A global regulator of secondary metabolite production in Pseudomonas fluorescens Pf-5.
Mutations in the apdA (for antibiotic production) gene of the plant root-colonizing bacterium Pseudomonas fluorescens Pf-5 pleiotropically abolish the production of an array of antibiotics, including pyrrolnitrin, pyoluteorin, and 2,4-diacetylphloroglucinol, as well as the production of tryptophan side chain oxidase, hydrogen cyanide, and an extracellular protease. The lack of production of secondary metabolites by ApdA- mutants was correlated with the loss of inhibition of the phytopathogenic fungus Rhizoctonia solani in culture. Sequencing of the apdA region identified an open reading frame of 2,751 bp. The predicted amino acid sequence of the apdA gene contains conserved domains of the histidine kinases that serve as sensor components of prokaryotic two-component regulatory systems. The apdA nucleotide and predicted amino acid sequences are strikingly similar to the sequences of lemA and repA, genes encoding putative sensor kinases that are required for the pathogenicity of Pseudomonas syringae pv. syringae and Pseudomonas viridiflava, respectively. Introduction of the cloned apdA+ gene restored the wild-type phenotype to both LemA- mutants of P. syringae and ApdA- mutants of Pf-5. The 101-kDa ApdA protein reacted with an anti-LemA antiserum, further demonstrating the similarity of ApdA to LemA. These results show that apdA encodes a putative sensor kinase component of a classical two-component regulatory system that is required for secondary-metabolite production by P. fluorescens Pf-5.


Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe.
To identify participants' characteristics that influence the anti-fracture efficacy of vitamin D or vitamin D plus calcium with respect to any fracture, hip fracture, and clinical vertebral fracture and to assess the influence of dosing regimens and co-administration of calcium. Individual patient data analysis using pooled data from randomised trials. Seven major randomised trials of vitamin D with calcium or vitamin D alone, yielding a total of 68 517 participants (mean age 69.9 years, range 47-107 years, 14.7% men). Studies included were randomised studies with at least one intervention arm in which vitamin D was given, fracture as an outcome, and at least 1000 participants. Logistic regression analysis was used to identify significant interaction terms, followed by Cox's proportional hazards models incorporating age, sex, fracture history, and hormone therapy and bisphosphonate use. Trials using vitamin D with calcium showed a reduced overall risk of fracture (hazard ratio 0.92, 95% confidence interval 0.86 to 0.99, P=0.025) and hip fracture (all studies: 0.84, 0.70 to 1.01, P=0.07; studies using 10 microg of vitamin D given with calcium: 0.74, 0.60 to 0.91, P=0.005). For vitamin D alone in daily doses of 10 microg or 20 microg, no significant effects were found. No interaction was found between fracture history and treatment response, nor any interaction with age, sex, or hormone replacement therapy. This individual patient data analysis indicates that vitamin D given alone in doses of 10-20 microg is not effective in preventing fractures. By contrast, calcium and vitamin D given together reduce hip fractures and total fractures, and probably vertebral fractures, irrespective of age, sex, or previous fractures.


Prenatal exposure to maternal low or high protein diets induces modest changes in the adipose tissue proteome of newborn piglets.
The possibility that maternal diets during gestation could affect growth and tissue development of offspring and program their later phenotype is an emerging challenge in pig production. The objective of the current study was to investigate the effects of contrasted protein levels in diets of pregnant sows on the proteomic features of subcutaneous adipose tissue (SCAT) of the offspring at birth and its possible persistence later in age. Sows were fed control (Con), low (LP), or high protein (HP) diets throughout gestation. A subset of piglets was killed at 1 d of age for SCAT sampling. The remaining piglets were cross-fostered to nonexperimental sows during lactation. They were fed standard diets during postweaning and fattening periods until 186 d of age. Modifications in SCAT protein abundance shortly after birth were investigated by 2-dimensional gel electrophoresis followed by mass spectrometry. A total of 65 spots were found differentially expressed (P <or= 0.10) in SCAT of 1-d-old experimental piglets vs. Con piglets. Proteins with a greater abundance in LP piglets compared with Con piglets were involved in pathways related to glucose and fatty acid metabolisms, lipid transport, and regulation of apoptosis. Upregulation of 5 proteins representative of these biological pathways in LP group vs. Con group were further validated (P < 0.05) by Western blot analyses. Furthermore, the specific activity of the key lipogenic enzyme fatty acid synthase was found greater (P = 0.06) in SCAT of 1-d-old LP piglets than in Con piglets. The main changes evidenced in SCAT of HP piglets compared with Con animals at 1 d of age rather concerned proteins putatively involved in AA metabolism or in protein turnover. Adipose tissue contents in some proteins that had displayed a greater (P <or= 0.10) abundance in experimental pigs compared with Con at d 1 (e.g., transaldolase, annexin II, and apolipoprotein A4) were, however, similar (P > 0.10) in the 3 groups at d 186 of age. Enolase 1 has less abundance (P < 0.05) in LP pigs compared with Con pigs at this stage. In conclusion, the proteomics tool has allowed the identification of early changes in various molecular pathways of SCAT in response to the levels of maternal protein supply during gestation.


From bulk crystallization of inorganic nanoparticles at the air/water interface: tunable organization and intense structural colors.
The "flipping method" is a new straightforward way to both adsorb and organize microparticles at a liquid interface, with ultralow amounts of a surfactant and no other external forces than gravity. Here we demonstrate that it allows the adsorption of a variety of inorganic nanoparticles at an air/water interface, in an organized way, which is directly controlled by the surfactant concentration, ranging from amorphous to highly crystalline two-dimensional assemblies. With micromolar amounts of a conventional cationic surfactant (dodecyltrimethylammonium bromide, DTAB), nanoparticles of different compositions (silica, silver, and gold), sizes (down to 100 nm) and shapes (spheres and cubes) adsorb from the bulk and directly organize at the air/water interface, resulting in marked optical properties such as reflectivity or intense structural coloration.


Tolerance to the luteinizing hormone and prolactin suppressive effects of delta-9-tetrahydrocannabinol develops during chronic prepubertal treatment of female rats.
To determine if prepubertal female rats develop tolerance to the hormone suppressive action of delta-9-tetrahydrocannabinol (THC), we tested the ability of THC (10 mg/kg i.p.) to block luteinizing hormone (LH) and prolactin (PRL) surges acutely at first proestrus in animals that were treated repetitively with THC before puberty. Rats were pretreated with 10 mg THC/kg b.wt. twice daily beginning at 27 days of age and the blocking efficacy of THC treatment at first proestrus was compared to that in animals that were previously untreated or were pretreated only with drug vehicle. Vaginae were opened at 30 days of age to permit identification of first proestrus by vaginal smears, and serial blood samples for LH and PRL radioimmunoassays were collected before and after treatment at proestrus. In previously untreated or vehicle-pretreated animals, THC treatment at 1300 hr on the day of first proestrus inhibited the afternoon surges of LH and PRL, whereas hormone surges occurred in control animals injected with only vehicle at 1300 hr proestrus (P less than .05). In contrast, animals pretreated with THC exhibited marked LH and PRL surges whether treated at 1300 hr proestrus with THC or vehicle. Among animals receiving only vehicle at proestrus, there was no difference in serum LH concentrations or in timing of the LH surge between the group pretreated with THC and the group pretreated with vehicle. These results are consistent with the hypothesis that ovulation eventually occurs in the pubertal rat treated chronically with THC because tolerance develops to its gonadotropin suppressive effects.


Photodynamic therapy with verteporfin for age-related macular degeneration or polypoidal choroidal vasculopathy: comparison of the presence of serous retinal pigment epithelial detachment.
To evaluate outcomes after photodynamic therapy (PDT) with verteporfin in Japanese patients with age-related macular degeneration (AMD) or polypoidal choroidal vasculopathy (PCV) and compare results with the presence/absence of a retinal pigment epithelial detachment (PED). We retrospectively reviewed 183 eyes with subfoveal choroidal neovascularisation secondary to AMD with more than 3 months' follow-up (range 3 to 36; mean 15.6). A serous PED developed in 44 of 183 eyes. A total of 124 eyes (67.8%) completed 12 months' follow-up. In 49 eyes with typical AMD, the best-corrected visual acuity (BCVA) improved a mean of 0.48 line. A significant (p<0.05 to p<0.0005) decline in VA occurred in eyes with a serous PED during any 3-month period. In 75 eyes with PCV, the BCVA at 12 months improved a mean of 1.79 lines. There was no significant difference between the BCVA in 22 eyes with a PED and 53 eyes without a PED during any 3 months. In eyes with typical AMD, a serous PED was associated with a significant decline in BCVA compared with eyes without a serous PED. In eyes with PCV, the visual outcomes were unaffected by a serous PED. When PDT is administered, differentiating PCV from typical AMD using indocyanine green angiography is important.


Operational Recommendations for Scarce Resource Allocation in a Public Health Crisis.
The coronavirus disease 2019 pandemic may require rationing of various medical resources if demand exceeds supply. Theoretical frameworks for resource allocation have provided much needed ethical guidance, but hospitals still need to address objective practicalities and legal vetting to operationalize scarce resource allocation schemata. To develop operational scarce resource allocation processes for public health catastrophes, including the coronavirus disease 2019 pandemic, five health systems in Maryland formed a consortium-with diverse expertise and representation-representing more than half of all hospitals in the state. Our efforts built on a prior statewide community engagement process that determined the values and moral reference points of citizens and health-care professionals regarding the allocation of ventilators during a public health catastrophe. Through a partnership of health systems, we developed a scarce resource allocation framework informed by citizens' values and by general expert consensus. Allocation schema for mechanical ventilators, ICU resources, blood components, novel therapeutics, extracorporeal membrane oxygenation, and renal replacement therapies were developed. Creating operational algorithms for each resource posed unique challenges; each resource's varying nature and underlying data on benefit prevented any single algorithm from being universally applicable. The development of scarce resource allocation processes must be iterative, legally vetted, and tested. We offer our processes to assist other regions that may be faced with the challenge of rationing health-care resources during public health catastrophes.


Testing scale-dependent effects of seminatural habitats on farmland biodiversity.
The effectiveness of conservation interventions for maximizing biodiversity benefits from agri-environment schemes (AESs) is expected to depend on the quantity of seminatural habitats in the surrounding landscape. To verify this hypothesis, we developed a hierarchical sampling design to assess the effects of field boundary type and cover of seminatural habitats in the landscape at two nested spatial scales. We sampled three types of field boundaries with increasing structural complexity (grass margin, simple hedgerow, complex hedgerow) in paired landscapes with the presence or absence of seminatural habitats (radius 0.5 km), that in turn, were nested within 15 areas with different proportions of seminatural habitats at a larger spatial scale (10 X 10 km). Overall, 90 field boundaries were sampled across a Mediterranean'region (northeastern Italy). We considered species richness response across three different taxonomic groups: vascular plants, butterflies, and tachinid flies. No interactions between type of field boundary and surrounding landscape were found at either 0.5 and 10 km, indicating that the quality of field boundary had the same effect irrespective of the cover of seminatural habitats. At the local scale, extended-width grass margins yielded higher plant species richness, while hedgerows yielded higher species richness of butterflies and tachinids. At the 0.5-km landscape scale, the effect of the proportion of seminatural habitats was neutral for plants and tachinids, while butterflies were positively related to the proportion of forest. At the 10-km landscape scale, only butterflies responded positively to the proportion of seminatural habitats. Our study confirmed the importance of testing multiple scales when considering species from different taxa and with different mobility. We showed that the quality of field boundaries at the local scale was an important factor in enhancing farmland biodiversity. For butterflies, AESs should focus particular attention on preservation'of forest patches in agricultural landscapes within 0.5 kin, as well as the conservation of seminatural habitats at a wider landscape scale.


Associations of dietary diversity scores and micronutrient status in adolescent Mozambican girls.
In low-income settings, dietary diversity scores (DDSs) often predict the micronutrient adequacy of diets, but little is known about whether they predict levels of biochemical indicators of micronutrient status. In 2010, we studied two samples of non-pregnant 14- to 19-year-old girls in central Mozambique, the first in January-February ('hunger season'; n = 227) and the second in May-June (harvest season; n = 223). In this paper, we examined whether a low Women's Dietary Diversity Score (WDDS) predicts a low concentration of haemoglobin, serum ferritin, zinc, and folate, and plasma retinol in adolescent Mozambican girls. We constructed three scores: WDDS based on 24-h recalls, WDDS15g based on 24-h recall and employing a 15 g limit, and 7dWDDS based on 7-day food frequency questionnaires. Logistic regression models, stratified by season, were used to estimate the odds of having a low concentration of a status indicator (≤25th percentile of the season-specific distribution or cut-off from the literature) in those with a low score compared to those with a higher score. In January-February, after adjusting for confounders, a low (≤3) WDDS and a low (≤5) 7dWDDS were each associated with higher odds of having low serum zinc compared to having a higher score, regardless of which of the two types of cut-offs for serum zinc was used. These associations were not present in May-June. Our data from Mozambique suggest that dietary diversity is associated with serum zinc, but this association seems to be limited to the hunger season.


Aluminum-induced entropy in biological systems: implications for neurological disease.
Over the last 200 years, mining, smelting, and refining of aluminum (Al) in various forms have increasingly exposed living species to this naturally abundant metal. Because of its prevalence in the earth's crust, prior to its recent uses it was regarded as inert and therefore harmless. However, Al is invariably toxic to living systems and has no known beneficial role in any biological systems. Humans are increasingly exposed to Al from food, water, medicinals, vaccines, and cosmetics, as well as from industrial occupational exposure. Al disrupts biological self-ordering, energy transduction, and signaling systems, thus increasing biosemiotic entropy. Beginning with the biophysics of water, disruption progresses through the macromolecules that are crucial to living processes (DNAs, RNAs, proteoglycans, and proteins). It injures cells, circuits, and subsystems and can cause catastrophic failures ending in death. Al forms toxic complexes with other elements, such as fluorine, and interacts negatively with mercury, lead, and glyphosate. Al negatively impacts the central nervous system in all species that have been studied, including humans. Because of the global impacts of Al on water dynamics and biosemiotic systems, CNS disorders in humans are sensitive indicators of the Al toxicants to which we are being exposed.


Preserving human potential as freedom: a framework for regulating epigenetic harms.
Epigenetics is a rapidly evolving scientific field of inquiry examining how a wide range of environmental, social, and nutritional exposures can dramatically control how genes are expressed without changing the underlying DNA. Research has demonstrated that epigenetics plays a large role in human development and in disease causation. In a sense, epigenetics blurs the distinction between "nature" and "nurture" as experiences (nurture) become a part of intrinsic biology (nature). Remarkably, some epigenetic modifications are durable across generations, meaning that exposures from our grandparents' generation might affect our health now, even if we have not experienced the same exposures. In the same vein, current exposures could affect the health of not only individuals currently living but also future generations. Given the relative novelty of epigenetics research and the multifactorial nature of human development and disease causation, it is unlikely that conclusive proof can be established showing that particular exposures lead to epigenetic risks that manifest into specific conditions. Using the Capabilities Approach ("CA") developed by Amartya Sen and Martha Nussbaum, this article argues that epigenetic risk is not merely a medical issue, but that it more generally implicates the underlying fairness and justice of our social contract. For instance, how we develop mentally or physically has a tremendous impact upon our inherent capabilities and our set of life options. The CA prompts us to ask questions such as: (1) what impact do particular epigenetic risks have on our ability to exercise free choices; (2) are these risks avoidable; and (3) how are these risks distributed across society? Due to the complex nature of epigenetic risk, tort law is predictably incapable of addressing this harm. Further, while regulatory agencies possess the statutory authority to begin addressing epigenetic harms, currently these agencies are not attuned to measure or to respond to this type of harm. This article argues that it is imperative to initiate a regulatory framework to address epigenetic risk from specific substances even if conclusive proof of disease causation cannot be established. Shifting the burden of generating epigenetic risk data to producers of suspected harmful substances serves as a start. As information concerning epigenetic risks accrues, the regulatory response should evolve concurrently. As part of a dynamic policy-making approach our goals need to encompass the following: (i) promotion of knowledge in the scientific, legal, and public domains; (ii) assessment and modification of current regulations to address preventable risk; and (iii) an overarching commitment to protect human capabilities in an equitable manner.


[Anger and health status in late school-age children].
This cross-sectional study was designed to identify anger-expression types in late school-age children and investigate the relation between the identified anger-expression types and their health status. One thousand twenty seven children in elementary school fifth and sixth grades were recruited from November to December, 2004. Data was analyzed using descriptive statistics, cluster analysis, 2-test, ANOVA, Duncan's multiple comparison test, and Wilcoxon rank sum test. Three anger-expression types in late school-age children were found; Anger-out/in, Anger-control, and Low anger-expression types. Children frequently using the anger-out/in type among the three types and with a higher state anger reported higher psychosomatic symptoms and depression. Children from a divorced or separated family reported higher state anger. This study suggests that a specific anger management program needs to be developed for late school-age children with high state anger and frequently using the anger out/in expression type. For understanding the anger level and the anger expression types of Korean school-age children, further research needs to be done with large samples using a randomized sampling method.


Darwin's Duchenne: eye constriction during infant joy and distress.
Darwin proposed that smiles with eye constriction (Duchenne smiles) index strong positive emotion in infants, while cry-faces with eye constriction index strong negative emotion. Research has supported Darwin's proposal with respect to smiling, but there has been little parallel research on cry-faces (open-mouth expressions with lateral lip stretching). To investigate the possibility that eye constriction indexes the affective intensity of positive and negative emotions, we first conducted the Face-to-Face/Still-Face (FFSF) procedure at 6 months. In the FFSF, three minutes of naturalistic infant-parent play interaction (which elicits more smiles than cry-faces) are followed by two minutes in which the parent holds an unresponsive still-face (which elicits more cry-faces than smiles). Consistent with Darwin's proposal, eye constriction was associated with stronger smiling and with stronger cry-faces. In addition, the proportion of smiles with eye constriction was higher during the positive-emotion eliciting play episode than during the still-face. In parallel, the proportion of cry-faces with eye constriction was higher during the negative-emotion eliciting still-face than during play. These results are consonant with the hypothesis that eye constriction indexes the affective intensity of both positive and negative facial configurations. A preponderance of eye constriction during cry-faces was observed in a second elicitor of intense negative emotion, vaccination injections, at both 6 and 12 months of age. The results support the existence of a Duchenne distress expression that parallels the more well-known Duchenne smile. This suggests that eye constriction-the Duchenne marker-has a systematic association with early facial expressions of intense negative and positive emotion.


On chip tunable micro ring resonator actuated by electrowetting.
We demonstrate a tunable on chip polymer waveguide micro ring resonator (MRR) device. The transmission spectrum and extinction ratio are controlled by electrowetting on dielectric (EWOD), via the application of voltage to a droplet. As a result the droplet covers a portion of the MRR waveguide and changes its effective refractive index. This method can be used for efficiently tuning a variety of on chip optical devices, as it offers high index contrast, electrical control and low power consumption.


A low-power 32-channel digitally programmable neural recording integrated circuit.
We report the design of an ultra-low-power 32-channel neural-recording integrated circuit (chip) in a 0.18 μ m CMOS technology. The chip consists of eight neural recording modules where each module contains four neural amplifiers, an analog multiplexer, an A/D converter, and a serial programming interface. Each amplifier can be programmed to record either spikes or LFPs with a programmable gain from 49-66 dB. To minimize the total power consumption, an adaptive-biasing scheme is utilized to adjust each amplifier's input-referred noise to suit the background noise at the recording site. The amplifier's input-referred noise can be adjusted from 11.2 μVrms (total power of 5.4 μW) down to 5.4 μVrms (total power of 20 μW) in the spike-recording setting. The ADC in each recording module digitizes the a.c. signal input to each amplifier at 8-bit precision with a sampling rate of 31.25 kS/s per channel, with an average power consumption of 483 nW per channel, and, because of a.c. coupling, allows d.c. operation over a wide dynamic range. It achieves an ENOB of 7.65, resulting in a net efficiency of 77 fJ/State, making it one of the most energy-efficient designs for neural recording applications. The presented chip was successfully tested in an in vivo wireless recording experiment from a behaving primate with an average power dissipation per channel of 10.1 μ W. The neural amplifier and the ADC occupy areas of 0.03 mm(2) and 0.02 mm(2) respectively, making our design simultaneously area efficient and power efficient, thus enabling scaling to high channel-count systems.


Antidepressant and Anxiolytic Effects of Medicinal Cannabis Use in an Observational Trial.
Background: Anxiety and depressive disorders are highly prevalent. Patients are increasingly using medicinal cannabis products to treat these disorders, but little is known about the effects of medicinal cannabis use on symptoms of anxiety and depression. The aim of the present observational study was to assess general health in medicinal cannabis users and non-using controls with anxiety and/or depression. Methods: Participants (368 Cannabis Users; 170 Controls) completed an online survey assessing anxiety and depressive symptoms, cannabis product use, sleep, quality of life, and comorbid chronic pain. Participants that completed this baseline survey were then invited to complete additional follow-up surveys at 3-month intervals. Baseline differences between Cannabis Users and Controls were assessed using independent-samples t-tests and generalized linear mixed effects models were used to assess the impact of initiating cannabis product use, sustained use, or discontinuation of use on anxiety and depressive symptoms at follow-up. Results: Medicinal cannabis use was associated with lower self-reported depression, but not anxiety, at baseline. Medicinal cannabis users also reported superior sleep, quality of life, and less pain on average. Initiation of medicinal cannabis during the follow-up period was associated with significantly decreased anxiety and depressive symptoms, an effect that was not observed in Controls that never initiated cannabis use. Conclusions: Medicinal cannabis use may reduce anxiety and depressive symptoms in clinically anxious and depressed populations. Future placebo-controlled studies are necessary to replicate these findings and to determine the route of administration, dose, and product formulation characteristics to optimize clinical outcomes.


Advancing pharmacological treatments for opioid use disorder (ADaPT-OUD): protocol for testing a novel strategy to improve implementation of medication-assisted treatment for veterans with opioid use disorders in low-performing facilities.
In the US, emergency room visits and overdoses related to prescription opioids have soared and the rates of illicit opioid use, including heroin and fentanyl, are increasing. Opioid use disorder (OUD) is associated with higher morbidity and mortality, higher HIV and HCV infection rates, and criminal behavior. Opioid agonist therapy (OAT; methadone and buprenorphine) is proven to be effective in treating OUD and decreasing its negative consequences. While the efficacy of OAT has been established, too few providers prescribe OAT to patients with OUD due to patient, provider, or system factors. While the Veterans Health Administration (VHA) has made great strides in OAT implementation, national treatment rates remain low (35% of patients with OUD) and several facilities continue to have much lower prescribing rates. Eight VA sites with low baseline prescribing rates (lowest quartile, < 21%) were randomly selected from the 35 low prescribing sites to receive an intensive external facilitation implementation intervention to increase OAT prescribing rates. The intervention includes a site-specific developmental evaluation, a kick-off site visit, and 12 months of ongoing facilitation. The developmental evaluation includes qualitative interviews with patients, substance use disorders clinic staff, and primary care and general mental health leadership to assess site-level barriers. The site visit includes: (1) a review of site-specific barriers and potential implementation strategies; (2) instruction on using available dashboards to track prescribing rates and identify actionable patients; and (3) education on OAT, including, if requested, buprenorphine certification training for prescribers. On-going facilitation consists of monthly conference calls with individual site teams and expert clinical consultation. The primary outcomes is the proportion of Veterans with OUD initiating and sustaining OAT, with intervention sites expected to have larger increases in prescribing compared to control sites. Final qualitative interviews and a cost assessment will inform future implementation efforts. This project will examine and respond to barriers encountered in low prescribing VHA clinics allowing refinement of an intervention to enhance access to medication treatment for OUD in additional facilities.


Olfactomedin 4 (OLFM4) expression is associated with nodal metastases in esophageal adenocarcinoma.
To date no informative biomarkers exist to accurately predict presence of lymph node metastases (LNM) in esophageal adenocarcinoma (EAC). We studied the discriminative value of Olfactomedin 4 (OLFM4), an intestinal stem cell marker, in EAC. Patients who had undergone esophagectomy as single treatment modality for both advanced (pT2-4) and early (pT1b) adenocarcinoma of the esophagus or gastro-esophageal junction were selected for this study from an institutional database (Erasmus MC University Medical Center, Rotterdam, The Netherlands). Surgical resection specimens of 196 advanced and 44 early EAC were examined. OLFM4 expression was studied by immunohistochemistry and categorized as low (<30%) or high (> = 30%) expression. Low OLFM4 was associated with poor differentiation grade in both advanced (60% vs. 34.8%, p = 0.001) and early EAC (39.1% vs. 9.5%, p = 0.023). LNM were present in 161 (82.1%) of advanced and 9 (20.5%) of early EAC respectively. Low OLFM4 was independently associated with the presence of LNM in advanced EAC in multivariable analysis (OR 2.7; 95% CI, 1.16-6.41; p = 0.022), but not in early EAC (OR 2.1; 95% CI, 0.46-9.84; p = 0.338). However, the difference in association with LNM between advanced (OR 2.7; 95% CI, 1.18-6.34; p = 0.019) and early (OR 2.3; 95% CI, 0.47-11.13; p = 0.302) EAC was non-significant (p = 0.844), suggesting that the lack of significance in early EAC is due to the small number of patients in this group. OLFM4 was not of significance for the disease free and overall survival. Overall, low expression of intestinal stem cell marker OLFM4 was associated with the presence of LNM. Our study suggests that OLFM4 could be an informative marker with the potential to improve preoperative assessment in patients with EAC. Further studies are needed to confirm the value of OLFM4 as a biomarker for LNM.


No significant changes in adult T-cell leukemia virus infection in Okinawa after intervals of 13 and 15 years.
Two separate studies were carried out between 1968 and 1984; a total of 2,021 serum samples from healthy subjects were collected in two districts of Okinawa-on Iriomote Island and in Ishigaki City. The first samples were collected in 1970 on Iriomote Island and in 1968 in Ishigaki City. The second samples were collected after an interval of 13 years in Ishigaki City and after an interval of 15 years on Iriomote Island. These serum samples were tested for the presence of antibody to adult T-cell leukemia-associated antigen (anti-ATLA). The overall prevalence of anti-ATLA in both areas combined was 9.9% from 1968 to 1970 and that from 1981 to 1984 was 8.9%. At both times, anti-ATLA prevalence increased with age and was higher in females than in males. No significant changes in anti-ATLA prevalence was observed: after intervals of 13 and 15 years, the prevalence decreased from 10.2 to 9.9% in Ishigaki City and from 9.4 to 8.2% on Iriomote Island. These data suggest that there has been no significant change in the rate of infection with adult T-cell leukemia virus in recent years in the areas studied.


Extensive retroperitoneal hematoma in blunt trauma.
To report our experience of managing extensive retroperitoneal hematoma (RH) in patients with blunt trauma and to determine any associated factors affecting causation and mortality. In this retrospective observational study, patients diagnosed with extensive RH following blunt trauma admitted to King Saud Medical Complex, Riyadh, Kingdom of Saudi Arabia between January 2004 and December 2009 were included. Patient data were explored for injury severity score (ISS), associated injuries, location of hematoma, amount of blood transfusions, coagulation profile, operative management, hospital stay, and mortality. The outcomes in surviving and non-surviving patients were compared. Out of 290 patients presenting with RH, extensive RH was found in 46 patients (15.8%). The overall mortality was 32.6%. The pelvis was the most frequent location of RH in combination with lateral and central zones (65.2%). The lower extremity and pelvic fractures were the most common injury. Associated intra-peritoneal injuries were present in 39.1% patients. An exploratory laparotomy was performed in 58.7% patients (n=27). A high ISS (55.9 versus 35.5, p<0.0001), abnormal coagulation profile (odds ratio [OR] 7.8, 95% confidence interval [CI] 1.974-30.932, p=0.005, and associated chest injuries OR 5.94, 95% CI 1.528-23.19, p=0.014) were independent factors associated with mortality. Multiple musculoskeletal injuries in addition to intra-abdominal injuries and abnormal coagulation are major factors associated with the presence of extensive RH. High ISS, abnormal coagulation, and associated chest injuries are independent factors associated with mortality.


Incident Type 2 diabetes and the effect of early regression to normoglycaemia in a population with impaired glucose regulation.
To report contemporary regression rates from impaired glucose regulation to normal glucose tolerance, identify modifiable factors associated with early regression, and establish whether it affects subsequent diabetes risk in a population-based cohort. Participants with impaired glucose regulation (impaired fasting glucose and/or impaired glucose tolerance on a 75-g oral glucose tolerance test) at baseline in the UK-based ADDITION-Leicester study had annual Type 2 diabetes re-screens for 5 years or until diabetes diagnosis. Logistic regression models investigated modifiable risk factors for regression to normal glucose tolerance at 1 year (n = 817). Cox regression models estimated subsequent diabetes risk (n = 630). At 1 year, 54% of participants had regressed to normal glucose tolerance, and 6% had progressed to diabetes. Regression to normal glucose tolerance was associated with weight loss of 0.1-3% [adjusted odds ratio 1.81 (95% CI 1.08, 3.03) compared with maintaining or gaining weight] and a waist circumference reduction of > 3 cm [adjusted odds ratio 1.78 (95% CI 1.03, 3.06) compared with maintaining or increasing waist circumference]. Those with normal glucose tolerance at 1 year subsequently had lower diabetes risk than those who remained with impaired glucose regulation [adjusted hazard ratio 0.19 (95% CI 0.10, 0.37)]. Early regression to normal glucose tolerance was associated with reduced diabetes incidence, and might be induced by small reductions in weight or waist circumference. If confirmed in experimental research, this could be a clear and achievable target for individuals diagnosed with impaired glucose regulation.


Vi-Vaccinations Induce Heterogeneous Plasma Cell Responses That Associate With Protection From Typhoid Fever.
Vi-polysaccharide conjugate vaccines are efficacious against cases of typhoid fever; however, an absolute correlate of protection is not established. In this study, we investigated the leukocyte response to a Vi-tetanus toxoid conjugate vaccine (Vi-TT) in comparison with a plain polysaccharide vaccine (Vi-PS) in healthy adults subsequently challenged with Salmonella Typhi. Immunological responses and their association with challenge outcome was assessed by mass cytometry and Vi-ELISpot assay. Immunization induced significant expansion of plasma cells in both vaccines with modest T follicular helper cell responses detectable after Vi-TT only. The Vi-specific IgG and IgM B cell response was considerably greater in magnitude in Vi-TT recipients. Intriguingly, a significant increase in a subset of IgA+ plasma cells expressing mucosal migratory markers α4β7 and CCR10 was observed in both vaccine groups, suggesting a gut-tropic, mucosal response is induced by Vi-vaccination. The total plasma cell response was significantly associated with protection against typhoid fever in Vi-TT vaccinees but not Vi-PS. IgA+ plasma cells were not significantly associated with protection for either vaccine, although a trend is seen for Vi-PS. Conversely, the IgA- fraction of the plasma cell response was only associated with protection in Vi-TT. In summary, these data indicate that a phenotypically heterogeneous response including both gut-homing and systemic antibody secreting cells may be critical for protection induced by Vi-TT vaccination.


Metabolic balance studies of mineral supplementation in osteoporosis.
1. We studied the effect of mineral supplementation and its duration in osteoporosis by analysing the calcium and phosphorus balances of 49 treated osteoporotic patients whose median length of calcium treatment was 19 weeks with a range of 8 days to over 4 years. Forty-four studies satisfied statistical criteria of reproducibility and included 35 women (10 also receiving oestrogen replacement therapy) and nine men. 2. Mean calcium balance was positive in women taking calcium supplements alone, +1.9 +/- 2.5 mmol daily (P less than 0.002), and was significantly more positive (P less than 0.05) in women also taking oestrogens, +4.2 +/- 2.1 mmol daily. Calcium balance was not significantly positive in men. 3. Calcium balance correlated negatively with duration of supplementation, but significantly, only when duration of supplementation was expressed logarithmically (r = -0.401, P less than 0.01) giving the regression equation y = 4.2-1.6 log x, where y = calcium balance in mol/day and x = duration of supplementation in weeks. Theoretical net calcium retention, without allowance for dermal loss, could be calculated by integration. 4. Mean phosphorus balance was significantly positive in both groups of women and in the whole population. Although its correlation with duration of supplementation did not reach statistical significance (P less than 0.1), the ratio of the regression slopes for calcium and phosphorus, 1.5:1, corresponded to their molar ratio in bone. 5. These statistics are, we believe, the first to describe an exponential decline in calcium balance during mineral treatment of osteoporosis, but they firmly suggest that such treatment, with or without oestrogen therapy, conveys temporary benefit.


Do Sex Differences Exist in the Establishment of "Do Not Attempt Resuscitation" Orders and Survival in Patients Successfully Resuscitated From In-Hospital Cardiac Arrest?
Background Women have higher utilization of "do not attempt resuscitation" (DNAR) orders during treatment for critical illness. Occurrence of sex differences in the establishment of DNAR orders after resuscitation from in-hospital cardiac arrest is unknown. Whether differences in DNAR use by sex lead to disparities in survival remains unclear. Methods and Results We identified 71 820 patients with return of spontaneous circulation (ROSC) after in-hospital cardiac arrest from the Get With The Guidelines-Resuscitation registry. Multivariable models evaluated the association between de novo DNAR (anytime after ROSC, within 12 hours of ROSC, or within 72 hours of ROSC) by sex and the association between sex and survival to discharge accounting for DNAR. All models accounted for clustering of patients within hospital and adjusted for demographic and cardiac arrest characteristics. The cohort included 30 454 (42.4%) women, who were slightly more likely than male participants to establish DNAR orders anytime after ROSC (45.0% versus 43.5%; adjusted relative risk: 1.15 [95% CI, 1.10-1.20]; P<0.0001). Of those with DNAR orders, women were more likely to be DNAR status within the first 12 hours (51.8% versus 46.5%; adjusted relative risk: 1.40 [95% CI, 1.30-1.52]; P<0.0001) and within 72 hours after ROSC (75.9% versus 70.9%; adjusted relative risk: 1.35 [95% CI, 1.26-1.45]; P<0.0001). However, no difference in survival to hospital discharge between women and men (34.5% versus 36.7%; adjusted relative risk: 1.00 [95% CI, 0.99-1.02]; P=0.74) was appreciated. Conclusions In patients successfully resuscitated from in-hospital cardiac arrest, there was no survival difference between men and women while accounting for DNAR. However, women had a higher rate of DNAR status early after resuscitation (<12 and <72 hours) in comparison to men.


High Sleep Disturbance and Longer Concussion Duration in Repeat Concussions.
Objectives: The relationship between repeated concussions and sleep disturbance is yet to be fully understood. The objective of this study was to examine the relationship between sleep disturbance, concussion duration, and repeated concussions by assessing postconcussive symptoms and cognition. Methods: Subjects (ages 13-33 years) underwent postconcussion cognitive function evaluation and reported postconcussion symptoms including severity of disturbed sleep (drowsiness, trouble falling asleep, sleeping more than usual, and sleeping less than usual), mood disturbance (sadness, irritability, nervousness, and emotional lability), and headache. Data on cognitive function and concussive symptoms were collected for 430 subjects after first concussion, 192 subjects after second concussion, and 118 subjects after three or more concussions. A subset of subjects (119) were monitored longitudinally to assess concussion duration. Analyses included group comparisons, regression, and correlation; data were adjusted for age and gender. Results: Sleep disturbance differed significantly by group (mean[SEM]: 1st concussion = 2.56[0.2]; 2nd concussion = 3.65[0.34]; 3+ concussions = 4.32[0.43]). Concussion history predicts concussion duration (R2 = 0.20, F[1,116] = 27.33, p < 0.001). Furthermore, trouble falling asleep (β = 0.15) and sleeping less than usual (β = 0.15) predicted concussion duration (R2 = 0.062, F[1,116] = 3.15, p = 0.047). Reported sleep disturbance after repeated concussions was higher in patients with higher headache (F[2,732] = 3.15, p = 0.043) and mood disturbance (F[2,733] = 3.35, p = 0.036) severity. In addition, after repeated concussions, the positive correlation between sleep disturbance and cognitive dysfunction strengthened. Conclusions: History of repeated concussion is associated with longer concussion duration and higher reported sleep disturbance. Furthermore, those with sleep disturbance after repeated concussion exhibit more severe headaches, mood disturbance, and cognitive dysfunction.Abbreviations: ImPACT: Immediate Postconcussion Assessment and Cognitive Assessment (ImPACT); this is a computer-based test that assesses an individual's cognitive function and cumulatively documents current concussion symptoms. PCSS: Post Concussion Symptom Scale; this scale assesses the severity of concussion symptoms. SPSS: Statistical Package for Social Sciences. This is a statistical software package.


Dynamic gene and protein expression patterns of the autism-associated met receptor tyrosine kinase in the developing mouse forebrain.
The establishment of appropriate neural circuitry depends on the coordination of multiple developmental events across space and time. These events include proliferation, migration, differentiation, and survival-all of which can be mediated by hepatocyte growth factor (HGF) signaling through the Met receptor tyrosine kinase. We previously found a functional promoter variant of the MET gene to be associated with autism spectrum disorder, suggesting that forebrain circuits governing social and emotional function may be especially vulnerable to developmental disruptions in HGF/Met signaling. However, little is known about the spatiotemporal distribution of Met expression in the forebrain during the development of such circuits. To advance our understanding of the neurodevelopmental influences of Met activation, we employed complementary Western blotting, in situ hybridization, and immunohistochemistry to comprehensively map Met transcript and protein expression throughout perinatal and postnatal development of the mouse forebrain. Our studies reveal complex and dynamic spatiotemporal patterns of expression during this period. Spatially, Met transcript is localized primarily to specific populations of projection neurons within the neocortex and in structures of the limbic system, including the amygdala, hippocampus, and septum. Met protein appears to be principally located in axon tracts. Temporally, peak expression of transcript and protein occurs during the second postnatal week. This period is characterized by extensive neurite outgrowth and synaptogenesis, supporting a role for the receptor in these processes. Collectively, these data suggest that Met signaling may be necessary for the appropriate wiring of forebrain circuits, with particular relevance to the social and emotional dimensions of behavior.


Genetics of human cardiovascular disease.
Cardiovascular disease encompasses a range of conditions extending from myocardial infarction to congenital heart disease, most of which are heritable. Enormous effort has been invested in understanding the genes and specific DNA sequence variants that are responsible for this heritability. Here, we review the lessons learned for monogenic and common, complex forms of cardiovascular disease. We also discuss key challenges that remain for gene discovery and for moving from genomic localization to mechanistic insights, with an emphasis on the impact of next-generation sequencing and the use of pluripotent human cells to understand the mechanism by which genetic variation contributes to disease.


A genomic study on distribution of human leukocyte antigen (HLA)-A and HLA-B alleles in Lak population of Iran.
Anthropological studies based on the highly polymorphic gene, human leukocyte antigen (HLA), provide useful information for bone marrow donor registry, forensic medicine, disease association studies, as well as infertility treatment, designing peptide vaccines against tumors, and infectious or autoimmune diseases. The aim of this study was to determine HLA-A and HLA-B allele frequencies in 100 unrelated Lak/lᴂk/individuals from Lorestan province of Iran. Finally, we compared the results with that previously described in Iranian population. Commercial HLA-Type kits from BAG (Lich, Germany) company were used for determination of the HLA-A and HLA-B allele frequencies in genomic DNA, based on polymerase chain reaction with sequence specific primer (PCR-SSP) assay. The differences between the populations in distribution of HLA-A and HLA-B alleles were estimated by chi-squared test with Yate's correction. The most frequent HLA-A alleles were *24 (20%), *02 (18%), *03 (12%) and *11 (10%), and the most frequent HLA-B alleles were *35 (24%), *51 (16%), *18 (6%) and *38 (6%) in Lak population. HLA-A*66 (1%), *74(1%) and HLA-B*48 (1%), *55(1%) were the least observed frequencies in Lak population. Our results based on HLA-A and HLA-B allele frequencies showed that Lak population possesses the previously reported general features of Iranians but still with unique.


Morphological and Molecular Description of Rhadinorhynchus hiansi Soota and Bhattacharya, 1981 (Acanthocephala: Rhadinorhynchidae) from Marine Fish off the Pacific Coast of Vietnam.
Rhadinorhynchus hiansi Soota and Bhattacharya, 1981 , has remained unknown since its original incomplete description from 2 male specimens collected from the flat needlefish Ablennes hians Valenciennes (Belonidae) off Trivandrum, Kerala, India. Recent collections of fishes along the Pacific coast of Vietnam in 2016 and 2017 produced many specimens of the same species from the striped bonito Sarda orientalis Temminck and Schlegel (Scombridae) off the southern Pacific coast of Vietnam at Nha Trang. We describe females for the first time, assign a female allotype status, and provide an expanded description of males from a larger collection completing missing information on hooks and hook roots, receptacle, lemnisci, cement glands, Saefftigen's pouch, and trunk spines. Specimens of R. hiansi characteristically have no dorsal spines in the posterior field of trunk spines and a long proboscis with 36-48 dorso-ventrally differentiated proboscis hooks per row becoming progressively smaller posteriorly then increasing in size near the posterior end to a maximum at the posterior-most ring. Trunk, testes, and lemnisci in our specimens were considerably larger than those reported in the original description, but the proboscis was relatively smaller. The females had long reproductive system and corrugated elliptic eggs without polar prolongation of fertilization membrane. Energy Dispersive X-ray Analysis (EDXA) demonstrates high levels of calcium and phosphorus in large gallium cut hooks and high levels of sulfur in tip cuts of large and small hooks and in spines. This EDXA pattern is a characteristic fingerprint of R. hiansi. The molecular profile of R. hiansi is described from 18S rDNA and COI genes, and phylogenetic relationships with most closely related species are discussed.


Müller cell expression of glial fibrillary acidic protein after genetic and experimental photoreceptor degeneration in the rat retina.
Glial fibrillary acidic protein (GFAP) is normally found in astrocytes. In the normal rat retina at all ages, only astrocytes stain for GFAP. This staining pattern is also found in RCS rats with inherited retinal dystrophy younger than 38 days. Beginning on day 38, when about 61% of the photoreceptors have degenerated, a few GFAP-positive fibers span the retina from the inner limiting membrane to the external limiting membrane. By day 41 and at all later ages examined, the radial fibers of Müller cells is a response to photoreceptor necrosis or might be a direct effect of the mutant gene, we induced photoreceptor degeneration in normal, adult Sprague-Dawley rats by exposing them to constant light for variable periods of time. After 3 days in constant light, there is a 20% reduction in the number of photoreceptors and many Müller cells are positive for GFAP. Immunoblot studies confirmed that the anti-GFAP reacted with a single protein from retina that corresponded in molecular weight and Triton-insolubility to GFAP. The immunoblots also corroborated the results from anti-GFAP immunostaining of control and experimental retinas. These results indicate that Müller cells express GFAP immunoreactivity in response to experimentally as well as genetically induced photoreceptor degeneration.


Generation of Domains for the Equine Musculoskeletal Rehabilitation Outcome Score: Development by Expert Consensus.
Outcome measures (OMs) are a requirement of professional practice standards in human and canine physiotherapy practice for measurement of health status. Measures such as pain and functional capacity of specific regions are used to track treatment impact and can be used to develop optimal management strategies. To achieve comparable patient care in equine physiotherapy, OMs must be incorporated into practice; however, no reliable and valid OMs exist for equine rehabilitation. This study utilised the experience and opinion of a panel of experts working in the equine rehabilitation sphere to gain consensus on the core areas (domains) to be included in a model, to lead to an OM scale for horses undergoing rehabilitation. The Delphi method and content validity ratio testing was used to determine agreement with domains reaching the critical value required for inclusion. The expert panel agreed on ten domains to be included in the OM scale: lameness, pain at rest, pain during exercise, behaviour during exercise, muscular symmetry, performance/functional capacity, behaviour at rest, palpation, balance and proprioception. An OM with these domains would provide a holistic objective assessment tool which could be used by equine rehabilitation professionals in clinical practice.


Immunosuppressive properties of mesenchymal stem cells: advances and applications.
Mesenchymal stem cells (MSCs) have been isolated from a variety of tissues, such as bone marrow, skeletal muscle, dental pulp, bone, umbilical cord and adipose tissue. MSCs are used in regenerative medicine mainly based on their capacity to differentiate into specific cell types and also as bioreactors of soluble factors that will promote tissue regeneration from the damaged tissue cellular progenitors. In addition to these regenerative properties, MSCs hold an immunoregulatory capacity, and elicit immunosuppressive effects in a number of situations. Not only are they immunoprivileged cells, due to the low expression of class II Major Histocompatibilty Complex (MHC-II) and costimulatory molecules in their cell surface, but they also interfere with different pathways of the immune response by means of direct cell-to-cell interactions and soluble factor secretion. In vitro, MSCs inhibit cell proliferation of T cells, B-cells, natural killer cells (NK) and dendritic cells (DC), producing what is known as division arrest anergy. Moreover, MSCs can stop a variety of immune cell functions: cytokine secretion and cytotoxicity of T and NK cells; B cell maturation and antibody secretion; DC maturation and activation; as well as antigen presentation. It is thought that MSCs need to be activated to exert their immunomodulation skills. In this scenario, an inflammatory environment seems to be necessary to promote their effect and some inflammation-related molecules such as tumor necrosis factor-α and interferon-γ might be implicated. It has been observed that MSCs recruit T-regulatory lymphocytes (Tregs) to both lymphoid organs and graft. There is great controversy concerning the mechanisms and molecules involved in the immunosuppressive effect of MSCs. Prostaglandin E2, transforming growth factor-β, interleukins- 6 and 10, human leukocyte antigen-G5, matrix metalloproteinases, indoleamine-2,3-dioxygenase and nitric oxide are all candidates under investigation. In vivo studies have shown many discrepancies regarding the immunomodulatory properties of MSCs. These studies have been designed to test the efficacy of MSC therapy in two different immune settings: the prevention or treatment of allograft rejection episodes, and the ability to suppress abnormal immune response in autoimmune and inflammatory diseases. Preclinical studies have been conducted in rodents, rabbits and baboon monkeys among others for bone marrow, skin, heart, and corneal transplantation, graft versus host disease, hepatic and renal failure, lung injury, multiple sclerosis, rheumatoid arthritis, diabetes and lupus diseases. Preliminary results from some of these studies have led to human clinical trials that are currently being carried out. These include treatment of autoimmune diseases such as Crohn's disease, ulcerative colitis, multiple sclerosis and type 1 diabetes mellitus; prevention of allograft rejection and enhancement of the survival of bone marrow and kidney grafts; and treatment of resistant graft versus host disease. We will try to shed light on all these studies, and analyze why the results are so contradictory.


Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players.
The cause of amyotrophic lateral sclerosis (ALS) is still unknown. A possible relationship between ALS and sport participation has been supposed, but never definitely demonstrated. We studied a cohort of 7325 male professional football players engaged by a football team from the Italian First or Second Division in the period 1970-2001. ALS cases were identified using different concurrent sources. Standardized morbidity ratios (SMRs) were calculated. During the 137,078 person-years of follow-up, five ALS cases were identified (mean age of onset, 43.4 years). Three cases had a bulbar onset, significantly more than expected (P = 0.003). Since the number of expected cases was 0.77, the overall SMR was 6.5 [95% confidence interval (CI), 2.1-15.1]. The SMR was significantly increased for an ALS onset before 49 years, but not for older subjects. A significant increase of the SMR was found in the periods 1980-1989 and 1990-2001, whereas no ALS case was found in the 1970-1979 period. A dose-response relationship between the duration of professional football activity and the risk of ALS was found (>5 years, 15.2, 95% CI, 3.1-44.4; < or =5 years, 3.5, 95% CI, 0.4-12.7). Our findings seem to indicate that playing professional football is a strong risk factor for ALS.


Did It Matter That the Cancer Drugs Fund Was Not NICE? A Retrospective Review.
The Cancer Drugs Fund (CDF) will have spent more than £1 billion between October 2010 and the introduction of reforms to its structure and operations in July 2016. There has been much more debate about the existence of the fund than about how it spent its substantial budget. It is important to undertake a retrospective examination of "where the money went" in light of the substantial reforms that will be introduced in 2016. We review the means by which the CDF made recent funding decisions for cancer drugs to provide an assessment of the merits of the CDF "model" as a basis for allocation decisions. We assess the extent to which proposed reforms could overcome defects in the original CDF model of prioritization, and lessons for other countries. We provide a narrative commentary on CDF's methods and processes since 2014. We evaluate methods against best practice in cost-effectiveness analysis, and processes against the "accountability for reasonableness" framework. We comment on reforms to the fund. There are no grounds for concluding that the opportunity costs imposed on cancer patients were well evidenced, or the product of legitimate deliberative processes. We note that some of these issues will be addressed in the next incarnation of the fund, but the rationale for the fund's existence remains unconvincing. It is important and timely to debate how cancer drugs appraisal ought to be conducted to confront the consequences of CDF's model of appraisal. We conclude that it did matter that the CDF was not NICE.


Friendship trust and psychological well-being from late adolescence to early adulthood: A structural equation modelling approach.
This study explored the sex-specific associations between friendship trust and the psychological well-being of young Swedes from late adolescence to early adulthood. A random sample of native Swedes born in 1990 was surveyed at age 19 years and again at age 23 years regarding their own well-being and their relationships with a maximum of five self-named peers. The response rate was 31.3%, resulting in 782 cases to be analysed. We used sex-stratified structural equation models to explore the associations between trust and well-being. Psychological well-being was constructed as the latent variable in the measurement part. The structural part accounted for the autocorrelation of trust with respect to well-being over time and incorporated the cross-lagged effects between late adolescence and early adulthood. It was found that trust increased while well-being decreased for young men and remained stable for young women from 19 to 23 years of age. The young women reported lower well-being at both time points, whereas no sex difference was found for trust. Based on model fit comparisons, a simple model without forward or reward causation was accepted for young men, whereas reversed causation from well-being to trust was suggested for young women. Subsequent analysis based on these assumptions confirmed the reversed effect for young women. The findings suggest that young people do not benefit from trustful social relations to the same extent as adult populations. Young women who express impaired well-being run a greater risk of being members of networks characterized by low friendship trust over time.


Performance of compostable baby used diapers in the composting process with the organic fraction of municipal solid waste.
In modern societies, disposable diapers constitute a significant percentage of municipal solid wastes. They have been traditionally landfilled or incinerated as only limited recycling processes are being implemented in some parts of Europe. With the implementation of separated collection systems for the organic fraction of municipal solid wastes (OFMSWs) and the need to preserve the environment, compostable diapers have appeared in the market to avoid the main environmental impacts associated to non-biodegradable disposable diapers. In this study, a full-scale composting of door-to-door collected OFMSW with a 3% (w/w) of compostable diapers has also been carried out. Previously, lab-scale experiments confirmed that almost 50% of carbon of compostable diapers is emitted as CO2 under aerobic controlled conditions. The results obtained at full-scale demonstrate that both the composting process and the final end product (compost) are not altered by the presence of compostable diapers in crucial aspects such as pathogenic content, stability and elemental composition (including nutrients and heavy metals). The main conclusion of this study is that the collection of the OFMSW with compostable diapers can be a new way to transform this waste into high-quality compost.


Biological Effect of a Hybrid Anticancer Agent Based on Kinase and Histone Deacetylase Inhibitors on Triple-Negative (MDA-MB231) Breast Cancer Cells.
We examined the effects of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) combined with the vascular endothelial growth factor receptor-1/2 inhibitor (3Z)-5-hydroxy-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-2-one on MDA-MB-231 breast cancer cells (triple-negative) in the form of both a cocktail of the separate compounds and a chemically synthesized hybrid (N-hydroxy-N'-[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-5-yl]octanediamide). Comparative flow cytometric and Western blot analyses were performed on cocktail- and hybrid-treated cells to evaluate cell cycle distribution, autophagy/apoptosis modulation, and mitochondrial metabolic state in order to understand the cellular basis of the cytotoxic effect. Cell cycle analysis showed a perturbation of the rate of progression through the cycle, with aspects of redistribution of cells over different cycle phases for the two treatments. In addition, the results suggest that the two distinct classes of compounds under investigation could induce cell death by different preferential pathways, i.e., autophagy inhibition (the cocktail) or apoptosis promotion (the hybrid), thus confirming the enhanced potential of the hybrid approach vs. the combination approach in finely tuning the biological activities of target cells and also showing the hybrid compound as an additional promising drug-like molecule for the prevention or therapy of "aggressive" breast carcinoma.


Differences in the pharmacokinetic properties of orally administered all-trans-retinoic acid and 9-cis-retinoic acid in the plasma of nude mice.
All trans-retinoic acid (tr-RA) has been used to induce leukemic cell differentiation in patients with acute promyelocytic leukemia (APL). However, the duration of remission is brief and is associated with a progressive decrease in peak plasma concentrations following chronic dosing. 9-Cis-retinoic acid (9-cis-RA) has the potential to elicit the same effects as tr-RA, because it can bind and activate the same family of nuclear receptors. It is not known whether the pharmacokinetics of this novel compound resemble those of tr-RA. In this study, we report major differences in the uptake and pharmacokinetics between orally administered tr-RA and 9-cis-RA in the plasma of nude mice. Following a single initial oral administration of either isomer, the plasma peak time of 9-cis-RA (15-30 min) occurred earlier than that of tr-RA (60-180 min), but with lower plasma concentrations and area under the concentration-time curve (AUC) value. A decrease in the AUC of plasma tr-RA was seen in animals that were given a second dose 2 days after the first dose. In contrast, an increase in the AUC of plasma 9-cis-RA was seen in animals that were given a second dose 2 days after the first dose. This increase was due to the appearance of a second 9-cis-RA peak at 180 min. When liarozole, an inhibitor of tr-RA metabolism, was coadministered with the initial tr-RA dose or a second tr-RA dose 2 weeks later, the AUC of plasma tr-RA was increased relative to tr-RA alone.(ABSTRACT TRUNCATED AT 250 WORDS)


Color matching of full ceramic versus metal-ceramic crowns - a spectrophotometric study.
To verify the color match of metal-ceramic and full ceramic crowns, using instrumental methods. A number of 153 teeth (anterior and posterior teeth), in 62 patients, were restored with metal ceramic (MC, n=119), pressed-ceramic (PC, n=28), and zirconia-ceramic (ZC, n=6) full coverage crowns. The shade of a reference natural tooth was recorded instrumentally with a dental spectrophotometer (Vitaeasyshade Advance 4.0) in "single tooth measurement", which provided the base color in Vita Classic (VC) and Vita 3D Master shades (3D).For verifying the outcome of the restoration "verify restoration" mode was used, and ΔE values were recorded for both VC and 3D Master shade guides. Moreover, matching symbols were also recorded (***=good, **=fair, *=poor). Descriptive statistics was performed and data were analyzed (One-sample z-Test, α=0.05) for comparison with visual thresholds in dentistry (Perceptibility Threshold - PT=1.2 and Acceptability Threshold - AT=2.7). The data did not follow a normal distribution (Kolmogorov-Smirnov test, p<0.05). Recorded color difference was significantly higher than PT and AT, for all types of restorations, regardless of the coding system (p<0.05). For MC crowns in 2.52% (4.20% for 3D) of the cases the color difference was smaller than PT, in 19.32% (the same for 3D) of cases was between PT and AT, and in 78.15% (76.47% for 3D) of cases was higher than the AT. For PC crowns in 3.57% (0% for 3D) of the cases the color difference was smaller than PT, in 25% (32.14% for 3D) of cases was between PT and AT, and in 71.42% (67.85% for 3D) of cases was higher than the AT. In the case of ZC crowns none of the restorations had color difference smaller than PT, but in 16.66% of cases was between PT and AT, and in 83.33% of cases was higher than the AT, for both VC and 3D. Within the limitations of the study, a better color match was achieved in the case of pressed ceramic crowns, made of lithium disilicate. In most of the situations the color difference between the restoration and the reference tooth exceeded the perceptibility thresholds, but the matching was recorded as "fair" by the spectrophotometer.


A single low-energy, iron-poor supernova as the source of metals in the star SMSS J031300.36-670839.3.
The element abundance ratios of four low-mass stars with extremely low metallicities (abundances of elements heavier than helium) indicate that the gas out of which the stars formed was enriched in each case by at most a few--and potentially only one--low-energy supernova. Such supernovae yield large quantities of light elements such as carbon but very little iron. The dominance of low-energy supernovae seems surprising, because it had been expected that the first stars were extremely massive, and that they disintegrated in pair-instability explosions that would rapidly enrich galaxies in iron. What has remained unclear is the yield of iron from the first supernovae, because hitherto no star has been unambiguously interpreted as encapsulating the yield of a single supernova. Here we report the optical spectrum of SMSS J031300.36-670839.3, which shows no evidence of iron (with an upper limit of 10(-7.1) times solar abundance). Based on a comparison of its abundance pattern with those of models, we conclude that the star was seeded with material from a single supernova with an original mass about 60 times that of the Sun (and that the supernova left behind a black hole). Taken together with the four previously mentioned low-metallicity stars, we conclude that low-energy supernovae were common in the early Universe, and that such supernovae yielded light-element enrichment with insignificant iron. Reduced stellar feedback both chemically and mechanically from low-energy supernovae would have enabled first-generation stars to form over an extended period. We speculate that such stars may perhaps have had an important role in the epoch of cosmic reionization and the chemical evolution of early galaxies.


Essential role of induced nitric oxide in the initiation of the inflammatory response after hemorrhagic shock.
Resuscitation from hemorrhagic shock induces profound changes in the physiologic processes of many tissues and activates inflammatory cascades that include the activation of stress transcriptional factors and upregulation of cytokine synthesis. This process is accompanied by acute organ damage (e.g., lungs and liver). We have previously demonstrated that the inducible nitric oxide synthase (iNOS) is expressed during hemorrhagic shock. We postulated that nitric oxide production from iNOS would participate in proinflammatory signaling. Using the iNOS inhibitor N6-(iminoethyl)-L-lysine or iNOS knockout mice we found that the activation of the transcriptional factors nuclear factor kappaB and signal transducer and activator of transcription 3 and increases in IL-6 and G-CSF messenger RNA levels in the lungs and livers measured 4 h after resuscitation from hemorrhagic shock were iNOS dependent. Furthermore, iNOS inhibition resulted in a marked reduction of lung and liver injury produced by hemorrhagic shock. Thus, induced nitric oxide is essential for the upregulation of the inflammatory response in resuscitated hemorrhagic shock and participates in end organ damage under these conditions.


Self-healing capacity of nuclear glass observed by NMR spectroscopy.
Safe management of high level nuclear waste is a worldwide significant issue for which vitrification has been selected by many countries. There exists a crucial need for improving our understanding of the ageing of the glass under irradiation. While external irradiation by ions provides a rapid simulation of damage induced by alpha decays, short lived actinide doping is more representative of the reality. Here, we report radiological NMR experiments to compare the damage in International Simplified Glass (ISG) when irradiated by these two methods. In the 0.1 mole percent (244)Cm doped glass, accumulation of high alpha decay only shows small modifications of the local structure, in sharp contrast to heavy ion irradiation. These results reveal the ability of the alpha particle to partially repair the damage generated by the heavy recoil nuclei highlighting the radiation resistance of nuclear glass and the difficulty to accurately simulate its behaviour by single ion beam irradiations.


Coexistence of phases in a protein heterodimer.
A heterodimer consisting of two or more different kinds of proteins can display an enormous number of distinct molecular architectures. The conformational entropy is an essential ingredient in the Helmholtz free energy and, consequently, these heterodimers can have a very complex phase structure. Here, it is proposed that there is a state of proteins, in which the different components of a heterodimer exist in different phases. For this purpose, the structures in the protein data bank (PDB) have been analyzed, with radius of gyration as the order parameter. Two major classes of heterodimers with their protein components coexisting in different phases have been identified. An example is the PDB structure 3DXC. This is a transcriptionally active dimer. One of the components is an isoform of the intra-cellular domain of the Alzheimer-disease related amyloid precursor protein (AICD), and the other is a nuclear multidomain adaptor protein in the Fe65 family. It is concluded from the radius of gyration that neither of the two components in this dimer is in its own collapsed phase, corresponding to a biologically active protein. The UNRES energy function has been utilized to confirm that, if the two components are separated from each other, each of them collapses. The results presented in this work show that heterodimers whose protein components coexist in different phases, can have intriguing physical properties with potentially important biological consequences.


Measuring the Protective Effect of Health Insurance Coverage on Out-of-Pocket Expenditures During the COVID-19 Pandemic in the Peruvian Population.
Health insurance coverage is expected to protect individuals from out-of-pocket (OOP) expenditures, potentially preventing them from falling into poverty. However, to date, the effect of health insurance on OOP spending during the coronavirus disease 2019 (COVID-19) pandemic has not been fully explored. This study aimed to estimate differences in the proportion and the amount of OOP expenditures among Peruvians during the pre- and post-mandatory lockdown response to COVID-19 in 2020 according to the health insurance coverage status. This study utilized repeated cross-sectional data from the National Household Survey on Living and Poverty Conditions (ENAHO) from the first quarter of 2017 until the fourth quarter of 2020. The outcomes were (i) the proportion of individuals who incurred OOP expenditures and (ii) the monetary value of OOP expenditures. An interrupted time series analysis (ITS) and a quasi-experimental difference-in-difference (DID) analysis were performed to examine the outcomes among the control (individuals without health insurance) and treatment groups (individuals with health insurance) after the COVID-19 pandemic. ITS analysis showed that the proportion of individuals reporting OOP expenditures after implementation of mandatory lockdown due to COVID-19 in Peru decreased in both groups, but no difference in the slope trend was found (P=.916). The average quarterly amount of OOP spending increased in both groups, but no difference in the slope trend was found (P=.073). Lastly, the DID analysis showed that the mandatory lockdown was associated with a higher amount of OOP, but there was no evidence to indicate that the higher amount was different between the control and treatment groups. The mandatory lockdown in response to the COVID-19 was associated with a higher amount of OOP expenditures and a lower likelihood of incurring OOP expenditures. However, our findings suggest that health insurance coverage does not lower OOP expenditures or reduce the likelihood of incurring OOP expenditures.


Socio-economic correlates of functional health literacy among patients of primary health care in Kosovo.
Functional health literacy (FHL) has been related to individual characteristics, ill-health and disease knowledge. However, the information about FHL in Kosovo is very limited and thus the aim of this study was to assess the demographic and socio-economic correlates of FHL among users of primary health care in Kosovo, a postconflict country in the Western Balkans. Cross-sectional study. A cross-sectional study was conducted in Kosovo between November 2012-February 2013, including a representative sample of 1035 consecutive primary care users aged ≥18 years (60% females; overall mean age: 44.3 ± 16.9 years; overall response rate: 86%). Test of Functional Health Literacy in Adults (TOFHLA) was used to assess FHL. General linear model and logistic regression were used to assess the association of TOFHLA score with demographic and socio-economic characteristics. Overall, four out of five participants exhibited inadequate or marginal FHL in this Kosovo sample. FHL score was independently and inversely related to age, but positively associated with educational attainment and being in a situation other than unemployed. Limited or marginal FHL was very common among primary care users in Kosovo and considerably higher than in the neighbouring Serbia. The low health literacy levels in Kosovo may provide an additional barrier towards achievement of health care goals. There is a need to design and implement suitable and effective educational and health system interventions in the Kosovo context.


Unexplained aspects of anemia of inflammation.
Anemia of inflammation (AI), also known as anemia of chronic inflammation or anemia of chronic disease was described over 50 years ago as anemia in association with clinically overt inflammatory disease, and the findings of low plasma iron, decreased bone marrow sideroblasts and increased reticuloendothelial iron. Pathogenic features underlying AI include a mild shortening of red cell survival, impaired erythropoietin production, blunted responsiveness of the marrow to erythropoietin, and impaired iron metabolism mediated by inflammatory cytokines and the iron regulatory peptide, hepcidin. Despite marked recent advances in understanding AI, gaps remain, including understanding of the pathogenesis of AI associated with "noninflammatory" or mildly inflammatory diseases, the challenge of excluding iron deficiency anemia in the context of concomitant inflammation, and understanding more precisely the contributory role of hepcidin in the development of AI in human inflammatory diseases.


Differential amplification of satellite PaB6 in chromosomally hypervariable Prospero autumnale complex (Hyacinthaceae).
Chromosomal evolution, including numerical and structural changes, is a major force in plant diversification and speciation. This study addresses genomic changes associated with the extensive chromosomal variation of the Mediterranean Prospero autumnale complex (Hyacinthaceae), which includes four diploid cytotypes each with a unique combination of chromosome number (x = 5, 6, 7), rDNA loci and genome size. A new satellite repeat PaB6 has previously been identified, and monomers were reconstructed from next-generation sequencing (NGS) data of P. autumnale cytotype B(6)B(6) (2n = 12). Monomers of all other Prospero cytotypes and species were sequenced to check for lineage-specific mutations. Copy number, restriction patterns and methylation levels of PaB6 were analysed using Southern blotting. PaB6 was localized on chromosomes using fluorescence in situ hybridization (FISH). The monomer of PaB6 is 249 bp long, contains several intact and truncated vertebrate-type telomeric repeats and is highly methylated. PaB6 is exceptional because of its high copy number and unprecedented variation among diploid cytotypes, ranging from 10(4) to 10(6) copies per 1C. PaB6 is always located in pericentromeric regions of several to all chromosomes. Additionally, two lineages of cytotype B(7)B(7) (x = 7), possessing either a single or duplicated 5S rDNA locus, differ in PaB6 copy number; the ancestral condition of a single locus is associated with higher PaB6 copy numbers. Although present in all Prospero species, PaB6 has undergone differential amplification only in chromosomally variable P. autumnale, particularly in cytotypes B(6)B(6) and B(5)B(5). These arose via independent chromosomal fusions from x = 7 to x = 6 and 5, respectively, accompanied by genome size increases. The copy numbers of satellite DNA PaB6 are among the highest in angiosperms, and changes of PaB6 are exceptionally dynamic in this group of closely related cytotypes of a single species. The evolution of the PaB6 copy numbers is discussed, and it is suggested that PaB6 represents a recent and highly dynamic system originating from a small pool of ancestral repeats.


Vertebroplasty with Decompression for Epidural Extending Vertebral Hemangiomas: An Alternative Technique.
To document the effectiveness of an alternative surgical technique with concurrent vertebroplasty and decompression without instrumentation for patients with vertebral hemangioma presenting with neural compression symptoms. This study is a technical note and a retrospective clinical evaluation. We analyzed the data of 8 patients operated with our alternative surgical technique for vertebral hemangiomas with epidural extension and neural compression, between 2013 and 2018. The preoperative, postoperative 1st month and postoperative 12th-month Visual Analogue Scale (VAS) scores were assessed and compared. Five of the patients had lumbar and 3 had thoracic hemangiomas. The difference between preoperative and 1st and 12thmonth Visual Analogue Scale scores were statistically significant. None of the patients received additional intervention, stabilization, or needed a blood transfusion. This technique is a safe and minimally invasive approach for vertebral hemangiomas with epidural extension allowing decompression of the spinal cord without massive hemorrhage.


Palliative radiotherapy for skin malignancies.
Palliative radiotherapy (PRT) improves patient quality of life (QoL) through alleviating cancer-associated symptoms such as pain, bleeding, and ulceration. Palliative management of patients with skin malignancies requires consideration of cosmetic and psychosocial outcomes as QoL measures. In this review, we highlight the current literature and advances in the use of PRT for patients with the three most commonly encountered forms of skin malignancies: basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma. The disease course and sensitivity to radiation varies, thus dictating the palliative goal and scheduling for PRT.


The discovery and development of aclidinium bromide for the treatment of chronic obstructive pulmonary disease.
Bronchodilators, including long-acting muscarinic receptor antagonists (LAMAs), are a mainstay of the pharmacological treatment of chronic obstructive pulmonary disease (COPD). LAMAs act as bronchodilators principally by antagonizing airway smooth muscle cells M3 muscarinic receptors. Aclidinium bromide is a twice-daily LAMA which was developed to improve on the efficacy and/or safety of previous LAMAs. Area covered: Herein, the authors present the pharmacotherapeutic role of aclidinium in COPD and point out unmet need in this research area. The following aspects are covered: a) the discovery and medicinal chemistry of aclidinium bromide; b) an overview of the market; c) its mechanism of action; d) its pharmacokinetic/pharmacodynamic profile derived from pre-clinical studies; e) the clinical studies which led to its licensing; f) the evidence from meta-analyses; g) the aclidinium/formoterol fixed dose combination for COPD and h) priorities in this area of research. Expert opinion: Aclidinium bromide has the pharmacological properties, safety and efficacy profile and inhaler characteristics which makes it a valuable therapeutic option for pharmacological management of patients with COPD. Due to its rapid biotransformation into inactive metabolites, aclidinium is potentially one of the safest LAMAs. Further head-to-head randomized clinical trials are required to define efficacy and safety of aclidinium when compared to once-daily LAMAs. The clinical relevance of airway anti-remodeling effects of aclidinium has to be defined.


Associations of physical activity and sedentary behavior with cardiometabolic biomarkers in prediabetes and type 2 diabetes: a compositional data analysis.
Objectives: To investigate the associations between objectively measured sedentary behavior (SB), light-intensity physical activity (LIPA) and moderate-to-vigorous physical activity (MVPA) and cardiometabolic and endocrine biomarkers, and to estimate the associations of reallocating time from one behavior to another with cardiometabolic and endocrine biomarkers.Methods: Baseline data from participants diagnosed with prediabetes or type 2 diabetes, n = 175, 58% men, mean (SD) age = 64.4 (7.7), recruited to a physical activity intervention was used. Time spent in SB, LIPA and MVPA was measured by accelerometer and transformed into isometric log-ratio coordinates. The associations between time spent in SB, LIPA and MVPA and biomarkers were examined by linear regression models. The change in each outcome of reallocating time between the three behaviors was estimated.Results: The findings show strong positive associations of time spent in MVPA and negative associations of time spent in SB relative to time spent in the other behaviors with sagittal abdominal diameter (SAD) and homeostasis model assessment for insulin resistance (HOMA-IR) and negative associations of time spent in SB with high-density lipoprotein (HDL) cholesterol. Theoretically, reallocation of 19 minutes MVPA to SB or to LIPA was associated with a 17% and 17% larger SAD, 39% and 36% larger HOMA-IR values and 3.3% and 2.3% lower levels of HDL, respectively.Conclusion: In conclusion, our analysis from a time-use perspective supports the current evidence that sedentary time is devastating for the cardiometabolic health. While LIPA probably requires more time, maintaining or increasing time in MVPA are the most important features of the time use behaviors when promoting a favorable cardiometabolic risk profile in adults with prediabetes and type 2 diabetes.Trial registration: ClinicalTrials.gov, NCT02374788. Registered 2 March 2015 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02374788.


The advantages of UK Biobank's open-access strategy for health research.
Ready access to health research studies is becoming more important as researchers, and their funders, seek to maximize the opportunities for scientific innovation and health improvements. Large-scale population-based prospective studies are particularly useful for multidisciplinary research into the causes, treatment and prevention of many different diseases. UK Biobank has been established as an open-access resource for public health research, with the intention of making the data as widely available as possible in an equitable and transparent manner. Access to UK Biobank's unique breadth of phenotypic and genetic data has attracted researchers worldwide from across academia and industry. As a consequence, it has enabled scientists to perform world-leading collaborative research. Moreover, open access to an already deeply characterized cohort has encouraged both public and private sector investment in further enhancements to make UK Biobank an unparalleled resource for public health research and an exemplar for the development of open-access approaches for other studies.


Oral Mycostatin as a possible alternative treatment for intractable Ménière's disease: preliminary cohort study.
Background: The potential efficacy of antifungal agents (e.g. Mycostatin) in treating acute attacks of Ménière's disease was first suggested in 1983 but few data have been published. Oral Mycostatin has been used as second-line medical treatment for intractable Ménière's disease at our institution for many years. Objective: This preliminary cohort study investigated the role of oral Mycostatin in intractable Ménière's disease. Methods: A retrospective review of patients with intractable Ménière's disease who started oral Mycostatin treatment between 2010 and 2012 was conducted. Results: Of 256 patients presenting with vertiginous disorders, 26 had definite Ménière's disease and had not responded to standard first-line treatment. Following oral Mycostatin treatment, improvements were reported for vertigo (n = 8), aural fullness (n = 7), tinnitus (n = 3) and subjective hearing loss (n = 3). Half of those with symptom improvement persisted with oral Mycostatin for two years and continued to remain asymptomatic. Conclusion: The use of oral Mycostatin to alleviate symptoms of intractable Ménière's disease showed promising results in this case series. Mycostatin may offer a safe and useful alternative for the management of Ménière's disease for patients with chronic unremitting symptoms in whom first-line treatment options have failed.


Ovarian serous borderline tumors with lymph node involvement. Clinicopathologic and DNA content study of seven cases and review of the literature.
Although several studies have established the excellent prognosis of ovarian serous borderline tumors (OSBTs) in general, the significance of lymph node involvement has not been thoroughly addressed. In this article, we describe seven OSBTs with lymph node involvement and their DNA content and S-phase fraction. Lymph node involvement was identified at presentation in four cases (pelvic, paraaortic, and omental) and after 4, 5, and 7 years in the other three (omental, scalene, and cervical, respectively). In the first group, clusters of cells cytologically similar to those of the OSBT were identified in the nodal sinusoids in all four cases and focally in the lymph node parenchyma in three of them. In contrast, the involved lymph nodes of the three cases with delayed nodal disease showed an almost complete replacement by tumor. In one of them, the tumor in the lymph node was histologically similar to the OSBT, while in the other two cases the tumor was more solid and poorly differentiated, suggesting true metastatic disease. Flow cytometric analysis of nuclear DNA content and S-phase fraction were performed on paraffin-embedded tissue of all of the primary OSBTs and of the involved lymph nodes in six cases; diploid DNA content and low S-phase fraction were seen in all cases. All patients were alive and free of disease 2-9 years after initial diagnosis. While the clinical significance of LN involvement in OSBT is still uncertain, DNA ploidy analysis seems to be unable to identify those cases at risk for tumor progression.


The precuneus may encode irrationality in human gambling.
Humans often make irrational decisions, especially psychiatric patients who have dysfunctional cognitive and emotional circuitry. Understanding the neural basis of decision-making is therefore essential towards patient management, yet current studies suffer from several limitations. Functional magnetic resonance imaging (fMRI) studies in humans have dominated decision-making neuroscience, but have poor temporal resolution and the blood oxygenation level-dependent signal is only a proxy for neural activity. On the other hand, lesion studies in humans used to infer functionality in decision-making lack characterization of neural activity altogether. Using a combination of local field potential recordings in human subjects performing a financial decision-making task, spectral analyses, and non-parametric cluster statistics, we analyzed the activity in the precuneus. In nine subjects, the neural activity modulated significantly between rational and irrational trials in the precuneus (p <; 0.001). In particular, high-frequency activity (70-100 Hz) increased when irrational decisions were made. Although preliminary, these results suggest suppression of gamma rhythms via electrical stimulation in the precuneus as a therapeutic intervention for pathological decision-making.


The phagocytosis of rod outer segments is inhibited by drugs linked to cyclic adenosine monophosphate production.
To study the effect of drugs that increase intracellular cyclic adenosine monophosphate on the ability of rat retinal pigment epithelial cells to phagocytize rod outer segments (ROS). Cultured rat retinal pigment epithelial cells were treated with cholera toxin, forskolin, isoproterenol, or isobutylmethylxanthine and the phagocytosis of ROS by such treated cells was compared to that of control specimens. All of the drugs examined inhibited the ingestion, but not the binding of ROS by cultured retinal pigment epithelial cells. Cell viability was not compromised by the drug treatment because they rapidly recovered their ability to ingest ROS when the drug was removed. Dose-response curves for the inhibition of ROS phagocytosis by forskolin and isoproterenol demonstrated that this process is exquisitely sensitive to these agonists, with an IC50 for these drugs of 33 nmol/l. The results showed no measurable quantitative correlation between cyclic adenosine monophosphate levels and the inhibition of ROS phagocytosis. Results showed that the ingestion of ROS by retinal pigment epithelial cells was inhibited by agents that increase intracellular cyclic adenosine monophosphate, but seems to be independent of the level of this second messenger. Alternatively, ROS phagocytosis may be exquisitely sensitive to changes in the intracellular concentration of cyclic adenosine monophosphate, which are too small to measure by available methods.


Childhood obesity and community food environments in Alabama's Black Belt region.
Childhood obesity has been rising rapidly in the USA. The rate is higher among those at a lower socioeconomic status and racial/ethnic minority groups. In Alabama, nearly half of the children from rural African American families are overweight or obese. Studies suggest that children's eating behaviours and weight could be influenced by surrounding food environments. The purpose of this paper is to assess the community food environment and examine the associations with childhood obesity in Alabama's Black Belt region. This research uses both qualitative and quantitative methods. Weight status of 613 African American students in four elementary schools in a rural county of Alabama was assessed. We examined community food environments around children's home through GIS (Geographic Information System) and statistical methods. The interrelations between children's weight and community food environments are explored with multi-level models. Approximately 42.1% of surveyed children were overweight or obese, much higher than the national average, 30.6%. In Model 1, convenience stores (3.44; P < 0.01), full service restaurants (8.99; P < 0.01) and supermarkets (-37.69; P < 0.01) were significantly associated with the percentile of body mass index. Fast food stores (-0.93; P = 0.88) were not related to children's weight. In Model 2, the additions of sociodemographic factors and school effects cause significant changes of the relationships between children's weight and four types of food outlets. The percentage of African American population (90.23, P < 0.01) and school (6.68, P < 0.01) were positively associated with children's weight; while median household income (-39.6; P < 0.01) was negatively related to it. Children's weight is influenced by community food environments, sociodemographic factors and school context. Findings suggest that policymakers and planners need to improve community food environments of low-income minority communities. Parents and schools should pay more attention to reduce the negative impacts of food environments on children.


Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer.
Toll like receptor (TLR) signaling has been suggested to play an important role in the inflammatory microenvironment of solid tumors and through this inflammation-mediated tumor growth. Here, we studied the role of tumor cells in their process of self-maintaining TLR expression independent of inflammatory cells and cytokine milieu for autoregulative tumor growth signaling in pancreatic cancer. We analyzed the expression of TLR2, -4, and -9 in primary human cancers and their impact on tumor growth via induced activation in several established pancreatic cancers. TLR-stimulated pancreatic cancer cells were specifically investigated for activated signaling pathways of VEGF/PDGF and anti-apoptotic Bcl-xL expression as well as tumor cell growth. The primary pancreatic cancers and cell lines expressed TLR2, -4, and -9. TLR-specific stimulation resulted in activated MAP-kinase signaling, most likely via autoregulative stimulation of demonstrated TLR-induced VEGF and PDGF expression. Moreover, TLR activation prompted the expression of Bcl-xL and has been demonstrated for the first time to induce tumor cell proliferation in pancreatic cancer. These findings strongly suggest that pancreatic cancer cells use specific Toll like receptor signaling to promote tumor cell proliferation and emphasize the particular role of TLR2, -4, and -9 in this autoregulative process of tumor cell activation and proliferation in pancreatic cancer.


Exploring the spatial and temporal organization of a cell's proteome.
To increase our current understanding of cellular processes, such as cell signaling and division, knowledge is needed about the spatial and temporal organization of the proteome at different organizational levels. These levels cover a wide range of length and time scales: from the atomic structures of macromolecules for inferring their molecular function, to the quantitative description of their abundance, and spatial distribution in the cell. Emerging new experimental technologies are greatly increasing the availability of such spatial information on the molecular organization in living cells. This review addresses three fields that have significantly contributed to our understanding of the proteome's spatial and temporal organization: first, methods for the structure determination of individual macromolecular assemblies, specifically the fitting of atomic structures into density maps generated from electron microscopy techniques; second, research that visualizes the spatial distributions of these complexes within the cellular context using cryo electron tomography techniques combined with computational image processing; and third, methods for the spatial modeling of the dynamic organization of the proteome, specifically those methods for simulating reaction and diffusion of proteins and complexes in crowded intracellular fluids. The long-term goal is to integrate the varied data about a proteome's organization into a spatially explicit, predictive model of cellular processes.