Interaction of hydantoin with solar wind minority ions: O6+ and He2.
The laboratory study of prebiotic molecules interacting with solar wind ions is important to understand their role in the emergence of life in the complex context of the astrochemistry of circumstellar environments. In this work, we present the first study of the interaction of hydantoin (C3N2O2H4, 100 a.m.u.) with solar wind minority multi-charged ions: O6+ at 30 keV and He2+ at 8 keV. The fragmentation mass spectra as well as correlation maps resulting from the interaction are presented and discussed in this paper. Prompt and delayed dissociations from metastable states of the ionized molecule have been observed and the corresponding lifetimes measured. Experimental results are completed by quantum Density Functional Theory (DFT) calculations for energies, structures and dynamics (Internal Reaction Coordinates and Dynamic Reaction Coordinates) of the molecule for its different reachable charge states and the major observed fragmentation pathways. These calculations show that the molecule can only support two charges before spontaneously dissociating in agreement with the experimental observations. Calculations also demonstrate that hydantoin's ring opens after double ionization of the molecule which may enhance its reactivity in the background of biological molecule formation in a cirmcumstellar environment. For the major experimentally observed fragmentations (like 44 a.m.u./56 a.m.u. dissociation), Internal Reaction Coordinate (IRC) calculations were performed pointing out for example the important role of hydrogen transfer in the fragmentation processes.


Identification of molecular markers for oocyte competence in bovine cumulus cells.
Cumulus cells (CCs) have an important role during oocyte growth, competence acquisition, maturation, ovulation and fertilization. In an attempt to isolate potential biomarkers for bovine in vitro fertilization, we identified genes differentially expressed in bovine CCs from oocytes with different competence statuses, through microarray analysis. The model of follicle size, in which competent cumulus-oocyte complexes (COCs) were recovered from bigger follicles (≥8.0 mm in diameter) and less competent ones from smaller follicles (1-3 mm), was used. We identified 4178 genes that were differentially expressed (P < 0.05) in the two categories of CCs. The list was further enriched, through the use of a 2.5-fold change in gene expression as a cutoff value, to include 143 up-regulated and 80 down-regulated genes in CCs of competent COCs compared to incompetent COCs. These genes were screened according to their cellular roles, most of which were related to cell cycle, DNA repair, energy metabolism, metabolism of amino acids, cell signaling, meiosis, ovulation and inflammation. Three candidate genes up-regulated (FGF11, IGFBP4, SPRY1) and three down-regulated (ARHGAP22, COL18A1 and GPC4) in CCs from COCs of big follicles (≥8.1 mm) were selected for qPCR analysis. The selected genes showed the same expression patterns by qPCR and microarray analysis. These genes may be potential genetic markers that predict oocyte competence in in vitro fertilization routines.


Increased Motor Activity During REM Sleep Is Linked with Dopamine Function in Idiopathic REM Sleep Behavior Disorder and Parkinson Disease.
Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by impaired motor inhibition during REM sleep, and dream-enacting behavior. RBD is especially associated with α-synucleinopathies, such as Parkinson disease (PD). Follow-up studies have shown that patients with idiopathic RBD (iRBD) have an increased risk of developing an α-synucleinopathy in later life. Although abundant studies have shown that degeneration of the nigrostriatal dopaminergic system is associated with daytime motor function in Parkinson disease, only few studies have investigated the relation between this system and electromyographic (EMG) activity during sleep. The objective of this study was to investigate the relationship between the nigrostriatal dopamine system and muscle activity during sleep in iRBD and PD. 10 iRBD patients, 10 PD patients with PD, 10 PD patients without RBD, and 10 healthy controls were included and assessed with (123)I-N-omega-fluoropropyl-2-beta-carboxymethoxy-3beta-(4-iodophenyl) nortropane ((123)I-FP-CIT) Single-photon emission computed tomography (SPECT) scanning ((123)I-FP-CIT SPECT), neurological examination, and polysomnography. iRBD patients and PD patients with RBD had increased EMG-activity compared to healthy controls. (123)I-FP-CIT uptake in the putamen-region was highest in controls, followed by iRBD patients, and lowest in PD patients. In iRBD patients, EMG-activity in the mentalis muscle was correlated to (123)I-FP-CIT uptake in the putamen. In PD patients, EMG-activity was correlated to anti-Parkinson medication. Our results support the hypothesis that increased EMG-activity during REM sleep is at least partly linked to the nigrostriatal dopamine system in iRBD, and with dopamine function in PD.


Microsatellite analysis of sperm-use patterns in the bushcricket Requena verticalis.
The proportion of offspring sired by the second male to mate with a doubly mated female, P2, is a ubiquitously measured statistic in the study of insect sperm competition. Nevertheless, the underlying mechanisms of sperm transfer, storage, and use that determine P2 are poorly understood. Typically the second male to mate gains moderate to high paternity. More rarely, the first male to mate gains the majority of fertilizations. Here we examine the transfer, storage, and use of sperm in the bushcricket Requena verticalis, a species with male parental investment and almost complete first male paternity. Sperm drain from an externally attached spermatophore into the female's reproductive tract, where they are transported to the sperm store or spermatheca. We find that only sperm from the first male to mate are transported to the spermatheca. We provide some data that address a number of different mechanisms that might account for the lack of storage of second-male sperm. DNA microsatellite markers are developed to assign paternity. By manipulating the numbers of sperm transferred by first and second males, we show that the size of the ejaculate transferred by the first male has a major impact on paternity; increasing ejaculate size of the first male assures his paternity. Paternity assurance in R. verticalis holds significant implications for the evolution of paternal investment via the male's nuptial gift.


Pulse retrieval algorithm for interferometric frequency-resolved optical gating based on differential evolution.
A novel algorithm for the ultrashort laser pulse characterization method of interferometric frequency-resolved optical gating (iFROG) is presented. Based on a genetic method, namely, differential evolution, the algorithm can exploit all available information of an iFROG measurement to retrieve the complex electric field of a pulse. The retrieval is subjected to a series of numerical tests to prove the robustness of the algorithm against experimental artifacts and noise. These tests show that the integrated error-correction mechanisms of the iFROG method can be successfully used to remove the effect from timing errors and spectrally varying efficiency in the detection. Moreover, the accuracy and noise resilience of the new algorithm are shown to outperform retrieval based on the generalized projections algorithm, which is widely used as the standard method in FROG retrieval. The differential evolution algorithm is further validated with experimental data, measured with unamplified three-cycle pulses from a mode-locked Ti:sapphire laser. Additionally introducing group delay dispersion in the beam path, the retrieval results show excellent agreement with independent measurements with a commercial pulse measurement device based on spectral phase interferometry for direct electric-field retrieval. Further experimental tests with strongly attenuated pulses indicate resilience of differential-evolution-based retrieval against massive measurement noise.


[B-lymphocytes of the blood in schizophrenia: effect of psychotropic therapy].
Using the method of immune rosette formation and rosette formation with murine erythrocytes, the authors studied the characteristics of blood B lymphocytes in schizophrenics with the continuously progressive course of the disease and the effects of psychotropic therapy on B lymphocyte production. The count of B lymphocytes (both mature and immature) was increased in the patients versus normal subjects. Psychotropic therapy reduced the number of B cells almost to the normal values.


A technique to sharpen the beam penumbra for Gamma Knife radiosurgery.
In stereotactic radiosurgery, a narrow beam penumbra is often desired for producing steep dose fall-off between the target volume and adjacent critical structures. Due to limited source sizes and the scattering effects, the physical penumbra of the Gamma Knife (GK) is often restricted to a width of 1-2 mm. In this work, we developed a technique to further reduce the beam penumbra and improve the dose profile for the Gamma Knife delivery. Under this technique, a conic filter is inserted into an individual plug collimator of a GK helmet to flatten the beam profile. Monte Carlo calculations were carried out to simulate the GK geometry of the individual plug collimator and to optimize the physical shapes of the filters. The calculations were performed for a series of filter shapes with different collimator sizes. Our results show that a proper filter significantly reduces the single GK beam penumbra width (defined as the distance from the 90% to 50% isodose lines) by 30-60%. The beam intensity is reduced by about 20-50% when the filter is used. A treatment plan was developed for a trigeminal neuralgia case by commissioning the filtered beam profile for Leksell Gamma Plan (version 5.31). Compared with the conventional treatment plan, a significant improvement was found on the critical structure sparing and on the target dose uniformity. In conclusion, the proposed technique is feasible and effective in sharpening the beam penumbra for Gamma Knife beam profiles.


Azithromycin for episodes with asthma-like symptoms in young children aged 1-3 years: a randomised, double-blind, placebo-controlled trial.
Bacteria and viruses are equally associated with the risk of acute episodes of asthma-like symptoms in young children, suggesting antibiotics as a potential treatment for such episodes. We aimed to assess the effect of azithromycin on the duration of respiratory episodes in young children with recurrent asthma-like symptoms, hypothesising that it reduces the duration of the symptomatic period. In this randomised, double-blind, placebo-controlled trial, we recruited children aged 1-3 years, who were diagnosed with recurrent asthma-like symptoms from the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort; a birth cohort consisting of the general Danish population of Zealand, including Copenhagen. Exclusion criteria were macrolide allergy, heart, liver, neurological, and kidney disease, and, before each treatment, one or more clinical signs of pneumonia (respiratory frequency of ≥50 breaths per min; fever of ≥39°C; C-reactive protein concentration of ≥476·20 nmol/L [≥50 mg/L]). Each episode of asthma-like symptoms lasting at least 3 days was randomly allocated to a 3-day course of azithromycin oral solution of 10 mg/kg per day or placebo after thorough examination by a study physician at the Copenhagen Prospective Studies on Asthma research unit. Each episode was randomly allocated independently of previous treatment from a computer-generated list of random numbers in blocks of ten (generated at the Pharmacy of Glostrup). Investigators and children were masked until the youngest child turned 3 years of age and throughout the data validation and analysis phases. The primary outcome was duration of the respiratory episode after treatment, verified by prospective daily diaries and analysed with Poisson regression. Analyses were per protocol (excluding those without a primary outcome measure or who did not receive treatment). This trial is registered with ClinicalTrials.gov, number NCT01233297. Between Nov 17, 2010, and Jan 28, 2014, we randomly allocated 158 asthma-like episodes in 72 children (79 [50%] to azithromycin and 79 [50%] to placebo). The mean duration of the episode after treatment was 3·4 days for children receiving azithromycin compared with 7·7 days for children receiving placebo. Azithromycin caused a significant shortening of the episode of 63·3% (95% CI 56·0-69·3; p<0·0001). The effect size increased with early initiation of treatment, showing a reduction in episode duration of 83% if treatment was initiated before day 6 of the episode compared with 36% if initiated on or after day 6 (p<0·0001). We noted no differences in clinical adverse events between the azithromycin (18 [23%] of 78 episodes included in final analysis) and placebo (24 [30%] of 79) groups (p=0·30), but we did not investigate bacterial resistance patterns after treatment. Azithromycin reduced the duration of episodes of asthma-like symptoms in young children, suggesting that this drug could have a role in acute management of exacerbations. Further research is needed to disentangle the inflammatory versus antimicrobial aspects of this relation. Lundbeck Foundation, Danish Ministry of Health, Danish Council for Strategic Research, Capital Region Research Foundation.


Bifid epiglottis associated with Joubert's syndrome.
This report presents the case of a 2-year-old boy who had a bifid epiglottis associated with Joubert's syndrome. He had episodic tachypnea and apnea, inspiratory stridor, aspiration, and growth and mental retardation. Direct laryngoscopy demonstrated agenesis of the right half of the epiglottis and hypertrophied mucosa over the arytenoid cartilage. After the hypertrophied mucosa was partially vaporized with a CO2 laser, the inspiratory stridor soon improved and the aspiration was alleviated. Brain magnetic resonance imaging showed cerebellar vermian agenesis and enlargement of the fourth ventricle.


The preparation of RNA-dependent RNA polymerase complex from virus infected plants.
Cucumber mosaic virus (CMV) is an icosahedrion plant virus and contains three different single-stranded positive sense genomic RNAs. The very 3' ends of each of the genomic RNAs can fold into a tRNA-like structure. Based on the structural analysis of the 3' tRNA-like structure of the brome mosaic virus (BMV), we superimposed and redrew the 3' tRNA-like structure of CMV. We homogenized virus infected or healthy tobacco leaves with polytron and carried out low speed centrifugation twice and ultra-centrifugation three times to get detergent solubilized membrane bound fractions. We accidentally found that these fractions were enriched with a host-encoded RNA-dependent RNA polymerase (RdRp) activity. Similar activity could also be found in other plants tested. Alternately, the membrane bound fraction could be simply precipitated by low speed centrifugation (3,000 g) and high speed ultra-centrifugation (40,000 g). The pellet was then suspended in a detergent-containing buffer, after which 25%-55% glycerol gradient fractionation was performed. Activity was tested through the incorporation of [alpha-32P]UTP using endogenous CMV RNAs as templates on each fraction collected. It was found that most of the fractions contained the viral-encoded RNA-dependent RNA polymerase. The products of RdRp reaction were found to have a double-stranded from through further analysis of the RNase protection assay.


Loss of ATM positively regulates the expression of hypoxia inducible factor 1 (HIF-1) through oxidative stress: Role in the physiopathology of the disease.
Ataxia Telangiectasia (AT) is an autosomal recessive disorder characterized by a wide variety of progressive clinical symptoms. This includes neuronal degeneration, oculocutaneous telangiectasias, diabetes mellitus, immunodeficiency, increased risk of cancer and sensitivity to ionizing radiation. The gene mutated in this disease, ATM (Ataxia Telangiectasia Mutated), encodes a protein kinase involved in DNA double strand breaks signalling and repair. ATM deficient cells also display an increase in oxidative stress, by poorly characterized mechanism(s), which clearly contributes to the neurodegenerative aspect of the disease. Despite these advances, the occurrence of the vascular abnormalities, glucose intolerance and insulin resistance remains poorly understood. In different cellular models where ATM expression was disrupted, we demonstrated that the absence of ATM leads to an increased expression of both subunits of the transcription factor Hypoxia Inducible Factor 1 (HIF-1). We also observed enhanced trans-activating functions of HIF-1. HIF-1 is the central regulator of responses to hypoxia which induces the transcription of genes involved in angiogenesis (e.g., VEGF-Vascular Endothelial Growth Factor) and cellular metabolism (e.g., GLUT-1). Interestingly, we demonstrated that ATM disruption positively regulates both expression and function of the basal glucose transporter GLUT-1 as well as the proangiogenic factor, VEGF. In addition, our results suggest that the absence of ATM increases HIF-1 proteins biosynthesis, and this effect is dependant on the oxidative stress existing in ATM deficient cells. Our compelling results highlight a new link between ATM deficiency and the clinical features of the disease and provide a molecular link between ATM downregulation and the increase in tumor angiogenesis observed in human breast cancers.


Insights into the molecular mechanism of translation inhibition by the ribosome-targeting antibiotic thermorubin.
Thermorubin (THR) is an aromatic anthracenopyranone antibiotic active against both Gram-positive and Gram-negative bacteria. It is known to bind to the 70S ribosome at the intersubunit bridge B2a and was thought to inhibit factor-dependent initiation of translation and obstruct the accommodation of tRNAs into the A site. Here, we show that thermorubin causes ribosomes to stall in vivo and in vitro at internal and termination codons, thereby allowing the ribosome to initiate protein synthesis and translate at least a few codons before stalling. Our biochemical data show that THR affects multiple steps of translation elongation with a significant impact on the binding stability of the tRNA in the A site, explaining premature cessation of translation. Our high-resolution crystal and cryo-EM structures of the 70S-THR complex show that THR can co-exist with P- and A-site tRNAs, explaining how ribosomes can elongate in the presence of the drug. Remarkable is the ability of THR to arrest ribosomes at the stop codons. Our data suggest that by causing structural re-arrangements in the decoding center, THR interferes with the accommodation of tRNAs or release factors into the ribosomal A site.


Parabacteroides faecis sp. nov., isolated from human faeces.
A bacterial strain, designated 157(T), isolated from human faeces was characterized by using a polyphasic taxonomic approach, which included analysis of physiological and biochemical features, cellular fatty acid profiles, menaquinone profiles and its phylogenetic position, based on 16S rRNA gene sequence analysis. The strain was obligately anaerobic, non-pigmented, non-spore-forming, non-motile, Gram-stain-negative rods. The isolate was able to grown on medium containing 20% (w/v) bile. 16S rRNA gene sequence analysis showed that the strain was a member of the genus Parabacteroides . Strain 157(T) was closely related to Parabacteroides gordonii JCM 15724(T) (96% sequence similarity). The results of hsp60 gene sequence analysis indicated that strain 157(T) was different from P. gordonii JCM 15724(T), with a hsp60 gene sequence similarity of 96.1%. The major cellular fatty acids of strain 157(T) were anteiso-C(15 : 0), iso-C(17 : 0) 3-OH, C(18 : 1)ω9c and anteiso-C(17 : 0) 3-OH. The major menaquinone of the isolate was MK-9. The DNA G+C content of strain 157(T) was 41.8 mol%. On the basis of these data, strain 157(T) represents a novel species of the genus Parabacteroides , for which the name Parabacteroides faecis sp. nov. is proposed; the type strain is 157(T) ( = JCM 18682(T) = CCUG 66681(T)).


Dynamic stabilization adjacent to single-level fusion: part II. No clinical benefit for asymptomatic, initially degenerated adjacent segments after 6 years follow-up.
Progression of degeneration is often described in patients with initially degenerated segment adjacent to fusion (iASD) at the time of surgery. The aim of the present study was to compare dynamic fixation of a clinically asymptomatic iASD, with circumferential lumbar fusion alone. 60 patients with symptomatic degeneration of L5/S1 or L4/L5 (Modic ≥ 2°) and asymptomatic iASD (Modic = 1°, confirmed by discography) were divided into two groups. 30 patients were treated with circumferential single-level fusion (SLF). In dynamic fixation transition (DFT) patients, additional posterior dynamic fixation of iASD was performed. Preoperatively, at 12 months, and at a mean follow-up of 76.4 (60-91) months, radiological (MRI, X-ray) and clinical (ODI, VAS, satisfaction) evaluations assessed fusion, progression of adjacent segment degeneration (PASD), radiologically adverse events, functional outcome, and pain. At final follow-up, two non-fusions were observed in both groups. 6 SLF patients and 1 DFT patient presented a PASD. In two DFT patients, a PASD occurred in the segment superior to the dynamic fixation, and in one DFT patient, a fusion of the dynamically fixated segment was observed. 4 DFT patients presented radiological implant failure. While no differences in clinical scores were observed between groups, improvement from pre-operative conditions was significant (all p < 0.001). Clinical scores were equal in patients with PASD and/or radiologically adverse events. We do not recommend dynamically fixating the adjacent segment in patients with clinically asymptomatic iASD. The lower number of PASD with dynamic fixation was accompanied by a high number of implant failures and a shift of PASD to the superior segment.


Supportive care of the patient with pancreatic cancer: the role of the oncology social worker.
The goals of oncology social work are to facilitate patient and family adjustment to the diagnosis and treatment of the disease; to promote psychosocial recovery and rehabilitation for both patient and family; and to facilitate utilization of health-care resources. The first step for the social worker is to develop a plan of psychosocial care for the patient and family, based on assessment of their physical and psychological functioning and available supportive resources. Social workers can help patients and their families overcome barriers to accessing services such as arrangements for transportation or the procurement of financial assistance. The oncology social worker can also be a valuable resource for information about the patient's disease, including explanation of treatment plans and pain management options.


Neuromuscular control of masticatory muscles in people with intellectual disability, middle-aged adults and older adults.
Motor control issues are common for people with intellectual disabilities (PWID), resulting in difficulties with basic activities of daily living, including eating. Mastication, which is crucial for digestion and overall health, is poorly understood in this population. PWID shows frailty similar to older people, highlighting the importance of comparing masticatory motor control with older adults. This study compared the neuromuscular control of the masticatory muscles in middle-aged, PWID and older adults. A cross-sectional analytical design was used. During the mastication task of a carrot piece (2 cm in diameter and weighing 0.5 g), surface electromyography was used to record muscle activity patterns from the right and left masseter and temporalis muscles. Principal component analysis (PCA) was used to assess neuromuscular control. A z-score normalisation of the first component's variance from PCA to identify those individuals with altered neuromuscular control. A mixed ANOVA was performed to assess the interaction between principal components, groups and body composition. Thirty PWIDs (aged 35-55 years), middle-aged adults and 32 older adults were recruited. PWID and older adults showed decreased neuromuscular control of the masticatory muscles compared to middle-aged control adults (P < 0.05). PWID had the highest proportion of individuals with altered neuromuscular control of the masticatory muscle (53%) compared to older adults (19%) and middle-aged adults (0%) (P < 0.05). Our results indicate that PWID and older adults have reduced neuromuscular control compared to middle-aged adults. Notably, a significant proportion of the PWID showed altered masticatory muscle control compared to older adults. Further research is needed to explore the potential benefits of masticatory muscle training for PWID.


2020 Korean Society of Myocardial Infarction Expert Consensus Document on Pharmacotherapy for Acute Myocardial Infarction.
Clinical practice guidelines published by the European Society of Cardiology and the American College of Cardiology/American Heart Association summarize the available evidence and provide recommendations for health professionals to enable appropriate clinical decisions and improve clinical outcomes for patients with acute myocardial infarction (AMI). However, most current guidelines are based on studies in non-Asian populations in the pre-percutaneous coronary intervention (PCI) era. The Korea Acute Myocardial Infarction Registry is the first nationwide registry to document many aspects of AMI from baseline characteristics to treatment strategies. There are well-organized ongoing and published randomized control trials especially for antiplatelet therapy among Korean patients with AMI. Here, members of the Task Force of the Korean Society of Myocardial Infarction review recent published studies during the current PCI era, and have summarized the expert consensus for the pharmacotherapy of AMI.


Fully Integrated Ratiometric Fluorescence Enrichment Platform for High-Sensitivity POC Testing of Salivary Cancer Biomarkers.
The point-of-care (POC) testing of cancer biomarkers in saliva with both high sensitivity and accuracy remains a serious challenge in modern clinical medicine. Herein, we develop a new fully integrated ratiometric fluorescence enrichment platform that utilizes acoustic radiation forces to enrich dual-emission sandwich immune complexes for a POC visual assay. As a result, the color signals from red and green fluorescence (capture probe and report probe, respectively) are enhanced by nearly 10 times, and colorimetric sensitivity is effectively improved. When illuminated using a portable UV lamp, the fluorescence color changing from red to green can be clearly seen with the naked eye, which allows a semiqualitative assessment of the carcinoembryonic antigen (CEA) level. In combination with a homemade smartphone-based portable device, cancer biomarkers like CEA are quantified, achieving a limit of detection as low as 0.012 ng/mL. We also directly quantify CEA in human saliva samples to investigate the reliability of this fully integrated platform, thus validating the usefulness of the proposed strategy for clinical diagnosis and home monitoring of physical conditions.


Local anesthetics for skin grafting and local flaps.
In plastic surgery, there are many procedures that can be performed using local instead of general anesthesia. Not only can this help mitigate health care costs, but precious operating-room resources can also be directed to areas of greater need. Common procedures that can be performed under local anesthetics include skin grafts and local flaps. However, as not all patients are suitable for local anesthesia, careful patient selection is necessary to maintain the standard of care. This article describes the detailed surgical approach to using local anesthetics for skin grafts and local flaps.


Accuracy of Psychiatrists' Assessment of Medication Adherence in an Outpatient Setting.
Many patients have uncontrolled psychiatric symptoms because they are not taking their medication as prescribed. Psychiatrists may have difficulty accurately assessing medication adherence, which is important because it helps guide them in how they prescribe. If nonadherence is the cause of uncontrolled symptoms, then strategies to improve adherence are advised. However, if nonadherence is not the cause, then the usual course of action would be to intensify or modify the medication regimen. Knowing whether nonadherence is a factor at the time of an appointment could help guide clinical decision making in real-time. A cohort of established patients in an outpatient mental health treatment clinic at a large health network was studied from November 2018 to August 2019. Blood drug levels of several oral antipsychotic medications were obtained and placed in the following three categories: below, within, or above the therapeutic range of published cutoff points. Treating physicians answered Likert-scale questions regarding their assessment of patient adherence. Subsequently, blood drug levels were compared to the psychiatrists' assessment of adherence using a Kappa coefficient. Results: Sixty-four patients being prescribed antipsychotic medications were analyzed. A total of 87.5% of treating psychiatrists thought their patients were always adherent or adherent greater than 50% of the time. However, based on blood levels, 14% of the 42 patients at target FDA dosing for their medication and diagnosis were below the therapeutic range. The Kappa coefficient was used to find the level of agreement between the treating psychiatrist's perception of patient adherence and the blood drug level. It was determined to be 0.14 which is consistent with no agreement between the two measurements. Conclusions: Treating psychiatrists inaccurately estimated oral antipsychotic medication adherence based on clinical impression alone. Making an objective measure of adherence available at the time of an appointment could help psychiatrists recognize nonadherence in real-time and inform prescribing decisions.


Neural Correlates of Direct Access Trading in a Real Stock Market: An fMRI Investigation.
Background: While financial decision making has been barely explored, no study has previously investigated the neural correlates of individual decisions made by professional traders involved in real stock market negotiations, using their own financial resources. Aim: We sought to detect how different brain areas are modulated by factors like age, expertise, psychological profile (speculative risk seeking or aversion) and, eventually, size and type (Buy/Sell) of stock negotiations, made through Direct Access Trading (DAT) platforms. Subjects and methods: Twenty male traders underwent fMRI while negotiating in the Italian stock market using their own preferred trading platform. Results: At least 20 decision events were collected during each fMRI session. Risk averse traders performed a lower number of financial transactions with respect to risk seekers, with a lower average economic value, but with a higher rate of filled proposals. Activations were observed in cortical and subcortical areas traditionally involved in decision processes, including the ventrolateral and dorsolateral prefrontal cortex (vlPFC, dlPFC), the posterior parietal cortex (PPC), the nucleus accumbens (NAcc), and dorsal striatum. Regression analysis indicated an important role of age in modulating activation of left NAcc, while traders' expertise was negatively related to activation of vlPFC. High value transactions were associated with a stronger activation of the right PPC when subjects' buy rather than sell. The success of the trading activity, based on a large number of filled transactions, was related with higher activation of vlPFC and dlPFC. Independent of chronological and professional age, traders differed in their attitude to DAT, with distinct brain activity profiles being detectable during fMRI sessions. Those subjects who described themselves as very self-confident, showed a lower or absent activation of both the caudate nucleus and the dlPFC, while more reflexive traders showed greater activation of areas involved in strategic decision making. Discussion: The neural correlates in DAT are similar to those observed in other decision making contexts. Trading is handled as a well-learned automatic behavior by expert traders; for those who mostly rely on heuristics, cognitive effort decreases, and transaction speed increases, but decision efficiency lowers following a poor involvement of the dlPFC.


Partial role of multiple pathways in infarct size limiting effect of quercetin and rutin against cerebral ischemia-reperfusion injury in rats.
Reperfusion therapy used in the treatment of cerebral ischemia often causes reperfusion neurological injury. Multiple pathological processes are involved in this injury including oxidative stress and components of the inflammatory response appear to play key roles in these deleterious effects. Thus new therapeutic strategies aimed at neutralization of OS-induced neurotoxicity support the application of natural antioxidant bioflavonoids. Both experimental and epidemiological evidence demonstrate that bioflavonoid such as quercetin and rutin are neuroprotective in models of cerebral ischemia reperfusion injury. However, recent studies indicate that the radical scavenger property of quercetin and rutin is unlikely to be the only reason for their cerebroprotective actions and in fact, a wide spectrum of cellular signaling events may well account for their biological actions. In this study we attempted to establish the various mechanisms involved in the cerebroprotective activity of quercetin and rutin. Adult Sprague Dawely rats were anesthetized with thiopentone and subjected to global cerebral ischemia by occlusion of bicommon carotid arteries. Infarct size (TTC staining), SOD, MDA, CAT and MPO levels was assessed 4 h after the onset of ischemia. Quercetin (50 mg/kg) and rutin (10 mg/kg) administered 10 min before reperfusion resulted in significant reduction of infarct size, MDA, and MPO levels and significant increase in SOD and CAT levels. Administration of L-NAME prior to administration of quercetin and rutin, significantly reduced the cerebroprotection offered by quercetin and rutin. Possible partial role of antioxidant, anti-inflammatory and involvement of NO in the beneficial effects of bioflavonoids quercetin and rutin against cerebral ischemia reperfusion injury was observed.


The Thai version of the PSS-10: An Investigation of its psychometric properties.
Among the stress instruments that measure the degree to which life events are perceived as stressful, the Perceived Stress Scale (PSS) is widely used. The goal of this study was to examine the psychometric properties of a Thai version of the PSS-10 (T-PSS-10) with a clinical and non-clinical sample. Internal consistency, test-retest reliability, concurrent validity, and the factorial structure of the scale were tested. A total sample of 479 adult participants was recruited for the study: 368 medical students and 111 patients from two hospitals in Northern Thailand. The T-PSS-10 was used along with the Thai version of State Trait Anxiety Inventory (STAI), the Thai Version of the Rosenberg Self-Esteem Scale (RSES), and the Thai Depression Inventory (TDI). Exploratory Factor Analysis (EFA) yielded 2 factors with eigenvalues of 5.05 and 1.60, accounting for 66 percent of variance. Factor 1 consisted of 6 items representing "stress"; whereas Factor 2 consisted of 4 items representing "control". The item loadings ranged from 0.547 to 0.881. Investigation of the fit indices associated with Maximum Likelihood (ML) estimation revealed that the two-factor solution was adequate [chi2 = 35.035 (df = 26, N = 368, p < 0.111)]; Goodness-of-Fit Index (GFI) = 0.981; Root Mean Square Residual (RMR) = 0.022; Standardized Root Mean square Residual (SRMR) = 0.037, Comparative Fit Index (CFI) = 0.989; Normed Fit Index (NFI) = 0.96, Non-Normed Fit Index (NNFI) = 0.981, Root Mean Square Error of Approximation (RMSEA) = 0.031. It was found that the T-PSS-10 had a significant positive correlation with the STAI (r = 0.60, p < 0.0001), and the TDI (r = 0.55, p < 0.0001); and was significantly negatively correlated with the RSES (r = -0.46, p < 0.0001, N = 368). The overall Cronbach's alpha was 0.85. The ICC was 0.82 (95% CI, 0.72 and 0.88) at 4 week-retest reliability. The Thai version of the PSS-10 demonstrated excellent goodness-of-fit for the two factor solution model, as well as good reliability and validity for estimating the level of stress perception with a Thai population. Limitations of the study are discussed.


Mast cells, basophils, and eosinophils: distinct but overlapping pathways for recruitment.
Mast cells, basophils and eosinophils are bone marrow-derived cells that contribute to a variety of allergic and other immune responses. For example, they are relatively abundant at mucosal sites where allergic inflammation is occurring, and their activation and release of preformed and newly-generated mediators at these sites is considered central to the pathophysiology of allergic diseases. Given their involvement in allergic and other diseases, it is important to understand how these cells are selectively recruited into tissues. These cells share many phenotypic features, including those involved in adhesion and migration, yet their localization within a given tissue can be quite distinct. In addition, there are examples of selective recruitment of one cell type without the others. From studies with human cells, it is now clear that mast cells, basophils and eosinophils share a number of recruitment pathways with one another and with other cells, but that each possesses unique adhesion and migration responses that can contribute to their preferential accumulation. This review will focus on cell surface structures implicated in adhesion and migration responses of human mast cells, basophils and eosinophils. Both shared and selective expression of these molecules will be highlighted, as well as differences in their relative levels of expression. Cell type-specific stimuli that alter adhesion and migration responses will also be considered.


Aerobic training reduces blood pressure and waist circumference and increases HDL-c in metabolic syndrome: a systematic review and meta-analysis of randomized controlled trials.
The objective of this study is to estimate the effect of aerobic training (AT) on metabolic syndrome (MetS) outcomes. The Medline, EMBASE, SPORTDiscus, The Cochrane Library, and PEDro databases were searched from inception to May 2017. Two independent reviewers selected the studies and assessed their quality and data. The pooled mean differences between intervention groups and the control group were calculated using a random-effect model. Only randomized controlled trials that compared the effect of AT on MetS with a control group were included. Seventeen published studies were included in the meta-analysis. Systolic and diastolic blood pressure were significantly reduced (-5.11 mmHg [95% confidence interval [CI] -7.36, -2.85] and -2.97 mmHg [-4.99, -0.94], respectively), following AT. There was also a significant reduction in waist circumference (-2.18 cm [95% CI -3.75, -0.62]) and a significant increase in high-density lipoprotein cholesterol (95% CI -3.15 mg/dL [-5.30, -1.01]). The pooled effect showed a reduction of -7.64 mg/dL [95% CI -17.65, 2.37] in triglycerides and -1.36 mg/dL [95% CI -4.11, 1.40] in fasting glucose. This systematic review and meta-analysis provides an overview of the evidence supporting AT as an effective approach to reduce blood pressure levels and waist circumference and increase high-density lipoprotein cholesterol levels. These changes may help to reduce the risk of stroke mortality and mortality from heart disease in people with MetS.


Fungal allergen-induced IL-33 secretion involves cholesterol-dependent, VDAC-1-mediated ATP release from the airway epithelium.
Alternaria aeroallergens induce the release of ATP from human bronchial epithelial (HBE) cells by activating a conductive pathway involving voltage-dependent anion channel-1 (VDAC-1) and by exocytosis of ATP localized within membrane vesicles. Inhibition of VDAC-1 blocked Alternaria-evoked Ca2+ uptake across the plasma membrane of HBE cells and interleukin (IL)-33 release into the extracellular media. Reducing cholesterol content with a cholesterol scavenger (β-methylcyclodextrin) or statin compound (simvastatin) blocked ATP and IL-33 release by lowering the expression of VDAC-1 in the plasma membrane. Pretreatment with simvastatin for 24 h also inhibited the increase in tight junction macromolecule permeability that occurs following Alternaria exposure. These results establish a novel role for VDAC-1 as a mechanism underlying ATP release induced by fungal allergens and suggests a possible therapeutic use for cholesterol lowering compounds in reducing Alternaria-stimulated allergic inflammation. Human bronchial epithelial (HBE) cells exposed to allergens derived from the common saprophytic fungus, Alternaria alternata release ATP, which in turn stimulates P2X7 receptor-mediated Ca2+ uptake across the plasma membrane. The subsequent increase in intracellular calcium concentration induces proteolytic processing and secretion of interleukin (IL)-33, a critical cytokine involved in the initiation of allergic airway inflammation. A major objective of the present study was to identify the mechanism responsible for conductive ATP release. The results show that pretreatment of HBE cells with inhibitors of the voltage-dependent anion channel-1 (VDAC-1) or treatment with a VDAC-1 selective blocking antibody or silencing mRNA expression of the channel by RNA interference, inhibit Alternaria-evoked ATP release. Moreover, inhibition of VDAC-1 channel activity or reducing protein expression blocked the secretion of IL-33. Similarly, reducing the cholesterol content of HBE cells with simvastatin or the cholesterol scavenger β-methylcyclodextrin also blocked ATP release and IL-33 secretion by decreasing the level of VDAC-1 expression in the plasma membrane. In addition, simvastatin inhibited the increase in tight junction macromolecule permeability that was previously observed after Alternaria exposure. These results demonstrate a novel function for VDAC-1 as the conductive mechanism responsible for Alternaria-induced ATP release, an essential early step in the processing, mobilization and secretion of IL-33 by the airway epithelium. Furthermore, the simvastatin-evoked reduction of VDAC-1 expression in the plasma membrane, suggests the possibility that cholesterol lowering compounds may be beneficial in alleviating allergic airway inflammation induced by fungal allergens.


Behavior therapy in a gait-training program for a child with myelomeningocele. A case report.
A behavior therapy program consisting of positive reinforcement contingent upon walking with braces and crutches was conducted with a four and one-half-year-old child with myelomeningocele. Behavioral physical therapy was begun first in the clinic setting and then in the home. Follow-up clinic assessments document maintenance of functionally independent ambulation over a seven-month period. The results support the efficacy of using behavioral techniques in a physical therapy program for a child with myelomeningocele. The need for further research and development of physical therapy programs using behavioral techniques is briefly discussed.


The appropriateness of red blood cell use and the extent of overtransfusion: right decision? Right amount?
Shrinkage of the donor pool coupled with an increasing demand for blood presents a major challenge to maintaining an adequate blood supply. Consequently it has become even more important to reduce inappropriate blood use, including decisions about when and how much blood to prescribe. This study aimed to ascertain the levels of inappropriate practice and factors associated with it. The medical records of a randomly selected sample of hospital patients in Northern Ireland who received a red blood cell transfusion during 2005 (n = 1474) were reviewed, and inappropriate transfusion and overtransfusion criteria were applied. Logistic regression models were used to identify factors associated with inappropriate practice and overtransfusion. In this study 23% of transfusions were considered inappropriate, occurring most commonly where the lowest hemoglobin (Hb) threshold for transfusion applied. Younger patients, those undergoing surgery, and those with lower comorbidity and higher Hb values were most likely to have an inappropriate transfusion. Among patients appropriately transfused, 19% were overtransfused. Females and those of lower weight (<65 kg) were most likely to be overtransfused. While the choice of criteria used to judge decisions will influence the absolute level of inappropriate or overtransfusion reported, our findings suggest that a significant minority of clinicians are either unaware of or are reluctant to accept lower transfusion thresholds. To improve further improve transfusion practice we suggest that barriers to the implementation of recommended transfusion thresholds should be examined and guidance on an appropriate posttransfusion Hb level developed.


Preservation of the activity state of hepatic branched-chain 2-oxo acid dehydrogenase during the isolation of mitochondria.
A comparison was conducted of current methods for estimation of the activity states (proportion of enzyme in active, dephosphorylated, form) of hepatic branched-chain 2-oxo acid dehydrogenase. Practically all of the enzyme was active in freeze-clamped liver obtained from chow-fed and 48 h-starved rats, regardless of the presence of fluoride in the extraction and assay media to inhibit phosphatase activity. Likewise, the enzyme was almost completely active in mitochondria isolated by a conventional method from livers of chow-fed and starved rats. However, when fluoride and 4-methyl-2-oxopentanoate were included in the mitochondrial isolation medium the activity state was decreased to 73% and 47% in mitochondria isolated from chow-fed and starved rats respectively. Furthermore, branched-chain 2-oxo acid dehydrogenase became partially inactivated upon incubation of isolated mitochondria on ice in fluoride- and/or 4-methyl-2-oxopentanoate-supplemented media. The rate of inactivation was greater in mitochondria prepared from starved than from chow-fed rats, which correlated with the lower activity state found in mitochondria of starved rats isolated in the fluoride- and 4-methyl-2-oxopentanoate-supplemented media. Thus the activity state of branched-chain 2-oxo acid dehydrogenase is underestimated in mitochondria isolated in media supplemented with fluoride plus 4-methyl-2-oxopentanoate.


Static magnetic fields promote osteoblastic/cementoblastic differentiation in osteoblasts, cementoblasts, and periodontal ligament cells.
Although static magnetic fields (SMFs) have been used in dental prostheses and osseointegrated implants, their biological effects on osteoblastic and cementoblastic differentiation in cells involved in periodontal regeneration remain unknown. This study was undertaken to investigate the effects of SMFs (15 mT) on the osteoblastic and cementoblastic differentiation of human osteoblasts, periodontal ligament cells (PDLCs), and cementoblasts, and to explore the possible mechanisms underlying these effects. Differentiation was evaluated by measuring alkaline phosphatase (ALP) activity, mineralized nodule formation based on Alizarin red staining, calcium content, and the expression of marker mRNAs assessed by reverse transcription polymerase chain reaction (RT-PCR). Signaling pathways were analyzed by western blotting and immunocytochemistry. The activities of the early marker ALP and the late markers matrix mineralization and calcium content, as well as osteoblast- and cementoblast-specific gene expression in osteoblasts, PDLCs, and cementoblasts were enhanced. SMFs upregulated the expression of Wnt proteins, and increased the phosphorylation of glycogen synthase kinase-3β (GSK-3β) and total β-catenin protein expression. Furthermore, p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB) pathways were activated. SMF treatment enhanced osteoblastic and/or cementoblastic differentiation in osteoblasts, cementoblasts, and PDLCs. These findings provide a molecular basis for the beneficial osteogenic and/or cementogenic effect of SMFs, which could have potential in stimulating bone or cementum formation during bone regeneration and in patients with periodontal disease.


Anosmia-A Clinical Review.
Anosmia and hyposmia, the inability or decreased ability to smell, is estimated to afflict 3-20% of the population. Risk of olfactory dysfunction increases with old age and may also result from chronic sinonasal diseases, severe head trauma, and upper respiratory infections, or neurodegenerative diseases. These disorders impair the ability to sense warning odors in foods and the environment, as well as hinder the quality of life related to social interactions, eating, and feelings of well-being. This article reports and extends on a clinical update commencing at the 2016 Association for Chemoreception Sciences annual meeting. Included were reports from: a patient perspective on losing the sense of smell with information on Fifth Sense, a nonprofit advocacy organization for patients with olfactory disorders; an otolaryngologist's review of clinical evaluation, diagnosis, and management/treatment of anosmia; and researchers' review of recent advances in potential anosmia treatments from fundamental science, in animal, cellular, or genetic models. As limited evidence-based treatments exist for anosmia, dissemination of information on anosmia-related health risks is needed. This could include feasible and useful screening measures for olfactory dysfunction, appropriate clinical evaluation, and patient counseling to avoid harm as well as manage health and quality of life with anosmia.


Serotonergic involvement in the amelioration of behavioral abnormalities in dopamine transporter knockout mice by nicotine.
Dopamine transporter knockout (DAT KO) mice exhibit elevated extracellular dopamine levels in brain regions that include the striatum and the nucleus accumbens, but not the prefrontal cortex. DAT KO mice model some aspects of psychiatric disorders, including schizophrenia. Smoking is more common in patients with schizophrenia, suggesting that nicotine might ameliorate aspects of the behavioral abnormalities and/or treatment side effects seen in these individuals. We report nicotine-induced normalization of effects on locomotion and prepulse inhibition of acoustic startle (PPI) in DAT KO mice that require intact serotonin 5-HT1A systems. First, we observed that the marked hyperactivity displayed by DAT KO mice was reduced by administration of nicotine. This nicotine effect was blocked by pretreatment with the non-specific nicotinic acetylcholine (nACh) receptor antagonist mecamylamine, or the 5-HT1A antagonist WAY100635. Secondly, we examined the effects of nicotine on PPI in DAT KO mice. Treatment with nicotine significantly ameliorated the PPI deficits observed in DAT KO mice. The ameliorating action of nicotine on PPI deficits in DAT KO mice was blocked by mecamylamine, the α₇ nACh receptor antagonist methyllycaconitine or WAY100635, while the α₄β₂ nACh receptor antagonist dihydro-β-erythroidinehydrobromide (DHβE) produced only a non-significant trend toward attenuation of nicotine effects. Finally, we observed that administration of the 5-HT1A receptor agonist 8-OH-DPAT also ameliorated the deficit in PPI observed in DAT KO mice. This amelioration was antagonized by pretreatment with WAY100635. These data support the idea that nicotine might ameliorate some of the cognitive dysfunctions found in schizophrenia in a 5-HT1A-dependent fashion. This article is part of a Special Issue entitled 'Cognitive Enhancers'.


Penetration capability of near infrared Laguerre-Gaussian beams through highly scattering media.
The higher capability of optical vortex beams of penetrating turbid media (e.g., biological fluids) with respect to the conventional Gaussian beams is, for the first time to our knowledge, demonstrated in the 1.3 µm wavelength range which is conventionally used for optical coherence tomography procedures in endoscopic intravascular scenarios. The effect has been demonstrated by performing transmittance measurements through suspensions of polystyrene microspheres in water with various particulate concentrations and, in reflection, by using samples of human blood with different thicknesses. The reduced backscattering/increased transmittance into such highly scattering media of Laguerre-Gaussian beams with respect to Gaussian ones, in the near infrared wavelength region, could be potentially exploited in clinical applications, leading to novel biomedical diagnoses and/or procedures.


Puerarin inhibits β‑amyloid peptide 1‑42‑induced tau hyperphosphorylation via the Wnt/β‑catenin signaling pathway.
Excessive tau protein phosphorylation is important in the pathogenesis and early abnormal signal transduction of Alzheimer's disease. Excessive phosphorylation of microtubules is associated with tau accumulation, which induces the formation of neurofibrillary tangles in neurons, leading to synaptic damage and ultimately, neurodegeneration. The present study aimed to investigate the possible mechanism underlying the inhibitory effects of puerarin on β‑amyloid peptide (Aβ)1‑42‑induced tau protein hyperphosphorylation in SH‑SY5Y cells. Following various treatments, the viability of SH‑SY5Y cells was determined using the MTT assay, and cell morphology was observed under an inverted fluorescence microscope. Western blotting was used to detect tau phosphorylation, and the protein expression levels of glycogen synthase kinase (GSK)‑3β, phosphorylated (p)‑GSK‑3β (Ser9), β‑catenin and cyclin D1, which are the key factors mediating the Wnt/β‑catenin signaling pathway in SH‑SY5Y cells. The results demonstrated that puerarin reversed the Aβ1‑42‑induced decrease in SH‑SY5Y cell viability. In addition, puerarin inhibited the degree of Aβ1‑42‑induced tau phosphorylation at Ser396, Ser199 and Thr231 in SH‑SY5Y cells, and reduced the expression of GSK‑3β by increasing the expression of p‑GSK‑3β (Ser9). Furthermore, puerarin increased the protein expression levels of β‑catenin and cyclin D1, which are key factors involved in the Wnt/β‑catenin signaling pathway. The results of the present study demonstrated that puerarin may attenuate Aβ1‑42‑induced tau hyperphosphorylation in SH‑SY5Y cells, by inhibiting the expression of GSK‑3β and activating the Wnt/β‑catenin signaling pathway; therefore, puerarin may exert protective effects against Alzheimer's disease.


Haplotype structure and copy number polymorphism of the beta-defensin 7 genes in diverse chicken breeds.
Beta-defensins is a family of avian peptides related to the innate immune system. Copy number variation was recently reported for the avian beta-defensin 7 gene (AvBD7) between the highly inbred Leghorn and Fayoumi lines. Here, we examined copy number variants in 35 different chicken breeds and found that 31 of them have at least the same representation of the duplicated AvBD7 allele. We also found haplotypes upstream of the AvBD6 regions that are strongly linked to the AvBD7 duplication. We observed a strong linkage disequilibrium spanning of the upstream region of the AvBD6 gene, with two SNPs being flanking markers to detect duplication of the AvBD7.


[Construction and validation of a risk prediction model for pneumoconiosis patients complicated with chronic pulmonary heart disease based on Tei index].
Objective: To conduct a statistical analysis on the condition of patients with pneumoconiosis complicated with chronic pulmonary heart disease based on the Tei index, and to establish a relevant prediction model. Methods: In March 2022, a retrospective analysis of 226 patients diagnosed with pneumoconiosis in the Department of Occupational Disease of Yantai Yantaishan Hospital from January 2016 to January 2022 was conducted. The patients with pneumoconiosis complicated by pulmonary heart disease were included in the pulmonary heart disease group and others were included in the non-pulmonary heart disease group. logistic regression analysis was used to screen out the relevant factors and establish a risk prediction model. Hosmer-Lemeshow test was applied to determine the goodness of fit of the model, and the receiver operating characteristic (ROC) area under the curve (AUC) was used to evaluate the predictive effect of the model. Results: Among the 226 patients with pneumoconiosis, 58 patients had chronic pulmonary heart disease, accounting for 25.7% of the surveyed population. The logistic analysis showed that the course of disease, pneumoconiosis stage and Tei index were influencing factors of pneumoconiosis complicated with pulmonary heart disease (P<0.05). A risk prediction model for pneumoconiosis patients complicated with pulmonary heart disease was developed: Z=6.253X(1)+1.265X(2)+1.423X(3)+9.264, in which X(1) was the stage of pneumoconiosis, X(2) was the course of disease, and X(3) was the Tei index. Hosmer-Lemeshow test was used to evaluate the goodness of fit of the risk prediction model for pneumoconiosis patients complicated with pulmonary heart disease, the results indicated that the prediction model was in good agreement with the actual situation (χ(2)=11.59, P=0.254). The diagnostic ability of the model was evaluated by the ROC curve, and the results showed that its AUC was 0.897, the sensitivity was 0.947, and the specificity was 0.784. Conclusion: The course of disease, pneumoconiosis stage and Tei index are the influencing factors of pneumoconiosis complicated with pulmonary heart disease. The model constructed based on these factors has a good prediction effect, which can provide a basis for the early detection and intervention of pneumoconiosis complicated with pulmonary heart disease.


Gender of physician as the usual source of care and patient health care utilization and mortality.
Practice styles differ by provider gender, but whether provider gender influences health care utilization and mortality is unknown. The objective of this study was to examine associations of the gender of a patient's usual source of health care (USOC) with health care utilization and mortality. This was a prospective observational study employing data from respondents aged ≥18 years entering the 2002 to 2008 United States Medical Expenditure Panel Surveys, reporting a USOC at entry, and participating for 2 years (N = 21,365). Analyses examined the association of gender of the USOC in survey participation year 1 with the following health care utilization outcomes in participation year 2: total health care expenditures, prescription drug expenditures, and number of office visits (Poisson regressions) and having more than one emergency visit and more than one hospitalization (logistic regressions). A Cox regression examined survival (ascertained via linkage with the National Death Index) through 2006 for the subset of respondents enrolled from 2002 to 2006 (n = 11,328). All analyses were adjusted for respondent sociodemographic and health characteristics and USOC specialty and race/ethnicity. Reporting a female USOC was associated with being younger, female, and urban. There were no significant adjusted associations of female USOC status with total expenditures (parameter estimate of increase [PE], 4.56%; 95% confidence interval [CI], -3.04 to 12.76), prescription expenditures (PE, 3.33% ; 95% CI, -4.32 to 11.59), number of office visits (PE, 1.28%; 95% CI, -3.30 to 6.08), having more than one emergency visit (odds ratio, 0.98; 95% CI, 0.87-1.11), having more than one hospitalization (odds ratio, 0.98; 95% CI, 0.87-1.11), or mortality (hazard ratio, 0.94; 95% CI, 0.64-1.38). Gender of the USOC was not associated with health care utilization or mortality. These findings suggest reported gender of the USOC may not have nationally important effects on health care utilization and mortality.


[Granulomas of axillae (zirconium?) (author's transl)].
Deodorant preparations containing Zirconium may induce axillary granulomas of allergic origin. The case of a 49 years old female patient is presented, who developed axillary granulomas after having used a deodorant preparation containing Zirconium.


Association score testing for rare variants and binary traits in family data with shared controls.
Genome-wide association studies have been an important approach used to localize trait loci, with primary focus on common variants. The multiple rare variant-common disease hypothesis may explain the missing heritability remaining after accounting for identified common variants. Advances of sequencing technologies with their decreasing costs, coupled with methodological advances in the context of association studies in large samples, now make the study of rare variants at a genome-wide scale feasible. The resurgence of family-based association designs because of their advantage in studying rare variants has also stimulated more methods development, mainly based on linear mixed models (LMMs). Other tests such as score tests can have advantages over the LMMs, but to date have mainly been proposed for single-marker association tests. In this article, we extend several score tests (χcorrected2, WQLS, and SKAT) to the multiple variant association framework. We evaluate and compare their statistical performances relative with the LMM. Moreover, we show that three tests can be cast as the difference between marker allele frequencies (AFs) estimated in each of the group of affected and unaffected subjects. We show that these tests are flexible, as they can be based on related, unrelated or both related and unrelated subjects. They also make feasible an increasingly common design that only sequences a subset of affected subjects (related or unrelated) and uses for comparison publicly available AFs estimated in a group of healthy subjects. Finally, we show the great impact of linkage disequilibrium on the performance of all these tests.


The impact of comprehensive tobacco control policies on cardiovascular diseases in Beijing, China.
China has a high smoking prevalence, but lacks effective tobacco control interventions. In 2015, comprehensive policies that incorporated all six aspects of MPOWER were implemented in Beijing and were considered the strictest tobacco control policy implemented in China to date. Decreases in the prevalence of active smoking and secondhand smoke (SHS) exposure were observed thereafter. This study aimed to evaluate the impact of Beijing's 2015 tobacco control policy package on cardiovascular diseases (CVDs). Interrupted time-series study. Beijing, China. A total of 17.7 million employees enrolled in Urban Employee Basic Medical Insurance (UEBMI) between January 2013 to June 2017. Beijing's 2015 comprehensive tobacco policy package, combining a complete ban on smoking in indoor public places, cessation support, more comprehensive bans on advertising, and tax rises. The main outcome was hospital admissions for all CVDs and five major cause-specific CVDs, including ischaemic heart disease (IHD), heart failure (HF), heart rhythm disturbances (HRDs), stroke and other cerebrovascular diseases (CBDs). The absolute number and proportion of reductions in the number of hospital admissions after the policies are reported. A total of 419 875 hospital admissions for CVD were identified. In total, 13.4% [95% confidence interval (CI) = 11.5%, 15.3%] of hospital admissions for CVD were averted by the tobacco control policies. For major cause-specific CVDs, significant hospital admission reductions occurred for IHD (5.4%, 95% CI = 2.6%, 8.3%), stroke (21.2%, 95% CI = 17.8%, 24.6%) and other CBDs (25.9%, 95% CI = 20.8%, 31.0%), but not for HF (4.7%, 95% CI = -4.2%, 13.5%) or HRDs (4.7%, 95% CI = -2.9%, 12.3%). Beijing's 2015 tobacco control policy package appears to have been associated with a more than 10% reduction in all cardiovascular hospital admissions, including a more than 20% reduction in admissions for cerebrovascular diseases.


Investigation of electrophoretic exclusion method for the concentration and differentiation of proteins.
This work presents a technique termed as "electrophoretic exclusion" that is capable of differentiation and concentration of proteins in bulk solution. In this method, a hydrodynamic flow is countered by the electrophoretic velocity to prevent a species from entering into a channel. The separation can be controlled by changing the flow rate or applied electric potential in order to exclude a certain species selectively while allowing others to pass through the capillary. The exclusion of various proteins is investigated using a flow-injection regime of the method. Concentration of myoglobin of up to 1200 times the background concentration in 60 s was demonstrated. Additionally, negatively charged myoglobin was separated from a solution containing negatively charged allophycocyanin. Cationic cytochrome c was also differentiated from a solution with allophycocyanin. The ability to differentially transport species in bulk solution enables parallel and serial separation modes not available with other separations schemes.


Historical thinking in clinical medicine: lessons from R.G. Collingwood's philosophy of history.
The aim of this article is to create a space for historical thinking in medical practice. To this end, we draw on the ideas of R.G. Collingwood (1889-1943), the renowned British philosopher of history, and explore the implications of his philosophy for clinical medicine. We show how Collingwood's philosophy provides a compelling argument for the re-centring of medical practice around the patient history as a means of restoring to the clinical encounter the human meaning that is too often lost in modern medicine. Furthermore, we examine how Collingwood's historical thinking offers a patient-centred epistemology and a more pluralistic concept of evidence that includes the qualitative, narrative evidence necessary for human understanding. We suggest that clinical medicine can benefit from Collingwood's historical thinking, and, more generally, illustrates how a philosophy of medicine that draws on diverse sources from the humanities offers a richer, more empathetic clinical practice.


A Research Note on Transitions in Out-of-Pocket Spending on Dental Services.
We analyze correlates of the direction and magnitude of changes in out-of-pocket (OOP) payments for dental care by older Americans over a recent 4-year period. We analyzed data from the 2006 and 2008 waves of the Health and Retirement Study. We estimated multinomial logistic models of the direction and linear regression models of the amounts of OOP changes over survey periods. Financial-based factors were more strongly associated with the direction and magnitude of changing self-payments for dental care than were health factors. Findings suggested that dental coverage, income, and wealth and changes in these financial factors were more strongly correlated with the persistence of and changes in OOP payments for dental care over time than were health status and changes in health status. The sensitivity to dental coverage changes should be considered as insurance and retirement policy reforms are deliberated.


Parallel-Self-Assembling Stack, Center-Capture Effect, and Reactivity-Enhancing Effect of N-Layer (N = 1, 2, 3) Cyclo[18]carbon.
Cyclo[18]carbon (C18) is an captivating allotrope of carbon synthesized recently, which has drawn the attention among scientists. There are still few studies on the dynamic behaviors of C18. To gain knowledge in this area, we systematically explored the stacking behaviors and the oxidation kinetics of C18, as well the electronic transport behaviors of C18 oxides, by density functional theory and nonequilibrium Green's function calculations combined with reactive force field molecular dynamics simulations. The parallel-self-assembling behaviors were observed in the stack of two- or three-layer C18. During the oxidation process of C18, we found an evident center-capture effect in which the hollow rings would preferentially attract an O2 molecule into their centers. Moreover, the adsorption of O2 on the O2-doped rings was dramatically enhanced by the O2 at the center of the ring, showing the reactivity-enhancing effect. The excellent electron transport property of central-O2-doped C18 among 13 types of C18 oxides demonstrates the potential of C18 oxides as promising molecular devices for various applications. This study reveals the dynamic behaviors of C18 and provides theoretical guidance for use of C18 and C18 oxides in molecular devices.


Redistribution of CB1 cannabinoid receptors in the acute and chronic phases of pilocarpine-induced epilepsy.
The endocannabinoid system plays a central role in retrograde synaptic communication and may control the spread of activity in an epileptic network. Using the pilocarpine model of temporal lobe epilepsy we examined the expression pattern of the Type 1 cannabinoid receptor (CB1-R) in the hippocampi of CD1 mice at survival times of 2 hours, 1 day, 3 days and 2 months (acute, latent and chronic phases). Based on the behavioral signs of the acute seizures, animals were classified as "weakly" or "strongly" epileptic using the modified Racine scale. Mice of the weak group had mild seizures, whereas seizures in the strong group were frequent with intense motor symptoms and the majority of these animals developed sclerosis in the chronic phase. In control samples the most intense staining of CB1-R-positive fibers was found in the molecular layer of the dentate gyrus and in str. pyramidale of the cornu Ammonis. In weak animals no significant changes were seen at any survival time compared to controls. In strong animals, however, in the acute phase, a massive reduction in CB1-R-stained terminals occurred in the hippocampus. In the latent phase CB1-R immunoreactivity gradually recovered. In the chronic phase, CB1-immunostaining in sclerotic samples was stronger throughout the hippocampus. Quantitative electron microscopic analysis showed an increase in the number of CB1-R-positive terminals in the dentate gyrus. Moreover, the number of immunogold particles significantly increased in GABAergic terminals. Our results suggest a proconvulsive downregulation of CB1 receptors in the acute phase most probably due to receptor internalization, followed by compensatory upregulation and sprouting in the chronic phase of epilepsy. In conclusion, the changes in CB1 receptor expression pattern revealed in this study are associated with the severity of hippocampal injury initiated by acute seizures that ultimately leads to sclerosis in the vulnerable regions in the chronic phase.


Streptococcus ruminantium-associated sheep mastitis outbreak detected in Italy is distinct from bovine isolates.
Streptococcus ruminantium is the causative agent of several bovine and ovine diseases, however reports are uncommon and application of whole genome sequencing to identify is rare. We report for the first time, a severe ovine mastitis outbreak caused by S. ruminantium in Italy, 2022. S. ruminantium was isolated from 12 adult lactating ewes with diffuse nodules in the mammary parenchyma and predominantly serous and clotted milk. All outbreak isolates, along with five additional historical Italian isolates (between 2011 and 2017), were genomically characterised and then analysed in the context of all publicly available S. ruminantium genomes. Antimicrobial susceptibility testing was performed to determine the MICs of 16 antibiotics. The results showed that all isolates were susceptible to all antimicrobials tested except kanamycin. Single Nucleotide Variant analysis confirmed this as a clonal outbreak across 10 sheep (≤ 15 SNVs), while the two others were colonised by more distantly related clones (≤ 53 pairwise SNVs), indicating the presence of multiple infecting lineages. The five historical S. ruminantium isolates were comprised of genetically-distant singletons (between 1259 and 5430 pairwise SNVs to 2022 outbreak isolates). Ovine isolates were found to be genetically distinct to bovine isolates, forming monophyletic groups. Bovine isolates were similarly made up of singleton clones in all but two isolates. Taken together, our genomic analysis using all globally available genomes is consistent with general opportunistic pathogenesis of S. ruminantium. We encourage future genomic surveillance efforts to facilitate outbreak detection, as well as improve our understanding of this poorly-understood, multi-host, zoonotic pathogen.


Novel lipid modifying drugs to lower LDL cholesterol.
Statins have long been the cornerstone for the prevention of cardiovascular disease (CVD). However, because of perceived adverse effects and insufficient efficacy in certain groups of patients, considerable interest exists in the search for alternatives to lower LDL-cholesterol (LDL-C), and the recent approvals of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors underlines the success of this quest. Here, we give an updated overview on the most recent developments in the area of LDL-C lowering agents. The clinical effects of the PCSK9 inhibitors are promising, especially now that the FOURIER and SPIRE programmes are published. Most cholesterylester-transfer protein inhibitors, however, except anacetrapib, have been discontinued because of either toxicity or lack of efficacy in large cardiovascular outcome trials. Other agents - like mipomersen, lomitapide, ETC-1002, and gemcabene - aim to lower LDL-C in different ways than solely through the LDL receptor, opening up possibilities for treating patients not responding to conventional therapies. New discoveries are also being made at the DNA and RNA level, with mipomersen being the first approved therapy based on RNA intervention in the United States for homozygous familial hypercholesterolemia. Recent years have witnessed a new beginning for cholesterol-lowering compounds. With increased knowledge of lipid metabolism a score of new therapeutic targets has been identified. Mechanisms for modulation of those targets are also becoming more diverse while statins remain the backbone of CVD prevention, the new alternatives, such as PCSK9 monoclonals will probably play an important additional role in treatment of patients at risk for CVD.


Ammoniation-dehydration of fatty acids into nitriles: heterogeneous or homogeneous catalysis?
Fatty nitriles have lately become of interest in the framework of biofuels and for the valorization of the oil part of biomass to form fine chemicals or polymers. The production of long-chain fatty nitriles by the direct reaction of acids with NH3 has not been extensively studied, although several catalysts have been developed and published as patents. The characterization of this reaction with and without catalyst is, to the best of our knowledge, performed for the first time in this study. Several catalysts with various acid-base features were tested, and the best catalysts at 250 °C (Zn- and In-based catalysts) were further studied. Catalytically active forms and models are proposed for the Zn- and In-based catalysts, and the kinetic parameters for the amide to nitrile reaction are evaluated.


Microinjection of catalytic subunit of cyclic AMP-dependent protein kinase enhances calcium action potentials of bag cell neurons in cell culture.
We have found that the calcium action potentials of bag cell neurons from the abdominal ganglion of Aplysia may be enhanced by intracellular microinjection of the catalytic subunit of cyclic AMP-dependent protein kinase (ATP:protein phosphotransferase, EC 188.8.131.52). The catalytic subunit was purified from bovine heart and shown to be effective in stimulating the phosphorylation of bag cell proteins in homogenates at concentrations of 10-50 nM. Intracellular injection into isolated bag cell neurons maintained in primary culture was through pressure applied to microelectrodes filled at the tip with catalytic subunit (5-22 muM). In 11 of 16 injected cells, both the slope of the rising phase and the height of the action potentials evoked by a constant depolarizing current were markedly enhanced relative to the pre-injection control (mean increases, 73% and 35%, respectively). This effect could occur with no change in resting potential or in the latency of the action potential from the onset of the depolarizing pulse. The effect was observed with enzyme dissolved in three different salt solutions (Na phosphate, K phosphate, or KCl). In two experiments, tetrodotoxin (50 muM) added to the extracellular medium had no effect on the enhanced action potentials. Subsequent addition of the calcium antagonist Co(2+), however, diminished or abolished the spikes. In more than half of the experiments, the injection of catalytic subunit was accompanied by an increase in the input resistance of the cells as measured by applying small hyperpolarizing current pulses. In three experiments, subthreshold oscillations in membrane potential resulted from the injections. Control injections (24 cells), carried out either with carrier medium alone or with heat-inactivated enzyme preparations, did not produce spike enhancement, increased input resistance, or oscillations. Our data suggest that the stimulation of intracellular protein phosphorylation by the catalytic subunit of cyclic AMP-dependent protein kinase enhances the excitability of bag cell neurons by modifying calcium and potassium channels or currents.


Abrupt Photoperiod Changes Differentially Modulate Hepatic Antioxidant Response in Healthy and Obese Rats: Effects of Grape Seed Proanthocyanidin Extract (GSPE).
Disruptions of the light/dark cycle and unhealthy diets can promote misalignment of biological rhythms and metabolic alterations, ultimately leading to an oxidative stress condition. Grape seed proanthocyanidin extract (GSPE), which possesses antioxidant properties, has demonstrated its beneficial effects in metabolic-associated diseases and its potential role in modulating circadian disruptions. Therefore, this study aimed to assess the impact of GSPE administration on the liver oxidant system of healthy and diet-induced obese rats undergoing a sudden photoperiod shift. To this end, forty-eight photoperiod-sensitive Fischer 344/IcoCrl rats were fed either a standard (STD) or a cafeteria diet (CAF) for 6 weeks. A week before euthanizing, rats were abruptly transferred from a standard photoperiod of 12 h of light/day (L12) to either a short (6 h light/day, L6) or a long photoperiod (18 h light/day, L18) while receiving a daily oral dose of vehicle (VH) or GSPE (25 mg/kg). Alterations in body weight gain, serum and liver biochemical parameters, antioxidant gene and protein expression, and antioxidant metabolites were observed. Interestingly, GSPE partially ameliorated these effects by reducing the oxidative stress status in L6 through an increase in GPx1 expression and in hepatic antioxidant metabolites and in L18 by increasing the NRF2/KEAP1/ARE pathway, thereby showing potential in the treatment of circadian-related disorders by increasing the hepatic antioxidant response in a photoperiod-dependent manner.


Dynamics of carbohydrate strands in water and interactions with clay minerals: influence of pH, surface chemistry, and electrolytes.
Carbohydrate hydrogels are extensively used in pharmaceuticals and engineered biomaterials. Molecular conformations, assembly, and interactions of the carbohydrate strands with stabilizers such as clay minerals in aqueous solution are difficult to quantify in experiments and the hydrogel properties remain largely a result of trial-and-error studies. We analyzed the assembly of gellan gum in aqueous solution and interactions with dispersed clay minerals in all-atomic detail using molecular dynamics simulation, atomic force microscopy (AFM), and comparisons to earlier measurements. Gellan strands associate at low pH values of 2 and gradually disassemble to double strands with weak association of -0.4 kcal per mole carbohydrate ring as the pH values increases to 9. Ionization of the carbonic acid side groups in the backbone extends the chains and accelerates the conformational dynamics via rapidly changing intramolecular ion bridges. Gellan interactions with clay minerals depend on the strength of electric triple layers between clay, cations, and anionic polymer strands, as well as weaker hydrogen bonds along the edges, which are tunable as a function of the clay surface chemistry, local ionic strength, and pH values. Interaction energies range from -4 to +6 kcal per mol carbohydrate ring and were most favorable for electric triple layers with high charge mobility, which can be achieved for intermediate cation exchange capacity of the clay mineral and high pH values to increase ionization of the clay edges and of the polymer. The findings provide understanding and help control the dynamics and stabilization of carbohydrate hydrogels by clay minerals.


Elevated 4R tau contributes to endolysosomal dysfunction and neurodegeneration in VCP-related frontotemporal dementia.
FTD and ALS are two untreatable neurodegenerative diseases that exist on a clinical, genetic, and pathological spectrum. The VCP gene is highly relevant, being directly implicated in both FTD and ALS. Here, we investigate the effects of VCP mutations on the cellular homoeostasis of hiPSC-derived cortical neurons, focusing on endo-lysosomal biology and tau pathology. We find that VCP mutations cause abnormal accumulation of enlarged endo-lysosomes accompanied with impaired interaction between nuclear FUS and SFPQ in human cortical neurons. The spatial dissociation of intra-nuclear FUS and SFPQ correlates with alternative splicing of the MAPT pre-mRNA and increased tau phosphorylation. Importantly, we show that increased 4R tau using antisense oligonucleotide technology is sufficient to drive toxic changes in control human neurons, which phenocopy VCP-mutant neurons. In summary, our findings demonstrate that tau hyperphosphorylation, endolysosomal dysfunction, lysosomal membrane rupture, endoplasmic reticulum stress and apoptosis are driven by a pathogenic increase in 4R tau.


Does an increase in body mass index over 10 years affect knee structure in a population-based cohort study of adult women?
Although obesity is a modifiable risk factor for knee osteoarthritis (OA), the effect of weight gain on knee structure in young and healthy adults has not been examined. The aim of this study was to examine the relationship between body mass index (BMI), and change in BMI over the preceding 10-year period, and knee structure (cartilage defects, cartilage volume and bone marrow lesions (BMLs)) in a population-based sample of young to middle-aged females. One hundred and forty-two healthy, asymptomatic females (range 30 to 49 years) in the Barwon region of Australia, underwent magnetic resonance imaging (MRI) during 2006 to 2008. BMI measured 10 years prior (1994 to 1997), current BMI and change in BMI (accounting for baseline BMI) over this period, was assessed for an association with cartilage defects and volume, and BMLs. After adjusting for age and tibial plateau area, the risk of BMLs was associated with every increase in one-unit of baseline BMI (OR 1.14 (95% CI 1.03 to 1.26) P = 0.009), current BMI (OR 1.13 (95% CI 1.04 to 1.23) P = 0.005), and per one unit increase in BMI (OR 1.14 (95% CI 1.03 to 1.26) P = 0.01). There was a trend for a one-unit increase in current BMI to be associated with increased risk of cartilage defects (OR 1.06 (95% CI 1.00 to 1.13) P = 0.05), and a suggestion that a one-unit increase in BMI over 10 years may be associated with reduced cartilage volume (-17.8 ml (95% CI -39.4 to 3.9] P = 0.10). Results remained similar after excluding those with osteophytes. This study provides longitudinal evidence for the importance of avoiding weight gain in women during early to middle adulthood as this is associated with increased risk of BMLs, and trend toward increased tibiofemoral cartilage defects. These changes have been shown to precede increased cartilage loss. Longitudinal studies will show whether avoiding weight gain in early adulthood may play an important role in diminishing the risk of knee OA.


YAP/TAZ-mediated activation of serine metabolism and methylation regulation is critical for LKB1-deficient breast cancer progression.
The crucial interplay between metabolic remodeling and the epigenetics could contribute to promote cancer progression. A remarkable association within interaction, LKB1 has been reported, suggesting that the expression of key enzymes involving de novo serine synthesis and DNA methyltransferases like DNMT1 and DNMT3A increase LKB1-deficiency cells. However, the complex interactional link between metabolic remodeling and the epigenetics is still unclear. Hence, we focus on the relationship between YAP/TAZ and serine metabolism to control methylation of DNA or histone in breast cancer with LKB1 deficiency. We hypothesize that YAP/TAZ may have the function to activate key enzymes involving serine metabolism like PSPH and up-regulate the amino acid transporters to supply sources of serine synthesis through activation of C-MYC with TEAD1. Further, we speculate that YAP/TAZ in dependent of FOS may promote DNMT1 and subsequently mediate DNMT1-G9A complex involving serine metabolism and the methylation of DNA and histone. We hope that our study will stimulate further studies and a new targeted therapy and early medical intervention for YAP/TAZ could be a useful option for breast cancer cases complicated with LKB1 deficiency.


Mineralocorticoid receptors in the mammalian olfactory mucosa.
Mineralocorticoid hormones regulate secretion and absorption in a wide variety of epithelial tissues, although specific mechanisms in the olfactory mucosa are currently unknown. Utilizing reverse transcription-polymerase chain reaction (RT-PCR) analysis, we have demonstrated the expression of mineralocorticoid (type I) receptor messenger RNA in the rodent olfactory mucosa. Amplification products of predicted size were obtained with nucleotide sequences corresponding to respective mineralocorticoid receptor (MR) kidney transcripts. Immunocytochemistry, using an antibody with known specificity for MRs, was then utilized in order to localize the cellular site(s) of MR protein expression in the olfactory mucosa. The highest levels of MR immunoreactivity were localized to the supranuclear region of sustentacular cells, as well as the acinar cells of the Bowman's glands. The respiratory regions of the nasal cavity were devoid of appreciable MR immunoreactivity. This study demonstrates both MR transcript and protein expression in the olfactory mucosa. We hypothesize that the mineralocorticoid hormones may have a role in modulation of olfactory secretion and/or sensory transduction in the peripheral olfactory system.


[Effect of the addition of a fiber-rich concentrate to a hay-based diet, offered at 2 dietary levels to adult rabbits. 1. Mean retention time of digesta].
The influence of adding a fibre rich concentrate feed (wheat bran or beet pulp) to a hay-based diet (orchard grass-lucerne mixture; 50/50) upon the rate of passage of digesta of these two fractions (hay and concentrate) was measured in three groups of 8 adult doe rabbits (White New Zealand x California). The three diets composed of either 90% hay, or hay + bran or hay + pulp were offered at two levels of feeding, i.e. ad libitum and 2/3 ad libitum. The retention time of the two main fractions was measured by means of two tracers, i.e. ytterbium-169 bound to hay and cerium-141 to bran or pulp. Animals fed on the 90% hay diet excreted more than 90% of the tracer during the first 24 h. The mean retention time (MRT) of this diet was the shortest (on an average 14.8 h). The addition of pulp or bran increased the MRT of the diet by 2 and 4 h, respectively. Feed restriction led to a 5 to 7 h earlier period of caecotrophy with a subsequent lengthening of the MRT by 2 to 4 h according to groups. The two hay + "concentrate" diets gave almost the same 169Yb and 141Ce excretion curves. Thus, the mean retention time seems to be the same for digesta from hay and "concentrate" (non significant deviations).


Progressive myelopathy caused by dural arteriovenous fistula at the craniocervical junction--case report.
A 68-year-old male presented an unusual dural arteriovenous fistula (AVF) located at the craniocervical junction. Magnetic resonance imaging revealed dilated perimedullary veins around the spinal cord at C-1 and C-2 levels, as well as high intensity signals in the spinal cord on T2-weighted images. Vertebral angiography identified an AVF at the point where the right vertebral artery penetrates the dura. The fistula was a single and direct communication between the vertebral artery and the spinal vein. Surgical interruption of the fistula at its venous side resulted in prompt improvement of both motor and sensory signs and symptoms.


Facile preparation of mesoporous titanium nitride microspheres for electrochemical energy storage.
In this study, mesoporous TiN spheres with tunable diameter have been fabricated via a facile template-free strategy. Under ammonia atmosphere, mesoporous TiO₂ spheres are directly converted into mesoporous TiN spheres with the addition of cyanamide to retain the original morphology. The electrochemical performance of the resultant mesoporous TiN spheres demonstrates that this material can be a promising electrode material for nonaqueous supercapacitors with high energy densities.


Phase transitions in KIO(3).
The high-pressure behavior of KIO(3) was studied up to 30 GPa using single crystal and powder x-ray diffraction, Raman spectroscopy, second harmonic generation (SHG) experiments and density functional theory (DFT)-based calculations. Triclinic KIO(3) shows two pressure-induced structural phase transitions at 7 GPa and at 14 GPa. Single crystal x-ray diffraction at 8.7(1) GPa was employed to solve the structure of the first high-pressure phase (space group R3, a = 5.89(1) Å, α = 62.4(1)°). The bulk modulus, B, of this phase was obtained by fitting a second order Birch-Murnaghan equation of state (eos) to synchrotron x-ray powder diffraction data resulting in B(exp,second) = 67(3) GPa. The DFT model gave B(DFT,second) = 70.9 GPa, and, for a third order Birch-Murnaghan eos, B(DFT,third) = 67.9 GPa with a pressure derivative of [Formula: see text]. Both high-pressure transformations were detectable by Raman spectroscopy and the observation of second harmonic signals. The presence of strong SHG signals shows that all high-pressure phases are acentric. By using different pressure media, we showed that the transition pressures are very strongly influenced by shear stresses. Earlier work on low- and high-temperature transitions was complemented by low-temperature heat capacity measurements. We found no evidence for the presence of an orientational glass, in contrast to earlier dielectric studies, but consistent with earlier low-temperature diffraction studies.


Correlations of inhibitor kinetics for Pneumocystis jirovecii and human dihydrofolate reductase with structural data for human active site mutant enzyme complexes.
To understand the role of specific active site residues in conferring selective dihydrofolate reductase (DHFR) inhibition from pathogenic organisms such as Pneumocystis carinii (pc) or Pneumocystis jirovecii (pj), the causative agent in AIDS pneumonia, it is necessary to evaluate the role of these residues in the human enzyme. We report the first kinetic parameters for DHFR from pjDHFR and pcDHFR with methotrexate (MTX), trimethoprim (TMP), and its potent analogue, PY957. We also report the mutagenesis and kinetic analysis of active site mutant proteins at positions 35 and 64 of human (h) DHFR and the crystal structure determinations of hDHFR ternary complexes of NADPH and PY957 with the wild-type DHFR enzyme, the single mutant protein, Gln35Lys, and two double mutant proteins, Gln35Ser/Asn64Ser and Gln35Ser/Asn64Phe. These substitutions place into human DHFR amino acids found at those sites in the opportunistic pathogens pcDHFR (Q35K/N64F) and pjDHFR (Q35S/N64S). The K(i) inhibition constant for PY957 showed greatest potency of the compound for the N64F single mutant protein (5.2 nM), followed by wild-type pcDHFR (K(i) 22 nM) and then wild-type hDHFR enzyme (K(i) 230 nM). Structural data reveal significant conformational changes in the binding interactions of PY957 in the hDHFR Q35S/N64F mutant protein complex compared to the other hDHFR mutant protein complexes and the pcDHFR ternary complex. The conformation of PY957 in the wild-type DHFR is similar to that observed for the single mutant protein. These data support the hypothesis that the enhanced selectivity of PY957 for pcDHFR is in part due to the contributions at positions 37 and 69 (pcDHFR numbering). This insight will help in the design of more selective inhibitors that target these opportunistic pathogens.


Spontaneous hypoglycemia associated with autoimmunity specific to human insulin.
A 55-yr-old woman with a history of Graves' disease experienced attacks of postprandial hypoglycemia for 6 yr. An insulinoma could not be confirmed by repeated fasting tests and by surgical pancreas revision. Extracted pancreatic insulin was chemically normal. Fasting plasma total insulin (1.22 nM = 183 microU/ml) and proinsulin (0.48 nM) were elevated and greatly increased after oral glucose. Glucose-clamp studies revealed delayed insulin clearance. Plasma free-insulin levels were normal. Insulin-binding antibodies were detected by enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay with human insulin as ligand but not with pork or beef insulins. Analysis with a modified ELISA suggested a monotypic and monoclonal human insulin autoantibody, which showed a restriction to the lambda-light chain. T-lymphocytes (predominantly helper) demonstrated increased responsiveness to beef, pork, and human insulins by proliferation assay. A T-lymphocyte line showed exclusively human insulin specificity. All this indicated cellular and humoral anti-human insulin autoimmunities. Clinically, the cause of hypoglycemia associated with elevated total insulin and proinsulin was misdiagnosed as atypical insulinoma. The study of total and free plasma insulin levels and sensitive antibody assays specific to human insulin were necessary to correctly diagnose autoimmune hypoglycemia.


High-content 3D multicolor super-resolution localization microscopy.
Super-resolution (SR) methodologies permit the visualization of cellular structures at near-molecular scale (1-30 nm), enabling novel mechanistic analysis of key events in cell biology not resolvable by conventional fluorescence imaging (∼300-nm resolution). When this level of detail is combined with computing power and fast and reliable analysis software, high-content screenings using SR becomes a practical option to address multiple biological questions. The importance of combining these powerful analytical techniques cannot be ignored, as they can address phenotypic changes on the molecular scale and in a statistically robust manner. In this work, we suggest an easy-to-implement protocol that can be applied to set up a high-content 3D SR experiment with user-friendly and freely available software. The protocol can be divided into two main parts: chamber and sample preparation, where a protocol to set up a direct STORM (dSTORM) sample is presented; and a second part where a protocol for image acquisition and analysis is described. We intend to take the reader step-by-step through the experimental process highlighting possible experimental bottlenecks and possible improvements based on recent developments in the field.


Soft-copy reading of digital chest radiographs: effect of ambient light and automatic optimization of monitor luminance.
We sought to evaluate whether soft-copy reading of simulated pulmonary chest lesions is influenced by ambient light and automatic optimization of cathode ray tube (CRT) monitor luminance. Four types of simulated lesions (nodules, lines, micronodules, and patchy opacities) were superimposed over an anthropomorphic chest phantom. Lesion detection with soft-copy reading was assessed using a high-contrast grayscale 2K CRT monitor under the following conditions: (1) subdued lighting (<50 lux); (2) normal lighting conditions (450 lux) without, and (3) with a sensitivity modulation to automatically adjust the CRT luminance to the increased amount of ambient light. Reading data were analyzed according to receiver operating curve. Significance of differences was tested using an analysis of variance for repeated measures. Ambient room light of 450 lux did not significantly influence the detection of nodules and patchy opacities. However, bright ambient light significantly decreased detection of micronodules (0.60 vs. 0.74) and lines (0.52 vs. 0.66) relative to subdued lighting conditions. Automatic luminance adjustment could compensate the effect of ambient light for the micronodules (0.77) but not for the lines (0.53). Bright ambient light significantly decreases detection of small low-contrast structures. This may be partially but not completely compensated by an automatic luminance adaptation.