Regional sensitivity of the rat brain to the inhibitory effects of morphine on wet shake behavior.
The aim of this investigation was to determine the brain regions which were most sensitive to the inhibitory effects of morphine on the shaking response of pentobarbital-anesthetized rats to ice water. The median inhibitory dose (ID50) of morphine sulfate administered intraventricularly was found to be 0.35 mug/rat. When morphine was bilaterally injected into different regions of the brain, the ID50 values ranged from 0.04 to 17.9 mug/rat. The lowest ID50 values (0.04-0.20 mug) were found in the periaqueductal gray, the medial preoptic area and the locus ceruleus. The ID50 values ranged from 0.65 to 1.6 mug for areas around the nucleus accumbens, the fasciculus retroflexus, the medical thalamus and the septal area; from 5.6 to 7.3 mug for various hypothalamic nuclei; and from 11.0 to 17.9 mug for the basal ganglia, reticular formation substantia nigra and the reticular nucleus of the thalamus. The brain areas with the lowest ID50 values are known to have thermoregulatory functions. The similarity of the shaking response to shivering is discussed. It is concluded that the central inhibitory effects of morphine on shaking are subserved by discrete neuroanatomical substrates located in medial subcortical structures.


Examination of implementation of intravenous and subcutaneous insulin protocols and glycemic control in heart transplant patients.
Perioperative glycemic management is particularly challenging in heart transplant (HT) patients who are on high-dose steroids and subject to surgical stress. The objective of the study was to examine the efficacy and safety of perioperative insulin administration in HT patients with and without diabetes. Medical records of 71 HT patients from June 1, 2005 to July 31, 2009 whose hyperglycemia was managed by our Glucose Management Service (GMS) were analyzed for up to 1 year after HT. Their daily blood glucose (BG) averages on intravenous (i.v.) insulin drips and subcutaneous (s.q.) insulin, hypoglycemia rates, reasons for hypoglycemia, and deviations from insulin protocols were analyzed. Daily BG averages between diabetic (DM) and nondiabetic (nonDM) patients were not significantly different while on the drip but were significantly different for first 5 days on s.q. (P<.05). The daily insulin glargine doses were similar. No patients developed severe hypoglycemia (BG ≤40 mg/dL) while on drip, and only 2.8% experienced hypoglycemia on s.q. Among 40 episodes of moderate hypoglycemia while on drip, 15 had nurse deviations from protocol prior to the episode. Posttransition day fasting glucose was at goal (mean 124.7 ± 35.4 mg/dL); however 39.4% (28/71) of patients received a transition insulin glargine dose that was different from the amount indicated by protocol. The likelihood of developing moderate hypoglycemia on s.q. was associated with the glargine dose used at the time of transition (odds ratio [OR] 1.03, P = .034). Inpatient insulin protocols implemented by a GMS are successful in obtaining glycemic control with minimal side effects in patients with and without diabetes, even when they are on a high-dose steroid regimen.


Urinary free-cortisol levels in posttraumatic stress disorder patients.
Urinary free-cortisol levels (micrograms per day) were measured by radioimmunoassay at 2-week intervals during the course of hospitalization in the following patient groups: posttraumatic stress disorder (PTSD); major depressive disorder; bipolar I, manic; paranoid schizophrenia; and undifferentiated schizophrenia. The mean cortisol level during hospitalization was significantly lower in PTSD (33.3 +/- 3.2) than in major depressive disorder (49.6 +/- 5.9), bipolar I, manic (62.7 +/- 6.7), and undifferentiated schizophrenia (50.1 +/- 8.9), but was similar to that in paranoid schizophrenia (37.5 +/- 3.9). The same differences across groups are evident in the first sample following hospital admission. This finding of low, stable cortisol levels in PTSD patients is especially noteworthy, first because of the overt signs of anxiety and depression, which would usually be expected to accompany cortisol elevations, and second because of the concomitant chronic increase in sympathetic nervous system activity shown in prior psychophysiological studies of PTSD and reflected in marked and sustained urinary catecholamine elevations previously reported in our own PTSD sample. The findings suggest a possible role of defensive organization as a basis for the low, constricted cortisol levels in PTSD and paranoid schizophrenic patients. The data also suggest the possible usefulness of hormonal criteria as an adjunct to the clinical diagnosis of PTSD.


Induction of antigen-specific immune responses in mice by recombinant baculovirus expressing premembrane and envelope proteins of West Nile virus.
West Nile Virus (WNV) is an emerging arthropod-born flavivirus with increasing distribution worldwide that is responsible for a large proportion of viral encephalitis in humans and horses. Given that there are no effective antiviral drugs available for treatment of the disease, efforts have been directed to develop vaccines to prevent WNV infection. Recently baculovirus has emerged as a novel and attractive gene delivery vehicle for mammalian cells. In the present study, recombinant baculoviruses expressing WNV premembrane (prM) and envelope (E) proteins under the cytomegalovirus (CMV) promoter with or without vesicular stomatitis virus glycoprotein (VSV/G) were constructed. The recombinant baculoviruses designated Bac-G-prM/E and Bac-prM/E, efficiently express E protein in mammalian cells. Intramuscular injection of the two recombinant baculoviruses (at doses of 108 or 109 PFU/mouse) induced the production of WNV-specific antibodies, neutralizing antibodies as well as gamma interferon (IFN-γ) in a dose-dependent pattern. Interestingly, the recombinant baculovirus Bac-G-prM/E was found to be a more efficient immunogen than Bac-prM/E to elicit a robust immune response upon intramuscular injection. In addition, inoculation of baculovirus resulted in the secretion of inflammatory cytokines, such as TNF-α, IL-2 and IL-6. These recombinant baculoviruses are capable of eliciting robust humoral and cellular immune responses in mice, and may be considered as novel vaccine candidates for West Nile Virus.


Deconstructing the Treatment Effect of Remdesivir in the Adaptive Coronavirus Disease 2019 (COVID-19) Treatment Trial-1: Implications for Critical Care Resource Utilization.
The Adaptive Coronavirus Disease 2019 (COVID-19) Treatment Trial-1 (ACTT-1) found that remdesivir therapy hastened recovery in patients hospitalized with COVID-19, but the pathway for this improvement was not explored. We investigated how the dynamics of clinical progression changed along 4 pathways: recovery, improvement in respiratory therapy requirement, deterioration in respiratory therapy requirement, and death. We analyzed trajectories of daily ordinal severity scores reflecting oxygen requirements of 1051 patients hospitalized with COVID-19 who participated in ACTT-1. We developed competing risks models that estimate the effect of remdesivir therapy on cumulative incidence of clinical improvement and deterioration, and multistate models that utilize the entirety of each patient's clinical course to characterize the effect of remdesivir on progression along the 4 pathways above. Based on a competing risks analysis, remdesivir reduced clinical deterioration (hazard ratio [HR], 0.73; 95% confidence interval [CI]: .59-.91) and increased clinical improvement (HR, 1.22; 95% CI: 1.08, 1.39) relative to baseline. Our multistate models indicate that remdesivir inhibits worsening to ordinal scores of greater clinical severity among patients on room air or low-flow oxygen (HR, 0.74; 95% CI: .57-.94) and among patients receiving mechanical ventilation or high-flow oxygen/noninvasive positive-pressure ventilation (HR, 0.73; 95% CI: .53-1.00) at baseline. We also find that remdesivir reduces expected intensive care respiratory therapy utilization among patients not mechanically ventilated at baseline. Remdesivir speeds time to recovery by preventing worsening to clinical states that would extend the course of hospitalization and increase intensive respiratory support, thereby reducing the overall demand for hospital care.


Effect of tumor promoters on sarc gene expression in normal and transformed chick embryo fibroblasts.
The effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) on the sarc protein kinase of normal chick embryo fibroblasts (CEF) and of the src kinase of cells transformed by a temperature-sensitive mutant of avian sarcoma virus (CEF-tsASV) were studied and compared with the known effects of TPA on cell morphology and plasminogen activator (PA) activity. One hr after the addition of TPA to normal CEF, there was a 3- to 8-fold stimulation of kinase activity when compared to control cultures; during the subsequent 24 hr, TPA produced less than a 2-fold stimulation. Although TPA induced levels of PA in CEF which were equivalent to those produced by cEF-tsASV grown at 36 degrees, the latter cells contained much higher levels of kinase activity than those of CEF plus TPA. In addition, TPA failed to enhance the kinase activity of CEF-tsASV at either 36 degrees or 40 degrees, even though at both temperatures TPA induced morphological changes and markedly enhanced PA activity. These results suggest that the effects of TPA on morphology and PA are not due to an effect on these protein kinases.


Effect of postpartum maternal or neonatal vitamin A supplementation on infant mortality among infants born to HIV-negative mothers in Zimbabwe.
Young infants are at risk of vitamin A deficiency. Supplementation of breastfeeding mothers improves the vitamin A status of their infants, but there are no data regarding its effect on infant mortality, and data on the effect of directly supplementing infants during the first few weeks of life are conflicting. The objective was to measure the effect on infant mortality of supplementing neonates and their HIV-negative mothers with single, large doses of vitamin A during the immediate postpartum period. A randomized, placebo-controlled, 2-by-2 factorial design trial was conducted in 14,110 mothers and their infants; 9208 of the mothers were HIV-negative at delivery, remained such during the postpartum year, and were retained in the current analysis. The infants were randomly assigned within 96 h of delivery to 1 of 4 treatment groups: mothers and infants received vitamin A (Aa), mothers received vitamin A and infants received placebo (Ap), mothers received placebo and infants received vitamin A (Pa), and both mothers and infants received placebo (Pp). The vitamin A dose in the mothers was 400,000 IU and in the infants was 50,000 IU. The mother-infant pairs were followed to 12 mo. Hazard ratios (95% CI) for 12 mo mortality among infants in the maternal-supplemented and infant-supplemented groups were 1.17 (0.87, 1.58) and 1.08 (0.80, 1.46), respectively. Hazard ratios (95% CI) for the Aa, Ap, and Pa groups compared with the Pp group were 1.28 (0.83, 1.98), 1.27 (0.82, 1.97), and 1.18 (0.76, 1.83), respectively. These data indicate no overall effect. Serum retinol concentrations among a subsample of women were similar to reference norms. Postpartum maternal or neonatal vitamin A supplementation may not reduce infant mortality in infants of HIV-negative women with an apparently adequate vitamin A status.


Nucleotide-binding oligomerization domain proteins are innate immune receptors for internalized Streptococcus pneumoniae.
Streptococcus pneumoniae, the major cause of community-acquired pneumonia and bacterial meningitis, has been shown to transiently invade epithelial and endothelial cells. Innate immune receptors including Toll-like receptors recognize various pathogens, such as S. pneumoniae, by identifying conserved pathogen-associated molecular patterns. Recently, two members of a novel class of pattern recognition receptors, the cytosolic proteins nucleotide-binding oligomerization domain 1 (Nod1)/CARD4 and Nod2/CARD15, have been found to detect cell wall peptidoglycans. Here we tested the hypothesis that Nod proteins are involved in the intracellular recognition of pneumococci. Data indicate that pneumococci invade HEK293 cells. Genetic complementation studies in these cells demonstrate that NF-kappaB activation induced by S. pneumoniae depends on Nod2. Moreover, intracellular transfection of inactivated pneumococci yielded similar effects, confirming the Nod2 dependence of NF-kappaB activation by pneumococci in HEK293 cells. By dominant negative overexpression and small interfering RNA experiments, we show for the first time that interleukin-1 receptor-associated kinase participates in Nod2-dependent NF-kappaB activation. Additionally, dominant negative interleukin-1 receptor-associated kinase 2, tumor necrosis factor receptor-associated factor 6, NF-kappaB-inducing kinase, transforming growth factor-beta-activated kinase-binding protein 2, and transforming growth factor-beta-activated kinase 1 also inhibited Nod2-dependent NF-kappaB activation. We finally demonstrate that in C57BL/6 mouse lung tissue in vivo as well as in the bronchial epithelial cell line BEAS-2B, Nod1 and Nod2 mRNA expressions were up-regulated after pneumococcal infection. Data presented suggest that Nod proteins contribute to innate immune recognition of S. pneumoniae. Furthermore, Rip-2 and members of the Toll-like receptor-signaling cascade are involved in the Nod2-dependent activation of NF-kappaB induced by pneumococci.


Vasopressin protects hippocampal neurones in culture against nutrient deprivation or glutamate-induced apoptosis.
Vasopressin (VP) secreted within the brain modulates neuronal function by acting as a neurotransmitter. Recent studies show that VP prevents serum deprivation-induced apoptosis in the neuronal cell line, H32. To determine whether VP is anti-apoptotic in hippocampal neurones, primary cultures of these neurones were used to examine the effect of VP on neuronal culture supplement (B27) deprivation-, or glutamate-induced apoptosis, and the signalling pathways mediating the effects. Removal of B27 supplement from the culture medium for 24 h or the addition of glutamate (3-10μm) decreased neuronal viability (P<0.05) and increased Tdt-mediated dUTP nick-end labelling (TUNEL) staining and caspase-3 activity (P<0.05), which is consistent with apoptotic cell death. VP (10 nm) reduced B27 deprivation- or glutamate-induced cell death (P<0.05). These anti-apoptotic effects of VP were completely blocked by a V1 but not a V2 receptor antagonist, indicating that they are mediated via V1 VP receptors. The anti-apoptotic effect of VP in neurones involves activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and inositol trisphosphate/protein kinase B (Akt) signalling pathways. This was shown by the transient increases in phospho-ERK and phospho-Akt after incubation with VP revealed by western blot analyses, and the ability of specific inhibitors to reduce the inhibitory effect of VP on caspase-3 activity and TUNEL staining by 70% and 35%, respectively (P<0.05). These studies demonstrate that VP has anti-apoptotic actions in hippocampal neurones, an effect that is mediated by the MAPK/ERK and phosphatidylinositol-3 kinase/Akt signalling pathways. The ability of VP to reduce nutrient deprivation or glutamate overstimulation-induced neuronal death suggests that VP acts as a neuroprotective agent within the brain.


[Effect of miliacin oil on the healing of purulent wounds].
The efficacy of miliaceum (millet) oil in local application for the treatment of purulent wounds was studied for the first time. The oil is obtained from the waste products of millet processing. It was demonstrated in experiments on 55 rabbits with a model of a purulent wound that the studied preparation causes a marked anti-inflammatory effect, promotes rapid cleansing of the wounds from the pyonecrotic contents, and significantly activates the reparative processes. With the use of millet oil the term of wound healing reduced by 6-12 days on the average as compared to healing in treatment with buckthorn oil and Vishnevsky's ointment.


Construction of a polymer-based fluorescent probe with dual responsive sites for monitoring changes of lysosomal viscosity.
As highly dynamic organelles, lysosomes are involved in various physiological processes. The viscosity of lysosomes plays critical roles in maintaining their normal physiological function and abnormal variations of viscosity are associated with many diseases. Monitoring the changes of lysosomal viscosity could contribute to understanding lysosome-related physiological and pathological processes. In this work, based on an indole fluorophore and fluorescent polymer, poly(2-hydroxyethyl methacrylate) (PHEM), a new polymeric fluorescent probe, In-PHEM, with dual responsive sites for tracking changes of lysosomal viscosity is presented. In-PHEM showed excellent fluorescence properties and high photostability. With this robust probe, the variation of the lysosomal viscosity in cells under different physiological conditions, including inducer stimulation, the process of starvation and apoptosis, was monitored using dual-channel imaging. Therefore, this work may provide a powerful tool for monitoring changes of lysosomal viscosity and helping to understand the relationship between the viscosity changes of lysosomes and their related diseases.


LINE-1 couples EMT programming with acquisition of oncogenic phenotypes in human bronchial epithelial cells.
Although several lines of evidence have established the central role of epithelial-to-mesenchymal-transition (EMT) in malignant progression of non-small cell lung cancers (NSCLCs), the molecular events connecting EMT to malignancy remain poorly understood. This study presents evidence that Long Interspersed Nuclear Element-1 (LINE-1) retrotransposon couples EMT programming with malignancy in human bronchial epithelial cells (BEAS-2B). This conclusion is supported by studies showing that: 1) activation of EMT programming by TGF-β1 increases LINE-1 mRNAs and protein; 2) the lung carcinogen benzo(a)pyrene coregulates TGF-β1 and LINE-1 mRNAs, with LINE-1 positioned downstream of TGF-β1 signaling; and, 3) forced expression of LINE-1 in BEAS-2B cells recapitulates EMT programming and induces malignant phenotypes and tumorigenesis in vivo. These findings identify a TGFβ1-LINE-1 axis as a critical effector pathway that can be targeted for the development of precision therapies during malignant progression of intractable NSCLCs.


Allogeneic peripheral blood progenitor cell transplantation in a murine model: evidence for an improved graft-versus-leukemia effect.
Peripheral blood progenitor cells (PBPCs) are increasingly being used to replace bone marrow cells (BMCs) as a source of hematopoietic stem cells also in the field of allogeneic transplantation. Whereas it is well known that PBPC grafts and BM differ significantly in progenitor cell content and lymphocyte dose, the clinical consequences of these differences with respect to engraftment, graft-versus-host disease (GVHD), and the graft-versus-leukemia (GVL) effect are more difficult to assess. We present a murine model that allows us to evaluate engraftment, GVHD, and GVL effect of allogeneic PBPC transplantation (PBPCT). Balb/c mice (H-2d) served as recipients. Donors were major histocompatibility complex-matched DBA/2 mice or syngeneic Balb/c mice, respectively. Experiments with increasing numbers of BMCs or Filgastrim-mobilized PBPCs showed that the number of progenitor cells in the graft was correlated with the probability to engraft, irrespective of the graft type. With identically high cell numbers transferred (1 x 10(9) nucleated cells/kg body weight [BW]), the mortality rates due to GVHD (25%) were about the same after allogeneic BM transplantation (BMT) and allogeneic PBPCT, although PBPC grafts contained four times more CD3+ T cells as compared with BM grafts (6.2 x 10(8) v 1.4 x 10(8)/kg BW). For investigation of GVL activity, Balb/c recipients were injected with syngeneic cells of the B-lymphocytic leukemia cell line A20 2 days before transplantation. After total body irradiation to a dose of 7.5 Gy, 1 x 10(9)/kg BW Balb/c PBPCs, DBA BMCs, or DBA PBPCs were infused. The relapse rates observed were 80% after syngeneic PBPCT (n = 22), 60% after allogeneic BMT (n = 23), and 34% after allogeneic PBPCT (n = 26) (allogeneic BMT v PBPCT, P = .032). We conclude that transplantation of allogeneic PBPCs instead of BM may enhance the GVL effect without an increase of GVHD.


Technical Note: Film-based measurement of gold nanoparticle dose enhancement for 192 Ir.
The purpose of this work is to introduce a simple yet accurate technique to measure the dose enhancement factor (DEF) of a citrate-capped gold nanoparticle (GNP) solution using EBT3 film in an 192 Ir setup. Dose enhancement factor is the ratio of absorbed dose in a solution compared to absorbed dose in water, assuming identical irradiation parameters. Citrate-capped GNPs were synthesized. An acrylic apparatus was constructed such that the EBT3 film was placed in charged particle equilibrium within the GNP solution with 0.28%, 0.56%, and 0.77% gold by mass. Sets of 12 dose measurements were collected for each GNP concentration as well as for water. The expected value of DEF was also calculated with the effective mass absorption coefficient of the GNP solution and water for an 192 Ir spectrum. Furthermore, Burlin cavity correction factors were calculated and experimentally verified. Experimental verification of the cavity correction was performed by measuring DEF using stacks of 1, 3, and 5 sheets of film and extrapolating the DEF to 0 sheets of film. Experimental cavity corrections agreed with those calculated with the Burlin cavity formalism. The calculated DEF was 1.013, 1.027, and 1.037 for the 0.28%, 0.56%, and 0.77% gold by mass GNP solutions, respectively. The corresponding uncorrected DEF measurement values were 1.013 ± 0.006, 1.024 ± 0.010, and 1.032 ± 0.006, respectively. When applying the Burlin cavity formalism, the final corrected DEF measurement values were 1.016 ± 0.006, 1.029 ± 0.010, and 1.039 ± 0.006, respectively. The experimental cavity correction results agreed with the theoretical Burlin calculations, which allowed for the Burlin corrections to be performed for all GNP concentrations and measured DEF values. The adjusted DEF values agreed with the theoretical calculations. Thus, these results indicate that a Burlin cavity calculation can be applied to correct film-based DEF measurements for 192 Ir.


Decreased cholesterol levels reflect a consumption of anti-inflammatory isoprenoids associated with an impaired control of inflammation in a mouse model of mevalonate kinase deficiency.
The aim of this study was to evaluate, in a mouse model of mevalonate kinase deficiency (MKD), the possible link between inflammatory symptoms and serum cholesterol levels. Balb/c mice were treated with alendronate and bacterial muramyl dipeptide. Body temperature, interleukin-1 beta (IL-1 beta) secretion and serum cholesterol levels were measured. An increased production of the pro-inflammatory cytokine IL-1 beta (p < 0.05) and a rise in body temperature (p < 0.05) was observed, while, in parallel, serum cholesterol concentration significantly decreased (p < 0.05). These effects were completely reversed when animals were treated with exogenous isoprenoids. In the mouse model of MKD, the inflammatory response is associated with a reduction in cholesterol levels, and hence this parameter could be used as an indicator of isoprenoid consumption. In addition, plant derived isoprenoids could represent candidate treatments for this disease.


Enhancing animal welfare by creating opportunities for positive affective engagement.
In line with an increasing emphasis on promoting positive welfare states in animals, this review extends previous accounts of how recent affective neuroscience observations may be used to identify and then to encourage animals to engage in reward-motivated behaviours. The terms affective states or affects are used to mean the subjective experiences, feelings or emotions that may motivate animals to behave in goal-directed ways and which may accompany success or failure to achieve those goals. These motivational affects may be positive, experienced as rewarding or pleasurable, or negative, experienced as aversive or punishing. There are two overall types: homeostasis-related negative affects that reflect an animal's internal physiological state, and situation-related positive or negative affects that reflect an animal's perception of its external circumstances. The major emphasis is on positive situation-related affects, in particular those that are potentially associated with exploration, feeding and animal-to-animal affiliative behaviours. The review introduces the new concept of positive affective engagement which represents the experience animals may have when they actively respond to motivations to engage in rewarding behaviours, and it incorporates all associated affects that are positive. For example, it would represent a state of engaged aliveness that may attend an animal's goal-directed, energised exploration of and interactions with a stimulus-rich environment. It also represents some states of equally energised, highly focused predatory stalking by carnivores or the focused and engaged foraging by herbivores when they are grazing in natural environments where food sources are abundant. Positive affective engagement may also be anticipated to accompany some aspects of reciprocated affiliative interactions between animals, the dedicated maternal nurturing and care of young, the joyfulness of rough-and-tumble play, and the eroticism and orgasmic pleasures of sexual activity. It is argued that highlighting the genetically pre-programmed, affectively positive impulses to engage in reward-motivated activities such as these, and the positive affects that may attend different facets of the process, draws attention to a wider spectrum of welfare enhancing experiences than has hitherto been considered to be important to animals. These neuroscience-supported observations strengthen many prior inferences made from predominantly behaviour-based investigations of animals' preferences, aversions and priorities, the associated development of successful environmental enrichments and the inclusion of these, where practicable, in more recent codes of practice or welfare.


Movement disorders associated with moyamoya disease: a report of 4 new cases and a review of literatures.
The aim of this study was to define the clinical characteristics of patients who developed movement disorders in association with moyamoya disease (MMD). Using PubMed and medical records of our hospital from 1985 to 2008, we searched for patients who developed movement disorders in association with MMD. This study included 38 patients described in previous studies and 4 patients found in the medical records. The onset of movement disorders was thought to be sudden. In 13 patients, the movement disorders were precipitated by hyperventilation or emotional stress. Twenty-seven of the 42 patients developed chorea, 4 patients developed dystonia, and 4 developed a mixture of both. The movement disorders of the remaining 7 patients were described as dyskinesia. A third of the 42 patients developed bilateral movement disorders, and their mean age was younger than that of those with unilateral movement disorders. In 37 of the 42 patients, brain imaging studies showed ischemic lesions, but the remaining 5 patients showed no parenchymal lesions. Cerebral perfusion studies showed hypoperfusion in the basal ganglia and in the cerebral cortical areas. Most patients improved whether they were treated or not. MMD must be included in the differential diagnosis of the sudden onset of dyskinesias, particularly chorea and focal dystonia. Even in patients with no parenchymal lesion in brain imaging studies, cerebral angiography and cerebral blood perfusion studies must be performed, if they develop a sudden onset or recurrent movement disorders preceded by emotional stress or hyperventilation.


Signal Processing in Periodically Forced Gradient Frequency Neural Networks.
Oscillatory instability at the Hopf bifurcation is a dynamical phenomenon that has been suggested to characterize active non-linear processes observed in the auditory system. Networks of oscillators poised near Hopf bifurcation points and tuned to tonotopically distributed frequencies have been used as models of auditory processing at various levels, but systematic investigation of the dynamical properties of such oscillatory networks is still lacking. Here we provide a dynamical systems analysis of a canonical model for gradient frequency neural networks driven by a periodic signal. We use linear stability analysis to identify various driven behaviors of canonical oscillators for all possible ranges of model and forcing parameters. The analysis shows that canonical oscillators exhibit qualitatively different sets of driven states and transitions for different regimes of model parameters. We classify the parameter regimes into four main categories based on their distinct signal processing capabilities. This analysis will lead to deeper understanding of the diverse behaviors of neural systems under periodic forcing and can inform the design of oscillatory network models of auditory signal processing.


A stochastic dynamical systems view of the Atlantic Multidecadal Oscillation.
We provide a dynamical systems framework to understand the Atlantic Multidecadal Oscillation and show that this framework is in many ways similar to that of the El Niño/Southern Oscillation. A so-called minimal primitive equation model is used to represent the Atlantic Ocean circulation. Within this minimal model, we identify a normal mode of multidecadal variability that can destabilize the background climate state through a Hopf bifurcation. Next, we argue that noise is setting the amplitude of the sea surface temperature variability associated with this normal mode. The results provide support that a stochastic Hopf bifurcation is involved in the multidecadal variability as observed in the North Atlantic.


The antiandrogen cyproterone acetate induces synthesis of transforming growth factor beta 1 in the parenchymal cells of the liver accompanied by an enhanced sensitivity to undergo apoptosis and necrosis without inflammation.
Recently, cases of liver damage and liver tumors have been reported after treatment of prostate cancer patients with the antiandrogen cyproterone acetate (CPA). In rat liver, CPA initiates a wave of DNA synthesis that is accompanied by apoptosis. In apoptotic hepatocytes, a latent form of transforming growth factor beta 1 (TGF-beta 1) is detectable by immunohistochemistry. Injection of a single dose of TGF-beta 1 induces apoptosis in the liver of animals pretreated with CPA but has an insignificant effect in untreated animals. In this study, we show by Northern analysis that there is increased expression of TGF-beta 1 in the liver after CPA treatment. Detection of TGF-beta 1 with in situ hybridization showed that TGF-beta 1 was synthesized in the parenchymal cells. Time course and dose-response experiments performed 48 hours after the last application of CPA showed that apoptotic nuclei with chromatin condensed at the nuclear periphery (AN) were already visible 2 hours after injection (0.13%), and apoptotic bodies (ABs) increased 2 to 9 hours after the injection (from 1.28% to 6.67%) after 25 micrograms TGF-beta 1/kg. At 4.5 hours after injection, an induction of apoptosis could be detected with 0.25 microgram TGF-beta 1/kg and after the maximum dose (250 micrograms TGF-beta 1/kg) ANs (0.24%) and ABs (16.74%) were homogeneously distributed throughout the liver lobe. Irrespective of the dose or time after injection of TGF-beta 1, 82% of the ABs were localized within hepatocytes. Liver enzymes were detected in high amounts in the serum (eightfold elevation of glutamate dehydrogenase, fivefold elevation of alanine transaminase [ALT]) 7 hours after the first visible sign of apoptosis. After an additional 20 hours, the liver contained many necrotic figures. These results suggest that the combination of TGF-beta 1 expression coupled with a strikingly enhanced sensitivity to the induction of apoptosis could be responsible both for the liver damage and the development of liver tumors observed after treatment with CPA.


Oxidation of Ikappa Balpha at methionine 45 is one cause of taurine chloramine-induced inhibition of NF-kappa B activation.
A band shift of IkappaBalpha was observed in Western blots with Jurkat cells treated with 1 mm taurine chloramine (TauCl) for 1 h. TauCl treatment inhibited tumor necrosis factor alpha (TNFalpha)-initiated nuclear factor kappaB (NF-kappaB) activation. TauCl did not inhibit either the upstream of IkappaB kinase (IKK) activation or IKK itself but did inhibit NF-kappaB activation induced by IKK overexpression. Deletion experiments showed that a TauCl modification site causing the band shift of IkappaBalpha is Met45. High performance liquid chromatography and mass spectrometry analyses of a small peptide containing Met45 revealed that TauCl oxidizes Met45. A mutant of IkappaBalpha whose Met45 was converted to alanine did not generate a band shift upon TauCl treatment and degraded in response to TNFalpha stimulation. However, a reporter assay revealed that NF-kappaB-dependent luciferase expression was not fully recovered in cells transfected with this mutant. These results indicate that Met45 oxidation of IkappaBalpha is a molecular mechanism underlying the TauCl-induced inhibition of NF-kappaB activation. A similar band shift was observed when HL-60 cells expressing myeloperoxidase were treated with 100 microm hydrogen peroxide for 5 min. When rat neutrophils were incubated with bacteria, intracellular taurine decreased interleukin-8 production. Therefore, taurine may help suppress excessive inflammatory reaction in neutrophils.


Political influence in the 1990s: from iron triangles to policy networks.
To assess the prospects of comprehensive health care reform during the Clinton administration, we must examine the changes that have occurred in the political and structural contexts in which reform is debated. The political context includes the status of the health care system itself as well as public attitudes and voting patterns associated with health care reform; it may be friendlier now to reform than it has been in any previous period, but it cannot on its own produce policy change. The structural context, the representational community of organized interests and government institutions, is the means by which politics is either thwarted or translated into action. Changes in these organized interests and in Congress have transformed the health care reform policy community from an "iron triangle" dominated by an antireform alliance of medicine, insurance, and business to a more loosely bound policy network in which a reform coalition may now be able to prevail, especially under the direction of an activist president like Bill Clinton. I consider three hypotheses: The first claims that, despite the apparent structural changes, the core power relationships will remain the same as in the past, and the antireform alliance either will continue to block policy change or will push through a reform program that protects its constituent interests. According to the second, the structural changes produce an atomization of power, making coalition building in support of reform impossible. The third and most plausible hypothesis proposes that the structural changes, in combination with the shift in politics and Clinton's election, have generated new opportunities for fundamental reform.


Concise review: reactive astrocytes and stem cells in spinal cord injury: good guys or bad guys?
Spinal cord injury (SCI) usually results in long lasting locomotor and sensory neuron degeneration below the injury. Astrocytes normally play a decisive role in mechanical and metabolic support of neurons, but in the spinal cord they cause injury, exerting well-known detrimental effects that contribute to glial scar formation and inhibition of axon outgrowth. Cell transplantation is considered a promising approach for replacing damaged cells and promoting neuroprotective and neuroregenerative repair, but the effects of the grafted cells on local tissue and the regenerative properties of endogenous neural stem cells in the injured spinal cord are largely unknown. During the last 2 decades cumulative evidence from diverse animal models has indicated that reactive astrocytes in synergy with transplanted cells could be beneficial for injury in multiple ways, including neuroprotection and axonal growth. In this review, we specifically focus on the dual opposing roles of reactive astrocytes in SCI and how they contribute to the creation of a permissive environment when combined with transplanted cells as the influential components for a local regenerative niche. Modulation of reactive astrocyte function might represent an extremely attractive new therapy to enhance the functional outcomes in patients.


Determination on the Coefficient of Thermal Expansion in High-Power InGaN-based Light-emitting Diodes by Optical Coherence Tomography.
The coefficient of thermal expansion (CTE) is a physical quantity that indicates the thermal expansion value of a material upon heating. For advanced thermal management, the accurate and immediate determination of the CTE of packaging materials is gaining importance because the demand for high-power lighting-emitting diodes (LEDs) is currently increasing. In this study, we used optical coherence tomography (OCT) to measure the CTE of an InGaN-based (λ = 450 nm) high-power LED encapsulated in polystyrene resin. The distances between individual interfaces of the OCT images were observed and recorded to derive the instantaneous CTE of the packaged LED under different injected currents. The LED junction temperature at different injected currents was established with the forward voltage method. Accordingly, the measured instantaneous CTE of polystyrene resin varied from 5.86 × 10-5 °C-1 to 14.10 × 10-5 °C-1 in the junction temperature range 25-225 °C and exhibited a uniform distribution in an OCT scanning area of 200 × 200 μm. Most importantly, this work validates the hypothesis that OCT can provide an alternative way to directly and nondestructively determine the spatially resolved CTE of the packaged LED device, which offers significant advantages over traditional CTE measurement techniques.


Giant Sporadic Low Grade Malignant Peripheral Nerve Sheath (MPNST) of Left Thigh.
Malignant Peripheral Nerve Sheath Tumours (MPNST) are rare spindle- cell sarcomas which are derived from the schwann cells or the pleuripotent cells of the neural crest. MPNSTs are usually located in the peripheral nerve trunk roots, extremities and in the head and neck region. These tumours may arise as sporadic variants or in patients with neurofibromatosis1 (NF1). The estimated incidence of MPNSTs in the patients with NF1is 2-5% as compared to a 0.001% incidence in the general population. Herein, we are reporting a case of a giant sporadic (NF1 independent) low grade MPNST of the left thigh in 65 year female patient, which had a good prognosis.


Association between metabolic syndrome and overactive bladder: a case-control study.
The aim of this case-control study was to investigate the association between overactive bladder (OAB) and metabolic syndrome (MetS). The primary hypothesis was that OAB is significantly more prevalent among patients with MetS than in control participants. A case-control study was conducted among 114 patients, with 57 patients in the MetS group and 57 in the control group. Study participants were recruited in a family medicine practice. They filled out a questionnaire including questions on age, gender, clinical symptoms, lifestyle and coping behaviors, and the Overactive Bladder Validated 8-question Awareness Tool (OAB-V8) questionnaire. In the MetS group, 74% (n = 42) of patients screened positive on the OAB-V8 questionnaire (score ≥8), which was significantly higher than 29% (n = 17) of patients in the control group (p < 0.001). Lifestyle and coping behaviors associated with OAB were more prevalent in the MetS group. Screening positive on the OAB screening tool was associated with having MetS (p < 0.001), older age (p = 0.004), higher prevalence of using a diuretic (p = 0.002), avoiding places if they think there will not be a restroom (toilet) nearby (p = 0.015), going to the restroom so often that it interferes with things they want to do (p = 0.046) and bladder symptoms making them feel like there is something wrong with them (p < 0.001). OAB is significantly more prevalent in patients suffering from MetS than in those without MetS. Assessment of the presence and monitoring of OAB should be part of the clinical management of patients with MetS.


New processing strategies in cochlear implantation.
New strategies for representing acoustic information with multichannel cochlear implants have produced substantial improvements in speech recognition for implant users. This report reviews within-subject comparison of a new continuous interleaved sampling (CIS) strategy with a compressed analog (CA) strategy used in a standard clinical device. In general, the comparison show higher levels of open-set speech recognition with CIS for each of the 11 subjects studied. Data on the importance of the patients variable in determining outcomes with cochlear implants are presented. A brief description of another new strategy, the spectral maxima sound processor (SMSP) strategy is given as well as information on the availability of CIS in various implant systems.


[Typology of defective states with a syndrome of monotonous activity in schizophrenic patients (problem of late remissions)].
The authors compared 2 types of defective states with a predominance of the syndrome of monotonous activity in the structure of a protracted remission in shift-like schizophrenia. Of the syndrome of monotonous activity of the 1st type the following conditions were most characteristic: autistic activity; a selective attraction to certain forms of work despite their relative high degree of organization and complexity; hyperactivity which was next to an overvalued approach to work. The 2nd type was characterized by a passive attitude to work, a significant restriction of forms of work and machine-like, similar to stereotypicity, character of activity.


Clonal Interference and Mutation Bias in Small Bacterial Populations in Droplets.
Experimental evolution studies have provided key insights into the fundamental mechanisms of evolution. One striking observation is that parallel and convergent evolution during laboratory evolution can be surprisingly common. However, these experiments are typically performed with well-mixed cultures and large effective population sizes, while pathogenic microbes typically experience strong bottlenecks during infection or drug treatment. Yet, our knowledge about adaptation in very small populations, where selection strength and mutation supplies are limited, is scant. In this study, wild-type and mutator strains of the bacterium Escherichia coli were evolved for about 100 generations towards increased resistance to the β-lactam antibiotic cefotaxime in millifluidic droplets of 0.5 µL and effective population size of approximately 27,000 cells. The small effective population size limited the adaptive potential of wild-type populations, where adaptation was limited to inactivating mutations, which caused the increased production of outer-membrane vesicles, leading to modest fitness increases. In contrast, mutator clones with an average of ~30-fold higher mutation rate adapted much faster by acquiring both inactivating mutations of an outer-membrane porin and particularly inactivating and gain-of-function mutations, causing the upregulation or activation of a common efflux pump, respectively. Our results demonstrate how in very small populations, clonal interference and mutation bias together affect the choice of adaptive trajectories by mediating the balance between high-rate and large-benefit mutations.


Clinical course of pathologically confirmed corticobasal degeneration and corticobasal syndrome.
The clinical presentation of corticobasal degeneration is diverse, while the background pathology of corticobasal syndrome is also heterogeneous. Therefore, predicting the pathological background of corticobasal syndrome is extremely difficult. Herein, we investigated the clinical findings and course in patients with pathologically, genetically and biochemically verified corticobasal degeneration and corticobasal syndrome with background pathology to determine findings suggestive of background disorder. Thirty-two patients were identified as having corticobasal degeneration. The median intervals from the initial symptoms to the onset of key milestones were as follows: gait disturbance, 0.0 year; behavioural changes, 1.0 year; falls, 2.0 years; cognitive impairment, 2.0 years; speech impairment, 2.5 years; supranuclear gaze palsy, 3.0 years; urinary incontinence, 3.0 years; and dysphagia, 5.0 years. The median survival time was 7.0 years; 50% of corticobasal degeneration was diagnosed as corticobasal degeneration/corticobasal syndrome at the final presentation. Background pathologies of corticobasal syndrome (n = 48) included corticobasal degeneration (33.3%), progressive supranuclear palsy (29.2%) and Alzheimer's disease (12.5%). The common course of corticobasal syndrome was initial gait disturbance and early fall. In addition, corticobasal degeneration-corticobasal syndrome manifested behavioural change (2.5 years) and cognitive impairment (3.0 years), as the patient with progressive supranuclear palsy-corticobasal syndrome developed speech impairment (1.0 years) and supranuclear gaze palsy (6.0 years). The Alzheimer's disease-corticobasal syndrome patients showed cognitive impairment (1.0 years). The frequency of frozen gait at onset was higher in the corticobasal degeneration-corticobasal syndrome group than in the progressive supranuclear palsy-corticobasal syndrome group [P = 0.005, odds ratio (95% confidence interval): 31.67 (1.46-685.34)]. Dysarthria at presentation was higher in progressive supranuclear palsy-corticobasal syndrome than in corticobasal degeneration-corticobasal syndrome [P = 0.047, 6.75 (1.16-39.20)]. Pyramidal sign at presentation and personality change during the entire course were higher in Alzheimer's disease-corticobasal syndrome than in progressive supranuclear palsy-corticobasal syndrome [P = 0.011, 27.44 (1.25-601.61), and P = 0.013, 40.00 (1.98-807.14), respectively]. In corticobasal syndrome, decision tree analysis revealed that 'freezing at onset' or 'no dysarthria at presentation and age at onset under 66 years in the case without freezing at onset' predicted corticobasal degeneration pathology with a sensitivity of 81.3% and specificity of 84.4%. 'Dysarthria at presentation and age at onset over 61 years' suggested progressive supranuclear palsy pathology, and 'pyramidal sign at presentation and personality change during the entire course' implied Alzheimer's disease pathology. In conclusion, frozen gait at onset, dysarthria, personality change and pyramidal signs may be useful clinical signs for predicting background pathologies in corticobasal syndrome.


Extending Correlation Filter-Based Visual Tracking by Tree-Structured Ensemble and Spatial Windowing.
Correlation filters have been successfully used in visual tracking due to their modeling power and computational efficiency. However, the state-of-the-art correlation filter-based (CFB) tracking algorithms tend to quickly discard the previous poses of the target, since they consider only a single filter in their models. On the contrary, our approach is to register multiple CFB trackers for previous poses and exploit the registered knowledge when an appearance change occurs. To this end, we propose a novel tracking algorithm [of complexity O(D) ] based on a large ensemble of CFB trackers. The ensemble [of size O(2D) ] is organized over a binary tree (depth D ), and learns the target appearance subspaces such that each constituent tracker becomes an expert of a certain appearance. During tracking, the proposed algorithm combines only the appearance-aware relevant experts to produce boosted tracking decisions. Additionally, we propose a versatile spatial windowing technique to enhance the individual expert trackers. For this purpose, spatial windows are learned for target objects as well as the correlation filters and then the windowed regions are processed for more robust correlations. In our extensive experiments on benchmark datasets, we achieve a substantial performance increase by using the proposed tracking algorithm together with the spatial windowing.


Room temperature activates human blood platelets.
Temperatures ranging from room temperature (20 degrees C) to 42 degrees C are generally not considered to have an activating effect on platelets. However, this assumption is not supported by clinical phenomena that result in hemostatic failure related to hypothermia. In this study, we investigated the effect of temperatures between room temperature (20 degrees C) and 42 degrees C on human blood platelets and found that room temperature causes marked activation of platelets. Major changes in platelet morphology were seen at 20 degrees C compared to resting platelets at 37 degrees C. Platelet morphology was investigated with noninvasive live cell techniques (light microscopy and dynamic and static light scattering), as well as with transmission and scanning electron microscopy. The changes in platelet morphology correlated with the expression of the activation marker, activated glycoprotein (GP) IIb-IIIa, measured by flow cytometry. Twenty-five percent to 30% of platelets expressed activated GPIIb-IIIa after exposure to 20 degrees C for 10 minutes. In the presence of serotonin re-uptake inhibitors, the serotonin content of platelets at 20 degrees C was twice that of resting platelets. In comparison, moderate heat shock conditions (42 degrees C for 10 minutes) caused no signs of platelet activation as indicated by the absence of morphological alterations, no expression of activated GPIIb-IIIa, and no changes in serotonin content. These results show that room temperature by itself significantly activates platelets and has an effect on the platelet serotonin content. This may contribute to both the functional lesion associated with 22 degrees C storage of platelets for transfusion and the in vivo hemostatic failure after hypothermia.


LDH levels and left atrial ultrastructural chances in patients with mitral paraprosthetic regurgitation.
The aim of this study was to assess the effect of paraprosthetic regurgitation of mitral mechanical valves to myocardial tissue and lactate dehydrogenase (LDH) level. We compared 19 patients (study group) who had mitral mechanical valve with severe mitral paravalvular regurgitation with 20 patients (control group) who had native valve with severe rheumatic mitral regurgitation. None of the patients had clinical hemolytic anemia. On transesophageal echocardiographic examination, semiquantative evaluation and spatial distribution of regurgitant jets were noted in both of the groups. Five LDH isoenzymes were studied in two groups. Myocardial tissue specimens were taken from the left atrial wall during reoperation. Grids randomly taken were studied under the transmission electron microscope. Total serum LDH levels of the study group (578 +/- 12 IU/L) were higher than the control group (495 +/- 6.2 IU/L) (p < 0.001). We found LDH1/LDH2 more than 1 in all patients; the ratio was not statistically different in the control group. Electron microscopy revealed the same degree of injury in both groups. Haptoglobin levels were decreased and reticulocyte counts were increased in patients with paraprosthetic valve regurgitation. Electron microscopic findings support that myocardial injury contributes to increase of total LDH level and high LDH1/LDH2 ratio. But statistically significant elevation in total LDH level in study group and the stable state of LDH1/LDH2 ratio between two groups showed that hemolysis caused by paraprosthetic regurgitation is the most important factor for the increase of total LDH level, so that high LDH level can be used as a reliable parameter for the diagnosis of intravascular hemolysis in paraprosthetic regurgitation.


Apathy in late-life depression among Taiwanese patients.
Apathy is defined as lack of motivation and occurs in a variety of neuropsychological disorders. The Apathy Evaluation Scale (AES) has been shown to be valid and reliable for assessing apathy in depression but the validity and reliability of the Chinese version has never been examined. The aims of the study were to (1) evaluate the validity and reliability of the Chinese version of the AES in late-life depression and (2) evaluate the severity of apathy in late-life depression. We translated the AES into Chinese and used a cross-sectional design to evaluate apathy in elderly subjects. Diagnostic and Statistical Manual of Mental Disorders (DSM) -IV criteria and Hamilton Depression Rating Scale (HDRS) were applied for diagnosis and assessment. Three groups of subjects were recruited including one group (n = 31) of patients with major depressive disorder with current depression, the second group (n = 30) with major depressed disorder with remission, and the third group (n = 31) of healthy controls. Convergent validity was tested using four apathy-related items from the HDRS (loss of interest, psychomotor retardation, loss of energy, and loss of insight). Multiple forms of reliability (including internal consistency, test-retest, and interrater) and discriminant validity were examined. We demonstrated that the internal consistency (coefficient alpha = 0.90) and test-retest reliability (p < 0.001) were satisfied. Discriminant validity of apathy severity among these three groups was significant. The convergent validity and correlation coefficients based on the four apathy-related items from the HDRS and AES were acceptable. Apathy is a distinct syndrome which may be treatable when depression is effective managed. Further application of the Chinese version of the AES to study the association of apathy with other neuropsychological symptoms is necessary.


Selective Epitaxial Growth of Oriented Hierarchical Metal-Organic Framework Heterostructures.
Metal-organic framework (MOF) heterostructures have shown promising applications in gas adsorption, gas separation, catalysis, and energy, arising from the synergistic effect of each component. However, owing to the difficulty in controlling the size, shape, nucleation, and growth of MOFs, it remains a great challenge to construct MOF heterostructures with precisely controlled orientation, morphology, dimensionality, and spatial distribution of each component. Here, we report a seeded epitaxial growth method to prepare a series of hierarchical MOF heterostructures by engineering the structures, sizes, dimensionalities, morphologies, and lattice parameters of both MOF seeds and the secondary MOFs. In these heterostructures, PCN-222 (also known as MOF-545) nanorods selectively grow along the major axis of the ellipsoid-like PCN-608 nanoparticles, on the two end facets of the hexagonal prism-like NU-1000 nanorods, and on the two basal planes of the hexagonal PCN-134 nanoplates, while Zr-BTB nanosheets selectively grow on the six edge facets of PCN-134 nanoplates. The selective epitaxial growth of MOFs opens the way to synthesize different hierarchical heterostructures with tunable architectures and dimensionalities, which could process various promising applications.


Intra-promoter switch of transcription initiation sites in proliferation signaling-dependent RNA metabolism.
Global changes in transcriptional regulation and RNA metabolism are crucial features of cancer development. However, little is known about the role of the core promoter in defining transcript identity and post-transcriptional fates, a potentially crucial layer of transcriptional regulation in cancer. In this study, we use CAGE-seq analysis to uncover widespread use of dual-initiation promoters in which non-canonical, first-base-cytosine (C) transcription initiation occurs alongside first-base-purine initiation across 59 human cancers and healthy tissues. C-initiation is often followed by a 5' terminal oligopyrimidine (5'TOP) sequence, dramatically increasing the range of genes potentially subjected to 5'TOP-associated post-transcriptional regulation. We show selective, dynamic switching between purine and C-initiation site usage, indicating transcription initiation-level regulation in cancers. We additionally detail global metabolic changes in C-initiation transcripts that mark differentiation status, proliferative capacity, radiosensitivity, and response to irradiation and to PI3K-Akt-mTOR and DNA damage pathway-targeted radiosensitization therapies in colorectal cancer organoids and cancer cell lines and tissues.


Selective Two-Step (STS) Photoionization of Atoms and Photodissociation of Molecules by Laser Radiation.
The general considerations for two-step photoionization of atoms and photodissociation of molecules using tunable laser sources are discussed. Experimental results are given for the (1) photoionization of rubidium vapor using a ruby-laser-pumped dye laser and a doubled ruby laser radiation, and (2) photodissociation of HCl using the Raman-shifted output and the fourth harmonic output of a tunable Nd-glass laser. The possibilities for other laser systems are also discussed.


Molecular dynamics simulations of Nafion and sulfonated polyether sulfone membranes. I. Effect of hydration on aqueous phase structure.
We measured the water uptakes and proton conductivities of a Nafion membrane and three sulfonated polyether sulfone membranes (SPESs) with different values of ion-exchange capacity (IEC = 0.75, 1.0 and 1.4 meq/g) in relation to relative humidity in order to apply the findings to polymer electrolyte membrane fuel cells. The number of water molecules per sulfonic acid group λ at each humidity level was independent of the relative humidity for all membranes, but the proton conductivities of the SPESs were inferior to that of Nafion for the same λ value. Classical molecular dynamics simulations for the same membranes were carried out using a consistent force field at λ = 3, 6, 9, 12 and 15. The structural properties of water molecules and hydronium ions at a molecular level were estimated from radial distribution functions and cluster size distributions of water. We found that the radial distribution function of S(sulfonic acid)-S(sulfonic acid) of Nafion at λ = 3 indicated a significant correlation between the S-S pair, due to water channels, while the S-S pair of the SPESs showed a poor correlation. The cluster size distribution of water was also calculated in order to estimate the connectivity of the water channel. It is clear that some water is present in the SPESs as small, isolated clusters, especially when the water content is low.


Cantharellaceae of Guyana II: new species of Craterellus, new South American distribution records for Cantharellus guyanensis and Craterellus excelsus, and a key to the Neotropical taxa.
Craterellus olivaceoluteus sp. nov. and Craterellus cinereofimbriatus sp. nov. are described as new to science. These fungi were collected from Guyana in association with ectomycorrhizal host trees in the genera Dicymbe (Fabaceae subfam. Caesalpinioideae) and Pakaraimaea (Dipterocarpaceae). Cantharellus guyanensis Mont., originally described from French Guiana, is redescribed from recent collections from Guyana, with additional range extensions for the species provided based on material examined from French Guiana, Venezuela, and north central, northeastern and southern Brazil, circumscribing nearly the entire Guiana Shield region and beyond. A new distribution record from French Guiana is provided for Craterellus excelsus T.W. Henkel & Aime. Macromorphological, micromorphological and habitat data are provided for the new species and C. guyanensis as well as DNA sequence data from the nuclear ribosomal regions of the internal transcribed spacer (ITS) and 28S large subunit (LSU); additional sequence data is provided for C. guyanensis and C. excelsus specimens collected outside Guyana. The relationships of these taxa within the Cantharellaceae were evaluated with phylogenetic analyses of ITS and LSU sequence data. This work brings the total number of Cantharellaceae species known from Guyana to eight. A key to the Cantharellus and Craterellus species known from the lowland Neotropics and extralimital montane Central and South America is provided.


Structural evolution of tunneling oxide passivating contact upon thermal annealing.
We report on the structural evolution of tunneling oxide passivating contact (TOPCon) for high efficient solar cells upon thermal annealing. The evolution of doped hydrogenated amorphous silicon (a-Si:H) into polycrystalline-silicon (poly-Si) by thermal annealing was accompanied with significant structural changes. Annealing at 600 °C for one minute introduced an increase in the implied open circuit voltage (Voc) due to the hydrogen motion, but the implied Voc decreased again at 600 °C for five minutes. At annealing temperature above 800 °C, a-Si:H crystallized and formed poly-Si and thickness of tunneling oxide slightly decreased. The thickness of the interface tunneling oxide gradually decreased and the pinholes are formed through the tunneling oxide at a higher annealing temperature up to 1000 °C, which introduced the deteriorated carrier selectivity of the TOPCon structure. Our results indicate a correlation between the structural evolution of the TOPCon passivating contact and its passivation property at different stages of structural transition from the a-Si:H to the poly-Si as well as changes in the thickness profile of the tunneling oxide upon thermal annealing. Our result suggests that there is an optimum thickness of the tunneling oxide for passivating electron contact, in a range between 1.2 to 1.5 nm.


Can digital transformation reduce corporate stock price crashes?
The purpose of this paper is to study the impact of enterprises' digital transformation on the risk of stock price crashes, but also to study the mediating role of enterprises' financialization and accounting conservatism in the enterprises' digital transformation on stock price crash risk. Based on the data of 2,599 listed companies in China from 2010 to 2019, this paper constructs indicators of enterprise digital transformation through word frequency analysis method, and uses fixed-effects model and mediated-effects model to explore the impact and mechanism of enterprise digital transformation on the stock price crash risk. This study shows that firms' digital transformation reduces the risk of stock price crashes and that financialization of firms and accounting conservatism play a significant mediating effect between enterprises' digital transformation and the risk of stock price crashes. This study enriches the study of stock price crash risk by including digital transformation in the field of stock price crash research, and it examines the mediating roles of financialization of enterprises and accounting conservatism, which provides a new explanatory mechanism to the study of the correlation between digital transformation of enterprises and the risk of stock price crash.


Left ventricular diastolic function in a population of healthy elderly subjects. An echocardiographic study.
Diastolic left ventricular function was comparatively assessed in 19 healthy elderly individuals (mean age 71 years) and in 20 young normal subjects (mean age 26 years), using digitized echocardiograms. Peak and average filling rates were slower in the group of elderly subjects than in the younger population (128 +/- 26 and 75 +/- 11 v 182 +/- 37 and 92 +/- 17 mm per second, respectively, P less than .001). The duration of the rapid filling phase and the time to peak filling rate were significantly longer in the older than in the younger population (207 +/- 39 and 125 +/- 21 v 174 +/- 38 and 90 +/- 26 ms, respectively, P less than .01). The atrial contribution to total ventricular filling was 18 +/- 6% in the elderly and 10 +/- 3% in the young (P less than .001). The group differences of most of these measurements of diastolic function retained statistical significance after correction for heart rate. Measurements of left ventricular systolic function were similar in both age groups. The authors conclude that aging is associated with a decline of left ventricular compliance, unrelated to heart rate or systolic performance. The contribution of atrial contraction to ventricular filling is quantitatively larger in elderly individuals.


Increased free fat-graft survival with the long-term, local delivery of insulin, insulin-like growth factor-I, and basic fibroblast growth factor by PLGA/PEG microspheres.
The present investigation evaluates the effects of long-term, local delivery of insulin, insulin-like growth factor-1 (IGF-1), and basic fibroblast growth factor (bFGF) on fat-graft survival using a poly (lactic-co-glycolic-acid)-polyethylene glycol (PLGA/PEG) microsphere delivery system. Twelve-micrometer PLGA/PEG microspheres incorporated separately with insulin, IGF-1, and bFGF were manufactured using a double-emulsion solvent-extraction technique. Inguinal fat from Sprague Dawley rats was harvested, diced, washed, and mixed with (1) insulin microspheres, (2) insulin-like growth factor-1 microspheres, (3) basic fibroblast growth factor microspheres, (4) a combination of the insulin and IGF-1 microspheres, and (5) a combination of insulin, IGF-1, and bFGF microspheres. The treated fat grafts were implanted autologously into subdermal pockets in six animals for each group. Animals receiving untreated fat grafts and fat grafts treated with blank microspheres constituted two external control groups (six animals per external control group). At 12 weeks, all fat-graft groups were compared on the basis of weight maintenance and a histomorphometric analysis of adipocyte area percentage, indices of volume retention and cell composition, respectively. Weight maintenance was defined as the final graft weight as a percent of the implanted graft weight. All growth factor treatments significantly increased fat-graft weight maintenance objectively, and volume maintenance grossly, in comparison with the untreated and blank microsphere-treated controls. Treatment with insulin and IGF-1, alone or in combination, was found to increase the adipocyte area percentage in comparison with fat grafts treated with bFGF alone or in combination with other growth factors. In conclusion, the findings of this study indicate that long-term, local delivery of growth factors with PLGA/PEG microspheres has the potential to increase fat-graft survival rates. Further, the type of growth factor delivered may influence the cellular/stromal composition of the grafted tissue.


Psychopathy: what apology making tells us about moral agency.
Psychopathy is often used to settle disputes about the nature of moral judgment. The "trolley problem" is a familiar scenario in which psychopathy is used as a test case. Where a convergence in response to the trolley problem is registered between psychopathic subjects and non-psychopathic (normal) subjects, it is assumed that this convergence indicates that the capacity for making moral judgments is unimpaired in psychopathy. This, in turn, is taken to have implications for the dispute between motivation internalists and motivation externalists, for instance. In what follows, we want to do two things: firstly, we set out to question the assumption that convergence is informative of the capacity for moral judgment in psychopathy. Next, we consider a distinct feature of psychopathy which we think provides strong grounds for holding that the capacity for moral judgment is seriously impaired in psychopathic subjects. The feature in question is the psychopathic subject's inability to make sincere apologies. Our central claim will be this: convergence in response to trolley problems does not tell us very much about the psychopathic subject's capacity to make moral judgments, but his inability to make sincere apologies does provide us with strong grounds for holding that this capacity is seriously impaired in psychopathy.


Use of Hydroxychloroquine, Remdesivir, and Dexamethasone Among Adults Hospitalized With COVID-19 in the United States : A Retrospective Cohort Study.
Relatively little is known about the use patterns of potential pharmacologic treatments of COVID-19 in the United States. To use the National COVID Cohort Collaborative (N3C), a large, multicenter, longitudinal cohort, to characterize the use of hydroxychloroquine, remdesivir, and dexamethasone, overall as well as across individuals, health systems, and time. Retrospective cohort study. 43 health systems in the United States. 137 870 adults hospitalized with COVID-19 between 1 February 2020 and 28 February 2021. Inpatient use of hydroxychloroquine, remdesivir, or dexamethasone. Among 137 870 persons hospitalized with confirmed or suspected COVID-19, 8754 (6.3%) received hydroxychloroquine, 29 272 (21.2%) remdesivir, and 53 909 (39.1%) dexamethasone during the study period. Since the release of results from the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial in mid-June, approximately 78% to 84% of people who have had invasive mechanical ventilation have received dexamethasone or other glucocorticoids. The use of hydroxychloroquine increased during March 2020, peaking at 42%, and started declining by April 2020. By contrast, remdesivir and dexamethasone use gradually increased over the study period. Dexamethasone and remdesivir use varied substantially across health centers (intraclass correlation coefficient, 14.2% for dexamethasone and 84.6% for remdesivir). Because most N3C data contributors are academic medical centers, findings may not reflect the experience of community hospitals. Dexamethasone, an evidence-based treatment of COVID-19, may be underused among persons who are mechanically ventilated. The use of remdesivir and dexamethasone varied across health systems, suggesting variation in patient case mix, drug access, treatment protocols, and quality of care. National Center for Advancing Translational Sciences; National Heart, Lung, and Blood Institute; and National Institute on Aging.


Nerve growth factor increases the number of functional Na channels and induces TTX-resistant Na channels in PC12 pheochromocytoma cells.
The PC12 clone is a line of rat pheochromocytoma cells that undergoes neuronal differentiation in the presence of NGF protein. In the absence of NGF, PC12 cells are electrically inexcitable, while after several weeks of NGF treatment they develope Na+ action potentials. Past estimates made by measuring binding of 3H-saxitoxin (STX) indicate that NGF treatment brings about a large increase in Na channel density that is of sufficient magnitude to account for the induction of excitability. We have now used 22Na uptake to measure the Na permeability of PC12 cells before and after long-term NGF treatment. Treatment with NGF does not change the resting Na+ permeability. The alkaloid toxins veratridine and batrachotoxin (BTX) and scorpion toxin were used to activate Na channels. Such studies demonstrate that these toxins induce TTX-sensitive Na uptake in both NGF-treated and untreated cells and reveal differences in functional Na channel numbers per cell and per unit of membrane area that are similar to those found in the STX binding studies. On the other hand, affinities for drugs that activate these channels are not affected by NGF treatment. We also find that NGF-treated PC12 cells contain a population of Na channels with low affinity for TTX. These channels account for 5-20% of total BTX or veratridine-stimulated flux. Thus, NGF has 2 effects regarding the Na channels of PC12 cells: it increases the number of functional Na channels that otherwise behave similarly to those present before NGF treatment, and it induces the presence of TTX-resistant Na channels. These findings indicate that the PC12 model system may serve to study the developmental regulation of Na channel expression and properties.


CNS-specific therapy for ongoing EAE by silencing IL-17 pathway in astrocytes.
The interleukin-17 (IL-17) cytokine family is crucial to the progression of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). It has been shown in a neuroectoderm-specific knockout study that astrocyte-restricted ablation of Act1, a key and common transcription factor for signals mediated by IL-17 family members (IL-17A, IL-17F, and IL-17C), ameliorates EAE. However, the effect of Act1 deficiency in astrocytes on ongoing disease, which is of clinical relevance for MS therapy, has not been investigated. Here we report that intracerebroventricular (i.c.v.) injection of a novel lentiviral vector (shAct1) to knockdown Act1 expression in astrocytes effectively inhibited disease progression at EAE induction, clinical onset, and peak of disease (ongoing phases), with significantly reduced numbers of infiltrating inflammatory cells and percentage of Th17 cells in the central nervous system (CNS). This was mainly due to the suppressed expression of Th17-related chemokines in astrocytes, while neurotrophic factors in the CNS and immune responses in the periphery were not affected. These results demonstrate that blocking the IL-17 pathways in astrocytes is a promising therapeutic approach for MS in a CNS-specific manner, which does not interfere with systemic immune responses, a major concern in conventional MS therapy.


Detection of minimal residual T cell acute lymphoblastic leukemia by flow cytometry.
We have developed a flow cytometric assay for the determination of cellular expression of terminal deoxynucleotidyl transferase (TdT) and applied this to the detection of minimal residual T cell acute lymphoblastic leukemia (T-ALL). The flow cytometric assay for TdT demonstrated requisite specificity: TdT was localized to the nucleus, and was detected in MOLT3 T lymphoblasts, clinical T-ALL samples, and normal bone marrow B lymphoid precursors, but in neither the KG1a myeloid leukemia cell line nor normal myeloid cells. Co-expression of TdT and the pan T cell marker CD5 was used to quantify T lymphoblasts. 0.25 +/- 0.13% of normal adult bone marrow CD5+ cells were TdT+; these may represent early T lymphoid precursors. When admixed with normal bone marrow, CD5+TdT+ leukemic cells could be detected above background levels at an added concentration of 0.035% (95% confidence interval 0.028-0.43%). Long term follow-up of a large number of patients will be required to determine the clinical significance of a minimal burden of leukemic cells.


Emotion regulation as a scientific construct: methodological challenges and directions for child development research.
Emotion regulation has emerged as a popular topic, but there is doubt about its viability as a scientific construct. This article identifies conceptual and methodological challenges in this area of study and describes exemplar studies that provide a substantive basis for inferring emotion regulation. On the basis of those studies, 4 methods are described that provide compelling evidence for emotion regulation: independent measurement of activated emotion and purported regulatory processes; analysis of temporal relations; measurement across contrasting conditions; and multiple, convergent measures. By offering this perspective, this article aims to engage thoughtful debate and critical analysis, with the goal of increasing methodological rigor and advancing an understanding of emotion regulation as a scientific construct.


Antigen-specific cellular hyporesponsiveness in a chronic human helminth infection is mediated by T(h)3/T(r)1-type cytokines IL-10 and transforming growth factor-beta but not by a T(h)1 to T(h)2 shift.
Exposure to infective larvae of the filarial nematode Onchocerca volvulus (Ov) either results in patent infection (microfilaridermia) or it leads to a status called putative immunity, characterized by resistance to infection. Similar to other chronic helminth infections, there is a T cell proliferative hyporesponsiveness to Ov antigen (OvAg) by peripheral blood mononuclear cells (PBMC) from individuals with patent infection, i.e. generalized onchocerciasis (GEO), compared to PBMC from putatively immune (PI) individuals. In this study, mechanisms mediating this cellular hyporesponsiveness in GEO were investigated: the low proliferative response in PBMC from GEO individuals was associated with a lack of IL-4 production and significantly lower production of IL-5 compared to those from PI individuals, arguing against a general shift towards a T(h)2 response being the cause of hyporesponsiveness. In contrast, IL-10 and transforming growth factor (TGF)-beta, two cytokines associated with a T(h)3 response, seemed to mediate hyporesponsiveness: PBMC from individuals with GEO produced significantly more IL-10, and T cell proliferative hyporesponsiveness in this group could be reversed by the addition of anti-IL-10 and anti-TGF-beta antibodies. Hyporesponsiveness was specific for OvAg and not observed upon stimulation with related nematode antigens, arguing for a T cell-mediated, Ov-specific down-regulation. Ov-specific T cells could be cloned from GEO PBMC which have a unique cytokine profile (no IL-2 but high IL-10 and/or TGF-beta production), similar to the T cell subsets known to suppress ongoing inflammation (T(h)3 and T(r)1), indicating that this cell type which has not been found so far in infectious diseases may be involved in maintaining Ov-specific hyporesponsiveness.


Regulation of insulin receptor substrate 1 pleckstrin homology domain by protein kinase C: role of serine 24 phosphorylation.
Phosphorylation of insulin receptor substrate (IRS) proteins on serine residues is an important posttranslational modification that is linked to insulin resistance. Several phosphoserine sites on IRS1 have been identified; the majority are located proximal to the phosphotryosine-binding domain or near key receptor tyrosine kinase substrate- and/or Src-homology 2 domain-binding sites. Here we report on the characterization of a serine phosphorylation site in the N-terminal pleckstrin homology (PH) domain of IRS1. Bioinformatic tools identify serine 24 (Ser24) as a putative substrate site for the protein kinase C (PKC) family of serine kinases. We demonstrate that this site is indeed a bona fide substrate for conventional PKC. In vivo, IRS-1 is also phosphorylated on Ser24 after phorbol 12-myristate 13-acetate treatment of cells, and isoform-selective inhibitor studies suggest the involvement of PKCalpha. By comparing the pharmacological characteristics of phorbol 12-myristate 13-acetate-stimulated Ser24 phosphorylation with phosphorylation at two other sites previously linked to PKC activity (Ser307 and Ser612), we show that PKCalpha is likely to be directly involved in Ser24 phosphorylation, but indirectly involved in Ser307 and Ser612 phosphorylation. Using Ser24Asp IRS-1 mutants to mimic the phosphorylated residue, we demonstrate that the phosphorylation status of Ser24 does play an important role in regulating phosphoinositide binding to, and the intracellular localization of, the IRS1-PH domain, which can ultimately impinge on insulin-stimulated glucose uptake. Hence we provide evidence that IRS1-PH domain function is important for normal insulin signaling and is regulated by serine phosphorylation in a manner that could contribute to insulin resistance.


Entangled photons from composite cascade emitters.
One of the most versatile sources for entangled photons are emitters that interact via more than one tunable mechanism. Here, we demonstrate how hybridization and dipole-dipole interactions-potentially simultaneously available in colloidal quantum dots and molecular aggregates-leveraged in conjunction can couple simple, well understood emitters into composite emitters with flexible control over the level structure. We show that cascade decay through carefully designed level structures can result in emission of frequency-entangled photons with Bell states and three-photon GHZ states as example cases. These results pave the way toward rational design of quantum optical emitters of entangled photons.


Cyclooxygenase-2 promotes hepatocellular carcinoma cell growth through Akt activation: evidence for Akt inhibition in celecoxib-induced apoptosis.
Cyclooxygenase-2 (COX-2)-controlled prostaglandin (PG) metabolism recently has been implicated in the pathogenesis of hepatocellular carcinoma (HCC). However, the biologic role and molecular mechanism of COX-2-mediated PGs in the control of liver cancer growth have not been established. This study was designed to examine the direct effect of COX-2 and its inhibitor celecoxib on the growth control of liver cancer cells. Human HCC cell lines Hep3B and HepG2 transfected with COX-2 expression vector showed increased cell growth and enhanced phosphorylation of serine/threonine protein kinase B (Akt). The level of COX-2 expression and Akt phosphorylation is correlated positively in cultured HCC cells and human liver cancer tissues. Inhibition of Akt activation by phosphatidylinositol 3-kinase (PI3-kinase) inhibitor LY294002 significantly decreased the viability of Hep3B and HepG2 cells (P <.01). These results reveal a novel role of Akt activation in COX-2-induced HCC cell survival. Furthermore, HCC cells treated with the COX-2 inhibitor celecoxib showed significant reduction of Akt phosphorylation and marked morphologic and biochemical characteristics of apoptosis. Overexpression of COX-2 or addition of exogenous PGE(2) partially prevented celecoxib-induced apoptosis (P <.01). In conclusion, our results suggest the involvement of COX-2-dependent and -independent mechanisms in celecoxib-mediated HCC cell apoptosis.


Importance of plasticity and decision-making strategies for plant resource acquisition in spatio-temporally variable environments.
* Plants must cope with environmental variation in space and time. Phenotypic plasticity allows them to adjust their form and function to small-scale variations in habitat quality. Empirical studies have shown that stoloniferous plants can exploit heterogeneous habitats through plastic ramet specialization and internal resource exchange (division of labour). * Here we present a spatially explicit simulation model to explore costs and benefits of plasticity in spatio-temporally heterogeneous environments. We investigated the performance of three plant strategies in pairwise competition. The nonplastic strategy was unable to specialize. The autonomous plastic strategy displayed localized responses to external resource signals. In the coordinated plastic strategy, localized responses could be modified by internal demand signals from connected modules. * Plasticity in resource uptake proved beneficial in a broad range of environments. Modular coordination was beneficial under virtually all realistic conditions, especially if resource supplies did not closely match resource needs. * The benefits of division of labour extend considerably beyond the parameter combination covered by empirical studies. Our model provides a general framework for evaluating the benefits, costs and limits of plasticity in spatio-temporally heterogeneous habitats.


Histocompatibility antigens in psoriatic arthritis.
Histocompatibility (HL-A) antigen typing was performed on 82 patients with psoriatic arthritis. The prevalance of HL-AB27 was increased (28%) compared with that in a control group (7-5%), and this was most marked in those with spinal changes. The prevalence in patients with sacroiliitis and syndesmophytes was 75%, with sacroiliitis alone 78%, but with syndesmophytes and normal sacroiliac joints only 36%. The overall prevalence in psoriatic spondylitis was 60%, with a prevalence of 71% in those fulfilling the New York criteria for anklosing spondylitis. The prevalence was not increased in those with only peripheral arthritis (11%). The prevalence of HLA-B13 was decreased in those with psoriatic spondylitis, though this was not statistically significant. The overall prevalence of HLA-BW17 was increased, this being particularly so in those with syndesmophytes, but values were not significant.


The validity and Reliability of the Turkish Version of Drug Attitude Inventory-10.
Compliance with drug treatment is an important issue in schizophrenia for which many scales have been devised. Turkish version of the Drug Attitude Inventory is frequently employed due to ease of use and high predictive value, although it is not as accurate as blood level testing.To determine the validity and reliability of the Turkish version of the Drug Attitude Inventory-10. Eighty-two schizophrenia patients were included in the study. Subjects were evaluated using Drug Attitude Inventory-10, a Sociodemographic Data Form, Positive and Negative Symptom Scale PANNS, Social Functioning Scale, and Quality of Life Scale for schizophrenia patients. Reliability analysis revealed Cronbach's α coefficient for internal consistency to be 0.798 and item-total item correlation coefficients to be between 0.420 and 0.647. Test-retest correlation coefficient (r) was 0.809. Construct validity analysis revealed a tri-factorial construct which accounts for 62.68% of variance. Good conformity to single factor construct was found with confirmatory factor analysis. Turkish version of the Drug Attitude Inventory-10 is valid and reliable for evaluation of schizophrenia patients which makes it suitable for research and clinical settings.


Progression of small, irregular opacities in chest radiographs of former asbestos workers.
Pulmonary parenchymal changes appear many years after the start of exposure to asbestos and their progression has been observed to continue many years after cessation of the exposure. The aim of the present analysis is to assess the risk of progression of radiological changes in the respiratory system, based on long-term follow-up of groups of workers occupationally exposed to asbestos dust. The analysis included 3144 individuals voluntarily applying for a medical examination in 2000-2010, who had performed at least two radiographs of the chest. Probability of progression in subsequent studies was based on the evaluation of radiographs for the presence of small, irregular type s, t, u opacities in the parenchymal lung tissue with profusion categories as specified in the classification of ILO, 1980. Multistate hidden Markov model was used in the statistical analysis. In the group of patients, small irregular opacities with a profusion of 1/1 or higher occurred in 640 (20%) patients in the first examination, and in 918 (29%) patients in the last examination. No parenchymal changes were observed in 1360 (43%) patients in the first examination (opacity profusion category 0/0), and in 645 (20%) patients in the last examination. The risk of progression of radiographic changes in former workers of asbestos processing plants is higher in smokers, from profusion category 0 to 1 - by 30% (HR = 1.30, 95% CI: 1.15-1.47), from profusion category 1 to 2 - by 50% (HR = 1.50, 95% CI: 0.92-2.45). The risk of progression of parenchymal changes decreases in the workers employed in subsequent calendar years: for category changes from 1 to 2, the decrease is nearly 40% for every 10 years of subsequent employment (HR = 0.60, 95% CI: 0.45-0.80). The probability of the progression increases with longer latency period: for change of category from 1 to 2, the increase is about 20% (HR = 1.19, 95% CI: 1.00-1.42) per 10 years of employment for blue collar workers. The risk of the 1 to 2 category progression is significant, nearly 2.5-fold higher in the workers employed in the asbestos-processing textile industry. Our results show that the risk of progression of pulmonary parenchymal fibrotic processes was higher in the smokers, workers employed during the earlier calendar years of the discussed period, those with longer latency period, blue collar workers involved directly in the production processes, and employees of the asbestos cement and/or textile industries.


Serotonin transporter and receptor expression in osteocytic MLO-Y4 cells.
Neurotransmitter regulation of bone metabolism has been a subject of increasing interest and investigation. We reported previously that osteoblastic cells express a functional serotonin (5-HT) signal transduction system, with mechanisms for responding to and regulating uptake of 5-HT. The clonal murine osteocytic cell line, MLO-Y4, demonstrates expression of the serotonin transporter (5-HTT), and the 5-HT1A, and 5-HT2A receptors by real-time RT-PCR and immunoblot analysis. Immunohistochemistry using antibodies for the 5-HTT, and the 5-HT1A and 5-HT2A receptors reveals expression of all three proteins in both osteoblasts and osteocytes in rat tibia. 5-HTT binding sites were demonstrated in the MLO-Y4 cells with nanomolar affinity for the stable cocaine analog [125I]RTI-55. Imipramine and fluoxetine, antagonists with specificity for 5-HTT, show the highest potency to antagonize [125I]RTI-55 binding in the MLO-Y4 cells. GBR-12935, a relatively selective dopamine transporter antagonist, had a much lower potency, as did desipramine, a selective norepinephrine transporter antagonist. The maximal [3H]5-HT uptake rate in MLO-Y4 cells was 2.85 pmol/15 min/well, with a Km value of 290 nM. Imipramine and fluoxetine inhibited specific [3H]5-HT uptake with IC50 values in the nanomolar range. 5-HT rapidly stimulated PGE2 release from MLO-Y4 cells; the EC50 for 5-HT was 0.1 microM, with a 3-fold increase seen at 60 min. The rate-limiting enzyme for serotonin synthesis, tryptophan hydroxylase, is expressed in MLO-Y4 cells as well as osteoblastic MC3T3-E1 cells. Thus, osteocytes, as well as osteoblasts, are capable of 5-HT synthesis, and express functional receptor and transporter components of the 5-HT signal transduction system.


Inhibition of renin-angiotensin system reverses endothelial dysfunction and oxidative stress in estrogen deficient rats.
Estrogen deficiency increases the cardiovascular risks in postmenopausal women. Inhibition of the renin-angiotensin system (RAS) and associated oxidative stress confers a cardiovascular protection, but the role of RAS in estrogen deficiency-related vascular dysfunction is unclear. The present study investigates whether the up-regulation of RAS and associated oxidative stress contributes to the development of endothelial dysfunction during estrogen deficiency in ovariectomized (OVX) rats. Adult female rats were ovariectomized with and without chronic treatment with valsartan and enalapril. Isometric force measurement was performed in isolated aortae. The expression of RAS components was determined by immunohistochemistry and Western blotting method while ROS accumulation in the vascular wall was evaluated by dihydroethidium fluorescence. Ovariectomy increased the expression of angiotensin-converting enzyme (ACE), angiotensin II type 1 receptor (AT(1)R), NAD(P)H oxidase, and nitrotyrosine in the rat aorta. An over-production of angiotensin II and ROS was accompanied by decreased phosphorylation of eNOS at Ser(1177) in OVX rat aortae. These pathophysiological changes were closely coupled with increased oxidative stress and decreased nitric oxide bioavailability, culminating in markedly impaired endothelium-dependent relaxations. Furthermore, endothelial dysfunction and increased oxidative stress in aortae of OVX rats were inhibited or reversed by chronic RAS inhibition with enalapril or valsartan. The novel findings highlight a significant therapeutic benefit of RAS blockade in the treatment of endothelial dysfunction-related vascular complications in postmenopausal states.


[Electroroentgenoscanning of the thyroid gland].
A significant drawback of the radioisotopic scanning of the thyroid gland is the absence of a distinct knowledge of topographo-anatomical associations of this gland with other organs and tissues. To eliminate the mentioned drawback the method of electroscanning (combined electroroentgenography and radioisotopic scanning in two interperpendicular projections) was introduced into practice of the regional hospital. Electroscannograms were prepared on paper by means of the apparatus made in the USSR: roentgenograph ERGA-MP, gammatopograph GT-2, and roentgenodiagnostic unit ARD-2. The principle of the method consists in recording the scannogram of the gland on the preliminarily prepared electroroentgenogram of the cervical area and of the upper part of the chest in the horizontal position of the patient. Lead labels attached to definite areas of the patient's skin were used for matching the scannogram with the electroroentogenogram. This method differs from routine seannography of the gland by the fact that it provides an additional topography-anatomical information; it can be used in any radioisotopic diagnostic laboratory equipped with a scanner.


Nonequilibrium generalised Langevin equation for the calculation of heat transport properties in model 1D atomic chains coupled to two 3D thermal baths.
We use a generalised Langevin equation scheme to study the thermal transport of low dimensional systems. In this approach, the central classical region is connected to two realistic thermal baths kept at two different temperatures [H. Ness et al., Phys. Rev. B 93, 174303 (2016)]. We consider model Al systems, i.e., one-dimensional atomic chains connected to three-dimensional baths. The thermal transport properties are studied as a function of the chain length N and the temperature difference ΔT between the baths. We calculate the transport properties both in the linear response regime and in the non-linear regime. Two different laws are obtained for the linear conductance versus the length of the chains. For large temperatures (T≳500 K) and temperature differences (ΔT≳500 K), the chains, with N>18 atoms, present a diffusive transport regime with the presence of a temperature gradient across the system. For lower temperatures (T≲500 K) and temperature differences (ΔT≲400 K), a regime similar to the ballistic regime is observed. Such a ballistic-like regime is also obtained for shorter chains (N≤15). Our detailed analysis suggests that the behaviour at higher temperatures and temperature differences is mainly due to anharmonic effects within the long chains.


Computer-Aided Prostate Cancer Diagnosis From Digitized Histopathology: A Review on Texture-Based Systems.
Prostate cancer (PCa) is currently diagnosed by microscopic evaluation of biopsy samples. Since tissue assessment heavily relies on the pathologists level of expertise and interpretation criteria, it is still a subjective process with high intra- and interobserver variabilities. Computer-aided diagnosis (CAD) may have a major impact on detection and grading of PCa by reducing the pathologists reading time, and increasing the accuracy and reproducibility of diagnosis outcomes. However, the complexity of the prostatic tissue and the large volumes of data generated by biopsy procedures make the development of CAD systems for PCa a challenging task. The problem of automated diagnosis of prostatic carcinoma from histopathology has received a lot of attention. As a result, a number of CAD systems, have been proposed for quantitative image analysis and classification. This review aims at providing a detailed description of selected literature in the field of CAD of PCa, emphasizing the role of texture analysis methods in tissue description. It includes a review of image analysis tools for image preprocessing, feature extraction, classification, and validation techniques used in PCa detection and grading, as well as future directions in pursuit of better texture-based CAD systems.


[Sealing of conjunctival fistulas by means of a fibrinogen adhesive (author's transl)].
The author reports on two patients who developed athalamia postoperatively due to external fistulas in the filtering bleb. After initial failure of both conservative and surgical treatment the fistulas were successfully sealed with highly concentrated fibrinogen in combination with thrombin and clotting factor XIII. There was no impairment of the filtering bleb. Principles and techniques of tissue adhesion are described.


Raised serum alkaline phosphatase activity in one family.
Eleven members of the same family were studied after an incidental detection of raised serum alkaline phosphatase activity in one of them without any apparent underlying cause. Three other members were found to have the same abnormality; none of them had an associated disease. In the four cases with elevated serum alkaline phosphatase levels, its activity showed a preponderance of the bone isoenzyme. Studies of the erythrocyte and histocompatibility antigens in nine members of the family, as well as idiograms of karyotypes of four of them, did not show any relation between histocompatibility antigens and the raised levels of serum alkaline phosphatase. Also, no chromosomal abnormality is shown from karyotypes. The data suggest a probable autosomal dominant pattern of inheritance.