Solar considerations in the development of cutaneous melanoma.
On the basis of these considerations, the possible action spectrum for melanoma can be narrowed considerably, but not confined to any one solar emission band. The physical factors discussed eliminate all but UV, visible, and NIR radiation as possible solar agents. Ionizing radiation fits neither the epidemiologic data nor first-order physical considerations. Wavelengths longer than the NIR wavelengths, although they could conceivably account for the occurrence of melanoma under clothed parts of the body, carry so little energy that they are probably unimportant. Epidemiologic evidence regarding the effects of skin pigment favors UV or visible radiation. A distinction between these two components is not obvious; UV-C and UV-B photons carry greater energy and are more likely to induce biochemical cutaneous effects, but the total flux in the UV-A and visible radiations is far greater. That UV-B radiation may play a role in melanoma is supported; at the same time, one cannot exclude the possibility that the action spectrum for melanoma is, instead, the UV-A, the visible, or even the NIR portion of the sunlight spectrum. The strong differential effect of altitude on the transmission of light of different wavelengths might serve as an important discriminating variable. If solar UV radiation is implicated in the development of melanoma, then altitude should emerge as a significant factor in epidemiologic studies. If visible or IR radiation is the active agent, then differences on the basis of altitude should be small or negligible. Intrinsic solar variations that follow the annual sunspot number appear inadequate in either the UV or the visible band to account directly for the apparent 11-year modulation of melanoma incidence found in some registries. Secondary atmospheric effects brought about by the action of solar UV changes on the ozone layer may be adequate to explain a weak 11-year modulation in melanoma incidence, although continuous measurements of UV-B flux made at sites in the United States through a full solar cycle have shown no such effect. Nor do these early measurements reveal the long-term increase in UV-B intensity expected from the destruction of stratospheric ozone by industrial pollutants over the last 10 years.


Development of infant sustained attention and its relation to EEG oscillations: an EEG and cortical source analysis study.
The current study examined the relation between infant sustained attention and infant EEG oscillations. Fifty-nine infants were tested at 6 (N = 15), 8 (N = 17), 10 (N = 14), and 12 (N = 13) months. Three attention phases, stimulus orienting, sustained attention, and attention termination, were defined based on infants' heart rate changes. Frequency analysis using simultaneously recorded EEG focused on infant theta (2-6 Hz), alpha (6-9 Hz), and beta (9-14 Hz) rhythms. Cortical source analysis of EEG oscillations was conducted with realistic infant MRI models. Theta synchronization was found over fontal pole, temporal, and parietal electrodes during infant sustained attention for 10 and 12 months. Alpha desynchronization was found over frontal, central and parietal electrodes during sustained attention. This alpha effect started to emerge at 10 months and became well established by 12 months. No difference was found for the beta rhythm between different attention phases. The theta synchronization effect was localized to the orbital frontal, temporal pole, and ventral temporal areas. The alpha desynchronization effect was localized to the brain regions composing the default mode network including the posterior cingulate cortex and precuneus, medial prefrontal cortex, and inferior parietal gyrus. The alpha desynchronization effect was also localized to the pre- and post-central gyri. The present study demonstrates a connection between infant sustained attention and EEG oscillatory activities.


Control of copula duration and sperm storage by female Queensland fruit flies.
Copula duration and sperm storage patterns can directly or indirectly affect fitness of male and female insects. Although both sexes have an interest in the outcome, research has tended to focus on males. To investigate female influences, we compared copula duration and sperm storage of Queensland fruit fly females that were intact, or had been incapacitated through decapitation or abdomen isolation. We found that copulations were far longer when females had been incapacitated, indicating that constraints imposed on copula duration by intact females had been relaxed. Repeatability of copula duration for males was very low regardless of female treatment, and this is also consistent with strong female influence. Number of sperm in the spermathecae was not influenced by female treatment, suggesting that female abdominal ganglia control the transport of sperm to these long-term storage organs. However, more sperm were found in the ventral receptacles of incapacitated females compared to intact females. Overall, results implicate cephalic ganglia in regulation of copula duration and short-term sperm storage in the ventral receptacle and abdominal ganglia in regulation of long-term sperm storage in the spermathecae.


Centroid molecular dynamics: comparison with exact results for model systems.
The relation between the accuracy of centroid molecular dynamics correlation functions, and the geometry of the centroid potential is investigated. It is shown that, depending on the temperature, there exist several regimes, and in each of them certain features of the exact Kubo correlation functions are reproduced. The change of regimes is related to the emergence of barriers in the centroid potential. In order to clarify how the above described picture of regimes is modified in real systems when dissipation is important, a methodology is developed to test the accuracy of centroid correlation functions for the model of a particle coupled to a harmonic heat bath. A modification of the centroid molecular dynamics method to include the influence of the heat bath is introduced. Preliminary results of comparison of centroid molecular dynamics with the numerically exact results of filtered propagator functional method are presented.


Localization of class-related mu-rhythm desynchronization in motor imagery based brain-computer interface sessions.
We localize the sources of class-dependent event-related desynchronisation (ERD) of the mu-rhythm related to different types of motor imagery in Brain-Computer Interfacing (BCI) sessions. Our approach is based on localization of single-trial Fourier coefficients using sparse basis field expansions (S-FLEX). The analysis reveals focal sources in the sensorimotor cortices, a finding which can be regarded as a proof for the expected neurophysiological origin of the BCI control signal. As a technical contribution, we extend S-FLEX to the multiple measurement case in a way that the activity of different frequency bins within the mu-band is coherently localized.


Role of the insulin receptor substrate 1 and phosphatidylinositol 3-kinase signaling pathway in insulin-induced expression of sterol regulatory element binding protein 1c and glucokinase genes in rat hepatocytes.
The mechanism by which insulin induces the expression of the sterol regulatory element binding protein 1c (SREBP-1c) and glucokinase genes was investigated in cultured rat hepatocytes. Overexpression of an NH(2)-terminal fragment of IRS-1 that contains the pleckstrin homology and phosphotyrosine binding domains (insulin receptor substrate-1 NH(2)-terminal fragment [IRS-1N]) inhibited insulin-induced tyrosine phosphorylation of IRS-1 as well as the association of IRS-1 with phosphatidylinositol (PI) 3-kinase activity, whereas the tyrosine phosphorylation of IRS-2 and its association with PI 3-kinase activity were slightly enhanced. The equivalent fragment of IRS-2 (IRS-2N) prevented insulin-induced tyrosine phosphorylation of both IRS-1 and IRS-2, although that of IRS-1 was inhibited more efficiently. The insulin-induced increases in the abundance of SREBP-1c and glucokinase mRNAs, both of which were sensitive to a dominant-negative mutant of PI 3-kinase, were blocked in cells in which the insulin-induced tyrosine phosphorylation of IRS-1 was inhibited by IRS-1N or IRS-2N. A dominant-negative mutant of Akt enhanced insulin-induced tyrosine phosphorylation of IRS-1 (but not that of IRS-2) and its association with PI 3-kinase activity, suggesting that Akt contributes to negative feedback regulation of IRS-1. The Akt mutant also promoted the effects of insulin on the accumulation of SREBP-1c and glucokinase mRNAs. These results suggest that the IRS-1-PI 3-kinase pathway is essential for insulin-induced expression of SREBP-1c and glucokinase genes.


Influence of surgical technique on mastectomy and reexcision rates in breast-conserving therapy for cancer.
Introduction. Breast conserving surgery (BCS) requires tumor excision with negative margins. Reexcision rates of 30-50% are reported. Ultrasound localization, intraoperative margin pathology, and specimen mammography have reduced reexcisions, but require new equipment. Cavity shave margin (CSM) is a technique, utilizing existing equipment, that potentially reduces reexcision. This study evaluates CSM reexcision impact. Methods. 522 cancers treated with BCS were reviewed. Patients underwent standard partial mastectomy (SPM) or CSM. Data collected included demographics, pathology, and treatments. Results. 455 SPMs were compared to 67 CSMs. Analysis revealed no differences in pathology, intraductal component, or neoadjuvant chemotherapy. Overall reexcision rate = 43%. Most reexcisions were performed for DCIS at margin. SPMs underwent 213 reexcisions (46.8%), versus 16/67 (23.9%) CSMs (P = 0.0003). Total mastectomy as definitive procedure was performed after more SPMs (P = 0.009). Multivariate analysis revealed CSM, % DCIS, tumor size, and race to influence reexcisions. Conclusions. CSM is a technique that reduces reexcisions and mastectomy rates.


[Remote results of treatment of patients with chronic lower-limb ischaemia by means of indirect revascularization and gene therapy].
Presented herein are comparative remote results of combined surgical treatment of 121 patients with stage IIB-III lower limb chronic ischaemia (LLCI) by means of indirect revascularization (lumbar sympathectomy--LSE and revascularizing osteotrepanation of the tibial bone--ROT) and gene therapy using the first registered Russian gene therapeutic agent Neovasculgen®. Depending on the LLCI degree and the method of treatment, during 3 years we assessed such parameters as the limb salvage rate, pain-free walk distance (PFWD), ankle-brachial index (ABI) and linear blood velocity (LBV). An increase in the PFWD in patients with initial stage IIB LLCI in the group of gene therapy was considerably higher than in other types of treatment (p=0.0001-0.0004). Using indirect methods of revascularization was accompanied and followed by less positive alterations in the PFWD values which by the end of the third year of follow up were observed to decrease. The values of PFWD after ROT at 2 and 3 years were higher than after LSE (p=0.006). During the first year of follow up the highest increment of the ABI was observed after ROT. At two years, the ABI values after ROT and gene therapy became equal. The worst result during 3 years as compared with other methods of treatment was demonstrated by LSE (p=0.006). Changes in ABI after gene therapy were statistically significant at all terms of follow up (p=0.008-0.02). There were no limb amputations in the remote period of follow up in patients with the initial stage IIB of the disease. Patients with initial stage III LLCI also showed a considerably better result by the increment of increased PFWD after gene-therapeutic treatment (p=0.001-0.0005). A small increment of the PFWD after LSE maintained during 1 year and after LSE during 2 years. The ABI values in all periods of follow up were higher after gene therapy (p=0.01-0.003). During the 2- and 3-year period the increment of this parameter after ROT was more significant than after LSE (p=0.046-0.05). Changes in the ABI after gene therapy at all terms also turned out to be more substantial (p=0.03-0.008). An increase in the LBV during the first and second years after ROT turned out more significant as compared to LSE (p=0.05). The limb salvage rate in patients with initial stage III LLCI during the whole period after gene therapy amounted to 78%, after ROT being 54% and after LSE equalling 45%.


Attosecond timing jitter pulse trains from semiconductor saturable absorber mode-locked Cr:LiSAF lasers.
The timing jitter of optical pulse trains from diode-pumped, semiconductor saturable absorber mode-locked femtosecond Cr:LiSAF lasers is characterized by a single-crystal balanced optical cross-correlator with an equivalent sensitivity in phase noise of -235 dBc/Hz. The RMS timing jitter is 30 attoseconds integrated from 10 kHz to 50 MHz, the Nyquist frequency of the 100 MHz repetition rate oscillator. The AM-to-PM conversion induced excess phase noise is calculated and compared with experiment. The self-steepening effect is proven to be the dominant AM-to-PM coupling mechanism, whereas the semiconductor saturable absorber operation does not adversely affect timing jitter. The results show that ultrafast Cr:LiSAF lasers are promising compact and efficient ultralow-jitter sources.


Correlation Between Metabolic Syndrome, Periodontitis and Reactive Oxygen Species Production. A Pilot Study.
Metabolic syndrome (MetS) is associated with an increased risk of periodontitis even if the mechanism is unknown. Since both MetS and periodontitis are characterized by an alteration of inflammation status, the aim of this pilot study was to determine if differences in ROS metabolism of phagocytes isolated from (A) patients with MetS, (B) patients with both MetS and mild periodontitis, (C) healthy subjects and (D) normal weight subjects with mild periodontitis, were present. ROS metabolism was studied by a Chemiluminescence (CL) technique: the system was made up of luminol (100 nmol/L) and cells (1 × 105) in the presence or absence of stimulus constituted by opsonized zymosan (0.5 mg). The final volume (1.0 mL) was obtained using modified KRP buffer. ROS production was measured at 25°C for 2 h, using an LB 953 luminometer (Berthold, EG & G Co, Germany). All the experiments were performed in triplicate. All results are mean ± standard deviation (SD). The group of means was compared by the analysis of variance "(ANOVA)". A value of p < 0.05 was considered significant. Results showed that basal ROS production (both from PMNs and from PBMs) of groups A, B and D was increased with respect to that obtained from group C (p <0.05). These results are congruent with literature data, although the actual clinical relevance of the phenomenon remains to be evaluated.


International guidelines for the treatment of community-acquired pneumonia in adults: the role of macrolides.
The significance of community-acquired pneumonia (CAP) has led to the publication of guidelines from numerous international organisations. Because the macrolide class of antimicrobials is active against most of the key pathogens associated with CAP, agents from this class are commonly included in recommendations from these guidelines. However, there are differences among the various guidelines concerning the positioning of the macrolides for empirical therapy. An important factor concerning the use of macrolides for CAP is the emergence of resistance of Streptococcus pneumoniae over the past decade. The rate of S. pneumoniae resistance to macrolides ranges from 4 to 70% of strains in worldwide surveillance studies. The most common mechanisms of resistance include methylation of a ribosomal target encoded by the erm gene and efflux of the macrolides by a cell membrane protein transporter, encoded by the mef gene. S. pneumoniae strains with the mef gene are resistant at a lower level (with minimum inhibitory concentration [MIC] values generally 1-16 microg/ml) than erm resistant strains; and it is possible that such strains may be inhibited if sufficiently high levels of macrolide can be obtained at the infected site. Currently mef-associated resistance predominates in North America, whereas erm predominates in Europe. Until recently, reports of failure of treatment of CAP with macrolides has been rare, particularly for patients with low-risk for drug-resistant strains. However, since 2000, several patients treated with an oral macrolide who have subsequently required admission to the hospital for macrolide-resistant S. pneumoniae (MRSP) bacteraemia have been reported in the literature. Major issues, which are fundamental to the use of the macrolides as recommended in the various guidelines, include the importance of providing therapy for 'atypical' pathogens and the clinical significance of MRSP. Presently, the macrolides are more prominently recommended in the North American guidelines than in other parts of the world. The difference in the emphasis placed on the importance of the atypical pathogens as well as the expression of MRSP in North America compared with Europe partly explains this variance.


Systematic review: terlipressin in acute oesophageal variceal haemorrhage.
Controversy exists surrounding pharmacological therapy in acute variceal bleeding. To determine the efficacy and safety of terlipressin. Randomized trials were identified and duplicate, independent, review identified 20 randomized trials involving 1609 patients that compared terlipressin with placebo, balloon tamponade, endoscopic treatment, octreotide, somatostatin or vasopressin for treatment of acute oesophageal variceal haemorrhage. Meta-analysis showed that compared to placebo, terlipressin reduced mortality (relative risk 0.66, 95% CI 0.49-0.88), failure of haemostasis (relative risk 0.63, 95% CI 0.45-0.89) and the number of emergency procedures per patient required for uncontrolled bleeding or rebleeding (relative risk 0.72, 95% CI 0.55-0.93). When used as an adjuvant to endoscopic sclerotherapy, terlipressin reduced failure of haemostasis (relative risk 0.75, 95% CI 0.58-0.96), and had an effect on reducing mortality that approached statistical significance (relative risk 0.74, 95% CI 0.53-1.04). No significant difference was demonstrated between terlipressin and endoscopic sclerotherapy, balloon tamponade, somatostatin or vasopressin. Haemostasis was achieved more frequently with octreotide compared to terlipressin (relative risk 1.62, 95% CI 1.05-2.50), but this result was based on unblinded studies. Adverse events were similar between terlipressin and the other comparison groups except for vasopressin, which caused more withdrawals due to adverse events. Terlipressin is a safe and effective treatment for acute oesophageal variceal bleeding, with or without adjuvant endoscopic sclerotherapy. Terlipressin appears to reduce mortality in acute oesophageal variceal bleeding compared to placebo, and is the only pharmacological agent shown to do so. Future studies will be required to detect potential mortality differences between terlipressin and other therapeutic approaches.


Dopamine, Salience, and Response Set Shifting in Prefrontal Cortex.
Dopamine is implicated in multiple functions, including motor execution, action learning for hedonically salient outcomes, maintenance, and switching of behavioral response set. Here, we used a novel within-subject psychopharmacological and combined functional neuroimaging paradigm, investigating the interaction between hedonic salience, dopamine, and response set shifting, distinct from effects on action learning or motor execution. We asked whether behavioral performance in response set shifting depends on the hedonic salience of reversal cues, by presenting these as null (neutral) or salient (monetary loss) outcomes. We observed marked effects of reversal cue salience on set-switching, with more efficient reversals following salient loss outcomes. L-Dopa degraded this discrimination, leading to inappropriate perseveration. Generic activation in thalamus, insula, and striatum preceded response set switches, with an opposite pattern in ventromedial prefrontal cortex (vmPFC). However, the behavioral effect of hedonic salience was reflected in differential vmPFC deactivation following salient relative to null reversal cues. l-Dopa reversed this pattern in vmPFC, suggesting that its behavioral effects are due to disruption of the stability and switching of firing patterns in prefrontal cortex. Our findings provide a potential neurobiological explanation for paradoxical phenomena, including maintenance of behavioral set despite negative outcomes, seen in impulse control disorders in Parkinson's disease.


Dynamic strain in gold nanoparticle supported graphene induced by focused laser irradiation.
Graphene on noble-metal nanostructures constitutes an attractive nanocomposite with possible applications in sensors or energy conversion. In this work we study the properties of hybrid graphene/gold nanoparticle structures by Raman spectroscopy and scanning probe methods. The nanoparticles (NPs) were prepared by local annealing of gold thin films using a focused laser beam. The method resulted in a patterned surface, with NPs formed at arbitrarily chosen microscale areas. Graphene grown by chemical vapour deposition was transferred onto the prepared, closely spaced gold NPs. While we found that successive higher intensity (6 mW) laser irradiation increased gradually the doping and the defect concentration in SiO2 supported graphene, the same irradiation procedure did not induce such irreversible effects in the graphene supported by gold NPs. Moreover, the laser irradiation induced a dynamic hydrostatic strain in the graphene on Au NPs, which turned out to be completely reversible. These results can have implications in the development of graphene/plasmonic nanoparticle based high temperature sensors operating in dynamic regimes.


Peptide-induced stabilization and intracellular localization of empty HLA class I complexes.
The human cell line T2 has been reported to be class I assembly deficient, and accordingly expresses reduced amounts of HLA-A2 and no HLA-B5 at the cell surface. By immunoblotting we observe the steady-state class I heavy chain levels of T2 to be near normal when compared with the identical class I alleles of the wild-type cell line T1. In pulse chase experiments, formation of heavy chain beta 2-microglobulin complexes is observed for both HLA-A2 and HLA-B5. Culture at reduced temperatures (26 or 20 degrees C) does not increase the amount of class I molecules transported, unlike what has been reported for the class I assembly-deficient mouse mutant cell line RMA-S. The HLA-B5 and the HLA-A2 complexes formed by T2 are thermolabile in cell lysates, albeit to different degrees. The thermolability of HLA-B5 can be overcome by addition of HLA-B5-presentable peptides, obtained by trifluoroacetic acid extraction from an HLA-B5-positive cell line, underlining the necessity of peptide for class I stability and indicating that T2-derived class I complexes are devoid of peptide. Cytoplast fusion of T2 cells with RMA-S cells shows the defect in class I assembly of RMA-S to be similar to that of T2. Localization of class I molecules observed by immuno-electron microscopy reveals the accumulation in the T2 cell line of both HLA-B5 and HLA-A2 in the endoplasmic reticulum (ER). Class I molecules are present in all the cisternae of the Golgi complex of T2, but the ratio of HLA-A and -B locus products in the Golgi area differs significantly from that at the cell surface. We conclude that the requirement for peptide in transport of class I molecules manifests itself at a stage beyond the ER, most likely the Golgi area.


The rotavirus enterotoxin NSP4 mobilizes intracellular calcium in human intestinal cells by stimulating phospholipase C-mediated inositol 1,4,5-trisphosphate production.
Rotavirus infection is the leading cause of severe diarrhea in infants and young children worldwide. The rotavirus nonstructural protein NSP4 acts as a viral enterotoxin to induce diarrhea and causes Ca2+-dependent transepithelial Cl- secretion in young mice. The cellular basis of this phenomenon was investigated in an in vitro cell line model for the human intestine. Intracellular calcium concentration ([Ca2+]i) was monitored in fura-2-loaded HT-29 cells using microscope-based fluorescence imaging. NSP4 (1 nM to 5 microM) induced both Ca2+ release from intracellular stores and plasmalemma Ca2+ influx. During NSP4-induced [Ca2+]i mobilization, [Na+]i homeostasis was not disrupted, demonstrating that NSP4 selectively regulated extracellular Ca2+ entry into these cells. The ED50 of the NSP4 effect on peak [Ca2+]i mobilization was 4.6 +/- 0.8 nM. Pretreatment of cells with either 2.3 x 10(-3) units/ml trypsin or 4.4 x 10(-2) units/ml chymotrypsin for 1-10 min abolished the NSP4-induced [Ca2+]i mobilization. Superfusing cells with U-73122, an inhibitor of phospholipase C, ablated the NSP4 response. NSP4 induced a rapid onset and transient stimulation of inositol 1,4,5-trisphosphate (IP3) production in an IP3-specific radioreceptor assay. Taken together, these results suggest that NSP4 mobilizes [Ca2+]i in human intestinal cells through receptor-mediated phospholipase C activation and IP3 production.


Lower mortality from coronary heart disease and stroke at higher altitudes in Switzerland.
Studies assessing the effect of altitude on cardiovascular disease have provided conflicting results. Most studies were limited because of the heterogeneity of the population, their ecological design, or both. In addition, effects of place of birth were rarely considered. Here, we examine mortality from coronary heart disease and stroke in relation to the altitude of the place of residence in 1990 and at birth. Mortality data from 1990 to 2000, sociodemographic information, and places of birth and residence in 1990 (men and women between 40 and 84 years of age living at altitudes of 259 to 1960 m) were obtained from the Swiss National Cohort, a longitudinal, census-based record linkage study. The 1.64 million German Swiss residents born in Switzerland provided 14.5 million person-years. Relative risks were calculated with multivariable Poisson regression. Mortality from coronary heart disease (-22% per 1000 m) and stroke (-12% per 1000 m) significantly decreased with increasing altitude. Being born at altitudes higher or lower than the place of residence was associated with lower or higher risk. The protective effect of living at higher altitude on coronary heart disease and stroke mortality was consistent and became stronger after adjustment for potential confounders. Being born at high altitude had an additional and independent beneficial effect on coronary heart disease mortality. The effect is unlikely to be due to classic cardiovascular disease risk factors and rather could be explained by factors related to climate.


Thrombin inhibits intercellular calcium wave propagation in corneal endothelial cells by modulation of hemichannels and gap junctions.
Thrombin, a serine protease, breaks down the barrier integrity of corneal endothelial cells by phosphorylation of the regulatory light chain of myosin II (myosin light chain; MLC), which induces contractility of the actin cytoskeleton. This study was undertaken to investigate the effect of thrombin on gap junctional (GJIC) and paracrine (PIC) intercellular communication in cultured bovine corneal endothelial cells (BCECs). An intercellular Ca(2+) wave, a form of cell-cell communication, was elicited by applying a mechanical stimulus to a single cell in a confluent monolayer. Changes in [Ca(2+)](i) were imaged by fluorescence microscopy with a fluorescent calcium indicator, and the images were used to calculate the area reached by the Ca(2+) wave (active area). GJIC was assessed by fluorescence recovery after photobleaching (FRAP). Activity of hemichannels was assayed by lucifer yellow (LY) uptake and also by adenosine triphosphate (ATP) release by using the luciferin-luciferase technique. RT-PCR showed transcripts for PAR-1 and -2 receptors, but not for PAR-4 receptors. Immunocytochemistry showed thrombin-sensitive PAR receptors as well as trypsin-sensitive PAR-2 receptors. Both thrombin and the selective PAR-1 agonist TRAP-6 reduced the active area of the Ca(2+) wave. These agents also reduced the fluorescence recovery in FRAP experiments. The effect of thrombin on the Ca(2+) wave was inhibited by a peptide antagonist of PAR-1, but not by a PAR-4 antagonist. Pretreatment with ML-7 (an MLCK inhibitor), Y-27632 (a Rho kinase inhibitor) or chelerythrine (a PKC inhibitor) prevented the effect of thrombin on the Ca(2+) wave. Activation of PAR-1 did not affect the Ca(2+) wave propagation in cells pretreated with Gap26, which blocks hemichannels. However, PAR-1 activation decreased the active area in cells pretreated with Gap27, which inhibits gap junctions. Thrombin abolished enhancement of the Ca(2+) wave propagation by ARL-67156 (inhibitor of ecto-ATPases). The effect of the PAR-1 agonists on the Ca(2+) wave was not detectable in cells pretreated with exogenous apyrases. Thrombin inhibits intercellular Ca(2+) wave propagation in BCECs. This effect is due to activation of PAR-1 receptors and involves MLC phosphorylation by MLCK-, PKC- and Rho kinase-sensitive pathways. Thrombin mainly inhibits the ATP-mediated PIC pathway, and also reduces GJIC to a lesser extent.


Sex Differences in Cardiometabolic Traits and Determinants of Exercise Capacity in Heart Failure With Preserved Ejection Fraction.
Sex differences in heart failure with preserved ejection fraction (HFpEF) have been established, but insights into the mechanistic drivers of these differences are limited. To examine sex differences in cardiometabolic profiles and exercise hemodynamic profiles among individuals with HFpEF. This cross-sectional study was conducted at a single-center tertiary care referral hospital from December 2006 to June 2017 and included 295 participants who met hemodynamic criteria for HFpEF based on invasive cardiopulmonary exercise testing results. We examined sex differences in distinct components of oxygen transport and utilization during exercise using linear and logistic regression models. The data were analyzed from June 2018 to May 2019. Resting and exercise gas exchange and hemodynamic parameters obtained during cardiopulmonary exercise testing. Of 295 participants, 121 (41.0%) were men (mean [SD] age, 64 [12] years) and 174 (59.0%) were women (mean [SD] age, 61 [13] years). Compared with men, women with HFpEF in this tertiary referral cohort had fewer comorbidities, including diabetes, insulin resistance, and hypertension, and a more favorable adipokine profile. Exercise capacity was similar in men and women (percent predicted peak oxygen [O2] consumption: 66% in women vs 68% in men; P = .38), but women had distinct deficits in components of the O2 pathway, including worse biventricular systolic reserve (multivariable-adjusted analyses: ΔLVEF β = -1.70; SE, 0.86; P < .05; ΔRVEF β = -2.39, SE=0.80; P = .003), diastolic reserve (PCWP/CO: β = 0.63; SE, 0.31; P = .04), and peripheral O2 extraction (C(a-v)O2 β=-0.90, SE=0.22; P < .001)). Despite a lower burden of cardiometabolic disease and a similar percent predicted exercise capacity, women with HFpEF demonstrated greater cardiac and extracardiac deficits, including systolic reserve, diastolic reserve, and peripheral O2 extraction. These sex differences in cardiac and skeletal muscle responses to exercise may illuminate the pathophysiology underlying the development of HFpEF and should be investigated further.


Adiponectin suppresses gluconeogenic gene expression in mouse hepatocytes independent of LKB1-AMPK signaling.
The adipocyte-derived hormone adiponectin signals from the fat storage depot to regulate metabolism in peripheral tissues. Inversely correlated with body fat levels, adiponectin reduction in obese individuals may play a causal role in the symptoms of metabolic syndrome. Adiponectin lowers serum glucose through suppression of hepatic glucose production, an effect attributed to activation of AMPK. Here, we investigated the signaling pathways that mediate the effects of adiponectin by studying mice with inducible hepatic deletion of LKB1, an upstream regulator of AMPK. We found that loss of LKB1 in the liver partially impaired the ability of adiponectin to lower serum glucose, though other actions of the hormone were preserved, including reduction of gluconeogenic gene expression and hepatic glucose production as assessed by euglycemic hyperinsulinemic clamp. Furthermore, in primary mouse hepatocytes, the absence of LKB1, AMPK, or the transcriptional coactivator CRTC2 did not prevent adiponectin from inhibiting glucose output or reducing gluconeogenic gene expression. These results reveal that whereas some of the hormone's actions in vivo may be LKB1 dependent, substantial LKB1-, AMPK-, and CRTC2-independent signaling pathways also mediate effects of adiponectin.


Relationship between quantity of IFNT estimated by IFN-stimulated gene expression in peripheral blood mononuclear cells and bovine embryonic mortality after AI or ET.
Interferon tau (IFNT), which is secreted into the uterine cavity during the maternal recognition period (MRP), is a key factor for establishment of pregnancy. The present study aims to clarify the relationship between the ability of a bovine conceptus to produce IFNT during the MRP and the conceptus's ability to establish pregnancy. In the first experiment, IFNT (0, 500, or 1000 micrograms) was administered into the uterine horn ipsilateral to the CL 16 or 17 d after standing estrus, and mRNA levels of IFN-stimulated gene 15-kDa protein (ISG15) and Mx2 in peripheral blood mononuclear cells (PBMCs) were determined. In the second experiment, we investigated ISG15 mRNA expression in PBMCs during the MRP in cattle after either artificial insemination (AI) or embryo transfer (ET). Intrauterine administration of IFNT stimulated ISG15 and Mx2 gene expressions in PBMCs in cattle, and there was a positive correlation between the expressions of peripheral markers and the quantity of IFNT administered. In pregnant and normal interestrous interval (< 25 d) cattle (nIEI cattle), expression levels of the ISG15 gene showed similar patterns after AI and ET, and ISG15 mRNA expression was increased in pregnant cattle but unchanged in nIEI cattle. In contrast, ISG15 gene expression in extended interestrous interval (greater than or equal to 25 d) cattle (eIEI cattle) differed after ET compared with AI. In eIEI cattle after ET, ISG15 gene expression increased, such that the value on day 18 was intermediate between those of pregnant and nIEI cattle. In eIEI cattle after AI, ISG15 gene expression did not increase throughout the observation period. The results of the current study indicate that the quantity of conceptus-derived IFNT can be estimated by measuring ISG15 mRNA levels in PBMCs from cattle. Using this approach, we demonstrate that ISG15 gene expression during the MRP in eIEI cattle differed after ET compared with AI. In addition, the modest increase in ISG15 gene expression in eIEI cattle after ET suggests that late embryo losses were due to delayed or insufficient growth of the conceptus during the MRP in cattle.


Source-detector spectral matching factors.
Procedures are described for simplifying the computation of detector responsivity (output per unit input) from known detector calibration data. These procedures involve the computation, tabulation, and use of certain dimensionless spectral matching factor ratios. These ratios effectively express the relative degree of overlap occurring between the spectral response distribution of the detector and the spectral distribution of the incident flux to be detected. All three basic systems of units for expressing detector responsivity (A/W, A/Im, and electrons/photon) are considered.


Fungicidal effect of resveratrol on human infectious fungi.
Resveratrol, a phenolic antioxidant found in grapes, has been known to mediate various biological activities on the human body. In the present study, we tested the antifungal activity of resveratrol against human pathogenic fungi before carrying out further studies to elucidate the antifungal mechanism(s) of resveratrol. Resveratrol displayed potent antifungal activity against human pathogenic fungi at concentration levels of 10-20 microg/mL. Furthermore, time-kill curve exhibited fungicidal effect of resveratrol on C. albicans, but the compound had no hemolytic activity against human erythrocytes. The destruction of C. albicans cells by resveratrol was confirmed by scanning electron microscopy. These results suggest that resveratrol could be employed as a therapeutic agent to treat fungal infections of humans.


Access to lexical information in language comprehension: semantics before syntax.
The recognition of a word makes available its semantic and syntactic properties. Using electrophysiological recordings, we investigated whether one set of these properties is available earlier than the other set. Dutch participants saw nouns on a computer screen and performed push-button responses: In one task, grammatical gender determined response hand (left/right) and semantic category determined response execution (go/no-go). In the other task, response hand depended on semantic category, whereas response execution depended on gender. During the latter task, response preparation occurred on no-go trials, as measured by the lateralized readiness potential: Semantic information was used for response preparation before gender information inhibited this process. Furthermore, an inhibition-related N2 effect occurred earlier for inhibition by semantics than for inhibition by gender. In summary, electrophysiological measures of both response preparation and inhibition indicated that the semantic word property was available earlier than the syntactic word property when participants read single words.


Influence and Correction from the Human Body on the Measurement of a Power-Frequency Electric Field Sensor.
According to the operating specifications of existing electric field measuring instruments, measuring technicians must be located far from the instruments to eliminate the influence of the human body occupancy on a spatial electric field. Nevertheless, in order to develop a portable safety protection instrument with an effective electric field warning function for working staff in a high-voltage environment, it is necessary to study the influence of an approaching human body on the measurement of an electric field and to correct the measurement results. A single-shaft electric field measuring instrument called the Type LP-2000, which was developed by our research team, is used as the research object in this study. First, we explain the principle of electric field measurement and describe the capacitance effect produced by the human body. Through a theoretical analysis, we show that the measured electric field value decreases as a human body approaches. Their relationship is linearly proportional. Then, the ratio is identified as a correction coefficient to correct for the influence of human body proximity. The conclusion drawn from the theoretical analysis is proved via simulation. The correction coefficient kb = 1.8010 is obtained on the basis of the linear fitting of simulated data. Finally, a physical experiment is performed. When no human is present, we compare the results from the Type LP-2000 measured with Narda EFA-300 and the simulated value to verify the accuracy of the Type LP-2000. For the case of an approaching human body, the correction coefficient kb* = 1.9094 is obtained by comparing the data measured with the Type LP-2000 to the simulated value. The correction coefficient obtained from the experiment (i.e., kb*) is highly consistent with that obtained from the simulation (i.e., kb). Two experimental programs are set; under these programs, the excitation voltages and distance measuring points are regulated to produce different electric field intensities. Using kb = 1.9094, the corrected measurement of electric field intensity can accurately reflect the original environmental electric field intensity, and the maximal error is less than 6% in all the data comparisons. These results verify the effectiveness of our proposed method.


When trust is lost: the impact of interpersonal trauma on social interactions.
Trauma due to deliberate harm by others is known to increase the likelihood of developing Post-Traumatic Stress Disorder (PTSD). This is the first study investigating basic and dynamic trust in 'interpersonal' PTSD. Thirty-two participants with PTSD and 22 healthy controls played a novel multi-round version of a monetary investment protocol, the so-called 'Trust Game', a task from the behavioural economics literature, which is considered to involve trust and reciprocity. We used two 'Trust Games' including cooperative and unfair partners. Findings showed an effect for lower basic investment in PTSD compared to healthy controls, that trended towards significance (p = 0.09). All participants showed behavioural flexibility and modified their trust based on behavioural cues from their cooperative and unfair game partners. However, participants with PTSD made significantly lower investments towards the cooperative partner than controls. Investments towards the unfair partner did not differ between groups. Higher trauma scores were associated with lower levels of trust-related investments towards the cooperative but not the unfair game partner. The association between reduced trust towards cooperative others in individuals who experienced interpersonal trauma could indicate acquired insensitivity to social rewards or inflexible negative beliefs about others as a sequel of the traumatic experience, which increases in a dose response relationship with the severity of the trauma. A specific focus on cooperation and trusting behaviour could provide a treatment target for future cognitive and pharmacological interventions.


Telomerase governs immunomodulatory properties of mesenchymal stem cells by regulating FAS ligand expression.
Bone marrow mesenchymal stem cells (BMMSCs) are capable of differentiating into multiple cell types and regulating immune cell response. However, the mechanisms that govern the immunomodulatory properties of BMMSCs are still not fully elucidated. Here we show that telomerase-deficient BMMSCs lose their capacity to inhibit T cells and ameliorate the disease phenotype in systemic sclerosis mice. Restoration of telomerase activity by telomerase reverse transcriptase (TERT) transfection in TERT(-/-) BMMSCs rescues their immunomodulatory functions. Mechanistically, we reveal that TERT, combined with β-catenin and BRG1, serves as a transcriptional complex, which binds the FAS ligand (FASL) promoter to upregulate FASL expression, leading to an elevated immunomodulatory function. To test the translational value of these findings in the context of potential clinical therapy, we used aspirin treatment to upregulate telomerase activity in BMMSCs, and found a significant improvement in the immunomodulatory capacity of BMMSCs. Taken together, these findings identify a previously unrecognized role of TERT in improving the immunomodulatory capacity of BMMSCs, suggesting that aspirin treatment is a practical approach to significantly reduce cell dosage in BMMSC-based immunotherapies.


Thyroid hormone attenuates vascular calcification induced by vitamin D3 plus nicotine in rats.
Thyroid hormones (THs) including thyroxine (T4) and triiodothyronine (T3) play critical roles in bone remodeling. However, the role and mechanism of THs in vascular calcification (VC) have been unclear. To explore the pathophysiological roles of T3 on VC, we investigated the changes in plasma and aortas of THs concentrations and the effect of T3 on rat VC induced by vitamin D3 plus nicotine (VDN). VDN-treated rat showed decreased plasma T3 content, increased vascular calcium deposition, and alkaline phosphatase (ALP) activity. Administration of T3 (0.2 mg/kg body weight IP) for 10 days greatly reduced vascular calcium deposition and ALP activity in calcified rat aortas when compared with controls. Concurrently, the loss of smooth muscle lineage markers α-actin and SM22a was restored, and the increased bone-associated molecules, such as runt-related transcription factor2 (Runx2), Osterix, and osteopontin (OPN) levels in calcified aorta, were reduced by administration of T3. The suppression of klotho in calcified rat aorta was restored by T3. Methimazole (400 mg/L) blocked the beneficial effect of T3 on VC. These results suggested that T3 can inhibit VC development.


Web and personal image annotation by mining label correlation with relaxed visual graph embedding.
The number of digital images rapidly increases, and it becomes an important challenge to organize these resources effectively. As a way to facilitate image categorization and retrieval, automatic image annotation has received much research attention. Considering that there are a great number of unlabeled images available, it is beneficial to develop an effective mechanism to leverage unlabeled images for large-scale image annotation. Meanwhile, a single image is usually associated with multiple labels, which are inherently correlated to each other. A straightforward method of image annotation is to decompose the problem into multiple independent single-label problems, but this ignores the underlying correlations among different labels. In this paper, we propose a new inductive algorithm for image annotation by integrating label correlation mining and visual similarity mining into a joint framework. We first construct a graph model according to image visual features. A multilabel classifier is then trained by simultaneously uncovering the shared structure common to different labels and the visual graph embedded label prediction matrix for image annotation. We show that the globally optimal solution of the proposed framework can be obtained by performing generalized eigen-decomposition. We apply the proposed framework to both web image annotation and personal album labeling using the NUS-WIDE, MSRA MM 2.0, and Kodak image data sets, and the AUC evaluation metric. Extensive experiments on large-scale image databases collected from the web and personal album show that the proposed algorithm is capable of utilizing both labeled and unlabeled data for image annotation and outperforms other algorithms.


Postembryonic development of the dorsal longitudinal flight muscle and its innervation in Manduca sexta.
The neuromuscular systems of holometabolous insects must be remodeled during metamorphosis to allow striking behavioral changes, such as the acquisition of flight. The fast contracting dorsal longitudinal flight muscle (DLM) of Manduca arises from an anlage containing both remnants of specific larval dorsal body wall muscles and extrinsic myoblasts. In the mesothorax, the DLM is innervated by five persisting larval motoneurons: one in the mesothoracic and four in the prothoracic ganglion. These motoneurons innervate two slowly contracting body wall muscles in the larva. 2 days before pupation, the DLM template fibers begin to degenerate, whereas other muscles remain intact until pupation. Correspondingly, the motor terminals retract from the template fibers while they remain on other muscle fibers until pupation. Accumulation and proliferation of putative myoblasts also starts 2 days before pupation in close spatial relationship to the retracted motor tufts around the degenerating larval template fibers. Proliferation increases through the early pupal stages, and is detected within the anlage until the ninth day after pupation. 2 days after pupation, the anlage splits into five bundles, each innervated by one motoneuron. Striations occur on the seventh day after pupation when the growing motor axons reach the attachment sites. Subsequently, the muscle grows in volume and higher-order motor branches are formed. Within the central nervous system, there is dramatic regression of larval dendrites followed by growth of new dendrites as the persistent motoneurons assume their new role in flight behavior. Both central and peripheral remodeling follow similar time courses.


Men's Intake of Vitamin C and β-Carotene Is Positively Related to Fertilization Rate but Not to Live Birth Rate in Couples Undergoing Infertility Treatment.
Randomized clinical trials show that men's use of antioxidant supplements during infertility treatment may improve clinical outcomes. However, important limitations in the design of most trials make it difficult to draw firm conclusions on their findings. We examined whether men's intake of antioxidants and biologically related compounds without direct antioxidant capacity is associated with outcomes of assisted reproductive technologies (ARTs). We conducted a prospective cohort study of men in couples who underwent infertility treatment with ART using their own gametes between 2007 and 2017. We followed 171 couples who presented at Massachusetts General Hospital Fertility Center and underwent 294 autologous ART cycles for infertility treatment. Diet was assessed in both partners using an FFQ. The primary study outcome was the probability of achieving a live birth as a result of infertility treatment. Secondary outcomes were fertilization, implantation, and clinical pregnancy rates. Generalized linear mixed models with random intercepts were fitted to account for multiple ART cycles per woman while adjusting for confounding. Men's vitamin C intake was positively associated with fertilization rate. The adjusted fertilization rate (95% CI) for couples in the lowest and highest quartiles of men's vitamin C intake were 69% (61-76%) and 81% (74-86%) (P-trend = 0.02). Men's β-carotene intake was positively associated with fertilization rate in intracytoplasmic sperm injection cycles but not in conventional in vitro fertilization cycles (P-interaction = 0.01). Men's α-carotene intake was inversely related to the probability of live birth. The adjusted probabilities of live birth for men in the lowest and highest quartiles of α-carotene intake were 43% (28-60%) and 22% (12-36%), respectively. Men's intake of vitamin C and β-carotene is positively related to fertilization rate but this does not translate into higher pregnancy or live birth rates in couples undergoing infertility treatment.


Manganese-induced trafficking and turnover of the cis-Golgi glycoprotein GPP130.
Manganese is an essential element that is also neurotoxic at elevated exposure. However, mechanisms regulating Mn homeostasis in mammalian cells are largely unknown. Because increases in cytosolic Mn induce rapid changes in the localization of proteins involved in regulating intracellular Mn concentrations in yeast, we were intrigued to discover that low concentrations of extracellular Mn induced rapid redistribution of the mammalian cis-Golgi glycoprotein Golgi phosphoprotein of 130 kDa (GPP130) to multivesicular bodies. GPP130 was subsequently degraded in lysosomes. The Mn-induced trafficking of GPP130 occurred from the Golgi via a Rab-7-dependent pathway and did not require its transit through the plasma membrane or early endosomes. Although the cytoplasmic domain of GPP130 was dispensable for its ability to respond to Mn, its lumenal stem domain was required and it had to be targeted to the cis-Golgi for the Mn response to occur. Remarkably, the stem domain was sufficient to confer Mn sensitivity to another cis-Golgi protein. Our results identify the stem domain of GPP130 as a novel Mn sensor in the Golgi lumen of mammalian cells.


Health economic analysis of ticagrelor in patients with acute coronary syndromes intended for non-invasive therapy.
To investigate the cost effectiveness of ticagrelor versus clopidogrel in patients with acute coronary syndromes (ACS) in the Platelet Inhibition and Patient Outcomes (PLATO) study who were scheduled for non-invasive management. A previously developed cost effectiveness model was used to estimate long-term costs and outcomes for patients scheduled for non-invasive management. Healthcare costs, event rates and health-related quality of life under treatment with either ticagrelor or clopidogrel over 12 months were estimated from the PLATO study. Long-term costs and health outcomes were estimated based on data from PLATO and published literature sources. To investigate the importance of different healthcare cost structures and life expectancy for the results, the analysis was carried out from the perspectives of the Swedish, UK, German and Brazilian public healthcare systems. Ticagrelor was associated with lifetime quality-adjusted life-year (QALY) gains of 0.17 in Sweden, 0.16 in the UK, 0.17 in Germany and 0.13 in Brazil compared with generic clopidogrel, with increased healthcare costs of €467, €551, €739 and €574, respectively. The cost per QALY gained with ticagrelor was €2747, €3395, €4419 and €4471 from a Swedish, UK, German and Brazilian public healthcare system perspective, respectively. Probabilistic sensitivity analyses indicated that the cost per QALY gained with ticagrelor was below conventional threshold values of cost effectiveness with a high probability. Treatment of patients with ACS scheduled for 12 months' non-invasive management with ticagrelor is associated with a cost per QALY gained below conventional threshold values of cost effectiveness compared with generic clopidogrel. NCT000391872.


SUGAR-DIP trial: oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial.
In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM. The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle. The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals. NTR6134; Pre-results.


Her2-specific multivalent adapters confer designed tropism to adenovirus for gene targeting.
Adenoviruses (Ads) hold great promise as gene vectors for diagnostic or therapeutic applications. The native tropism of Ads must be modified to achieve disease site-specific gene delivery by Ad vectors and this should be done in a programmable way and with technology that can realistically be scaled up. To this end, we applied the technologies of designed ankyrin repeat proteins (DARPins) and ribosome display to develop a DARPin that binds the knob domain of the Ad fiber protein with low nanomolar affinity (K(D) 1.35 nM) and fused this protein with a DARPin specific for Her2, an established cell-surface biomarker of human cancers. The stability of the complex formed by this bispecific targeting adapter and the Ad virion resulted in insufficient gene transfer and was subsequently improved by increasing the valency of adapter-virus binding. In particular, we designed adapters that chelated the knob in a bivalent or trivalent fashion and showed that the efficacy of gene transfer by the adapter-Ad complex increased with the functional affinity of these molecules. This enabled efficient transduction at low stoichiometric adapter-to-fiber ratios. We confirmed the Her2 specificity of this transduction and its dependence on the Her2-binding DARPin component of the adapters. Even the adapter molecules with four fused DARPins could be produced and purified from Escherichia coli at very high levels. In principle, DARPins can be generated against any target and this adapter approach provides a versatile strategy for developing a broad range of disease-specific gene vectors.


Toward the assessment of psychological empowerment in health promotion: initial tests of validity and reliability.
Because of the importance of empowerment in health promotion, the measurement of empowerment is a priority for health promotion research. The present study sought to develop a valid and reliable instrument to assess psychological empowerment and to resolve the theoretical question of whether psychological empowerment is a topic-specific or general construct. University of Minnesota employees (n = 160) completed two different versions of empowerment questionnaires. One of the questionnaires measured general empowerment; the other was specific to alcohol use prevention. Reasonable reliability was demonstrated in a previously developed general empowerment instrument (Cronbach's alpha coefficient of 0.84) and for an alcohol-specific instrument (Cronbach's alpha coefficient of 0.78). Construct validity for the alcohol-specific instrument was demonstrated by appropriate significant correlations between subscales and overall scores for both instruments. Predictive validity tests partially supported the concept that psychological empowerment is topic-specific, although further testing with a more representative population may be needed to resolve this question. The results suggest that the alcohol-specific psychological empowerment instrument could be used in the evaluation of community alcohol abuse prevention programmes.


Interpreting new molecular genetics in myelodysplastic syndromes.
The myelodysplastic syndromes (MDS) are a clinically and cytogenetically heterogeneous group of clonal diseases characterized by ineffective hematopoiesis, peripheral blood cytopenias, and an increased risk of progression to acute myeloid leukemia. The precise molecular mechanisms behind the development of MDS have remained elusive; however, the distinct sensitivity of this disease to DNA methyltransferase inhibitors and the presence of markedly abnormal epigenetic profiles suggested the existence of an epigenetic mechanism underlying the disease. Recently, the advent of new technologies for the detection of genetic abnormalities has led to the description of a set of novel recurrent mutations in patients with this disease. The majority of these novel mutations have been described in genes encoding different components of the epigenetic machinery, many of which are associated with distinct clinical outcomes. Finally, mutations in mRNA splicing genes have also been described recently in MDS, underscoring the molecular complexity that underlies the development of this heterogeneous disease.


Baseline T cell immune phenotypes predict virologic and disease control upon SARS-CoV infection in Collaborative Cross mice.
The COVID-19 pandemic has revealed that infection with SARS-CoV-2 can result in a wide range of clinical outcomes in humans. An incomplete understanding of immune correlates of protection represents a major barrier to the design of vaccines and therapeutic approaches to prevent infection or limit disease. This deficit is largely due to the lack of prospectively collected, pre-infection samples from individuals that go on to become infected with SARS-CoV-2. Here, we utilized data from genetically diverse Collaborative Cross (CC) mice infected with SARS-CoV to determine whether baseline T cell signatures are associated with a lack of viral control and severe disease upon infection. SARS-CoV infection of CC mice results in a variety of viral load trajectories and disease outcomes. Overall, a dysregulated, pro-inflammatory signature of circulating T cells at baseline was associated with severe disease upon infection. Our study serves as proof of concept that circulating T cell signatures at baseline can predict clinical and virologic outcomes upon SARS-CoV infection. Identification of basal immune predictors in humans could allow for identification of individuals at highest risk of severe clinical and virologic outcomes upon infection, who may thus most benefit from available clinical interventions to restrict infection and disease.


Promoting active transport in a workplace setting: evaluation of a pilot study in Australia.
Promoting active transport is an increasingly important focus of recent health promotion initiatives addressing the major public health concerns of car dependence, decreased levels of physical activity and environmental health. Using active transport that relies less on the use of private cars and more on alternatives such as walking, cycling and public transport has the potential to increase population levels of physical activity and to improve the environment. Over 12 months, a combined social and individualized marketing campaign was delivered to a cohort of randomly selected health service employees (n = 68) working at a health care facility in inner-city Sydney, Australia. Pre- and post-intervention surveys measured changes in mode of transport, awareness of active transport and attitudes towards mode of transport. Following the intervention, we found there was a reduction in the proportion of participants who drove to work 5 days per week and a decrease in trips travelled by car on weekends. In addition, there was high awareness of the intervention amongst participants and their understanding of the concept of active transport improved from 17.6% at baseline to 94.1% at the follow-up survey (p < 0.01). There was also a significant shift in attitudes, which suggested increased positive regard for active transport. Our findings suggest that a combined social and individualized marketing campaign in the workplace setting can increase the use of active transport for the journey to work and trips on weekends. However, before these findings are widely applied, the intervention needs to be tested in a controlled study with a larger sample size.


Effect of essential oils of Syzygium aromaticum and Cinnamomum zeylanicum and their major components on biofilm production in Staphylococcus aureus strains isolated from milk of cows with mastitis.
Bovine mastitis is an inflammation of the mammary glands of cows and causes significant economic losses in dairy cattle. Staphylococcus aureus is one of the microorganisms most commonly isolated. Novel agents are required in agricultural industries to prevent the development of mastitis. The production of biofilm by Staph. aureus facilitates the adhesion of bacteria to solid surfaces and contributes to the transmission and maintenance of these bacteria. The effect of the essential oils of Syzygium aromaticum (clove; EOSA) and Cinnamomum zeylanicum (cinnamon; EOCZ) and their major components, eugenol and cinnamaldehyde, on Staph. aureus biofilm formation on different surfaces was investigated. The results showed a significant inhibition of biofilm production by EOSA on polystyrene and stainless steel surfaces (69.4 and 63.6%, respectively). However, its major component, eugenol, was less effective on polystyrene and stainless steel (52.8 and 19.6%, respectively). Both EOCZ and its major component, cinnamaldehyde, significantly reduced biofilm formation on polystyrene (74.7 and 69.6%, respectively) and on stainless steel surfaces (45.3 and 44.9%, respectively). These findings suggest that EOSA, EOCZ, and cinnamaldehyde may be considered for applications such as sanitization in the food industry.


A system for studying the effect(s) of familial Alzheimer disease mutations on the processing of the beta-amyloid peptide precursor.
Three different point mutations have been observed in some familial Alzheimer's disease pedigrees at a unique valine, Val717, near the carboxyl end of the beta Amyloid Peptide Precursor (beta APP). The effects of these mutations on the processing and cellular functions of beta APP can best be determined in the absence of the normal form(s) of the protein. We have used targeted mRNA degradation by a trans-acting hammerhead ribozyme to cleave and inactivate beta APP expression in vitro. The consensus ribozyme cleavage site, 5'GUC decreases X3, matches the Val717 nucleotide sequence in beta APP mRNA. Introduction of FAD point mutations which change Val717 decrease the rate of ribozyme cleavage by more than three orders of magnitude. Thus, ribozyme targeting of this site should allow the study of protein processing in vivo. Furthermore, a ribozyme targeted to mutant beta APP mRNA (Val717-->Ile) cleaved the mutant sequence 300-fold faster than the normal sequence. This suggests that ribozymes might lower mutant beta APP mRNA levels in FAD cells.


Osteoblast differentiation of rabbit adipose-derived stem cells by polyethylenimine-mediated BMP-2 gene transfection in vitro.
The aim of this study was to examine the efficiency of polyethylenimine-mediated transfection of the human bone morphogenetic protein-2 (BMP-2) gene into rabbit adipose-derived stem cells (ADSCs), and its effect on osteoblast differentiation. Adipose tissue was isolated from the necks of adult Japanese white rabbits and cultured in vitro to obtain ADSCs. Gene delivery of BMP-2 was mediated by polyethylenimine and stable transformants were selected by G-418. The expression of BMP-2 mRNA was confirmed by reverse transcription-polymerase chain reaction, and of the BMP-2 protein by ELISA. Osteocalcin and collagen type I were detected by western blot and by an alkaline phosphatase kit. Alizarin red S stain was also utilized to examine osteogenesis. The non-transfected group was considered as a control. In this study, we successfully derived ADSCs from rabbit adipose tissue. Through passages 3-6, the expression of CD29 and CD44 gradually increased, whereas the expression of CD34 and CD45 gradually decreased. Both mRNA and protein expression of BMP-2 were confirmed following polyethylenimine-mediated BMP-2 gene delivery. In addition, the expression of alkaline phosphatase, osteocalcin, and collagen type I was found to be upregulated and alizarin red S staining was positive in transfected ADSCs, indicating BMP-2-induced osteogenesis. Therefore, this study determined that polyethylenimine was able to mediate BMP-2 gene delivery and induce osteogenic differentiation of ADSCs.


Transabdominal and transvaginal ultrasound findings help to guide the clinical management of placenta accreta spectrum cases.
The clinical management of placenta accreta spectrum (PAS) depends on placental topography and vascular involvement. Our aim was to determine whether transabdominal and transvaginal ultrasound signs can predict PAS management. We conducted a retrospective cohort study of consecutive prenatally suspected PAS cases in a single tertiary-care PAS center between January 2021 and July 2022. When PAS was confirmed during surgery, abdominal and transvaginal ultrasound scans were analyzed in relation to PAS management. The preferred surgical approach of PAS was one-step conservative surgery (OSCS). Massive blood loss and PAS topography in the lower bladder trigone necessitated cesarean hysterectomy. Transvaginal ultrasound-diagnosed intracervical hypervascularity was split into three categories based on their quantity. Anatomically, the internal cervical os is located at the level of the bladder trigone and was used as landmark for upper and lower bladder trigone PAS. Ninety-one women underwent OSCS and 35 women underwent cesarean hysterectomy (total 126 women with PAS). Abdominal and transvaginal ultrasound features differed significantly between women that underwent OSCS and cesarean hysterectomy: decreased myometrial thickness (<1 mm), 82.4% vs. 100%, p = 0.006; placental bulge, 51.6% vs. 94.3%, p < 0.001; bladder wall interruption, 62.6% vs. 97.1%, p < 0.001; abnormal placental lacunae, 75.8% vs. 100%, p < 0.001; hypervascularity (large lacunae feeding vessels, 57.8% vs. 94.6%, p < 0.001; parametrial hypervascularity, 15.4% vs. 60%, p < 0.001; the rail sign, 6.6% vs. 28.6%, p = 0.003; three-dimensional Doppler intra-placental hypervascularity, 81.3% vs. 100%, p < 0.001; intracervical hypervascularity 60.4% vs. 94.3%, p < 0.001); and cervical length 2.5 ± 0.94 vs. 2.2 ± 0.73, p = 0.038. Other ultrasound signs were not significantly different. The results of multivariable logistic regression showed placental bulge (odds ratio [OR] 9.3; 95% CI 1.9-44.3; p = 0.005), parametrial hypervascularity (OR 4.1; 95% CI 1.541-11.085; p = 0.005), and intracervical hypervascularity (OR 9.2; 95% CI 1.905-44.056; p = 0.006) were weak predictors of OSCS. Intracervical hypervascularity Grade 1 (vascularity <50% of cervical tissue) was more present in OSCS than higher gradings two and three (91% vs. 27.6% vs. 14.3%; p < 0.001). Cesarean hysterectomy is associated with the PAS signs of placental bulge and Grade 2 and 3 intracervical hypervascularity. OSCS is associated with intracervical hypervascularity Grade 1 on transvaginal ultrasound. Prospective validation is required to formulate predictors for PAS management.


CD70 (TNFSF7) is expressed at high prevalence in renal cell carcinomas and is rapidly internalised on antibody binding.
In order to identify potential markers of renal cancer, the plasma membrane protein content of renal cell carcinoma (RCC)-derived cell lines was annotated using a proteomics process. One unusual protein identified at high levels in A498 and 786-O cells was CD70 (TNFSF7), a type II transmembrane receptor normally expressed on a subset of B, T and NK cells, where it plays a costimulatory role in immune cell activation. Immunohistochemical analysis of CD70 expression in multiple carcinoma types demonstrated strong CD70 staining in RCC tissues. Metastatic tissues from eight of 11 patients with clear cell RCC were positive for CD70 expression. Immunocytochemical analysis demonstrated that binding of an anti-CD70 antibody to CD70 endogenously expressed on the surface of A498 and 786-O cell lines resulted in the rapid internalisation of the antibody-receptor complex. Coincubation of the internalising anti-CD70 antibody with a saporin-conjugated secondary antibody before addition to A498 cells resulted in 50% cell killing. These data indicate that CD70 represents a potential target antigen for toxin-conjugated therapeutic antibody treatment of RCC.


Shift work trends and risk of work injury among Canadian workers.
The aim of this study was to examine the risk of work injury across shift work types in a -representative sample of Canadian workers. We used the Survey of Labour and Income Dynamics to investigate trends in work injury by shift type between 1996-2006. Work injury was defined by receipt of workers' compensation. Logistic regression was used to estimate the risk between shift type and worker injury after adjusting for potential confounders. The rate of work injury decreased overall between 1996-2006, but did not decline for night shift -workers. Night shift work was associated with work injury for women [odds ratio (OR) 2.04, 95% confidence interval (95% CI) 1.13-3.69] and men (OR 1.91, 95% CI 1.21-3.03), while rotating shift work was associated with work injury for women (OR 2.29, 95% CI 1.37-3.82). The excess risk of work injury attributed to shift work was 14.4% for women and 8.2% for men based on population attributable fraction estimates. Rotating and night shift workers appear to have a higher risk of work injury, particularly among women. Regulatory agencies and employers need to identify and mitigate factors that give rise to increased work injury among these types of shift workers.


A comprehensive epigenomic analysis of phenotypically distinguishable, genetically identical female and male Daphnia pulex.
Daphnia species reproduce by cyclic parthenogenesis involving both sexual and asexual reproduction. The sex of the offspring is environmentally determined and mediated via endocrine signalling by the mother. Interestingly, male and female Daphnia can be genetically identical, yet display large differences in behaviour, morphology, lifespan and metabolic activity. Our goal was to integrate multiple omics datasets, including gene expression, splicing, histone modification and DNA methylation data generated from genetically identical female and male Daphnia pulex under controlled laboratory settings with the aim of achieving a better understanding of the underlying epigenetic factors that may contribute to the phenotypic differences observed between the two genders. In this study we demonstrate that gene expression level is positively correlated with increased DNA methylation, and histone H3 trimethylation at lysine 4 (H3K4me3) at predicted promoter regions. Conversely, elevated histone H3 trimethylation at lysine 27 (H3K27me3), distributed across the entire transcript length, is negatively correlated with gene expression level. Interestingly, male Daphnia are dominated with epigenetic modifications that globally promote elevated gene expression, while female Daphnia are dominated with epigenetic modifications that reduce gene expression globally. For examples, CpG methylation (positively correlated with gene expression level) is significantly higher in almost all differentially methylated sites in male compared to female Daphnia. Furthermore, H3K4me3 modifications are higher in male compared to female Daphnia in more than 3/4 of the differentially regulated promoters. On the other hand, H3K27me3 is higher in female compared to male Daphnia in more than 5/6 of differentially modified sites. However, both sexes demonstrate roughly equal number of genes that are up-regulated in one gender compared to the other sex. Since, gene expression analyses typically assume that most genes are expressed at equal level among samples and different conditions, and thus cannot detect global changes affecting most genes. The epigenetic differences between male and female in Daphnia pulex are vast and dominated by changes that promote elevated gene expression in male Daphnia. Furthermore, the differences observed in both gene expression changes and epigenetic modifications between the genders relate to pathways that are physiologically relevant to the observed phenotypic differences.


Role of visual pigment properties in rod and cone phototransduction.
Retinal rods and cones share a phototransduction pathway involving cyclic GMP. Cones are typically 100 times less photosensitive than rods and their response kinetics are several times faster, but the underlying mechanisms remain largely unknown. Almost all proteins involved in phototransduction have distinct rod and cone variants. Differences in properties between rod and cone pigments have been described, such as a 10-fold shorter lifetime of the meta-II state (active conformation) of cone pigment and its higher rate of spontaneous isomerization, but their contributions to the functional differences between rods and cones remain speculative. We have addressed this question by expressing human or salamander red cone pigment in Xenopus rods, and human rod pigment in Xenopus cones. Here we show that rod and cone pigments when present in the same cell produce light responses with identical amplification and kinetics, thereby ruling out any difference in their signalling properties. However, red cone pigment isomerizes spontaneously 10,000 times more frequently than rod pigment. This high spontaneous activity adapts the native cones even in darkness, making them less sensitive and kinetically faster than rods. Nevertheless, additional factors are probably involved in these differences.


Inappropriate prescribing and adverse drug events in older people.
Inappropriate prescribing (IP) in older patients is highly prevalent and is associated with an increased risk of adverse drug events (ADEs), morbidity, mortality and healthcare utilisation. Consequently, IP is a major safety concern and with changing population demographics, it is likely to become even more prevalent in the future. IP can be detected using explicit or implicit prescribing indicators. Theoretically, the routine clinical application of these IP criteria could represent an inexpensive and time efficient method to optimise prescribing practice. However, IP criteria must be sensitive, specific, have good inter-rater reliability and incorporate those medications most commonly associated with ADEs in older people. To be clinically relevant, use of prescribing appropriateness tools must translate into positive patient outcomes, such as reduced rates of ADEs. To accurately measure these outcomes, a reliable method of assessing the relationship between the administration of a drug and an adverse clinical event is required. The Naranjo criteria are the most widely used tool for assessing ADE causality, however, they are often difficult to interpret in the context of older patients. ADE causality criteria that allow for the multiple co-morbidities and prescribed medications in older people are required. Ultimately, the current high prevalence of IP and ADEs is unacceptable. IP screening criteria need to be tested as an intervention to assess their impact on the incidence of ADEs in vulnerable older patients. There is a role for IP screening tools in everyday clinical practice. These should enhance, not replace good clinical judgement, which in turn should be based on sound pharmacogeriatric training.


Rhubarb Protect Against Tubulointerstitial Fibrosis by Inhibiting TGF-β/Smad Pathway and Improving Abnormal Metabolome in Chronic Kidney Disease.
Tubulointerstitial fibrosis is the final common pathway for all kidney diseases leading to chronic kidney disease (CKD). TGF-β/Smad signaling pathway plays a key role in renal fibrosis. Previous studies have revealed that rhubarb extracts attenuated the increase of transforming growth factor-β 1 (TGF-β1) in CKD rats. To gain an in-depth insight into the mechanism of the anti-fibrotic activities of the rhubarb extracts, we investigated the influence of rhubarb extracts on TGF-β/Smad signaling pathway and the influence on metabolome in a rat model of CKD with adenine-induced chronic tubulointerstitial nephropathy. Male Sprague-Dawley rats were divided into four groups, including control, CKD, CKD + petroleum ether extract, CKD + ethyl acetate extract, and CKD + n-butanol extract groups. Kidneys harvested on the week three were evaluated for renal fibrosis, the expression of proteins in TGF-β/Smad signaling pathway and metabolomic study. We found rhubarb extracts suppressed TGF-β/Smad3-mediated renal fibrosis by reducing the TGF-β1, transforming growth factor-β receptor I (TGF-β RI), transforming growth factor-β receptor II (TGF-β RII), Smad2, p-Smad2, Smad3, p-Smad3, and Smad4, meanwhile increased Smad7. In addition, rhubarb extracts mitigated renal injury and dysfunction, and either fully or partially reversed the abnormalities of tissue metabolites. Thus, rebalancing the disorder of TGF-β/Smad signaling and metabolic dysfunction by treatment with rhubarb extracts may represent as an effective therapy for CKD associated with fibrosis.


Functional impact of a spectrum of interstitial lung abnormalities in rheumatoid arthritis.
Approximately 10% of patients with rheumatoid arthritis (RA) have interstitial lung disease (ILD), and one-third have subclinical ILD on chest CT scan. In this study, we aimed to further characterize functional decrements in a spectrum of RA-associated ILD. All subjects were enrolled in the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS). The presence of interstitial lung abnormalities (ILAs) on clinically indicated chest CT scans was determined using a previously validated sequential reading method. Univariate and multivariate analyses were used to assess the association between degree of ILAs and physiologic, functional, and demographic variables of interest. Of 1,145 BRASS subjects, 91 subjects (8%) were included in this study. Twelve had radiologically severe ILAs, 34 had ILAs, and 38 had no ILAs on CT scan. Subjects with radiologically severe ILAs were older (P = .0037), had increased respiratory symptoms (cough, P = .027; dyspnea, P = .010), and more severe RA disease (rheumatoid factor, P = .018; total swollen joints, P = .046) compared with subjects with no ILAs. Participants also had a trend toward having an increased smoking history (P = .16) and having lower FVC % predicted (77% vs 94%, P = .097) and diffusion capacity of carbon monoxide % predicted (52% vs 77%, P = .068). Similar but attenuated increases in respiratory symptoms, functional decrements, and RA disease severity were observed in subjects with ILAs compared with those with no ILAs. We have shown that patients with RA have varying degrees of ILAs that are associated with a spectrum of functional and physiologic decrements. Our findings suggest that improved risk stratification and detection of ILAs will provide a therapeutic window that could improve RA-ILD outcomes.


First Report of Iris yellow spot virus Infecting Onion in Pennsylvania.
Iris yellow spot virus (IYSV; genus Tospovirus; family Bunyaviridae) is an economically important pathogen of onion. It is vectored by onion thrips (Thrips tabaci Lindeman) and causes widespread disease of onion in all major onion growing states in the western United States (1). In the eastern United States, IYSV was first reported in Georgia in 2004 (4) and then in New York in 2006 (2). In mid-July of 2010, symptomatic onion (Allium cepa) plants (cv. Candy) were found in New Holland, Pennsylvania, in Lancaster County on a small, diversified commercial farm (40.06°N, 76.06°W). Bleached, elongated lesions with tapered ends occurred on middle-aged leaves on approximately 30% of the 13,760 plants in an area approximately one tenth of an acre. Leaf tissue from five symptomatic plants tested positive for IYSV in a double-antibody sandwich (DAS)-ELISA with IYSV-specific serological reagents from Agdia Inc. (Elkhart, IN). A reverse transcription (RT)-PCR assay was used to verify the presence of IYSV in a subset of symptomatic leaf samples that reacted to IYSV antibodies in DAS-ELISA. Primers specific to the nucleocapsid (N) gene of IYSV (5'-ACTCACCAATGTCTTCAAC-3' and 5'-GGCTTCCTCTGGTAAGTGC-3') were used to characterize a 402-bp fragment (3). The resulting amplicons were ligated in TOPO TA cloning vector (Invitrogen, Carlsbad, CA) and two clones of each isolate were sequenced in both directions. Sequence analysis showed a consensus sequence for the partial N gene of the five IYSV isolates from Pennsylvania (GenBank Accession No. JQ952568) and an 87 to 100% nucleotide sequence identity with other IYSV N gene sequences that are available in GenBank. The highest nucleotide sequence identity (100%) was with an IYSV isolate from Texas (GenBank Accession No. DQ658242) and the lowest was with an isolate from India (GenBank Accession No. EU310291). To our knowledge, this is the first report of IYSV infection of onion in Pennsylvania. This finding confirms further spread of the virus within North America. Further study is warranted to determine the impact of IYSV on the Pennsylvania onion industry and to determine viable management strategies, if necessary. References: (1) D. H. Gent et al. Plant Dis. 88:446, 2004 (2) C. A. Hoepting et al. Plant Dis. 91:327, 2007 (3) C. L. Hsu et al. Plant Dis. 95:735-743. (4) S. W. Mullis et al. Plant Dis. 88: 1285, 2004.


Inappropriate association of semantics and context to novel stimuli can give rise to the false recognition of unfamiliar people.
This paper reports further experiments with a patient (MR) who has a tendency to claim that unfamous people are familiar together with good ability at identifying truly famous people. The first experiment examines the role that the typicality of stimuli plays in his false recognition. Although, typicality may have some influence over false recognition (as it does for normal controls) there is little evidence to suggest that MR is over-reliant on such information. It is unlikely that perceptual fluency can entirely explain his deficit. This is bolstered by a further study using morphed images of famous and unfamous faces, suggesting that false recognition is associated with inappropriate retrieval of semantic-biographical information. It is argued that MR's judgement of 'fame' is subjectively appropriate, given the information that he retrieves. This information is thought to derive from currently activated, or recently activated, contextual information which becomes inappropriately bound to the novel stimulus, giving rise to a false sense of familiarity. These findings underscore the importance of viewing memory as an attributional process, whereby current mental constructions/processes are attributed to some event(s) in the past.


Brain Changes Induced by Electroconvulsive Therapy Are Broadly Distributed.
Electroconvulsive therapy (ECT) is associated with volumetric enlargements of corticolimbic brain regions. However, the pattern of whole-brain structural alterations following ECT remains unresolved. Here, we examined the longitudinal effects of ECT on global and local variations in gray matter, white matter, and ventricle volumes in patients with major depressive disorder as well as predictors of ECT-related clinical response. Longitudinal magnetic resonance imaging and clinical data from the Global ECT-MRI Research Collaboration (GEMRIC) were used to investigate changes in white matter, gray matter, and ventricle volumes before and after ECT in 328 patients experiencing a major depressive episode. In addition, 95 nondepressed control subjects were scanned twice. We performed a mega-analysis of single subject data from 14 independent GEMRIC sites. Volumetric increases occurred in 79 of 84 gray matter regions of interest. In total, the cortical volume increased by mean ± SD of 1.04 ± 1.03% (Cohen's d = 1.01, p < .001) and the subcortical gray matter volume increased by 1.47 ± 1.05% (d = 1.40, p < .001) in patients. The subcortical gray matter increase was negatively associated with total ventricle volume (Spearman's rank correlation ρ = -.44, p < .001), while total white matter volume remained unchanged (d = -0.05, p = .41). The changes were modulated by number of ECTs and mode of electrode placements. However, the gray matter volumetric enlargements were not associated with clinical outcome. The findings suggest that ECT induces gray matter volumetric increases that are broadly distributed. However, gross volumetric increases of specific anatomically defined regions may not serve as feasible biomarkers of clinical response.


Local Heat Treatment for Suppressing Gastroduodenal Stent-Induced Tissue Hyperplasia Using Nanofunctionalized Self-Expandable Metallic Stent in Rat Gastric Outlet Model.
Despite the promising results from the placement of covered or uncovered self-expandable metallic stent (SEMS) as a nonsurgical therapeutic option for the malignant gastric outlet obstruction (GOO), the long patency of the stent is still limited because of stent-induced tissue hyperplasia. Here, a local heat treatment using a nanofunctionalized SEMS is proposed for suppressing stent-induced tissue hyperplasia during GOO treatment. Highly efficient photothermal gold nanoparticle (GNP) transducer-coated SEMSs (GNP-SEMSs) were prepared for local heat treatment in rat gastric outlet. The in vivo heating temperature in rat gastric outlet model was evaluated and compared with in vitro heating temperature. Three groups of our developed 45 rat gastric outlet models were used: group A, noncoated SEMS only; group B, GNP-SEMS plus local heating; and group C, GNP-SEMS only to investigate in vivo efficacy of GNP-SEMS mediated local heating. Ten rats per group were sacrificed for 4 weeks, and five rats per group were sacrificed immediately after local heat treatment. The in vivo heating temperature was found to be 10.8% lower than the in vitro heating temperatures. GNP-SEMSs were successfully placed through a percutaneous approach into the rat gastric outlet (n = 45). The therapeutic effects of GNP-SEMS were assessed by histologic examination including hematoxylin-eosin, Masson trichrome, immunohistochemistry (TUNEL and CD31), and immunofluorescence (Ki67), and the results showed significant prevention of tissue hyperplasia following stent placement without adjacent gastrointestinal tissue damage. GNP-SEMS-mediated local heating could be an alternative therapeutic option for the suppression of tissue hyperplasia following stent placement in benign and malignant GOOs.


Assessing the implementation effectiveness and safety of 1% tenofovir gel provision through family planning services in KwaZulu-Natal, South Africa: study protocol for an open-label randomized controlled trial.
The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial demonstrated a 39% reduction in HIV infection, with a 54% HIV reduction in women who used tenofovir gel consistently. A confirmatory trial is expected to report results in early 2015. In the interim, we have a unique window of opportunity to prepare for and devise effective strategies for the future policy and programmatic scale-up of tenofovir gel provision. One approach is to integrate tenofovir gel provision into family planning (FP) services. The CAPRISA 008 implementation trial provides an opportunity to provide post-trial access to tenofovir gel while generating empiric evidence to assess whether integrating tenofovir gel provision into routine FP services can achieve similar levels of adherence as the CAPRISA 004 trial. This is a two-arm, open-label, randomized controlled non-inferiority trial. A maximum of 700 sexually active, HIV-uninfected women aged 18 years and older who previously participated in an antiretroviral prevention study will be enrolled from an urban and rural site in KwaZulu-Natal, South Africa. The anticipated study duration is 30 months, with active accrual requiring approximately 12 months (following which an open cohort will be maintained) and follow-up continuing for approximately 18 months. At each of the two sites, eligible participants will be randomly assigned to receive tenofovir gel through either FP services (intervention arm) or through the CAPRISA research clinics (control arm). As part of the study intervention, a quality improvement approach will be used to assist the FP services to expand their current services to include tenofovir gel provision. This protocol aims to address an important implementation question on whether FP services are able to effectively incorporate tenofovir gel provision for this at-risk group of women in South Africa. Provision of tenofovir gel to the women from the CAPRISA 004 trial meets the ethical obligation for post-trial access, and helps identify a potential avenue for future scale-up of microbicides within the public health system of South Africa. This trial was registered with the South Africa Department of Health (reference: DOH-27-0812-4129) and ClinicalTrials.gov (reference: NCT01691768) on 05 July 2012.


Astrocyte gp130 expression is critical for the control of Toxoplasma encephalitis.
Toxoplasma gondii infects astrocytes, neurons and microglia cells in the CNS and, after acute encephalitis, persists within neurons. Robust astrocyte activation is a hallmark of Toxoplasma encephalitis (TE); however, the in vivo function of astrocytes is largely unknown. To study their role in TE we generated C57BL/6 GFAP-Cre gp130(fl/fl) mice (where GFAP is glial fibrillary acid protein), which lack gp130, the signal-transducing receptor for IL-6 family cytokines, in their astrocytes. In the TE of wild-type mice, the gp130 ligands IL-6, IL-11, IL-27, LIF, oncostatin M, ciliary neurotrophic factor, B cell stimulating factor, and cardiotrophin-1 were up-regulated. In addition, GFAP(+) astrocytes of gp130(fl/fl) control mice were activated, increased in number, and efficiently restricted inflammatory lesions and parasites, thereby contributing to survival from TE. In contrast, T. gondii- infected GFAP-Cre gp130(fl/fl) mice lost GFAP(+) astrocytes in inflammatory lesions resulting in an inefficient containment of inflammatory lesions, impaired parasite control, and, ultimately, a lethal necrotizing TE. Production of IFN-gamma and the IFN-gamma-induced GTPase (IGTP), which mediate parasite control in astrocytes, was even increased in GFAP-Cre gp130(fl/fl) mice, indicating that instead of the direct antiparasitic effect the immunoregulatory function of GFAP-Cre gp130(fl/fl) astrocytes was disturbed. Correspondingly, in vitro infected GFAP-Cre gp130(fl/fl) astrocytes inhibited the growth of T. gondii efficiently after stimulation with IFN-gamma, whereas neighboring noninfected and TNF-stimulated GFAP-Cre gp130(fl/fl) astrocytes became apoptotic. Collectively, these are the first experiments demonstrating a crucial function of astrocytes in CNS infection.


Fine-tuning autophagy: from transcriptional to posttranslational regulation.
Macroautophagy (hereafter called autophagy) is a vacuolar lysosomal pathway for degradation of intracellular material in eukaryotic cells. Autophagy plays crucial roles in tissue homeostasis, in adaptation to stress situations, and in immune and inflammatory responses. Alteration of autophagy is associated with cancer, diabetes and obesity, cardiovascular disease, neurodegenerative disease, autoimmune disease, infection, and chronic inflammatory disease. Autophagy is controlled by autophagy-related (ATG) proteins that act in a coordinated manner to build up the initial autophagic vacuole named the autophagosome. It is now known that the activities of ATG proteins are modulated by posttranslational modifications such as phosphorylation, ubiquitination, and acetylation. Moreover, transcriptional and epigenetic controls are involved in the regulation of autophagy in stress situations. Here we summarize and discuss how posttranslational modifications and transcriptional and epigenetic controls regulate the involvement of autophagy in the proteostasis network.


Protection of Personal Information Act No. 4 of 2013: Implications for biobanks.
The Protection of Personal Information Act (POPIA) No. 4 of 2013 is the first comprehensive data-protection regulation to be passed in South Africa (SA). Its objectives include giving effect to the constitutional right to privacy by regulating the way in which personal information must be processed, balancing the right to privacy against other rights, and establishing an Information Regulator to ensure that the rights protected by POPIA are respected. POPIA will have an impact on health research, including biobanks. As sharing of samples and data is a central feature of biobanks, POPIA could change the way in which data are obtained, shared and exported. In particular, the provisions regarding data minimisation, requirements pertaining to the transfer of data abroad, consent provisions and identification of the 'responsible person' will impact the operation of biobanks in SA. With POPIA soon to come into force, it is now time to consider its implications for biobanks in SA.


Living kidney donation and masked nationalism in Israel.
This paper draws attention to a current trend of masked conditional-nationalist living kidney donation in Israel, to which the local transplant system has been turning a blind eye. The paper seeks to make the international transplant and bioethics communities aware of this disturbing trend. It also explains why it is wrong and suggests how to tackle it. Finally, it calls on the Israeli system to bring the practice to a halt for the benefit of all parties involved.


Family health history communication networks of older adults: importance of social relationships and disease perceptions.
Older individuals play a critical role in disseminating family health history (FHH) information that can facilitate disease prevention among younger family members. This study evaluated the characteristics of older adults and their familial networks associated with two types of communication (have shared and intend to share new FHH information with family members) to inform public health efforts to facilitate FHH dissemination. Information on 970 social network members enumerated by 99 seniors (aged 57 years and older) at 3 senior centers in Memphis, Tennessee, through face-to-face interviews was analyzed. Participants shared FHH information with 27.5% of the network members; 54.7% of children and 24.4% of siblings. Two-level logistic regression models showed that participants had shared FHH with those to whom they provided emotional support (odds ratio [OR] = 1.836) and felt close to (OR = 1.757). Network-members were more likely to have received FHH from participants with a cancer diagnosis (OR = 2.617) and higher familiarity with (OR = 1.380) and importance of sharing FHH with family (OR = 1.474). Participants intended to share new FHH with those who provide tangible support to (OR = 1.804) and were very close to them (OR = 2.112). Members with whom participants intend to share new FHH were more likely to belong to the network of participants with higher perceived severity if family members encountered heart disease (OR = 1.329). Many first-degree relatives were not informed of FHH. Perceptions about FHH and disease risk as well as quality of social relationships may play roles in whether seniors communicate FHH with their families. Future studies may consider influencing these perceptions and relationships.