Maternal insulin-like growth factors-I and -II act via different pathways to promote fetal growth.
The placenta transports substrates and wastes between the maternal and fetal circulations. In mice, placental IGF-II is essential for normal placental development and function but, in other mammalian species, maternal circulating IGF-II is substantial and may contribute. Maternal circulating IGFs increase in early pregnancy, and early treatment of guinea pigs with either IGF-I or IGF-II increases placental and fetal weights by mid-gestation. We now show that these effects persist to enhance placental development and fetal growth and survival near term. Pregnant guinea pigs were infused with IGF-I, IGF-II (both 1 mg/kg.d), or vehicle sc from d 20-38 of pregnancy and killed on d 62 (term = 69 d). IGF-II, but not IGF-I, increased the mid-sagittal area and volume of placenta devoted to exchange by approximately 30%, the total volume of trophoblast and maternal blood spaces within the placental exchange region (+29% and +46%, respectively), and the total surface area of placenta for exchange by 39%. Both IGFs reduced resorptions, and IGF-II increased the number of viable fetuses by 26%. Both IGFs increased fetal weight by 11-17% and fetal circulating amino acid concentrations. IGF-I, but not IGF-II, reduced maternal adipose depot weights by approximately 30%. In conclusion, increased maternal IGF-II abundance in early pregnancy promotes fetal growth and viability near term by increasing placental structural and functional capacity, whereas IGF-I appears to divert nutrients from the mother to the conceptus. This suggests major and complementary roles in placental and fetal growth for increased circulating IGFs in early to mid-pregnancy.


Treatment with angiotensin receptor neprilysin inhibitor for Taiwan heart failure patients: Rationale and baseline characteristics of the TAROT-HF study.
This study used a real-world database to investigate the prescription patterns of sacubitril/valsartan (Sac/Val) among Taiwanese patients with heart failure with reduced ejection fraction (HFrEF). The Treatment with Angiotensin Receptor neprilysin inhibitor fOr Taiwan Heart Failure patients (TAROT-HF) study is a principal investigator-initiated, multicenter, observational, retrospective study on Taiwanese HFrEF patients. A total of 1772 patients with HFrEF (mean age 62.5 years, 75.3% male, mean left ventricular ejection fraction [LVEF] 29.3%) who received Sac/Val at 10 hospitals between 2017 and 2018 were enrolled at the date of Sac/Val initiation. Among these patients, 585 (33%) initially received Sac/Val during acute decompensated heart failure (HF) hospitalization (TAROT-AHF arm), whereas 1187 (67%) initially received the same at the outpatient clinic (TAROT-CHF arm). A total of 1343 (75.8%) patients received an initial dose of 50 mg twice daily or fewer, whereas 422 (23.8%) received the standard initiation dose (100 mg twice daily). During outpatient Sac/Val initiation, the mean dosages were significantly higher than that following hospitalization (117 ± 55 mg vs 109 ± 57 mg; p = 0.014). Multivariate analysis identified younger age, higher systolic blood pressure, higher LVEF, prior use of renin-angiotensin system inhibitors, use of ivabradine, and a history of diabetes mellitus as independent factors for initiating a standard Sac/Val dose. Over a follow-up period of 18 months, incidences of cardiovascular death or first unplanned HF hospitalization were 18.69 and 33.11 per 100-person years for the TAROT-CHF and TAROT-AHF arms, respectively. The TAROT-HF study provided an opportunity to describe the clinical features of patients with HFrEF who received Sac/Val, assess the real-world utilization and efficacy of Sac/Val, and compare these patients with those included in prior registries.


[Variants of ossification of the stylohyoid chain].
Evaluation of age-related differences in the incidence, length and topographic location of ossifications in the stylohyoid chain. Panoramic radiographs of 380 patients (718 reviewed stylohyoid chains), subdivided into 4 age groups (up to 20 years, 21 to 40 years, 41 to 60 years, older than 60 years), were reviewed and examined for the incidence, length and topographic location of stylohyoidal ossification. 221 (30.8%) of 718 reviewed stylohyoidal chains showed radiological variants (elongation of the stylold process and/or ossification of the stylohyoid ligament). With increasing age, there was an increase in the incidence and length of stylohyoidal ossifications (p < 0.01). A significant linear correlation between the length of the stylohyoidal ossifications and age was only found in the young age group (up to 20 years; p < 0.01). In the young age group(up to 20 years), there was also a preferred presence of isolated locations in the superior stylohyoidal segment. With increasing age, there was a pronounced presence of ossifications in the middle and inferior stylohyoid segments and combinations of ossified varibilities. Stylohyoidal ossifications show age-related differences in incidence, length and topography and can also be put down to different pathological events. Stylohyoidal ossifications gain a different importance in adult patients from that in young people.


A 3' splice site mutation in the thyroglobulin gene responsible for congenital goiter with hypothyroidism.
A case of congenital goiter with defective thyroglobulin synthesis has been studied in molecular terms. The patient is the fifth of a kindred of six, three of which have a goiter. The parents are first cousins. Segregation of thyroglobulin alleles in the family was studied by Southern blotting with a probe revealing a diallelic restriction fragment length polymorphism (RFLP). The results demonstrated that the three affected siblings were homozygous for the RFLP. Northern blotting analysis of the goiter RNA with a thyroglobulin probe suggested that thyroglobulin mRNA size was slightly reduced. Polymerase chain reaction amplification of the 8.5-kb thyroglobulin mRNA as overlapping cDNA fragments demonstrated that a 200-bp segment was missing from the 5' region of the goiter mRNA. Subcloning and sequencing of the cDNA fragments, and of the patient genomic DNA amplified from this region, revealed that exon 4 is missing from the major thyroglobulin transcript in the goiter, and that this aberrant splicing is due to a C to G transversion at position minus 3 in the acceptor splice site of intron 3. The presence in exon 4 of a putative donor tyrosine residue (Tyrosine nr 130) involved in thyroid hormone formation provides a coherent explanation to the hypothyroid status of the patient.


Spontaneous Mn2+ entry is specifically inhibited by calyculin A in human leukemic HL-60 cells.
The effects of calyculin A and other agents which enhance protein Ser/Thr phosphorylation, on the cytosolic free Ca2+ concentration ([Ca2+]i) and spontaneous Mn2+ entry were investigated in fura-2-loaded human leukemic HL-60 cells. Calyculin A (30 nM), a specific inhibitor of protein Ser/Thr phosphatase (PP) 1 and 2A, significantly decreased [Ca2+]i. By contrast, another structurally unrelated inhibitor of PP1 and 2A, okadaic acid (1 microM), caused a slight elevation in [Ca2+]i. Forskolin (30 microM), which could enhance protein kinase A activity by raising cAMP concentration, also caused a rise in [Ca2+]i. Phorbol myristate acetate (PMA, 300 nM), an activator of protein kinase C, did not have a significant effect on [Ca2+]i. Spontaneous entry of Mn2+ (a surrogate ion for Ca2+) was strongly inhibited by calyculin A, but not okadaic acid, forskolin or phorbol myristate acetate. Such inhibition was not significantly affected by staurosporine (300 nM), a non-specific inhibitor of protein Ser/Thr kinases. Our results suggest that calyculin A inhibited a plasmalemmal leak pathway to Mn2+ (and Ca2+), probably leading to a decrease in [Ca2+]i. Inhibition of spontaneous Mn2+ entry by calyculin A may depend on a specific protein phosphorylation pattern induced by staurosporine-insensitive protein kinase(s).


Defining the genetic control of human blood plasma N-glycome using genome-wide association study.
Glycosylation is a common post-translational modification of proteins. Glycosylation is associated with a number of human diseases. Defining genetic factors altering glycosylation may provide a basis for novel approaches to diagnostic and pharmaceutical applications. Here we report a genome-wide association study of the human blood plasma N-glycome composition in up to 3811 people measured by Ultra Performance Liquid Chromatography (UPLC) technology. Starting with the 36 original traits measured by UPLC, we computed an additional 77 derived traits leading to a total of 113 glycan traits. We studied associations between these traits and genetic polymorphisms located on human autosomes. We discovered and replicated 12 loci. This allowed us to demonstrate an overlap in genetic control between total plasma protein and IgG glycosylation. The majority of revealed loci contained genes that encode enzymes directly involved in glycosylation (FUT3/FUT6, FUT8, B3GAT1, ST6GAL1, B4GALT1, ST3GAL4, MGAT3 and MGAT5) and a known regulator of plasma protein fucosylation (HNF1A). However, we also found loci that could possibly reflect other more complex aspects of glycosylation process. Functional genomic annotation suggested the role of several genes including DERL3, CHCHD10, TMEM121, IGH and IKZF1. The hypotheses we generated may serve as a starting point for further functional studies in this research area.


Sedation for Endoscopic Retrograde Cholangiopancreatography in Elderly Patients - the Effect of Intravenous Lidocaine Infusion. A Randomised, Double-Blind, Placebo Controlled Trial.
Sedation of elderly patients with associated comorbidities, subjected to ERCP procedure, can produce serious complications including respiratory instability and hemodynamics caused by the administration of anesthetic substances. In this study we aimed to evaluate whether the administration of lidocaine in continuous infusion during ERCP procedure reduces the consumption of propofol and the rate of complications in these patients. 83 patients over 65-year old, ASA II-IV score, undergoing an ERCP procedure were randomized in two groups: lidocaine group (group L) who received 1.5 mg/kg lidocaine 1% and propofol 1mg/kg at induction and then 2 mg/kg lidocaine 1% in continuous infusion during the procedure and control group (group C) who received saline in the same amount as group L and propofol 1mg/kg. The consumption of propofol, intraprocedural complications, the time of awakening and recovery, the quality of postprocedural analgesia, the satisfaction of the endoscopist were registered. Propofol consumption was statistically significantly lower in group L compared to group C [135.37 (±43.23) vs. 214.88 (±51.83), p=0.001]. The same result was obtained related to the awakening time [2.85 (±1.50) vs. 5.38 (±1.36), p=0.001] and recovery time [23.90 (±12.66) vs. 26.17 (±12.41), p<0.001], the episodes of intraprocedural desaturation (p=0.001), the involuntary intraprocedural movements (p=0.001), the endoscopist's satisfaction (p=0.006). No differences were found in terms of post-procedure pain scores (p=0.54). Lidocaine can be administered to reduce the need for propofol, faster awakening and lower intraprocedural complications in elderly patients undergoing the ERCP procedure.


Psychosocial risk factors in relation to other cardiovascular risk factors in coronary heart disease: Results from the EUROASPIRE IV survey. A registry from the European Society of Cardiology.
Background Depression and anxiety are established psychosocial risk factors for coronary heart disease. Contemporary data on their prevalence and associations with other risk factors were evaluated as part of the EUROASPIRE IV survey. Design The design of this study was cross-sectional. Methods The study group consisted of 7589 patients from 24 European countries examined at a median of 1.4 years after hospitalisation due to coronary heart disease events. Depression and anxiety were assessed using the Hospital Anxiety and Depression Scale. Results Symptoms of anxiety (Hospital Anxiety and Depression Scale-Anxiety score ≥8) were seen in 26.3% of participants and were more prevalent in women (39.4%) vs men (22.1%). Of the patients, 22.4% (30.6% of women and 19.8% of men) had symptoms of depression (Hospital Anxiety and Depression Scale-Depression score ≥8). Nevertheless, antidepressants and anti-anxiety medications were prescribed to only 2.4% of patients at hospital discharge, and 2.7% and 5.0% of patients, respectively, continued to take them at interview. Both anxiety and depression were associated with female gender, lower educational level and more sedentary lifestyle. Anxiety was more prevalent in younger age groups and depression rates increased with advancing age. Depression was positively associated with current smoking, central obesity and self-reported diabetes. A number of positive lifestyle changes reduced the odds of anxiety and depression. Conclusions A substantial proportion of patients have anxiety and depression symptoms after coronary heart disease events but these conditions are undertreated. These disorders, especially depression, are associated with other risk factors, including educational level, sedentary lifestyle, smoking, unhealthy diet and reduced compliance with risk factor modification.


Characterization of occupational smoke exposure among wildland firefighters in the midwestern United States.
Wildland firefighters are repeatedly exposed to elevated levels of wildland fire smoke (WFS) while protecting lives and properties from wildland fires. Studies reporting personal exposure concentrations of air pollutants in WFS during fire suppression or prescribed burn activities have been geographically limited to the western and southeastern United States. The objective of this study is to characterize exposure concentrations of air pollutants in WFS emissions among wildland firefighters who conducted prescribed burns in the Midwest. Between 2016 and 2019, a total of 35 firefighters (31 males and 4 females, age of 35.63 ± 9.31 years) were recruited to participate in this study. Personal particulate matter 2.5 (PM2.5) and carbon monoxide (CO) exposure concentrations were measured during prescribed burns. The level of black carbon (BC) in WFS particulates was determined using the light transmission technique, while trace metal composition was analyzed using inductively coupled plasma mass spectrometry (ICP-MS). The results showed geometric means for PM2.5, CO, and BC concentrations were 1.43 ± 0.13 mg/m3, 7.02 ± 0.69 ppm, and 58.79 ± 5.46 μg/m3, respectively. Although no occupational exposure limits (OELs) were exceeded by 8-h time-weighted average (TWA) exposure concentration observed in the firefighters, a total of 28 personal CO exposure concentrations were above the National Institute for Occupational Safety and Health (NIOSH) Recommended Exposure Limit (REL) Ceiling (200 ppm) for CO. PM2.5 and CO concentrations were about 2-7 times higher in the Midwest than the other regions. Firefighters who performed holding had higher CO exposure concentrations compared to firefighters who performed lighting (p < 0.01), while lighters were exposed to higher level of BC in the smoke particulates (p < 0.01), possibly due to the domination of exposure by different combustion sources and stages. The levels of trace metals in WFS particulates were well below the corresponding OELs and no task-related difference was observed except for manganese. Our results suggest that wildland firefighters in the midwestern region have higher WFS exposures while working at prescribed burns compared to those western and southeastern United States.


Ursolic acid as a potential inhibitor of Mycobacterium tuberculosis cytochrome bc1 oxidase-a molecular modelling perspective.
The escalating burden of tuberculosis disease and drastic effects of current medicine has stimulated a search for alternative drugs. A medicinal plant Warburgia salutaris has been reported to possess inhibitory properties against M. tuberculosis. In this study, we apply computational methods to investigate the probability of W. salutaris compounds as potential inhibitors of M. tuberculosis QcrB protein. We performed molecular docking, molecular dynamics simulations, radius of gyration, principal component analysis (PCA), and molecular mechanics-generalized born surface area (MM-GBSA) binding-free energy calculations in explicit solvent to achieve our objective. The results suggested that ursolic acid (UA) and ursolic acid acetate (UAA) could serve as preferred potential inhibitors of mycobacterial QcrB compared to lansoprazole sulphide (LSPZ) and telacebec (Q203)-UA and UAA have a higher binding affinity to QcrB compared to LSPZ and Q203 drugs. UA binding affinity is attributed to hydrogen bond formation with Val120, Arg364 and Arg366, and largely resonated from van der Waals forces resulting from UA interactions with hydrophobic amino acids in its vicinity. UAA binds to the porphyrin ring binding site with higher binding affinity compared to LSPZ. The binding affinity results primarily from van der Waals forces between UAA and hydrophobic residues of QcrB in the porphyrin ring binding site where UAA binds competitively. UA and UAA formed stable complexes with the protein with reduced overall residue mobility, consequently supporting the magnitude of binding affinity of the respective ligands. UAA could potentially compete with the porphyrin ring for the binding site and deprive the mycobacterial cell from oxygen, consequently disturbing mycobacterial oxygen-dependent metabolic processes. Therefore, discovery of a compound that competes with porphyrin ring for the binding site may be useful in QcrB pharmocological studies. UA proved to be a superior compound, although its estimated toxicity profile revealed UA to be hepatotoxic within acceptable parameters. Although preliminary findings of this report still warrant experimental validation, they could serve as a baseline for the development of new anti-tubercular drugs from natural resources that target QcrB.


Thermodynamic limits to the ATP/site stoichiometries of oxidative phosphorylation by rat liver mitochondria.
From measurements of reactants, products, and the oxidation-reduction state of cytochrome c + c1 during 3-hydroxybutyrate-supported oxidative phosphorylation by rat liver mitochondria at static head (state 4), we determined the free energy change of ATP formation from ADP and Pi (phosphorylation potential or delta GP) and the oxidation-reduction free energy changes (redox potentials or delta GR values) across Sites 1 + 2 (delta GR1 + 2), across Site 3 (delta GR3), and across Sites 1 + 2 + 3 (delta GR). At pH 7.4, -delta GR1 + 2/delta GP, -delta GR3/delta GP, and -delta GR/delta GP were maximally 1.80, 1.56, and 3.37. These can be taken as thermodynamic upper limits to the ATP/Sites 1 + 2, ATP/Site 3, and ATP/O stoichiometry of 3-hydroxybutyrate-supported oxidative phosphorylation. The theory of linear nonequilibrium thermodynamics were employed to estimate lower limits to the ATP/site stoichiometries. The lower limit is given by the expression, q2(-delta GRsite/delta GP). The degree of coupling, q, was 0.977 as determined from the dependence of respiratory rate on delta GP. Determined in this way, lower limits of the ATP/Sites 1 + 2, ATP/Site 3, and ATP/O stoichiometries were 1.67, 1.44, and 3.11, respectively. ADP addition to mitochondria incubated at static head lowered delta GP by 1.1 kcal/mol and stimulated respiration by a factor of about 2.5 but caused negligible changes in delta GR1 + 2 and delta GR3. This observation demonstrates that the respiratory reactions from substrate to cytochrome c and from cytochrome c to oxygen both move away from thermodynamic equilibrium with delta GP during the transition from resting to active oxidative phosphorylation. The findings are discussed in terms of current schemes of chemiosmotic coupling.


Transcriptional regulation of the steroid receptor genes.
Steroid hormones, via their binding to specific receptors, are involved in the development, differentiation, and physiological response of cells to diverse stimuli. Activation by hormonal ligands induces conformational change in the receptor, enabling interaction with the target genes. The steroid receptor superfamily includes androgen, glucocorticoid, mineralocorticoid, progesterone, estrogen, thyroid, vitamin D, retinoic acid, and orphan receptors. This review will focus on the classic steroid receptors, i.e., the androgen, glucocorticoid, progesterone, and estrogen receptors, with emphasis on their transcriptional regulation. Readers are directed to several authoritative reviews for further details of steroid receptors (1-11).


Psychiatrists who use and do not use ECT: a comparative study.
Cross-section survey data were used to test eight hypotheses derived from the New Haven studies of psychiatric treatment practices. Eighty percent of the psychiatrists in Maryland completed a 10-page questionnaire, and those 29 who had used electroconvulsive therapy (ECT) during the preceding year were compared with 441 who had not. Respondents did not differ significantly from non-respondents or from respondents to a national survey in distribution by demographic variables. Five hypotheses were supported: ECT users are less frequently psychoanalytically trained, treat more working- and lower-class patients, use more pharmacotherapy, use less intensive psychotherapy, and use less psychoanalysis. The hypotheses that ECT users are more frequently affiliated with public hospitals and use more short-term psychotherapy were not supported, and the hypothesis that ECT users are less frequently Jewish was refuted. Other noteworthy findings are that none of the female psychiatrists or child psychiatrists in this sample used ECT, and that ECT users used less behavior therapy. These data on ECT users are more consistent with the recent concept of a somatotherapeutic orientation among ECT users than with the original concept of a directive-organic orientation.


Evaluation of feeding various sources of distillers dried grains with solubles in non-feed-withdrawal molt programs for laying hens.
An experiment was conducted using 588 Hy-Line W-36 hens (68 wk of age) to evaluate if laying hens can be successfully molted by ad libitum feeding various levels of 3 sources of distillers dried grains with solubles (DDGS). Treatment 1 consisted of a 47% corn (C):47% soy hulls (SH) molt diet (C:SH) fed for 28 d (positive control). Treatments 2, 3, and 4 were molt diets containing 94% DDGS from the 3 sources fed for 28 d. Treatments 5, 6, and 7 were 32% C: 42% SH: 20% DDGS, from each of the 3 DDGS sources, also fed for 28 d. At the end of the 28-d molt period, all hens were fed a 16% CP corn-soybean meal layer diet. Body weight loss during the molt period was significantly greater (P < 0.05) for hens fed the C:SH diet (26%) than hens fed the diets containing DDGS, and the reduction in BW loss varied among DDGS sources. Feed intake was lower (P < 0.05) for the C:SH control treatment compared with most DDGS treatments. Hens fed the C:SH diet had egg production near 0% during the last 3 wk of the molt period. Hens on the other treatments did not have mean egg production below 17% during the molt period (wk 1 to 4), and the reduction in egg production varied among DDGS sources. Postmolt hen-day egg production (5-41 wk) did not significantly differ among treatments; however, egg mass and egg specific gravity were generally reduced (P < 0.05) for hens fed the 94% DDGS molt diets compared with hens fed the C:SH diet. This study showed that molt and postmolt performance responses varied among DDGS sources; however, none of the molt diets containing 20 to 94% DDGS yielded molt period reductions in BW or egg production similar to a 47% C: 47% SH diet.


Permissive role of interleukin 3 (IL-3) in proliferation and differentiation of multipotential hemopoietic progenitors in culture.
We studied the effects of interleukin-3 (IL-3) on colony formation by hemopoietic progenitors in methylcellulose cultures of spleen cells from 5-fluorouracil (FU)-treated mice. Purified IL-3 supported the growth of various types of multilineage colonies including blast cell colonies. The types of colonies were similar to those supported by pokeweed-mitogen spleen cell conditioned medium (PWM-SCM), except that IL-3 supported eosinophil and neutrophil expression better. Delayed addition of IL-3 to cultures 7 days after cell plating decreased the number of colonies to one-half the number in cultures with IL-3 added on day 0. It did not alter the proliferative and differentiation characteristics of late emerging multipotential blast cell colonies. These observations suggest that IL-3 does not trigger hemopoietic progenitors into active cell proliferation but is necessary for their continued proliferation. This permissive role of IL-3 is consistent with a stochastic model of stem cell proliferation which features random entry into cell cycle. IL-3 also supported the growth of multilineage colonies from single cells isolated from blast cell colonies by micromanipulation. This result shows that IL-3 acts directly on multipotential progenitors. Analysis of colonies derived from paired progenitors revealed disparate lineage expression and was in accordance with the stochastic model of stem cell differentiation.


Plus and minus single-stranded DNA separately encapsidated in adeno-associated satellite virions.
Based on physical and chemical determinations, the mnolecular weight of the type 4 adeno-satellite virus is 5.4 X 10(6) daltons, and the virion contains 1.4 X 10(6) daltons of DNA. Denaturation and renaturation studies indicate that the viral genome is a single-stranded DNA molecule and that each virion contains either a minus or a plus strand. Upon extraction, the minus and plus strands unite to form double-stranded DNA molecules with no obvious excess of unpaired strands.


A new concept of transforaminal ventral facetectomy including simultaneous decompression of foraminal and lateral recess stenosis: Technical considerations in a fresh cadaver model and a literature review.
Percutaneous endoscopic surgery for the lumbar spine, which was established in the last decade, requires only an 8-mm skin incision and causes minimal damage to the paravertebral muscles; thus, it is considered to be a minimally invasive technique for spinal surgery. It has been used to perform percutaneous endoscopic discectomy via two main approaches: the TF approach is a posterolateral one through the intervertebral foramen and can be done under local anesthesia; the IL approach is a more traditional one through the interlaminar space and is difficult to perform under local anesthesia. Recently, these techniques have been applied for lumbar spinal stenosis (LSS), the TF method for foraminal stenosis under local anesthesia, and the IL method for central and lateral recess stenosis under general anesthesia. In this study, using a fresh human cadaver model, we performed simultaneous decompression of the lateral recess and foraminal stenosis at L4-5 using the TF approach. Computed tomography confirmed enlargement of the lateral recess and intervertebral foramen. This technique, which can be performed under local anesthesia, should benefit elderly patients with LSS and poor general condition due to multiple comorbidities. Finally, we introduce the concept of percutaneous transforaminal ventral facetectomy using a spinal percutaneous endoscope. J. Med. Invest. 64: 1-6, February, 2017.


[Papillary glioneuronal tumor is a new nosological entity in the WHO classification of central nervous system tumors (2007)].
The paper describes a case of cystic papillary glioneuronal tumor of the temporal lobe in an 18-year-old girl. It is shown that in addition to the characteristic histological pattern, the diagnosis of this rare neoplasm recently included into the WHO classification text s should be verified by the immunohistological evidence suggesting the coexpression of glial and neuronal markers.


Deliberately provoking local inflammation drives tumors to become their own protective vaccine site.
Anti-cancer immunotherapies aim to generate resolution of all existing tumors, including inaccessible ones, and provide long-term protection against recurrence. This is rarely achieved. Thus, we aimed to determine if the tumor microenvironment could be turned into a potent 'self'-vaccine site. Our target was to eradicate larger tumor burdens. Our models respond to single-agent immunotherapies; however, they fail at a precisely defined 'cut-off' tumor burden. Thus, this system was used to define the immune mechanisms required to mediate regression of larger tumors that are resistant to mono-immunotherapies. We report that direct injection of IL-2 with agonist anti-CD40 antibody into the tumor bed resulted in permanent resolution of treated and untreated distal tumors. Tumor-infiltrating CD8(+) T cells and neutrophils collaborated to eradicate treated tumors, IFNgamma was not critical and protective memory was preserved. This approach relied only on tumor antigens expressed within the tumor microenvironment. It also avoided systemic toxicities, did not require chemotherapy or surgery and is clinically useful because only one tumor site has to be accessible for treatment. We conclude that provoking intra-tumoral inflammation skews the tumor microenvironment from tumorigenic to immunogenic, resulting in the resolution of treated and untreated distal tumors, as well long-term protective memory.


Personal protective equipment for viral hemorrhagic fevers.
Viral hemorrhagic fevers (VHF) encompass many organisms that have caused sporadic outbreaks with high case fatality rates. This article reviews VHF with reported human-to-human transmission and describes updates about personal protective equipment (PPE) for healthcare personnel (HCP) and others. We summarize existing information about appropriate PPE use, training, and compliance for care of VHF patients in endemic and nonendemic countries, as well as addresses the challenges HCP experience when using PPE. PPE is essential in protecting HCP from exposure to disease-causing pathogens. Recent evidence shows that anyone involved in care, management, and transport of certain VHF patients must use elements of PPE as part of appropriate infection prevention and control (IPC) practices. Strict adherence to standard precautions has effectively interrupted human-to-human transmission of a number of VHF. However, unclear protocols, inconsistent training, climate challenges, and cultural sensitivities impede proper PPE use. Appropriate PPE use can drastically reduce the risk of HCP exposure to VHF. Infections caused by certain VHFs can be highly pathogenic and associated with significant morbidity and mortality. Though it is well documented that use of PPE and good IPC practices are critical to reducing transmission, little conclusive evidence exists about the ideal PPE ensemble or components. Concerns with comfort, compliance, training, and usability may impede proper PPE use. Basic PPE elements, used appropriately as part of stringent IPC, must always form the foundation of care for HCP-treating patients with VHF. More research is required to identify the ideal PPE ensemble for caring for VHF patients in various settings.


Awareness and symbol use improves future-oriented decision making in preschoolers.
A child version of the Iowa Gambling task was used to explore the development of decision-making during the preschool period in two experiments. One hundred eighty-one children, 3.5 and 4.5 years of age, were asked to choose between a bad deck with higher immediate but lower long-term rewards and a good deck with lower immediate but higher long-term rewards. Experiment 1 explored age differences and the association of the gambling task with a delay of gratification task. Age differences in performance were found, supporting previous findings (Kerr & Zelazo, 2004) of a development difference between 3- and 4-year-old children in future-oriented decision making. Performance on the gambling task was found to be significantly associated with delay of gratification for 3.5-year-old children only. Experiment 2 explored the effect of labeling and symbol use on performance. Although having 4.5-year-old children label decks as good or bad improved their performance on the task, this labeling had no effect on 3.5-year-old childrens performance. However, having 3.5-year-old children place a symbol representing good and bad next to the decks did improve performance, but only for those children who were able to correctly label the decks. These results suggest an interaction between conscious awareness, symbol use, and making advantageous future-oriented decisions during the preschool period.


The hyaluronan-mediated motility receptor RHAMM promotes growth, invasiveness and dissemination of colorectal cancer.
In colorectal cancer (CRC), RHAMM is an independent adverse prognostic factor. The aim of the study was therefore to investigate on the role of RHAMM as a potential direct driver of cell proliferation and migration in CRC cell lines and to identify pathways dependent on RHAMM in human CRC. Proliferation, cell cycle alterations and invasive capacity were tested in two RHAMM- and control- knockdown CRC cell lines by flow cytometry and in vitro assays. Tumorigenicity and metastasis formation was assessed in immunodeficient mice. RNA-Seq and immunohistochemistry was performed on six RHAMM+/- primary CRC tumors. In vitro, silencing of RHAMM inhibited CRC cell migration and invasion by 50% (p<0.01). In vivo, RHAMM knockdown resulted in slower growth, lower tumor size (p<0.001) and inhibition of metastasis (p<0.001). Patients with RHAMM-high CRC had a worse prognosis (p=0.040) and upregulated pathways for cell cycle progression and adhesion turnover. RHAMM overexpression is correlated with increased migration and invasion of CRC cells, leads to larger, fast growing tumors, and its downregulation essentially abolishes metastasis in mouse models. RHAMM is therefore a promising therapeutic target in all CRC stages as its inhibition affects growth and dissemination of the primary CRC as well as the metastases.


A history of facial and ocular prosthetics.
This article traces the history of facial and ocular prosthetics. Creative individuals who have made significant contributions are highlighted and the evolution of techniques and materials is presented. In view of the significance placed upon facial beauty in today's society, it becomes incumbent upon us to recognize the ingenuity and skill of those in the past to gain appreciation for the present state of the art and to provide incentive for improving facial and ocular prosthetic restorations in the future.


Angiogenesis in hereditary hemorrhagic telangiectasia: VEGF165 plasma concentration in correlation to the VEGF expression and microvessel density.
Angiogenesis defines the physiologic process of capillary blood vessel formation. It is a multistep process, which is controlled by a large number of pro- and anti-angiogenic factors. Vascular endothelial growth factors (VEGF) are the best characterized pro-angiogenic factors, which play a key role in angiogenesis. Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant, multi-systemic disorder of angiogenesis, clinically characterized by severe and recurrent hemorrhages. We assume in HHT patients with increased VEGF plasma levels a high VEGF expression also correlates with the degree of microvesssel density (MVD). In 41 HHT patients and 47 healthy patients, the VEGF165 plasma concentration was determined by standard ELISA technique. Cryostat sections of 13 HHT patients were immunostained for VEGF and endothelial cells by an anti-vWF monoclonal antibody using a standard streptavidinbiotin complex procedure. The degree of vessel density was quantified by light microscopy (x200) within 'hot spot' areas of the HHT-tissue. All HHT cryostat sections showed a medium to strong staining for VEFG compared to healthy control tissue. The VEGF expression correlated with the VEGF165 plasma concentration and the mean MVD in HHT patients. HHT patients with medium VEGF staining revealed significantly lower VEGF165 plasma concentrations and a lower mean MVD (204+/-12 vessels/per microscopic field) than HHT patients with strong VEGF staining (327+/-76 vessels/per microscopic field). High VEGF expression in patients with HHT in correlation to their VEGF165 plasma levels and the microvessel density may support the theory that VEGF functions as an important regulator and key protein of angiogenesis, even in HHT.


Intracapsular Femoral Neck Fractures-A Surgical Management Algorithm.
Background and Objectives: Femoral neck fractures are common and constitute one of the largest healthcare burdens of the modern age. Fractures within the joint capsule (intracapsular) provide a specific surgical challenge due to the difficulty in predicting rates of bony union and whether the blood supply to the femoral head has been disrupted in a way that would lead to avascular necrosis. Most femoral neck fractures are treated surgically, aiming to maintain mobility, whilst reducing pain and complications associated with prolonged bedrest. Materials and Methods: We performed a narrative review of intracapsular hip fracture management, highlighting the latest advancements in fixation techniques, generating an evidence-based algorithm for their management. Results: Multiple different fracture configurations are encountered within the category of intracapsular hip fractures, with each pattern having different optimal surgical strategies. Additionally, these injuries typically occur in patients where further procedures due to operative complications are associated with a considerable increase in mortality, highlighting the need for choosing the correct index operation. Conclusions: Factors such as pathological causes for the fracture, pre-existing symptomatic osteoarthritis, patient's physiological age and fracture displacement all need to be considered when choosing optimal management.


Social distribution of cardiovascular disease risk factors: change among men in England 1984-1993.
To investigate change in the social distribution of some of the main risk factors for cardiovascular disease in men in England during a period when inequality in cardiovascular disease mortality widened Age standardised comparison of the social distribution of seven known risk factors for cardiovascular disease (body mass index, waist to hip ratio, systolic and diastolic blood pressure, consumption of fresh green vegetables, leisure time exercise, cigarette smoking and levels of social support) in two large cross sectional representative samples of the English population. Men aged 20-64 years in the 1984 Health and Lifestyle Survey (excluding Scotland and Wales) first sweep and the 1993 Health Survey for England. Mean values of continuous variables; age adjusted proportions of categorical variables; change in the relative index of inequality for each risk factor. The overall prevalence of cardiovascular disease risk factors improved during the period in which cardiovascular disease mortality was falling. The social distribution of cardiovascular disease risk factors, in contrast, did not become more extreme. Increases in the relative index of inequality for angina from 1.75 to 1.86, for eating vegetables less than once a day from 1.76 in 1984 to 1.96 in 1993, and an apparently larger increase in inequality of social support, from 1.92 to 2.53 were not statistically significant. In most cases the degree of inequality in risk factors tended to narrow non-significantly: for example the relative index of inequality fell from 5.02 in 1984 to 3.07 in 1993 for systolic blood pressure, from 5.60 to 4.29 for current smoking and from 6.24 to 4.19 for eating other than wholemeal bread as the main form of bread in the diet. The two statistically significant changes in inequality were in the direction of narrowing inequality: from a relative index of inequality of 2.12 to 0.90 for diastolic blood pressure (p<0.01) and from 19.3 to 0.87 (p<0.01) for psychological distress as indicated by the General Health Questionnaire. Healthier lifestyle options have not been adopted at a significantly faster rate by middle class than working class people over this time period. At the population level the change in risk factors is consistent with falling cardiovascular mortality. The change in the social distribution of risk factors within the population, however, shows little or no relation to the pattern of widening inequality in cardiovascular mortality. This may be because the effect is lagged, or because the adoption of healthier behaviour confers greater benefits on those in higher socioeconomic status groups.


Reproducibility of A Posteriori Dietary Patterns across Time and Studies: A Scoping Review.
Few studies have considered if a posteriori dietary patterns (DPs) are generalizable across different centers or studies, or if they are consistently seen over time. To date, no systematic search of the literature on these topics has been carried out. A scoping review was conducted through a systematic search on the PubMed database. In the current review, we included the 34 articles examining the extent to which a posteriori DPs were consistently seen: 1) across centers from the same study or across different studies potentially representing different populations or countries (here indicated as cross-study reproducibility) and 2) over longer time periods (i.e., ≥2 y) (here indicated as stability over time). Selected articles (published in 1981-2019, 32% from 2010 onwards) were based on observational studies, mostly from Europe and North America. Five articles were based on children and/or adolescents and 14 articles included adults (2 men; 12 women, of whom 3 were pregnant women). A posteriori DPs were mostly derived (32 articles) with principal component or factor analyses. Among the 9 articles assessing DP reproducibility across studies (number of centers/studies: 2-27; median: 3), 5 provided a formal assessment using statistical methods (4 index-based approaches of different complexity, 1 statistical model). A median of 4 DPs was reproduced across centers/studies (range: 1-7). Among the 25 articles assessing DP stability over time (number of time-occasions: 2-6; median: 3), 19 provided a formal assessment with statistical methods (17 index-based and/or test-based approaches, 1 statistical model, 1 with both strategies). The number and composition of DPs remained mostly stable over time. Based on the limited evidence collected, most identified DPs showed good reproducibility across studies and stability over time. However, when present within the single studies, the criteria for the formal assessment of cross-study reproducibility or stability over time were generally very basic.


Osteochondral and Meniscal Allograft Transplantation in the Football (Soccer) Player.
Knee injuries are common in football, frequently involving damage to the meniscus and articular cartilage. These injuries can cause significant disability, result in loss of playing time, and predispose players to osteoarthritis. Osteochondral allografting is an increasingly popular treatment option for osteoarticular lesions in athletes. Osteochondral allografts provide mature, orthotopic hyaline cartilage on an osseous scaffold that serves as an attachment vehicle, which is rapidly replaced via creeping substitution, leading to reliable graft integration that allows for simplified rehabilitation and accelerated return to sport. The indications for meniscal replacement in football players are currently still evolving. Meniscus allografts offer potential functional, analgesic, and chondroprotective benefits in the meniscectomized knee. In the player at the end of his or her professional/competitive career, meniscal allografts can play a role in averting progression of chondropenia and facilitating knee function and an active lifestyle. This article is intended to present a concise overview of the limited published results for osteochondral and meniscal allografting in the athletic population and to provide a practical treatment algorithm that is of relevance to the clinician as well as the patient/football player, based on current consensus of opinion.


The Zuckerkandl's tubercle: a useful anatomical landmark for detecting both the recurrent laryngeal nerve and the superior parathyroid during thyroid surgery.
Zuckerkandl's tubercle (ZT) is a well-documented anatomical structure. This study evaluated ZT anatomical characteristics in terms of the recurrent laryngeal nerve (RLN) and the superior parathyroid (SP). The study involved 325 (10 with benign tumors and 315 with malignancies) patients who underwent thyroidectomy between February and June 2007. ZTs were classified according to size: Grade 0 (unrecognizable), Grade I (</=5 mm), Grade II (6~10 mm) and Grade III (>10 mm). The incidence and size of the ZT and its positional relationship to the RLN and SP were investigated during thyroid surgery. ZTs were identified in most patients (right 89.3%, left 85.6%). The distribution of ZTs according to grade was as follows: Grade 0, right 10.7% and left 14.4%; Grade I, right 7.9% and left 11.1%; Grade II, right 43.5% and left 38.5%; and Grade III, right 37.9% and left 35.9%. The most common RLN course was in a groove between the ZT and the main body of the thyroid. The majority of SPs were cranial to the ZT which was located at the 1 or 2 o'clock position (96.1%) in the left, and at 10 or 11 o'clock (95.2%) in the right. The smaller the size of the ZT, the greater the distance between the ZT and the SP. There was a constant relationship between the ZT and RLN and SP. Therefore, an identification of ZT and an understanding of the relationship between the ZT and RLN and SP are essential for performing safe thyroid surgery.


Evaluation of a Mindfulness-Based Mobile App Aimed at Promoting Awareness of Weight-Related Behaviors in Adolescents: A Pilot Study.
Mindfulness-based interventions are reported to be highly acceptable and have positive effects on youth, yet most are clinic- or school-based aimed at emotional regulation or academic performance. To provide flexible program delivery, we developed and tested a standalone mindfulness-based app aimed at improving weight-related behaviors (eg, diet, physical activity, sleep) in adolescents. Our objective was to assess the feasibility, acceptability, and utility of a mindfulness-based mobile app. In a single-arm pilot study, 15 adolescents (14-18 years) were prompted to access the app once a day, every day for 6 weeks. Outcomes were measured by in-app and poststudy surveys, and descriptive statistical analyses were performed. Time within a mindfulness state was self-reported during weekly timed practices. The app was rated highly for content and encouraging the practice of activities to promote mindfulness states. Teens reported increased awareness of eating behaviors and high adherence, particularly during physically active practices. Average self-reported time spent in a mindfulness state increased 2.5 times by week 6 (78 [SD 17] seconds) compared to week 1 (31 [SD 21] seconds). The high acceptability and utility ratings of the app, increases in reported time in mindfulness states, and high frequency of participation, including mindful eating and physical activity, suggest the mindfulness-based mobile app has the potential to improve awareness of weight-related behaviors.


Mitochondrial deafness.
The last decade has led to the identification of several mitochondrial DNA mutations associated with hearing loss. Since the only known function of the human mitochondrial chromosome is to participate in the production of chemical energy through oxidative phosphorylation, it was not unexpected that mitochondrial mutations interfering with energy production could cause systemic neuromuscular disorders, which have as one of their features hearing impairment. Surprisingly, however, inherited mitochondrial mutations also have been found to be a cause of non-syndromic hearing loss, and predispose to aminoglycoside induced hearing loss, while acquired mitochondrial mutations have been proposed as one of the causes of presbycusis. After a brief review of mitochondrial genetics, we will outline the different mitochondrial mutations associated with hearing loss, describe the audiological features, and discuss the clinical relevance of diagnosing these mutations. Clinical expression of these mitochondrial mutations is dependent on environmental exposures and nuclear-encoded modifier genes. Preventive and therapeutic strategies will depend on identification and avoidance of the environmental exposures, and the identification of the nuclear-encoded modifier genes. Experimental approaches to identify these modifier genes will be presented.


Effective association of Kv channel-interacting proteins with Kv4 channel is mediated with their unique core peptide.
Kv channel-interacting proteins (KChIPs) and neuronal calcium sensor-1 (NCS-1) have been shown to interact with Kv4 channel alpha-subunits to regulate the expression and/or gating of these channels. Here we examine the specificity and sites of these proteins for interaction with Kv channel proteins. Immunoprecipitation and green fluorescent protein imaging show that KChIPs (but not NCS-1) effectively bind to Kv4.3 protein and localize at the plasma membrane when channel proteins are coexpressed. Analysis with chimeric proteins between KChIP2 and NCS-1 reveals that the three regions of KChIP2 (the linker between the first and second EF hands, the one between the third and fourth EF hands, and the C-terminal peptide after the fourth EF hand) are necessary and sufficient for its effective binding to Kv4.3 protein. The chimera with these three KChIP2 portions slowed inactivation and facilitated recovery from inactivation of Kv4.3 current. These results indicate that the sequence difference in these three regions between KChIPs and NCS-1 determines the specificity and affinity for interaction with Kv4 protein. Because the three identified regions surround the large hydrophobic crevice based on the NCS-1 crystal structure, this crevice may be the association site of KChIPs for the channel protein.


Using the postpartum hospital stay to address mothers' and fathers' smoking: the NEWS study.
The objective of this study was to test the feasibility and acceptability of introducing an intervention to address mothers' and fathers' smoking during the postpartum hospitalization. During a 14-month period (February 2005 to April 2006), we assessed the smoking status of both parents of all newborns who were delivered at a hospital child birth center. Parents who were current smokers (1 cigarette, even a puff, in past 30 days) or recent quitters (smoked since 1 month before conception) were eligible for the study. Parents were assigned to intervention or usual care control condition on the basis of day of study enrollment. Smoking outcomes were assessed at 3 months by telephone survey and cotinine confirmation; quitline use was assessed at 3 months by using quitline database. A total of 101 (64%) of 159 eligible parents enrolled in the study (n = 53 control subject, n = 48 intervention), including 72 (71%) current smokers and 29 (29%) recent quitters. All parents in the intervention group received the in-hospital counseling session, 94% had a fax sent to a provider, and 36 (75%) accepted quitline enrollment. In an intention-to-treat analysis that included both current smokers and recent quitters, self-reported 7-day abstinence decreased from 31% to 25% among intervention parents versus 38% to 23% among control subjects (effect size 9.4%; nonsignificant). Among current smokers at baseline who were reached at follow-up (n = 36), self-reported 24-hour quit attempts were higher in the intervention group versus control group (64% vs 18%; P = .005), whereas the cotinine-confirmed 7-day abstinence rates at follow-up were 9% in the intervention group and 3% in the control group (nonsignificant). Enrolling mothers and fathers into tobacco treatment services during the immediate postpartum hospital stay is feasible and seems to stimulate quit attempts. The birth of an infant presents a teachable moment to reach both parents and to provide cessation assistance.


Interventions for family members of adolescents with disruptive behavior disorders.
The family members of adolescents diagnosed with disruptive behavior disorders (DBDs) experience profound stress and burden. Despite the need for empirically supported interventions that address the challenges faced by these family members, few such interventions are available. In this qualitative descriptive study, we conducted in-depth interviews with 15 families of adolescents diagnosed with DBD. We asked the family members to identify what types of mental health services they needed and to describe the "ideal" program that would best address their concerns. Family members identified several intervention modalities that would fit their needs, including multifamily groups, family therapy, individual therapy, and community-based hotlines. They indicated that programs should address the following topics: family communication, conflict resolution, education about DBD, and strategies to improve interactions with child service agencies. Clinicians should recognize that all family members may need support to manage the stressors associated with caring for or living with adolescents with DBD. When working with families, clinicians should provide information about the etiology and management of DBD, help navigate interactions with child service agencies, and employ strategies to improve family communication and functioning.


Use of an instrumented treadmill for real-time gait symmetry evaluation and feedback in normal and trans-tibial amputee subjects.
The purpose of this research was to evaluate a newly developed system for assessing and providing feedback of gait symmetry information in real time to subjects walking on a motorised treadmill (the CCF Treadmill). The advantages of the system are that it allows the rapid collection and comparison of temporal and kinetic parameters of gait for multiple successive strides, at a constant known speed, without forcing subjects to target their footsteps. Gait asymmetries of six normal (mean age 42.7 years) and six unilateral transtibial amputee subjects (mean age 41.7, and average 6.0 years using a prosthesis) were quantified. The amputee group was the reevaluated after receiving five minutes of training with each of three different types of real-time visual feedback (RTVF). Asymmetries in the measured parameters before feedback were 4.6 times greater in the amputee population than in the normal group, and were consistent with the finding of previous authors. Significant decreases in gait asymmetry were demonstrated for all forms of feedback after amputees received feedback training. Results, however, indicated that gait asymmetries for different variables are not necessarily related, and that more work needs to be done to identify those variables for which attaining a more symmetrical gait pattern is most beneficial. Further work also needs to be done to determine the long term effects of such RTVF training. The CCF Treadmill and RTVF were shown to be potentially useful tools both for defining rehabilitation targets and for quantifying patients' progress towards those goals.


Analysis of apolipoprotein genes and their involvement in disease response of channel catfish after bacterial infection.
Apolipoproteins are protein component of plasma lipoproteins. They exert crucial roles in lipoprotein metabolism and serve as enzyme cofactors, receptor ligands, and lipid transfer carriers in mammals. In teleosts, apolipoproteins are also involved in diverse processes including embryonic and ontogenic development, liver and digestive system organogenesis, and innate immunity. In this study, we identified a set of 19 apolipoprotein genes in channel catfish (Ictalurus punctatus). Phylogenetic analysis and syntenic analysis were conducted to determine their identities and evolutionary relationships. The expression signatures of apolipoproteins in channel catfish were determined in healthy tissues and after infections with two major bacterial pathogens, Edwardsiella ictaluri and Flavobacterium columnare. In healthy channel catfish, most apolipoprotein genes exhibited tissue-specific expression patterns in channel catfish. After ESC and columnaris infections, 5 and 7 apolipoprotein genes were differentially expressed respectively, which presented a pathogen-specific and time-dependent pattern of regulation. After ESC infection, three exchangeable apolipoproteins (apoA-IB, apoC-I, and apoE-B) were suppressed in catfish intestine, while two nonexchangeable apolipoproteins (apoB-A and apoB-B) were slightly up-regulated. After columnaris infection, apoB-B, apoD-B, and apoE-A were significantly down-regulated in catfish gill, while apoF, apoL-IV, apoO-like, and apo-14 kDa showed significantly up-regulation. Taken together, these results suggested that apolipoprotein genes may play significant roles in innate immune responses to bacterial pathogens in channel catfish.


FGF23 antagonism: the thin line between adaptation and maladaptation in chronic kidney disease.
For more than 10 years, we have been convinced by overwhelming epidemiological evidence with a high biological plausibility that hyperphosphataemia imposes one of the most sustained cardiovascular and mortality risks on patients suffering from chronic kidney disease (CKD). With the discovery of the fibroblast growth factor-23 (FGF23)/klotho axis, we not only gained a new and mechanistic understanding of phosphate handling of the body, we also felt that novel therapeutic strategies may arise counteracting the deleterious consequences of phosphate retention, dysregulation and maldistribution. Two recent experimental studies shed additional and important light on what we can expect from such new insights. Faul et al. showed us that FGF23 excess may directly induce left ventricular hypertrophy (LVH) and that FGF-receptor antagonism ameliorates CKD-induced LVH in rats. Shalhoub et al. demonstrated that FGF23 antibodies successfully ameliorated the development and progression of most features of secondary hyperparathyroidism in a rat model of CKD, however, at the expense of hyperphosphataemia, progressive vascular calcification and death. Such studies not only help to continuously improve our understanding, but also especially sharpen our perception of how thin the line may be between adaptation and maladaptation in chronic disease scenarios.


Sodium nitrate supplementation does not enhance performance of endurance athletes.
Supplementation with inorganic nitrate has been suggested to be an ergogenic aid for athletes as nitric oxide donor. The purpose of this study was to determine whether ingestion of inorganic sodium nitrate benefits well-trained athletes performing a 40-min exercise test in laboratory conditions. In addition, we investigated the effect of this supplement on plasma levels of endothelin-1 (ET-1) and in nitrated proteins. Thirteen trained athletes participated in this randomized, double-blind, crossover study. They performed a 40-min cycle ergometer distance-trial test after two 3-d periods of dietary supplementation with sodium nitrate (10 mg·kg of body mass) or placebo. Concentration of plasma nitrate (256 ± 35 μM) and nitrite (334 ± 86 nM) increased significantly (P < 0.05) after nitrate supplementation compared with placebo (nitrate: 44 ± 11 μM; nitrite: 187 ± 43 nM). In terms of exercise performance, there were no differences in either the mean distance (nitrate: 26.4 ± 1.1 km; placebo: 26.3 ± 1.2 km; P = 0.61) or mean power output (nitrate: 258 ± 28 W; placebo: 257 ± 28 W; P = 0.89) between treatments. Plasma ET-1 increased significantly (P < 0.05) just after exercise in nitrate (4.0 ± 0.8 pg·mL) and placebo (2.4 ± 0.4 pg·mL) conditions. This increase was significantly greater (P < 0.05) in the nitrate group. Levels of nitrated proteins did not differ between treatments (nitrate: preexercise, 91% ± 23%; postexercise, 81% ± 23%; placebo: preexercise, 95% ± 20%; postexercise, 99% ± 19%). Sodium nitrate supplementation did not improve a 40-min distance-trial performance in endurance athletes. In addition, concentration of plasma ET-1 increased significantly after exercise after supplementation with sodium nitrate.


Understanding the Activity Trends in Electrocatalytic Nitrate Reduction to Ammonia on Cu Catalysts.
Cu-based catalysts possess great potential in the electrocatalytic nitrate (NO3-) reduction reaction for ammonia (NH3) synthesis. However, the low atomic economy limits their further application. Here we report a Cu single-atom (SA) incorporated in nitrogen-doped carbon (Cu SA/NC) with high atomic economy, which exhibits superior NH3 Faradaic efficiency (FE) of 100% along with an impressive NH3 yield rate of 7480 μg h-1 mgcat.-1. As counterparts, Cus+n/NC, with mixed SA and nanoparticles (NPs), shows decreasing NH3 FE with decreasing SA content, but the production of N2 and N2O increases gradually, which reaches the maximum on pure Cu NPs. In situ characterizations and theoretical calculations reveal that a higher NH3 FE of Cu SA/NC is ascribed to a lower free energy of the rate-limiting step (HNO* → N*) and effective inhibition for the N-N coupled process. This work provides the intuitive activity trends of Cu-based catalysts, opening an avenue for subsequent catalysts design.


Central nervous system cryptococcosis in solid organ transplant recipients: clinical relevance of abnormal neuroimaging findings.
Prognostic implications of cryptococcal antigen and outcomes associated with central nervous system (CNS) cryptococcal lesions in solid organ transplant recipients have not been fully defined. Patients were derived form a cohort of 122 solid organ transplant recipients with cryptococcosis in a multicenter study from 1999 to 2006. Central nervous system cryptococcosis was documented in 61 patients. Serum or cerebral spinal fluid antigen titers did not correlate with mortality at 90 days or cerebral spinal fluid sterilization at 2 weeks. Central nervous system lesions were identified in 16 patients and included leptomeningeal lesions in eight, parenchymal lesions in six, and hydrocephalus in two. Overall, 13/16 CNS lesions were present at the time of diagnosis. One parenchymal and two hydrocephalus lesions, however, developed after diagnosis and fulfilled the criteria for immune reconstitution syndrome. Cerebral spinal fluid antigen titers were higher with meningeal versus parenchymal lesions, and hydrocephalus (P=0.015). Mortality was 50% (3/6) for patients with parenchymal, 12.5% (1/8) for those with leptomeningeal, and 0/3 for patients with hydrocephalus. Mortality was 31% (4/13) for patients with CNS lesions at baseline and 0/3 in those with new onset lesions. Despite a higher antigen titer with meningeal lesions, outcomes tended to be worse with parenchymal compared with meningeal lesions or hydrocephalus. New onset CNS lesions may represent immune reconstitution syndrome and seemed to be associated with better outcome.


Informed consent and disclosure in the physician-patient relationship: expanding obligations for physicians in the United States.
In recent years, the doctrine of informed consent has been one of the primary vehicles by which American courts and legislatures have evaluated the nature and scope of information that physicians must disclose to patients in a variety of treatment situations. Historically, physicians have had the primary responsibility to disclose to patients the nature of a proposed course of treatment, material risks and benefits, as well as reasonably available alternatives, in obtaining consent to treatment. Statutory and common-law developments in the United States appear to suggest that disclosure obligations of physicians in this context are continuing to evolve. This article examines recent judicial and legislative developments in the United States, which appear to underlie expanding disclosure obligations in a variety of situations that arise within the context of the physician-patient relationship. Emphasis is placed on disclosure obligations with respect to the physician's physical condition and its impact on the provision of medical care, information regarding the physician's general ability to perform certain surgeries or other medical procedures, as well as disclosure of research interests, financial interests, and other incentives that may bear upon clinical decision making. This article concludes that physicians should be aware of recent statutory and common-law developments in the United States that may give rise to heightened potential for legal accountability arising out of failure to disclose an increasingly diverse array of information to patients in the physician-patient relationship.


[Comparison of acute bronchodilator tests in patients with chronic obstructive lung disease and bronchial asthma].
Three hundred and thirty-five patients with bronchial asthma (BA) and 534 patients with chronic obstructive lung disease (COLD) were examined. Before and after tests using salbutamol, phenoterol, ipratropium bromide and a fixed combination of phenoterol and ipratropium bromide, the forced expiratory flow-volume curve was recorded in the patients on each visit (1008 and 1398 visits of patients with BA and COLD, respectively). The study was controlled open-labeled, and prospective. All the bronchodilators were found to be effective in both BA and COLD. However, in asthmatic patients without (less than 4%) and with (more than 5%) eosinophilia, the increase in forced expiratory volume per second (FEV1) was 23.7+/-22.1% and 16.0+/-14.6% of the baseline values, respectively (p < 0.05). Among these patients with ESR of less than 100 mm/hour, the increase in FEV1 was significantly higher--21.7+/-19.7% than in those who had ERS more than 15 mm/hour and this was 13.8+/-17.9% of the baseline values (p < 0.05). Among asthmatic patients, more than 15% increases in FEV1 after administration of bronchodilators were noted in 48% of the patients untreated with inhaled corticosteroids (ICS) and in 61% of the ICS-treated patients (chi2 = 6.55; d.f. = 1; p = 0.01). Among ICS-treated and untreated patients with BA, the mean increase in FEV1 was 24.4+/-22.5% and 19.6+/-22.0% of the baseline values, respectively (p < 0.05). In COLD patients, these differences were absent. It has been concluded that eosinophilic inflammation typical of BA decreases the effect of bronchodilators in BA and that inhaled steroids improve it.


Ocular disease pattern induced by herpes simplex virus is genetically determined by a specific region of viral DNA.
The pattern of ocular disease produced in the rabbit eye by HSV-1 (F) and HSV-1(MP) strains and recombinants F(MP)A, F(MP)B, F(MP)C, F(MP)D, F(MP)E, and F(MP)F was studied. The characteristics of ocular herpetic disease such as morphology of dendritic ulcers, severity of epithelial disease and incidence and duration of stromal disease produced in the rabbit eye are genetically determined by the virus strain. Our studies show that transfer of a defined part of the genome of the stromal disease-producing virus, HSV-1(MP), to the genome of an epithelial disease-producing virus, HSV-1(F), yielded recombinants with one or more of the disease characteristics of the donor strain. Specifically, recombinant F(MP)D produced lesions characteristic of the donor HSV-1(MP) strain; recombinants F(MP)C and F(MP)E produced stromal disease approaching the severity of the disease produced by the donor HSV-1(MP) strain, and only recombinants F(MP)A and F(MP)B retained the typically elongate lesions of the recipient HSV-1(F), whereas the recombinant strain F(MP)F produced no disease. The viral functions pertaining to the ocular disease pattern map between 0.70 and 0.83 map units in HSV-1 DNA within the BglII F DNA fragment. The pattern of stromal disease is independent of the production of glycoprotein C and fusion of HEp-2-infected cells. The functions relating to these aspects of ocular disease segregate but are closely linked.


Binding studies of molecular linkers to ZnO and MgZnO nanotip films.
Two bifunctional linkers, a rigid-rod p-ethynyl-isophthalic acid capped with a Ru(II)-polypyridyl complex and 3-mercaptopropionic acid, were covalently bound to ZnO nanotip films grown by metal-organic chemical vapor deposition (MOCVD) technology. This highly vertically aligned, crystalline form of ZnO had not been functionalized before. The binding was studied by Fourier transform (FT) IR and UV spectroscopies and probed, in the case of the Ru complex, by static and dynamic fluorescence quenching. The molecules did bind through the carboxylic acid groups, and the FT-IR attenuated total reflectance spectra are indicative of a bidentate carboxylate binding mode. Other molecules (heptanoic acid, isophthalic acid, and trimethoxy(2-phenylethyl)silane) were also bound to the ZnO nanotips. A comparison was made with epitaxial ZnO films grown by MOCVD and ZnO mesoporous films prepared from colloidal solutions to investigate the effect of the ZnO morphology. The ZnO nanotips were excellent binding substrates, particularly for the rigid-rod linker. Since ZnO films are etched at low pH (< 4), novel nanotip films made of ternary MgxZn1-xO, which is formed by alloying ZnO with MgO and is more resistant to acids, were developed. The MgxZn1-xO nanotip films were employed to use linkers with acidic groups and to study the effect of pH pretreatment of the surface on the binding.


Incidence of Initial Renal Replacement Therapy Over the Course of Kidney Disease in Children.
The Chronic Kidney Disease in Children Study, a prospective cohort study with data collected from 2003 to 2018, provided the first opportunity to characterize the incidence of renal replacement therapy (RRT) initiation over the life course of pediatric kidney diseases. In the current analysis, parametric generalized gamma models were fitted and extrapolated for RRT overall and by specific treatment modality (dialysis or preemptive kidney transplant). Children were stratified by type of diagnosis: nonglomerular (mostly congenital; n = 650), glomerular-hemolytic uremic syndrome (HUS; n = 49), or glomerular-non-HUS (heterogeneous childhood onset; n = 216). Estimated durations of time to RRT after disease onset for 99% of the nonglomerular and glomerular-non-HUS groups were 42.5 years (95% confidence interval (CI): 31.0, 54.1) and 25.4 years (95% CI: 14.9, 36.0), respectively. Since onset for the great majority of children in the nonglomerular group was congenital, disease duration equated with age. A simulation-based estimate of age at RRT for 99% of the glomerular population was 37.9 years (95% CI: 33.6, 63.2). These models performed well in cross-validation. Children with glomerular disease received dialysis earlier and were less likely to have a preemptive kidney transplant, while the timing and proportions of dialysis and transplantation were similar for the nonglomerular group. These diagnosis-specific estimates provide insight into patient-centered prognostic information and can assist in RRT planning efforts for children with moderate-to-severe kidney disease who are receiving regular specialty care.


Induction of IG9 monocyte adhesion molecule expression in smooth muscle and endothelial cells after balloon arterial injury in cholesterol-fed rabbits.
The expression of monocyte-specific adhesion molecules and chemokines by cell types within the vessel wall plays an important role in foam cell accumulation during atherosclerotic plaque development. We previously identified IG9, a novel monocyte adhesion protein that is expressed on endothelial cells (ECs) overlying human and rabbit advanced atherosclerotic plaques. The present study was designed to determine the temporal and spatial expression of IG9 and the chemokine, monocyte chemoattractant protein-1 (MCP-1), after balloon injury with (double injury) or without (single injury) prior air desiccation EC injury in the femoral arteries of rabbits fed a high-cholesterol diet. By immunohistochemical analyses, intense reactivity with monoclonal antibodies to IG9 and MCP-1 was detected 24 hours after single injury in medial smooth muscle cells (SMCs) and in SMCs of adventitial microvessels. However, monocyte infiltration of the tunica media was minimal or not detected in these sections. IG9 and MCP-1 antibody reactivity in vessel sections 28 days after single injury and 24 hours, 7 days, and 28 days after double injury was localized to medial and neointimal SMCs, foam cells, and luminal ECs overlying the plaques. Uninjured rabbit (cholesterol or normal diet) vessel sections exhibited minimal IG9 and MCP-1 immunostaining. In vitro studies using human aortic SMCs demonstrated IG9 protein induction after 24 hours of treatment with platelet-derived growth factor-BB and interferon-gamma or epidermal growth factor. IG9 expression was further increased by pretreatment of SMCs with the proatherogenic lipid, minimally oxidized low density lipoprotein. After balloon injury (24 hours), IG9 is induced in vascular SMCs before the detectable accumulation of monocytes within the vessel wall. Thus, the expression of IG9 by SMCs as well as by ECs may be an important factor in the accumulation of foam cells in atherosclerotic plaque development after arterial injury.


Exploring the binding dynamics of BAR proteins.
We used a continuum model based on the Helfrich free energy to investigate the binding dynamics of a lipid bilayer to a BAR domain surface of a crescent-like shape of positive (e.g. I-BAR shape) or negative (e.g. F-BAR shape) intrinsic curvature. According to structural data, it has been suggested that negatively charged membrane lipids are bound to positively charged amino acids at the binding interface of BAR proteins, contributing a negative binding energy to the system free energy. In addition, the cone-like shape of negatively charged lipids on the inner side of a cell membrane might contribute a positive intrinsic curvature, facilitating the initial bending towards the crescent-like shape of the BAR domain. In the present study, we hypothesize that in the limit of a rigid BAR domain shape, the negative binding energy and the coupling between the intrinsic curvature of negatively charged lipids and the membrane curvature drive the bending of the membrane. To estimate the binding energy, the electric potential at the charged surface of a BAR domain was calculated using the Langevin-Bikerman equation. Results of numerical simulations reveal that the binding energy is important for the initial instability (i.e. bending of a membrane), while the coupling between the intrinsic shapes of lipids and membrane curvature could be crucial for the curvature-dependent aggregation of negatively charged lipids near the surface of the BAR domain. In the discussion, we suggest novel experiments using patch clamp techniques to analyze the binding dynamics of BAR proteins, as well as the possible role of BAR proteins in the fusion pore stability of exovesicles.


Experimental warming increases herbivory by leaf-chewing insects in an alpine plant community.
Climate warming is predicted to affect species and trophic interactions worldwide, and alpine ecosystems are expected to be especially sensitive to changes. In this study, we used two ongoing climate warming (open-top chambers) experiments at Finse, southern Norway, to examine whether warming had an effect on herbivory by leaf-chewing insects in an alpine Dryas heath community. We recorded feeding marks on the most common vascular plant species in warmed and control plots at two experimental sites at different elevations and carried out a brief inventory of insect herbivores. Experimental warming increased herbivory on Dryas octopetala and Bistorta vivipara. Dryas octopetala also experienced increased herbivory at the lower and warmer site, indicating an overall positive effect of warming, whereas B. vivipara experienced an increased herbivory at the colder and higher site indicating a mixed effect of warming. The Lepidoptera Zygaena exulans and Sympistis nigrita were the two most common leaf-chewing insects in the Dryas heath. Based on the observed patterns of herbivory, the insects life cycles and feeding preferences, we argue that Z. exulans is the most important herbivore on B. vivipara, and S. nigrita the most important herbivore on D. octopetala. We conclude that if the degree of insect herbivory increases in a warmer world, as suggested by this study and others, complex interactions between plants, insects, and site-specific conditions make it hard to predict overall effects on plant communities.


[Under registration of occupational accidents in São Paulo, Brazil, 1997].
To estimate the number of occupational accidents that occurred in a certain municipality during a specific period of time as well as the extent of sub-registration. The study sample was comprised of 4.782 households within the municipality of Botucatu, São Paulo occupied by a total 17,219 inhabitants on the 1st of July, 1997. In each household, an adult inhabitant was interviewed in order to identify the occurrence of occupational accidents in the three months preceding the interview. When such occurrences were identified, the injured workers were interviewed. The Cochran formula was utilized to calculate the confidence interval. Seventy-six individuals confirmed that they had suffered occupational accidents during these three months. In 1997, there were approximately 1,810 occupational accidents in Botucatu, according to our estimates, and the incidence of work related injuries in the population was approximately 4.1% (CI 95% 3.0%-5.3%). Thirty-nine (51.3%, CI 95% 41.1%61.6%) of the above 76 workers were not covered by the Social Security System. Consequently, their injuries were not reported for there was no legally binding obligation to fill out and emit the official registration form - Comunicação de Acidente do Trabalho (CAT) [the work injury report]. Included among the latter are civil servants and informal sector workers, such as self-employed, casual workers and others. Although the remaining 37 workers (48.7%) were covered by the Social Security System and emission of the work injury report was obligatory, 20 of the cases (54.1% CI 95% 39.4%-68.7%) had not been registered. A greater proportion of cases of sub-registration were found among those workers employed in micro, small and medium sized businesses than among those working in large firms. Only 22.4% (CI 13.8%-30.9%) of the occupational accidents reported in this study were registered by the Social Security System. Research findings confirm that analyses based on the number of officially registered workplace accidents are limited. It highlights the importance of utilizing other sources of data, besides the registration form for occupational accidents used currently by the Social Security System, Comunicação de Acidente do Trabalho or CAT, in order to elaborate official statistics on occupational accidents.


Population genomics as a new tool for wildlife management.
Admixture and introgression have varied effects on population viability and fitness. Admixture might be an important source of new alleles, particularly for small, geographically isolated populations. However, admixture might also cause outbreeding depression if populations are adapted to different ecological or climatic conditions. Because of the emerging use of translocation and admixture as a conservation and wildlife management strategy to reduce genetic load (termed genetic rescue), the possible effects of admixture have practical consequences (Bouzat et al. 2009; Hedrick & Fredrickson 2010). Importantly, genetic load and local adaptation are properties of individual loci and epistatic interactions among loci rather than properties of genomes. Likewise, the outcome and consequences of genetic rescue depend on the fitness effects of individual introduced alleles. In this issue of Molecular Ecology, Miller et al. (2012) use model-based, population genomic analyses to document locus-specific effects of a recent genetic rescue in the bighorn sheep population within the National Bison Range wildlife refuge (NBR; Montana, USA). They find a subset of introduced alleles associated with increased fitness in NBR bighorn sheep, some of which experienced accelerated introgression following their introduction. These loci mark regions of the genome that could constitute the genetic basis of the successful NBR bighorn sheep genetic rescue. Although population genomic analyses are frequently used to study local adaptation and selection (e.g. Hohenlohe et al. 2010; Lawniczak et al. 2010), this study constitutes a novel application of this analytical framework for wildlife management. Moreover, the detailed demographic data available for the NBR bighorn sheep population provide a rare and powerful source of information and allow more robust population genomic inference than is often possible.


High-fidelity probing of the structure and heterogeneity of extracellular vesicles by resonance-enhanced atomic force microscopy infrared spectroscopy.
Extracellular vesicles (EVs) are highly specialized nanoscale assemblies that deliver complex biological cargos to mediate intercellular communication. EVs are heterogeneous, and characterization of this heterogeneity is paramount to understanding EV biogenesis and activity, as well as to associating them with biological responses and pathologies. Traditional approaches to studying EV composition generally lack the resolution and/or sensitivity to characterize individual EVs, and therefore the assessment of EV heterogeneity has remained challenging. We have recently developed an atomic force microscope IR spectroscopy (AFM-IR) approach to probe the structural composition of single EVs with nanoscale resolution. Here, we provide a step-by-step procedure for our approach and show its power to reveal heterogeneity across individual EVs, within the same population of EVs and between different EV populations. Our approach is label free and able to detect lipids, proteins and nucleic acids within individual EVs. After isolation of EVs from cell culture medium, the protocol involves incubation of the EV sample on a suitable substrate, setup of the AFM-IR instrument and collection of nano-IR spectra and nano-IR images. Data acquisition and analyses can be completed within 24 h, and require only a basic knowledge of spectroscopy and chemistry. We anticipate that new understanding of EV composition and structure through AFM-IR will contribute to our biological understanding of EV biology and could find application in disease diagnosis and the development of EV therapies.


Core stabilization exercises versus scoliosis-specific exercises in moderate idiopathic scoliosis treatment.
There are several kinds of scoliosis-specific and general physiotherapeutic exercise methods used in scoliosis rehabilitation. But there is need for comparable studies on the effectiveness of different exercise approaches for the treatment of adolescent idiopathic scoliosis. Comparison of the effects of combined core stabilization exercise and bracing treatment with Scientific Exercises Approach to Scoliosis and bracing treatment in patients with moderate adolescent idiopathic scoliosis. Thirty females with adolescent idiopathic scoliosis, who have moderate curves (20°-45°), were randomly divided into two groups. In addition to brace wearing for 4 months, one group received core stabilization exercise therapy, while the other received scientific exercises approach to scoliosis exercise therapy. The outcome measures were based on Cobb angle, angle of trunk rotation, body symmetry, cosmetic trunk deformity, and quality of life. Thoracic and lumbar Cobb angles and trunk rotation angles, body symmetry, and cosmetic trunk deformity improved for both groups. Quality of life did not change in either group. The pain domain of the Scoliosis Research Society-22 questionnaire improved in the core stabilization group only. Both treatment conditions including core stabilization with bracing and scientific exercises approach to scoliosis with bracing had similar effects in the short-term treatment of moderate adolescent idiopathic scoliosis. This study showed that when scientific exercises approach to scoliosis (SEAS) and core stabilization (CS) exercises were administered with equal intensity, the effects of the two treatment protocols including CS and bracing and SEAS and bracing were similar in the treatment of patients with moderate adolescent idiopathic scoliosis (AIS).


Intestinal tumors in mice treated with a single injection of N-nitroso-N-butylurea.
N-Nitroso-N-butylurea was injected once at dosage levels of 150 or 75 mg/kg into 3- or 6-week-old male C57BL/L mice. Intestinal tumors occurred in 100% of the mice that survived more than 15 weeks after injection with a high dose of N-nitroso-N-butylurea at 6 weeks of age, and in 35 to 70% of the mice in other treatment groups. These intestinal tumors were seen primarily at the junction of the pylorus and duodenum and in the anterior portion of the small intestine, with a few in the cecum, colon, and rectum. The tumors at the junction were not very invasive tumors and frequently appeared as polypoid growths. Tumors not at this location were adenocarcinomas that invaded all the layers of the gut wall but which did not metastasize. Colorectal tumors were adenomas and adenocarcinomas. N-Nitroso-N-butylurea also induced tumors of the stomach, hematopoietic system, lung, and liver.


Day-time melatonin administration: effects on core temperature and sleep onset latency.
Significant hypothermic and hypnotic effects have been reported for melatonin at a wide range of doses. It has been suggested that this decrease in core temperature (Tc) following melatonin administration may mediate the observed increase in sleepiness. To test this, melatonin was administered to young adults during the day, and the concurrent effects on Tc and sleep onset latency (SOL) were recorded. Sixteen healthy males received either a 5 mg oral formulation of melatonin or placebo at 14.00 hours. Core temperature was recorded continuously. Sleep onset latency to stage 1 (SOL1) and stage 2 (SOL2) were recorded using an hourly multiple sleep latency test (MSLT). Compared with placebo, melatonin significantly decreased Tc 1.5 h after administration for 6 h. Between 15.00 and 18.00 hours, the drop in Tc was associated with a concurrent decrease in SOL1 and SOL2. Following administration mean SOL1 and SOL2 were reduced by 40 and 25%, respectively. In this study, daytime melatonin administration produced a significant decrease in Tc with a corresponding decrease in SOL. Taken together, these data are not inconsistent with the suggestion that melatonin may facilitate sleep onset via a hypothermic effect. In addition, this study provides support for the idea that melatonin may play a role in regulating circadian and/or age-related variations in sleep/wake propensity. From a practical perspective, exogenous melatonin may be useful in the treatment of sleep disorders associated with increased nocturnal Tc.


Effect of angiotensin II on the apical K+ channel in the thick ascending limb of the rat kidney.
We have used the patch-clamp technique to study the effect of angiotensin II (AII) on the activity of the apical 70 pS K+ channel and used Na(+)-sensitive fluorescent dye (SBFI) to investigate the effect of AII on intracellular Na+ concentration (Na+i) in the thick ascending limb (TAL) of the rat kidney. Addition of 50 pM AII reversibly reduced NPo, a product of channel open probability (Po) and channel number (N), to 40% of the control value and reduced the Na+i by 26%. The AII (50 pM)-induced decrease in channel activity defined by NPo was partially reversed by addition of 5 microM 17-octadecynoic acid (17-ODYA), an agent which blocks the cytochrome P450 monooxygenase. The notion that P450 metabolites of arachidonic acid (AA) may mediate the inhibitory effect of AII was further suggested by experiments in which addition of 10 nM of 20-hydroxyeicosatetraenoic acid (20-HETE) blocked the channel activity in cell-attached patches in the presence of 17-ODYA. We have used gas chromatography mass spectrometry (GC/MS) to measure the production of 20-HETE, a major AA metabolite of the P450-dependent pathway in the TAL of the rat. Addition of 50 pM AII increased the production of 20-HETE to 260% of the control value, indicating that 20-HETE may be involved in mediating the effect of AII (50 pM). In contrast to the inhibitory effect of 50 pM AII, addition of 50-100 nM AII increased the channel activity to 270% of the control value and elevated the Na+i by 45%. The effect of AII on the activity of the 70 pS K+ channel was also observed in the presence of 5 microM 17-ODYA and 5 microM calphostin C, an inhibitor of protein kinase C. However, addition of 100 microM NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, abolished completely the AII (50-100 nM)-induced increase in channel activity and addition of an exogenous nitric oxide (NO) donor, S-nitroso-N-acetyl-penicillamine (SNAP), increased channel activity in the presence of L-NAME. These data suggest that the stimulatory effect of AII is mediated by NO. We conclude that AII has dual effects on the activity of the apical 70 pS K+ channel. The inhibitory effect of AII is mediated by P450-dependent metabolites whereas the stimulatory effect may be mediated via NO.


The stigma of obesity in the general public and its implications for public health - a systematic review.
Up to this date, prevalence rates of obesity are still rising. Aside from co-morbid diseases, perceived discrimination and stigmatization leads to worsen outcomes in obese individuals. Higher stigmatizing attitudes towards obese individuals may also result in less support of preventive and interventive measures. In light of the immense burden of obesity on health care systems and also on the individuals' quality of life, accepted and subsidized preventive measures are needed. Policy support might be determined by views of the lay public on causes of obesity and resulting weight stigma. This study seeks to answer how representative samples of the lay public perceive people with obesity or overweight status (stigmatizing attitudes); what these samples attribute obesity to (causal attribution) and what types of interventions are supported by the lay public and which factors determine that support (prevention support). A systematic literature search was conducted. All studies of representative samples reporting results on (a) stigmatizing attitudes towards overweight and obese individuals, (b) causal beliefs and (c) prevention support were included. Only 7 articles were found. One study reported prevalence rates of stigmatizing attitudes. About a quarter of the population in Germany displayed definite stigmatizing attitudes. Other studies reported causal attributions. While external influences on weight are considered as well, it seems that internal factors are rated to be of higher importance. Across the studies found, regulative prevention is supported by about half of the population, while childhood prevention has highest approval rates. Results on sociodemographic determinants differ substantially. Further research on public attitudes toward and perception of overweight and obesity is urgently needed to depict the prevailing degree of stigmatization. Introducing a multidimensional concept of the etiology of obesity to the lay public might be a starting point in stigma reduction.


Pre-existing neurological conditions and COVID-19 co-infection: Data from systematic reviews, meta-analyses, and scoping reviews.
Pre-existing neurological diseases have been identified as risk factors for severe COVID-19 infection and death. There is a lack of comprehensive literature review assessing the relationship between pre-existing neurological conditions and COVID-19 outcomes. Identification of high risk groups is critical for optimal treatment and care. A literature review was conducted for systematic reviews, meta-analyses, and scoping reviews published between January 1, 2020 and January 1, 2023. Literature assessing individuals with pre-existing neurological diseases and COVID-19 infection was included. Information regarding infection severity was extracted, and potential limitations were identified. Thirty-nine articles met inclusion criteria, with data assessing >3 million patients from 51 countries. 26/51 (50.9%) of countries analyzed were classified as high income, while the remaining represented middle-low income countries (25/51; 49.0%). A majority of evidence focused on the impact of cerebrovascular disease (17/39; 43.5%) and dementia (5/39; 12.8%) on COVID-19 severity and mortality. 92.3% of the articles (36/39) suggested a significant association between neurological conditions and increased risk of severe COVID-19 and mortality. Cerebrovascular disease, dementia, Parkinson's disease, and epilepsy were associated with increased COVID severity and mortality. Pre-existing neurological diseases including cerebrovascular disease, Alzheimer's disease and other dementias, epilepsy, and Parkinson's disease are significant risk factors for severity of COVID-19 infection and mortality in the acute infectious period. Given that 61.5% (24/39) of the current evidence only includes data from 2020, further updated literature is crucial to identify the relationship between chronic neurological conditions and clinical characteristics of COVID-19 variants.


Waveguide taper engineering using coordinate transformation technology.
Spatial coordinate transformation is a suitable tool for the design of complex electromagnetic structures. In this paper, we define three spatial coordinate transformations which show the possibility of designing a taper between two different waveguides. A parametric study is presented for the three transformations and we propose achievable values of permittivity and permeability that can be obtained with existing metamaterials. The performances of such defined structures are demonstrated by finite element numerical simulations.


Orthographic Perspective Mappings for Consistent Wide-Area Motion Feature Maps From Multiple Cameras.
Spatiotemporal activity maps have been used to visualize where activity occurs over time, and are often displayed as pseudo-color heat maps. Our multi-dimensional activity map includes the following motion features: density, direction, bi-direction, velocity, and dwell. The primary contribution of this paper is to describe a set of mappings that will transform the activity maps captured from the cameras of different perspectives to the ones from a single orthographic perspective. The purpose of this is to be able to view and compare multiple activity maps from different camera views over a wide area with consistently comparable data. A second contribution is that the most mappings are based upon statistically learned camera perspectives to minimize manual camera calibration. We demonstrate mapping results with multiple video data sets and describe applications for visualization and wide-area spatial probability estimation.


Beat the diffraction limit in 3D direct laser writing in photosensitive glass.
Three-dimensional (3D) femtosecond laser direct structuring in transparent materials is widely used for photonic applications. However, the structure size is limited by the optical diffraction. Here we report on a direct laser writing technique that produces subwavelength nanostructures independently of the experimental limiting factors. We demonstrate 3D nanostructures of arbitrary patterns with feature sizes down to 80 nm, less than one tenth of the laser processing wavelength. Its ease of implementation for novel nanostructuring, with its accompanying high precision will open new opportunities for the fabrication of nanostructures for plasmonic and photonic devices and for applications in metamaterials.


Longitudinal Associations between Physical Activity and Educational Outcomes.
This longitudinal study examined the role of leisure-time physical activity in academic achievement at the end of compulsory basic education and educational attainment in adulthood. The data were drawn from the ongoing longitudinal Cardiovascular Risk in Young Finns Study, which was combined with register-based data from Statistics Finland. The study consisted of children who were 12 yr (n = 1723, 49% boys) and 15 yr (n = 2445, 48% boys) of age at the time when physical activity was measured. The children were followed up until 2010, when their mean age was 40 yr. Physical activity was self-reported and included several measurements: overall leisure-time physical activity outside school hours, participation in sports club training sessions, and participation in sports competitions. Individuals' educational outcomes were measured with the self-reported grade point average at age 15 yr and register-based information on the years of completed postcompulsory education in adulthood. Ordinary least squares models and the instrumental variable approach were used to analyze the relationship between physical activity and educational outcomes. Physical activity in adolescence was positively associated with educational outcomes. Both the physical activity level at age 15 yr and an increase in the physical activity level between the ages of 12 and 15 yr were positively related to the grade point average at age 15 yr and the years of postcompulsory education in adulthood. The results were robust to the inclusion of several individual and family background factors, including health endowments, family income, and parents' education. The results provide evidence that physical activity in adolescence may not only predict academic success during compulsory basic education but also boost educational outcomes later in life.