Suitability of the Depression, Anxiety, and Stress Scale in Parkinson's Disease.
The Depression, Anxiety, and Stress Scale -21 (DASS-21) is a frequently used measure of emotional disturbance symptoms in Parkinson's disease (PD). However, the factor structure of the DASS-21 in PD has yet to be explored. To assess whether the scale is measuring these symptoms in PD in the same way as the general population. The present study fit a series of established DASS-21 factor structures with both confirmatory factor analysis (CFA) and exploratory structural equation modelling (ESEM) using data from 251 participants with PD. The 3-factor ESEM provided the best fit. The depression and stress scales fit well, however, few items on the anxiety subscale loaded clearly, with several items significantly loading onto the depression or stress factors. Whilst the depression and stress subscales appear suitable in PD, poor loadings and internal consistency indicate the anxiety subscale may not accurately assess anxiety symptomology in PD. This may be due to the scale's reliance on physiological symptoms as indicators of anxiety, when many of these are present in PD. Thus, the anxiety subscale of the DASS-21 may not be a suitable measure of anxiety in PD.


An adaptive EEG derivation technique.
The amount of common components in EEG tracings relating to any two electrodes in the 10-20 array depends partly on the distance between these electrodes, i.e. potentials on the scalp surface have an average mutual coupling which is related to distance along the surface. This coupling is expressed by the spatial correlation function which can be computed from the tracings. Information contained in the correlation functions relating to 30 individual subjects was used to modify the derivation technique to yield 'focussed' tracings in each case, i.e., tracings from which the distance-related coupling ('blur') had been removed. Obtained results were considered representative of the topographical resolution achievable within the limitations of the 10-20 system of electrode placement. The tracings were in most cases found to be almost identical to those obtained by means of the non-adaptive deconvolving technique known as source derivation. In some cases the adaptive technique produced tracings with slightly higher topographical differentiation than did source derivation.


Using a Modified Delphi Method to Reach Consensus on Best Practices for Medical Education Abstract Submissions to Multiple Conferences.
Medical education researchers are often uncertain whether they should submit abstracts to certain conferences. Therefore, we aimed to elicit consensus among medical education conference organizers to answer the question: what are best practices for research abstract submissions to multiple conferences? Using a 44-question online survey, we conducted a modified Delphi process to identify best practices for abstract submissions to medical education conferences. Consistent with the Delphi process, we identified conference representatives from non-specialty medical education conferences and across four conference types (institutional, regional, national, and international) to serve as panelists. Eleven expert panelists, representing all four conference types-two institutional conferences, five regional conferences, two national conferences, and two international conferences-completed three rounds of the survey. After three rounds, panelists reached consensus on 39/44 survey items-26 items in round 1, 10 items in round 2, and three items in round 3. Panelists' consensus and rationale indicated that it is most appropriate to resubmit abstracts to conferences with a larger or different audience, but not to more homogeneous audiences. Among the four conference types, abstract resubmission from institutional conferences to other conference types was the most widely accepted. Panelists agreed that abstracts using data and results submitted or accepted for publication could be submitted to any conference type. The results of this study provide best practices for presenting scholarship to medical education conferences. We recommend that guidelines for medical education conference abstract submissions provide consistent, clear instructions regarding the appropriate life cycle of an abstract.


Time Delay Embedding Increases Estimation Precision of Models of Intraindividual Variability.
This paper investigates the precision of parameters estimated from local samples of time dependent functions. We find that time delay embedding, i.e. structuring data prior to analysis by constructing a data matrix of overlapping samples, increases the precision of parameter estimates and in turn statistical power compared to standard independent rows of panel data. We show that the reason for this effect is that the sign of estimation bias depends on the position of a misplaced data point if there is no a priori knowledge about initial conditions of the time dependent function. Hence, we reason that the advantage of time delayed embedding is likely to hold true for a wide variety of functions. We support these conclusions both by mathematical analysis and two simulations.


Epidemiological survey on incidence and treatment of community acquired pneumonia in Italy.
To estimate annual incidence of community acquired pneumonia (CAP) in an Italian general population sample. Two hundred and eighty-seven family practitioners (64.6% of those selected) recorded suspected or ascertained CAP cases for 1 year. Information on smoking habit, respiratory symptoms and signs, co-morbidity, antibiotic and corticosteroid therapy, hospitalization, mortality and recovery were obtained. Six hundred and ninety-nine case forms were collected (53.1% females, mean age 59.6+/-19.5, 20.6% smokers). CAP incidence rates per 1000 population were: 1.69 in men vs. 1.71 in women; 2.33 in the North vs. 1.29 in the Centre-South of Italy; between 0.73 in 14-, and 3.34 in 64+year-old subjects. Main symptoms and signs were cough (73.3%), crackles (72.8%), dullness (57.3%), asthenia (53.4%). 59.5% of subjects had concurrent diseases, mostly cardiac and respiratory. 77.2% of cases had chest X-ray (with parenchymal density in 90.6%). Phlegm microbiological examination was performed in 12.8% of cases. First choice antibiotics were cephalosporins (45.8%), macrolides (20.2%), other beta-lactams (18.6%), and fluoroquinolones (12.2%). Rates of hospitalization and of mortality were 31.8% and 6.0%, respectively. This study confirmed that the annual CAP incidence rate in the general population of South Europe is about 2 per 1000 population and showed a wide choice of antibiotic treatment.


Effect of RFRP-3, the mammalian ortholog of GnIH, on apoptosis and autophagy in porcine ovarian granulosa cells via the p38MAPK pathway.
RFamide-related peptide-3 (RFRP-3) has been proposed as a key inhibitory regulator of mammalian reproduction. Our previous studies demonstrated that RFRP-3 mediated apoptosis and autophagy of the epididymis in rats and inhibited porcine granulosa cell (GC) proliferation. However, the molecular mechanisms of the RFRP-3 effect on porcine GC apoptosis and autophagy have not been studied before. Herein, we first investigated the role of RFRP-3 in apoptosis and autophagy in cultured porcine GCs in vitro. Our results showed that different doses of RFRP-3 dose-dependently elevated the expression of autophagy markers at both the mRNA and protein levels, whereas the expression of apoptosis markers exhibited a bidirectional, dose-dependent effect. Because the p38MAPK signaling pathway plays essential roles in apoptosis and autophagy, we subsequently evaluated the effect of RFRP-3 on p38MAPK activation. The results showed that 10-6 M RFRP-3 treatment not only significantly decreased p38MAPK phosphorylation but also inhibited the p38MAPK activator U-46619 to promote p38MAPK activation in porcine GCs. Finally, we applied U-46619 to investigate the role of the p38MAPK signaling pathway in apoptosis and autophagy in RFRP-3-treated porcine GCs. The results showed that all doses of RFRP-3 significantly inhibited the U-46619-induced increase in apoptosis in a dose-dependent manner. However, except for the U-46619-induced Beclin-1 expression increase, which was significantly suppressed in high-dose RFRP-3-treated porcine GCs, other doses of RFRP-3 treatment strengthened the U-46619-induced increase in other autophagy markers. In summary, our data demonstrate a critical role for the p38MAPK signaling pathway in the porcine GC cellular response to RFRP-3 by controlling the balance between apoptosis and autophagy.


Structural features and nucleotide-binding capability of the C subunit are integral to the regulation of the eukaryotic V1Vo ATPases.
V-ATPases (vacuolar ATPases) are responsible for acidification of intracellular compartments and, in certain cases, proton transport across the plasma membrane of eukaryotic cells. They are composed of a catalytic V1 sector, in which ATP hydrolysis takes place, and the Vo sector, which functions in proton conduction. The best established mechanism for regulating the V-ATPase activity in vivo involves reversible dissociation of the V1 and Vo domains, in which subunit C is intimately involved. In the last year, impressive progress has been made in elucidating the structure of the C subunit and its arrangement inside the V-ATPase. Nucleotide occupancy by subunit C, followed by conformational changes of this subunit has shed light on the mechanism of V-ATPase regulation.


Wave Propagation in Composites of Plasma and Metamaterials with Negative Permittivity and Permeability.
Wave propagation is observed through a negative permeability metamaterial immersed in gaseous plasma. A 3D array of split ring resonators (SRR) is enveloped by an inductively heated argon plasma with a nominal plasma frequency of 2.65 GHz. Transmission spectra show electromagnetic waves traverse the composite medium from 1.3-1.7 GHz for which the permeability of the SRRs and the permittivity of the plasma are simultaneously negative. Only surface waves and evanescence are observed outside this frequency band. The edge of the transmission band also shows negative group velocity, albeit with high wave attenuation. The free electron density of the plasma is coupled to the inductive heating, allowing dynamic reconfiguration of the metamaterial's frequency band and wave impedance.


The cellular and behavioral consequences of interleukin-1 alpha penetration through the blood-brain barrier of neonatal rats: a critical period for efficacy.
Proinflammatory cytokines circulating in the periphery of early postnatal animals exert marked influences on their subsequent cognitive and behavioral traits and are therefore implicated in developmental psychiatric diseases such as schizophrenia. Here we examined the relationship between the permeability of the blood-brain barrier to interleukin-1 alpha (IL-1 alpha) in neonatal and juvenile rats and their later behavioral performance. Following s.c. injection of IL-1 alpha into rat neonates, IL-1 alpha immunoreactivity was first detected in the choroid plexus, brain microvessels, and olfactory cortex, and later diffused to many brain regions such as neocortex and hippocampus. In agreement, IL-1 alpha administration to the periphery resulted in a marked increase in brain IL-1 alpha content of neonates. Repeatedly injecting IL-1 alpha to neonates triggered astrocyte proliferation and microglial activation, followed by behavioral abnormalities in startle response and putative prepulse inhibition at the adult stage. Analysis of covariance with a covariate of startle amplitude suggested that IL-1 alpha administration may influence prepulse inhibition. However, adult rats treated with IL-1 alpha as neonates exhibited normal learning ability as measured by contextual fear conditioning, two-way passive shock avoidance, and a radial maze task and had no apparent sign of structural abnormality in the brain. In comparison, when IL-1 alpha was administered to juveniles, the blood-brain barrier permeation was limited. The increases in brain IL-1 alpha content and immunoreactivity were less pronounced following IL-1 alpha administration and behavioral abnormalities were not manifested at the adult stage. During early development, therefore, circulating IL-1 alpha efficiently crosses the blood-brain barrier to induce inflammatory reactions in the brain and influences later behavioral traits.


Integrin-like substrate adhesion in RTG-2 cells, a fibroblastic cell line derived from rainbow trout.
Fluorometric cell attachment assays together with competitive inhibitors of adhesion were used to probe for the presence of integrins, a diverse family of heterodimeric cell-surface glycoproteins involved in cell-cell and cell-extracellular matrix adhesion, in the fibroblastic rainbow trout cell line, RTG-2. The adhesive properties of this cell line were evaluated. RTG-2 cells adhered poorly to TC plastic in the absence of serum but as little as 2.5% fetal bovine serum allowed over 75% of the cells to attach after 5 h. Surfaces coated with the extracellular matrix proteins collagen I, collagen IV, fibrin, fibrinogen, or fibronectin were able to support attachment of RTG-2 cells. Adhesion of RTG-2 cells to fibronectin varied linearly with fibronectin coating densities in the range 0 to 65 ng/mm(2). Oligopeptides containing the sequence Arg-Gly-Asp (RGD) caused dose-dependent inhibition of adhesion to microtiter plates coated with fibrin, fibrinogen, and fibronectin, whereas attachment to collagen I and collagen IV was less severely affected. In all cases, peptides containing Arg-Gly-Glu (RGE) or Asp-Gly-Arg (DGR) sequences caused no reduction of cell attachment. Since many integrins mediate adhesion by binding to RGD sequences in their target ligands, these results suggest the presence of integrin-like adhesion molecules on the surface of RTG-2 cells.


Post-Separation Abuse of Women and their Children: Boundary-setting and Family Court Utilization among Victimized Mothers.
Continued abuse of themselves and their children is a concern for many mothers leaving intimate partner violence (IPV) perpetrating husbands. This research examines women's responses to abuse committed by ex-husbands with whom they had undergone custody disputes. In-depth, qualitative interviews were conducted with 19 mothers who had divorced IPV-perpetrating husbands between one and three years prior. Participants were located through publicly available family court divorce records and interviews were examined using analytic induction. Women's strategies to protect themselves and their children from abuse involved setting boundaries to govern their interactions with ex-husbands. Mothers often turned to family court for assistance in setting boundaries to keep children safe, but found that family court did not respond in ways they believed protected their children. Conversely, when women turned to the justice system for restraining orders or called the police for help against IPV, they generally found the justice system responsive.


Human aldehyde dehydrogenase-catalyzed oxidation of ethylene glycol ether aldehydes.
Ethylene glycol ethers (EGEs) are primary alcohols commonly used as solvents in numerous household and industrial products. Exposure to EGEs has been correlated with delayed encephalopathy, metabolic acidosis, sub-fertility and spermatotoxicity in humans. In addition, they also cause teratogenesis, carcinogenesis, hemolysis, etc., in various animal models. Metabolism EGEs parallels ethanol metabolism, i.e., EGEs are first converted to 2-alkoxy acetaldehydes (EGE aldehydes) by alcohol dehydrogenases, and then to alkoxyacetic acids by aldehyde dehydrogenases (ALDHs). The acid metabolite of EGEs is considered responsible for toxicities associated with EGEs. The role of human ALDHs in EGE metabolism is not clear; accordingly, we have investigated the ability of five different human ALDHs (ALDH1A1, ALDH2, ALDH3A1, ALDH5A1 and ALDH9A1) to catalyze the oxidation of various EGE aldehydes. The EGE aldehydes used in this study were synthesized via Swern oxidation. All of the human ALDHs were purified from human cDNA clones over-expressing these enzymes in E. coli. The ALDHs tested, so far, differentially catalyze the oxidation of EGE aldehydes to their corresponding acids (K(m) values range from approximately 10 microM to approximately 20.0mM). As judged by V(max)/K(m) ratios, short-chain alkyl-group containing EGE aldehydes are oxidized to their acids more efficiently by ALDH2, whereas aryl- and long-chain alkyl-group containing EGE aldehydes are oxidized to their acid more efficiently by ALDH3A1. Given the product of ALDH-catalyzed reaction is toxic, this process should be considered as a bio-activation (toxification) process.


Speech-evoked ABR: Effects of age and simulated neural temporal jitter.
The speech-evoked auditory brainstem response (sABR) provides a measure of encoding complex stimuli in the brainstem, and this study employed the sABR to better understand the role of neural temporal jitter in the response patterns from older adults. In experiment 1, sABR recordings were used to investigate age-related differences in periodicity encoding of the temporal envelope and fine structure components of the response to a /da/speech token. A group of younger and a group of older adults (n = 22 per group) participated. The results demonstrated reduced amplitude of the fundamental frequency and harmonic components in the spectral domain of the recorded response of the older listeners. In experiment 2, a model of neural temporal jitter was employed to simulate in a group of young adults (n = 22) the response patterns measured from older adults. A small group of older adults (n = 7) were also tested under the jitter simulation conditions. In the young adults, the results showed a systematic reduction in the response amplitude of the most robust response components as the degree of applied jitter increased. In contrast, the older adults did not demonstrate significant response reduction when tested under jitter conditions. The overall pattern of results suggests that older adults have reduced neural synchrony for encoding periodic, complex signals at the level of the brainstem, and that this reduced synchrony can be modeled by simulating neural jitter via disruption of the temporal waveform of the stimulus.


Categorical Auditory Working Memory in Crows.
The ability to group sensory data into behaviorally meaningful classes and to maintain these perceptual categories active in working memory is key to intelligent behavior. Here, we show that carrion crows, highly vocal and cognitively advanced corvid songbirds, possess categorical auditory working memory. The crows were trained in a delayed match-to-category task that required them to flexibly match remembered sounds based on the upward or downward shift of the sounds' frequency modulation. After training, the crows instantaneously classified novel sounds into the correct auditory categories. The crows showed sharp category boundaries as a function of the relative frequency interval of the modulation. In addition, the crows generalized frequency-modulated sounds within a category and correctly classified novel sounds kept in working memory irrespective of other acoustic features of the sound. This suggests that crows can form and actively memorize auditory perceptual categories in the service of cognitive control of their goal-directed behaviors.


Depression in Turkey in the 1980s: epidemiological and clinical approaches.
A review is presented of knowledge about the following issues in Turkey: prevalence of depression, suicidal attempts and suicide, clinical picture of depression, and etiological factors responsible for causing depression. Epidemiological studies of depression are reviewed and their results are discussed in detail, with special emphasis on conclusions with valid generalizations. As in almost all countries, depression, though exhibiting some differences clinically, is a major public health problem in Turkey. The point prevalence rate for depressive symptoms is nearly 20% and clinical depression has a rate of approximately 10%. Besides, about one-third of depressive patients are chronically ill. Specific risk groups for depression by various sociodemographic characteristics include women, widowed persons aged 40 years and over, close relatives of depressive persons, and members of lower socio-economic classes. An increase in the prevalence rates of depression in Turkey is expected due to changes in public attitudes, which do not consider depression a medical disorder at present; increase in life expectancy; rapid changes in socio-economic, cultural environments; and in family structures and lifestyles.


[Local infectious complications in cardiac surgery: etiology and the role of antimicrobial prophylaxis].
To investigate the relationship between antimicrobial prophylaxis protocol, prevalence and etiology of local infectious complications after open cardiac surgery. A retrospective cohort observational study was performed between 2010 and 2019 at the Ural Institute of Cardiology. Antimicrobial prophylaxis was performed using the main (cefuroxime 1.5 g IV every 6 hours) and alternative protocols (vancomycin 15 mg/kg IV every 12 hours). The prevalence of local infectious complications throughout the entire follow-up period was 4.5±0.3% [95% CI 4.45-4.54]. There were 42 cases of deep infection (0.9±0.13%). Coagulase-negative staphylococci prevailed (15.9±2.5% of cases, 35 cultures). Resistant flora included coagulase-negative methicillin-resistant staphylococci (13 cultures, 37.1±8.2%) and representatives of Enterobacteriaceae family, producers of extended-spectrum beta-lactamase (8 cultures, 50.0±18.2%). Antimicrobial prophylaxis with vancomycin increases the risk of local infectious complications (OR 1.75, 95% CI 1.20, 2.55, p=0.001). Both protocols of antimicrobial prophylaxis demonstrated comparable efficacy against gram-positive and gram-negative microorganisms. Coagulase-negative staphylococci are the most common cause of local infectious complications in cardiac surgery. Modern antimicrobial prophylaxis regimens are relevant despite resistant flora.


Effects of chronic exposure to ozone on collagen in rat lung.
Pulmonary fibrosis is a consequence of severe injury from some toxic agents including high doses of ozone. It is not known, however, whether chronic exposure to low doses of ozone, such as those encountered in polluted ambient atmospheres, could also result in abnormal accumulations of lung collagen. Rats were exposed to ozone for 20 hr per day, 7 days per week for 3, 6, 12, and 18 months at concentrations of 0.12, 0.25, or 0.50 ppm. Controls were exposed under identical conditions to purified air. Upon removal from the chambers, rats were euthanized and lung tissue slices incubated with [14C]proline. The incorporation of 14C into hydroxyproline and the total hydroxyproline content of lung tissue were measured as estimates of lung collagen synthesis and content, respectively. The formation of labeled hydroxyproline tended to decrease significantly with time in controls and at the three ozone doses. There were, however, no significant dose-related changes at any of the time points tested. Total lung hydroxyproline increased with age in all groups, but no dose-related changes were detected at any time point. It was concluded that chronic exposure of rats to ozone at concentrations which approximate ambient urban concentrations did not affect normal age-related changes in either synthesis or accumulation of lung collagen.


How do repeat suicide attempters differ from first timers? An exploratory record based analysis.
Evidence indicates that repeat suicide attempters, as a group, may differ from 1(st) time attempters. The identification of repeat attempters is a powerful but underutilized clinical variable. In this research, we aimed to compare individuals with lifetime histories of multiple attempts with 1(st) time attempters to identify factors predictive of repeat attempts. This was a retrospective record based study carried out at a teaching cum Tertiary Care Hospital in South India. Relevant data was extracted from the clinical records of 1(st) time attempters (n = 362) and repeat attempters (n = 61) presenting to a single Tertiary Care Center over a 4½ year period. They were compared on various sociodemographic and clinical parameters. The clinical measures included Presumptive Stressful Life Events Scale, Beck Hopelessness Scale, Coping Strategies Inventory - Short Form, and the Global Assessment of Functioning Scale. First time attempters and repeaters were compared using appropriate inferential statistics. Logistic regression was used to identify independent predictors of repeat attempts. The two groups did not significantly differ on sociodemographic characteristics. Repeat attempters were more likely to have given prior hints about their act (χ(2) = 4.500, P = 0.034). In the final regression model, beck hopelessness score emerged as a significant predictor of repeat suicide attempts (odds ratio = 1.064, P = 0.020). Among suicide attempters presenting to the hospital, the presence of hopelessness is a predictor of repeat suicide attempts, independent of clinical depression. This highlights the importance of considering hopelessness in the assessment of suicidality with a view to minimize the risk of future attempts.


Multidisciplinary approach to the management of complex bony and soft tissue orbitocranial disorders.
Orbital reconstructive surgery is entering a new age as progress in surgical techniques and diagnostic imaging are applied to the patient with severe acquired orbital and periorbital deformities. The authors present a series of six patients with orbitocranial neoplasms and congenital and traumatic deformities whose management involved a multidisciplinary approach. Particular emphasis is placed on the use of reformatting two-dimensional orbital scans into three-dimensional images and surgical techniques using composite flaps and periorbital microsurgical vascular anastomoses. Advancements in technology and sophisticated reconstructive surgical techniques have exciting potential. Ophthalmologists can play an important role in this expanding field since they frequently serve as the entry point or provide long-term follow-up to patients with these complex problems.


Correction to: Feasibility study: one year fortnightly follow-up of the evolution of supra-spinatus degeneration via text-messages.
An amendment to this paper has been published and can be accessed via the original article.


Engineering a thermostable β-1,3-1,4-glucanase from Paecilomyces thermophila to improve catalytic efficiency at acidic pH.
To fulfill the need for acid-tolerant and thermostable β-1,3-1,4-glucanases, an error-prone PCR and DNA-shuffling approach was employed to enhance the activity of thermostable β-1,3-1,4-glucanases from Paecilomyces thermophila (PtLic16A) at acidic pH. Mutant PtLic16AM2 was selected and characterized, and showed optimal activity at pH 5.0, corresponding to an acidic shift of 2.0 pH units relative to the wild-type enzyme. Other properties of PtLic16A such as temperature optimum and substrate specificity that are beneficial for industrial applications did not change. Based on the substituted residues of PtLic16AM2, three site-directed mutations, D56G, D221G and C263S, were designed to study these residues' roles. The amino acid residues at positions 56 and 263 were found to be important in determining optimal pH activity. Activity of the D221G variant showed no significant difference from the wild-type. Thus, it appears that the change in optimal pH for PtLic16AM2 was mainly caused by the combination of substitutions D56G and C263S. This study provides a β-1,3-1,4-glucanase (PtLic16AM2) with high potential for industrial applications.


Structural Insights into SHARPIN-Mediated Activation of HOIP for the Linear Ubiquitin Chain Assembly.
The linear ubiquitin chain assembly complex (LUBAC) is the sole identified E3 ligase complex that catalyzes the formation of linear ubiquitin chain, and it is composed of HOIP, HOIL-1L, and SHARPIN. The E3 activity of HOIP can be effectively activated by HOIL-1L or SHARPIN, deficiency of which leads to severe immune system disorders. However, the underlying mechanism governing the HOIP-SHARPIN interaction and the SHARPIN-mediated activation of HOIP remains elusive. Here, we biochemically and structurally demonstrate that the UBL domain of SHARPIN specifically binds to the UBA domain of HOIP and thereby associates with and activates HOIP. We further uncover that SHARPIN and HOIL-1L can separately or synergistically bind to distinct sites of HOIP UBA with induced allosteric effects and thereby facilitate the E2 loading of HOIP for its activation. Thus, our findings provide mechanistic insights into the assembly and activation of LUBAC.


The Vitamin D requirement in health and disease.
Advances in Vitamin D nutritional physiology since publication of the DRIs in 1997 are briefly summarized. Available data indicate that (1) Vitamin D's canonical function, optimizing intestinal calcium absorption, is fully expressed at serum 25-hydroxyvitamin D (25OHD) concentration of approximately 80nmol/L; (2) elevated parathyroid activity, typical of aging populations, is minimized at the same 25OHD value and (3) osteoporotic fractures are reduced when serum 25OHD is raised to near 80nmol/L. Depending upon starting value, achieving 25OHD concentrations of 80 or higher may require a daily oral intake of 2200IU (55microg) or more in addition to prevailing cutaneous inputs. The tolerable upper intake level (TUIL), currently set at 2000IU (50microg)/day, is too low to permit optimization of Vitamin D status in the general population. Actual toxicity is not seen below serum 25OHD values of 250nmol/L, a value that would be produced only at continuing oral intakes in excess of 10,000IU (250microg)/day.


Effect of morphine and naloxone on shock avoidance learning in headless cockroaches (Periplaneta americana L.).
Systemic administration of high doses of morphine (56 micrograms morphine/g body weight) or of naloxone (54 micrograms naloxone/g body weight) results in a significant improvement of shock avoidance behavior in headless cockroaches. In both cases the learning parameter stimulation time (time during which an animal receives shocks) is significantly decreased. The behavioral parameters, stimulation rate (activity) and mean stimulation duration (shock responsiveness), as the two factors of the stimulation time considered individually, do not significantly change with morphine. Only the responses of both parameters together give the significant decrease of stimulation time (improvement of shock avoidance behavior) as mentioned above. However, the administration of naloxone causes a significant shortening of the mean stimulation duration indicating that these animals avoid the shocks by learning to lift their legs more quickly out of electrified saline in order to terminate the shocks (escape learning). Combined administration of both drugs together also causes a significant improvement of the leg-lifting response even at lower doses (morphine: 0.56 microgram plus naloxone: 0.54 microgram/g; morphine: 0.0056 microgram/g plus naloxone: 0.0054 microgram/g). Although the various effective doses of these drugs administered in combination have similar effects on the stimulation time, they affect the behavioral parameters in different ways. These different actions on activity and shock responsiveness as well as the efficacy of doses smaller than those known from vertebrates are discussed as behavioral evidence of opiate receptors in the cockroach.


[Diagnosis, clinical picture and therapy of acute radiation disease in victims of the accident at the Chernobyl nuclear power station. I. Conditions of irradiation, dose levels, bone marrow syndrome and its therapy].
A follow-up of 115 patients with acute radiation disease resulting from external gamma-beta-radiation confirmed a high value of the previously proposed principles of predicting a degree of severity on the basis of the clinical manifestations of a primary reaction of disease and some syndromes using methods of hematological and cytogenetic analysis. Early isolation of patients with ARD of II-IV degree, selective intestinal decontamination, administration of antibiotics of a broad spectrum of action, antimycotic and antiviral drugs, and gamma-globulin can practically eliminate the risk of development of fatal infectious complications in medullary and transient types of radiation disease. The efficient use of thrombomass transfusion completely prevents development of the thrombocytopenic hemorrhagic syndrome. Experience in bone marrow transplantation requires a review of therapeutic indications.


Collagen Turnover in Wound Repair--A Macrophage Connection.
In this issue, Rohani et al. (2015) report on the role of macrophage-derived stromelysin-2 (matrix metalloproteinase (MMP)-10) in promoting the turnover of extracellular matrix (ECM) during cutaneous wound repair. They provide evidence that MMP-10 specifically enhances collagenolytic activity of murine MMP-13 produced by M2-like macrophages. These results emphasize the important role of macrophage-derived MMP-10 in regulating tissue remodeling and scar formation during wound healing.


Development and Validation of a Syndrome Definition for Suspected Nonfatal Unintentional/Undetermined Intent Stimulant-Involved Overdoses.
To monitor stimulant-involved overdose (SOD) trends, the Centers for Disease Control and Prevention (CDC) developed and evaluated the validity of a syndromic surveillance definition for suspected nonfatal, unintentional/undetermined intent stimulant-involved overdose (UUSOD). We analyzed all emergency department (ED) visits in CDC's surveillance system that met the UUSOD syndrome definition (January 2018-December 2019). We classified visits as true positive, possible, or not UUSODs after reviewing diagnosis codes and chief complaints. We first assessed whether visits were acute SODs, subsequently classifying acute SODs by intent. The percentage of true-positive UUSODs did not include intentional or possibly intentional visits. We considered all visits with UUSOD diagnosis codes to be acute SODs and reviewed them for intent. We manually reviewed and double-coded a 10% random sample of visits without UUSOD diagnosis codes using decision rules based on signs and symptoms. The overall percentage of true-positive UUSODs was a weighted average of the percentage of true-positive UUSODs based on diagnosis codes and the percentage of true-positive UUSODs determined by manually reviewing visits without codes. During 2018-2019, 40 045 ED visits met the syndrome definition for UUSOD. Approximately half (n = 18 793; 46.9%) of 40 045 visits had UUSOD diagnosis codes, indicating acute SOD; of these, 98.6% (n = 18 534) were true-positive UUSODs. Of 2125 manually reviewed visits without UUSOD diagnosis codes, 32.6% (n = 693) were true-positive UUSODs, 54.2% (n = 1151) were possible UUSODs, and 13.2% (n = 281) were not UUSODs. Overall, 63.6% of visits were true-positive UUSODs, 29.3% were possible UUSODs, and 7.1% were not UUSODs. CDC's UUSOD definition may assist in surveillance efforts with further refinement to capture data on SOD clusters and trends.


Prophylactic antibiotic use during labor and delivery in China: a nationwide, multicenter, hospital-based, cross-sectional study.
Prophylactic antibiotic use during delivery is common in routine obstetric practice to prevent infection globally, especially in low- and middle-income countries. In China, however, little is currently known about the national estimates for prophylactic antibiotic use during delivery. Therefore, we aimed to describe the prevalence of prophylactic antibiotic use and guideline adherence using national data in China. This cross-sectional study analyzed a national dataset from the China Labor and Delivery Survey in 2015-2016. The primary outcomes were prophylactic antibiotic use and clinician adherence to WHO recommendations for the prevention and treatment of maternal peripartum infections. We estimated the weighted prevalence of the outcomes with Taylor series linearization and investigated the associated factors of the outcomes with logistic regression. Of the 72,519 deliveries, the prevalence of antibiotic prophylaxis was 52.0%, varying from 92.8% in Shanxi to 17.3% in Hainan. The prevalence of clinician adherence to the WHO guideline was 79.9%, ranging from 93.4% in Shandong to 50.0% in Shanxi. Prophylactic antibiotic use was associated with cesarean delivery (AOR, 55.77; 95%CI, 25.74-120.86), operative vaginal delivery (AOR, 4.00; 95%CI, 1.64-9.78), preterm (AOR, 1.96; 95%CI, 1.60-2.41), premature rupture of membranes (PROM) (AOR, 2.80; 95%CI, 1.87-4.18), and meconium-stained amniotic fluid (AOR, 1.91; 95%CI, 1.30-2.81) in all deliveries and also episiotomy (AOR, 1.48; 95%CI, 1.02-2.16) in vaginal deliveries. Clinician adherence was positively associated with cesarean delivery (AOR, 5.72; 95%CI, 2.74-11.93) while negatively associated with operative vaginal delivery (AOR, 0.26; 95%CI, 0.11-0.61), PROM (AOR, 0.50; 95%CI, 0.35-0.70), and meconium-stained amniotic fluid (AOR, 0.66; 95%CI, 0.48-0.91) in all deliveries. In vaginal deliveries, clinician adherence was negatively associated with episiotomy (AOR, 0.67; 95%CI, 0.46-0.96) and severe perineal trauma (AOR, 0.09; 95%CI, 0.02-0.44). Besides, clinicians in general hospitals prescribed prophylactic antibiotics more likely (AOR, 2.79; 95%CI, 1.50-5.19) and had a lower adherence (AOR, 0.38; 95%CI, 0.20-0.71) than their peers in maternity hospitals. We observed that about half of all deliveries in China received antibiotics for prophylaxis, and most deliveries were prescribed according to the WHO guideline. Furthermore, the two prevalence rates for prophylactic antibiotic use and clinician adherence varied widely across provinces of China.


Comparison of peginterferon pharmacokinetic and pharmacodynamic profiles.
The pharmacokinetics and in dosing regimens of the currently available pegylated interferon (peginterferon) alfa molecules differ greatly, depending on the size and nature of their polyethylene glycol (PEG) moiety. Peginterferon alfa-2a has a branched 40 kDa PEG chain covalently attached to lysine residues and circulates as an intact molecule. On the other hand, peginterferon alfa-2b has a linear 12 kDa PEG chain covalently attached to interferon-a-2b via an unstable urethane bond that is hydrolysed after injection, releasing native interferon alfa-2b. The difference in pegylation between the two peginterferons has a significant impact on their pharmacokinetic properties. Data from comparative and non-comparative studies indicate that peginterferon alfa-2b has a shorter half-life in serum than peginterferon alfa-2a, and a significant proportion of patients receiving peginterferon alfa-2b may have trough concentrations below the limit of detection during the latter part of the 7-day dosing schedule. However, the pharmacodynamic parameters of the two drugs appear to be similar.


The PARsylation activity of tankyrase in adipose tissue modulates systemic glucose metabolism in mice.
Tankyrase (TNKS) is a ubiquitously expressed molecular scaffold that is implicated in diverse processes. The catalytic activity of TNKS modifies substrate proteins through poly-ADP-ribosylation (PARsylation) and is responsive to cellular energetic state. Global deficiency of the TNKS protein in mice accelerates glucose utilisation and raises plasma adiponectin levels. The aim of this study was to investigate whether the PARsylation activity of TNKS in adipocytes plays a role in systemic glucose homeostasis. To inhibit TNKS-mediated PARsylation, we fed mice with a diet containing the TNKS-specific inhibitor G007-LK. To genetically inactivate TNKS catalysis in adipocytes while preserving its function as a molecular scaffold, we used an adipocyte-selective Cre transgene to delete TNKS exons that encoded the catalytic domain at the C-terminus. Tissue-specific insulin sensitivity in mice was investigated using hyperinsulinaemic-euglycaemic clamps. To model adipose-liver crosstalk ex vivo, we applied adipocyte-conditioned media to hepatocytes and assessed the effect on gluconeogenesis. The TNKS inhibitor G007-LK improved glucose tolerance and insulin sensitivity and promptly increased plasma adiponectin levels. In female mice, but not in male mice, adipocyte-selective genetic inactivation of TNKS catalysis improved hepatic insulin sensitivity and post-transcriptionally increased plasma adiponectin levels. Both pharmacological and genetic TNKS inhibition in female mouse-derived adipocytes induced a change in secreted factors to decrease gluconeogenesis in primary hepatocytes. Systemic glucose homeostasis is regulated by the PARsylation activity of TNKS in adipocytes. This regulation is mediated in part by adipocyte-secreted factors that modulate hepatic glucose production. Pharmacological TNKS inhibition could potentially be used to improve glucose tolerance.


Directing integrin-linked endocytosis of recombinant AAV enhances productive FAK-dependent transduction.
Recombinant adeno-associated virus (rAAV) is a widely used gene therapy vector. Although a wide range of rAAV serotypes can effectively enter most cell types, their transduction efficiencies (i.e., transgene expression) can vary widely depending on the target cell type. Integrins play important roles as coreceptors for rAAV infection, however, it remains unclear how integrin-dependent and -independent mechanisms of rAAV endocytosis influence the efficiency of intracellular virus processing and ultimately transgene expression. In this study, we examined the contribution of integrin-mediated endocytosis to transduction of fibroblasts by rAAV2. Mn(++)-induced integrin activation significantly enhanced (~17-fold) the efficiency of rAAV2 transduction, without altering viral binding or endocytosis. rAAV2 subcellular localization studies demonstrated that Mn(++) promotes increased clustering of rAAV2 on integrins and recruitment of intracellular vinculin (an integrin effector) to sites of rAAV2 binding at the cell surface. Focal adhesion kinase (FAK), a downstream effector of integrin signals, was essential for rAAV2/integrin complex internalization and transduction. These findings support a model whereby integrin activation at the cell surface can redirect rAAV2 toward a FAK-dependent entry pathway that is more productive for cellular transduction. This pathway appears to be conserved for other rAAV serotypes that contain a capsid integrin-binding domain (AAV1 and AAV6).


Writing a letter to patients.
This paper considers the potential utility in clinical practice of writing a letter to patients. Letters written by psychiatrists to patients may be helpful in some clinical situations.


Utility of serial rectal swab cultures for detection of ceftazidime- and imipenem-resistant gram-negative bacilli from patients in the intensive care unit.
Forty-four patients receiving intensive care were studied prospectively to assess the utility of serial rectal swab cultures and clinical correlates of resistance for Pseudomonas aeruginosa, Enterobacter spp., Citrobacter spp., Morganella morganii, and Serratia marcescens strains resistant to ceftazidime or imipenem. Strains of Pseudomonas aeruginosa, Enterobacter spp., Citrobacter spp., or Morganella morganii were found in 26 of 44 (59%) patients: 17 (65%) in clinical sites (11 with concomitant rectal isolates) and nine (35%) in a rectal site only. Of 49 total isolates, 13 (26.5%) were resistant: 10 (20.4%) to ceftazidime and three (6.1%) to imipenem. Surveillance rectal swabs from 27 patients without a clinical isolate identified two patients with resistant organisms (15% of all resistant isolates). The majority of resistance to ceftazidime or imipenem among Pseudomonas or Enterobacter can be detected by the use of clinical specimens alone.


Comparison of botulinum toxin injection and neurotomy in patients with distal lower limb spasticity.
We compared the efficacy of botulinum toxin injection (BTI) and tibial nerve neurotomy (TNN) in an open-label study of 34 post-stroke hemiplegic patients with distal lower limb deformation. The dose of BT was 300 U (Botox). TNN was performed with a 6-12 month delay on the motor branches of the tibial nerve. Muscles to be treated were selected according to the distal deformity (equinus, varus and clawing toes). Patients were assessed following each treatment for spasticity, motor control, range of movements, balance, gait and the Rivermead Motor Assessment. TNN (M3, M6 and Y1) resulted in a more significant effect than BTI (D15, M2 and M5) on most of the measures: ankle plantar flexor spasticity, range of movement in dorsiflexion and eversion, foot position in upright situation, Functional Ambulation Categories (barefoot), RMA, gait velocity (comfortable condition), subjective benefit and use of walking aids. Patients treated for tibialis posterior or flexor digitorum longus spasticity often complained of subjective sensory disorders at the plantar sole over a period of 4-6 weeks. In conclusion, TNN is more effective than BTI on most of the functional parameters. The interest of BTI lies in the preliminary testing of the efficacy of a technique for reducing spasticity on lower limb function.


The evolutionary pattern of aromatic amino acid biosynthesis and the emerging phylogeny of pseudomonad bacteria.
Pseudomonad bacteria are a phylogenetically diverse assemblage of species named within contemporary genera that include Pseudomonas, Xanthomonas and Alcaligenes. Thus far, five distinct rRNA homology groups (Groups I through V) have been established by oligonucleotide cataloging and by rRNA/DNA hybridization. A pattern of enzymic features of aromatic amino acid biosynthesis (enzymological patterning) is conserved at the level of rRNA homology, five distinct and unambiguous patterns therefore existing in correspondence with the rRNA homology groups. We sorted 87 pseudomonad strains into Groups (and Subgroups) by aromatic pathway patterning. The reliability of this methodology was tested in a blind study using coded cultures of diverse pseudomonad organisms provided by American type Culture Collection. Fourteen of 14 correct assignments were made at the Group level (the level of rRNA homology), and 12 of 14 correct assignments were made at the finer-tuned Subgroup levels. Many strains of unknown rRNA-homology affiliation had been placed into tentative rRNA groupings based upon enzymological patterning. Positive confirmation of such strains as members of the predicted rRNA homology groups was demonstrated by DNA/rRNA hybridization in nearly every case. It seems clear that the combination of these molecular approaches will make it feasible to deduce the evolution of biochemical-pathway construction and regulation in parallel with the emerging phylogenies of microbes housing these pathways.


Effect of deuterium oxide on gastrin release from rat antral mucosal fragments.
The effects of the microtubule stabilizing agent, deuterium oxide, on in vitro rat antral gastrin release were examined under basal conditions and during stimulation with isobutyl methylxanthine and bombesin plus isobutyl methylxanthine. Basal gastrin release from antral mucosal fragments was unaffected by increasing media concentration of deuterium oxide (12.5 to 75% v/v) during 1 h incubations. Gastrin release stimulated by isobutyl methylxanthine (0.1 mM), a potent inhibitor of phosphodiesterase activity, was inhibited completely by 12.5% deuterium oxide. Bombesin (1 X 10(-8) M) in the presence of IBMX (0.1 mM) stimulated gastrin release (29.7 +/- 1.9% of total gastrin). This was significantly greater than gastrin released under control conditions and with IBMX alone: 12.0 +/- 1.1 (P less than 0.001) and 20.2 +/- 2.6% of total gastrin (P less than 0.02), respectively. Partial inhibition of bombesin-IBMX stimulated gastrin release was achieved with 12.5% and 25% deuterium oxide and stimulation of gastrin release was inhibited completely by 50% deuterium oxide. In contrast to these results, gastrin release stimulated by the calcium ionophore A23187 was not inhibited by 50% deuterium oxide. Additional studies were performed to assess reversibility of the effects of deuterium oxide on stimulated gastrin release. Antral tissue exposed to initial culture medium containing deuterium oxide (50%) and bombesin-IBMX for 60 min was exchanged for medium without deuterium oxide. Restimulation of antral tissue during the second hour of culture resulted in gastrin release that was comparable to that observed in cultures not exposed to deuterium oxide during the first hour of culture. Reversibility of the effects of deuterium oxide suggest that a functional alteration in microtubular function is restored by removal of heavy water from the culture medium. Results of these experiments indicate that deuterium oxide is capable of inhibiting gastrin release stimulated by the peptide hormone bombesin and by the phosphodiesterase inhibitor isobutyl methylxanthine. Furthermore, these results suggest that increased levels of intracellular calcium achieved by the action of ionophore A23187 prevent microtubular stabilization by deuterium oxide.


[Criminal psychology in Franco's police].
Francisco J. de Echalecu (1897-1957) was a Spanish psychiatrist who held important positions, such as Psychology Professor at the Academia General de Policía and Neuropsychiatrist at the Dirección General de Seguridad. This work provides a brief biography of Echalecu and analyzes the transcriptions of his classes on Criminal Psychology of 1942, his Criminal Psychology from 1947 as well as his involvement in the case of the torture of Communist leader Heriberto Quiñones. We describe his project of a totalitarian Psychology and his proposal of social intervention, including eugenic methodologies as well as forced reclusion for those labeled as asocial. The adaptation in Spain of the totalitarian psychological project to the new international reality after the Second World War is also described. In Spain a "final solution" for criminals and political dissidents has been prepared, which was inspired by the Nazi criminal policies and promoted by Dr. Echalecu from Spain's higher police body, the DGS. This project was frustrated by the German defeat in the world war and the only thing left from the original project was the arbitrary application of the Ley de Vagos y Maleantes [an antivagrancy law] to those individuals labeled as "asocial".


[Results of the ciliary body exposure (CBE) in secondary angle closure glaucomas. 1. A clinical study (author's transl)].
The authors present their clinical results of the ciliary body exposure following Benedikt and Hiti. This technique has been performed in 23 patients suffering from secondary angle closure glaucoma. As far as the intraocular tension is concerned good results have been obtained in nearly half of the patients. The results are compared with those of other surgical techniques against secondary angle closure glaucomas.


Sweet preference predicts mood altering effect of and impaired control over eating sweet foods.
The purpose of the present study was to examine association between hedonic response to sweet taste and a mood altering effect associated with eating sweet foods and impaired control over eating sweets. Participants (n=163, 39% males) rated a series of sucrose solutions for intensity of sweetness and palatability and completed a newly developed 12-item Sweet Taste Questionnaire (STQ). It was shown that STQ identifies two factors in the individual's attitude towards sweet foods: sensitivity to the mood altering effect of sweets and impaired control over eating sweet foods. Individuals preferring the taste of the strongest offered sucrose concentration reported a stronger mood altering effect associated with eating of sweet foods and were more likely to have an impaired control over eating sweets than the rest of the group. Women generally had higher scores on both factors compared to men. The results of the present study support the hypothesis that hedonic response to sweet taste is associated with elevated sensitivity to mood altering effects of sweet foods and impaired control over eating sweets.


Self-identity barcodes encoded by six expansive polymorphic toxin families discriminate kin in myxobacteria.
Myxobacteria are an example of how single-cell individuals can transition into multicellular life by an aggregation strategy. For these and all organisms that consist of social groups of cells, discrimination against, and exclusion of, nonself is critical. In myxobacteria, TraA is a polymorphic cell surface receptor that identifies kin by homotypic binding, and in so doing exchanges outer membrane (OM) proteins and lipids between cells with compatible receptors. However, TraA variability alone is not sufficient to discriminate against all cells, as traA allele diversity is not necessarily high among local strains. To increase discrimination ability, myxobacteria include polymorphic OM lipoprotein toxins called SitA in their delivered cargo, which poison recipient cells that lack the cognate, allele-specific SitI immunity protein. We previously characterized 3 SitAI toxin/immunity pairs that belong to 2 families. Here, we discover 4 additional SitA families. Each family is unique in sequence, but share the characteristic features of SitA: OM-associated toxins delivered by TraA. We demonstrate that, within a SitA family, C-terminal nuclease domains are polymorphic and often modular. Remarkably, sitA loci are strikingly numerous and diverse, with most genomes possessing >30 and up to 83 distinct sitAI loci. Interestingly, all SitA protein families are serially transferred between cells, allowing a SitA inhibitor cell to poison multiple targets, including cells that never made direct contact. The expansive suites of sitAI loci thus serve as identify barcodes to exquisitely discriminate against nonself to ensure populations are genetically homogenous to conduct cooperative behaviors.


[Present possibilities of prevention of infectious complications associated with central venous catheter systems].
Central venous access devices are a major source of nosocomial infection. The skin and catheter hub are the two major sources for the introduction of the colonizing organisms. Authors reviewed up-to-date prophylactic possibilities in this paper. Prophylactic measures include a skilled team, topical disinfectants, topical antibiotics, new types of devices such as coating catheter with antiseptic agent and catheter with silver impregnated cuffs, maximal barrier precautions during insertion, systemic vancomycin therapy of high risk patients. Exchanging central venous catheters over a guidewire might be useful diagnostically but have not been used to be of any therapeutic or prophylactic goal. Prophylactic antibiotic lock of device and use of fibrinolytic agent to clean the device may be useful but can not be a standard recommendation.


Lin28a regulates neuronal differentiation and controls miR-9 production.
microRNAs shape the identity and function of cells by regulating gene expression. It is known that brain-specific miR-9 is controlled transcriptionally; however, it is unknown whether post-transcriptional processes contribute to establishing its levels. Here we show that miR-9 is regulated transcriptionally and post-transcriptionally during neuronal differentiation of the embryonic carcinoma cell line P19. We demonstrate that miR-9 is more efficiently processed in differentiated than in undifferentiated cells. We reveal that Lin28a affects miR-9 by inducing the degradation of its precursor through a uridylation-independent mechanism. Furthermore, we show that constitutively expressed untagged but not GFP-tagged Lin28a decreases differentiation capacity of P19 cells, which coincides with reduced miR-9 levels. Finally, using an inducible system we demonstrate that Lin28a can also reduce miR-9 levels in differentiated P19 cells. Together, our results shed light on the role of Lin28a in neuronal differentiation and increase our understanding of the mechanisms regulating the level of brain-specific microRNAs.


Development of a scale to evaluate medical professional identity formation.
Medical educators now focus on professional identity formation (PIF), which is a process of psychological development and socialization in the community of practice. This study aimed to develop an instrument to evaluate PIF that can be applied to a large group of medical trainees. A self-administered questionnaire was created with items on priorities, behavior standards, attitudes, and emotional control of well-developed physicians, in addition to items on their background and experience in playing the role of a physician. The participants were divided into four respondent groups: 4th- and 6th-year medical students and 2nd-year residents at Kagoshima University, and experienced medical doctors (instructors). Using factor analysis of data from 318 respondents and respondent group comparison, a developing scale (DS) with 15 items was created. The DS has a five-factor structure and evaluates self-control as a professional (factor 1), awareness of being a medical doctor (factor 2), reflection as a medical doctor (factor 3), execution of social responsibility (factor 4), and external and internal self-harmonization (factor 5). The mean DS score of the instructors was significantly higher than that of the residents (p < 0.01), the mean score of residents and instructors was significantly higher than that of students (p < 0.01), and the mean score of instructors was significantly higher than that of all other respondents (p < 0.01). Respondent group, but not gender, was a significant variable of the DS. The DS and scores of factors 2 and 4 correlated with 6th-year medical students' experience in playing the role of a physician during clinical training, and scores of factors 3 and 4 correlated with 2nd-year residents' experience in playing the role of a physician. There was no significant difference between the mean DS score of 4th- and 6th-year medical students, which might due to less clinical experience among 6th-year medical students or a limitation of the scale to evaluate pre-clinical medical students. The DS could be a useful indicator of medical trainees' personal and professional development and socialization. Experience in playing the role of a physician might facilitate medical trainees' PIF.


A near-infrared fluorescent probe for the ratiometric detection and living cell imaging of β-galactosidase.
β-Galactosidase (β-gal) has captured the attention of biologists, chemists, and medical researchers as an important biomarker for cell senescence and primary ovarian cancer. Therefore, many fluorescent probes with visible light emission have been developed for the detection and imaging of β-gal in living cells. However, near-infrared (NIR) ratiometric probes are more suitable for bioimaging because near-infrared light can effectively avoid the interference of autofluorescence and the ratiometric approach can improve sensitivity and accuracy of the detection. In this work, we designed an NIR ratiometric probe (TMG) for the highly sensitive detection of β-gal. Using a spontaneous degradation mechanism based on the ICT effect, the change in ratio (F650/F580) exhibited a prominent β-gal-dependent performance and proved a strong linear response to the activity of β-gal at an enzyme concentration between 0 and 200 U L-1, with a limit of detection as low as 0.86 U L-1, and the response speed is much faster than the same type of probes previously reported. The probe also revealed an excellent biocompatibility and a large Stokes shift. Moreover, fluorescence microscopy imaging experiments confirmed that this probe could be successfully used for the detection of endogenous β-gal in living cells. Graphical abstract.


Genetic architecture of thoracic aortic dissection in the female population.
Sex-related differences in cardiovascular disease are now gaining much more attention and their importance is increasingly being recognized, but little is known about the genetic distribution, genotype-phenotype correlation, and outcomes in the female population with thoracic aortic dissection (TAD). One hundred seventy-nine Chinese female probands with TAD were enrolled from Tongji Hospital between October 2009 and October 2020. Genetic analysis was performed among 12 genes, and participants were subsequently followed up for a median of 38.2 months for TAD-related death. We identified 18 pathogenic or likely pathogenic variants among 18 (10.1%) probands and 21 variants of uncertain significance in 21 (11.7%) patients. Individuals with positive variants presented with a significant risk of TAD (OR: 12.0, 95% CI: 5.87-26.8), and an association between FBN1 (p = 2.60E-11, OR = 19.8), MYLK (p = 0.006, OR = 14.0) variants and an increased risk for female TAD was identified as well. Furthermore, nearly half of the variants were found in the FBN1 gene, which was significantly linked to early aortic dissection and tended to cause death at a young age. This study revealed the monogenic contribution of known TAD genes to the female TAD population with East Asian ancestry. Patients who tested positive for FBN1 were significantly younger at the time of aortic dissection and had a higher probability of dying at an early age.


Engineering cell de-adhesion dynamics on thermoresponsive poly(N-isopropylacrylamide).
Poly(N-isopropylacrylamide) (PIPAAm) has been demonstrated as an effective thermoresponsive polymer for non-invasive cell regeneration/recovery. However, little is known about the intricate relationship between the biophysical response of cells and physiochemical properties of PIPAAm during cell recovery. In this study, the de-adhesion kinetics of smooth muscle cell (SMC) on PIPAAm surfaces is probed with unique biophysical techniques. Water-immersion atomic force microscope (AFM) first showed that the nanotopology of PIPAAm surfaces is dependent on the polymerization time and collagen coating. It is found that the initial rate of cell de-adhesion increases with the increase in polymerization time. Moreover, the degree of cell deformation (a/R) and average adhesion energy are reduced with the increase of grafted PIPAAm density during 40min of cell de-adhesion. It has been shown that collagen coating regulates cell adhesion on biomaterial surface. Interestingly, lower collagen density on PIPAAm leads to higher adhesion energy per cell during the initial 20min compared with as-prepared PIPAAm, while the initial rate of cell de-adhesion remains unchanged. In contrast, higher collagen density leads to 50% reduction in the initial rate of cell de-adhesion and higher adhesion energy per cell during the entire 90min. Furthermore, immunostaining of actin provides supporting evidence that the de-adhesion kinetics is correlated with the cytoskeleton transformation during cell de-adhesion below the lower solution critical temperature (LCST).


A case of successful laparoscopic resection of adrenal gland endometriosis.
To present a case of successful laparoscopic resection of adrenal endometriosis. Case report. University Hospital. Forty-eight-year-old woman with left-sided abdominal and flank pain. Laparoscopic radical adrenalectomy. Diagnosis and surgical approach to adrenal endometriosis. There have been two case reports of adrenal endometriosis. Based on a search of Medline and Google for "adrenal endometriosis," this is the first known successful laparoscopic resection of adrenal endometriosis. We report the first case of successful laparoscopic adrenalectomy for the treatment of endometriosis.


DMDRMR promotes angiogenesis via antagonizing DAB2IP in clear cell renal cell carcinoma.
Clear cell renal cell carcinoma (ccRCC) patients are highly angiogenic and treated by targeted therapies against VEGFA/VEGFR signaling pathway. However, tumors with such targeted therapies remain a significant clinic challenge. Understanding the underlying mechanism against angiogenesis is highly desired. Here, we demonstrated that the lncRNA DMDRMR serves as a sponge of miR-378a-5p to increase EZH2 and SMURF1 expression, thus promoting EZH2-mediated transcriptional repression of DAB2IP and SMURF1-mediated degradation of DAB2IP. Consequently, this axis activates VEGFA/VEGFR2 signaling pathway, resulting in angiogenesis and resistance of tumor cells to sunitinib in ccRCC. Moreover, the competing endogenous RNA regulatory axis of DMDRMR is clinically relevant to ccRCC pathogenesis and prognosis of patients with ccRCC. Our results support that the DMDRMR/miR-378a-5p/DAB2IP axis may serve as a novel target for combination diagnosis or therapy of ccRCC patients. Our findings may have highly clinical relevance for future translation to develop the targeted therapies for patients with ccRCC.


Revisiting diagnostic criteria for myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis: Borderline cases without anemia exist.
Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare disease in the 2016 revised World Health Organization (WHO) classification. Diagnostic criteria include the following: persistent thrombocytosis (>450 × 109 /L) with clustering of atypical megakaryocytes, refractory anemia, dyserythropoiesis with ring sideroblasts, and the presence of the spliceosome factor 3b subunit (SF3B1) mutation. It is unclear if anemia should be a required criterion for this diagnosis as cases which show all other features of MDS/MPN-RS-T but without anemia exist. We searched for borderline cases of MDS/MPN-RS-T in which refractory anemia was absent at diagnosis in two major academic institutes. Three cases without anemia were identified. These cases all showed other classic morphologic and clinical features of MDS/MPN-RS-T, including thrombocytosis, atypical megakaryocytes with clustering, and characteristic SF3B1 and JAK2 V617F mutations. Given these findings, the requirement of refractory anemia as a diagnostic criterion for MDS/MPN-RS-T should be re-evaluated. Removal of refractory anemia as a diagnostic criterion would incorporate current borderline cases and extend the spectrum of this disorder.


Bioactive fractions of Eucalyptus camaldulensis inhibit important foodborne pathogens, reduce listeriolysin O-induced haemolysis, and ameliorate hydrogen peroxide-induced oxidative stress on human embryonic colon cells.
Extract of E. camaldulensis was partitioned into aqueous and ethanol fractions by a precipitation and sedimentation-based technique and profiled for phytochemical components. Antimicrobial evaluation yielded inhibitory concentrations of 16-64 and 158-316 µg/mL, and bactericidal concentrations of 32-64 and 316->2528 µg/mL for ethanol and aqueous fractions, respectively. Antioxidant activities evaluated using 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic) acid assays showed IC50 values of 7.07 and 65.67 µg/mL, and 17.96 and 201.3 µg/mL for aqueous and ethanol fractions. Total phenolic content of 9.04 ± 0.26 and 3.58 ± 0.04 GAE/mg fraction, and flavonoid content of 2.07 ± 0.02 and 3.37 ± 0.05 QE/mg fraction were recorded for aqueous and ethanol fractions. At subinhibitory concentrations fractions significantly reduced listeriolysin O-induced haemolysis (p < 0.05), and ameliorated H2O2-induced toxicity by 8-23 and 15-83%. Nitrite production reduced by 4-17 and 3-14 µM following fractions treatment. The fractions showed bioactive properties, with oxidative stress amelioratory effects, and could be a potentials source of preservatives and functional food additives.


A combined pig model to determine the net absorption of volatile fatty acids in the large intestine under different levels of crude fiber.
This study aimed to develop a combined model to quantify the net absorption of volatile fatty acids (VFA) in the large intestine (LI) of pigs. Fifteen female growing pigs (Duroc × Large White × Landrace) were ranked by body weight (30 ± 2.1 kg) on day 0 and assigned to one of three treatments, namely the basal diet containing different crude fiber (CF) levels (LCF: 3.0% CF, MCF: 4.5% CF, and HCF: 6.0% CF). The pigs were implanted with the terminal ileum fistula and the cannulation of the ileal mesenteric vein (IMV), portal vein (PV), and left femoral artery (LFA) from days 6 to 7. [13 C]-Labeled VFA and P-aminohippuric acid were constantly perfused into the terminal ileum fistula and the cannulation of the IMV (day 15), respectively. Blood samples were collected from the PV and the LFA during perfusion (5 h), and LI samples were collected. The net flux of [12 C]-acetic acid in the PV was greater for LCF versus MCF (p = 0.045), but no difference was observed in the net flux of [12 C]-propionic acid (p = 0.505) and [12 C]-butyric acid (p = 0.35) in the PV among treatments. The deposition of [12 C]-acetic acid in the LI was greater for LCF versus MCF (p = 0.014), whereas the deposition of [12 C]-propionic acid (p = 0.007) and [12 C]-butyric acid (p = 0.037) in the LI was greater for LCF versus HCF. In conclusion, this pig model was found conducive to study the net absorption of VFAs in the LI, and LCF had more net absorption of VFAs in the LI than MCF and HCF.


Association of subtle alterations in thyroid function with presarcopenia in patients with type 2 diabetes mellitus.
To investigate the association of subtle alterations in thyroid function with presarcopenia among patients with type 2 diabetes mellitus. A total of 1,865 adult patients with type 2 diabetes mellitus were enrolled in this cross-sectional study, excluding patients with overt thyroid dysfunction. Skeletal muscle mass measured by dual energy X-ray absorptiometry was used to assess presarcopenia. Logistic regression models were used to estimate the effects of thyroid hormones on presarcopenia, and subgroup analyses were carried out in different strata of age, sex and body mass index, respectively. Compared with the euthyroid group (Euthy), the subclinical hyperthyroidism group had an increased odds of presarcopenia (multivariate-adjusted odds ratio 1.99, 95% confidence interval 1.09-3.63), but the subclinical hypothyroidism group did not (P > 0.05). In the subclinical hyperthyroidism group, age and body mass index <24 kg/m2 were independent risk factors for presarcopenia. In the overall Euthy group, an increased odds of presarcopenia was correlated with the elevated free thyroxine : free triiodothyronine ratio (all P for trend <0.05), whereas not with increment in free triiodothyronine level (P for trend >0.05). Additionally, in Euthy subgroup analyses stratified by middle-age, sex and body mass index, a similar association was noted (all P for trend <0.05), but not in the older-aged patients (P for trend >0.05). Subclinical hyperthyroidism was an independent risk factor for presarcopenia in patients with type 2 diabetes mellitus, but subclinical hypothyroidism was not. In the Euthy group with type 2 diabetes mellitus, a high free thyroxine : free triiodothyronine ratio was a good index of presarcopenia in addition to older age.


Perception-related EEG is more sensitive to Alzheimer's disease effects than resting EEG.
To characterize the effects of Alzheimer's disease (AD) on cortical functional connectivity in perception, we analyzed interhemispheric lagged synchronization (ILS) in the source space of high-density EEG recorded in aged controls and patients with amnestic mild cognitive impairment (aMCI) or AD while they viewed collinear and noncollinear bilateral moving gratings. Beta-band ILS was lower in aMCI and AD compared with controls in a large region centered on BA39. As previously reported, in young adults, collinear iso-oriented gratings versus noncollinear gratings synchronizes EEG reflecting perceptual grouping. Only aged controls showed the expected beta-band ILS increase originating in the dorsal visual stream (BA18). The aMCI group only showed a theta-band increase in an adjacent region (BA19). In AD patients, there was no ILS increase. Regression analysis revealed that the posterior callosal area and EEG slowing predict reduction of beta but not emergence of theta ILS response. Considering that we found no between-group differences in resting ILS, perception-related EEG appears to be more sensitive to AD effects, including ILS signs of neurodegeneration and compensation.


Effects of dietary selenium of organic form against lead toxicity on the antioxidant system in Cyprinus carpio.
In this study was evaluated potential protective effect of organic selenium (Se) on heavy metal stress induced by lead (Pb) in Cyprinus carpio. For this reason, C. carpio was exposed to sublethal concentration of Pb (1.5 mg/L Pb(NO3)2) for 14 days. The fish were fed a basal (control; measured 0.55 mg/kg Se) diet or a basal diet supplemented with 2.50 mg/kg (measured 2.92 mg/kg Se) organic Se (Sel-Plex(®)) during the experiment period. The variations in glutathione peroxidase (GSH-Px), glutathione S-transferase (GST) activities, and levels of reduced glutathione (GSH) with malondialdehyde (MDA) in liver and brain tissues of C. carpio were investigated in experimental groups. GSH levels in liver and brain tissues were significantly decreased by exposure to Pb. GST activity was significantly increased (p < 0.05) in liver tissue, but decreased in brain of treated fish by exposure to Pb. Also, GSH-Px activity was significantly increased in liver tissue, but decreased in brain of Pb-treated fish. Levels of MDA were increased in liver and brain of Pb-treated fish. The organic Se treatment for Pb-intoxicated animals improved activities of GSH-Px, GST and levels of MDA within normal limits. Supplemented Se could be able to improve Pb-induced oxidative stress by decreasing lipid peroxidation and regulating antioxidant defense system in tissues.


Relationship between testosterone and male bladder cancer.
Researches had proven that the occurrence of bladder cancer (BC) is much higher in men than those in women, which induced us to explore whether androgen plays a role in BC. A total of 147 patients who were diagnosed with primary BC by histopathological biopsy were included. Meanwhile 154 non-tumor patients were matched as the control group. The continuous variables were expressed as median (interquartile range, IQR) and compared by Mann-Whitney U test, for the reason that the data were not matched the requirementsthe of normal test. A Chi-square test was used to compare the categorical variables, which were expressed as frequency (percentage). Meanwhile univariate and multivariate logistic regression was done to further evaluating the potential independent factor of BC. P < 0.05 was considered statistically significant. Univariate multivariate analyse showed significant difference between two groups in hemoglobin (OR 0.979, 95% CI 0.968-0.991, P < 0.001), hypertension (OR 3.026, 95% CI 1.731-5.288, P < 0.001), diabetes (OR 4.294, 95% CI 1.887-9.771, P = 0.001) and smoking (OR 1.729, 95% CI 1.096-2.729, P = 0.019). Furthermore, multivariate logistic regression analysis was conducted to eliminate the interference of confounding factors, which showed that testosterone seems to be great correlated with the BC (OR 1.002, 95% CI 1.000-1.003, P = 0.017). Similar results were also found in hemoglobin (OR 0.981, 95% CI 0.968-0.993, P = 0.002), hypertension (OR 2.780, 95% CI 1.509-5.120, P = 0.001), diabetes (OR 3.313 95% CI 1.373-7.991, P = 0.008) and smoking (OR 1.938, 95% CI 1.184-3.174, P = 0.009). As a conclusion, our study showed that there was significant correlation between serum total testosterone levels and the occurrence of BC, similar results were shown in hemoglobin, hypertension, diabetes and smoking.


Correction: Intrasession and Between-Visit Variability of Sector Peripapillary Angioflow Vessel Density Values Measured with the Angiovue Optical Coherence Tomograph in Different Retinal Layers in Ocular Hypertension and Glaucoma.
[This corrects the article DOI: 10.1371/journal.pone.0161631.].


Interaction of hydrated protons with octyl-phenyl-N,N-diisobutylcarbamoylmethyl phosphine oxide (CMPO): NMR and theoretical study.
Interaction of octyl-phenyl-N,N-diisobutylcarbamoylmethylphosphine oxide (CMPO, the 'classical' rare metal extraction agent) with fully ionized hydrated protons (HP) was studied in acetonitrile-d(3) using (1)H, (13)C, (31)P NMR, PFG NMR and magnetic relaxation. The experimental results were confronted with high-precision ab initio DFT calculations. Relative chemical shifts of NMR signals of CMPO (0.01 mol/L) under the presence of HP in the molar ratio β = 0-2.0 mol/mol show binding between CMPO and HP. Self-diffusion measurements using (1)H PFG NMR demonstrate that larger complexes with higher content of CMPO are generally formed at β < 0.75. Analyzing the collective dependence of (13)C and (31)P NMR chemical shifts on β by the use of program LETAGROP, we obtained very good fitting for the assumed coexistence of two complexes (CMPO)(2)·HP (C(2)) and CMPO.HP (C(1)). The logarithms of the respective stabilization constants log K(i) were found to be 7.518 (C(2)) and 4.581 (C(1)). The system dynamics was studied by measuring the transverse (1)H NMR relaxation using CPMG sequence with varying delays t(p) between the π pulses in the mixtures with β = 0.4-0.8. The following exchange correlation times were obtained: τ(10) = 2.35 × 10(-5), τ(20) = 0.82 × 10(-4), τ(21) = 0.45 × 10(-3) s. The DFT calculations support the conclusion that the complexes C(1) and C(2) are the main species in the mixtures of CMPO with HP. They also agree with the NMR and FTIR observation that the main site to which H(3) O(+) is bound is the P=O group, whereas the amide group does not form a strong bond with the ion when excess water molecules are present.


Unusual manifestation of a multiple myeloma in the hyoid bone.
The most common manifestation of plasma cell neoplasms is multiple myeloma. Solitary and localized tumours in the form of solitary plasmacytoma of the bone or extramedullary plasmacytoma are rare. In the late stages of multiple myeloma, bulky bone tumour infiltrates may be found which may be the primary clinical manifestation of the previously unknown malignancy. We report a case of a hyoid bone tumour with extramedullary plasma cell infiltrates in the oropharynx in multiple myeloma.


A step-by-step classification algorithm of protein secondary structures based on double-layer SVM model.
In this paper, a step-by-step classification algorithm based on double-layer SVM model is constructed to predict the secondary structure of proteins. The most important feature of this algorithm is to improve the prediction accuracy of α+β and α/β classes through transforming the prediction of two classes of proteins, α+β and α/β classes, with low accuracy in the past, into the prediction of all-α and all-β classes with high accuracy. A widely-used dataset, 25PDB dataset with sequence similarity lower than 40%, is used to evaluate this method. The results show that this method has good performance, and on the basis of ensuring the accuracy of other three structural classes of proteins, the accuracy of α+β class proteins is improved significantly.


Improved method for comparative evaluation of aldosterone antagonists in healthy man.
A method of assessing the qualitative and quantitative activity of competitive aldosterone antagonists in healthy man is described. It requires intravenous infusion of aldosterone (0.5 mg/6 h), iv and oral water loading for six hours and fractionated collection of urine over eight hours. Aldosterone antagonists were administered orally 1.5 h before the start of the infusion (spironolactone 50, 200 or 800 mg) or added to the infused solution (potassium cnarenoate 300, 600 or 1000-1200 mg). The effect was assessed by changes in urinary sodium and potassium excretion and in urinary Na+/K+ ratio. The plasma levels and urinary excretion of canrenone, canrenoate and canrenoate ester glucuronide, respectively, were determined after administration of spironolactone and potassium canrenoate. Between 4-8 h (spironolactone) or 2-8 h (potassium canrenoate) after commencement of the infusion there was linear dose-dependent reversal of the mineralocorticoid-induced sodium retention and/or decrease in the Na+/K+ ratio. The plasma levels and urinary excretion of the metabolites measured were also dose-dependent. The method appears suitable for comparison of the potency of aldosterone antagonists and for defining the time course of drug action within the observation period employed.


SOX3 is required during the formation of the hypothalamo-pituitary axis.
The pituitary develops from the interaction of the infundibulum, a region of the ventral diencephalon, and Rathke's pouch, a derivative of oral ectoderm. Postnatally, its secretory functions are controlled by hypothalamic neurons, which also derive from the ventral diencephalon. In humans, mutations affecting the X-linked transcription factor SOX3 are associated with hypopituitarism and mental retardation, but nothing is known of their etiology. We find that deletion of Sox3 in mice leads to defects of pituitary function and of specific central nervous system (CNS) midline structures. Cells in the ventral diencephalon, where Sox3 is usually highly expressed, have altered properties in mutant embryos, leading to abnormal development of Rathke's pouch, which does not express the gene. Pituitary and hypothalamic defects persist postnatally, and SOX3 may also function in a subset of hypothalamic neurons. This study shows how sensitive the pituitary is to subtle developmental defects and how one gene can act at several levels in the hypothalamic-pituitary axis.


Male-related chemical cues promote sexual receptivity in the female musk shrew.
The role of conspecific chemical cues in the activation of sexual behavior was investigated in the female musk shrew (Suncus murinus). In Experiment 1, virgin female musk shrews were exposed to either clean cages or cages recently vacated by an adult male. Regardless of whether the male used for the sexual behavior test was "familiar" to the female (having spent the 24 h exposure in his vacant cage) or "unfamiliar," females exposed to male-related cues received mounts from males significantly sooner than females exposed to clean cages. In Experiment 2, females housed for 24 h in a cage soiled by an adult male allowed males to mount significantly sooner than females housed in a cage soiled by a castrated male, another female, or a clean cage. These results demonstrate that chemical cues, produced exclusively by adult males, promote sexual receptivity in female musk shrews.


Neutrophil chemotaxis in patients with burns.
In a group of 22 patients with second and third degree burns, seven were found to have impaired chemotaxis. The chemotactic defect was present from two to 68 days and eventually became normal. The impairment was found to be due to a primary transient defect in polymorphonuclear leukocytes and not to an inhibitor or inactivator in the serum.


RNA silencing in Drosophila.
Knowledge of the role of RNA in affecting gene expression has expanded in the past several years. Small RNAs serve as homology guides to target messenger RNAs for destruction at the post-transcriptional level in the experimental technique known as RNA interference and in the silencing of some transgenes. These small RNAs are also involved in sequence-specific targeting of chromatin modifications for transcriptional silencing of transgenes, transposable elements, heterochromatin and some cases of Polycomb-mediated gene silencing. RNA silencing processes in Drosophila are described.


Failure analysis of sandwich-type ceramic-on-ceramic hip joints: A spectroscopic investigation into the role of the polyethylene shell component.
The mechanisms leading to systematic failure in modular acetabular components with a sandwich insertion (alumina/polyethylene/titanium) have been reconsidered in light of the newly collected Raman spectroscopic results. Raman assessments were conducted on the polyethylene shells, which belonged to a series of six failed sandwich implants with in vivo lifetimes ranging between 2 and 9yr. With only one exception, all implants commonly showed dislodgment of the polyethylene shell during radiographic analyses prior to revision surgery. The polyethylene shell slipped out of the backing titanium shell, while always remaining integer to the ceramic liner. Four implants fractured at the ceramic liners, but their fractures occurred according to distinctly different patterns, which could be rationalized and classified. The insertion of the polyethylene layer, originally conceived to reduce the rigidity of the ceramic-on-ceramic bearing and to prevent impingement between the ceramic liner rim and the femoral neck, played a role in implant failure with its initial (asymmetric) thickness reduction due to creep deformation (eventually followed by cup rotation and backside wear). The results of the present spectroscopic investigation suggest that a simplistic failure classification of the sandwich-type implant as a "ceramic fracture failure" could be misleading and might represent a confounding factor in judging about the reliability of modern ceramic implants.


Attention and inhibitory control deficits in patients with genetic generalized epilepsy and psychogenic nonepileptic seizure.
This study aimed to evaluate the attention and inhibitory control functions in patients with genetic generalized epilepsy (GGE) and psychogenic nonepileptic seizure (PNES) and compare the results with the healthy control subjects. A total of 30 patients with GGE, 30 patients with PNES, and 32 healthy control subjects were included in the study. The severity of attention and inhibitory control deficit, general intelligence status, and psychopathology screening in all subjects were respectively investigated with the Integrated Visual and Auditory Continuous Performance Test (IVA-CPT), the Wechsler Adult Intelligence Scale (WAIS), and the Symptoms Checklist 90-revised (SCL-90-R). Patients with PNES had severe impairments in all performed tasks compared with the control group and the group with GGE (p < 0.01), whereas patients with GGE had significantly lower attention quotient versus healthy subjects (p < 0.01). The full-scale attention quotient (FSAQ) and full-scale response control quotient (FSRCQ) in patients with PNES were significantly lower in comparison with GGE (47.83 ± 32.68, 60.18 ± 35.35, p < 0.01), respectively. Multiple regression analysis did not demonstrate any significant effect of seizure frequency or epilepsy duration on attention and inhibitory control deficits, but patient's intelligence quotient (IQ) showed a significant effect on FSAQ and FSRCQ (β: 0.997, p < 0.001; β: 0.933, p < 0.001, respectively). Attention and inhibitory control are significantly impaired in patients with GGE and PNES. The cognitive deficits in patients with GGE and PNES have potentially important clinical implications in planning their neuropsychological rehabilitation.


Preparation of a dibenzylated 1,4-diazacyclohexane-derived strong anion-exchange stationary phase.
This paper reports the preparation of a novel, silica-based, strong anion-exchange stationary phase from a 1,4-diazacyclohexane derivative. To prepare the difunctional strong anion-exchange stationary phase, activated silica beads were first bonded with 3-chloropropyltriethoxysilane and then reacted with 1-methylpiperazine followed by benzyl chloride. The silica beads, the strong anion-exchange stationary phase and its precusors were instrumentally characterized. Aromatic acids were separated with non-aqueous anion-exchange chromatography. After elution with eluant prepared in mixed solvents of water and methanol, the resulting 1,4-diazacyclohexane-derived, difunctional, strong anion-exchange stationary phase exhibited good separation and selectivity for the aromatic acids investigated. The effects of eluant pH, eluant ion concentration and solvent composites on the separations were investigated. Organic acids with different substituents were eluted in order of decreasing dissociation coefficients, with no observable peak shape differences.


Exposure-response relationships for personal exposure to fine particulate matter (PM2·5), carbon monoxide, and black carbon and birthweight: an observational analysis of the multicountry Household Air Pollution Intervention Network (HAPIN) trial.
Household air pollution (HAP) from solid fuel use is associated with adverse birth outcomes, but data for exposure-response relationships are scarce. We examined associations between HAP exposures and birthweight in rural Guatemala, India, Peru, and Rwanda during the Household Air Pollution Intervention Network (HAPIN) trial. The HAPIN trial recruited pregnant women (9-<20 weeks of gestation) in rural Guatemala, India, Peru, and Rwanda and randomly allocated them to receive a liquefied petroleum gas stove or not (ie, and continue to use biomass fuel). The primary outcomes were birthweight, length-for-age, severe pneumonia, and maternal systolic blood pressure. In this exposure-response subanalysis, we measured 24-h personal exposures to PM2·5, carbon monoxide, and black carbon once pre-intervention (baseline) and twice post-intervention (at 24-28 weeks and 32-36 weeks of gestation), as well as birthweight within 24 h of birth. We examined the relationship between the average prenatal exposure and birthweight or weight-for-gestational age Z scores using multivariate-regression models, controlling for the mother's age, nulliparity, diet diversity, food insecurity, BMI, the mother's education, neonate sex, haemoglobin, second-hand smoke, and geographical indicator for randomisation strata. Between March, 2018, and February, 2020, 3200 pregnant women were recruited. An interquartile increase in the average prenatal exposure to PM2·5 (74·5 μg/m3) was associated with a reduction in birthweight and gestational age Z scores (birthweight: -14·8 g [95% CI -28·7 to -0·8]; gestational age Z scores: -0·03 [-0·06 to 0·00]), as was an interquartile increase in black carbon (7·3 μg/m3; -21·9 g [-37·7 to -6·1]; -0·05 [-0·08 to -0·01]). Carbon monoxide exposure was not associated with these outcomes (1·7; -3·1 [-12·1 to 5·8]; -0·003 [-0·023 to 0·017]). Continuing efforts are needed to reduce HAP exposure alongside other drivers of low birthweight in low-income and middle-income countries. US National Institutes of Health (1UM1HL134590) and the Bill & Melinda Gates Foundation (OPP1131279).


Endothelial cells and cathepsins: Biochemical and biomechanical regulation.
Cathepsins are mechanosensitive proteases that are regulated not only by biochemical factors, but are also responsive to biomechanical forces in the cardiovascular system that regulate their expression and activity to participate in cardiovascular tissue remodeling. Their elastinolytic and collagenolytic activity have been implicated in atherosclerosis, abdominal aortic aneurysms, and in heart valve disease, all of which are lined by endothelial cells that are the mechanosensitive monolayer of cells that sense and respond to fluid shear stress as the blood flows across the surfaces of the arteries and valve leaflets. Inflammatory cytokine signaling is integrated with biomechanical signaling pathways by the endothelial cells to transcribe, translate, and activate either the cysteine cathepsins to remodel the tissue or to express their inhibitors to maintain healthy cardiovascular tissue structure. Other cardiovascular diseases should now be included in the study of the cysteine cathepsin activation because of the additional biochemical cues they provide that merges with the already existing hemodynamics driving cardiovascular disease. Sickle cell disease causes a chronic inflammation including elevated TNFα and increased numbers of circulating monocytes that alter the biochemical stimulation while the more viscous red blood cells due to the sickling of hemoglobin alters the hemodynamics and is associated with accelerated elastin remodeling causing pediatric strokes. HIV-mediated cardiovascular disease also occurs earlier in than the broader population and the influence of HIV-proteins and antiretrovirals on endothelial cells must be considered to understand these accelerated mechanisms in order to identify new therapeutic targets for prevention.


Hippocampal volume changes following electroconvulsive therapy: a systematic review and meta-analysis.
Reduced hippocampal volume is one of the most consistent morphological findings in Major Depressive Disorder (MDD). Electroconvulsive therapy (ECT) is the most effective therapy for MDD, yet its mechanism of action remains poorly understood. Animal models show that ECT induces several neuroplastic processes, which lead to hippocampal volume increases. We conducted a meta-analysis of ECT studies in humans to investigate its effects on hippocampal volume. PubMed was searched for studies examining hippocampal volume before and after ECT. A random-effects model was used for meta-analysis with standardized mean difference (SMD) of the change in hippocampal volume before and after ECT as the primary outcome. Nine studies involving 174 participants were included. Total hippocampal volumes increased significantly following ECT compared to pre-treatment values (SMD=1.10; 95% CI 0.80-1.39; z=7.34; p<0.001; k=9). Both right (SMD=1.01; 95% CI 0.72-1.30; z=6.76; p<0.001; k=7) and left (SMD=0.87; 95% CI 0.51-1.23; z=4.69; p<0.001; k=7) hippocampal volumes were also similarly increased significantly following ECT. We demonstrated no correlation between improvement in depression symptoms with ECT and change in total hippocampal volume (beta=-1.28, 95% CI -4.51-1.95, z=-0.78, p=0.44). We demonstrate fairly consistent increases in hippocampal volume bilaterally following ECT treatment. The relationship among these volumetric changes and clinical improvement and cognitive side effects of ECT should be explored by larger, multisite studies with harmonized imaging methods.


Complement activation by polymer binding IgG.
It was found that immobilized IgG on polymer carriers activates complement on contact with the serum. As polymers were microspherical in this study, complement fragments bound to polymers were detected by the agglutination of the polymer microspheres with the corresponding antisera or rosette formation with cells having complement receptors. Without the immobilization of IgG, polymers having amino, carboxyl, cyano or phenyl groups activated complement in the serum, while the presence of hydroxyl and carbamoyl groups in polymers did not cause complement activation. When intact IgG was bound to poly(glyceryl methacrylate) by the use of glutaraldehyde, the IgG-polymer conjugate activated complement in spite of the inertness of the polymer itself. The polymers immobilizing F(ab')2 activated complement less than the polymers immobilizing intact IgG. When dextran aldehyde prepared by periodate oxidation of dextran was used as a binder instead of glutaraldehyde, complement activation by F(ab')2-polymer conjugate was remarkably reduced, though antibody activity for binding the antigen remained. These results should be taken into consideration in the design of an immunosorption therapy.


Multi-laboratory validation of SkinEthic HCE test method for testing serious eye damage/eye irritation using liquid chemicals.
A prospective multicentric study of the reconstructed human corneal epithelial tissue-based in vitro test method (SkinEthic™ HCE) was conducted to evaluate its usefulness to identify chemicals as either not classified for serious eye damage/eye irritation (No Cat.) or as classified (Cat. 1/Cat. 2) within UN GHS. The aim of this study was to demonstrate the transferability and reproducibility of the SkinEthic™ HCE EITL protocol for liquids and define its predictive capacity. Briefly, 60 chemicals were three times tested (double blinded) in 3 laboratories and 45 additional chemicals were tested three times in one laboratory. Good within laboratory reproducibility was achieved of at least 88.3% (53/60) and 92.4% (97/105) for the extended data set. Furthermore, the overall concordance between the laboratories was 93.3% (56/60). The accuracy of the SkinEthic™ HCE EITL for the extended dataset, based on bootstrap resampling, was 84.4% (95% CI: 81.9% to 87.6%) with a sensitivity of 99.0% (95% CI: 96.4% to 100%) and specificity of 68.5% (95% CI: 64.0% to 74.0%), thereby meeting all acceptance criteria for predictive capacity. This efficient transferable and reproducible assay is a promising tool to be integrated within a battery of assays to perform an eye irritation risk assessment.


Using a Knowledge-Based Clinical Decision Support System to Reduce the Time to Appropriate Antimicrobial Therapy in Hospitalized Patients With Bloodstream Infections: A Single-Center Observational Study.
Inappropriate antimicrobial use is a crucial determinant of mortality in hospitalized patients with bloodstream infections. Current literature reporting on the impact of clinical decision support systems on optimizing antimicrobial prescription and reducing the time to appropriate antimicrobial therapy is limited. Kaohsiung Veterans General Hospital implemented a hospital-wide, knowledge-based, active-delivery clinical decision support system, named RAPID (Real-time Alert for antimicrobial Prescription from virtual Infectious Diseases experts), to detect whether there was an antimicrobial agent-pathogen mismatch when a blood culture result was positive. Once RAPID determines the current antimicrobials as inappropriate, an alert text message is immediately sent to the clinicians in charge. This study evaluated how RAPID impacted the time to appropriate antimicrobial therapy among patients with bloodstream infections. During the study period, 633 of 11 297 recorded observations (5.6%) were determined as inappropriate antimicrobial prescriptions. The time to appropriate antimicrobial therapy was significantly shortened after the implementation of RAPID (1.65 vs 2.45 hours, P < .001), especially outside working hours (1.24 vs 6.43 hours, P < .001), in the medical wards (1.40 vs 2.14 hours, P < .001), in participants with candidemia (0.74 vs 5.36 hours, P < .001), and for bacteremia due to non-multidrug-resistant organisms (1.66 vs 2.49 hours, P < .001). Using a knowledge-based clinical decision support system to reduce the time to appropriate antimicrobial therapy in a real-world scenario is feasible and effective. Our results support the continued use of RAPID.