Intranasal midazolam administration enhances amnesic effect in rats.
Intranasal (i.n.) administration of midazolam has been shown to be effective and safe for its sedative, anxiolytic, and anticonvulsant effects. However, there has been no investigation on the influence of i.n. administration on midazolam-induced anterograde amnesia. In addition, although the potential of direct drug delivery from the nose to the central nervous system (CNS) has recently become a topic of great interest, it remains unclear whether this pathway is also involved after i.n. midazolam. In this study, we examined the efficacy and the underlying mechanism of i.n. administration compared with intramuscular (i.m.) administration on midazolam-induced amnesia in rats. Equivalent doses of 0.6 mg/kg midazolam were administered via either the i.m or the i.n. route. Anterograde amnesia was assessed by a contextual/cued fear conditioning test. Each animal was conditioned 20 min after drug administration and then tested for a freezing response 24 h later. Midazolam administration by either route produced a similar level of light sedation (minimum spontaneous activity). However, i.n. administration of midazolam induced significantly less freezing behavior compared with i.m. midazolam. Furthermore, in rats with disrupted electrical input from the olfactory epithelium after an olfactotoxicant 3-methylindole administration, the i.n.-mediated enhanced amnesic effect of midazolam was not observed. Our findings indicate that i.n midazolam could probably generate olfactory signals to the brain via benzodiazepine receptors and, compared with i.m. administration, can produce a more significant amnesic effect without alteration in sedative levels. Further clinical studies are warranted.


Regional vascular reactivity in rats with Guérin carcinoma (GC).
Increased sensitivity to phenylephrin and a decreased one to isoproterenol has been found in regional vascular beds of GC implanted rats. Circulatory sympathetic reflex adaptation, alfa- and beta-adrenergic stimulation or blockade provoked a uniform response pattern: i.e. increase in vascular resistance of GC.


Adsorption of benzalkonium chlorides onto polyethylene microplastics: Mechanism and toxicity evaluation.
Usage of disposable plastic products and disinfectants has been skyrocketing due to the COVID-19 pandemic. The random disposal of plastic products may result in greater microplastic pollution. Benzalkonium chloride is known as one of the most common ingredients of disinfectants. In this study, the adsorption behavior of benzalkonium chlorides (BAC12, BAC14, BAC16) on polyethylene microplastics (PE-MPs) and the combined toxic effects were investigated using batch adsorption experiment and Daphnia magna. The results showed that PE-MPs had strong adsorption capacity for BACs and the adsorption capacity increased (11.03-22.77 mg g-1) with their octanol-water distribution coefficients. The effect of pH was negligible while dissolved organic matter inhibited the adsorption. A slightly inverse relationship between particle size of PE-MPs and adsorption was observed. Additionally, the MP aging with UV/H2O2 increased the adsorption of BAC12 but decreased that of relatively hydrophobic BAC14 and BAC16. The survival rate of Daphnia magna increased up to 100% in the presence of PE-MPs depending upon their adsorption capacities, suggesting that PE-MPs do not act as a carrier but rather as a scavenger for BACs. This study provides important information necessary for environmental risk assessment with regard to the combined pollution of MPs and toxic chemicals.


CUDC-101, a Novel Inhibitor of Full-Length Androgen Receptor (flAR) and Androgen Receptor Variant 7 (AR-V7) Activity: Mechanism of Action and In Vivo Efficacy.
Castration-resistant prostate cancer (CRPC) is an androgen receptor (AR)-dependent disease expected to cause the death of more than 27,000 Americans in 2015. There are only a few available treatments for CRPC, making the discovery of new drugs an urgent need. We report that CUDC-101 (an inhibitor od HER2/NEU, EGFR and HDAC) inhibits both the full length AR (flAR) and the AR variant AR-V7. This observation prompted experiments to discover which of the known activities of CUDC-101 is responsible for the inhibition of flAR/AR-V7 signaling. We used pharmacologic and genetic approaches, and found that the effect of CUDC-101 on flAR and AR-V7 was duplicated only by other HDAC inhibitors, or by silencing the HDAC isoforms HDAC5 and HDAC10. We observed that CUDC-101 treatment or AR-V7 silencing by RNAi equally reduced transcription of the AR-V7 target gene, PSA, without affecting viability of 22Rv1 cells. However, when cellular proliferation was used as an end point, CUDC-101 was more effective than AR-V7 silencing, raising the prospect that CUDC-101 has additional targets beside AR-V7. In support of this, we found that CUDC-101 increased the expression of the cyclin-dependent kinase inhibitor p21, and decreased that of the oncogene HER2/NEU. To determine if CUDC-101 reduces growth in a xenograft model of prostate cancer, this drug was given for 14 days to castrated male SCID mice inoculated with 22Rv1 cells. Compared to vehicle, CUDC-101 reduced xenograft growth in a statistically significant way, and without macroscopic side effects. These studies demonstrate that CUDC-101 inhibits wtAR and AR-V7 activity and growth of 22Rv1 cells in vitro and in vivo. These effects result from the ability of CUDC-101 to target not only HDAC signaling, which was associated with decreased flAR and AR-V7 activity, but multiple additional oncogenic pathways. These observations raise the possibility that treatment of CRPC may be achieved by using similarly multi-targeted approaches.


Tyrosine capped silver nanoparticles: A new fluorescent sensor for the quantitative determination of copper(II) and cobalt(II) ions.
Nanoparticles have been increasingly used as sensors for several organic and inorganic analytes. In this work, we report a study on the synthesis of novel highly fluorescent l-Tyr capped silver nanoparticles (AgNPs) and their use for the determination of metal ions. The AgNPs have been characterized by TEM, UV-Vis and Photoluminescence (PL) spectroscopy and dynamic light scattering (DLS) measurements and used for the quantitative determination of Co(II) and Cu(II) ions. In the l-Tyr capped AgNPs, the α-amino and α-carboxyl groups of the surface-confined amino acid can coordinate the entitled metal ions, giving rise to a decrease of the silver surface plasmon absorption, that is linearly correlated with the metal ions concentrations. The addition of Co(II) and Cu(II) solutions to the l-Tyr AgNPs also induces a paramagnetic quenching of the fluorescence in the PL spectra and the related Stern Volmer plots highlight a linear correlation over the whole concentration range for both metal ions, with a more pronounced effect for the copper(II) ion.


Trajectories of Sexual Risk Behaviors and the Associated Factors Among Young Men Who Have Sex With Men in China.
Young men who have sex with men (YMSM) are at high risk of HIV infection that accounts for an increasing proportion of new human immunodeficiency virus (HIV) infections in China. However, little is known about the trajectories of sexual risk behaviors in this population. The study aimed to investigate longitudinal patterns of sexual risk behaviors among YMSM in China. Study data were collected from a prospective cohort study among 460 YMSM from 2017 to 2020. Based on the predicted HIV infection risk scores, distinct sexual risk behaviors trajectories of YMSM were estimated and plotted using the group-based censored normal model to identify the predictors of trajectories change over time. Three sexual risk behaviors trajectories were identified: a decreasing low-risk group (7.6%), an intermediate-risk group (67.4%), and an ascending high-risk group (25.0%).Compared to the decreasing low-risk group, intermediate-risk group membership was associated with being from rural areas, current smoker and higher depressive symptoms; ascending high-risk group membership was associated with an education level of high school or lower, being from rural areas, younger age at sex debut with a man, current smoker, higher depressive symptoms and sexual minority stress. Sexual risk behaviors among YMSM changed over time within different trajectories. Identifying YMSM belonging to high-risk trajectories before HIV infection is vital for the intervention and may reduce HIV transmission.


Green synthesized carbon quantum dots from Prosopis juliflora leaves as a dual off-on fluorescence probe for sensing mercury (II) and chemet drug.
In this article, a facile and green dual fluorescence sensor was developed for mercury and chemet as an anti-poisoning drug for heavy metal ions. The method is based on "off-on" fluorescence of carbon quantum dots (CQDs) prepared from Prosopis juliflora leaves as a green and low cost source. The synthesis of CQDs was easily performed with a rapid one pot process and the prepared CQDs exhibited a blue luminescence with a 5% quantum yield. The off fluorescent is observed in the presence of different concentrations of mercury (II) that is specifically recovered with the addition of chemet. The gradually recovered fluorescence is due to the high affinity of chelating property of succimer drug towards mercury (II) with a good restoration. Under the optimized condition, two linear calibrations were validated in the range of 5-500 ng mL-1 and 2.5-22.5 ng mL-1 for Hg (II) and chemet, respectively. The limit of detection (LOD) based on 3Sb was 1.26 ng mL-1 (or 6.3 nM) for Hg (II) and 1.4 ng mL-1 for chemet. The relative standard deviation of the fluorescent probe for 50 ng mL-1 of Hg (II) and 10 ng mL-1 of chemet was 4.5% and 1.3% (n = 10), respectively. This methodology was applied to successful measurements of Hg (II) and chemet in the water and human serum samples, respectively.


Predictors of loss to follow-up among adult tuberculosis patients in Southern Ethiopia: a retrospective follow-up study.
Loss to follow-up (LTFU) from tuberculosis (TB) treatment and care is a major public health problem as patients can be infectious and also may develop a multi-drug resistant TB (MDR-TB). The study aimed to assess whether LTFU differs by the distance TB patients travelled to receive care from the nearest health facility. A total of 402 patient cards of TB patients who received care were reviewed from March 1-30, 2020. The Kaplan-Meir curve with the Log-rank test was used to compare differences in LTFU by the distance travelled to reach to the nearest health facility for TB care. The Cox proportional hazard regression model was used to identify predictors. All statistical tests are declared significant at a p-value< 0.05. A total of 37 patients were LTFU with the incidence rate of 11.26 per 1000 person-months of observations (PMOs) (95% CI: 8.15-15.53). The incidence rate ratio was 12.19 (95% CI: 5.01-35.73) among the groups compared (those who travelled 10 km or more versus those who travelled less than 10 km). Age ≥ 45 years (aHR = 7.71, 95% CI: 1.72, 34.50), educational status (primary schooling, aHR = 3.54, 95% CI: 1.49, 8.40; secondary schooling, aHR = 2.75, 95% CI: 1.08, 7.03), lack of family support (aHR = 2.80, 95% CI: 1.27, 6.19), nutritional support (aHR = 3.40, 95% CI:1.68, 6.89), ≥ 10 km distance to travel to a health facility (aHR = 6.06, 95% CI: 2.33, 15.81) had significantly predicted LTFU from TB treatment and care. LTFU from adult TB care and treatment was 12 times higher among those who travelled ≥10 km to reach a health facility compared to those who travelled less. To retain adult TB patients in care and ensure appropriate treatment, health professionals and other stakeholders should give due attention to the factors that drive LTFU. We suggest identifying concerns of older patients at admission and those who travel long distance and establish social support platforms that could help people to complete TB treatment.


Mechanism of Ca2+ inhibition of inositol 1,4,5-trisphosphate (InsP3) binding to the cerebellar InsP3 receptor.
Ca2+ efficiently inhibits binding of inositol 1,4,5-trisphosphate (InsP3) to the InsP3 receptor in cerebellar membranes but not to the purified receptor. We have now investigated the mechanism of action by which Ca2+ inhibits InsP3 binding. Our results suggest that Ca2+ does not cause the stable association of a Ca(2+)-binding protein with the receptor. Instead, Ca2+ leads to the production of a soluble, heat-stable, low molecular weight substance from cerebellar membranes that competes with InsP3 for binding. This inhibitory substance probably represents endogenously generated InsP3 as judged by the fact that it co-purifies with InsP3 on anion-exchange chromatography, competes with [3H]InsP3 binding in a pattern similar to unlabeled InsP3, and is in itself capable of releasing 45Ca2+ from permeabilized cells. A potent Ca(2+)-activated phospholipase C activity producing InsP3 was found in cerebellar microsomes that exhibited a Ca2+ dependence identical to the Ca(2+)-dependent inhibition of InsP3 binding. Together these results suggest that the Ca(2+)-dependent inhibition of InsP3 binding to the cerebellar receptor is due to activation of a Ca(2+)-sensitive phospholipase C enriched in cerebellum. Nevertheless, Ca2+ probably also modulates the InsP3 receptor function by a direct interaction with the receptor that does not affect InsP3 binding but regulates InsP3-dependent channel gating.


Facile synthesis of pectin-stabilized magnetic graphene oxide Prussian blue nanocomposites for selective cesium removal from aqueous solution.
This work focused on the development of pectin-stabilized magnetic graphene oxide Prussian blue (PSMGPB) nanocomposites for removal of cesium from wastewater. The PSMGPB nanocomposite showed an improved adsorption capacity of 1.609mmol/g for cesium, compared with magnetic graphene oxide Prussian blue, magnetic pectin Prussian blue, and magnetic Prussian blue nanocomposites, which exhibited adsorption capacities of 1.230, 0.901, and 0.330mmol/g, respectively. Increased adsorption capacity of PSMGPB nanocomposites was attributed to the pectin-stabilized separation of graphene oxide sheets and enhanced distribution of magnetites on the graphene oxide surface. Scanning electron microscopy images showed the effective separation of graphene oxide sheets due to the incorporation of pectin. The optimum temperature and pH for adsorption were 30°C and 7.0, respectively. A thermodynamic study indicated the spontaneous and the exothermic nature of cesium adsorption. Based on non-linear regression, the Langmuir isotherm fitted the experimental data better than the Freundlich and Tempkin models.


Obligatory role of Schwann cell-specific erythropoietin receptors in erythropoietin-induced functional recovery and neurogenic muscle atrophy after nerve injury.
Erythropoietin (EPO) promotes myelination and functional recovery in rodent peripheral nerve injury (PNI). While EPO receptors (EpoR) are present in Schwann cells, the role of EpoR in PNI recovery is unknown because of the lack of EpoR antagonists or Schwann cell-specific EpoR knockout animals. Using the Cre-loxP system, we developed a myelin protein zero (Mpz) promoter-driven knockout mouse model of Schwann cell EpoR (MpzCre-EpoRflox/flox , Mpz-EpoR-KO). Mpz-EpoR-KO and control mice were assigned to sciatic nerve crush injury followed by EPO treatment. EPO treatment significantly accelerated functional recovery in control mice in contrast to significantly reduced functional recovery in Mpz-EpoR-KO mice. Significant muscle atrophy was found in the injured hindlimb of EPO-treated Mpz-EpoR-KO mice but not in EPO-treated control mice. These preliminary findings provide direct evidence for an obligatory role of Schwann-cell specific EpoR for EPO-induced functional recovery and muscle atrophy following PNI.


Impact of hormone therapy side effects on health-related quality of life, distress, and well-being of breast cancer survivors.
To explore the modulatory role of Adjuvant Hormone Therapy (AHT) on health-related quality of life (QoL), subjective well-being and distress prevalence in Breast Cancer (BC) survivors, considering the survival phase. Cross-sectional study with control group. 616 BC survivors participated. Examination of interaction effect between AHT and time since end of primary treatment showed that many of the positive changes observed through the survival phases were experienced exclusively by survivors without AHT. When AHT was not prescribed, longer time elapsed was associated with a decrease in distress prevalence and an improvement in subjective well-being and QoL. It seems there is a turning point around the fifth year after finalization of primary treatment, from which the survivors without AHT significantly improve in several areas and those with AHT do so to a lesser extent. It is expected that the improvement in QoL throughout the different survival phases will have a significant impact on the adherence and maintenance of AHT and, consequently, the likelihood of survival. Thus, AHT side-effects should be routinely assessed by health care providers to gain accurate knowledge that allows improving the QoL of BC survivors.


Thinking ethical and regulatory frameworks in medicine from the perspective of solidarity on both sides of the Atlantic.
This article provides a concise overview of the history of scholarship on solidarity in Europe and North America. While recent decades have seen an increase in conceptual and scholarly interest in solidarity in North America and other parts of the Anglo-Saxon world, the concept is much more strongly anchored in Europe. Continental European politics in particular have given rise to two of the most influential traditions of solidarity, namely, socialism and Christian ethics. Solidarity has also guided important public instruments and institutions in Europe (e.g., welfare, healthcare, etc.). Despite the much stronger affinity of continental European societies to solidaristic thinking, we argue that solidarity has much to offer for addressing societal challenges on both sides of the Atlantic and beyond. After proposing a working definition of solidarity that highlights its utility for guiding policy and practice, we give an example of how a solidarity-based perspective can shape instruments for the governance of data use.


Microgravity and bone cell mechanosensitivity.
The capacity of bone tissue to alter its mass and structure in response to mechanical demands has long been recognized but the cellular mechanisms involved remained poorly understood. Bone not only develops as a structure designed specifically for mechanical tasks, but it can adapt during life toward more efficient mechanical performance. Mechanical adaptation of bone is a cellular process and needs a biological system that senses the mechanical loading. The loading information must then be communicated to the effector cells that form new bone or destroy old bone. The in vivo operating cell stress derived from bone loading is likely the flow of interstitial fluid along the surface of osteocytes and lining cells. The response of bone cells in culture to fluid flow includes prostaglandin (PG) synthesis and expression of prostaglandin G/H synthase inducible cyclooxygenase (COX-2). Cultured bone cells also rapidly produce nitric oxide (NO) in response to fluid flow as a result of activation of endothelial nitric oxide synthase (ecNOS), which enzyme also mediates the adaptive response of bone tissue to mechanical loading. Earlier studies have shown that the disruption of the actin-cytoskeleton abolishes the response to stress, suggesting that the cytoskeleton is involved in cellular mechanotransduction. Microgravity, or better near weightlessness, is associated with the loss of bone in astronauts, and has catabolic effects on mineral metabolism in bone organ cultures. This might be explained as resulting from an exceptional form of disuse under near weightlessness conditions. However, under near weightlessness conditions the assembly of cytoskeletal elements may be altered since it has been shown that the direction of the gravity vector determines microtubular pattern formation in vivo. We found earlier that the transduction of mechanical signals in bone cells also involves the cytoskeleton and is related to PGE2 production. Therefore it is possible that the mechanosensitivity of bone cells is altered under near weightlessness conditions, and that this abnormal mechanosensation contributes to disturbed bone metabolism observed in astronauts. In our current project for the International Space Station, we wish to test this hypothesis experimentally using an in vitro model. The specific aim of our research project is to test whether near weightlessness decreases the sensitivity of bone cells for mechanical stress through a decrease in early signaling molecules (NO, PGs) that are involved in the mechanical loading-induced osteogenic response. Bone cells are cultured with or without gravity prior to and during mechanical loading, using our modified in vitro oscillating fluid flow apparatus. In this "FlowSpace" project we are developing a cell culture module that is used to provide further insight in the mechanism of mechanotransduction in bone.


Characterization of tire and road wear microplastic particle contamination in a road tunnel: From surface to release.
Road pollution is one of the major sources of microplastic particles to the environment. The distribution of tire, polymer-modified bitumen (PMB) and tire and road wear particles (TRWP) in different tunnel compartments were explored: road surface, gully-pots and tunnel wash water. A new method for calculating TRWP using Monte Carlo simulation is presented. The highest concentrations on the surface were in the side bank (tire:13.4 ± 5.67;PMB:9.39 ± 3.96; TRWP:22.9 ± 8.19 mg/m2), comparable to previous studies, and at the tunnel outlet (tire:7.72 ± 11.2; PMB:5.40 ± 7.84; TRWP:11.2 ± 16.2 mg/m2). The concentrations in gully-pots were highest at the inlet (tire:24.7 ± 26.9; PMB:17.3 ± 48.8; TRWP:35.8 ± 38.9 mg/g) and comparable to values previously reported for sedimentation basins. Untreated wash water was comparable to road runoff (tire:38.3 ± 10.5; PMB:26.8 ± 7.33; TRWP:55.3 ± 15.2 mg/L). Sedimentation treatment retained 63% of tire and road wear particles, indicating a need to increase the removal efficiency to prevent these from entering the environment. A strong linear relationship (R2-adj=0.88, p < 0.0001) between total suspended solids (TSS) and tire and road wear rubber was established, suggesting a potential for using TSS as a proxy for estimating rubber loads for monitoring purposes. Future research should focus on a common approach to analysis and calculation of tire, PMB and TRWP and address the uncertainties related to these calculations.


Static magnetic fields promote osteoblast-like cells differentiation via increasing the membrane rigidity.
The aim of this study was to test the differentiative effects of osteoblasts after treatment with a static magnetic field (SMF). MG63 osteoblast-like cells were exposed to a 0.4-T SMF. The differentiation markers were assessed by observing the changes in alkaline phosphatase activity and electron microscopy images. Membrane fluidity was used to evaluate alterations in the biophysical properties of the cellular membranes after the SMF simulation. Our results show that SMF exposure increases alkaline phosphatase activity and extracellular matrix release in MG63 cells. On the other hand, MG63 cells exposed to a 0.4-T SMF exhibited a significant increase in fluorescence anisotropy at 6 h, with a significant reduction in the proliferation effects of growth factors noted at 24 h. Based on these findings, the authors suggest that one of the possible mechanisms that SMF affects osteoblastic maturation is by increasing the membrane rigidity and reducing the proliferation-promoting effects of growth factors at the membrane domain.


Arabidopsis Yak1 protein (AtYak1) is a dual specificity protein kinase.
Yak1 is a member of dual-specificity Tyr phosphorylation-regulated kinases (DYRKs) that are evolutionarily conserved. The downstream targets of Yak1 and their functions are largely unknown. Here, a homologous protein AtYAK1 was identified in Arabidopsis thaliana and the phosphoprotein profiles of the wild type and an atyak1 mutant were compared on two-dimensional gel following Pro-Q Diamond phosphoprotein gel staining. Annexin1, Annexin2 and RBD were phosphorylated at serine/threonine residues by the AtYak1 kinase. Annexin1, Annexin2 and Annexin4 were also phosphorylated at tyrosine residues. Our study demonstrated that AtYak1 is a dual specificity protein kinase in Arabidopsis that may regulate the phosphorylation status of the annexin family proteins.


Reversible parkinsonism from shunt failure.
Parkinsonism developed as the result of shunt malfunction in a 16-year-old girl with aqueductal stenosis. Her symptoms responded to levodopa and shunt revision. Possible pathogenetic mechanisms are discussed.


Affective syndrome during perimenopause.
Perimenopause is characterized by decreasing levels of estrogens and progesterone until gonadal secretion comes to a complete halt. There are still very different views and positions on the significance of the menopause. Physical, mental-vegetative and depressive symptoms during climacteric are different in each culture. Currently, there is some controversy as to whether or not there really is a rise in actual depression during the perimenopausal phase of woman's life. The observations from humans taken together indicate that depressive disorders, as defined in ICD-10, do not occur more frequently during perimenopause. In this context, the terms subthreshold depression and or subsyndromal depression are important, describing depressive symptoms which do not fulfil the complete clinical picture of a depressive episode, either because there are not enough symptoms or because they are not severe enough. The affected women still suffer, but until now not enough studies have been carried out on this particular area. In view of the complexity and relevance of the perimenopausal period in a woman's life, it is necessary to establish and maintain a network of treatment between the family physician, gynecologist, psychiatrist and or psychotherapist, as soon as significant depressive symptoms occur.


Polariton-driven phonon laser.
Efficient generation of phonons is an important ingredient for a prospective electrically-driven phonon laser. Hybrid quantum systems combining cavity quantum electrodynamics and optomechanics constitute a novel platform with potential for operation at the extremely high frequency range (30-300 GHz). We report on laser-like phonon emission in a hybrid system that optomechanically couples polariton Bose-Einstein condensates (BECs) with phonons in a semiconductor microcavity. The studied system comprises GaAs/AlAs quantum wells coupled to cavity-confined optical and vibrational modes. The non-resonant continuous wave laser excitation of a polariton BEC in an individual trap of a trap array, induces coherent mechanical self-oscillation, leading to the formation of spectral sidebands displaced by harmonics of the fundamental 20 GHz mode vibration frequency. This phonon "lasing" enhances the phonon occupation five orders of magnitude above the thermal value when tunable neighbor traps are red-shifted with respect to the pumped trap BEC emission at even harmonics of the vibration mode. These experiments, supported by a theoretical model, constitute the first demonstration of coherent cavity optomechanical phenomena with exciton polaritons, paving the way for new hybrid designs for quantum technologies, phonon lasers, and phonon-photon bidirectional translators.


Cost analysis comparing adjuvant epimacular brachytherapy with anti-VEGF monotherapy for the management of neovascular age-related macular degeneration.
To consider the cost implication of adopting epimacular brachytherapy (EMB) for the treatment of neovascular (wet) age-related macular degeneration (wAMD), compared with ranibizumab or bevacizumab monotherapy. This analysis compared the cumulative 3-year costs of anti-VEGF (vascular endothelial growth factor) monotherapy to EMB combined with anti-VEGF therapy. Two patient groups were considered: newly diagnosed (treatment-naïve) patients; and patients already receiving chronic anti-VEGF therapy. In the treatment-naïve patients, the highest cumulative treatment costs were associated with ranibizumab monotherapy (£25,658), followed by bevacizumab monotherapy (£16,177), EMB with ranibizumab (£14,002), then EMB with bevacizumab (£10,289). In previously treated patients, the highest treatment costs were ranibizumab monotherapy (£18,355), followed by EMB with ranibizumab (£17,428), bevacizumab monotherapy (£16,177), then EMB with bevacizumab (£12,129). EMB combined with anti-VEGF treatment has the potential to yield considerable cost savings, compared with anti-VEGF monotherapy. If the ongoing large studies of EMB confirm the published feasibility data, then adjuvant EMB may represent a cost-effective alternative to anti-VEGF monotherapy.


Globular adiponectin attenuates myocardial ischemia/reperfusion injury by upregulating endoplasmic reticulum Ca²⁺-ATPase activity and inhibiting endoplasmic reticulum stress.
The aim of this study was to explore the mechanisms underlying the effects of globular adiponectin (gAd) on myocardial ischemia/reperfusion (I/R) injury. An in vivo myocardial I/R model and an in vitro neonatal rat cardiomyocyte hypoxia/reoxygenation (H/R) model simulating I/R injury in vivo were adopted to investigate whether and how the cardioprotective effects of gAd are mediated by the inhibition of endoplasmic reticulum (ER) stress. gAd (1 μg/g, intravenously) attenuated the myocardial infarct size, myocardial enzyme activity, and apoptosis in rats with I/R, and similar protection was observed in primary cultures of neonatal rat cardiomyocytes. The protective effects of gAd were associated with the suppression of ER stress, as evidenced by reversing the upregulation of 78-kDa glucose-regulated protein, C/EBP homologous protein, and caspase-12 that were induced by H/R and thapsigargin. In addition, gAd conferred resistance to ER stress and cardiomyocyte injury by modulating ER Ca²⁺-ATPase (SERCA) activity. Moreover, gAd further increased H/R-enhanced Akt phosphorylation. The protective effects of gAd on ER stress and SERCA activity were abolished by preincubation of rat neonatal cardiomyocytes with the PI3K inhibitor LY294002. Consistent with this finding, I/R-induced ER stress and SERCA dysfunction were also significantly ameliorated by gAd. These effects involved PI3K/Akt signaling pathway. The protective effects of gAd during I/R are mediated, at least in part, by modulating SERCA activity and consequently suppressing ER stress via the activation of PI3K/Akt signaling.


Curcumin analogs (B2BrBC and C66) supplementation attenuates airway hyperreactivity and promote airway relaxation in neonatal rats exposed to hyperoxia.
This study was undertaken to test the hypothesis that the newly synthesized curcuminoids B2BrBC and C66 supplementation will overcome hyperoxia-induced tracheal hyperreactivity and impairment of relaxation of tracheal smooth muscle (TSM). Rat pups (P5) were exposed to hyperoxia (>95% O2 ) or normoxia for 7 days. At P12, tracheal cylinders were used to study in vitro contractile responses induced by methacholine (10-8 -10-4 M) or relaxation induced by electrical field stimulation (5-60 V) in the presence/absence of B2BrBC or C66, or to study the direct relaxant effects elicited by both analogs. Hyperoxia significantly increased contraction and decreased relaxation of TSM compared to normoxia controls. Presence of B2BrBC or C66 normalized both contractile and relaxant responses altered by hyperoxia. Both, curcuminoids directly induced dose-dependent relaxation of preconstricted TSM. Supplementation of hyperoxic animals with B2BrBC or C66, significantly increased catalase activity. Lung TNF-α was significantly increased in hyperoxia-exposed animals. Both curcumin analogs attenuated increases in TNF-α in hyperoxic animals. We show that B2BrBC and C66 provide protection against adverse contractility and relaxant effect of hyperoxia on TSM, and whole lung inflammation. Both analogs induced direct relaxation of TSM. Through restoration of catalase activity in hyperoxia, we speculate that analogs are protective against hyperoxia-induced tracheal hyperreactivity by augmenting H2 O2 catabolism. Neonatal hyperoxia induces increased tracheal contractility, attenuates tracheal relaxation, diminishes lung antioxidant capacity, and increases lung inflammation, while monocarbonyl CUR analogs were protective of these adverse effects of hyperoxia. Analogs may be promising new therapies for neonatal hyperoxic airway and lung disease.


Malignant tumor-like gastric lesion due to Candida albicans in a diabetic patient treated with cyclosporin: a case report and review of the literature.
The gastrointestinal tract of healthy individuals is colonized by hundreds of saprophytes and mycetes, especially the Candida species, are habitual ones. Under certain conditions, the fungal flora may overgrow, resulting in lesions of the digestive mucosa which, rarely, can have a local diffusion and/or spread to the lympho-hematogenous system. Mycotic infections of the stomach can sometimes look like benign gastric ulcers. Here, we present the case report of a woman, aged 64, who presented with type II diabetes mellitus and psoriasis, on chronic treatment with cyclosporin A and with endoscopic evidence of an ulcerated, vegetating gastric lesion secondary to Candida albicans infection. Although strongly suggestive of malignancy, it completely healed after cyclosporin withdrawal and the administration of oral antifungal drugs.


Long Non-Coding RNA PVT1 and Its Target miRNA-146a as Potential Prognostic Biomarkers in Rheumatoid Arthritis Patients.
Long non-coding RNAs (lncRNAs) and their target microRNAs were documented in multiple studies to have a significant role in different joint disorders such as rheumatoid arthritis (RA) and osteoarthritis (OA). The current work aimed to determine the potential role of lnc-PVT1 and miR-146a as promising biomarkers to distinguish between RA, OA patients, and healthy individuals. The expression levels of lnc-PVT1 and its target miR-146a in the serum were measured for three different groups, including patients with RA (40), OA patients (40), and healthy controls (HCs) (40). Participating individuals were subjected to a full history investigation and clinical examination. Blood samples were tested for ESR, RF, CBC, as well as liver and renal functions. Serum was used to detect the relative expression levels of lnc-PVT1 and miR-146a and we correlated the levels with RA and OA activity and severity signs. Lnc-PVT1 expression level was greater among patients with RA compared to that of OA patients, with a fold change median of 2.62 and 0.22, respectively (p = 0.001). The miR-146a fold change was significantly demonstrated between the RA, OA, and HCs groups. There was no correlation between both biomarkers with the disease activity scales (DAS28) of RA, the Knee injury Osteoarthritis Outcome Score (KOOS), or any sign of detection of the disease severity of OA. lnc-PVT1 and miR-146a could be considered as promising biomarkers for the diagnosis of RA and OA and may have an important role as therapeutic targets in the future.


Comparing complications of small-bore chest tubes to large-bore chest tubes in the setting of delayed hemothorax: a retrospective multicenter cohort study.
Previous studies have provided initial data suggesting that small-bore (SB, ≤ 14Fr) chest tubes have the same efficacy as large-bore (LB, > 14 Fr) chest tubes for acute hemothorax (HTX), but data continue to be lacking in the setting of delayed HTX. This study compared complications of SB chest tubes to LB tubes in patients with delayed HTX. This was a retrospective observational study across 7.5 yrs. at 6 Level 1 trauma centers. Patients were included if 1) diagnosed with a HTX or > 1 rib fracture with bloody effusion from chest tube; 2) initial chest tube placed ≥36 h of hospital admission. Patients were excluded for hemopneumothoraces. The primary endpoint was having at least one of the following chest tube complications: tube replacement, VATS, tube falling out, tube clogging, pneumonia, retained HTX, pleural empyema. Secondary outcomes included chest tube output volume and drainage rate. Dependent/independent and parametric/non-parametric analyses were used to assess primary and secondary outcomes. There were 160 SB patients (191 tubes) and 60 LB patients (72 tubes). Both comparison groups were similar in multiple demographic, injury, clinical features. The median (IQR) tube size for each group was as follows: SB [12 Fr (12-14)] and LB [32 Fr (28-32)]. The risk of having at least one chest tube complication was similar for LB and SB chest tubes (14% vs. 18%, p = 0.42). LB tubes had significantly larger risk of VATS, while SB tubes had significantly higher risk of pneumonia. SB tubes had significantly slower least squares (LS) mean initial output drainage rate compared to LB tubes (52.2 vs. 213.4 mL/hour, p < 0.001), but a non-parametric analysis suggested no significant difference in median drainage rates between groups 39.7 [23.5-242.0] mL/hr. vs. 38.6 [27.5-53.8], p = 0.81. LB and SB groups had similar initial output volume (738.0 mL vs. 810.9, p = 0.59). There was no clearly superior chest tube diameter size; both chest tube sizes demonstrated risks and benefits. Clinicians must be aware of these potential tradeoffs when deciding on the diameter of chest tube for the treatment of delayed HTXs.


Re-inventing progressive community psychiatry: the use of history.
Over the last half-century progressives in community psychiatry have challenged the social order while addressing the needs of persons with psychiatric disorders. Recently, however, their vision and energy has faltered. A re-evaluation of the progressive position is essential, beginning with a review of its historical experience. Unfortunately, modern psychiatry has become increasingly ahistorical. Those histories that do exist reveal little about the experiences of progressive practice and tend to attack it from the right or from the left. There is a tremendous need to synthesize new socially-oriented histories of the progressive movement in community psychiatry.


Clinical validity of proliferating cell nuclear antigen as an objective marker for evaluating biologic features in patients with untreated prostate cancer.
Although Gleason grading may be the most useful system for evaluating biological activity of untreated prostate cancer, lack of interobserver validity with Gleason scores (GS) is an unsolved issue. In this study, the proliferating cell nuclear antigen labeling index (PCNA LI) in untreated prostate cancer was investigated in order to clarify the usefulness of supplemental and objective markers for evaluating the biologic features of prostate cancer. Sixty cases of prostate cancer were randomly selected from the cancer registry in Gunma University Hospital for this study. PCNA LI were evaluated using paraffin-embedded biopsy cores taken at diagnosis. Correlation of PCNA LI with the Gleason grading system, clinical stage, serum prostate-specific antigen (PSA) levels and age were evaluated. Cumulative rates of freedom from cause-specific death were also evaluated stratified by various clinicopathologic features, including PCNA LI using Kaplan-Meier analysis. Proliferating cell nuclear antigen labeling index was significantly higher in patients with PSA levels over 100 ng/mL, advanced clinical stage (>T4, N1 or M1 disease), higher Gleason grade or with a higher GS than in those with other clinicopathologic features. The 5-year cumulative rate of death from prostate cancer was significantly higher at 62% in patients with a PCNA LI of 20 or more than those with PCNA LI of less than 20, who accounted for 4%. Proliferating cell nuclear antigen labeling index in combination with Gleason grading system may be of clinical value in evaluating biologic features and also in predicting cause specific survival of prostate cancer in an objective, reliable and reproducible manner.


Earliest memories and recall by modality usually involve recollections of different memories: memories are not amodal.
66 students recalled a first memory and indicated whether sensory impressions from each sensory modality were a part of this memory and, if so, how clear and important these impressions were. After a distraction, they also recalled in each sense modality the very first memory they could. Only visual impressions were always a part of first memories. The clarity and importance of sensory attributes were evaluated similarly. Recall by modality led to memories of equivalent clarity, and these were usually memories other than the one recalled as the earliest memory or recalled using other modalities. Memories are more modality-specific than assumed before in theory or practice.


Mesocaval and distal splenorenal shunts: effect on hepatic function, hepatic hemodynamics, and portal systemic encephalopathy.
The effect of the mesocaval interposition shunt (n = 12) and the distal splenorenal shunt (n = 9) on the wedged hepatic venous pressure, the estimated hepatic blood flow, quantitative hepatic function, and the rate of portal systemic encephalopathy was evaluated in 21 patients who had bled from esophageal varices. After mesocaval shunt the wedged hepatic venous pressure was significantly reduced by 42% (from 26 +/- 3 mm Hg to 15 +/- 5 mm Hg, P less than 0.001) compared to 16% only (from 25 +/- 3 mm Hg to 21 +/- 2 mm Hg, P less than 0.005) after distal splenorenal shunt. The estimated hepatic blood flow also decreased significantly after mesocaval shunt by 61% (from 1.45 +/- 0.46 l/min to 0.56 +/- 0.25 l/min, P less than 0.001) compared to 29% (from 1.29 +/- 0.32 l/min to 0.91 +/- 0.39 l/min, P less than 0.05) after distal splenorenal shunt. Despite significantly different influences of both types of shunt operations on wedged hepatic venous pressure and estimated hepatic blood flow (P less than 0.001), postoperative changes of hepatic function were comparable in both groups of patients. The galactose elimination capacity, the initial plasma disappearance rate of Bromsulphalein, and the plasma ratio of valine, leucine, and isoleucine to phenylalanine and tyrosine were reduced by 13%, 26%, and 29%, respectively, after mesocaval shunt, compared to 12%, 25%, and 17% after distal splenorenal shunt. Only two patients of the mesocaval shunt group with the largest decrease in estimated hepatic blood flow developed portal systemic encephalopathy postoperatively, and the distal splenorenal shunt patients with their minor hemodynamic sequelae remained free of portal systemic encephalopathy.


Hypozincemia in patients with malignant melanoma.
In patients with malignant melanoma a decreased zinc content in the serum was observed, and our previous studies had demonstrated an increased urinary zinc excretion in these patients. These results support our hypothesis of association of zinc with melanin structures. The significant redistribution of zinc in malignant melanoma is suggested for monitoring of this disease.


Residual risk of transfusion-transmitted human immunodeficiency virus, hepatitis C virus, and hepatitis B virus infections in Italy.
Estimating the risk of transfusion-transmitted infections (TTIs) is essential for monitoring blood safety. The residual risk of TTI was estimated for nearly 90 percent of the blood supply in Italy. Data were analyzed from 1,079,281 repeat donors, corresponding to 5,361,000 donations made in blood transfusion centers throughout Italy in the period 1999 through 2001. The residual risk of transfusion-transmitted human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) infections was estimated with the incidence rate-window period model. The denominator for the incidence rate (i.e., the number of person-years at risk) was estimated on a sample of 5850 donors. The risk of an infectious donation entering the blood supply, per 1 million donations, was 1.91 (probable range, 0.52-3.32) for HIV, 16.74 (9.57-24.01) for HCV, and 69.16 (43.12-102.70) for total HBV (adjusted for vaccination and hepatitis B surface antigen transience). In Italy, the estimated residual risk of TTI is apparently low, particularly for HIV infection. Although the estimated risks are higher for HCV and HBV, the introduction of mandatory viral detection tests for HCV in 2002 should account for an 80 percent reduction in the HCV risk. Moreover, the ongoing HBV vaccination program will contribute to reducing the risk of transfusion-transmitted HBV.


Effect of plate position on tibial displacement and posterior tibial slope after cyclic loading in medial open wedge high tibial osteotomy: A biomechanical study using porcine tibia.
Medial open wedge high tibial osteotomy is currently the most common osteotomy, but its complication is an increased posterior tibial slope over time. However, no study has clarified whether the plate position of medial open wedge high tibial osteotomy could reduce the increase in posterior tibial slope after cyclic loading. Fourteen porcine bones were biomechanically evaluated by performing medial open wedge high tibial osteotomy and placing TOMOFIX medially and anteromedially. Cyclic testing was performed to investigate the posterior tibial slope over time for medial open wedge high tibial osteotomy with medial or anteromedial plate. The displacement along the mechanical axis during cyclic testing from 10 to 100th, 100-500th, 500-1000th, 1000-1500th, and 1500-2000th cycles, and changes in anterior and posterior gaps after 2000 cycles were compared between plate position. There were no significant differences in displacement. A significant difference was found in posterior gap changes (-0.20 ± 0.84 mm in group of using medial plate, 1.07 ± 0.82 mm in group of using anteromedial plate) (P = 0.014), but none was found in anterior gap changes. Medial plate placement in medial open wedge high tibial osteotomy resulted in significantly less increased posterior tibial slope than anteromedial plate placement after cyclic loading.


Low dose rate vs. high dose rate brachytherapy in the treatment of carcinoma of the uterine cervix: a clinical trial.
This study is a prospective randomized clinical trial undertaken at our center to compare low dose rate versus high dose rate intracavitary brachytherapy for the treatment of carcinoma uterine cervix. From June 1986 to June 1989, 482 patients with previously untreated invasive squamous cell carcinoma of the uterine cervix were entered into the study. After an initial clinical examination and investigative work-up the patients were staged according to FIGO staging system. Depending upon the stage of the disease, the size of the local growth and the local cervical anatomy, the patients were divided into two main groups. In group I patients, the predominant treatment was by intracavitary therapy and in group II patients, the predominant therapy was by external beam radiation. In both the groups at the time of intracavity brachytherapy the patients were alternately randomized to receive either low dose rate or high dose rate brachytherapy. There were thus two hundred forty-six patients in the low dose rate group and two hundred thirty-six patients in the high dose rate group. The patients were analyzed for local control, 5 years survival and late radiation morbidity. Stage for stage the local control rates in the low dose rate group and high dose rate group were similar. The overall local control achieved in the low dose rate group was 79.7% as compared to 75.8% in the high dose rate group. The 5 years survival figures in the low dose rate and high dose rate group were also comparable. In Stage I, it was 73% for low dose rate patients and 78% for high dose rate patients, for Stage II it was 62% and 64% respectively and for Stage III patients it was 50% and 43%. The only statistically significant difference was found in the incidence of overall rectal complications which was 19.9% for the low dose rate group as compared to only 6.4% for the high dose rate group. However, the more severe grade 3-4 complications were not significantly different between the two groups (2.4% vs. 0.4%, respectively). The bladder morbidity in both the groups was similar. Thus high dose rate intracavitary brachytherapy is an equally good alternative to conventional low dose rate brachytherapy in the treatment of carcinoma of the uterine cervix.


A case of ovarian endometrial stromal sarcoma: Radiological and histopathological findings.
Endometrial stromal sarcoma (ESS) is an uncommon uterine mesenchymal neoplasm. The primary extra-uterine location of ESS is a very rare occurrence. We present a case of a 39-year-old woman presented with severe abdominal pain, MRI showed bilateral ovarian tumors with heterogeneous intensity on T2-weighted imaging (T2WI) and T1-weighted imaging (T1WI), with restricted diffusion, including hyperintense areas on T1WI, not erased on T1-weighted fat-suppressed imaging, hypointense on T2WI, and not enhanced after contrast. This mass extended to the Douglas and invaded the uterine and the rectum serosa suggesting an underlying endometriosis. No abnormalities were suspected in the endometrium. The exploration revealed a friable mass arising from ovaries associated with nodules in the small intestine and sigmoid. The patient underwent bilateral adnexectomy and the anatomopathological study revealed a low-grade endometrial stromal sarcoma. This is one of the few reports covering the radiological features of low-grade extra-uterine ESS in the ovary which is probably secondary to degeneration of endometriosis with no evidence of primary uterine ESS.


Polymorphisms within the Boule Gene Detected by Tetra-Primer Amplification Refractory Mutation System PCR (T-ARMS-PCR) are Significantly Associated with Goat Litter Size.
As a gene contributing to spermatogenesis, the Boule gene (also called Boll), whose mutations result in azoospermia and sterility of flies and mice, was conserved in reductional maturation divisions. However, in goats, the polymorphisms of Boule, especially with regard to their fundamental roles in female reproduction traits, are still unknown. Therefore, the aims of this study were to detect a potential mutation (rs661484476: g.7254T>C) located in intron 2 of the Boule gene by tetra-primer amplification refractory mutation system PCR (T-ARMS-PCR) and to explore its potential association with the litter size of Shaanbei White-Cashmere goats (SBWGs). In this study, g.7254T>C was firstly detected. The TT genotype was the dominant genotype in the single-lamb group, and T was also the dominant allele in all tested groups. Additionally, the detected locus displayed moderate polymorphism with polymorphism information content (PIC) values among all studied goats ranging from 0.303 to 0.344. Notably, according to the χ2 test, the distribution differences for the genotypic frequencies between the single- and multi-lamb groups was significant (p = 0.014). Furthermore, the polymorphisms of the goat Boule gene were significantly associated with the goat litter size in SBWGs (p < 0.05), which indicated that g.7254T>C could be a potential marker in the marker-assisted selection process for potential litter size in goats. These results also indicated that the Boule gene might exercise important functions in female goat reproduction, which provided new insight for female goat breeding and could accelerate the process of goat breeding.


Periductal mastitis/duct ectasia.
Periductal mastitis/duct ectasia affects major breast ducts and is poorly understood. A variety of different terms have been used for this condition and these probably reflect different stages in one disease process. It appears to be responsible for 1-2% of all symptomatic breast conditions. Although the incidence is higher in postmortem studies, much of what is included as so-called "periductal mastitis" or "duct ectasia" in these studies is duct dilatation, which occurs as part of normal breast involution. Periductal mastitis appears to be the primary condition with duct ectasia being the outcome. The cause of this periductal mastitis is uncertain, although bacteria, particularly anaerobic organisms, appear to play some role. Clinically, this condition can present with noncyclical mastalgia, nipple discharge, nipple retraction, a subareolar breast mass with or without overlying breast inflammation, a periareolar abscess, or a mammillary fistula. Antibiotics effective against the organisms isolated from this condition are effective in resolving periareolar inflammation and are useful when combined with surgery in mammillary fistula.


Designing therapeutic strategies to combat severe acute respiratory syndrome coronavirus-2 disease: COVID-19.
A highly contagious coronavirus disease COVID-19 caused by a recently identified severe acute respiratory syndrome CoV-2 (SARS-CoV-2) initially detected in Wuhan, China has spread worldwide and become a major health crisis in the absence of specific vaccine or antiviral drugs. SARS-CoV-2 infection has resulted in overwhelming number of reported deaths. Unfortunately it is still spreading uncontrollably despite implementing stringent protective measures. Rapid development of effective therapeutic strategies for treatment and prevention of infection is crucially required. Although genomic characterization has assisted in unfolding various aspects of SARS-CoV-2 but development of specific antiviral drugs and vaccine against COVID-19 is still a worldwide challenge. Understanding the disease pathological course underlying the clinical manifestations of COVID-19 is imperative to identify the vital targets for drug development. SARS-CoV-2 uses angiotensin converting enzyme 2 (ACE2) receptor to enter the host cell and primarily target type II alveolar cells. COVID-19 disease progression is associated with distressed immune functions and hyper active inflammatory system leading to development of cytokine storm which is a vital factor involved in disease advancement. The current review elucidates the disease pathology and summarizes the possible therapeutic options to battle against COVID-19 on the basis of current state of understanding about SARS-CoV-2 pathogenic pathways and knowledge gained from previous SARS and MERS-CoV epidemics. Therapeutic strategies to treat and prevent infection as well as to suppress the disease progression to reduce severity and mortality rate is discussed. Drug candidates currently under consideration and undergoing clinical trials for COVID-19 treatment are highlighted.


No acceleration of UV-induced skin carcinogenesis from evenly spread dietary intake of cyclosporine in contrast to oral bolus dosages.
Organ transplant recipients using the immunosuppressant cyclosporine have an increased risk for developing nonmelanoma skin cancer. Disparate effects of cyclosporine have, however, been reported on UV-induced skin carcinogenesis in mouse experiments. Therefore, we set out to compare three experimental protocols using mice, with the aim to emulate most closely the increased skin cancer risk in organ transplant recipients. UV carcinogenesis was performed in hairless SKH-1 mice by three protocols: dietary cyclosporine and daily UV exposures, dietary cyclosporine after a period of UV exposures, and bolus dosing cyclosporine by gavage and repeated UV exposures. Using chronic UV exposure, continuous dietary administration of cyclosporine was shown to inhibit tumor formation. Dietary cyclosporine after a period of UV exposures did not affect ensuing UV carcinogenesis. However, in contrast with dietary cyclosporine, bolus dosages of cyclosporine by gavage, resulting in strongly varying blood levels of cyclosporine, increased tumor development in chronically UV-exposed mice. There was no difference in tumor development between mice UV-irradiated during peak or trough levels of cyclosporine in the blood. Time-averaged levels in these mice were similar to those with cyclosporine in the diet. Cyclosporine in bolus doses appears to increase skin cancer development, whereas cyclosporine administration more evenly spread over time does not. Extrapolation to transplant patients suggests that the mode of administrating cyclosporine may be crucial for the increased skin cancer risk and that this risk might be lowered with a more steady release of cyclosporine in the body.


Niches and size relationships in Coleoptera associated with Cardueae host plants: adaptations to resource gradients.
The ecological meaning of size relationships within guilds is still a matter of debate. We analyzed the niches and size relationships in Coleoptera associated with Cardueae host plants. Species were grouped into guilds using distributional data, host records and feeding strategies: a) The species of the genus Larinus are inhabitants of flower heads within the Cynaroideae. Two types of Larinus species were distinguished: one type attacks immature flower heads, the other exploits the floer heads in a more advanced stage. The females of the first group have elongated rostres adapted to piercing through the bracts of closed flower heads, the other group possesses blunt, short rostres. For an oligophagous group of four Larinus species we are able to show that the distribution of average female rostre length is non-random. b) In southern France four stem boring species of the genera Agapanthia and Lixus coexist within the same hosts. The frequency distributions of body length from these species are clearly overdispersed. c) Coexisting species of the folivorous genus Cassida show no differences in body sizes. We conclude that morphometric differences within the investigated guild of endophytic species (Larinus and Agapanthia/Lixus) evolved in response to size of the used plant structures and the size of potentially competing species, a pattern not evident in ectophytic species. We suggest that these differences are part of a general pattern as the evolution of herbivorous guild may strongly depend on the way how the host resource is exploited (endophagy vs ectophagy). So current differences in statements on the organization of herbivore communities could perhaps be reconciled.


Biogenic silver nanoparticles production and characterization from native stain of Corynebacterium species and its antimicrobial activity.
In the present study, synthesis, characterization, and the antibacterial activity of silver nanoparticles from native isolate of Corynebacterium glutamicum has been reported. Silver nanoparticles were synthesized by challenging the dried biomass of C. glutamicum with aqueous diamine silver ([Ag (NH3)2]+) containing 1 mM AgNO3. Synthesized silver nanoparticles (AgNPs) were characterized by ultraviolet-visible spectroscopy and energy-dispersive X-ray (EDX) spectroscopy analysis. Morphological study of silver nanoparticles was carried out using transmission electron microscopy (TEM) and scanning electron microscope (SEM). The spherical morphology of silver nanoparticles was confirmed from SEM image. The TEM image showed the average particle size of silver nanoparticles was about 15 nm. Silver nanoparticles synthesized from C. glutamicum were found to have enhanced antimicrobial activity against selected pathogenic strains. Silver nanoparticles from pure strains of Corynebacterium species was done by many investigators, but as per the present literature, this is the first report on the production of silver nanoparticles using a native strain of Corynebacterium.


Immunohistochemical Detection of Modified Cytosine Bases in Rodent Brain.
The modified cytosine base 5-hydroxymethylcytosine (5hmC) is abundantly present in the central nervous system (CNS), and visualization of global 5hmC levels is possible through use of immunohistochemistry. In this chapter we describe an adaptable method of brain tissue collection and immunohistochemical staining that allows for detection of 5hmC in mouse or rat brain, meaning that the method can be applied to many rodent models of CNS diseases and disorders.


High-molecular-weight kininogen is cleaved in active erythema multiforme.
Erythema multiforme (EM) is an inflammatory disorder of the skin, which may include mucous membrane involvement, that features target (iris) lesions. Mediators specifically involved in EM are not well characterized; its pathogenesis remains enigmatic. In this study, evidence for participation of kinins in the pathophysiology of inflammation in EM was investigated by assessing cleavage of high-molecular-weight kininogen (HMWK) in plasma. These data were compared with analyses of plasmas from patients with serum sickness, chronic idiopathic urticaria/angioedema, and from normal control subjects. Patients with EM demonstrated significant levels of circulating cleaved HMWK in plasma during active disease (p less than 0.01), which declined during remission/recovery. Plasmas from patients with EM obtained during active disease also demonstrated significant levels of 94 kd C1 inhibitor (p less than 0.01) and C1 inhibitor-kallikrein complexes. Patients with serum sickness and chronic idiopathic urticaria/angioedema did not demonstrate these findings and did not differ from normal control subjects (p = not significant). Although the kininogenase responsible for HMWK cleavage in EM has not been conclusively demonstrated, these findings suggest that HMWK cleavage resulted from activation of the contact system and that some of the manifestations of EM in selected patients may in part be accounted for by inflammatory and proinflammatory actions of kinins. Based on these preliminary findings, it will be important to establish whether or not HMWK cleavage in EM is a general finding in patients with this disorder. Further investigation is needed to characterize more clearly kininogenase activity and elucidate the possible role of kinin generation in EM.


Schwann cell abnormalities in 2,5-hexanedione neuropathy.
Distinctive cytoplasmic alterations of Schwann cells were observed by electron microscopy in rats and mice with peripheral neuropathy induced by chronic exposure to 2,5-hexanedione. Pronounced enlargement of Schwann cells was due to accumulation of 100 angstrom cytoplasmic filaments and endoplasmic reticulum and was most often observed after 12--15 weeks exposure to 2,5-hexanedione. Examination of teased nerve fibres revealed segmental demyelination and remyelination involving axons of normal diameter as well as giant axons. The filament disorder induced by 2,5-hexanedione administration is not limited solely to axoplasmic contents. Possible mechanisms of demyelination are discussed and the changes are compared to those observed in human neuropathy for which 2,5-hexanedione appears to be the closest experimental model.


Mysterious SiB3: Identifying the Relation between α- and β-SiB3.
Binary silicon boride SiB3 has been reported to occur in two forms, as disordered and nonstoichiometric α-SiB3-x , which relates to the α-rhombohedral phase of boron, and as strictly ordered and stoichiometric β-SiB3. Similar to other boron-rich icosahedral solids, these SiB3 phases represent potentially interesting refractory materials. However, their thermal stability, formation conditions, and thermodynamic relation are poorly understood. Here, we map the formation conditions of α-SiB3-x and β-SiB3 and analyze their relative thermodynamic stabilities. α-SiB3-x is metastable (with respect to β-SiB3 and Si), and its formation is kinetically driven. Pure polycrystalline bulk samples may be obtained within hours when heating stoichiometric mixtures of elemental silicon and boron at temperatures 1200-1300 °C. At the same time, α-SiB3-x decomposes into SiB6 and Si, and optimum time-temperature synthesis conditions represent a trade-off between rates of formation and decomposition. The formation of stable β-SiB3 was observed after prolonged treatment (days to weeks) of elemental mixtures with ratios Si/B = 1:1-1:4 at temperatures 1175-1200 °C. The application of high pressures greatly improves the kinetics of SiB3 formation and allows decoupling of SiB3 formation from decomposition. Quantitative formation of β-SiB3 was seen at 1100 °C for samples pressurized to 5.5-8 GPa. β-SiB3 decomposes peritectoidally at temperatures between 1250 and 1300 °C. The highly ordered nature of β-SiB3 is reflected in its Raman spectrum, which features narrow and distinct lines. In contrast, the Raman spectrum of α-SiB3-x is characterized by broad bands, which show a clear relation to the vibrational modes of isostructural, ordered B6P. The detailed composition and structural properties of disordered α-SiB3-x were ascertained by a combination of single-crystal X-ray diffraction and 29Si magic angle spinning NMR experiments. Notably, the compositions of polycrystalline bulk samples (obtained at T ≤ 1200 °C) and single crystal samples (obtained from Si-rich molten Si-B mixtures at T > 1400 °C) are different, SiB2.93(7) and SiB2.64(2), respectively. The incorporation of Si in the polar position of B12 icosahedra results in highly strained cluster units. This disorder feature was accounted for in the refined crystal structure model by splitting the polar position into three sites. The electron-precise composition of α-SiB3-x is SiB2.5 and corresponds to the incorporation of, on average, two Si atoms in each B12 icosahedron. Accordingly, α-SiB3-x constitutes a mixture of B10Si2 and B11Si clusters. The structural and phase stability of α-SiB3-x were explored using a first-principles cluster expansion. The most stable composition at 0 K is SiB2.5, which however is unstable with respect to the decomposition β-SiB3 + Si. Modeling of the configurational and vibrational entropies suggests that α-SiB3-x only becomes more stable than β-SiB3 at temperatures above its decomposition into SiB6 and Si. Hence, we conclude that α-SiB3-x is metastable at all temperatures. Density functional theory electronic structure calculations yield band gaps of similar size for electron-precise α-SiB2.5 and β-SiB3, whereas α-SiB3 represents a p-type conductor.


Meningiomas of the lateral ventricles. Clinical, neuroradiologic, and surgical considerations in 19 cases.
The clinical and neuroradiologic findings and surgical results in a series of 19 patients with lateral ventricle meningioma, operated on during a 33-year period, are described. This experience is compared with that of previous workers and the following conclusions are drawn: these tumors have no characteristic symptoms; preoperative diagnosis requires both computed tomography scans and carotid and vertebral angiography; the safest surgical approach is through a sagittal or oblique parietooccipital cortical incision to avoid damage to motor, visual, and speech areas of the cortex.


Effect of dosage regimen on the development of tolerance to nitroglycerin in rats.
The recent introduction of several sustained delivery systems of nitroglycerin (NTG) raises the question whether the mode of drug input (e.g., sustained versus intermittent) may be a critical determinant in the development of nitrate tolerance. This hypothesis was tested in an animal model. Sixty male Sprague-Dawley rats (weighing 240-260 g) were administered a total intravenous dose of 2.5 mg NTG either as a continuous 6-h infusion (6.8 micrograms/min) or as six hourly pulse injections of 425 micrograms each. Animals were sacrificed 5 min following the termination of the infusion and 65 min following the last injection. A blood sample was taken from a central vein for plasma NTG determination, and the aorta and portal vein were isolated. Dose-response curves to NTG were determined on some of these blood vessels and on controls using an isolated tissue bath apparatus. Other blood vessels were incubated with 94 ng [14C]NTG for 60 min, and the incorporation of [14C]NTG into these tissues was determined after thin-layer chromatographic separation of NTG from its metabolites. There was no difference between the plasma NTG concentration measured at the time of sacrifice following either regimen. For the artery preparation, there was also no difference in the dose response to NTG or in the incorporation of [14C]NTG into the blood vessel from rats treated by either regimen. For the portal vein preparation, however, rats treated by continuous infusion had a similar sensitivity to NTG as controls, but there was a marked downward shift in the dose response to NTG in the veins of rats treated by the intermittent regimen.(ABSTRACT TRUNCATED AT 250 WORDS)


Modular Classification of Endoscopic Endonasal Transsphenoidal Approaches to Sellar Region: Anatomic Quantitative Study.
Endoscopic visualization does not necessarily correspond to an adequate working space. The need for balancing invasiveness and adequacy of sellar tumor exposure has recently led to the description of multiple endoscopic endonasal transsphenoidal approaches. Comparative anatomic data on these variants are lacking. We sought to quantitatively compare endoscopic endonasal transsphenoidal approaches to the sella and parasellar region, using the concept of "surgical pyramid." Four endoscopic transsphenoidal approaches were performed in 10 injected specimens: 1) hemisphenoidotomy; 2) transrostral; 3) extended transrostral (with superior turbinectomy); and 4) extended transrostral with posterior ethmoidectomy. ApproachViewer software (part of GTx-Eyes II, University Health Network, Toronto, Canada) with a dedicated navigation system was used to quantify the surgical pyramid volume, as well as exposure of sellar and parasellar areas. Statistical analyses were performed with Friedman's tests and Nemenyi's procedure. Hemisphenoidotomy provided limited exposure of the sellar area and a small working volume. A transrostral approach was necessary to expose the entire sella. Exposure of lateral parasellar areas required superior turbinectomy or posterior ethmoidectomy. The differences between each of the modules was statistically significant. The present study validates, from an anatomic point of view, a modular classification of endoscopic endonasal transsphenoidal approaches to the sellar region.


Pharmacovigilance Agreements: Negotiating Safety Data Exchange Timelines: To Agree to Disagree? That is the Question.
Pharmaceutical companies often enter into contractual arrangements with other companies to advance the development or expand patient access of licensed medicines. These partnerships include specific agreements detailing the exchange of safety-related data between the companies. Such agreements are used to fulfil regulatory reporting obligations, thereby ensuring timely awareness of potential safety considerations and formal maintenance of clinical trial applications and marketing authorisations. The authors conducted potentially the first benchmarking survey of contracts covering safety data exchange within the pharmaceutical industry. Data were analysed to establish the most common types of safety data exchanged, and the associated data exchange timelines. These data may provide an opportunity for companies to assess how their own timelines compare with others, and to consider whether there are actions they may take that could potentially improve negotiation and procedural efficiency. Ninety percent of the recipients responded to the survey, providing information from 378 individual contracts which included data from clinical trials and from postmarketing sources. Results showed less variability in the safety data exchange timelines of clinical trial ICSRs compared to the timelines of postmarketing ICSRs; these results may reflect greater harmonisation of regulatory reporting requirements for clinical trials. The variability captured in the benchmarking data reflects the challenges that contribute to the complexity of safety data exchange agreements between partner companies. The goal of the survey was to serve as a basis for future research and pursuit of additional insights that foster transparency. The aim was also to encourage the consideration of alternative approaches to address some of the challenges that we identified. Use of technology could facilitate the process of recording, tracking, and monitoring of safety data exchange within a partnership, improve efficiency through real time monitoring, and provide further insights. A proactive approach to developing agreements is essential for improved patient access and to maintain patient safety.


An Echocardiographic Study of Left Ventricular Size and Cardiac Function in Adolescent Females with Anorexia Nervosa.
This retrospective case-control study investigated cardiac dimensions and ventricular function in female adolescents with anorexia nervosa (AN) compared with controls. Echocardiographic measurements of left ventricular (LV) dimensions, LV mass index, left atrial size and cardiac index were made. Detailed measures of systolic and diastolic ventricular function were made including tissue Doppler imaging. Patients were stratified by body mass index ≤10th percentile (AN ≤ 10th) and >10th percentile (AN > 10th). Ninety-five AN patients and 58 controls were included. AN and AN ≤ 10th groups had reduced LV dimensions, LV mass index, left atrial size and cardiac index compared with controls. There were no differences between groups in measures of systolic function. Measures of diastolic tissue Doppler imaging were decreased in AN and AN ≤ 10th. No differences in echocardiographic measurements existed between controls and AN > 10th. Female adolescents with AN have preserved systolic function and abnormalities of diastolic ventricular function. AN ≤ 10th may be a higher risk group.


Coexistent minocycline-induced systemic lupus erythematosus and autoimmune hepatitis.
This study was performed to raise awareness among rheumatologists about two autoimmune disorders associated with long-term minocycline therapy that can coexist in the same patient. We provide an update on the occurrence of these disorders, their main characteristics, and the current knowledge of potential pathogenic mechanisms. We searched the medical literature in English indexed in MEDLINE from 1966 through April 1998 for the term minocycline combined with each of the following: autoimmune hepatitis (AIH), chronic hepatitis, lupus, systemic lupus erythematosus (SLE), anti-myeloperoxidase (anti-MPO), arthritis, vasculitis, and toxicity. We also reviewed relevant references cited in the articles our search uncovered. We identified over 60 minocycline-induced cases of SLE and 24 cases of minocycline-induced AIH. Both autoimmune disorders coexisted in the same patient in 12 cases reported in the literature and in one case seen at our clinic. These 13 patients were characterized by symmetrical polyarthralgias/polyarthritis, elevated liver enzymes, and positive antinuclear antibodies (ANA); they also were generally anti-histone-negative, and only two patients had perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA). After withdrawal of minocycline, their symptoms resolved, and abnormal laboratory results normalized or markedly improved. Although data on the actual prevalence of autoimmune disorders induced by minocycline are not available, numerous case reports or small series deal with such disorders. Probable pathogenic mechanisms for each of these conditions are discussed.


Postnatal growth in children born small for gestational age with and without smoking mother.
Maternal smoking impairs fetal growth; however, if postnatal growth differs between children born small for gestational age (SGA) with smoking and non-smoking mother is unknown. Cohort-study of term born children born appropriate for gestational age with non-smoking mother (AGA-NS, n = 30,561), SGA (birthweight <10th percentile) with smoking mother (SGA-S, n = 171) or SGA with non-smoking mother (SGA-NS, n = 1761). Means of height and weight measurements, collected at birth, 1.5, 3, 4, and 5 years, were compared using a generalized linear mixed effect model. Relative risks of short stature (<10th percentile) were expressed as adjusted risk ratios (aRR). At birth, children born SGA-S were shorter than SGA-NS, but they did not differ in weight. At 1.5 years, SGA-S had reached the same height as SGA-NS. At 5 years, SGA-S were 1.1 cm taller and 1.2 kg heavier than SGA-NS. Compared with AGA-NS, SGA-S did not have increased risk of short stature at 1.5 or 5 years, while SGA-NS had increased risk of short stature at both ages; aRRs 3.0 (95% CI 2.6;3.4) and 2.3 (95% CI 2.0;2.7), respectively. Children born SGA-S have a more rapid catch-up growth than SGA-NS. This may have consequences for metabolic and cardiovascular health in children with smoking mothers.


3D Printing Technology in Pediatric Orthopedics: a Primer for the Clinician.
This article reviews the basics of 3D printing and provides an overview of current and future applications of this emerging technology in pediatric orthopedic surgery. Both preoperative and intraoperative utilization of 3D printing technology have enhanced clinical care. Potential benefits include more accurate surgical planning, shortening of a surgical learning curve, decrease in intraoperative blood loss, less operative time, and fluoroscopic time. Furthermore, patient-specific instrumentation can be used to improve the safety and accuracy of surgical care. Patient-physician communication can also benefit from 3D printing technology. 3D printing is rapidly advancing in the field of pediatric orthopedic surgery. It has the potential to increase the value of several pediatric orthopedic procedures by enhancing safety and accuracy while saving time. Future efforts in cost reduction strategies, making patient-specific implants including biologic substitutes and scaffolds, will further increase the relevance of 3D technology in the field of pediatric orthopedic surgery.


Single-item migraine screening tests, self-reported bothersome headache or stripe pattern hypersensitivity?
A simple screening tool may potentially help the migraine diagnosis in a primary care setting. The use of single-item tests, such as stripe pattern hypersensitivity test and self-reported bothersome headache (HA) question, as migraine screening tools have not been fully explored. Two hundred and fifty-four subjects (patients and companions) were randomly enrolled from an OB/GYN clinic (men 82, women 172; age 38 ± 14). They were instructed to rate the stripe sensitivity level (0-4) and to report any bothersome HA (yes/no). A brief structured HA interview was conducted to describe the HA characteristics and for migraine diagnosis based on the ICHD-IIIβ criteria. In a multivariate model, bothersome HA question and stripe pattern hypersensitivity test were both significantly associated with EM+PM+CM (odds ratio: 24.0, P < 0.01 vs 2.6, P = 0.01) or EM (odds ratio: 16.2, P < 0.01 vs 3.0, P < 0.01). Bothersome HA question had a greater screening power than stripe pattern hypersensitivity for screening EM+PM+CM (area under the ROC curve: 0.84 [95% CI 0.78-0.89] vs 0.62 [95% CI 0.55-0.69]) or EM (area under the ROC curve: 0.80 [95% CI 0.73-0.86] vs 0.64 [95% CI 0.56-0.72]). When performed in an OB/GYN clinic, self-reported bothersome HA question seemed more powerful than visual stripe pattern test in screening migraine thus could potentially be used as a single-item screening test.


Proposed symptom-based model of the origins of schizophrenia.
Schizophrenia is considered a severe mental illness and effects an estimated 1% of the world population. The evidence suggests that incidence rate has been and will continue to be stable over time. Here we adopt a symptomatology-focused evolutionary informed approach to discuss the possible biological adaptations of various presentations of schizophrenia. It is our contention that rather than thinking about schizophrenia as a single disorder, or even a spectrum of disorders, marked by social maladaptation and personal subjective distress, that an evolutionary interpretation based on adaptive nature of individual, or small clusters of, symptoms could prove to be more useful in better understanding the pathophysiology of schizophrenia and its relationship with other psychiatric diagnoses.


Developmental validation of the PowerPlex® Y23 System: a single multiplex Y-STR analysis system for casework and database samples.
The PowerPlex® Y23 System combines the seventeen Y-STR loci in current commercially available Y-STR kits (DYS19, DYS385a/b, DYS389I/II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635, and Y-GATA-H4) with six new highly discriminating Y-STR loci (DYS481, DYS533, DYS549, DYS570, DYS576, and DYS643). These six new loci have higher gene diversities than most of the loci in other commercial Y-STR analysis kits, allowing for further distinction between unrelated male individuals. In addition, the inclusion of two rapidly mutating Y-STR loci may allow for the discrimination of related individuals. The PowerPlex® Y23 System is designed to amplify DNA from purified extracts as well as direct amplification from substrates used to collect database samples (e.g. swabs and storage cards). Validation of the PowerPlex® Y23 System includes all of the studies required by the FBI and SWGDAM. The results demonstrate that the PowerPlex® Y23 System is a robust and reliable amplification kit capable of overcoming high concentrations of commonly encountered inhibitors such as hematin, humic acid, and tannic acid. Full profiles are consistently detected with 62.5 pg of male DNA, even in the presence of excessive amounts of female DNA, establishing the PowerPlex(®) Y23 System as a sensitive method for Y-STR testing. Complete Y-STR profiles are detected from mixed samples with 62.5 pg of male DNA in a background of 400 ng of female DNA or 125 pg of male DNA mixed with 3000 ng of female DNA.


Distribution of substance P and enkephalin-like immunoreactivity in the substantia nigra of rat, cat and monkey.
A comparative study of the distribution of substance P (SP) and enkephalin (ENK) immunoreactivity in the substantia nigra (SN) of the rat, cat and squirrel monkey (Saimiri sciureus) was undertaken by means of the indirect immunofluorescence technique. In the rat a dense neuronal network composed of fine fibers displaying SP immunoreactivity is uniformely distributed throughout the rostrocaudal extent of the substantia nigra pars reticulata (SNr) and in the ventral part of substantia nigra pars compacta (SNc). Some coarse SP-positive fibers also occur in SNc. In addition, ENK-immunoreactive fibers are scattered amongst SNc neurons but abound particularly in the caudolateral part of SNr. In cat innumerable fine SP-positive fibers are distributed in SNr according to a pattern similar to that found in rat. ENK-immunoreactive fine fibers are densely packed in the ventromedial part of SNr whereas coarse ENK fibers are scattered in both SNc and SNr but abound particularly in the caudolateral portion of SNr. In monkey fine SP and ENK-immunoreactive fibers occur in very large number in SNr. These two types of fibers are distributed according to a similar but strikingly complex and heterogeneous pattern. In addition, coarse fibers displaying either SP or ENK immunoreactivity are scattered amongst the SNc neurons in monkey. These findings reveal that SP immunoreactive fibers are present in large number and are distributed according to a somewhat similar pattern in rat, cat and monkey. In contrast, the number of ENK-positive fibers and the complexity of their organizational feature in SN increase strikingly from rodent to primate.


Circadian rhythms of RNA, DNA and protein in the rat thyroid, adrenal and testis in chronic pesticide exposure. III. Effects of the insecticides (dichlorvos and trichlorphon).
Chronic exposure of the rats to Trichlorphon (10 ppm/day, over a time span of 90 days) leads to marked changes in the time structure of the thyroid and the adrenal, e.g. the loss of the circadian rhythms as a group phenomenon in thyroid DNA and protein and adrenal RNA content, phase alterations in thyroid RNA and adrenal DNA rhythms, marked decrease in amplitude of the adrenal DNA and protein rhythms. Ninety days of exposure to Dichlorvos (5 ppm/day) leads to phase alterations, without a change in the time-qualified mean (mesor), of the circadian rhythms in DNA, RNA and protein content and marked decrease in amplitude of the DNA rhythm, in the thyroid and the adrenal. In the testis, there is no alterations of the rhythms studied. The phase alterations encountered in this study are different in extent and also in direction, between and within the organs, indicating an external and internal desynchronization of metabolic and cell proliferative functions. The variability of the acrophases obtained by the separate analysis of each of the three days of study may suggest free-running rhythms.


Soluble epoxide hydrolase deficiency ameliorates acute pancreatitis in mice.
Acute pancreatitis (AP) is a frequent gastrointestinal disorder that causes significant morbidity and its incidence has been progressively increasing. AP starts as a local inflammation in the pancreas that often leads to systemic inflammatory response and complications. Soluble epoxide hydrolase (sEH) is a cytosolic enzyme whose inhibition in murine models has beneficial effects in inflammatory diseases, but its significance in AP remains unexplored. To investigate whether sEH may have a causal role in AP we utilized sEH knockout (KO) mice to determine the effects of sEH deficiency on ceruelin- and arginine-induced AP. sEH expression increased at the protein and messenger RNA levels, as well as sEH activity in the early phase of cerulein- and arginine-induced AP in mice. In addition, amylase and lipase levels were lower in cerulein-treated sEH KO mice compared with non-treated controls. Moreover, pancreatic mRNA and serum concentrations of the inflammatory cytokines IL-1ß and IL-6 were lower in sEH KO mice compared with controls. Further, sEH KO mice exhibited decreased cerulein- and arginine-induced NF-?B inflammatory response, MAPKs activation and decreased cell death. These findings demonstrate a novel role for sEH in the progression of cerulein- and arginine-induced AP.


A review of psychologically oriented treatment of alcoholism. II. The relative effectiveness of different treatment approaches and the effectiveness of treatment versus no treatment.
A review of 384 studies of psychologically oriented alcoholism treatment showed that differences in treatment methods did not significantly affect long-term outcome. Mean abstinence rates did not differ between treated and untreated alcoholics, but more treated than nontreated alcoholics improved, suggesting that formal treatment at least increases an alcoholic's chances of reducing his drinking problem.


Recruitment to doping and help-seeking behavior of eight female AAS users.
Doping with anabolic androgenic steroids in sports has now developed to a widespread use of these agents among young people outside the sport. This is of major concern to the society. The purpose of the use is mainly for aesthetic reasons and is seen as a male phenomenon. But use also occurs in women where the knowledge is scarce. Our aim was to identify the pattern of doping agents in eight female cases and compare them with similar data from men. Eight female users were recruited through Anti-Doping Hot-Line, a national telephone counseling service on doping issues during the years 1998-2004. The use was confirmed with urine doping analysis at the Doping Laboratory. The characteristic of use, co-use of narcotics/other doping agents, exercise pattern, adverse-side effects, family history and reason to begin was evaluated. The women used on average 1.9 different anabolic androgenic steroids and clenbuterol preparations. Ephedrine and growth hormone were co-used in five and one of the women, respectively. Three women reported co-use of narcotics (cannabis and cocaine). The average duration of anabolic agent use before contacting health care was 58 weeks (range 7-104). Side effects for anabolic androgenic steroids (n = 5) included voice changes, clitoral enlargement, body hair growth, whereas women using clenbuterol (n = 2) reported tachycardia and depression. All women except one had a man in close relationship encouraging them to begin with the doping agents. The use of doping agents in our eight women was different from that in male users. The women used less doping agents and were more prone to contact the health care, at an earlier stage, probably due to the adverse effects. The co-use with ephedrine, growth hormone and cannabis appeared to be in the same range as in men. This is the first study showing that a man in close relationship may motivate a woman to use anabolic agents.


Multidimensional profiling indicates the shifts and functionality of wheat-origin microbiota during high-temperature Daqu incubation.
Wheat-origin microbiota is a critical factor in the assembly of the microbial community during high-temperature Daqu incubation. However, the succession and functional mechanisms of these microbial communities in Daqu are still unclear. This study investigated the shifts in microbiota diversity from the wheat to the end of incubation by the third generation Pacific Biosciences (PacBio) single-molecule, real-time (SMRT) sequencing technology. Results indicated that Staphylococcus, Pantoea, Alternaria, and Mycosphaerella were the dominant genera of wheat-origin microbiota while Bacillus and Thermoascus were the most predominant bacterial and fungal genera of Daqu microbiota, respectively. Metabolite detection revealed that volatile organic compounds (VOCs) changed obviously in different incubation stages and the 7th day to the 15th day of incubation was the critical period for the formation of VOCs. The content of non-VOCs, especially sugars, increased steeply in the first four days of incubation. The network analysis between microbes and metabolites showed that Thermoactinomyces and Staphylococcus had opposite correlations with most non-VOCs. Alternaria and Mycosphaerella had strong positive correlations with fructose. As key functional fungal genera in wheat-origin microbiota, Mycosphaerella, Aspergillus, and Alternaria participated in multiple metabolic pathways (gluconeogenesis I, sucrose degradation III, pentose phosphate pathway, 5-aminoimidazole ribonucleotide biosynthesis I, methyl ketone biosynthesis, and GDP-mannose biosynthesis) at the early stage of incubation, which played an important role in the formation of flavors and succession of microbiota. This work highlighted the shifts and functionality of wheat-origin microbiota in Daqu incubation, which can be a guideline to stabilize Daqu quality by wheat-origin microbiota control.


An improved RT-IPCR for detection of pyrene and related polycyclic aromatic hydrocarbons.
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous homogeneous chemicals which are well known by carcinogens, mutagens and endocrine disorder. Here, an improved real-time immuno-PCR (RT-IPCR) was developed for detection of pyrene and its homologs in water samples. The PAHs in sample compete with pyrene-modified DNA to bind with monoclonal antibody (McAb) coated on PCR plate. The reporter DNA was exponentially amplified by real-time PCR instrument using Fast Start universal SYBR Green Master (ROX) kit. Only two reaction steps were needed to accomplish the detection. The assay had a good linear range from 5 pmol L(-1) to 5 nmol L(-1) with a detection limit of 3.5 pmol L(-1). For application assay, the average recoveries from tap water, lake water and mineral water were 98.4%, 98.2% and 99.7%, respectively which showed a good correlation (R(2)=0.9906) with those from GC-MS. The results indicated that the improved RT-IPCR seems to be a potential method for simple and ultrasensitive detection of pyrene and some homologues in environment water samples.


Discrimination of glioma patient-derived cells from healthy astrocytes by exploiting Raman spectroscopy.
Glioblastoma multiforme (GBM) is one of the most common and aggressive brain tumors. It presents a very bad prognosis with a patients' overall survival of 12-15 months; treatment failure is mainly ascribable to tumor recurrence. The development of new tools, that could help the precise detection of the tumor border, is thus an urgent need. During the last decades, different vibrational spectroscopy techniques have been developed to distinguish cancer tissue from heathy tissue; in the present work, we compared GBM cells deriving from four patients with healthy human astrocytes using Raman spectroscopy. We have shown that the region between 1000 and 1300 cm-1 is enough informative for this discrimination, indeed highlighting that peaks related to DNA/RNA and cytochrome c are increased in cancer cells. Finally, our model has been able to discriminate cancer cells from healthy cells with an average accuracy of 92.5%. We believe that this study might help to further understand which are the essential Raman peaks exploitable in the detection of cancer cells, with important perspectives under a diagnostic point of view.


L-carnitine and neuroprotection in the animal model of mitochondrial dysfunction.
We have shown previously that pretreatment with l-carnitine (LC) prior to 3-nitropropionic acid (3-NPA) exposure, while not significantly attenuating succinate dehydrogenase (SDH) inhibition, prevented hypothermia and oxidative stress. The plant and fungal toxin, 3-NPA, acts as an inhibitor of mitochondrial function via irreversible inactivation of the mitochondrial inner membrane enzyme, SDH. Inhibition of SDH disturbs electron transport, leading to cellular energy deficits and oxidative stress-related neuronal injury. In the study presented here, a neurohistological method was applied to examine the mitochondriotropic effect of LC pretreatment against 3-NPA-induced neurotoxicity. Twenty adult male Sprague-Dawley rats randomly divided into two groups (n = 10/group) were injected twice with 3-NPA at 30 mg/kg sc, at 2 days apart, or received LC pretreatment at 100 mg/kg, at 30-40 min before 3-NPA administration. Rats in both groups were perfused 7 days later and their brains harvested. Degenerating neurons were identified and localized via the fluorescent marker Fluoro-Jade B. Data analysis showed that LC was protective against 3-NPA-induced toxicity, as reflected by both reduced mortality and significantly reduced neuronal degeneration.


A Rasch-based validity study of the Harvard Trauma Questionnaire.
The Harvard Trauma Questionnaire (HTQ) is the predominant questionnaire for assessing PTSD in trauma-affected refugees. Although the scale is increasingly used for measuring treatment outcomes, it has never been specifically validated for such use. The current study does so by testing the HTQ with the Rasch model. The analysis is based on 641 Arabic and Persian speaking refugees, diagnosed with PTSD and undergoing psychiatric treatment in Denmark. The responses were tested against the assumptions of the Rasch model, including unidimensionality, local independence and the absence of differential item function across subgroups. Results reveal two subscales that, when accounting for local dependence and differential item functioning, meet criteria for the Rasch model in the included samples: An arousal/intrusion subscale and an avoidance/numbing subscale. The included sample was highly chronic and suffered from major depressive disorder. Results may not be fully representative of less chronic populations, e.g. recently arrived refugees. We recommend the use of the arousal/intrusion subscale and the avoidance/numbing subscale as an optimized way of summarizing responses to the HTQ, which remains simple to administer while effectively summarizing all the information available in the scores.


Ethylene glycol intoxication: evaluation of kinetics and crystalluria.
Ethylene glycol and glycolate kinetics were studied in two cases of ethylene glycol intoxication with maximal ethylene glycol/glycolate concentrations of 40.9/26.8 and 56.4/22.4 mmol/liter, respectively. Both patients survived, but with prolonged renal failure, upon treatment with bicarbonate, ethanol, and hemodialysis. Glycolic acid was the major cause of the metabolic acidosis in both cases; lactate levels were only slightly elevated. Kinetic calculations showed that both ethylene glycol and glycolate were distributed in total body water with plasma half-lives of 8.4 and 7.0 hours, respectively. The half-life of ethylene glycol was increased more than 10-fold by ethanol treatment alone. Calcium oxalate monohydrate crystalluria was dominant in both cases, but in one was preceded by a short period with mainly dihydrate excretion; crystalluria was not present upon admission. Repetitive urine microscopy in search of needle- or envelope-shaped crystals should be performed when ethylene glycol intoxication is suspected.


Ultrasensitive detection of clenbuterol by a covalent imprinted polymer as a biomimetic antibody.
As an ideal biomimetic antibody, molecularly imprinted polymer (MIP) has shown great promise in immunoassays. Here, we developed a covalent imprinting method to prepare MIP artificial antibody towards clenbuterol on the well surface of a microtiter plate. Template molecule (clenbuterol) was splited by hydrolysis with functional monomer and removed by methanol/acetic acid solution, and then three-dimensional cavities were fabricated in the MIP, which can rebind template molecule via hydrogen bond interaction. Using this artificial antibody, we developed a novel biomimetic enzyme-linked immunosorbent assay (ELISA) with excellent sensitivity and specificity. The linear range for clenbuterol was 10-5 to 1000μgL-1, with a detection limit of 10-7μgL-1. Cross reactivity of this MIP artificial antibody to other four structural analogs was less than 0.93%. This method was applied to determine clenbuterol in real samples with satisfactory result, suggesting a promising application of the biomimetic ELISA in food and environmental analysis.