Virulence strategies for infecting phagocytes deduced from the in vivo transcriptional program of Legionella pneumophila.
Adaptation to the host environment and exploitation of host cell functions are critical to the success of intracellular pathogens. Here, insight to these virulence mechanisms was obtained for the first time from the transcriptional program of the human pathogen Legionella pneumophila during infection of its natural host, Acanthamoeba castellanii. The biphasic life cycle of L. pneumophila was reflected by a major shift in gene expression from replicative to transmissive phase, concerning nearly half of the genes predicted in the genome. However, three different L. pneumophila strains showed similar in vivo gene expression patterns, indicating that common regulatory mechanisms govern the Legionella life cycle, despite the plasticity of its genome. During the replicative phase, in addition to components of aerobic metabolism and amino acid catabolism, the Entner-Doudoroff pathway, a NADPH producing mechanism used for sugar and/or gluconate assimilation, was expressed, suggesting for the first time that intracellular L. pneumophila may also scavenge host carbohydrates as nutrients and not only proteins. Identification of genes only upregulated in vivo but not in vitro, may explain higher virulence of in vivo grown L. pneumophila. Late in the life cycle, L. pneumophila upregulates genes predicted to promote transmission and manipulation of a new host cell, therewith priming it for the next attack. These including substrates of the Dot/Icm secretion system, other factors associated previously with invasion and virulence, the motility and the type IV pilus machineries, and > 90 proteins not characterized so far. Analysis of a fliA (sigma28) deletion mutant identified genes coregulated with the flagellar regulon, including GGDEF/EAL regulators and factors that promote host cell entry and survival.


Surgical reconstruction of peripheral pulmonary artery stenosis in Williams and Alagille syndromes.
Peripheral pulmonary artery stenosis is a rare congenital heart defect frequently found in association with Williams and Alagille syndromes. Controversy exists regarding the optimal treatment of peripheral pulmonary artery stenosis, with most centers favoring catheter-based interventions. In contrast, we have preferentially used surgical reconstruction of peripheral pulmonary artery stenosis. The purpose of the present study was to review our experience with surgical reconstruction of peripheral pulmonary artery stenosis. We performed a retrospective review of patients who underwent surgical reconstruction of peripheral pulmonary artery stenosis. A total of 16 patients were identified: 7 had Williams syndrome, 6 had Alagille syndrome, and 3 had no identifiable syndrome. Detailed pulmonary angiography was performed in all patients to define stenoses at the main, branch, lobar, and segmental arterial levels. The mean preoperative right ventricular/left ventricular pressure ratio was 0.88 ± 0.07. The surgical approach was a median sternotomy with cardiopulmonary bypass. All peripheral stenoses were augmented with pulmonary artery homograft tissue. The median age at surgery was 14 months, and concomitant procedures were performed in 9 of the 16 patients. There was 1 operative mortality (6%). The mean right ventricular/left ventricular pressure ratio decreased to 0.40 ± 0.04 postoperatively (P < .005), representing a 55% reduction compared with the preoperative values. The patients were followed up for a median of 5 years. No late mortality occurred and reoperation was not required. The data have demonstrate that this comprehensive surgical approach to the treatment of peripheral pulmonary artery stenosis was associated with low early and no late mortality. Surgical reconstruction of the peripheral pulmonary artery stenosis resulted in a significant decrease in right ventricular pressure. We hypothesize that this reduction in right ventricular pressures will confer a long-term survival advantage for this cohort of patients.


Discovery and partial characterization of primate motor-system toxins.
beta-N-Oxalylamino-L-alanine (BOAA) and beta-N-methylamino-L-alanine (BMAA) are chemically related excitant amino acids isolated from the seed of Lathyrus sativus (BOAA) and Cycas circinalis (BMAA), consumption of which has been linked to lathyrism (an upper motor neuron disorder) and Guam amyotrophic lateral sclerosis (ALS), respectively. Both diseases are associated with degeneration of motor neurons. Experimentally, single doses of BOAA or BMAA induce seizures in neonatal mice and postsynaptic neuronal oedema and degeneration in explants of mouse spinal cord and frontal cortex. Preliminary studies show that these behavioural and pathological effects are differentially blocked by glutamate-receptor antagonists. In macaques, several weeks of daily oral doses of BOAA produce clinical and electrophysiological signs of corticospinal dysfunction identical to those seen in comparably well-nourished animals receiving a fortified diet based on seed of Lathyrus sativus. By contrast, comparable oral dosing with BMAA precipitates tremor and weakness, bradykinesia and behavioural changes, with conduction deficits in the principal motor pathway. BOAA and BMAA (or a metabolite thereof) are the first members of the excitotoxin family to have been shown to possess chronic motor-system toxic potential. These observations provide a rational basis for searching for comparable endogenous neurotoxins in sporadic and inherited forms of human motor neuron disease.


The structure-activity relationship of the salicylimide derived inhibitors of UDP-sugar producing pyrophosphorylases.
UDP-sugars are key precursors for biomass production in nature (synthesis of cellulose, hemicellulose, etc.). They are produced de novo by distinct UDP-sugar producing pyrophosphorylases. Studies on the roles of these enzymes using genetic knockouts were hampered by sterility of the mutants and by functional-complementation from related enzyme(s), hindering clear interpretation of the results. In an attempt to override these difficulties, we turned to the reverse chemical genetics approaches to identify compounds which interfere with the activity of those enzymes in vivo. Hit expansion on one of such compounds, a salicylimide derivative, allowed us to identify several inhibitors with a range of activities. The present study provides a structure-activity relationship for these compounds.


Impact of a standardized protocol and antibiotic-impregnated catheters on ventriculostomy infection rates in cerebrovascular patients.
Ventriculostomy infections create significant morbidity. To reduce infection rates, a standardized evidence-based catheter insertion protocol was implemented. A prospective observational study analyzed the effects of this protocol alone and with antibiotic-impregnated ventriculostomy catheters. To compare infection rates after implementing a standardized protocol for ventriculostomy catheter insertion with and without the use of antibiotic-impregnated catheters. Between 2003 and 2008, 1961 ventriculostomies and infections were documented. A ventriculostomy infection was defined as 2 positive CSF cultures from ventriculostomy catheters with a concurrent increase in cerebrospinal fluid white blood cell count. A baseline (preprotocol) infection rate was established (period 1). Infection rates were monitored after adoption of the standardized protocol (period 2), institution of antibiotic-impregnated catheter A (period 3), discontinuation of antibiotic-impregnated catheter A (period 4), and institution of antibiotic-impregnated catheter B (period 5). The baseline infection rate (period 1) was 6.7% (22/327 devices). Standardized protocol (period 2) implementation did not change the infection rate (8.2%; 23/281 devices). Introduction of catheter A (period 3) reduced infections to 1.0% (2/195 devices, P=.0005). Because of technical difficulties, this catheter was discontinued (period 4), resulting in an increase in infection rate (7.6%; 12/157 devices). Catheter B (period 5) significantly decreased infections to 0.9% (9 of 1001 devices, P=.0001). The Staphylococcus infection rate for periods 1, 2, and 4 was 6.1% (47/765) compared with 0.2% (1/577) during use of antibiotic-impregnated catheters (periods 3 and 5). The use of antibiotic-impregnated catheters resulted in a significant reduction of ventriculostomy infections and is recommended in the adult neurosurgical population.


Morphological Characterization of Basally Located Uninucleate Trophoblast Cells as Precursors of Bovine Binucleate Trophoblast Giant Cells.
Binucleate trophoblast giant cells (TGCs) are one characteristic feature of the ruminant placenta. In cows, the frequency of TGCs remains constant for most of the duration of pregnancy. As TGCs are depleted by their fusion with uterine epithelial cells, they need to be constantly formed. It is still unclear whether they develop from stem cells within the trophectoderm or whether they can arise from any uninucleate trophoblast cell (UTC). Within the latter, generally accepted theory, a basally located uninucleate cell (BUC) without contact to the feto-maternal interface would represent a transient cell between a UTC and a TGC. So far, no evidence for the existence of such transient cells or for the presence of stem cells has been shown. The aim of the present study is to morphologically characterize the early stages of TGC development. Placentomal tissue of 6 pregnant cows from different gestational stages (gestational days 51-214) was examined for BUCs, UTCs, and TGCs either in serial sections (light and transmission electron microscopy, TEM, n = 3), in single sections (TEM, n = 2), or by serial block face-scanning electron microscopy (n = 1). These investigations revealed the occurrence of BUCs, as well as young TGCs showing contact with the basement membrane (BM), but without apical contact to the feto-maternal interface. The study morphologically defines these 2 cell types as early stages of TGC development and shows that binucleation of TGCs can precede detachment from the BM.


Quiescence and activation of stem and precursor cell populations in the subependymal zone of the mammalian brain are associated with distinct cellular and extracellular matrix signals.
The subependymal zone (SEZ) of the lateral ventricles is one of the areas of the adult brain where new neurons are continuously generated from neural stem cells (NSCs), via rapidly dividing precursors. This neurogenic niche is a complex cellular and extracellular microenvironment, highly vascularized compared to non-neurogenic periventricular areas, within which NSCs and precursors exhibit distinct behavior. Here, we investigate the possible mechanisms by which extracellular matrix molecules and their receptors might regulate this differential behavior. We show that NSCs and precursors proceed through mitosis in the same domains within the SEZ of adult male mice--albeit with NSCs nearer ependymal cells--and that distance from the ventricle is a stronger limiting factor for neurogenic activity than distance from blood vessels. Furthermore, we show that NSCs and precursors are embedded in a laminin-rich extracellular matrix, to which they can both contribute. Importantly, they express differential levels of extracellular matrix receptors, with NSCs expressing low levels of alpha6beta1 integrin, syndecan-1, and lutheran, and in vivo blocking of beta1 integrin selectively induced the proliferation and ectopic migration of precursors. Finally, when NSCs are activated to reconstitute the niche after depletion of precursors, expression of laminin receptors is upregulated. These results indicate that the distinct behavior of adult NSCs and precursors is not necessarily regulated via exposure to differential extracellular signals, but rather via intrinsic regulation of their interaction with their microenvironment.


Biodiversity increases ecosystem functions despite multiple stressors on coral reefs.
Positive relationships between biodiversity and ecosystem functioning (BEF) highlight the importance of conserving biodiversity to maintain key ecosystem functions and associated services. Although natural systems are rapidly losing biodiversity due to numerous human-caused stressors, our understanding of how multiple stressors influence BEF relationships comes largely from small, experimental studies. Here, using remote assemblages of coral reef fishes, we demonstrate strong, non-saturating relationships of biodiversity with two ecosystem functions: biomass and productivity. These positive relationships were robust both to an extreme heatwave that triggered coral bleaching and to invasive rats which disrupt nutrient subsidies from native seabirds. Despite having only minor effects on BEF relationships, both stressors still decreased ecosystem functioning via other pathways. The extreme heatwave reduced biodiversity, which, due to the strong BEF relationships, ultimately diminished both ecosystem functions. Conversely, the loss of cross-system nutrient subsidies directly decreased biomass. These results demonstrate multiple ways by which human-caused stressors can reduce ecosystem functioning, despite robust BEF relationships, in natural high-diversity assemblages.


Mesenchymal stem cells in acute kidney injury.
The potential role of mesenchymal stem cells (MSCs, also called mesenchymal stromal cells) in endogenous repair and cell-based therapies for acute kidney injury (AKI) is under intensive investigation. Preclinical studies indicate that administered MSCs both ameliorate renal injury and accelerate repair. These versatile cells home to sites of injury, where they modulate the repair process. The mechanisms responsible for their protective and regenerative effects are incompletely understood. Some have reported that MSCs are capable of direct engraftment into injured nephrons under certain circumstances. This is highly controversial, however, and even those who argue there is engraftment acknowledge that the primary means of repair by these cells most likely involves paracrine and endocrine effects, including mitogenic, antiapoptotic, anti-inflammatory, and angiogenic influences. There is a good deal of interest in MSC-based approaches for the treatment of human kidney injury, thanks to positive preclinical results, the strong clinical need for novel therapies to treat AKI, the ease of isolation and expansion of MSCs, and encouraging preliminary clinical trial results in other fields. This review summarizes current knowledge and identifies gaps in our understanding of MSC biology that will need to be filled in order to translate recent discoveries into therapies for AKI in humans.


Analysis of monoPEGylated human galectin-2 by small-angle X-ray and neutron scattering: concentration dependence of PEG conformation in the conjugate.
Protein conjugation with polyethylene glycol (PEG) is a valuable means for improving stability, solubility, and bioavailability of pharmaceutical proteins. Using human galectin-2 (hGal-2) and 5 kDa PEG as a model system we first produced a PEG-hGal-2 conjugate exclusively at the Cys75 residue, resulting in two monosubstituted subunits per hGal-2 homodimer. Small angle X-ray and neutron scattering (SAXS and SANS) were combined to provide complementary structural information about the PEG-hGal-2 conjugate, wherein signal generation in SAXS depends mainly on the protein while SANS data presents signals from both the protein and PEG moieties. SAXS data gave a constant radius of gyration (R(g) = 21.5 Å) for the conjugate at different concentrations and provided no evidence for an alteration of homodimeric structure or hGal-2 ellipsoidal shape upon PEGylation. In contrast, SANS data revealed a concentration dependence of R(g) for the conjugate, with the value decreasing from 31.5 Å at 2 mg/mL to 26 Å at 14 mg/mL (based on hGal-2 concentration). Scattering data have been successfully described by the model of the ellipsoidal homogeneous core (hGal-2) attached with polymer chains (PEG) at the surface. Evidently, the PEG conformation of the conjugate strongly depends on conjugate concentration and PEG's radius of gyration decreases from 24.5 to 15 Å. An excluded volume effect, arising from steric clashes between PEG molecules at high concentration, was quantified by estimating the second virial coefficient, A(2), of PEGylated hGal-2 from the SANS data. A positive value of A(2) (6.0 ± 0.4 × 10(-4) cm(3) mol g(-2)) indicates repulsive interactions between molecules, which are expected to protect the PEGylated protein against aggregation.


Serum Levels of Androgen-Associated Hormones Are Correlated with Curative Effect in Androgenic Alopecia in Young Men.
BACKGROUND Androgenic alopecia (AGA) is the most common type of hair loss in men. However, the pathogenesis is not yet fully understood and therapeutic approaches are limited. This retrospective study investigated the association between levels of androgen-associated hormones and curative effect in androgenic alopecia in young male AGA patients. MATERIAL AND METHODS By using chemiluminescence immunoassay, serum levels of androgens and upstream regulated hormones were measured in 178 young male patients with AGA and in 61 normal controls before therapy, 1 and 2 weeks after administration of finasteride. RESULTS Before oral finasteride therapy, we found significantly higher levels of serum free testosterone (FT) and dihydrotestosterone (DHT) in AGA patients than in normal controls. The levels of serum sex hormone-binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were similar in the 2 groups. There were no significant differences in serum androgen levels, including DHT and FT, among AGA patients with different grades of hair loss severity (p>0.05). After finasteride therapy, the levels of DHT decreased significantly (p<0.05). Increased serum levels of LSH or LH were also observed in 55 patients after therapy (p<0.05). The levels of SHGB did not change significantly after therapy (p>0.05). Patients with lower levels of serum FT and DHT than before who accepted finasteride therapy had a higher ratio of curative effect manifested by improved severity grade (p<0.05). Patients with higher levels of LSH or LH had a lower curative rate compared to those without change after therapy (p<0.05). CONCLUSIONS We confirmed the role of the androgens hypothalamus-hypophysis-sexual gland axis in the pathogenesis of AGA and the treatment effect of oral anti-androgen therapy in young male Chinese patients.


The use of covariates to identify records with implausible gestational ages using the birthweight distribution.
The objective of this study was to evaluate the usefulness of covariates in identifying birth records with implausible values of gestational age. Birthweight distributions for births with early reported gestational ages are markedly bimodal, suggesting a mixture of two distributions. Most births form a normal-shaped left-hand (primary) distribution and a smaller number form the right-hand (secondary) distribution. The births in the secondary distribution are thought to have gestational age mistakenly reported. Prior work has found that births in the secondary distribution are at higher risk of poor outcomes than those in the primary distribution. Using 2002 US Natality data for gestational ages 26-35 weeks, we fit normal mixture models to birthweight with and without covariates (maternal race, education, parity, age, region of the country, prenatal care initiation) by reported gestational age. Additional models were stratified by infant sex. This approach allowed for the relationship between the covariates and birthweight to differ between the components. Mixture models fit reasonably well for reported gestational ages <33 weeks, but not for later weeks. Counter to the hypothesis, results were similar for models with and without covariates or stratification or both, although stratified models without covariates predicted slightly more girls and slightly fewer boys in the secondary distribution than did the corresponding unstratified models. For reported gestational ages <33 weeks, predictions from the four sets of models were highly correlated and predictions were similar for subgroups defined by the clinical estimates of gestational age and other covariates. For births with reported gestational ages of 29 or more weeks, the proportion in the secondary distribution exceeded 30%, although this varied by maternal characteristics. The use of covariates and stratification complicated model fitting without materially improving identification of implausible gestational age values, supporting inferences from prior studies using data 'cleaned' without consideration of maternal or infant characteristics.


Background potassium current active during the plateau of the action potential in guinea pig ventricular myocytes.
Background outward K+ currents in guinea pig ventricular myocytes were characterized over a broad range of membrane potentials, including those corresponding to the plateau of the action potential. The background current that is blocked by 1 mM Ba2+ (IK,p) activates within 5 msec at positive potentials, does not inactivate, and deactivates very rapidly on repolarization. IK,p is insensitive to Cl- channel blockers, internal or external [Cl-], dihydropyridines, and sulfonylureas. In contrast, the delayed rectifier K+ current (IK) was not completely blocked even by 30 mM Ba2+. Ba(2+)-sensitive current density increased progressively from 0.16 +/- 0.04 pA/pF at 0 mV to 0.52 +/- 0.21 pA/pF at +80 mV (n = 13, mean +/- SEM). The background current remains present when [K+]o is reduced to 0 mM, which suppresses the inward rectifier K+ current (IK1). These and other features suggest that IK,p is generated by K+ channels that are distinct from IK1 or IK. The kinetics and voltage dependence of IK,p render it capable of modulating both the height and duration of the cardiac action potential.


Model analysis of biological oxygen transfer enhancement in surface-aerated bioreactors.
A model was developed to evaluate the effects of cells and surfactants on oxygen transfer in surface-aerated bioreactors. The model assumed the presence of serial layers of adsorbed surfactants and microorganisms directly adjacent to the gas-liquid interface due to their surface activities, followed by a stagnant liquid layer to account for the oxygen transfer resistance in the liquid phase. The interfacial surfactant film, although posing as an additional resistance, was found to have negligible effect on the oxygen transfer rate because of its extremely small thickness as compared to the cell monolayer and the stagnant liquid layer. On the other hand, cells affect oxygen transfer by two mechanisms: the biological enhancement due to the respiration of interfacial cells and the physical blocking resulting from the semipermeable nature of cell bodies. Due to the low specific oxygen uptake rates of the sludges, the two mechanisms were found to be of comparable importance in activated-sludge systems; the oxygen transfer enhancement factor, E, varied from about 0.97 to 1.10 depending on the operating conditions. The biological enhancement effect, however, predominated in fermentations of actively growing bacteria. At relatively low agitation speed (e. g., 300 rpm), the value of E could reach about 3 to 5 in fermentations with high cell concentrations. Effects of other operating variables, such as the agitation intensity, the oxygen content in the mixed liquor, and the bulk cell concentration, on biological oxygen transfer enhancement were also studied.


A theory of organizational readiness for change.
Change management experts have emphasized the importance of establishing organizational readiness for change and recommended various strategies for creating it. Although the advice seems reasonable, the scientific basis for it is limited. Unlike individual readiness for change, organizational readiness for change has not been subject to extensive theoretical development or empirical study. In this article, I conceptually define organizational readiness for change and develop a theory of its determinants and outcomes. I focus on the organizational level of analysis because many promising approaches to improving healthcare delivery entail collective behavior change in the form of systems redesign--that is, multiple, simultaneous changes in staffing, work flow, decision making, communication, and reward systems. Organizational readiness for change is a multi-level, multi-faceted construct. As an organization-level construct, readiness for change refers to organizational members' shared resolve to implement a change (change commitment) and shared belief in their collective capability to do so (change efficacy). Organizational readiness for change varies as a function of how much organizational members value the change and how favorably they appraise three key determinants of implementation capability: task demands, resource availability, and situational factors. When organizational readiness for change is high, organizational members are more likely to initiate change, exert greater effort, exhibit greater persistence, and display more cooperative behavior. The result is more effective implementation. The theory described in this article treats organizational readiness as a shared psychological state in which organizational members feel committed to implementing an organizational change and confident in their collective abilities to do so. This way of thinking about organizational readiness is best suited for examining organizational changes where collective behavior change is necessary in order to effectively implement the change and, in some instances, for the change to produce anticipated benefits. Testing the theory would require further measurement development and careful sampling decisions. The theory offers a means of reconciling the structural and psychological views of organizational readiness found in the literature. Further, the theory suggests the possibility that the strategies that change management experts recommend are equifinal. That is, there is no 'one best way' to increase organizational readiness for change.


Spinal astroglial cannabinoid receptors control pathological tremor.
Cannabinoids reduce tremor associated with motor disorders induced by injuries and neurodegenerative disease. Here we show that this effect is mediated by cannabinoid receptors on astrocytes in the ventral horn of the spinal cord, where alternating limb movements are initiated. We first demonstrate that tremor is reduced in a mouse model of essential tremor after intrathecal injection of the cannabinoid analog WIN55,212-2. We investigate the underlying mechanism using electrophysiological recordings in spinal cord slices and show that endocannabinoids released from depolarized interneurons activate astrocytic cannabinoid receptors, causing an increase in intracellular Ca2+, subsequent release of purines and inhibition of excitatory neurotransmission. Finally, we show that the anti-tremor action of WIN55,212-2 in the spinal cords of mice is suppressed after knocking out CB1 receptors in astrocytes. Our data suggest that cannabinoids reduce tremor via their action on spinal astrocytes.


The effect of various mixing and placement techniques on the compressive strength of mineral trioxide aggregate.
The aim of this study was to evaluate the effect of various mixing techniques including mechanical and manual mixing as well as the effect of ultrasonic agitation during placement on the compressive strength of mineral trioxide aggregate (MTA). Tooth-colored ProRoot MTA (Dentsply Maillefer, Ballaigues, Switzerland) and white MTA Angelus (Angelus Soluções Odontologicas, Londrina, Brazil) were used. One gram of each powder was mixed with a 0.34-g aliquot of distilled water. Specimens were mixed either by mechanical mixing of capsules for 30 seconds at 4,500 rpm or by a saturation technique and the application of a condensation pressure of 3.22 MPa for 1 minute. Half of the specimens were placed in stainless steel molds and agitated using indirect ultrasonic activation. All specimens were subjected to compressive strength testing after 4 days. The compressive strength values of ProRoot MTA were significantly greater than those of MTA Angelus (P < .05). The highest compressive strength values were recorded from ProRoot MTA samples that were mixed mechanically and placed using ultrasonic activation (mean = 101.71 MPa), whereas the lowest values were recorded for MTA Angelus samples that were mixed manually and placed without ultrasonic activation (mean = 53.47 MPa). Ultrasonically agitated groups had higher compressive strength values (P < .001). The specimens mixed mechanically had higher compressive strength values than those mixed manually (P < .05). The compressive strength values of ProRoot MTA were significantly greater than those of MTA Angelus. Mechanical mixing enhanced the compressive strength of the material. Regardless of the mixing techniques applied, ultrasonic agitation improved the compressive strength of the material.


Effects of vitamin D supplementation on cognitive and emotional functioning in young adults--a randomised controlled trial.
Epidemiological research links vitamin D status to various brain-related outcomes. However, few trials examine whether supplementation can improve such outcomes and none have examined effects on cognition. This study examined whether Vitamin D supplementation led to improvements in diverse measures of cognitive and emotional functioning, and hypothesised that supplementation would lead to improvements in these outcomes compared to placebo. Healthy young adults were recruited to a parallel-arm, double-blind trial conducted at The University of Queensland. Participants were randomly allocated to receive Vitamin D (one capsule daily, containing 5000 IU cholecalciferol) or identical placebo capsule for six weeks. All participants and outcome assessors were blinded to group assignment. Primary outcome measures assessed at baseline and 6 weeks were working memory, response inhibition and cognitive flexibility. Secondary outcomes were: hallucination-proneness, psychotic-like experiences, and ratings of depression, anxiety and anger. 128 participants were recruited, randomised and included in primary analyses (vitamin D n = 63; placebo n = 65). Despite significant increases in vitamin D status in the active group, no significant changes were observed in working memory (F = 1.09; p = 0.30), response inhibition (F = 0.82; p = 0.37), cognitive flexibility (F = 1.37; p = 0.24) or secondary outcomes. No serious adverse effects were reported. Our findings indicate that vitamin D supplementation does not influence cognitive or emotional functioning in healthy young adults. Future controlled trials in targeted populations of interest are required to determine whether supplementation can improve functioning in these domains. Australian and New Zealand Clinical Trials Registry; ACTRN12610000318088.


Frailty in Wild-Type Transthyretin Cardiac Amyloidosis: The Tip of the Iceberg.
ATTRwt-CA occurs in elderly patients and leads to severe heart failure. The disease mechanism involves cardiac and extracardiac infiltration by amyloid fibrils. The objectives of this study are to describe the frailty phenotype in patients with ATTRwt-CA and to assess the associations between frailty parameters, the severity of cardiac involvement, and the course of amyloid disease. We used multidimensional geriatric tools to prospectively assess frailty in patients with ATTRwt-CA consulting (in 2018-2019) in the French National Reference Center for Cardiac Amyloidosis. We included 36 patients (35 males; median age: 82 years (76-86). A third of the patients were categorized as NYHA class III or IV, and 39% had an LVEF below 45%. The median serum NTproBNP was 3188 (1341-8883) pg/mL. The median duration of amyloidosis was 146 months (73-216). The frequency of frailty was 50% and 33% according to the physical frailty phenotype and the Short Emergency Geriatric Assessment questionnaire, respectively. Frailty affected a large number of domains, namely autonomy (69%), balance (58%), muscle weakness (74%), malnutrition (39%), dysexecutive syndrome (72%), and depression (49%). The severity of CA was significantly associated with many frailty parameters independently of age. Balance disorders and poor mobility were also significantly associated with a longer course of amyloid disease. Frailty is frequent in patients with ATTRwt-CA. Some frailty parameters were significantly associated with a longer course of amyloid disease and CA severity. Taking into account frailty in the assessment and management of ATTRwt should improve patients' quality of life.


Abscisic Acid-Cytokinin Antagonism Modulates Resistance Against Pseudomonas syringae in Tobacco.
Phytohormones are known as essential regulators of plant defenses, with ethylene, jasmonic acid, and salicylic acid as the central immunity backbone, while other phytohormones have been demonstrated to interact with this. Only recently, a function of the classic phytohormone cytokinin in plant immunity has been described in Arabidopsis, rice, and tobacco. Although interactions of cytokinins with salicylic acid and auxin have been indicated, the complete network of cytokinin interactions with other immunity-relevant phytohormones is not yet understood. Therefore, we studied the interaction of kinetin and abscisic acid as a negative regulator of plant immunity to modulate resistance in tobacco against Pseudomonas syringae. By analyzing infection symptoms, pathogen proliferation, and accumulation of the phytoalexin scopoletin as a key mediator of kinetin-induced resistance in tobacco, antagonistic interaction of these phytohormones in plant immunity was identified. Kinetin reduced abscisic acid levels in tobacco, while increased abscisic acid levels by exogenous application or inhibition of abscisic acid catabolism by diniconazole neutralized kinetin-induced resistance. Based on these results, we conclude that reduction of abscisic acid levels by enhanced abscisic acid catabolism strongly contributes to cytokinin-mediated resistance effects. Thus, the identified cytokinin-abscisic acid antagonism is a novel regulatory mechanism in plant immunity.


Interplay between Mutations and Efflux in Drug Resistant Clinical Isolates of Mycobacterium tuberculosis.
Numerous studies show efflux as a universal bacterial mechanism contributing to antibiotic resistance and also that the activity of the antibiotics subject to efflux can be enhanced by the combined use of efflux inhibitors. Nevertheless, the contribution of efflux to the overall drug resistance levels of clinical isolates of Mycobacterium tuberculosis is poorly understood and still is ignored by many. Here, we evaluated the contribution of drug efflux plus target-gene mutations to the drug resistance levels in clinical isolates of M. tuberculosis. A panel of 17 M. tuberculosis clinical strains were characterized for drug resistance associated mutations and antibiotic profiles in the presence and absence of efflux inhibitors. The correlation between the effect of the efflux inhibitors and the resistance levels was assessed by quantitative drug susceptibility testing. The bacterial growth/survival vs. growth inhibition was analyzed through the comparison between the time of growth in the presence and absence of an inhibitor. For the same mutation conferring antibiotic resistance, different MICs were observed and the different resistance levels found could be reduced by efflux inhibitors. Although susceptibility was not restored, the results demonstrate the existence of a broad-spectrum synergistic interaction between antibiotics and efflux inhibitors. The existence of efflux activity was confirmed by real-time fluorometry. Moreover, the efflux pump genes mmr, mmpL7, Rv1258c, p55, and efpA were shown to be overexpressed in the presence of antibiotics, demonstrating the contribution of these efflux pumps to the overall resistance phenotype of the M. tuberculosis clinical isolates studied, independently of the genotype of the strains. These results showed that the drug resistance levels of multi- and extensively-drug resistant M. tuberculosis clinical strains are a combination between drug efflux and the presence of target-gene mutations, a reality that is often disregarded by the tuberculosis specialists in favor of the almost undisputed importance of antibiotic target-gene mutations for the resistance in M. tuberculosis.


Cap completion and C-terminal repeat domain kinase recruitment underlie the initiation-elongation transition of RNA polymerase II.
After transcription initiation, RNA polymerase (Pol) II escapes from the promoter and recruits elongation factors. The molecular basis for the initiation-elongation factor exchange during this transition remains poorly understood. Here, we used chromatin immunoprecipitation (ChIP) to elucidate the initiation-elongation transition of Pol II in the budding yeast Saccharomyces cerevisiae. We show that the early Pol II elongation factor Spt5 contributes to stable recruitment of the mRNA capping enzymes Cet1, Ceg1, and Abd1. Genome-wide occupancy for Cet1 and Ceg1 is restricted to the transcription start site (TSS), whereas occupancy for Abd1 peaks at ~110 nucleotides downstream, and occupancy for the cap-binding complex (CBC) rises subsequently. Abd1 and CBC are important for recruitment of the kinases Ctk1 and Bur1, which promote elongation and capping enzyme release. These results suggest that cap completion stimulates productive Pol II elongation.


Case report: hemosiderotic fibrohistiocytic lipomatous lesion: a clinicopathologic characterization.
A hemosiderotic fibrohistiocytic lipomatous lesion, also called hemosiderotic fibrolipomatous tumor, is a rare and recently described fibrolipomatous entity. Initially considered the result of a reactive inflammatory process from trauma or vascular disease, newer evidence suggests it may be neoplastic in origin. We report the case of a 56-year-old woman with a painful mass in the dorsal aspect of the foot diagnosed as a hemosiderotic fibrohistiocytic lipomatous lesion. We reviewed all 31 published cases of hemosiderotic fibrohistiocytic lipomatous lesions looking for common clinical, imaging, and histologic patterns. Hemosiderotic fibrohistiocytic lipomatous lesions occur predominantly in the fifth and sixth decades of life (average age, 49.5 years; range, 0.67-74 years). Females predominate 22 to 9. Thirteen of 28 patients had histories of trauma or vasculopathy. Twenty-six of 31 lesions were in the foot. The MRI signal of a hemosiderotic fibrohistiocytic lipomatous lesion follows fat in all sequences. Stranding or septations also frequently are seen. Histologically, the lesions are composed of three main elements in varying proportions: mature adipocytes, spindle cells, and hemosiderin pigment. Ten of 27 resected lesions recurred. Resection types are not reported in many cases. Four of 15 lesions recurred after marginal/intralesional excision, whereas none of three lesions treated by wide excision recurred. The high recurrence rate may be related to the difficulty in determining intraoperatively that a resection is complete, secondary to the lack of anatomic boundaries such as a pseudocapsule. Any attempt at wide resection must weigh the morbidity of this surgery against that of a recurrence after a resection which seemed complete intraoperatively. There have been no reports of metastasis.


Time-domain simulations of nonlinear interaction in microring resonators using finite-difference and coupled mode techniques.
Nonlinear interactions within compact, on-chip microring resonant cavities is a topic of increasing interest in current silicon photonics research. Frequency combs, one of the emerging nonlinear applications in microring optics, offers great potential from both scientific and practical perspectives. However, the mechanisms of comb formation appear to differ from traditional frequency combs formed by pulsed femtosecond lasers, and thus require detailed elucidation through theory and simulation. Here we propose a technique to mimic the accuracy of finite-difference time domain (FDTD) full wave nonlinear optical simulations with only a small fraction of the computational resources. Our new hybrid approach combines a single linear FDTD simulation of the key interaction parameters, then directly inserts them into a coupled-mode theory simulation. Comparison of the hybrid approach and full FDTD shows a good match both in frequency domain and in time domain. Thus, it retains the advantage of FDTD in terms of direct connection with experimental designs, while finishing much faster and sidestepping stability issues associated with direct simulation of nonlinear phenomena. The hybrid technique produces several key results explored in this paper, including: demonstrating that comb formation can occur with both anomalous and normal dispersion; suggesting a new mechanism for incoherent (Type II) frequency comb formation; and illustrating a method for creating soliton-like pulses in on-chip microresonators.


A recombinant adenovirus encoding hepatitis C virus core and E1 proteins protects mice against cytokine-induced liver damage.
Hepatitis C virus (HCV) infection has a strong tendency to evolve to chronicity despite up-regulation of proapoptotic cytokines in the inflamed liver. The mechanisms responsible for persistent viral replication in this inflammatory environment are obscure. It is conceivable that viral replication would be facilitated if the infected hepatocytes are rendered resistant to cytokine-induced cytotoxicity. In this study, we investigated if an adenovirus encoding HCV core and E1 (RAdCE1) could reduce liver cell injury in different in vivo models of cytokine-mediated hepatotoxicity in mice. We show that RAdCE1 markedly attenuates hepatocellular apoptosis and the increase in serum transaminase levels after concanavalin A (con A) challenge. This protective effect is accompanied by an inhibition of nuclear translocation of nuclear factor kappaB (NF-kappaB); reduced expression of inducible nitric oxide synthase (iNOS); decreased hepatic messenger RNA levels of chemokines macrophage inflammatory protein 2 (MIP-2), monocyte chemoattractant protein 1 (MCP-1), and interferon-inducible protein 10 (IP-10); and abrogation of liver leukocyte infiltration. RAdCE1 also causes a reduction in serum transaminase levels and inhibits hepatocellular apoptosis in mice given tumor necrosis factor (TNF)-alpha plus D-galactosamine. In conclusion, HCV structural antigens can protect liver cells against the proapoptotic effects of proinflammatory cytokines. The antiapoptotic status of infected liver cells may represent a mechanism favoring viral persistence. Our findings also suggest that, in chronic hepatitis C, the burden of hepatocellular damage mainly affects noninfected liver cells.


Untargeted metabolomics predicts the functional outcome of ischemic stroke.
Metabolites in blood have been found associated with the occurrence of vascular diseases, but its role in the functional recovery of stroke is unclear. The aim of this study is to investigate whether the untargeted metabolomics at the acute stage of ischemic stroke is able to predict functional recovery. One hundred and fifty patients with acute ischemic stroke were recruited and followed up for 3 months. Fasting blood samples within 7 days of stroke were obtained, liquid chromatography and mass spectrometry were applied to identify outcome-associated metabolites. The patients' clinical characteristics and identified metabolites were included for constructing the outcome prediction model using machine learning approaches. By using multivariate analysis, 220 differentially expressed metabolites (DEMs) were discovered between patients with favorable outcomes (modified Rankin Scale, mRS ≤ 2 at 3 months, n = 77) and unfavorable outcomes (mRS ≥ 3 at 3 months, n = 73). After feature selection, 63 DEMs were chosen for constructing the outcome prediction model. The predictive accuracy was below 0.65 when including patients' clinical characteristics, and could reach 0.80 when including patients' clinical characteristics and 63 selected DEMs. The functional enrichment analysis identified platelet activating factor (PAF) as the strongest outcome-associated metabolite, which involved in proinflammatory mediators release, arachidonic acid metabolism, eosinophil degranulation, and production of reactive oxygen species. Metabolomics is a potential method to explore the blood biomarkers of acute ischemic stroke. The patients with unfavorable outcomes had a lower PAF level compared to those with favorable outcomes.


Weapon involvement in home invasion crimes.
To study the epidemiology of home invasion crimes and determine the frequency with which firearms are used to resist these crimes. Prospective case series. Atlanta, Ga (population 402,877). Between June 1 and August 31, 1994; Atlanta Police Department reports were screened to identify every case of unwanted entry into an occupied, single-family dwelling. Cases of sexual assault and incidents that involved cohabitants were excluded. A total of 198 cases were identified during the study interval. Half (99 cases) involved forced entry into the home. The victim and offender were acquainted in one third of cases. A firearm was carried by one or more offenders in 32 cases (17%). Seven offenders (3.5%) carried knives. In 42% of cases, the offender fled without confronting the victim. Victims who avoided confrontation were more likely to lose property but much less likely to be injured than those who were confronted by the offender. Resistance was attempted in 62 cases (31%), but the odds of injury were not significantly affected by the method of resistance. Forty cases (20%) resulted in one or more victims' being injured, including six (3%) who were shot. No one died. Three victims (1.5%) employed a firearm in self-protection. All three escaped injury, but one lost property. A minority of home invasion crimes result in injury. Measures that increase the difficulty of forced entry or enhance the likelihood of detection could be useful to prevent these crimes. Although firearms are often kept in the home for protection, they are rarely used for this purpose.


Photoinduced peeling of molecular crystals.
Block-like microcrystals composed of cis-dimethyl-2(3-(anthracen-9-yl)allylidene)malonate are grown from aqueous surfactant solutions. A pulse of 405 nm light converts a fraction of molecules to the trans isomer, creating an amorphous mixed layer that peels off the parent crystal. This photoinduced delamination can be repeated multiple times on the same block.


Vibrotactile perception thresholds as determined by two different devices in a working population.
The purpose of this study was to investigate whether two devices for measuring vibrotactile perception thresholds produced similar results on an individual basis and to compare the thresholds in the presence or absence of sensorineural hand symptoms and vibration exposure. Vibrotactile perception thresholds were measured with a vibrameter and a tactilometer in 178 men. The tactilometer uses seven discrete frequencies from 8 to 500 Hz, and the vibrameter uses one frequency (100 Hz). Agreement was assessed from the correlations and from a comparison of subjects who had thresholds above the upper quartile of each device as to the presence of sensorineural hand symptoms and occupational vibration exposure. The correlation between the vibrameter and the tactilometer (125 Hz) was 0.59. The agreement between the vibrameter and the tactilometer (63 Hz), when the upper quartile was used as a limit, had a sensitivity of 0.56 and a specificity of 0.85. The sensitivity and specificity for the agreement with symptoms were 0.44 and 0.79, respectively, for the tactilometer and 0.40 and 0.78, respectively, for the vibrameter. The indices combined from the different frequencies of the tactilometer did not improve the agreement. Some of the discrepancy between the measurement of the vibrameter and tactilometer can be explained by differences in the equipment, the measurement procedures, and the examiner, combined with high inter-and intraindividual variability. Neither of the two devices was superior when the results were compared as to the occurrence of hand symptoms and vibration exposure. As evaluated in this study vibrotactile perception threshold has a restricted value for screening and diagnostic purposes on an individual basis.


Dietary Aloe Vera Supplementation Improves Facial Wrinkles and Elasticity and It Increases the Type I Procollagen Gene Expression in Human Skin in vivo.
No studies have yet been undertaken to determine the effect of aloe gel on the clinical signs and biochemical changes of aging skin. We wanted to determine whether dietary aloe vera gel has anti-aging properties on the skin. Thirty healthy female subjects over the age of 45 were recruited and they received 2 different doses (low-dose: 1,200 mg/d, high-dose: 3,600 mg/d) of aloe vera gel supplementation for 90 days. Their baseline status was used as a control. At baseline and at completion of the study, facial wrinkles were measured using a skin replica, and facial elasticity was measured by an in vivo suction skin elasticity meter. Skin samples were taken before and after aloe intake to compare the type I procollagen and matrix metalloproteinase 1 (MMP-1) mRNA levels by performing real-time RT-PCR. After aloe gel intake, the facial wrinkles improved significantly (p<0.05) in both groups, and facial elasticity improved in the lower-dose group. In the photoprotected skin, the type I procollagen mRNA levels were increased in both groups, albeit without significance; the MMP-1 mRNA levels were significantly decreased in the higher-dose group. Type I procollagen immunostaining was substantially increased throughout the dermis in both groups. Aloe gel significantly improves wrinkles and elasticity in photoaged human skin, with an increase in collagen production in the photoprotected skin and a decrease in the collagen-degrading MMP-1 gene expression. However, no dose-response relationship was found between the low-dose and high-dose groups.


Single-layer MoS2 nanopores as nanopower generators.
Making use of the osmotic pressure difference between fresh water and seawater is an attractive, renewable and clean way to generate power and is known as 'blue energy'. Another electrokinetic phenomenon, called the streaming potential, occurs when an electrolyte is driven through narrow pores either by a pressure gradient or by an osmotic potential resulting from a salt concentration gradient. For this task, membranes made of two-dimensional materials are expected to be the most efficient, because water transport through a membrane scales inversely with membrane thickness. Here we demonstrate the use of single-layer molybdenum disulfide (MoS2) nanopores as osmotic nanopower generators. We observe a large, osmotically induced current produced from a salt gradient with an estimated power density of up to 10(6) watts per square metre--a current that can be attributed mainly to the atomically thin membrane of MoS2. Low power requirements for nanoelectronic and optoelectric devices can be provided by a neighbouring nanogenerator that harvests energy from the local environment--for example, a piezoelectric zinc oxide nanowire array or single-layer MoS2 (ref. 12). We use our MoS2 nanopore generator to power a MoS2 transistor, thus demonstrating a self-powered nanosystem.


DNA polymerase kappa produces interrupted mutations and displays polar pausing within mononucleotide microsatellite sequences.
Microsatellites are ubiquitously present in eukaryotic genomes and are implicated as positive factors in evolution. At the nucleotide level, microsatellites undergo slippage events that alter allele length and base changes that interrupt the repetitive tract. We examined DNA polymerase errors within a [T](11) microsatellite using an in vitro assay that preferentially detects mutations other than unit changes. We observed that human DNA polymerase kappa (Pol kappa) inserts dGMP and dCMP within the [T](11) mononucleotide repeat, producing an interrupted 12-bp allele. Polymerase beta produced such interruptions at a lower frequency. These data demonstrate that DNA polymerases are capable of directly producing base interruptions within microsatellites. At the molecular level, expanded microsatellites have been implicated in DNA replication fork stalling. Using an in vitro primer extension assay, we observed sequence-specific synthesis termination by DNA polymerases within mononucleotides. Quantitatively, intense, polar pausing was observed for both pol kappa and polymerase alpha-primase within a [T](11) allele. A mechanism is proposed in which pausing results from DNA bending within the duplex stem of the nascent DNA. Our data support the concept of a microsatellite life-cycle, and are consistent with the models in which DNA sequence or secondary structures contributes to non-uniform rates of replication fork progression.


The influence of EPA and DHA on markers of inflammation in 3T3-L1 cells at different stages of cellular maturation.
EPA and DHA have been reported to have anti-obesity and anti-inflammatory properties. Recent studies revealed that these positive actions of n-3 PUFA at least partially are connected with their influence on metabolism and secretory functions of the adipose tissue. However, their impact on old adipocytes is still poorly understood. Therefore the aim of the present study was to evaluate the influence of EPA and DHA on markers of inflammation in 3T3-L1 cells at different stages of cellular maturation. Young, mature and old differentiated 3T3-L1 adipocytes were cultured for 48 h in the presence of 100 μM EPA, or 50 μM DHA complexed to albumin, whereas in control conditions only albumin was added to the medium. The Oil Red O staining was used to confirm adipocytes differentiation, and measure triglycerides content in cells. The concentration of adipokines (interleukin 6, adiponectin and leptin) in conditioned media was measured using mouse-specific ELISA kits. The fat accumulation in 3T3-L1 adipocytes was positively correlated with their age; however, EPA and DHA did not affect lipid accumulation on any stage of maturation. EPA and DHA increased the concentration of secreted adiponectin when compared with control, but only in the case of young adipocytes (58% and 35%, respectively). Moreover, EPA supplementation increased interleukin 6 concentration in conditioned medium, while DHA exerted an opposite effect on all stages of cellular maturation. Furthermore, EPA treatment increased leptin release from young cells, while DHA did not affect the secretion of this adipokine. In mature 3T3-L1 adipocytes both experimental factors decreased synthesis of leptin; however, in old cells no impact of these PUFA was noted. In summary, age is an important determinant of fat accumulation in adipocytes and affects adipokines secretion by these cells. Moreover, the impact of investigated fatty acids: EPA and DHA on fat cells varies depending on the stage of maturation, and seems to be stronger in young cells than in mature and old ones. Docosahexaenoic acid exerts an anti-inflammatory action; however, on the basis of the obtained data it was not possible to determine whether eicosapentaenoic acid shows anti- or pro-inflammatory properties.


Prevalence of clustered regulatory interspaced short palindromic repeat (CRISPR)-like sequences in mitis-group streptococci.
Clustered regulatory interspaced short palindromic repeats (CRISPRs) have been discovered in many bacteria and archaea. Many CRISPR-like sequences have been identified in an increasing number of studies on the function of CRISPRs. One CRISPR-like sequence of approximately 240 base pairs has been found to be highly conserved within 11 genome sequences of Streptococcus pneumoniae. A specific CRISPR-like polymerase chain reaction (PCR) assay was designed with the novel primers CRISPR 5F (forward primer) 5'-CTA ATY TCA TAA CCA TAR GAA TC-3' and CRISPR 3R (reverse primer) 5'-GAT AAR ATC CTY TAA WCT TCT AG-3' to detect the presence of this CRISPR-like sequence in pneumococci, as well as in viridans-group streptococci (VGS). This study investigates the prevalence of this CRISPR-like sequence in S. pneumoniae and 12 viridans-group streptococcal species and shows its existence to be shared by the majority of S. pneumoniae and, to a lesser extent, S. mitis. This CRISPR-like sequence was also found in S. australis and it is highly conserved among these strains, suggesting possible biological functional differences from true CRISPR because this CRISPR-like sequence has relatively few repeat numbers, and adjacent homology of CRISPR-associated (cas) genes was absent. The sharing of this CRISPR-like sequence between pneumococci, the mitis group and other VGS, as well as its high sequence homology, may suggest close evolutionary emergence of this sequence between these species.


Self-awareness, self-evaluation, and creativity.
The present research examined when self-evaluation influences creativity. Based on objective self-awareness theory, the authors predicted that feeling able to improve would buffer against the detrimental effects of self-evaluation on creativity. Two experiments manipulated self-evaluation (varying self-awareness, Study 1; providing objective performance standards, Study 2) and perceived ability to improve potential failure on the creativity task. Self-evaluation reduced creativity (generating remote associates, finding unusual uses for a knife) in both experiments, but only when people did not expect to improve. When people felt able to improve, self-evaluation did not affect creativity. Connections between self-motives, creativity, and defensiveness are discussed.


Animal models as predictors of the safety and efficacy of antibiotics.
As opposed to the testing of safety, the testing of the efficacy of antibiotics in animals is not specified in any directives or guidelines and not explicitly required by regulatory authorities. There exists, however, no doubt that in the evaluation of new compounds testing of both safety and efficacy forms an essential link between in vitro tests and clinical trials. It is inconceivable that clinicians would be prepared to conduct a trial in patients without evidence of the efficacy of the antibiotic in question in an appropriate animal model of infection. Both the models for testing safety and those for testing efficacy suffer from a number of shortcomings. If investigators are aware of these deficiencies and take them into account when interpreting the results, the predictive value of the models can be significantly enhanced.


Effectiveness of lanthanum carbonate treatment used in combination with other phosphate binders in peritoneal dialysis patients.
Phosphate binders are used in the treatment of hyperphosphatemia in peritoneal dialysis (PD) patients. An ideal phosphate binder for long-term use must be effective with little or no side effects. We evaluated the long-term efficacy and side effects of lanthanum carbonate (LaC) used in combination with other phosphate binders in PD patients. The subjects of this retrospective study were 30 PD patients who received LaC at Kyushu University. The effect of LaC on various biochemical parameters (serum phosphate, calcium and parathyroid hormone), daily dose of other phosphate binders, gastrointestinal side effects, and nutritional status were determined during the 24-week treatment. We also evaluated the rate of achievement of the Japanese Society of Dialysis Treatment guidelines for secondary hyperparathyroidism and used multivariate analysis to determine the factors associated with the efficacy of LaC. LaC (960 ± 412 mg/day) reduced serum phosphate from 6.2 to 5.3 mg/dL. The rate of achievement of the guideline target improved after 24 weeks of LaC treatment. The dose of other phosphate binders and dialysis volume remained unchanged during the treatment. Although 53% of patients experienced at least one gastrointestinal side effect, LaC treatment did not affect the nutritional status, and none of the patients discontinued LaC. Multivariate analysis identified low stature, old age and high baseline total creatinine clearance as significant factors that determine the effectiveness of LaC in PD patients. Low dose LaC treatment used in combination with other phosphate binders improved serum phosphate control with tolerable gastrointestinal symptoms in PD patients.


Nobiletin Reduces Intracellular and Extracellular β-Amyloid in iPS Cell-Derived Alzheimer's Disease Model Neurons.
Alzheimer's disease (AD) is the most common cause of dementia, with progressive memory impairment. Recently, neprilysin, a β-amyloid (Aβ)-degrading enzyme has become featured as a drug target for AD. Previously, we identified nobiletin from citrus peels as a natural compound possessing anti-dementia activity. In addition, we demonstrated that nobiletin improved memory in memory-impaired animals and, further, that Aβ levels were markedly decreased in the brains of these animals. We demonstrated in vitro that nobiletin up-regulates neprilysin expression and activity in human neuroblastoma cells. However, the action of nobiletin with regard to Aβ degradation under in vitro AD pathological conditions remains unclear. In this study, we examined whether nobiletin could enhance the degradation of intra- and extracellular Aβ using human induced pluripotent stem cell-derived AD model neurons, which generate an excess of Aβ1-42 due to the familial AD presenilin-1 mutation. The neurons were treated in the presence or absence of nobiletin. The results of real-time quantitative RT-PCR indicated that neprilysin mRNA levels were significantly up-regulated by nobiletin. Furthermore, immunostaining with an anti-Aβ antibody revealed that nobiletin substantially reduced the intraneuronal content of Aβ. Interestingly, the results of Aβ1-42 immunoassays confirmed that nobiletin also significantly decreased the levels of Aβ1-42 released into the cellular medium. These results suggest that nobiletin enhanced the reduction of intra- and that extracellular Aβ levels under AD pathologic conditions, and this is associated with the up-regulation of neprilysin expression. Collectively, nobiletin appears to be a promising novel prophylactic seed drug or functional food for AD.


Basic concepts and clinical findings in the treatment of seizure disorders with EEG operant conditioning.
Two issues concerning sensorimotor EEG operant conditioning, or biofeedback, as a therapeutic modality for the treatment of seizure disorders are the focus of this review. The first relates to the question of whether relevant physiological changes are associated with this procedure. This question is addressed through review of an extensive neurophysiological literature that is likely unfamiliar to many clinicians but that documents both immediate and sustained functional changes that are consistent with elevation of seizure thresholds. The second focuses on the clinical efficacy of this method and whether it should carry the designation of "experimental". This designation is challenged through an assessment of over 25 years of peer-reviewed research demonstrating impressive EEG and clinical results achieved with the most difficult subset of seizure patients.


Asymmetric C-C bond-formation reaction with Pd: how to favor heterogeneous or homogeneous catalysis?
The enantioselective allylic alkylation of (E)-1,3-diphenylallyl acetate was studied to clarify the heterogeneous or homogeneous character of the Pd/Al(2)O(3)-(R)-BINAP catalyst system. A combined approach was applied: the catalytic tests were completed with in situ XANES measurements to follow the oxidation state of Pd as a function of the reaction conditions. The study revealed that the oxidized Pd (after exposure to ambient air) is efficiently reduced by the solvents THF and dioxane, and by the nucleophile sodium dimethyl malonate, and thus these conditions prevent Pd leaching. The chiral modifier BINAP plays a dual role: a considerable coverage of the Pd surface by the bulky compound slows down the initial reduction of the surface oxides but BINAP itself may consume surface oxygen (through its conversion to BINAPO and BINAPO(2)) and contribute to the maintenance of the active metal surface during the reaction. Carrying out the reaction under pressure in an inert gas atmosphere is important to minimize the oxygen diffusion into the reaction mixture and to avoid leaching. The (known) effect of temperature is critical as well: our catalyst system is inactive at room temperature, which is a clear deviation from the behavior of the corresponding homogeneous system. In contrast, halogenated solvents are easily dehalogenated on Pd/Al(2)O(3) and thus they favor leaching of the metal and formation of soluble compounds, analogous to classical metal corrosion in the presence of halide ions. The frequently observed dissolution of Pd in the presence of halogenated substrates may be explained similarly.


Visual seizure annotation and automated seizure detection using behind-the-ear electroencephalographic channels.
Seizure diaries kept by patients are unreliable. Automated electroencephalography (EEG)-based seizure detection systems are a useful support tool to objectively detect and register seizures during long-term video-EEG recording. However, this standard full scalp-EEG recording setup is of limited use outside the hospital, and a discreet, wearable device is needed for capturing seizures in the home setting. We are developing a wearable device that records EEG with behind-the-ear electrodes. In this study, we determined whether the recognition of ictal patterns using only behind-the-ear EEG channels is possible. Second, an automated seizure detection algorithm was developed using only those behind-the-ear EEG channels. Fifty-four patients with a total of 182 seizures, mostly temporal lobe epilepsy (TLE), and 5284 hours of data, were recorded with a standard video-EEG at University Hospital Leuven. In addition, extra behind-the-ear EEG channels were recorded. First, a neurologist was asked to annotate behind-the-ear EEG segments containing selected seizure and nonseizure fragments. Second, a data-driven algorithm was developed using only behind-the-ear EEG. This algorithm was trained using data from other patients (patient-independent model) or from the same patient (patient-specific model). The visual recognition study resulted in 65.7% sensitivity and 94.4% specificity. By using those seizure annotations, the automated algorithm obtained 64.1% sensitivity and 2.8 false-positive detections (FPs)/24 hours with the patient-independent model. The patient-specific model achieved 69.1% sensitivity and 0.49 FPs/24 hours. Visual recognition of ictal EEG patterns using only behind-the-ear EEG is possible in a significant number of patients with TLE. A patient-specific seizure detection algorithm using only behind-the-ear EEG was able to detect more seizures automatically than what patients typically report, with 0.49 FPs/24 hours. We conclude that a large number of refractory TLE patients can benefit from using this device.


SOLITAIRE™ with the intention for thrombectomy (SWIFT) trial: design of a randomized, controlled, multicenter study comparing the SOLITAIRE™ Flow Restoration device and the MERCI Retriever in acute ischaemic stroke.
Self-expanding stent retrievers are a promising new device class designed for rapid flow restoration in acute cerebral ischaemia. The SOLITAIRE™ Flow Restoration device (SOLITAIRE) has shown high rates of recanalization in preclinical models and in uncontrolled clinical series. (1) To demonstrate non-inferiority of SOLITAIRE compared with a legally marketed device, the MERCI Retrieval System®; (2) To demonstrate safety, feasibility, and efficacy of SOLITAIRE in subjects requiring mechanical thrombectomy diagnosed with acute ischaemic stroke. DESIGN : Multicenter, randomized, prospective, controlled trial with blinded primary end-point ascertainment. Key entry criteria include: age 22-85; National Institute of Health Stroke Scale (NIHSS) ≥8 and <30; clinical and imaging findings consistent with acute ischaemic stroke; patient ineligible or failed intravenous tissue plasminogen activator; accessible occlusion in M1 or M2 middle cerebral artery, internal carotid artery, basilar artery, or vertebral artery; and patient able to be treated within 8 h of onset. Sites first participate in a roll-in phase, treating two patients with the SOLITAIRE device, before proceeding to the randomized phase. In patients unresponsive to the initially assigned therapy, after the angiographic component of the primary end-point is ascertained (reperfusion with the initial assigned device), rescue therapy with other reperfusion techniques is permitted. The primary efficacy end-point is successful recanalization with the assigned study device (no use of rescue therapy) and with no symptomatic intracranial haemorrhage. Successful recanalization is defined as achieving Thrombolysis In Myocardial Ischemia 2 or 3 flow in all treatable vessels. The primary safety end-point is the incidence of device-related and procedure-related serious adverse events. A major secondary efficacy end-point is time to achieve initial recanalization. Additional secondary end-points include clinical outcomes at 90 days and radiologic haemorrhagic transformation.


Superior mesenteric artery syndrome in the modern trauma patient.
In 1861, von Rokitansky described obstruction of the third part of the duodenum by external compression of the duodenum by the superior mesenteric artery (SMA). In 1926, this entity was furthermore described by Wilke in his presentation of 75 patients with "chronic duodenal compression". In 1968, Mansberger used angiography to define anatomical measurements as the diagnostic criteria for this condition. Current modalities of diagnosis of SMA syndrome include esophagogastroduodenoscopy, computerized tomography angiogram, fluoroscopy, transabdominal ultrasound, and endoscopic ultrasound. The SMA syndrome has been associated with prolonged confinement in the supine position, loss of weight, loss of abdominal wall muscle tone, application of a body cast, and severe burns. With current surgical techniques allowing early ambulation, patients are able to avoid prolonged bed rest. The use of parenteral and enteral nutritional support has limited the loss of weight associated with trauma and burn patients, making this syndrome uncommon in this patient population. Recent reports of SMA syndrome focus on the association with corrective surgical procedures for scoliosis and obesity.


Acting on delusions. I: Prevalence.
Associations between delusions and abnormal behaviour were retrospectively assessed in a sample of 83 consecutively admitted deluded subjects. All were interviewed about events in the previous month using a new measure of delusional phenomenology and action. For 59 subjects this information was supplemented by informant interviews. Clinical consensus was reached concerning the probability that actions reported by informants were linked to delusions. Half of the sample reported that they had acted at least once in accordance with their delusions. Violent behaviour in response to delusions was uncommon. Information provided by informants suggested that some aspect of the actions of half of the sample was either probably or definitely congruent with the content of their delusions. However, there was no link between self-reports and informants' reports of such action. A latent class analysis of self-reported delusional action suggested three classes of action, namely aggressive to self or other, defensive action, and either none or single action. Self-reported action was associated with delusions of catastrophe. Informant data suggested that persecutory delusions were the most likely to be acted upon, but in contrast delusions of guilt or catastrophe appeared to decrease the chance of delusional behaviour. Actions associated with abnormal beliefs are more common than has been suggested.


Tuberculosis in liver transplant recipients: a systematic review and meta-analysis of individual patient data.
Mycobacterium tuberculosis (MTB) causes substantial morbidity and mortality in liver transplant recipients. We examined the efficacy of isoniazid latent Mycobacterium tuberculosis infection (LTBI) treatment in liver transplant recipients and reviewed systematically all cases of active MTB infection in this population. We found 7 studies that evaluated LTBI treatment and 139 cases of active MTB infection in liver transplant recipients. Isoniazid LTBI treatment was associated with reduced MTB reactivation in transplant patients with latent MTB risk factors (0.0% versus 8.2%, P = 0.02), and isoniazid-related hepatotoxicity occurred in 6% of treated patients, with no reported deaths. The prevalence of active MTB infection in transplant recipients was 1.3%. Nearly half of all recipients with active MTB infection had an identifiable pretransplant MTB risk factor. Among recipients who developed active MTB infection, extrapulmonary involvement was common (67%), including multiorgan disease (27%). The short-term mortality rate was 31%. Surviving patients were more likely to have received 3 or more drugs for MTB induction therapy (P = 0.003) and to have been diagnosed within 1 month of symptom onset (P = 0.01) and were less likely to have multiorgan disease (P = 0.01) or to have experienced episodes of acute transplant rejection (P = 0.02). Compared with the general population, liver transplant recipients have an 18-fold increase in the prevalence of active MTB infection and a 4-fold increase in the case-fatality rate. For high-risk transplant candidates, isoniazid appears safe and is probably effective at reducing MTB reactivation. All liver transplant candidates should receive a tuberculin skin test, and isoniazid LTBI treatment should be given to patients with a positive skin test result or MTB pretransplant risk factors, barring a specific contraindication. Liver Transpl 15:894-906, 2009. (c) 2009 AASLD.


Anatomical variability of the arcuate fasciculus: a systematical review.
The arcuate fasciculus (AF) is a white matter fibers tract that links the lateral temporal with the frontal cortex. The AF can be divided into three components: two superficial indirect short tracts (anterior and posterior) and one deep direct long tract. Both DTI and white matter dissections studies find differences regarding the anatomy of the AF, especially its cortical connections. This paper aims at providing a comprehensive anatomical classification of the AF, using the terminologia anatomica. Articles (n = 478) were obtained from a systematical PRISMA review. Studies which focused on primates, unhealthy subjects, as well as studies without cortical termination description and review articles were excluded from the analysis. One hundred and ten articles were retained for full-text examination, of which 19 finally fulfilled our criteria to be included in this review. We classified main descriptions and variations of each segment of the AF according to fiber orientation and cortical connections. Three types of connections were depicted for each segment of the AF. Concerning the anterior segment, most of the frontal fibers (59.35%) ran from the ventral portion of the precentral gyrus and the posterior part of the pars opercularis, to the supramarginal gyrus (85.0%). Main fibers of the posterior segment of the AF ran from the posterior portion of the middle temporal gyrus (100%) to the angular gyrus (92.0%). In main descriptions of the long segment of the AF, fibers ran from both the ventral portion of the precentral gyrus and posterior part of the pars opercularis (63.9%) to the middle and inferior temporal gyrus (60.3%). Minor subtypes were described in detail in the article. We provide a comprehensive classification of the anatomy of the AF, regarding the orientation and cortical connections of its fibers. Although fiber orientation is very consistent, cortical endings of the AF may be different from one study to another, or from one individual to another which is a key element to understand the anatomical basis of current models of language or to guide intraoperative stimulation during awake surgery.


Hypermethylation of CpG islands in primary and metastatic human prostate cancer.
Aberrant DNA methylation patterns may be the earliest somatic genome changes in prostate cancer. Using real-time methylation-specific PCR, we assessed the extent of hypermethylation at 16 CpG islands in DNA from seven prostate cancer cell lines (LNCaP, PC-3, DU-145, LAPC-4, CWR22Rv1, VCaP, and C42B), normal prostate epithelial cells, normal prostate stromal cells, 73 primary prostate cancers, 91 metastatic prostate cancers, and 25 noncancerous prostate tissues. We found that CpG islands at GSTP1, APC, RASSF1a, PTGS2, and MDR1 were hypermethylated in >85% of prostate cancers and cancer cell lines but not in normal prostate cells and tissues; CpG islands at EDNRB, ESR1, CDKN2a, and hMLH1 exhibited low to moderate rates of hypermethylation in prostate cancer tissues and cancer cell lines but were entirely unmethylated in normal tissues; and CpG islands at DAPK1, TIMP3, MGMT, CDKN2b, p14/ARF, and CDH1 were not abnormally hypermethylated in prostate cancers. Receiver operator characteristic curve analyses suggested that CpG island hypermethylation changes at GSTP1, APC, RASSF1a, PTGS2, and MDR1 in various combinations can distinguish primary prostate cancer from benign prostate tissues with sensitivities of 97.3-100% and specificities of 92-100%. Hypermethylation of the CpG island at EDNRB was correlated with the grade and stage of the primary prostate cancers. PTGS2 CpG island hypermethylation portended an increased risk of recurrence. Furthermore, CpG island hypermethylation patterns in prostate cancer metastases were very similar to the primary prostate cancers and tended to show greater differences between cases than between anatomical sites of metastasis.


Prognostic markers in patients with antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis.
The purpose of this study was to determine the prognostic value of clinical, laboratory, and pathologic features at the time of presentation on patient and renal survival in patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated microscopic polyangiitis and glomerulonephritis (excluding Wegener's granulomatosis). One hundred seven ANCA-positive patients with necrotizing and crescentic glomerulonephritis, including 69 with evidence for microscopic polyangiitis, were evaluated for this study. The relative risk of death was calculated for the following potential prognostic indicators: (1) ANCA pattern; (2) pulmonary hemorrhage at onset; (3) presence of extrarenal manifestations versus renal limited disease; and (4) treatment with corticosteroids and cyclophosphamide (intravenous or oral), compared with corticosteroids alone. Cox's proportional hazard model was used to assess the predictive value of the following variables on renal survival: (1) age; (2) race; (3) pulmonary symptoms at onset of disease; (4) renal pathology; (5) ANCA pattern; and (6) peak serum creatinine values obtained near the time of renal biopsy. Patients were followed prospectively for 2.5 yr (range, 5 days to 12 yr 2 months). There were 12 disease-related deaths and 46 patients who reached ESRD. The relative risk (and 95% confidence interval) of patient death was 8.65 (3.36, 22.2) times greater in patients who presented with pulmonary hemorrhage, and 3.78 (1.22, 11.70) times greater in patients with cytoplasmic ANCA compared to those with perinuclear ANCA. The relative risk of pulmonary hemorrhage was no different by ANCA pattern. The risk of death was 5.56 times lower in the cyclophosphamide-treated patients versus those treated with corticosteroids alone. The predictors of renal survival were entry serum creatinine value (P = 0.0002), race (African Americans having a worse outcome compared with Caucasians, P = 0.0008), and the presence of arterial sclerosis on kidney biopsy (P = 0.0076) when controlling for age, ANCA pattern, microscopic polyangiitis versus glomerulonephritis alone, and pulmonary involvement. Pathology indices such as glomerular necrosis, glomerular crescents, glomerular sclerosis, and interstitial sclerosis were not predictive of renal survival when controlling for entry serum creatinine value, race, and arterial sclerosis. However, in the subgroup of patients with a peak creatinine value of < or = 3.0 mg/dL (N = 29), increased interstitial sclerosis was a predictor of a poor renal outcome (P = 0.04).


A computational study of a thin-walled three-dimensional left ventricle during early systole.
A numerical study was conducted to solve the three-dimensional Navier-Stokes equations for time-dependent flow in a compliant thin-walled, anatomically correct left ventricle during early systole. Model parameters were selected so that the simulation results could be compared to clinical data. The results produced endocardial wall motion which was consistent with human heart data, and velocity fields consistent with those occurring in a normally-contracting left ventricle. During isovolumetric contraction the posterior wall moved basally and posteriorly, while the septal wall moved apically and anteriorly. During ejection, the short axis of the ventricle decreased 1.1 mm and the long axis increased 4.2 mm. At the end of the isovolumetric contraction, most of the flow field was moving form the apex toward the base with recirculation regions at the small pocket formed by the concave anterior leaflet, adjacent to the septal wall and near the left ventricular posterior wall. Fluid velocities in the outflow tract matched NMR data to within 10 percent. The results were also consistent with clinical measurements of mitral valve-papillary muscle apparatus displacement, and changes in the mitral valve annular area. The results of the present study show that the thin-walled, three-dimensional left ventricular model simulates observed normal heart phenomena. Validation of this model permits further studies to be performed which involve altered ventricular function due to a variety of cardiac diseases.


The simplicity of planar networks.
Shortest paths are not always simple. In planar networks, they can be very different from those with the smallest number of turns--the simplest paths. The statistical comparison of the lengths of the shortest and simplest paths provides a non trivial and non local information about the spatial organization of these graphs. We define the simplicity index as the average ratio of these lengths and the simplicity profile characterizes the simplicity at different scales. We measure these metrics on artificial (roads, highways, railways) and natural networks (leaves, slime mould, insect wings) and show that there are fundamental differences in the organization of urban and biological systems, related to their function, navigation or distribution: straight lines are organized hierarchically in biological cases, and have random lengths and locations in urban systems. In the case of time evolving networks, the simplicity is able to reveal important structural changes during their evolution.


Predicting optimal interventions for clinical depression: Moderators of outcomes in a positive psychological intervention vs. cognitive-behavioral therapy.
Identifying differences in the clinical response to specific interventions is an important challenge in the field of Clinical Psychology. This is especially true in the treatment of depression where many treatments appear to have comparable outcomes. In a controlled trial, we compared a positive psychology group intervention, the Integrative Positive Psychological Intervention for Depression (IPPI-D; n = 62) to a cognitive-behavioral therapy group intervention (CBT; n = 66) for depression. No statistically or clinically-significant differences between the treatments were found, but a slight advantage was observed, on average, for IPPI-D. The aim of the present study was to identify and combine moderators of the differential efficacy of these two psychological interventions for clinical depression. For this purpose, a secondary analysis using the Personalized Advantage Index (PAI) was performed to identify the intervention predicted to produce the better outcome for each patient. Six of the 21 potential moderators were found to predict differential efficacy between the treatments. IPPI-D was predicted to be the optimal treatment for 73% of the sample. Baseline features that characterized these individuals were: mental and physical comorbidity, prior antidepressant medication, higher levels of negative thoughts, and higher personal growth. The 27% who were predicted to achieve better outcomes in CBT than in IPPI-D tended to have these baseline features: no comorbidities, no prior antidepressant medication, lower levels of negative thoughts, and lower personal growth.


Obesity, An Emerging Epidemic In Pakistan-A Review Of Evidence.
In Pakistan, the disease pattern is facing a huge changeover from acute and communicable diseases to the non-communicable diseases. Moreover, an emerging epidemic of obesity is still under recognized in Pakistan. A detailed review and dissemination of the existing knowledge to determine the extent of burden of obesity can help understand this important public health issue. A detailed literature review was conducted through PubMed search engines, regarding obesity burden in Pakistan. The original peer reviewed research articles, reports of WHO in English language, non-government organizations reports were included in the review. "Obesity AND Pakistan" were used as a search terms. Pakistan is suffering from epidemic of obesity, affecting all age groups. Urban population, particularly women shows considerable higher burden of obesity as compared to men and women from rural population. However, among children and adolescents there is variation in prevalence of obesity. Girls from all age groups are predominantly more obese as compared to boys. Most of the studies have estimated child obesity among school going children of different age groups and need careful interpretation. Pakistan is currently suffering from an emerging epidemic of obesity. The rising burden of obesity is widespread among adults (man and women) and children. The burden of obesity is higher among females in all age groups as compare to males. Effective interventions are required at population level to prevent and control this emerging public health issue.


Deletion of pH Regulator pac-3 Affects Cellulase and Xylanase Activity during Sugarcane Bagasse Degradation by Neurospora crassa.
Microorganisms play a vital role in bioethanol production whose usage as fuel energy is increasing worldwide. The filamentous fungus Neurospora crassa synthesize and secrete the major enzymes involved in plant cell wall deconstruction. The production of cellulases and hemicellulases is known to be affected by the environmental pH; however, the regulatory mechanisms of this process are still poorly understood. In this study, we investigated the role of the pH regulator PAC-3 in N. crassa during their growth on sugarcane bagasse at different pH conditions. Our data indicate that secretion of cellulolytic enzymes is reduced in the mutant Δpac-3 at alkaline pH, whereas xylanases are positively regulated by PAC-3 in acidic (pH 5.0), neutral (pH 7.0), and alkaline (pH 10.0) medium. Gene expression profiles, evaluated by real-time qPCR, revealed that genes encoding cellulases and hemicellulases are also subject to PAC-3 control. Moreover, deletion of pac-3 affects the expression of transcription factor-encoding genes. Together, the results suggest that the regulation of holocellulase genes by PAC-3 can occur as directly as in indirect manner. Our study helps improve the understanding of holocellulolytic performance in response to PAC-3 and should thereby contribute to the better use of N. crassa in the biotechnology industry.


The master negative regulator REST/NRSF controls adult neurogenesis by restraining the neurogenic program in quiescent stem cells.
Transcriptional regulation is a critical mechanism in the birth, specification, and differentiation of granule neurons in the adult hippocampus. One of the first negative-acting transcriptional regulators implicated in vertebrate development is repressor element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF)--thought to regulate hundreds of neuron-specific genes--yet its function in the adult brain remains elusive. Here we report that REST/NRSF is required to maintain the adult neural stem cell (NSC) pool and orchestrate stage-specific differentiation. REST/NRSF recruits CoREST and mSin3A corepressors to stem cell chromatin for the regulation of pro-neuronal target genes to prevent precocious neuronal differentiation in cultured adult NSCs. Moreover, mice lacking REST/NRSF specifically in NSCs display a transient increase in adult neurogenesis that leads to a loss in the neurogenic capacity of NSCs and eventually diminished granule neurons. Our work identifies REST/NRSF as a master negative regulator of adult NSC differentiation and offers a potential molecular target for neuroregenerative approaches.


Exploring the temporal dynamics of the spatial working memory n-back task using steady state visual evoked potentials (SSVEP).
The neural networks associated with spatial working memory (SWM) are well established. However, the temporal dynamics of SWM-related brain activity are less clear. This study examined changes in temporal neurophysiology during the spatial n-back task using steady state probe topography (SSPT) to record cortical steady state visual evoked potentials (SSVEPs) at 64 scalp locations. Twenty healthy male volunteers participated in the study. The findings identified three different time periods of significance during the spatial n-back task--an early perceptual/encoding period (approximately 0-500 ms), an early delay period just following the stimulus disappearing from view (approximately 850-1400 ms), and a late period lasting the final second of the delay and anticipation of the new stimulus (approximately 2500-3500 ms). The delay period was associated with increases in frontal and occipital region amplitude, consistent with previous findings in more basic working memory tasks. The two different SSVEP components during the delay appear reflective of the additional "executive" demands associated with the n-back and may suggest variable roles for the PFC during different stages of the delay. All three n-back levels demonstrated a relative consistent electrophysiological profile, indicating that this pattern is specific to the spatial n-back task. Nevertheless, these findings supported the hypothesis that memory load modulates activity within the networks identified, consistent with previous neuroimaging studies. The current findings may offer a framework in which to further investigate the temporal aspects of SWM.


Changes in quality of bone mineral on aging and in disease.
This paper reviews the changes in the quality of bone mineral with age and in disease. After a brief review of morphological changes with aging in mammalian bones, microradiography is compared to backscattered electron imaging and their use in bringing out subtle changes in bone mineralization outlined. Changes in the quality of bone with disease is described using osteoporosis as an example. Chemical changes in the skeleton are then discussed and related to morphological changes. Finally, some examples of localized and generalized changes in bone mineral are given. This paper emphasizes that understanding the nature of the mineral phase in bone as well as its heterogeneity and its changes with age and in disease is essential to the elucidation of skeletal physiology and pathology.


Apigenin exhibits protective effects in a mouse model of d-galactose-induced aging via activating the Nrf2 pathway.
The aim of the present research was to study the protective effects and underlying mechanisms of apigenin on d-galactose-induced aging mice. Firstly, apigenin exhibited a potent antioxidant activity in vitro. Secondly, d-galactose was administered by subcutaneous injection once daily for 8 weeks to establish an aging mouse model to investigate the protective effect of apigenin. We found that apigenin supplementation significantly ameliorated aging-related changes such as behavioral impairment, decreased organic index, histopathological injury, increased senescence-associated β-galactosidase (SAβ-gal) activity and advanced glycation end product (AGE) level. Further data showed that apigenin facilitated Nrf2 nuclear translocation both in aging mice and normal young mice, and the Nrf2 expression of normal young mice was higher than that of natural senile mice. In addition, the expressions of Nrf2 downstream gene targets, including HO-1 and NQO1, were also promoted by apigenin administration. Moreover, apigenin also decreased the MDA level and elevated SOD and CAT activities. In conclusion, focusing on the Nrf2 pathway is a suitable strategy to delay the aging process, and apigenin may exert an anti-senescent effect process via activating the Nrf2 pathway.


The effects of spirulina on allergic rhinitis.
The prevalence of allergic rhinitis is increasing globally due to various causes. It affects the quality life of a large group of people in all around the world. Allergic rhinitis still remains inadequately controlled with present medical means. The need of continuous medical therapy makes individuals anxious about the side effects of the drugs. So there is a need for an alternative strategy. Effects of spirulina, tinospora cordifolia and butterbur were investigated recently on allergic rhinitis in just very few investigations. Spirulina represents a blue-green alga that is produced and commercialized as a dietary supplement for modulating immune functions, as well as ameliorating a variety of diseases. This double blind, placebo controlled study, evaluated the effectiveness and tolerability of spirulina for treating patients with allergic rhinitis. Spirulina consumption significantly improved the symptoms and physical findings compared with placebo (P < 0.001***) including nasal discharge, sneezing, nasal congestion and itching. Spirulina is clinically effective on allergic rhinitis when compared with placebo. Further studies should be performed in order to clarify the mechanism of this effect.


Modeling and Simulations in Time Domain of a Stimulation Set-up for Cortical Applications.
Electrical stimulation is used for example to treat neuronal disorders and depression with deep brain stimulation or transcranial electrical stimulation. Depending on the application, different electrodes are used and thus different electrical characteristics exist, which have to be handled by the stimulator. Without a measuring device the user would have to rely on the stimulator being able to deliver the needed stimulation signal. Therefore, the objective of this paper is to present a method to increase the level of confidence with characterization and modelling of the electrical behavior by using the example of one channel of our stimulation device for experimental use. In several simulation studies with an electrode model with values in a typical range for cortical applications the influence of the load onto the stimulator and the possibility to pre-estimate measuring signals in complex networks are shown.


[Thromboelastograph in cardiac surgery: state of the art.].
Management of hemostasis of cardiopulmonary bypass (CPB) patients is still a major challenge. New monitoring methods, new hemostatic drugs and new platelet function inhibitors are being added to the pre, intra and postoperative periods. The multifactorial nature of CBP-induced hemostasis disorders requires the understanding of their pathophysiology and the accurate hemostasis evaluation for effective coagulation during CPB, in addition to the maintenance of adequate postoperative hemostasis. Activated clotting time (ACT) and coagulogram are not enough for this management. A broader evaluation is needed with monitors able to measure platelet function and hemostatic process dynamics as a whole. Hemostasis is the result of the balance of coagulation, anticoagulation and fibrinolysis systems components. This balance is disrupted during CPB making patients susceptible to microvascular bleeding. CPB induces multifactorial changes in platelet force growth and clot elastic properties. Blood products are often used and there is the need for protocols to guide transfusion decisions. It is important to determine platelet function with monitors measuring clot visco-elastic properties, such as thromboleastograph (TEG) and Sonoclot. Thromboelastograph is an important hemostasis monitor for patients submitted to CPB. It has been incorporated to hemostatic disorders evaluation protocols and transfusion therapy, with good results.