Meeting radiation dosimetry capacity requirements of population-scale exposures by geostatistical sampling.
Accurate radiation dose estimates are critical for determining eligibility for therapies by timely triaging of exposed individuals after large-scale radiation events. However, the universal assessment of a large population subjected to a nuclear spill incident or detonation is not feasible. Even with high-throughput dosimetry analysis, test volumes far exceed the capacities of first responders to measure radiation exposures directly, or to acquire and process samples for follow-on biodosimetry testing. To significantly reduce data acquisition and processing requirements for triaging of treatment-eligible exposures in population-scale radiation incidents. Physical radiation plumes modelled nuclear detonation scenarios of simulated exposures at 22 US locations. Models assumed only location of the epicenter and historical, prevailing wind directions/speeds. The spatial boundaries of graduated radiation exposures were determined by targeted, multistep geostatistical analysis of small population samples. Initially, locations proximate to these sites were randomly sampled (generally 0.1% of population). Empirical Bayesian kriging established radiation dose contour levels circumscribing these sites. Densification of each plume identified critical locations for additional sampling. After repeated kriging and densification, overlapping grids between each pair of contours of successive plumes were compared based on their diagonal Bray-Curtis distances and root-mean-square deviations, which provided criteria (<10% difference) to discontinue sampling. We modeled 30 scenarios, including 22 urban/high-density and 2 rural/low-density scenarios under various weather conditions. Multiple (3-10) rounds of sampling and kriging were required for the dosimetry maps to converge, requiring between 58 and 347 samples for different scenarios. On average, 70±10% of locations where populations are expected to receive an exposure ≥2Gy were identified. Under sub-optimal sampling conditions, the number of iterations and samples were increased, and accuracy was reduced. Geostatistical mapping limits the number of required dose assessments, the time required, and radiation exposure to first responders. Geostatistical analysis will expedite triaging of acute radiation exposure in population-scale nuclear events.


Association Between HIV Infection and the Risk of Heart Failure With Reduced Ejection Fraction and Preserved Ejection Fraction in the Antiretroviral Therapy Era: Results From the Veterans Aging Cohort Study.
With improved survival, heart failure (HF) has become a major complication for individuals with human immunodeficiency virus (HIV) infection. It is unclear if this risk extends to different types of HF in the antiretroviral therapy (ART) era. Determining whether HIV infection is associated with HF with reduced ejection fraction (HFrEF), HF with preserved ejection fraction (HFpEF), or both is critical because HF types differ with respect to underlying mechanism, treatment, and prognosis. To investigate whether HIV infection increases the risk of future HFrEF and HFpEF and to assess if this risk varies by sociodemographic and HIV-specific factors. This study evaluated 98 015 participants without baseline cardiovascular disease from the Veterans Aging Cohort Study, an observational cohort of HIV-infected veterans and uninfected veterans matched by age, sex, race/ethnicity, and clinical site, enrolled on or after April 1, 2003, and followed up through September 30, 2012. The dates of the analysis were October 2015 to November 2016. Human immunodeficiency virus infection. Outcomes included HFpEF (EF≥50%), borderline HFpEF (EF 40%-49%), HFrEF (EF<40%), and HF of unknown type (EF missing). Among 98 015 participants, the mean (SD) age at enrollment in the study was 48.3 (9.8) years, 97.0% were male, and 32.2% had HIV infection. During a median follow-up of 7.1 years, there were 2636 total HF events (34.6% were HFpEF, 15.5% were borderline HFpEF, 37.1% were HFrEF, and 12.8% were HF of unknown type). Compared with uninfected veterans, HIV-infected veterans had an increased risk of HFpEF (hazard ratio [HR], 1.21; 95% CI, 1.03-1.41), borderline HFpEF (HR, 1.37; 95% CI, 1.09-1.72), and HFrEF (HR, 1.61; 95% CI, 1.40-1.86). The risk of HFrEF was pronounced in veterans younger than 40 years at baseline (HR, 3.59; 95% CI, 1.95-6.58). Among HIV-infected veterans, time-updated HIV-1 RNA viral load of at least 500 copies/mL compared with less than 500 copies/mL was associated with an increased risk of HFrEF, and time-updated CD4 cell count less than 200 cells/mm3 compared with at least 500 cells/mm3 was associated with an increased risk of HFrEF and HFpEF. Individuals who are infected with HIV have an increased risk of HFpEF, borderline HFpEF, and HFrEF compared with uninfected individuals. The increased risk of HFrEF can manifest decades earlier than would be expected in a typical uninfected population. Future research should focus on prevention, risk stratification, and identification of the mechanisms for HFrEF and HFpEF in the HIV-infected population.


Creating social policy to support women's agency in coercive settings: A case study from Uganda.
Many emphasise the need for policies that support women's agency in highly coercive settings, and the importance of involving target women in public deliberation to inform policy design. The Ugandan Marriage and Divorce Bill seeks to strengthen women's agency in marriage, but has faced many obstacles, including objections from many women themselves in public consultations. We explore key stakeholders' accounts of the difficulties facing the Bill's progress to date, through focus groups with 24 rural and urban men and women, interviews with 14 gender champions in government, non-governmental organisations and legal sectors, and 25 relevant media and radio reports. Thematic analysis revealed an array of representations of the way the Bill's progress was shaped by the public consultation process, the nature of the Ugandan public sphere, the understanding and manipulation of concepts such as 'culture' and 'custom' in public discourse, the impact of economic inequalities on women's understandings of their gendered interests and low women's trust in the law and the political process. We discuss the complexities of involving highly marginalised women in public debates about gender issues and highlight possible implications for conceptualising agency, gender and social change as tools for gender policy and activism in extreme inequality.


Attention to movement modulates activity in sensori-motor areas, including primary motor cortex.
Attention to sensory stimulation modulates behavioural responses and cortical activity. Attention to movement can also modulate motor responses. For example, directing attention away from cued movements can increase reaction times. This study used fMRI to determine where in the motor cortex attention to movement modulates activity. Attention to movement was reduced by asking subjects to perform a concurrent distractor task (counting backwards). Sensori-motor areas showing a negative interaction between counting and movement (i.e. reduced activation in the dual task condition relative to the sum of the single task conditions) included the supplementary motor area (SMA), cingulate cortex, insula and post-central gyrus. A separate volumes-of-interest analysis revealed significant reductions in mean percent signal change in the dual task compared to the single task in a portion of the pre-central gyrus, deep in the central sulcus (thought to correspond to area 4p) and SMA. We conclude that the brain network for motor control is modulated by attention at multiple sites, including the primary motor cortex. These results are also discussed with reference to theories concerning the neural correlates of dual task performance and mental calculation and have implications for the interpretation of functional imaging studies of normal and impaired motor performance.


TNFR2 and IL-12 coactivation enables slanDCs to support NK-cell function via membrane-bound TNF-α.
Human blood NK cells exert strong cytotoxicity against transformed cells and produce different cytokines and chemokines with an important role in modulating immune responses. However, the nature of NK-cell function depends on NK-cell interaction with other immune cells. One type of immune cells that communicate with NK cells are 6-sulfo LacNAc DCs (slanDCs), which comprise a major subpopulation of proinflammatory human blood DCs. In this study, we investigated the molecular mechanisms by which slanDCs interact with NK cells. Our in vitro studies demonstrate that LPS-stimulated slanDCs enhance activation and function of NK cells essentially via membrane-bound TNF-α (mTNF-α). LPS stimulation upregulates expression of mTNF-α in slanDCs, and surface TNF receptor 2 (TNFR2) is upregulated on NK cells after coincubation with slanDCs. IL-12 secreted by slanDCs increases surface expression of TNFR2 in NK cells. TNFR2 signaling in NK cells leads to activation of NF-kB, a transcription factor for cytokines such as GM-CSF. GM-CSF provided by NK cells is responsible for enhancing IL-12 secretion in slanDCs. In conclusion, TNFR2 and IL-12 signaling, which support one another, enables slanDCs to enhance NK-cell function through mTNF-α, thereby regulating immune responses.


Influence of modification of Ti3C2 MXene with ceramic oxide and noble metal nanoparticles on its antimicrobial properties and ecotoxicity towards selected algae and higher plants.
The number of investigations regarding the application of 2D nanosheets of MXenes in different technological areas is growing rapidly. Different surface modifications of MXenes have been introduced to date in order to tailor their properties. As a result, surface-modified MXenes could be released in the environment from filtration membranes, adsorbents, or photocatalysts. On the other hand, assessment of their environmental impact is practically unexplored. In the present study, we examined how modification of the antimicrobial Ti3C2 MXene with ceramic oxide and noble metal nanoparticles affects its toxic behavior. The expanded 2D sheets of the Ti3C2 MXene phase were modified with Al2O3/Ag, SiO2/Ag, and SiO2/Pd nanoparticles using the sol-gel method and extensively characterized. The obtained 2D nanocomposite structures were characterized by antibacterial properties. The ecotoxicological assays considered green algae (Desmodesmus quadricauda) as well as two higher plants: sorghum (Sorghum saccharatum) and charlock (Sinapis alba). Our results revealed that obtained nanomaterials can cause both stimulating and inhibiting effects towards algae, and the ecotoxicity depended on the concentration and the type of modification. The study reveals the intriguing property of pristine Ti3C2 which highly stimulated green algae growth at low concentrations. It also shows that modification of pristine Ti3C2 MXene with different nanoparticles changes the ecotoxicological effects of the resulting nanocomposite 2D structures. We have also indicated nanocomposite structures that does not revealed the toxic effect on tested organisms i.e. the Ti3C2 MXene surface-modified with Al2O3/Ag was not phyto- and eco-toxic. This work helps with better understanding of the reactivity of surface-modified MXenes towards chosen organisms, giving more information concerning the potential impact of tested nanocomposites on the ecosystems.


Addiction: definition and implications.
Integration of addiction into the theory and practice of psychiatry has been hampered by the lack of a definition of addiction which is scientifically useful. A definition is proposed, with diagnostic criteria specified in a format similar to that of DSM-III-R. Essentially, addiction designates a process whereby a behavior, that can function both to produce pleasure and to provide escape from internal discomfort, is employed in a pattern characterized by (1) recurrent failure to control the behaviour (powerlessness) and (2) continuation of the behaviour despite significant negative consequences (unmanageability). Some practical and theoretical implications of this definition are then explored.


The acute effects of exercise on cigarette cravings, withdrawal symptoms, affect, and smoking behaviour: systematic review update and meta-analysis.
Smoking cessation is associated with cigarette cravings and tobacco withdrawal symptoms (TWS), and exercise appears to ameliorate many of these negative effects. A number of studies have examined the relationships between exercise, cigarette cravings, and TWS. The objectives of this study were (a) to review and update the literature examining the effects of short bouts of exercise on cigarette cravings, TWS, affect, and smoking behaviour and (b) to conduct meta-analyses of the effect of exercise on cigarette cravings. A systematic review of all studies published between January 2006 and June 2011 was conducted. Fifteen new studies were identified, 12 of which found a positive effect of exercise on cigarette cravings. The magnitude of statistically significant effect sizes for 'desire to smoke' and 'strength of desire to smoke' ranged from 0.4 to 1.98 in favour of exercise compared to passive control conditions, and peaked either during or soon after treatment. Effects were found up to 30 min post-exercise. Cigarette cravings were reduced following exercise with a wide range of intensities from isometric exercise and yoga to activity as high as 80-85 % heart rate reserve. Meta-analyses revealed weighted mean differences of -1.90 and -2.41 in 'desire to smoke' and 'strength of desire to smoke' outcomes, respectively. Measures of TWS and negative affect were reduced following light-moderate intensity exercise, but increased during vigorous exercise. Exercise can have a positive effect on cigarette cravings and TWS. However, the most effective exercise intensity to reduce cravings and the underlying mechanisms associated with this effect remain unclear.


Diet and Psychosis: A Scoping Review.
Schizophrenia spectrum disorders (SSD) represent a cluster of severe mental illnesses. Diet has been identified as a modifiable risk factor and opportunity for intervention in many physical illnesses and more recently in mental illnesses such as unipolar depression; however, no dietary guidelines exist for patients with SSD. This review sought to systematically scope the existing literature in order to identify nutritional interventions for the prevention or treatment of mental health symptoms in SSD as well as gaps and opportunities for further research. This review followed established methodological approaches for scoping reviews including an extensive a priori search strategy and duplicate screening. Because of the large volume of results, an online program (Abstrackr) was used for screening and tagging. Data were extracted based on the dietary constituents and analyzed. Of 55,330 results identified by the search, 822 studies met the criteria for inclusion. Observational evidence shows a connection between the presence of psychotic disorders and poorer quality dietary patterns, higher intake of refined carbohydrates and total fat, and lower intake or levels of fibre, ω-3 and ω-6 fatty acids, vegetables, fruit, and certain vitamins and minerals (vitamin B12 and B6, folate, vitamin C, zinc, and selenium). Evidence illustrates a role of food allergy and sensitivity as well as microbiome composition and specific phytonutrients (such as L-theanine, sulforaphane, and resveratrol). Experimental studies have demonstrated benefit using healthy diet patterns and specific vitamins and minerals (vitamin B12 and B6, folate, and zinc) and amino acids (serine, lysine, glycine, and tryptophan). Overall, these findings were consistent with many other bodies of knowledge about healthy dietary patterns. Many limitations exist related to the design of the individual studies and the ability to extrapolate the results of studies using dietary supplements to dietary interventions (food). Dietary recommendations are presented as well as recommendations for further research including more prospective observational studies and intervention studies that modify diet constituents or entire dietary patterns with statistical power to detect mental health outcomes.


Constitution of fibrin-based niche for in vitro differentiation of adipose-derived mesenchymal stem cells to keratinocytes.
Epithelialization of chronic cutaneous wound is troublesome and may require use of skin/cell substitutes. Adipose-derived mesenchymal stem cells (ADMSCs) have immense potential as autologous cell source for treating wounds; they can cross the germ layer boundary of differentiation and regenerate skin. When multipotent adult stem cells are considered for skin regeneration, lineage committed keratinocytes may be beneficial to prevent undesirable post-transplantation outcome. This study hypothesized that ADMSCs may be directed to epidermal lineage in vitro on a specifically designed biomimetic and biodegradable niche. Cells were seeded on the test niche constituted with fibrin, fibronectin, gelatin, hyaluronic acid, laminin V, platelet growth factor, and epidermal growth factor in the presence of cell-specific differentiation medium (DM). The ADMSCs grown on bare tissue culture polystyrene surface in DM is designated DM-control and those grown in basal medium (BM) is the BM-control. Lineage commitment was monitored with keratinocyte-specific markers such as cytokeratin 14, cytokeratin 5, cytokeratin 19, and integrin α6 at the transcriptional/translational level. The in vitro designed biomimetic fibrin composite matrix may have potential application as cell transplantation vehicle.


Tele-yoga for Chronic Pain: Current Status and Future Directions.
Pain is a pervasive, debilitating disorder that is resistant to long-term pharmacological interventions. Although psychological therapies such as cognitive behavior therapy demonstrate moderate efficacy, many individuals continue to have ongoing difficulties following treatment. There is a current trend to establish complementary and integrative health interventions for chronic pain, for which yoga has been found to have exciting potential. Nevertheless, an important consideration within the field is accessibility to adequate care. Telehealth can be used to provide real-time interactive video conferencing leading to increased access to health care for individuals located remotely or who otherwise have difficulty accessing services, perhaps through issues of mobility or proximity of adequate services. This article assesses the current status and feasibility of implementing tele-yoga for chronic pain. Methodological limitations and recommendations for future research are discussed.


The UL97 gene product of human cytomegalovirus is an early-late protein with a nuclear localization but is not a nucleoside kinase.
The temporal expression of the UL97 gene product during human cytomegalovirus (HCMV) infection of human foreskin fibroblasts (HFF) and subcellular localization of this protein were analyzed by using a polyclonal antiserum raised against a truncated UL97 protein of 47 kDa. The UL97 protein was detectable 16 h after infection by Western blot (immunoblot) analysis. Since only reduced UL97 expression occurred in the presence of two inhibitors of DNA replication, phosphonoacetic acid and ganciclovir, we conclude that UL97 is an early-late gene, requiring DNA replication for maximum expression. By indirect immunofluorescence, the protein could be visualized in the nuclei of virus-infected HFF 22 h after infection. Nuclear localization of the UL97 protein was also detected in thymidine kinase-deficient 143B cells infected with a recombinant vaccinia virus containing the entire UL97 open reading frame (ORF), as well as in HFF transiently expressing the entire UL97 ORF under the control of HCMV major immediate-early promoter. However, transiently expressed 5'-terminal deletion mutants of the UL97 ORF in addition showed a cytoplasmic localization of the UL97 protein, confirming the presence of a nuclear localization site in the N-terminal region of the protein. Our high-pressure liquid chromatography analyses confirmed the ganciclovir phosphorylation by the UL97 protein, but no specific phosphorylation of natural nucleosides was observed, indicating that the UL97 protein is not a nucleoside kinase. During plaque purification of recombinant UL97-deficient HCMV, this virus was growth defective; hence, we presume that UL97 may be essential for the viral life cycle.


Executive Functioning in Children and Adolescents With Perinatal HIV Infection.
Perinatal HIV (PHIV) infection may place youth at risk for impairments in executive functioning (EF). We examined associations of EF with HIV infection, disease severity and other factors among youth with PHIV and perinatally HIV-exposed, uninfected youth (PHEU). Within the US-based Pediatric HIV/AIDS Cohort Study, 354 PHIV and 200 PHEU youth completed a standardized EF measure (Children's Color Trails Test, CCTT) and youth and/or caregivers completed a questionnaire measuring everyday EF (Behavior Rating Inventory of Executive Function, BRIEF). Covariates included HIV status, current and historical disease severity, demographic and caregiver variables and other cognitive measures. Analyses used linear and logistic regression and proportional odds models. No significant HIV status group differences were found on CCTT scores. Caregiver BRIEF ratings indicated significantly fewer problems for PHIV than PHEU youth. However, PHIV youth with past encephalopathy self-endorsed significantly greater metacognitive (ie, cognitive regulation) problems on the BRIEF and performed more slowly on the CCTT than PHEU youth. CCTT and caregiver BRIEF scores had significant associations with indicators of past and present disease severity. Both PHIV and PHEU had significantly worse scores than population means on CCTT and BRIEF; scores had significant associations with demographic covariates. Youth with PHIV show EF problems likely associated with risk factors other than HIV. However, cognitive slowing and self-reported metacognitive problems were evident in PHIV youth with a history of encephalopathy. Assessment and treatment of EF impairment may be important to identifying PHIV youth at particular risk for poor health and behavioral outcomes.


Characterization of the structural modifications accompanying the loss of HBsAg particle immunogenicity.
The aim of this work was to further understand the relationship between the immunogenicity and the structure of Hepatitis B surface antigen (HBsAg) particles used in Hepatitis B vaccines. To reach this aim, we compared by using a large range of techniques, the structure and properties of untreated particles with those of particles stored for 3 weeks at +60°C, a treatment which resulted in a loss of HBsAg antigenicity (toward RF-1 mAb) and immunogenicity (in mice). While untreated particles imaged by electron microscopy and atomic force microscopy appeared as isolated nanoparticles of ∼ 20nm, heated particles appeared as long chains of particle aggregates with a partial loss of their protein protrusions. Moreover, infrared spectroscopy and circular dichroism revealed that the secondary structure of the S proteins was significantly affected, with a loss of 10% of their α-helix content. Steady-state and time-resolved fluorescence data further revealed strong modifications of the most emitting Trp residues at the particle surface, confirming significant changes in the conformation of the S proteins. Moreover, modifications in the organization of both the lipid core and lipid membrane surface of the heated particles were evidenced by environment-sensitive 3-hydroxyflavone probes. Taken together, our data evidenced a clear relationship between the bona fide S protein structure and lipid organization notably at the particle surface and the particle immunogenicity.


Radiofrequency ablation for benign thyroid nodules according to different ultrasound features: an Italian multicentre prospective study.
Background The purpose of this study was to confirm the generalisation of radiofrequency ablation (RFA) in the treatment of benign thyroid nodules (BTN) and to look for a correlation between final shrinkage and some ultrasound (US) findings in a large Italian population data set. Methods This prospective study included 337 patients with solid cold BTN from six Italian institutions. Nodule volume, US pattern, thyroid function, symptom/cosmetic scores and complications were evaluated before treatment and at 6 and 12 months. The primary outcome was to find a correlation between basal volume and US pattern of the nodules and final shrinkage. The secondary outcome was to confirm the efficacy and safety of RFA in a large data set. Results The median basal volume was 20.7 mL, and this significantly decreased after RFA at 6 months (7.3 mL (-63.5%), P < 0.001) and at 12 months (6 mL (-70%), P vs 6 months = 0.009). A significant correlation was found for US structure (a spongiform pattern showing a 76% reduction vs 67 and 66% of mix and solid patterns respectively, P < 0.01) as well as for vascularity (intense peripheral and intranodal patterns showing 71 vs 68 and 67% of weak peripheral and intranodal and peripheral patterns respectively, P < 0.03), but not for macrocalcifications. A slight inverse correlation was found between nodule basal volume and shrinkage (Spearman: -0.23). Mean symptoms/cosmetic scores were significantly reduced. No major complications were encountered. Conclusions This multicentre study validated the efficacy and safety of RFA for treating BTN and showed a clear correlation between final shrinkage and some common US findings.


A comparison of the frequency, risk factors, and type of self-medication in pregnant and nonpregnant women presenting to Shahid Akbar Abadi Teaching Hospital in Tehran.
Self-medication is a serious health problem that leads to an increased per capita consumption of medications, drug resistance, lack of optimal treatment, drug poisoning, and other unwanted complications. This study was conducted to compare self-medication in pregnant and nonpregnant women presenting to Shahid Akbar Abadi Teaching Hospital in Tehran, Iran. To conduct this cross-sectional study, 210 pregnant women and 210 nonpregnant women aged 15-45 years presenting to Shahid Akbar Abadi Teaching Hospital, Tehran, Iran, were selected through random sampling. Data were collected through interviews using a semi-structured questionnaire. The Chi-square test, t-test, and logistic regression model were used to analyze the data. The prevalence of self-medication was 34.8% in the pregnant and 77.1% in the nonpregnant women. The age group in which the most frequent instances of self-medication were observed (53.4%) was the 21-30 age group in the pregnant women and the 31-40 age group (44.4%) in the nonpregnant women, suggesting a statistically significant intergroup difference in terms of age (P = 0.0001). Medicinal plants were the most common medications used by the pregnant women (19.6%) and synthetic medications were the most common used by the nonpregnant women (38.1%). The reasons for using medications without a prescription included believing in the illness being mild (22.8%), not having health insurance (9%), easy access in the pregnant women, a previous history of the illness, and easy access in the nonpregnant women. As medicinal plants are the most common medications used by pregnant women and since assessing the risk of herbal substances is difficult, pregnant women should be advised against the arbitrary use of these substances.


Sprinting performance on the Woodway Curve 3.0 is related to muscle architecture.
To determine if unilateral measures of muscle architecture in the rectus femoris (RF) and vastus lateralis (VL) were related to (and predictive of) sprinting speed and unilateral (and bilateral) force (FRC) and power (POW) during a 30 s maximal sprint on the Woodway Curve 3.0 non-motorized treadmill. Twenty-eight healthy, physically active men (n = 14) and women (n = 14) (age = 22.9 ± 2.4 years; body mass = 77.1 ± 16.2 kg; height = 171.6 ± 11.2 cm; body-fa t = 19.4 ± 8.1%) completed one familiarization and one 30-s maximal sprint on the TM to obtain maximal sprinting speed, POW and FRC. Muscle thickness (MT), cross-sectional area (CSA) and echo intensity (ECHO) of the RF and VL in the dominant (DOM; determined by unilateral sprinting power) and non-dominant (ND) legs were measured via ultrasound. Pearson correlations indicated several significant (p < 0.05) relationships between sprinting performance [POW (peak, DOM and ND), FRC (peak, DOM, ND) and sprinting time] and muscle architecture. Stepwise regression indicated that POW(DOM) was predictive of ipsilateral RF (MT and CSA) and VL (CSA and ECHO), while POW(ND) was predictive of ipsilateral RF (MT and CSA) and VL (CSA); sprinting power/force asymmetry was not predictive of architecture asymmetry. Sprinting time was best predicted by peak power and peak force, though muscle quality (ECHO) and the bilateral percent difference in VL (CSA) were strong architectural predictors. Muscle architecture is related to (and predictive of) TM sprinting performance, while unilateral POW is predictive of ipsilateral architecture. However, the extent to which architecture and other factors (i.e. neuromuscular control and sprinting technique) affect TM performance remains unknown.


Two-pore channels: going with the flows.
In recent years, our understanding of the structure, mechanisms and functions of the endo-lysosomal TPC (two-pore channel) family have grown apace. Gated by the second messengers, NAADP and PI(3,5)P2, TPCs are an integral part of fundamental signal-transduction pathways, but their array and plasticity of cation conductances (Na+, Ca2+, H+) allow them to variously signal electrically, osmotically or chemically. Their relative tissue- and organelle-selective distribution, together with agonist-selective ion permeabilities provides a rich palette from which extracellular stimuli can choose. TPCs are emerging as mediators of immunity, cancer, metabolism, viral infectivity and neurodegeneration as this short review attests.


Prevalence of and management factors contributing to Cryptosporidium sp. infection in pre-weaned and post-weaned calves in Johor, Malaysia.
A cross-sectional study was carried out to identify species and determine the prevalence of Cryptosporidium sp. shedding in pre-weaned and post-weaned dairy calves and to identify management factors that may be contributing to disease. A total of 240 calf faecal samples were collected from 16 farms in two districts in Johor, Malaysia, and screened by PCR. The overall Cryptosporidium prevalence was 27.1%. The prevalence of Cryptosporidium species in pre-weaned calves was 32.4% for C. parvum, 26.5% for C. bovis, followed by C. andersoni (20.6%), C. ryanae (11.8%) and mixed sp. (8.8%). The prevalence of Cryptosporidium species in post-weaned calves was 35% for C. bovis followed by C. andersoni and C. ryanae (30% each) and mixed sp. (5%). Subtyping analysis of 8 of the 11 C. parvum isolates at the gp60 locus identified five isolates as IIdA15G1, one as IIa18A3R1 and two isolates as IIa17G2R1. Management factors that increased the risk of Cryptosporidium infection included having other cattle farms close by, feeding calves with saleable milk, keeping pre-weaned calves in pens with slatted floors and keeping post-weaned calves in pens with a sand floor.


A Novel User Control for Lower Extremity Rehabilitation Exoskeletons.
Lower extremity exoskeletons offer the potential to restore ambulation to individuals with paraplegia due to spinal cord injury. However, they often rely on preprogrammed gait, initiated by switches, sensors, and/or EEG triggers. Users can exercise only limited independent control over the trajectory of the feet, the speed of walking, and the placement of feet to avoid obstacles. In this paper, we introduce and evaluate a novel approach that naturally decodes a neuromuscular surrogate for a user's neutrally planned foot control, uses the exoskeleton's motors to move the user's legs in real-time, and provides sensory feedback to the user allowing real-time sensation and path correction resulting in gait similar to biological ambulation. Users express their desired gait by applying Cartesian forces via their hands to rigid trekking poles that are connected to the exoskeleton feet through multi-axis force sensors. Using admittance control, the forces applied by the hands are converted into desired foot positions, every 10 milliseconds (ms), to which the exoskeleton is moved by its motors. As the trekking poles reflect the resulting foot movement, users receive sensory feedback of foot kinematics and ground contact that allows on-the-fly force corrections to maintain the desired foot behavior. We present preliminary results showing that our novel control can allow users to produce biologically similar exoskeleton gait.


Predictors of pretreatment CA125 at ovarian cancer diagnosis: a pooled analysis in the Ovarian Cancer Association Consortium.
Cancer antigen 125 (CA125) is a glycoprotein expressed by epithelial cells of several normal tissue types and overexpressed by several epithelial cancers. Serum CA125 levels are mostly used as an aid in the diagnosis of ovarian cancer patients, to monitor response to treatment and detect cancer recurrence. Besides tumor characteristics, CA125 levels are also influenced by several epidemiologic factors, such as age, parity, and oral contraceptive use. Identifying factors that influence CA125 levels in ovarian cancer patients could aid in the interpretation of CA125 values for individuals. We evaluated predictors of pretreatment CA125 in 13 studies participating in the Ovarian Cancer Association Consortium. This analysis included a total of 5,091 women with invasive epithelial ovarian cancer with pretreatment CA125 measurements. We used probit scores to account for variability in CA125 between studies and linear regression to estimate the association between epidemiologic factors and tumor characteristics and pretreatment CA125 levels. In age-adjusted models, older age, history of pregnancy, history of tubal ligation, family history of breast cancer, and family history of ovarian cancer were associated with higher CA125 levels while endometriosis was associated with lower CA125 levels. After adjusting for tumor-related characteristics (stage, histology, grade), body mass index (BMI) higher than 30 kg/m2 was associated with 10% (95% CI 2, 19%) higher CA125 levels, while race (non-white vs. white) was associated with 15% (95% CI 4, 27%) higher CA125 levels. Our results suggest that high BMI and race may influence CA125 levels independent of tumor characteristics. Validation is needed in studies that use a single assay for CA125 measurement and have a diverse study population.


Calorimetric investigation of aerobic fermentations.
A modified bench scale calorimeter has been employed to determine the heat generated by various microbial strains growing on a range of different substrates, covering degrees of reduction from 3 to 6.13. The results are analyzed, and interpreted in the light of coupled enthalpy and elemental balances. The heat released by the microbial cultures has been found to correlate linearly with other process variables, such as biomass generation and oxygen uptake. The ratio between the heat generated and the biomass formed, the so-called "heat yield" (Y(Q/x)), has been shown both on theoretical and experimental grounds to increase with increasing degree of reduction of the substrate and to decrease with increasing biomass yield. The two effects could be combined into a simple model which permits the amount of heat released per unit of biomass formed to be predicted from the degree of reduction of the substrate as the only independent variable. The ratio between the heat generated and the oxygen taken up was constant at 440 kJ (mol O(2))(-1) throughout all experiments as expected from theoretical considerations for strongly aerobic processes.


Earth observations and integrative models in support of food and water security.
Global food production depends upon many factors that Earth observing satellites routinely measure about water, energy, weather, and ecosystems. Increasingly sophisticated, publicly-available satellite data products can improve efficiencies in resource management and provide earlier indication of environmental disruption. Satellite remote sensing provides a consistent, long-term record that can be used effectively to detect large-scale features over time, such as a developing drought. Accuracy and capabilities have increased along with the range of Earth observations and derived products that can support food security decisions with actionable information. This paper highlights major capabilities facilitated by satellite observations and physical models that have been developed and validated using remotely-sensed observations. Although we primarily focus on variables relevant to agriculture, we also include a brief description of the growing use of Earth observations in support of aquaculture and fisheries.


COVID-19 Vaccine Donations-Vaccine Empathy or Vaccine Diplomacy? A Narrative Literature Review.
Introduction: Vaccine inequality inflames the COVID-19 pandemic. Ensuring equitable immunization, vaccine empathy is needed to boost vaccine donations among capable countries. However, damaging narratives built around vaccine donations such as "vaccine diplomacy" could undermine nations' willingness to donate their vaccines, which, in turn, further exacerbate global vaccine inequality. However, while discussions on vaccine diplomacy are on the rise, there is limited research related to vaccine diplomacy, especially in terms of its characteristics and effects on vaccine distribution vis-à-vis vaccine empathy. Thus, to bridge the research gap, this study aims to examine the defining attributes of vaccine diplomacy and its potential effects on COVID-19 immunization, particularly in light of vaccine empathy. Methods: A narrative review was conducted to shed light on vaccine diplomacy's defining attributes and effects in the context of COVID-19 vaccine distribution and dissemination. Databases such as PubMed and Medline were utilized for literature search. Additionally, to ensure up-to-date insights are included in the review, validated reports and reverse tracing of eligible articles' reference lists in Google Scholar have also been conducted to locate relevant records. Results: Vaccine empathy is an individual or a nation's capability to sympathize with other individuals or nations' vaccine wants and needs, whereas vaccine diplomacy is a nation's vaccine efforts that aim to build mutually beneficial relationships with other nations ultimately. Our findings show that while both vaccine empathy and vaccine diplomacy have their strengths and weaknesses, they all have great potential to improve vaccine equality, particularly amid fast-developing and ever-evolving global health crises such as COVID-19. Furthermore, analyses show that, compared to vaccine empathy, vaccine diplomacy might be a more sustainable solution to improve vaccine donations mainly because of its deeper and stronger roots in multilateral collaboration and cooperation. Conclusion: Similar to penicillin, automated external defibrillators, or safety belts amid a roaring global health disaster, COVID-19 vaccines are, essentially, life-saving consumer health products that should be available to those who need them. Though man-made and complicated, vaccine inequality is nonetheless a solvable issue-gaps in vaccine distribution and dissemination can be effectively addressed by timely vaccine donations. Overall, our study underscores the instrumental and indispensable role of vaccine diplomacy in addressing the vaccine inequality issue amid the COVID-19 pandemic and its potentials for making even greater contributions in forging global solidarity amid international health emergencies. Future research could investigate approaches that could further inspire and improve vaccine donations among capable nations at a global scale to advance vaccine equity further.


Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration.
In patients with a first unprovoked venous thromboembolism (VTE) the risk of recurrent VTE remains high after anticoagulant treatment is discontinued. The Aspirin for the Prevention of Recurrent Venous Thromboembolism (the Warfarin and Aspirin [WARFASA]) and the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) trials showed that aspirin reduces this risk, but they were not individually powered to detect treatment effects for particular outcomes or subgroups. An individual patient data analysis of these trials was planned, before their results were known, to assess the effect of aspirin versus placebo on recurrent VTE, major vascular events (recurrent VTE, myocardial infarction, stroke, and cardiovascular disease death) and bleeding, overall and within predefined subgroups. The primary analysis, for VTE, was by intention to treat using time-to-event data. Of 1224 patients, 193 had recurrent VTE over 30.4 months' median follow-up. Aspirin reduced recurrent VTE (7.5%/yr versus 5.1%/yr; hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.51-0.90; P=0.008), including both deep-vein thrombosis (HR, 0.66; 95% CI, 0.47-0.92; P=0.01) and pulmonary embolism (HR, 0.66; 95% CI, 0.41-1.06; P=0.08). Aspirin reduced major vascular events (8.7%/yr versus 5.7%/yr; HR, 0.66; 95% CI, 0.50-0.86; P=0.002). The major bleeding rate was low (0.4%/yr for placebo and 0.5%/yr for aspirin). After adjustment for treatment adherence, recurrent VTE was reduced by 42% (HR, 0.58; 95% CI, 0.40-0.85; P=0.005). Prespecified subgroup analyses indicate similar relative, but larger absolute, risk reductions in men and older patients. Aspirin after anticoagulant treatment reduces the overall risk of recurrence by more than a third in a broad cross-section of patients with a first unprovoked VTE, without significantly increasing the risk of bleeding. www.anzctr.org.au. Unique identifier: ACTRN12611000684921.


Methanogenic Archaea dominate mature heartwood habitats of Eastern Cottonwood (Populus deltoides).
While recent reports demonstrate that the direct emission of methane from living tree trunks may be a significant terrestrial emission source, there has been debate whether tree emissions are due to transport from soils or produced in the wood environment itself. Reports of methanogens from wood of trees were prominent in the literature 40 years ago but have not been revisited with molecular ecology approaches. We examined communities associated with Populus deltoides using rRNA gene sequence analyses and how these vary with tree and wood properties. Our data indicate that wood environments are dominated by anaerobic microbiomes. Methanogens are prominent in heartwood (mean 34% relative abundance) compared to sapwood environments (13%), and dominant operational taxonomic units (OTUs) were classified as the Methanobacterium sp. Members of the Firmicutes phylum comprised 39% of total sequences and were in 42% greater abundance in sapwood over heartwood niches. Tree diameter was the strongest predictor of methanogen abundance, but wood moisture content and pH were also significant predictors of taxon abundance and overall community composition. Unlike microbiomes of the soil, rhizosphere and phyllosphere, wood associated communities are shaped by unique environmental conditions and may be prominent and overlooked sources of methane emissions in temperate forest systems.


Solution structure and backbone dynamics of the human alpha3-chain type VI collagen C-terminal Kunitz domain,.
The solution structure and backbone dynamics of the 58-residue C-terminal Kunitz domain fragment [alpha3(VI)] of human alpha3-chain type VI collagen has been studied by two-dimensional 1H-1H and 1H-15N nuclear magnetic resonance spectroscopy at 303 K. The solution structure is represented by an ensemble of 20 structures calculated with X-PLOR using 612 distance and 47 dihedral angle restraints. The distance restraints were obtained by a complete relaxation matrix analysis using MARDIGRAS. The root mean squared (rms) deviation is 0.91 A for the backbone atoms of the residues Thr2(8)-Gly12(18), Arg15(21)-Tyr35(41), and Gly40(46)-Pro57(63). The central beta-sheet [residues Ile18(24)-Tyr35(41)] and the C-terminal alpha-helix [residues Gln48(54)-Cys55(61)] are better defined with a backbone rms deviation of 0.46 A. The solution structure of alpha3(VI) is virtually identical to the crystal structure of alpha3(VI) and to the solution structure of bovine pancreatic trypsin inhibitor (BPTI). The 15N spin-lattice and spin-spin relaxation rates and the 1H-15N heteronuclear nuclear Overhauser enhancement (NOE) were analyzed using both the "model-free" formalism [Lipari, G., & Szabo, A. (1982) J. Am. Chem. Soc. 104, 4546-4559 and 4559-4570] and the reduced spectral density mapping procedure [Farrow, N. A., Szabo, A., Torchia, D. A., & Kay, L. E. (1995) J. Biomol.NMR 6, 153-162]. The results obtained from the "model-free" analysis include an overall correlation time tauc of 3. 00 ns and backbone order parameters S2 in the range from 0.28 to 0. 93. The necessity of including an exchange term in the analysis of the relaxation data from 14 residues indicated that these residues are involved in motions on the micro- to millisecond time scale. The majority of the 14 residues are located in the vicinity of the Cys14(20)-Cys38(44) disulfide bond, suggesting the presence of a disulfide bond isomerization similar to the one observed in BPTI [Otting, G., Liepinsh, E., & Wüthrich, K. (1993) Biochemistry 32, 3571-3582]. It is suggested that this disulfide bond isomerization is the main reason for the surprisingly small effect on trypsin inhibition observed when Thr13(19) of alpha3(VI) is substituted with Pro.


Mediterranean diet and quality of life: Baseline cross-sectional analysis of the PREDIMED-PLUS trial.
We assessed if a 17-item score capturing adherence to a traditional Mediterranean diet (MedDiet) was associated with better health-related quality of life among older Spanish men and women with overweight or obesity harboring the metabolic syndrome. We analyzed baseline data from 6430 men and women (age 55-70 years) participating in the PREDIMED-Plus study. PREDIMED-Plus is a multi-centre randomized trial testing an energy-restricted MedDiet combined with promotion of physical activity and behavioral therapy for primary cardiovascular prevention compared to a MedDiet alone. Participants answered a 36-item questionnaire about health-related quality of life (HRQoL) and a 17-item questionnaire that assessed adherence to an MedDiet. We used ANCOVA and multivariable-adjusted linear regression models to compare baseline adjusted means of the quality of life scales according to categories of adherence to the MedDiet. Higher adherence to the MedDiet was independently associated with significantly better scores in the eight dimensions of HRQoL. Adjusted differences of > = 3 points between the highest and the lowest dietary adherence groups to the MedDiet were observed for vitality, emotional role, and mental health and of > = 2 points for the other dimensions. In conclusion, this study shows a positive association between adherence to a MedDiet and several dimensions of quality of life.


Efficacy of treating pain to reduce behavioural disturbances in residents of nursing homes with dementia: cluster randomised clinical trial.
To determine whether a systematic approach to the treatment of pain can reduce agitation in people with moderate to severe dementia living in nursing homes. Cluster randomised controlled trial. 60 clusters (single independent nursing home units) in 18 nursing homes within five municipalities of western Norway. 352 residents with moderate to severe dementia and clinically significant behavioural disturbances randomised to a stepwise protocol for the treatment of pain for eight weeks with additional follow-up four weeks after the end of treatment (33 clusters; n = 175) or to usual treatment (control, 27 clusters; n = 177). Participants in the intervention group received individual daily treatment of pain for eight weeks according to the stepwise protocol, with paracetamol (acetaminophen), morphine, buprenorphine transdermal patch, or pregabaline. The control group received usual treatment and care. Primary outcome measure was agitation (scores on Cohen-Mansfield agitation inventory). Secondary outcome measures were aggression (scores on neuropsychiatric inventory-nursing home version), pain (scores on mobilisation-observation-behaviour-intensity-dementia-2), activities of daily living, and cognition (mini-mental state examination). Agitation was significantly reduced in the intervention group compared with control group after eight weeks (repeated measures analysis of covariance adjusting for baseline score, P < 0.001): the average reduction in scores for agitation was 17% (treatment effect estimate -7.0, 95% confidence interval -3.7 to -10.3). Treatment of pain was also significantly beneficial for the overall severity of neuropsychiatric symptoms (-9.0, -5.5 to -12.6) and pain (-1.3, -0.8 to -1.7), but the groups did not differ significantly for activities of daily living or cognition. A systematic approach to the management of pain significantly reduced agitation in residents of nursing homes with moderate to severe dementia. Effective management of pain can play an important part in the treatment of agitation and could reduce the number of unnecessary prescriptions for psychotropic drugs in this population. Trial registration ClinicalTrials.gov NCT01021696 and Norwegian Medicines Agency EudraCTnr 2008-007490-20.


Two types of well followed users in the followership networks of Twitter.
In the Twitter blogosphere, the number of followers is probably the most basic and succinct quantity for measuring popularity of users. However, the number of followers can be manipulated in various ways; we can even buy follows. Therefore, alternative popularity measures for Twitter users on the basis of, for example, users' tweets and retweets, have been developed. In the present work, we take a purely network approach to this fundamental question. First, we find that two relatively distinct types of users possessing a large number of followers exist, in particular for Japanese, Russian, and Korean users among the seven language groups that we examined. A first type of user follows a small number of other users. A second type of user follows approximately the same number of other users as the number of follows that the user receives. Then, we compare local (i.e., egocentric) followership networks around the two types of users with many followers. We show that the second type, which is presumably uninfluential users despite its large number of followers, is characterized by high link reciprocity, a large number of friends (i.e., those whom a user follows) for the followers, followers' high link reciprocity, large clustering coefficient, large fraction of the second type of users among the followers, and a small PageRank. Our network-based results support that the number of followers used alone is a misleading measure of user's popularity. We propose that the number of friends, which is simple to measure, also helps us to assess the popularity of Twitter users.


Internalized Homonegativity, Emotion Dysregulation, and Isolating Behaviors Perpetration among Gay and Lesbian Couples.
Same-sex intimate partner violence (SSIPV) is a serious health concern and may manifest in various forms. Nevertheless, controlling behaviors of isolation are still poorly investigated. Due to their marginalized status, sexual minorities can face SSIPV-specific risk factors, such as internalized homonegativity, as well as general psychological stress factors, such as emotion dysregulation. While the literature is growing, there is still a lack of understanding of the complex pathways linking sexual minorities and minority stress to IPV and isolating controlling behavior. To fill this gap, we explored the relation between internalized homonegativity and controlling behaviors of isolation, assessing the mediating role of emotion dysregulation. In total, 120 gay and lesbian people (mean age = 33.8, SD = 11.5) involved in a same-sex relationship participated in the study. Results showed a direct and positive association between internalized homonegativity and difficulties in emotion regulation and a direct and positive association between emotion dysregulation and controlling behaviors of isolation; the mediating role of emotion dysregulation in the relation between internalized homonegativity and isolating controlling behaviors was supported as well. Emerging results can provide valuable information at the clinical level, although further studies are needed to confirm these preliminary findings.


Azithromycin is associated with increased survival in lung transplant recipients with bronchiolitis obliterans syndrome.
Previous studies have suggested that azithromycin improves lung function in lung transplant recipients with bronchiolitis obliterans syndrome (BOS). However, these studies did not include a non-treated BOS control cohort or perform survival analysis. This study was undertaken to estimate the effect of azithromycin treatment on survival in lung transplant recipients with BOS. We conducted a retrospective cohort study of consecutive lung transplant recipients who developed BOS between 1999 and 2007. An association between azithromycin treatment and death was assessed using univariate and multivariate time-dependent Cox regression analysis. Of the 178 recipients who developed BOS in our study, 78 did so after 2003 and were treated with azithromycin. The azithromycin-treated and untreated cohorts had similar baseline characteristics. Univariate analysis demonstrated that azithromycin treatment was associated with a survival advantage and this beneficial treatment effect was more pronounced when treatment was initiated during BOS Stage 1. Multivariate analysis demonstrated azithromycin treatment during BOS Stage 1 (adjusted hazard ratio = 0.23, p = 0.01) and absolute forced expiratory volume in 1 second (FEV(1)) at the time of BOS Stage 1 (adjusted hazard ratio = 0.52, p = 0.003) were both associated with a decreased risk of death. In lung transplant recipients with BOS Stage 1, azithromycin treatment initiated before BOS Stage 2 was independently associated with a significant reduction in the risk of death. This finding supports the need for a randomized, controlled trial to confirm the impact of azithromycin on survival in lung transplant recipients.


Oxygen deprivation and the cellular response to hypoxia in adipocytes - perspectives on white and brown adipose tissues in obesity.
Relative hypoxia has been shown to develop in white adipose tissue depots of different types of obese mouse (genetic, dietary), and this leads to substantial changes in white adipocyte function. These changes include increased production of inflammation-related adipokines (such as IL-6, leptin, Angptl4, and VEGF), an increase in glucose utilization and lactate production, and the induction of fibrosis and insulin resistance. Whether hypoxia also occurs in brown adipose tissue depots in obesity has been little considered. However, a recent study has reported low pO2 in brown fat of obese mice, this involving mitochondrial loss and dysfunction. We suggest that obesity-linked hypoxia may lead to similar alterations in brown adipocytes as in white fat cells - particularly changes in adipokine production, increased glucose uptake and lactate release, and insulin resistance. This would be expected to compromise thermogenic activity and the role of brown fat in glucose homeostasis and triglyceride clearance, underpinning the development of the metabolic syndrome. Hypoxia-induced augmentation of lactate production may also stimulate the "browning" of white fat depots through recruitment of UCP1 and the development of brite adipocytes.


Regulation of osteogenic differentiation of human bone marrow stromal cells: interaction between transforming growth factor-beta and 1,25(OH)(2) vitamin D(3) In vitro.
Bone marrow stromal cells are believed to play a major role in bone formation as a major source of osteoprogenitor cells, however, very little is known about how the osteogenic differentiation of these cells is regulated by systemic hormones and local growth factors. We examined the effects of TGF-beta and its interaction with 1, 25(OH)(2) Vitamin D(3) [1,25(OH)(2)D(3)] on the differentiation and proliferation of human bone marrow stromal cells (hBMSC) in secondary cultures. Alkaline phosphatase (ALP) activity was inhibited by TGF-beta (0.1-10 ng/ml) and increased by 1, 25(OH)(2)D(3) (50 nM), however, co-treatment of TGF-beta and 1, 25(OH)(2)D(3) synergistically enhanced ALP activity with maximal stimulation occurring at about 8 days after treatment. This synergistic effect was independent of proliferation because, in contrast to TGF-beta alone, combined treatment with TGF-beta and 1, 25(OH)(2)D(3) had no effect on hBMSC proliferation. As no synergistic effect was seen with combinations of 1,25(OH)(2)D(3) and other osteotrophic growth factors, including BMP-2, IGF-I, and basic fibroblast growth factor (bFGF), it would seem likely that the synergistic interaction is specific for TGF-beta. The increased ALP activity was due to an enhancement of 1,25(OH)(2)D(3)-induced ALP activity by TGF-beta, rather than vice versa. In contrast, TGF-beta inhibited 1,25(OH)(2)D(3)-induced osteocalcin production. Taken together, these results indicate that TGF-beta and 1,25(OH)(2)D(3) act synergistically to stimulate the recruitment of BMSC to the osteoblast lineage. This interaction may play an important role in bone remodeling.


Pharmaceuticals and personal care products (PPCPs) in treated wastewater discharges into Charleston Harbor, South Carolina.
This study assessed seasonal and regional trends of pharmaceuticals and personal care products (PPCPs) detected in monthly samples from two local wastewater treatment plants (WWTPs) in Charleston, South Carolina, USA, over the period of one year. Surface water of Charleston Harbor was also analyzed to examine environmental distribution in an estuarine ecosystem. Of the 19 compounds examined, 11 were quantified in wastewater influent, 9 in effluent, and 7 in surface water. Aqueous concentrations of many PPCPs were reduced by >86% in wastewater effluent compared with influent, though some compounds showed low removal and greater effluent concentrations compared with influent (e.g. estrone and fluoxetine). Differences in effluent concentrations and estimated removal between facilities were likely related to variations in the facilities' operating procedures. Surface water concentrations were generally reduced by >90% for those chemicals found in effluent. Additionally, there were seasonal trends that indicate reduced degradation in colder months in wastewater and surface water. To our knowledge, this is the first study examining PPCPs in the South Atlantic Bight.


Large and small tumor antigens from simian virus 40 have identical amino termini mapping at 0.65 map units.
Large and small tumor (T)antigens of simian virus 40 were synthesized in vitro with L-cell extracts that had been treated by the method of Palmiter to prevent amino-terminal acetylation of nascent proteins. Partial amino-terminal amino acid sequences of both forms of T-antigen were determined and found to be identical. Methionine residues were located at positions 1 and 14, a lysine residue at position 3, and leucine residues at positions 5, 11, 13,16, 17, and 19. These amino acid sequence data match perfectly the amino acid sequence predicted from a sequence of nucleotides in the E strand of simian virus 40 DNA which begins near the junction between HindII/III fragments A and C at about 0.65 map units. This strongly suggests that the sequence coding for the amino terminus of both proteins is located at this position. Furthermore, the data are consistent with a model for the synthesis of both forms of T-antigen that predicts that (i) small T-antigen is coded for by a sequence of nucleotides from the 5' end of the early region and (ii) large T-antigen is coded for by nucleotide sequences from two noncontiguous regions of simian virus 40 DNA.


Exploring Spatial-Temporal Changes in 18F-Sodium Fluoride PET/CT and Circulating Tumor Cells in Metastatic Castration-Resistant Prostate Cancer Treated With Enzalutamide.
Intrapatient treatment response heterogeneity is under-recognized. Quantitative total bone imaging (QTBI) using 18F-NaF positron emission tomography/computed tomography (PET/CT) scans is a tool that allows characterization of interlesional treatment response heterogeneity in bone. Understanding spatial-temporal response is important to identify individuals who may benefit from treatment beyond progression. Men with progressive metastatic castration-resistant prostate cancer (mCRPC) with at least two lesions on bone scintigraphy were enrolled and treated with enzalutamide 160 mg daily (ClinicalTrials.gov identifier: NCT02384382). 18F-NaF PET/CT scans were obtained at baseline (PET1), week 13 (PET2), and at the time of prostate-specific antigen (PSA) progression, standard radiographic or clinical progression, or at 2 years without progression (PET3). QTBI was used to determine lesion-level response. The primary end point was the proportion of men with at least one responding bone lesion on PET3 using QTBI. Twenty-three men were enrolled. Duration on treatment ranged from 1.4 to 34.1 months. In general, global standardized uptake value (SUV) metrics decreased while on enzalutamide (PET2) and increased at the time of progression (PET3). The most robust predictor of PSA progression was change in SUVhetero (PET1 to PET3; hazard ratio, 3.88; 95% CI, 1.24 to 12.1). Although overall functional disease burden improved during enzalutamide treatment, an increase in total burden (SUVtotal) was seen at the time of progression, as measured by 18F-NaF PET/CT. All (22/22) evaluable men had at least one responding bone lesion at PET3 using QTBI. We found that the proportion of progressing lesions was low, indicating that a substantial number of lesions appear to continue to benefit from enzalutamide beyond progression. Selective targeting of nonresponding lesions may be a reasonable approach to extend benefit.


Serum AMH Level to Predict the Hyper Response in Women with PCOS and Non-PCOS Undergoing Controlled Ovarian Stimulation in ART.
It is essential to determine the cut-off value of serum anti-Mullerian hormone (AMH) to predict the hyper response in assisted reproductive technology (ART). There are few studies mentioning the cut-off value for the hyper response in infertile women but not specifically for polycystic ovary syndrome (PCOS) and non-PCOS groups. With this in background, this study was conducted. To determine the cut-off value of serum AMH to predict the hyper response in women with PCOS and non-PCOS undergoing a controlled ovarian stimulation (COS) in ART. To compare the outcome of stimulation in PCOS and non-PCOS groups. All 246 women enrolled for Intra Cytoplasmic Sperm Injection (ICSI) fulfilling the selection criteria were recruited. On the day 3 of the cycle, the serum AMH, Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), estradiol and antral follicle count (AFC) were measured. They underwent COS as per the unit protocol. They were divided into PCOS and non-PCOS groups as per the Rotterdam's criteria. The mean age, duration of infertility, Body Mass Index (BMI), Ovarian reserve markers and outcome of stimulation were compared. Using the Statistical Package for the Social Sciences version 16.0 software, the significant difference was measured by multivariate analysis, as well as a one-way analysis of variance with Tukey's post-hoc test was used. Among 246 women, 31.3% were in PCOS group, and 68.7% were in non-PCOS group. Comparison of PCOS and non-PCOS groups showed a significant difference in the age with the mean age being 29.2 and 31.5 years, respectively. The mean AMH and AFC were 2-fold higher in PCOS group. The mean number of follicles, oocytes retrieved, MII and oocytes fertilised were significantly higher in PCOS group. The pregnancy rate was 52.6% in PCOS and 30.9% in non-PCOS group. In the PCOS group, 22.1% had ovarian hyper stimulation syndrome (OHSS), and only 4.7% had OHSS in non-PCOS group (P = 0.0005). Receiving Operator Curve (ROC) curve was plotted to predict the hyper response, which showed a cut-off value of 6.85 ng/ml with a sensitivity of 66.7% and a specificity of 68.7% for PCOS group and 4.85 ng/ml with a sensitivity of 85.7% and a specificity of 89.7% in non-PCOS group. The cut-off value of serum AMH to predict the hyper response in PCOS group is 6.85 ng/ml and in non-PCOS group is 4.85 ng/ml.


Effects of luteolin on regulatory proteins and enzymes for myocyte calcium circulation in hypothermic preserved rat heart.
Heart transplantation has been applied in the clinic as an optimal solution for patients with end stage cardiac failure for a number of years. However, hypothermic preservation of the heart remains limited to 4-6 h and calcium accumulation over time is an important factor resulting in cell death. To provide longer and safer storage for donor hearts, it was demonstrated in our previous study that luteolin, a traditional Chinese medicine used to treat cardiovascular diseases, inhibits cell death and L-type calcium currents during hypothermic preservation. In the current study, the protective role of luteolin in modulating cardiomyocyte calcium cycling was further investigated. Intracellular calcium overload has already been implicated in hypothermia-induced dysfunction of cardiomyocytes. University of Wisconsin (UW) solution supplemented with 7.5, 15 or 30 µmol/l luteolin was used to preserve fresh isolated cardiomyocytes at 4°C. The results demonstrated that all three doses of luteolin supplementation attenuated calcium overload over a 6 h preservation period. Luteolin also suppressed the accumulation of important regulatory proteins and enzymes for cardiomyocyte calcium circulation, mitochondria Ca2+ uniporter and calmodulin, which are normally induced by cold storage in UW solution. Protein Kinase A activity was also suppressed in cardiomyocytes preserved in luteolin supplemented UW solution, while Ca2+-Mg2+-ATPase activity was increased. The results demonstrated that luteolin confers a cardioprotective effect through inhibiting the changes of calcium regulators during cold storage and therefore ameliorates Ca2+ overload in rat cardiomyocytes.


The gluconeogenic enzyme fructose-1,6-bisphosphatase is dispensable for growth of the yeast Yarrowia lipolytica in gluconeogenic substrates.
The genes encoding gluconeogenic enzymes in the nonconventional yeast Yarrowia lipolytica were found to be differentially regulated. The expression of Y. lipolytica FBP1 (YlFBP1) encoding the key enzyme fructose-1,6-bisphosphatase was not repressed by glucose in contrast with the situation in other yeasts; however, this sugar markedly repressed the expression of YlPCK1, encoding phosphoenolpyruvate carboxykinase, and YlICL1, encoding isocitrate lyase. We constructed Y. lipolytica strains with two different disrupted versions of YlFBP1 and found that they grew much slower than the wild type in gluconeogenic carbon sources but that growth was not abolished as happens in most microorganisms. We attribute this growth to the existence of an alternative phosphatase with a high K(m) (2.3 mM) for fructose-1,6-bisphosphate. The gene YlFBP1 restored fructose-1,6-bisphosphatase activity and growth in gluconeogenic carbon sources to a Saccharomyces cerevisiae fbp1 mutant, but the introduction of the FBP1 gene from S. cerevisiae in the Ylfbp1 mutant did not produce fructose-1,6-bisphosphatase activity or growth complementation. Subcellular fractionation revealed the presence of fructose-1,6-bisphosphatase both in the cytoplasm and in the nucleus.


DNA Methylation on N6-Adenine in C. elegans.
In mammalian cells, DNA methylation on the fifth position of cytosine (5mC) plays an important role as an epigenetic mark. However, DNA methylation was considered to be absent in C. elegans because of the lack of detectable 5mC, as well as homologs of the cytosine DNA methyltransferases. Here, using multiple approaches, we demonstrate the presence of adenine N(6)-methylation (6mA) in C. elegans DNA. We further demonstrate that this modification increases trans-generationally in a paradigm of epigenetic inheritance. Importantly, we identify a DNA demethylase, NMAD-1, and a potential DNA methyltransferase, DAMT-1, which regulate 6mA levels and crosstalk between methylations of histone H3K4 and adenines and control the epigenetic inheritance of phenotypes associated with the loss of the H3K4me2 demethylase spr-5. Together, these data identify a DNA modification in C. elegans and raise the exciting possibility that 6mA may be a carrier of heritable epigenetic information in eukaryotes.


Agaricus blazei hot water extract shows anti quorum sensing activity in the nosocomial human pathogen Pseudomonas aeruginosa.
The edible mushroom Agaricus blazei Murill is known to induce protective immunomodulatory action against a variety of infectious diseases. In the present study we report potential anti-quorum sensing properties of A. blazei hot water extract. Quorum sensing (QS) plays an important role in virulence, biofilm formation and survival of many pathogenic bacteria, including the Gram negative Pseudomonas aeruginosa, and is considered as a novel and promising target for anti-infectious agents. In this study, the effect of the sub-MICs of Agaricus blazei water extract on QS regulated virulence factors and biofilm formation was evaluated against P. aeruginosa PAO1. Sub-MIC concentrations of the extract which did not kill P. aeruginosa nor inhibited its growth, demonstrated a statistically significant reduction of virulence factors of P. aeruginosa, such as pyocyanin production, twitching and swimming motility. The biofilm forming capability of P. aeruginosa was also reduced in a concentration-dependent manner at sub-MIC values. Water extract of A. blazei is a promising source of antiquorum sensing and antibacterial compounds.


Discovery of Stromal Regulatory Networks that Suppress Ras-Sensitized Epithelial Cell Proliferation.
Mesodermal cells signal to neighboring epithelial cells to modulate their proliferation in both normal and disease states. We adapted a Caenorhabditis elegans organogenesis model to enable a genome-wide mesodermal-specific RNAi screen and discovered 39 factors in mesodermal cells that suppress the proliferation of adjacent Ras pathway-sensitized epithelial cells. These candidates encode components of protein complexes and signaling pathways that converge on the control of chromatin dynamics, cytoplasmic polyadenylation, and translation. Stromal fibroblast-specific deletion of mouse orthologs of several candidates resulted in the hyper-proliferation of mammary gland epithelium. Furthermore, a 33-gene signature of human orthologs was selectively enriched in the tumor stroma of breast cancer patients, and depletion of these factors from normal human breast fibroblasts increased proliferation of co-cultured breast cancer cells. This cross-species approach identified unanticipated regulatory networks in mesodermal cells with growth-suppressive function, exposing the conserved and selective nature of mesodermal-epithelial communication in development and cancer.


EULAR recommendations for the management of familial Mediterranean fever.
Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease, but many rheumatologists are not well acquainted with its management. The objective of this report is to produce evidence-based recommendations to guide rheumatologists and other health professionals in the treatment and follow-up of patients with FMF. A multidisciplinary panel, including rheumatologists, internists, paediatricians, a nurse, a methodologist and a patient representative, was assembled. Panellists came from the Eastern Mediterranean area, Europe and North America. A preliminary systematic literature search on the pharmacological treatment of FMF was performed following which the expert group convened to define aims, scope and users of the guidelines and established the need for additional reviews on controversial topics. In a second meeting, recommendations were discussed and refined in light of available evidence. Finally, agreement with the recommendations was obtained from a larger group of experts through a Delphi survey. The level of evidence (LoE) and grade of recommendation (GR) were then incorporated. The final document comprises 18 recommendations, each presented with its degree of agreement (0-10), LoE, GR and rationale. The degree of agreement was greater than 7/10 in all instances. The more controversial statements were those related to follow-up and dose change, for which supporting evidence is limited. A set of widely accepted recommendations for the treatment and monitoring of FMF is presented, supported by the best available evidence and expert opinion. It is believed that these recommendations will be useful in guiding physicians in the care of patients with FMF.


Folate, related B vitamins, and homocysteine in childhood and adolescence: potential implications for disease risk in later life.
Folate and the metabolically related B vitamins are an important priority throughout life, but few studies have examined their status through childhood and adolescence. The aims of the current study were to investigate age, gender, and lifestyle factors as determinants of folate, related B-vitamin status, and homocysteine concentrations among British children and adolescents and to propose age-specific reference ranges for these biomarkers, which, at present, are unavailable. Data from the National Dietary and Nutritional Survey of 2127 young people aged 4 to 18 years were accessed to provide a representative sample of British children. All of the subjects who provided a blood sample for homocysteine concentrations were included in the current study (n = 840). Of these, laboratory biomarkers of folate (serum and red cell folate: n = 832 and 774, respectively), vitamin B(12) (n = 828), vitamin B(6) (n = 770), and riboflavin (n = 839) were also examined. The biomarker status of all 4 of the relevant B vitamins decreased significantly with age. Correspondingly, homocysteine concentrations progressively increased, with median values of 5.6, 6.3, and 7.9 mumol/L for children aged 4 to 10 years, 11 to 14 years, and 15 to 18 years, respectively, and were higher in boys compared with girls (15-18 years only). Independent of age and gender, fortified breakfast cereal intake (consumed by 89% of the sample) was associated with significantly higher B-vitamin status and lower homocysteine concentrations. It is not generally appreciated that the well-established progressive increase in homocysteine from 4 to 18 years reflects decreases in the biomarker status of all 4 metabolically related B vitamins. We suggest age-specific laboratory reference ranges for homocysteine and related B-vitamin concentrations for potential use within a pediatric setting.


Recommendations for incorporating patient-reported outcomes into clinical comparative effectiveness research in adult oncology.
Examining the patient's subjective experience in prospective clinical comparative effectiveness research (CER) of oncology treatments or process interventions is essential for informing decision making. Patient-reported outcome (PRO) measures are the standard tools for directly eliciting the patient experience. There are currently no widely accepted standards for developing or implementing PRO measures in CER. Recommendations for the design and implementation of PRO measures in CER were developed via a standardized process including multistakeholder interviews, a technical working group, and public comments. Key recommendations are to include assessment of patient-reported symptoms as well as health-related quality of life in all prospective clinical CER studies in adult oncology; to identify symptoms relevant to a particular study population and context based on literature review and/or qualitative and quantitative methods; to assure that PRO measures used are valid, reliable, and sensitive in a comparable population (measures particularly recommended include EORTC QLQ-C30, FACT, MDASI, PRO-CTCAE, and PROMIS); to collect PRO data electronically whenever possible; to employ methods that minimize missing patient reports and include a plan for analyzing and reporting missing PRO data; to report the proportion of responders and cumulative distribution of responses in addition to mean changes in scores; and to publish results of PRO analyses simultaneously with other clinical outcomes. Twelve core symptoms are recommended for consideration in studies in advanced or metastatic cancers. Adherence to methodologic standards for the selection, implementation, and analysis/reporting of PRO measures will lead to an understanding of the patient experience that informs better decisions by patients, providers, regulators, and payers.


State authority, medical dominance, and trends in the regulation of the health professions: the Ontario case.
The relationships amongst the health professions and between them and the state are rapidly changing. I argue that analysis of these relationships has to take into consideration: the fact that medicine played an intermediary role (through medical dominance in health care) between the state and the other health occupations; the permeability of the boundaries of the state and the professions; and the dual nature of professional organizations (as sites of intra-occupational conflict and as possible vehicles of extra-occupational control). In Ontario the medical profession partially 'mediated' the relationships between 'non-physician' health occupations and the state through medical control over other health care occupations. National/provincial health insurance brought the state into the health care system as an actor and forced a reconsideration of its relationships with medicine and with the other health care occupations. The state came to be directly involved in 'rationalizing' health care. This involvement meant curbing the power of medicine and modifying the relationships between medicine and the para-medical occupations. State influence is partly constructed through a particular kind of professional organization, namely, the professional College. These changing relationships are illustrated by historical and recent developments regarding medicine, nursing and chiropractic in Ontario.


Mesoglia & microglia--a historical review of the concept of mononuclear phagocytes within the central nervous system.
More than a century and a half has elapsed since the first accounts of mesodermal phagocytic elements were proposed within the central nervous system. Over the intervening decades, body and substance were added to this concept through the advancement of histological techniques at the disposal of the researcher and the acute and keen-minded skills of the pathologist. Notable among these pioneering efforts were the contributions of W. Ford Robertson, Santiago Ramon y Cajal, Pio del Rio-Hortega and Wilder Penfield amongst an entire cavalcade of other noteworthy figures. The term 'mesoglia' and 'third element of the nervous system' was bestowed upon these cells towards the beginning of the twentieth century to account for their separate origins from neurons and macroglia. It was later amended by del Rio-Hortega in 1919, to 'microglia' in order to further discriminate between true mesodermal elements and oligodendrocytes, previously regarded as a component of 'mesoglia'. This particular contention sparked much controversy among del Rio-Hortega's peers and resulted in an escalation of fruitful research throughout Europe that eventually declined up to the outbreak of the Second World War. The post-war years were a period of the 'dark ages' that cast doubt on the very existence and nature of microglia, until the 'renaissance' of research was once again rejuvenated in the 1960s, by a new cohort of intrigued minds: Cammermeyer, Blinzinger, Kreutzberg and others who saw in the 'third element' the potential that is now commonly ascribed to microglia: the intrinsic immune effector cells of the CNS. It is now universally accepted that microglia are involved as the first line of rapid defence in any pathology of the nervous system, and as such, present a diagnostic tool for the neuropathologist. Although our knowledge of microglia stems from an extensive body of work conducted over the last two decades, much of the earlier work (pre-1960s) has remained somewhat obscure. This is partly accountable due to the limited availability of translated works, and additionally to the lack of a compendium of these articles. This paper will present a comprehensive overview of the pioneering research on mononuclear phagocytes within the central nervous system, which has direct bearing on our present-day understanding of the concept of microglia.


Cardiovascular risk factors and diseases in women undergoing hysterectomy with ovarian conservation.
This study aims to determine the association of preexisting cardiovascular risk factors and cardiovascular diseases with hysterectomy with bilateral ovarian conservation using a case-central design. Using the Rochester Epidemiology Project records-linkage system, we identified all Olmsted County, MN women who underwent hysterectomy with ovarian conservation between January 1, 1965 and December 31, 2002 (cases). Each case was age-matched (± 1 y) with a randomly selected woman who resided in the county and did not undergo hysterectomy or oophorectomy before the index date (date of hysterectomy in her matched case). Using electronic codes, we identified cardiovascular risk factors (diabetes, hypertension, hyperlipidemia, obesity, metabolic syndrome, and polycystic ovary syndrome) and cardiovascular diseases (coronary artery disease, congestive heart failure, myocardial infarction, and stroke) that occurred before the index date. Analyses were stratified by age at hysterectomy and indication for surgical operation. During the study period, 3,816 women underwent hysterectomy with ovarian conservation for a benign indication. Preexisting hyperlipidemia, obesity, and metabolic syndrome were significantly more frequent in cases than in controls in univariable analyses. In multivariable analyses, obesity remained significantly associated overall, for nearly all age groups, and across all indications. Stroke was significantly more frequent in cases than in controls among women younger than 36 years. Congestive heart failure and stroke were significantly less common in cases than in controls among women older than 50 years. Hysterectomy with ovarian conservation is associated with cardiovascular risk factors, particularly obesity. Obesity may contribute to underlying gynecologic conditions leading to hysterectomy; however, surgical selection may also play a role.


Investigating the association between serum human papillomavirus type 16 E7 antibodies and risk of head and neck cancer.
Human papillomavirus (HPV) is recognized as a major cause of oropharyngeal cancer (OPC) in Western countries. Less is known regarding its contribution to the OPC occurring in Asia. The current study aimed to investigate the association between antibody responses to HPV16 E7 and head and neck cancer (HNC) risk in a hospital-based case-control study conducted in Taiwan with 693 HNC cases and 1,035 controls. A positive association was observed between seropositivity to HPV16 E7 and OPC risk, whereas no significant association was found in the non-OPC cases. The increased OPC risk associated with seropositivity to HPV16 E7 was more significant among nonbetel quid or noncigarette users. Seropositivity to HPV16 E7 showed moderate agreement with P16 expression in OPC. OPC patients that were seropositive to HPV16 E7 or p16 positive were more highly educated and less likely to use alcohol, betel quids, and cigarettes compared to HPV16 E7 seronegative or p16 negative OPC patients. Furthermore, patients with p16 positive OPC were more likely to be women compared to patients with p16 negative OPC, likely owing to the low prevalence of alcohol, betel quid, and cigarette users among women. Overall, this study suggested that similar to Western countries, HPV may also be an important risk factor of OPC in Taiwan. With the declining consumption of betel quids and cigarettes in Taiwan, a higher percentage of OPC cases in Taiwan will be attributed to HPV in the future. Public health measures, including HPV vaccination, need to be implemented to prevent the occurrence of HPV-positive OPC.


Histamine and spermidine content in brain during development.
Histamine concentration in fetal rat brain is high at 17 days gestation but decreases sharply just before birth. Values subsequently increase to a maximum postnatal concentration 5 to 10 days after birth, and then steadily decline to low adult values by time of weaning. Spermidine follows a pattern similar to that of histamine but with a 24- to 48-hour lag. The developmental pattern for histamine in the central nervous system is different from that for other neural amines. It appears that the marked fetal and neonatal changes in brain histamine correlate best with periods of rapid cell proliferation and growth during brain maturation.


Choosing antibiotics for intra-abdominal infections: what do we mean by "high risk"?
The definition of "high risk" in intra-abdominal infections remains vague. The purpose of this study was to investigate patient characteristics associated with a high risk of isolation of resistant pathogens from an intra-abdominal source. All complicated intra-abdominal and abdominal organ/space surgical site infections treated over a ten-year period in a single hospital were analyzed. Infections were categorized by pathogen(s). Organisms designated "resistant" were those that had a reasonable probability of being resistant to the broad-spectrum agents imipenem/cilastatin and piperacillin/tazobactam, and included non-fermenting gram-negative bacilli (e.g., Pseudomonas aeruginosa), resistant gram-positive pathogens, vancomycin-resistant enterococci, and fungi. Patient characteristics were analyzed to define associations with the risk of isolation of "resistant" pathogens. A total of 2,049 intra-abdominal infections were treated during the period of study, of which 1,182 had valid microbiological data. The two genera of pathogens isolated from more than 25% of health care-associated infections and more commonly than from community-acquired infections were Enterococcus spp. (29%) and Candida spp. (33%). Health care association, corticosteroid use, organ transplantation, liver disease, pulmonary disease, and a duodenal source all were associated with resistant pathogens. By multivariable analysis, several acute and chronic measures of disease were predictive of death, with a strong interaction between solid organ transplantation, resistant pathogens, and death. Other links between specific pathogens and patient characteristics were documented, for example, between fungal infection and a gastric, duodenal, or small bowel source, and between liver transplantation and vancomycin-resistant enterococci. On the basis of clinical characteristics, it may be possible to identify patients with intra-abdominal infections caused by pathogens that are potentially resistant to broad-spectrum antibacterial agents. Under these circumstances, and if warranted clinically, broadened coverage probably ought to include specific anti-enterococcal and anti-candidal therapy.


Cyclic AMP-regulated synthesis of the tissue inhibitors of metalloproteinases suppresses the invasive potential of the human fibrosarcoma cell line HT1080.
Tissue inhibitors of metalloproteinases (TIMPs) play an important role in regulating the activity of matrix metalloproteinases (MMPs). Tumor cell invasion and metastasis closely correlate with the activities of two members of MMPs, MMP2 and MMP9, both of which degrade type IV collagen in basement membranes. We herein report that the treatment of HT1080 cells with 8-bromo-cAMP and other chemicals that activate cyclic adenylase activity induces the expression of TIMP1 and TIMP2 both at the mRNA and the protein levels and that this induction of TIMPs correlates with suppression of invasive phenotypes of HT1080 cells. Treatment with various cAMP-elevating reagents induced the expression of TIMPs and MMP2 in HT1080 cells, whereas the expression of MMP9 was not significantly affected. The protein amounts of TIMP1, TIMP2, and MMP2 secreted into the medium from HT1080 cells treated with 1 mM 8-bromo-cAMP were 7.9-, 9.3-, and 8.5-fold higher than those secreted from untreated cells, respectively. Induction of these mRNAs by 8-bromo-cAMP was blocked by HA1004, a protein kinase A inhibitor, but not by calphostin C, a protein kinase C inhibitor. Cycloheximide abolished the induction of TIMPs and MMP2 mRNAs by 8-bromo-cAMP, indicating that the induction depends on a newly synthesized protein(s) whose expression may be regulated by cAMP. Type IV collagenolytic activity and the invasiveness of HT1080 cells, both of which were suppressed by 8-bromo-cAMP, were efficiently restored when the cells were exposed to anti-TIMP antibodies, demonstrating the importance of the increased levels of TIMP1 and TIMP2 proteins for the cAMP-mediated suppression of both type IV collagenolytic activity and the invasiveness of HT1080 cells.


The Otology Data Collection project: report from the CHEER network.
To describe and communicate data collected in the CHEER (Creating Healthcare Excellence through Education and Research) infrastructure proof-of-concept study to facilitate understanding of the potential capabilities of practice-based research networks and to present pilot data for development of future research initiatives. Prospective observational study of CHEER infrastructure operational capacity using a convenience sample of all patients presenting to the practices with tinnitus, dizziness, or a combination of these symptoms. The CHEER network of community and academic practice sites. The data collection exercise collected demographic, clinical, treatment, and health-related quality-of-life surveys on tinnitus, dizziness, and migraine disorders. Descriptive analysis of the data is presented. Of the sites in the CHEER network, 73% (16/22) successfully enrolled subjects; a total of 1532 patients were enrolled in 8 months. Tinnitus alone, dizziness alone, and both occurred in 28%, 34%, and 29%, respectively. Patients complaining of tinnitus and dizziness had lower quality of life than those sufferers with 1 disorder. Migraine was associated with 27% of patients. The most frequent diagnoses for patients with tinnitus and dizziness were Ménière disease (34%), vertiginous migraine (18%), and benign paroxysmal positional vertigo (16%). Descriptive data on patients with common disorders can be rapidly collected within the framework of a practice-based research network. The data in this study provide valuable pilot information on the targeted disorders, providing a baseline for development of future epidemiological data and clinical trials.


Optical near-field mapping of plasmonic nanoprisms.
The optical local-field enhancement on nanometer length scales provides the basis for plasmonic metal nanostructures to serve as molecular sensors and as nanophotonic devices. However, particle morphology and the associated surface plasmon resonance alone do not uniquely reflect the important details of the local field distribution. Here, we use interferometric homodyne tip-scattering near-field microscopy for plasmonic near-field imaging of crystalline triangular silver nanoprisms. Strong spatial field variation on lengths scales as short as 20 nm are observed sensitively depending on structural details and environment. The poles of the dipole and quadrupole plasmon modes, as identified by phase-sensitive probing and calculations performed in the discrete dipole approximation (DDA), reflect the particle symmetry. Together with the observation that the largest enhancement is not necessarily found to be associated with the tips of the nanoprisms, our results provide critical information for the selection of particle geometries as building blocks for plasmonic device applications.


Home-based rehabilitation for COPD using minimal resources: a randomised, controlled equivalence trial.
Pulmonary rehabilitation is a cornerstone of care for COPD but uptake of traditional centre-based programmes is poor. We assessed whether home-based pulmonary rehabilitation, delivered using minimal resources, had equivalent outcomes to centre-based pulmonary rehabilitation. A randomised controlled equivalence trial with 12 months follow-up. Participants with stable COPD were randomly assigned to receive 8 weeks of pulmonary rehabilitation by either the standard outpatient centre-based model, or a new home-based model including one home visit and seven once-weekly telephone calls from a physiotherapist. The primary outcome was change in 6 min walk distance (6MWD). We enrolled 166 participants to receive centre-based rehabilitation (n=86) or home-based rehabilitation (n=80). Intention-to-treat analysis confirmed non-inferiority of home-based rehabilitation for 6MWD at end-rehabilitation and the confidence interval (CI) did not rule out superiority (mean difference favouring home group 18.6 m, 95% CI -3.3 to 40.7). At 12 months the CI did not exclude inferiority (-5.1 m, -29.2 to 18.9). Between-group differences for dyspnoea-related quality of life did not rule out superiority of home-based rehabilitation at programme completion (1.6 points, -0.3 to 3.5) and groups were equivalent at 12 months (0.05 points, -2.0 to 2.1). The per-protocol analysis showed the same pattern of findings. Neither group maintained postrehabilitation gains at 12 months. This home-based pulmonary rehabilitation model, delivered with minimal resources, produced short-term clinical outcomes that were equivalent to centre-based pulmonary rehabilitation. Neither model was effective in maintaining gains at 12 months. Home-based pulmonary rehabilitation could be considered for people with COPD who cannot access centre-based pulmonary rehabilitation. NCT01423227, clinicaltrials.gov.


Influenza and COVID-19: What does co-existence mean?
The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 continues to have a major impact on healthcare and social systems throughout the world. As the clinical and epidemiological features of COVID-19 have many parallels with influenza, it is important to ensure optimal management of both respiratory diseases as we anticipate their continued co-circulation. In particular, there is a need to ensure that effective surveillance and diagnostic capacities are in place to monitor these and other respiratory viruses, as this will underpin decisions on the appropriate clinical management of the respective diseases. As such, we propose a series of key recommendations for stakeholders, public health authorities, primary care physicians and surveillance bodies that will help mitigate the combined risks of concurrent influenza epidemics and the COVID-19 pandemic. We advocate the judicious use of influenza vaccines and antivirals, particularly among groups at high risk of complications, with healthcare workers also considered a priority for vaccination. It is likely that the increased use of emerging technologies such as telemedicine and contact tracing will permanently change our approach to managing infectious disease. The use of these technologies, alongside existing pharmaceutical strategies, will ensure that we achieve a holistic approach to the global public health measures needed to deal with the combined threat of influenza and COVID-19. Ensuring that this approach is optimal will be key as we move from a reactive pandemic response towards preparing for the long-term management of the remarkable clinical burden associated with these respiratory pathogens.


Cooperation between C/EBPalpha TBP/TFIIB and SWI/SNF recruiting domains is required for adipocyte differentiation.
Chromatin remodeling is an important step in promoter activation during cellular lineage commitment and differentiation. We show that the ability of the C/EBPalpha transcription factor to direct adipocyte differentiation of uncommitted fibroblast precursors and to activate SWI/SNF-dependent myeloid-specific genes depends on a domain, C/EBPalpha transactivation element III (TE-III), that binds the SWI/SNF chromatin remodeling complex. TE-III collaborates with C/EBPalpha TBP/TFIIB interaction motifs during induction of adipogenesis and adipocyte-specific gene expression. These results indicate that C/EBPalpha acts as a lineage-instructive transcription factor through SWI/SNF-dependent modification of the chromatin structure of lineage-specific genes, followed by direct promoter activation via recruitment of the basal transcription-initiation complex, and provide a mechanism by which C/EBPalpha can mediate differentiation along multiple cellular lineages.