also an effort for their use in biomedical imaging and photothermal therapy. The primary reason behind the effort for their utility in biomedicine and therapy is their unique plasmonic properties and easy surface chemistry for a variety of functionalizations. In this study, AgNPs modified with glucose, lactose, oligonucleotides and combinations of these ligands are investigated for their cytotoxicity and cellular uptake in living non-cancer (L929) and cancer (A549) cells. It is found that the chemical nature of the ligand strongly influences the toxicity and cellular uptake into the model cells. While the lactose-and glucose-modified AgNPs enter the L929 cells at about the same rate, a significant increase in the rate of lactose-modified AgNPs into the A549 cells is observed. The binding of oligonucleotides along with the carbohydrate on the AgNP surfaces influences the differential uptake rate pattern into the cells. The cytotoxicity study with the modified AgNPs reveals that only naked AgNPs influence the viability of the A549 cells. The findings of this study may provide the key to developing effective applications in medicine such as cancer therapy.


Photographic optical systems with nonrotational aspheric surfaces.
Sections of nonrotational aspheric surfaces can be useful in a variety of optical situations. In several examples, image-forming objectives, as for photographic or electronic camera products, are described in which suitably located asymmetric pairs of refractive surfaces are devised, such that relative rotation about a displaced axis of one with respect to the other can be used to produce a focusing effect that is satisfactory for imaging purposes over reasonable fields of view and for practicable apertures and achromatic corrections. Taylor expansions about assignable reference points in any given surface of a sequence, together with suitable coordinate systems, can be employed to relate performance to shape parameters.


Prognostic Significance of Long-term HbA1c Variability for All-Cause Mortality in the ACCORD Trial.
The association between high glycemic variability and all-cause mortality has been widely investigated in epidemiological studies but rarely validated in glucose-lowering clinical trials. We aimed to identify the prognostic significance of visit-to-visit HbA1c variability in treated patients in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial population. We studied the risk of all-cause mortality in relation to long-term visit-to-visit HbA1c variability, expressed as coefficient of variation (CV), variability independent of the mean (VIM), and average real variability (ARV), from the 8th month to the transition from intensive to standard glycemic therapy. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratio (HR) and 95% CI. Compared with the standard therapy group (n = 4,728), the intensive therapy group (n = 4,755) had significantly lower mean HbA1c (6.6% [49 mmol/mol] vs. 7.7% [61 mmol/mol], P < 0.0001) and lower CV, VIM, and ARV (P < 0.0001). In multivariate adjusted analysis, all three HbA1c variability indices were significantly associated with total mortality in all patients as well as in the standard- and intensive-therapy groups analyzed separately. The hazard ratios for a 1-SD increase in HbA1c variability indices for all-cause mortality were 1.19 and 1.23 in intensive and standard therapy, respectively. Cross-tabulation analysis showed the third tertile of HbA1c mean and VIM had significantly higher all-cause mortality (HR 2.05; 95% CI 1.17-3.61; P < 0.01) only in the intensive-therapy group. Long-term visit-to-visit HbA1c variability was a strong predictor of all-cause mortality. HbA1c VIM combined with HbA1c mean conferred an increased risk for all-cause mortality in the intensive-therapy group.


From dynamic self-assembly to networked chemical systems.
Although dynamic self-assembly, DySA, is a relatively new area of research, the past decade has brought numerous demonstrations of how various types of components - on scales from (macro)molecular to macroscopic - can be arranged into ordered structures thriving in non-equilibrium, steady states. At the same time, none of these dynamic assemblies has so far proven practically relevant, prompting questions about the field's prospects and ultimate objectives. The main thesis of this Review is that formation of dynamic assemblies cannot be an end in itself - instead, we should think more ambitiously of using such assemblies as control elements (reconfigurable catalysts, nanomachines, etc.) of larger, networked systems directing sequences of chemical reactions or assembly tasks. Such networked systems would be inspired by biology but intended to operate in environments and conditions incompatible with living matter (e.g., in organic solvents, elevated temperatures, etc.). To realize this vision, we need to start considering not only the interactions mediating dynamic self-assembly of individual components, but also how components of different types could coexist and communicate within larger, multicomponent ensembles. Along these lines, the review starts with the discussion of the conceptual foundations of self-assembly in equilibrium and non-equilibrium regimes. It discusses key examples of interactions and phenomena that can provide the basis for various DySA modalities (e.g., those driven by light, magnetic fields, flows, etc.). It then focuses on the recent examples where organization of components in steady states is coupled to other processes taking place in the system (catalysis, formation of dynamic supramolecular materials, control of chirality, etc.). With these examples of functional DySA, we then look forward and consider conditions that must be fulfilled to allow components of multiple types to coexist, function, and communicate with one another within the networked DySA systems of the future. As the closing examples show, such systems are already appearing heralding new opportunities - and, to be sure, new challenges - for DySA research.


Investigation of a pulsed molecular nitrogen laser at low temperature.
Accurate wavelength measurements in the molecular nitrogen pulsed laser have been made. Four new ir laser bands were discovered. In addition, about two hundred new stimulated emission lines belonging to the first and second positive systems were obtained and identified as to rotational quantum number. An analysis of the possible pumping mechanisms in accordance with experimental results is given.


Disentangling size effects and spectral inhomogeneity in carbon nanodots by ultrafast dynamical hole-burning.
Carbon nanodots (CDs) are a novel family of nanomaterials exhibiting unique optical properties. In particular, their bright and tunable fluorescence redefines the paradigm of carbon as a "black" material and is considered very appealing for many applications. While the field keeps growing, understanding CDs fundamental properties and relating them to their variable structures becomes more and more critical. Two crucial problems concern the effect of size on the electronic structure of CDs, and to what extent their optical properties are influenced by structural disorder. Furthermore, it remains largely unclear whether traditional concepts borrowed from the photo-physics of semiconductor quantum dots can be applied to any type of CDs. We used femtosecond optical hole burning to address the excited-state properties of a family of CDs with the specific structure of β-C3N4. The experiments provide compelling evidence of the dramatic effects of structural heterogeneity on the optical spectra, and reveal the remarkably simple pattern of the electronic transitions of these CDs, normally obscured by disorder. Moreover, the data conclusively clarify the different effects of the nanometric size and of the disordered surface structure on the fluorescence tunability, ruling out for these CDs any quantum confinement effect comparable to semiconductor quantum dots.


Reclassification of Eubacterium hallii as Anaerobutyricum hallii gen. nov., comb. nov., and description of Anaerobutyricum soehngenii sp. nov., a butyrate and propionate-producing bacterium from infant faeces.
A bacterial strain designated L2-7T, phylogenetically related to Eubacterium hallii DSM 3353T, was previously isolated from infant faeces. The complete genome of strain L2-7T contains eight copies of the 16S rRNA gene with only 98.0-98.5 % similarity to the 16S rRNA gene of the previously described type strain E. hallii. The next closest validly described species is Anaerostipes hadrus DSM 3319T (90.7 % 16S rRNA gene similarity). A polyphasic taxonomic approach showed strain L2-7T to be a novel species, related to type strain E. hallii DSM 3353T. The experimentally observed DNA-DNA hybridization value between strain L2-7T and E. hallii DSM 3353T was 26.25 %, close to that calculated from the genomes (34.3 %). The G+C content of the chromosomal DNA of strain L2-7T was 38.6 mol%. The major fatty acids were C16 : 0, C16 : 1cis9 and a component with summed feature 10 (C18 : 1c11/t9/t6c). Strain L2-7T had higher amounts of C16 : 0 (30.6 %) compared to E. hallii DSM 3353T (19.5 %) and its membrane contained phosphatidylglycerol and phosphatidylethanolamine, which were not detected in E. hallii DSM 3353T. Furthermore, 16S rRNA gene phylogenetic analysis advocates that E. hallii DSM 3353T is misclassified, and its reclassification as a member of the family Lachnospiraceae is necessary. Using a polyphasic approach, we propose that E. hallii (=DSM 3353T=ATCC 27751T) be reclassified as the type strain of a novel genus Anaerobutyricum sp. nov., comb. nov. and we propose that strain L2-7T should be classified as a novel species, Anaerobutyricum soehngenii sp. nov. The type strain is L2-7T (=DSM 17630T=KCTC 15707T).


Mapping the onset and progression of atrophy in familial frontotemporal lobar degeneration.
Frontotemporal lobar degeneration (FTLD) may be inherited as an autosomal dominant disease. Studying patients "at risk" for developing FTLD can provide insights into the earliest onset and evolution of the disease. We carried out approximately annual clinical, MRI, and neuropsychological assessments on an asymptomatic 51 year old "at risk" family member from a family with FTLD associated with ubiquitin-positive and tau-negative inclusion bodies. We used non-linear (fluid) registration of serial MRI to determine areas undergoing significant regional atrophy at different stages of the disease. Over the first 26 months of the study, the patient remained asymptomatic, but subsequently developed progressive speech production difficulties, and latterly severe orofacial dyspraxia, dyscalculia, frontal executive impairment, and limb dyspraxia. Regional atrophy was present prior to the onset of symptoms, and was initially centred on the left dorsolateral prefrontal cortex and the left middle frontal gyrus. Latterly, there was increasing asymmetric left frontal and parietal atrophy. Imaging revealed excess and increasing global atrophy throughout the study. Neuropsychological evaluation revealed mild intellectual impairment prior to the onset of these clinical symptoms; frontal executive and left parietal impairment subsequently emerged, culminating in widespread cognitive impairment. Fluid registered MRI allowed the emerging atrophy patterns to be delineated. We have demonstrated the onset and progressive pattern of in vivo atrophy in familial FTLD using fluid registered MRI and correlated this with the clinical features. Fluid registered MRI may be a useful technique in assessing patterns of focal atrophy in vivo and demonstrating the progression of degenerative diseases.


The impact of structural relaxation on spin polarization and magnetization reversal of individual nano structures studied by spin-polarized scanning tunneling microscopy.
The application of low temperature spin-polarized scanning tunneling microscopy and spectroscopy in magnetic fields for the quantitative characterization of spin polarization, magnetization reversal and magnetic anisotropy of individual nano structures is reviewed. We find that structural relaxation, spin polarization and magnetic anisotropy vary on the nm scale near the border of a bilayer Co island on Cu(1 1 1). This relaxation is lifted by perimetric decoration with Fe. We discuss the role of spatial variations of the spin-dependent electronic properties within and at the edge of a single nano structure for its magnetic properties.


QTc interval prolongation by fexofenadine in healthy human volunteers and its correlation with plasma levels of fexofenadine: A demonstration of anticlockwise hysteresis.
The study was designed to establish relationship between the plasma concentration and QTc interval prolonging effect of fexofenadine and demonstrate the phenomenon of anticlockwise hysteresis. Six subjects were given fexofenadine 60 mg tablet orally under stable conditions, and their drug concentrations were measured at regular intervals. At predetermined time, their ECGs were recorded. Data were analyzed and plotted graphically. Randomized parallel design, single group study conducted at clinical research organization of Ahmadabad. In all subjects time taken for maximum plasma concentration of fexofenadine (T(max)) was around 3 h and the value of average maximum plasma concentration was 460.63 ng/mL, the effect of fexofenadine on the heart (measured as QTc interval prolongation) was maximum (E(max)) after 6 h and average QTc interval was 469.75 ms. Thus, the time to maximum concentration of fexofenadine did not match with the maximum effect on the heart as measured by QTc interval. The relationship between the drug concentration and drug effect on the heart are at two different time scales. It can be understood by two-compartment model of pharmacokinetics, and this retardation or lagging of an effect behind the concentration is known as hysteresis. The increase of QTc was not beyond 500 ms and not sustained, demonstrating overall cardiac safety of fexofenadine.


Identifying metabolic pathways for production of extracellular polymeric substances by the diatom Fragilariopsis cylindrus inhabiting sea ice.
Diatoms are significant primary producers in sea ice, an ephemeral habitat with steep vertical gradients of temperature and salinity characterizing the ice matrix environment. To cope with the variable and challenging conditions, sea ice diatoms produce polysaccharide-rich extracellular polymeric substances (EPS) that play important roles in adhesion, cell protection, ligand binding and as organic carbon sources. Significant differences in EPS concentrations and chemical composition corresponding to temperature and salinity gradients were present in sea ice from the Weddell Sea and Eastern Antarctic regions of the Southern Ocean. To reconstruct the first metabolic pathway for EPS production in diatoms, we exposed Fragilariopsis cylindrus, a key bi-polar diatom species, to simulated sea ice formation. Transcriptome profiling under varying conditions of EPS production identified a significant number of genes and divergent alleles. Their complex differential expression patterns under simulated sea ice formation was aligned with physiological and biochemical properties of the cells, and with field measurements of sea ice EPS characteristics. Thus, the molecular complexity of the EPS pathway suggests metabolic plasticity in F. cylindrus is required to cope with the challenging conditions of the highly variable and extreme sea ice habitat.


Characterization of the phosphocholine-substituted oligosaccharide in lipopolysaccharides of type b Haemophilus influenzae.
Haemophilus influenzae expresses heterogeneous populations of short-chain lipopolysaccharide (LPS) which exhibit extensive antigenic diversity among multiple oligosaccharide epitopes. These LPS oligosaccharide epitopes can carry phosphocholine (PCho) substituents, the expression of which is subject to high frequency phase variation mediated by genes in the lic1 genetic locus. The location and site of attachment of PCho substituents were determined by structural analysis of LPS from two type b H. influenzae strains, Eagan and RM7004. The lic2 locus is involved in phase variation of oligosaccharide expression. LPS obtained from the parent strains, from mutants generated by insertion of antibiotic resistance cassettes in the lic2 genetic locus, and from phase-variants showing high levels of PCho expression was characterized by electrospray ionization-mass spectrometry (ESI-MS) and 1H NMR spectroscopy of derived O-deacylated samples. ESI-MS of O-deacylated LPS from wild-type strains revealed mixtures of related glycoform structures differing in the number of hexose residues. Analysis of LPS from PCho-expressing phase-variants revealed similar mixtures of glycoforms, each containing a single PCho substituent. O-Deacylated LPS preparations from the lic2 mutants were much less complex than their respective parent strains, consisting only of Hex3 and/or Hex2 glycoforms, were examined in detail by high-field NMR techniques. It was found that the LPS samples contain the phosphoethanolamine (PEtn) substituted inner-core element, L-alpha-D-Hepp-(1-->2)-[PEtn-->6]-L-alpha-D-Hepp-(1--> 3)-L-alpha-D-He pp-(1-->5)-alpha-Kdo in which the major glycoforms carry a beta-D-Glcp or beta-D-Glcp-(1-->4)-beta-D-Glcp at the O-4 position of the 3-substituted heptose (HepI) and a beta-D-Galp at the O-2 position of the terminal heptose (HepIII). LPS from the lic2 mutants of both type b strains were found to carry PCho groups at the O-6 position of the terminal beta-D-Galp residue attached to HepIII. In the parent strains, the central heptose (HepII) of the LPS inner-core element is also substituted by hexose containing oligosaccharides. The expression of the galabiose epitope in LPS of H. influenzae type b strains has previously been linked to genes comprising the lic2 locus. The present study provides definitive evidence for the role of lic2 genes in initiating chain extension from HepII. From the analysis of core oligosaccharide samples, LPS from the lic2 mutant strain of RM7004 was also found to carry O-acetyl substituents. Mono-, di-, and tri-O-acetylated LPS oligosaccharides were identified. The major O-acetylated glycoforms were found to be substituted at the O-3 position of HepIII. A di-O-acetylated species was characterized which was also substituted at the O-6 postion of the terminal beta-D-Glc in the Hex3 glycoform. This is the first report pointing to the occurrence of O-acetyl groups in the inner-core region of H. influenzae LPS. We have previously shown that in H. influenzae strain Rd, a capsule-deficient type d strain, PCho groups are expressed in a different molecular environment, being attached at the O-6 position of a beta-D-Glcp, which is in turn attached to HepI.


VRK1 signaling pathway in the context of the proliferation phenotype in head and neck squamous cell carcinoma.
The vaccinia-related kinase (VRK) proteins are a new family with three members in the human kinome. The VRK1 protein phosphorylates several transcription factors and has been postulated to be involved in regulation of cell proliferation. In normal squamous epithelium, VRK1 is expressed in the proliferation area. Because VRK1 can stabilize p53, the expression of the VRK1 protein was analyzed in the context of the p53 pathway and the proliferation phenotype in a series of 73 head and neck squamous cell carcinomas. VRK1 protein level positively correlated with p53 response proteins, particularly hdm2 and p21. The VRK1 protein also correlated positively with several proteins associated with proliferation, such as cyclin-dependent kinase 2 (CDK2), CDK6, cdc2, cyclins B1 and A, topoisomerase II, survivin, and Ki67. The level of VRK1 protein behaves like a proliferation marker in this series of head and neck squamous cell carcinomas. To identify a possible regulatory role for VRK1 and because it regulates gene transcription, the promoters of two genes were studied, CDK2 and SURVIVIN, whose proteins correlated positively with VRK1. VRK1 increases the activity of both the CDK2 and SURVIVIN gene promoters. The expression of VRK1 was analyzed in the context of regulators of the G1-S transition. VRK1 protein levels increase in response to E2F1 and are reduced by retinoblastoma and p16. These data suggest that VRK1 might play a role in cell cycle regulation and is likely to represent the beginning of a new control mechanism of cell cycle, particularly late in the G1-S phase.


Barriers, facilitators and preferences for the physical activity of school children. Rationale and methods of a mixed study.
Physical activity interventions in schools environment seem to have shown some effectiveness in the control of the current obesity epidemic in children. However the complexity of behaviors and the diversity of influences related to this problem suggest that we urgently need new lines of insight about how to support comprehensive population strategies of intervention. The aim of this study was to know the perceptions of the children from Cuenca, about their environmental barriers, facilitators and preferences for physical activity. We used a mixed-method design by combining two qualitative methods (analysis of individual drawings and focus groups) together with the quantitative measurement of physical activity through accelerometers, in a theoretical sample of 121 children aged 9 and 11 years of schools in the province of Cuenca, Spain. Mixed-method study is an appropriate strategy to know the perceptions of children about barriers and facilitators for physical activity, using both qualitative methods for a deeply understanding of their points of view, and quantitative methods for triangulate the discourse of participants with empirical data. We consider that this is an innovative approach that could provide knowledges for the development of more effective interventions to prevent childhood overweight.


Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity: clinical outcomes in advanced melanoma.
Programmed cell death protein 1 (PD-1) blocking monoclonal antibodies improve the overall survival of patients with advanced melanoma but the optimal duration of treatment has not been established. This academic real-world cohort study investigated the outcome of 185 advanced melanoma patients who electively discontinued anti-PD-1 therapy with pembrolizumab (N = 167) or nivolumab (N = 18) in the absence of disease progression (PD) or treatment limiting toxicity (TLT) at 14 medical centres across Europe and Australia. Median time on treatment was 12 months (range 0.7-43). The best objective tumour response at the time of treatment discontinuation was complete response (CR) in 117 (63%) patients, partial response (PR) in 44 (24%) patients and stable disease (SD) in 16 (9%) patients; 8 (4%) patients had no evaluable disease (NE). After a median follow-up of 18 months (range 0.7-48) after treatment discontinuation, 78% of patients remained free of progression. Median time to progression was 12 months (range 2-23). PD was less frequent in patients with CR (14%) compared with patients with PR (32%) and SD (50%). Six out of 19 (32%) patients who were retreated with an anti-PD-1 at the time of PD obtained a new antitumour response. In this real-world cohort of advanced melanoma patients discontinuing anti-PD-1 therapy in the absence of TLT or PD, the duration of anti-PD-1 therapy was shorter when compared with clinical trials. In patients obtaining a CR, and being treated for >6 months, the risk of relapse after treatment discontinuation was low. Patients achieving a PR or SD as best tumour response were at higher risk for progression after discontinuing therapy, and defining optimal treatment duration in such patients deserves further study. Retreatment with an anti-PD-1 at the time of progression may lead to renewed antitumour activity in some patients. NCT02673970 (https://clinicaltrials.gov/ct2/show/NCT02673970?cond=melanoma&cntry=BE&city=Jette&rank=3).


High-Level Genetic Diversity among Invasive Streptococcus pneumoniae Isolates in Turkey.
This study obtained information on the serotypes and molecular typing characteristics of Streptococcus pneumoniae strains causing invasive diseases in Turkey. Sixty-eight S. pneumoniae isolates causing invasive pneumococcal diseases were collected from different regions of Turkey from 2009 to 2011. The isolates were characterized by performing multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE), and capsular serotyping, and 25 different serotypes were identified. Serotypes 19F, 23F, 1, 14, and 7F were common and accounted for 52.9% of all the serotypes. In addition, 54 different PFGE profiles (pulsotypes) were observed. Twenty-three of the 68 (33.8%) isolates were clustered into 9 pulsotypes. MLST analysis yielded 36 sequence types, of which 12 (33.3%) were novel. A comparison of results with the global pneumococcal MLST database by performing eBURST analysis showed that our strains belonged to 20 different clonal complexes and 5 singletons. In addition, we identified 4 new alleles: 2 gdh, 1 xpt, and 1 ddl. Thus, the results of this study highlighted a high level of diversity among pneumococcal isolates. In addition, the study identified a case of possible capsular switching.


Suicidal behavior and alcohol abuse.
Suicide is an escalating public health problem, and alcohol use has consistently been implicated in the precipitation of suicidal behavior. Alcohol abuse may lead to suicidality through disinhibition, impulsiveness and impaired judgment, but it may also be used as a means to ease the distress associated with committing an act of suicide. We reviewed evidence of the relationship between alcohol use and suicide through a search of MedLine and PsychInfo electronic databases. Multiple genetically-related intermediate phenotypes might influence the relationship between alcohol and suicide. Psychiatric disorders, including psychosis, mood disorders and anxiety disorders, as well as susceptibility to stress, might increase the risk of suicidal behavior, but may also have reciprocal influences with alcohol drinking patterns. Increased suicide risk may be heralded by social withdrawal, breakdown of social bonds, and social marginalization, which are common outcomes of untreated alcohol abuse and dependence. People with alcohol dependence or depression should be screened for other psychiatric symptoms and for suicidality. Programs for suicide prevention must take into account drinking habits and should reinforce healthy behavioral patterns.


Reinventing primaquine for endemic malaria.
After sixty years of continuous use, primaquine remains the only therapy licensed for arresting transmission and relapse of malaria. The US Army developed primaquine for soldiers in a wartime crisis setting. Dosing strategies suited to that narrow population were adopted without modification or validation for the broader population of humans exposed to risk of malaria. The poor suitability of these strategies in populations exhibiting greater vulnerability to hemolytic toxicity among glucose-6-phosphate dehydrogenase deficient patients has not been addressed. Primaquine requires chemotherapeutic reinvention delivering less threatening doses by leveraging unexplored co-drug synergies.


A comprehensive two-hybrid analysis to explore the yeast protein interactome.
Protein-protein interactions play crucial roles in the execution of various biological functions. Accordingly, their comprehensive description would contribute considerably to the functional interpretation of fully sequenced genomes, which are flooded with novel genes of unpredictable functions. We previously developed a system to examine two-hybrid interactions in all possible combinations between the approximately 6,000 proteins of the budding yeast Saccharomyces cerevisiae. Here we have completed the comprehensive analysis using this system to identify 4,549 two-hybrid interactions among 3,278 proteins. Unexpectedly, these data do not largely overlap with those obtained by the other project [Uetz, P., et al. (2000) Nature (London) 403, 623-627] and hence have substantially expanded our knowledge on the protein interaction space or interactome of the yeast. Cumulative connection of these binary interactions generates a single huge network linking the vast majority of the proteins. Bioinformatics-aided selection of biologically relevant interactions highlights various intriguing subnetworks. They include, for instance, the one that had successfully foreseen the involvement of a novel protein in spindle pole body function as well as the one that may uncover a hitherto unidentified multiprotein complex potentially participating in the process of vesicular transport. Our data would thus significantly expand and improve the protein interaction map for the exploration of genome functions that eventually leads to thorough understanding of the cell as a molecular system.


Antimicrobial Usage in Animal Production: A Review of the Literature with a Focus on Low- and Middle-Income Countries.
Antimicrobial use (AMU) in animal production is a key contributor to antimicrobial resistance (AMR) worldwide. As consumption of animal protein and associated animal production is forecast to increase markedly over coming years in low- and middle-income countries (LMICs), accurate monitoring of AMU has become imperative. We summarized data from 89 scientific studies reporting AMU data in animal production published in English since 1998, identified through the 'ISI Web of Knowledge' search engine. The aims were as follows: (a) to describe methodologies and metrics used to quantify AMU; (b) to summarize qualitative (on-farm prevalence of use) and quantitative (amounts of antimicrobial active principle) data, in order to identify food animal species at the highest risk of AMU; and (c) to highlight data gaps from LMICs. Only 17/89 (19.1%) studies were conducted in LMICs. Sixty (67.3%) reported quantitative data use, with 'daily doses per animal-time' being the most common metric. AMU was greatest in chickens (138 doses/1000 animal-days [inter quartile range (IQR) 91.1⁻438.3]), followed by swine (40.2 [IQR 8.5⁻120.4]), and dairy cattle (10.0 [IQR 5.5⁻13.6]). However, per kg of meat produced, AMU was highest in swine, followed by chickens and cattle. Our review highlights a large deficit of data from LMICs, and provides a reference for comparison with further surveillance and research initiatives aiming to reduce AMU in animal production globally.


Data distribution in public veterinary service: health and safety challenges push for context-aware systems.
Today's globalised and interconnected world is characterized by intertwined and quickly evolving relationships between animals, humans and their environment and by an escalating number of accessible data for public health. The public veterinary services must exploit new modeling and decision strategies to face these changes. The organization and control of data flows have become crucial to effectively evaluate the evolution and safety concerns of a given situation in the territory. This paper discusses what is needed to develop modern strategies to optimize data distribution to the stakeholders. If traditionally the system manager and knowledge engineer have been concerned with the increase of speed of data flow and the improvement of data quality, nowadays they need to worry about data overflow as well. To avoid this risk an information system should be capable of selecting the data which need to be shown to the human operator. In this perspective, two aspects need to be distinguished: data classification vs data distribution. Data classification is the problem of organizing data depending on what they refer to and on the way they are obtained; data distribution is the problem of selecting which data is accessible to which stakeholder. Data classification can be established and implemented via ontological analysis and formal logic but we claim that a context-based selection of data should be integrated in the data distribution application. Data distribution should provide these new features: (a) the organization of situation types distinguishing at least ordinary vs extraordinary scenarios (contextualization of scenarios); (b) the possibility to focus on the data that are really important in a given scenario (data contextualization by scenarios); and (c) the classification of which data is relevant to which stakeholder (data contextualization by users). Public veterinary services, to efficaciously and efficiently manage the information needed for today's health and safety challenges, should contextualize and filter the continuous and growing flow of data by setting suitable frameworks to classify data, users' roles and possible situations.


The role of the paravertebral ganglia in human sympathetic neural discharge patterns.
The mechanisms affecting recruitment patterns of postganglionic sympathetic nerves remain unclear. The divergent and convergent preganglionic innervation patterns of postganglionic neurons and the presence of differently sized postganglionic nerves suggest that the ganglia may participate in modifying the discharge patterns of single sympathetic postganglionic neurons innervating the skeletal muscle circulation. Whether the ganglia affect the ordered behaviour of varying sized postganglionic sympathetic neurons in humans has not been studied. Trimethaphan infusion produced an ordered pattern of action potential (AP) de-recruitment whereby the firing of larger, low probability APs present at baseline was abolished first, followed by progressive decreased probability of smaller APs. Although integrated sympathetic bursts were no longer detected after several minutes of trimethaphan, firing of the smallest APs was detected. These data suggest the ganglia affect the distribution of firing probabilities exhibited by differently sized sympathetic neurons. The ganglia may contribute to sympathetic neural emission patterns involved in homeostatic regulation. Do the ganglia contribute to the ordered behaviour of postganglionic neuronal discharge within the sympathetic nervous system? To further understand the functional organization of the sympathetic nervous system we employed the microneurographic approach to record muscle sympathetic nerve activity (MSNA) and a continuous wavelet transform to study postganglionic action potential (AP) behaviour during nicotinic blockade at the ganglia (trimethaphan camsylate, 1-7 mg min-1 ) in seven females (37 ± 5 years). Trimethaphan elicited a progressive reduction in sympathetic outflow characterized by fewer integrated bursts with decaying amplitude. Underlying trimethaphan-mediated attenuations in integrated MSNA were reductions in AP incidence (186 ± 101 to 29 ± 31 AP (100 beats)-1 ) and AP content per integrated burst (7 ± 2 to 3 ± 1 APs burst-1 ) (both P < 0.01) in the final minute of detectable bursting activity in the trimethaphan condition, compared to baseline. We observed an ordered de-recruitment of larger to smaller AP clusters active at baseline (14 ± 3 to 8 ± 2 active AP clusters, P < 0.01). Following cessation of integrated bursts in the trimethaphan condition, the smallest 6 ± 2 sympathetic AP clusters persisted to fire in an asynchronous pattern (49 ± 41 AP (100 beats)-1 ) in all participants. Valsalva's manoeuvre did not increase the incidence of these persistent APs (60 ± 42 AP (100 beats)-1 , P = 0.52), or recruit any larger APs in six of seven participants (6 ± 1 total AP clusters, P = 0.30). These data suggest that the ganglia participate in the ordered recruitment of differently sized postganglionic sympathetic nerves.


Distinct cortical networks activated by auditory attention and working memory load.
Auditory attention and working memory (WM) allow for selection and maintenance of relevant sound information in our minds, respectively, thus underlying goal-directed functioning in everyday acoustic environments. It is still unclear whether these two closely coupled functions are based on a common neural circuit, or whether they involve genuinely distinct subfunctions with separate neuronal substrates. In a full factorial functional MRI (fMRI) design, we independently manipulated the levels of auditory-verbal WM load and attentional interference using modified Auditory Continuous Performance Tests. Although many frontoparietal regions were jointly activated by increases of WM load and interference, there was a double dissociation between prefrontal cortex (PFC) subareas associated selectively with either auditory attention or WM. Specifically, anterior dorsolateral PFC (DLPFC) and the right anterior insula were selectively activated by increasing WM load, whereas subregions of middle lateral PFC and inferior frontal cortex (IFC) were associated with interference only. Meanwhile, a superadditive interaction between interference and load was detected in left medial superior frontal cortex, suggesting that in this area, activations are not only overlapping, but reflect a common resource pool recruited by increased attentional and WM demands. Indices of WM-specific suppression of anterolateral non-primary auditory cortices (AC) and attention-specific suppression of primary AC were also found, possibly reflecting suppression/interruption of sound-object processing of irrelevant stimuli during continuous task performance. Our results suggest a double dissociation between auditory attention and working memory in subregions of anterior DLPFC vs. middle lateral PFC/IFC in humans, respectively, in the context of substantially overlapping circuits.


Occupational Lung Diseases among Soldiers Deployed to Iraq and Afghanistan.
Military personnel deployed to Iraq and Afghanistan, from 2004 to the present, has served in a setting of unique environmental conditions. Among these are exposures to burning trash in open air "burn pits" lit on fire with jet fuel JP-8. Depending on trash burned--water bottles, styrofoam trays, medical waste, unexploded munitions, and computers--toxins may be released such as dioxins and n-hexane and benzene. Particulate matter air pollution culminates from these fires and fumes. Additional environmental exposures entail sandstorms (Haboob, Shamal, and Sharqi) which differ in direction and relationship to rain. These wars saw the first use of improvised explosive devices (roadside phosphate bombs),as well as vehicle improvised explosive devices (car bombs), which not only potentially aerosolize metals, but also create shock waves to induce lung injury via blast overpressure. Conventional mortar rounds are also used by Al Qaeda in both Iraq and Afghanistan. Outdoor aeroallergens from date palm trees are prevalent in southern Iraq by the Tigris and Euphrates rivers, while indoor aeroallergen aspergillus predominates during the rainy season. High altitude lung disease may also compound the problem, particularly in Kandahar, Afghanistan. Clinically, soldiers may present with new-onset asthma or fixed airway obstruction. Some have constrictive bronchiolitis and vascular remodeling on open lung biopsy - despite having normal spirometry and chest xrays and CT scans of the chest. Others have been found to have titanium and other metals in the lung (rare in nature). Still others have fulminant biopsy-proven sarcoidiosis. We found DNA probe-positive Mycobacterium Avium Complex in lung from a soldier who had pneumonia, while serving near stagnant water and camels and goats outside Abu Gharib. This review highlights potential exposures, clinical syndromes, and the Denver Working Group recommendations on post-deployment health.


Fine-tuning the Predictive Model for Proximal Junctional Failure in Surgically Treated Patients With Adult Spinal Deformity.
Multicenter retrospective study. To validate and improve the predictive model for proximal junctional failure (PJF) with or without the bone mineral density (BMD) score. PJF is a serious complication of surgery for adult spinal deformity (ASD). A predictive model for PJF was recently reported that has good accuracy, but does not include BMD, a known PJF risk factor, as a variable. We included 145 surgically treated ASD patients who were older than 50 at the time of surgery and had been followed up for at least 2 years. Variables included age, sex, body mass index (BMI), fusion level, upper and lower instrumented vertebral (UIV and LIV) level, primary or revision surgery, pedicle subtraction osteotomy (PSO), Schwab-SRS type, and BMD. PJF was defined as a ≥ 20° increase from baseline (immediately postoperative) of the proximal junctional angle with concomitant deterioration of at least 1 SRS-Schwab sagittal modifier grade, or any proximal junctional kyphosis requiring revision. Decision-making trees were constructed using the C5.0 algorithm with 10 different bootstrapped models, and validated by a 7:3 data split for training and testing; 112 patients were categorized as training and 33 as testing samples. PJF incidence was 20% in the training samples. Univariate analyses showed that BMD, BMI, pelvic tilt (PT), UIV level, and LIV level were PJF risk factors. Our predictive model was 100% accurate in the testing samples with an AUC of 1.0, indicating excellent fit. The best predictors were (strongest to weakest): PT, BMD, LIV level (pelvis), UIV level (lower thoracic), PSO, global alignment, BMI, pelvic incidence minus lumbar lordosis, and age. A successful model was developed for predicting PJF that included BMD. Our model could inform physicians about patients with a high risk of developing PJF in the perioperative period. 4.


A comparative analysis of whole genome sequencing of esophageal adenocarcinoma pre- and post-chemotherapy.
The scientific community has avoided using tissue samples from patients that have been exposed to systemic chemotherapy to infer the genomic landscape of a given cancer. Esophageal adenocarcinoma is a heterogeneous, chemoresistant tumor for which the availability and size of pretreatment endoscopic samples are limiting. This study compares whole-genome sequencing data obtained from chemo-naive and chemo-treated samples. The quality of whole-genomic sequencing data is comparable across all samples regardless of chemotherapy status. Inclusion of samples collected post-chemotherapy increased the proportion of late-stage tumors. When comparing matched pre- and post-chemotherapy samples from 10 cases, the mutational signatures, copy number, and SNV mutational profiles reflect the expected heterogeneity in this disease. Analysis of SNVs in relation to allele-specific copy-number changes pinpoints the common ancestor to a point prior to chemotherapy. For cases in which pre- and post-chemotherapy samples do show substantial differences, the timing of the divergence is near-synchronous with endoreduplication. Comparison across a large prospective cohort (62 treatment-naive, 58 chemotherapy-treated samples) reveals no significant differences in the overall mutation rate, mutation signatures, specific recurrent point mutations, or copy-number events in respect to chemotherapy status. In conclusion, whole-genome sequencing of samples obtained following neoadjuvant chemotherapy is representative of the genomic landscape of esophageal adenocarcinoma. Excluding these samples reduces the material available for cataloging and introduces a bias toward the earlier stages of cancer.


Uberon, an integrative multi-species anatomy ontology.
We present Uberon, an integrated cross-species ontology consisting of over 6,500 classes representing a variety of anatomical entities, organized according to traditional anatomical classification criteria. The ontology represents structures in a species-neutral way and includes extensive associations to existing species-centric anatomical ontologies, allowing integration of model organism and human data. Uberon provides a necessary bridge between anatomical structures in different taxa for cross-species inference. It uses novel methods for representing taxonomic variation, and has proved to be essential for translational phenotype analyses. Uberon is available at http://uberon.org.


MHC class I and class II structures.
The basic structures of MHC class I and class II molecules are now well established. Over the past twelve months structural data on MHC class I molecules have provided details of the peptide binding groove for a number of alleles and have elaborated the mechanisms that allow binding of a range of peptides. Recent MHC class II structures have illustrated the mode of peptide binding both in mature complexes and in the MHC class II complex with a fragment of invariant chain (CLIP) during maturation.


Combined laser therapy for difficult dermal pigmentation: resurfacing and selective photothermolysis.
Treating pigmented lesions of the skin, especially deep dermal pigmentations, are difficult to achieve satisfactory results without complications. To treat dermal pigmentations, such as nevus of Ota and congenital nevus, the combined therapy of a resurfacing laser (CO2) and a selective photothermolytic laser (the Q-Switched Ruby Laser [QSRL]) was tried, and the results were compared with those treated with the QSRL alone. Combined laser therapy has been performed in 47 patients with nevus of Ota since 1995. The mean treatment period was 6 months and the mean number of treatment was five. Of 47 patients, 46 (98%) showed excellent results. To treat congenital nevus, combined laser therapy was used in 15 patients, and 12 (80%) showed good to excellent results. By combining resurfacing and selective lasers, the treatment period has been reduced by 2 to 3 months, and the number of treatments has been reduced two- to threefold. Furthermore, treatment of congenital nevus has become possible, which was not the case with the QSRL alone. The Er:YAG laser can be used for resurfacing instead of the CO2 laser because it causes less thermal damage and faster wound healing.


Autofocus for a multiscale gigapixel camera.
In recent studies, the advanced wide field of view architectures for image reconstruction and exploitation (AWARE) multiscale camera, which is composed of a monocentric objective lens and an array of microcameras, was developed for the realization of snapshot wide field of view and high resolution imaging. This paper describes accelerated autofocus (AF) methods for the AWARE system based on a hierarchical spatial algorithm and an iterative temporal algorithm. In the algorithms, sensor positions of each microcamera are hierarchically scanned with contrast detection to effectively search for a focusing distance. The positions are then updated iteratively for dynamic scenes using temporal information. The algorithms are theoretically analyzed and experimentally demonstrated. The developed AF methods can be used for the realization of the temporal gigapixel imaging by the AWARE system.


Low levels of pyrazinamide and ethambutol in children with tuberculosis and impact of age, nutritional status, and human immunodeficiency virus infection.
Recent pharmacokinetic studies that included children found that serum drug levels were low compared to those of adults for whom the same dosages were used. This study aimed to characterize the pharmacokinetics of pyrazinamide and ethambutol in Malawian children and to examine the impact of age, nutritional status, and human immunodeficiency virus (HIV) infection. We conducted a pharmacokinetic study of children treated for tuberculosis with thrice-weekly pyrazinamide (n = 27; mean age, 5.7 years) and of a separate group of children treated with thrice-weekly ethambutol (n = 18; mean age, 5.5 years) as portions of tablets according to national guidelines. Malnutrition and HIV infection were common in both groups. Blood samples were taken just prior to oral administration of the first dose, and subsequent samples were taken at intervals of 2, 3, 4, 7, 24, and 48 h after drug administration. Serum drug levels were low in all children for both drugs; in almost all cases, the maximum concentration of the drug in serum (Cmax) failed to reach the MIC for Mycobacterium tuberculosis. The Cmax of pyrazinamide was significantly lower in younger children (<5 years) than in older children. The Cmax of pyrazinamide was also lower for HIV-infected children and children with severe malnutrition, but these differences did not reach statistical significance. No differences were found for ethambutol in relation to age, HIV infection, or malnutrition, but the Cmax was <2 mg/liter in all cases. Studies of pharmacokinetic parameters and clinical outcomes obtained by using higher dosages of drugs for treatment of childhood tuberculosis are needed, and recommended dosages may need to be increased.


The prevalence of adverse postnatal outcomes for mother and infant in the Netherlands.
In high-income countries delivery usually takes place in a short-stay hospital setting and includes limited specific care after discharge. Perinatal system performance is therefore predominantly expressed in direct terms of delivery outcomes such as preterm birth (PTB), small for gestational age (SGA) or, in case of the mother, perineal rupture and haemorrhage. Additional postnatal complications may emerge, but their incidence is largely unknown. The Dutch obstetric system includes an 8-10 day episode of professional postnatal home maternity care. Our aim was to establish, under routine conditions, the incidence of a comprehensive set of 67 predefined complications and their predictors. A second aim was to address interaction between maternal and child complications. The study design was a prospective cohort study of all clients of one large maternity care organization receiving home maternity care in November 2014. We combined maternal background and intrapartum and postnatal characteristics with complication data, routinely recorded by home maternity care assistants. Complication prevalence rates per postnatal day were calculated. Univariate and multivariable logistic regression were used to predict the presence of postnatal complications. Complications occurred throughout the entire episode of home maternity care and prevalence was high, with 55% of all mother-baby pairs experiencing at least one complication (e.g. cracked nipples, >10% weight loss of the baby) and 5% at least one major complication (e.g. mastitis, cyanosis of the baby). Predictive ability of maternal background and intrapartum and postnatal variables on presence of complications was moderate (max. 62.9%), even when a cumulative risk score was used. The prevalence rates of maternal and neonatal postnatal complications with care as usual in high-income countries was higher than expected. Professional postnatal follow-up is to be considered in order to timely detect and manage emerging complications with minimal delay. Opportunities for risk-guided care should be investigated further. The pattern of complications in low-income countries remains to be established.