Individual variation in response to thiopentone.
The purpose of this study was twofold. The first one was to quantify differences in dose requirements for thiopentone in different patient groups and the second one was to point out and elucidate possible explanations for the observed differences. Pharmacodynamic aspects were studied by comparisons of doses and serum concentrations associated with the achievement of obtundance of the eyelash reflex. Also the effect of thiopentone on cardiovascular system was studied in vivo and in vitro. For the study of the in vitro effect rings of the rabbit pulmonary artery were used in vivo the cardiac effect of thiopentone was assessed by impedance cardiography. Classical compartmental analysis of serum concentration/time relationship after administration of anaesthetic doses of thiopentone was performed to establish comparable pharmacokinetic data. Furthermore unbound and protein-bound levels of thiopentone were measured and assessed. The analysis of thiopentone was based on high pressure liquid chromatography and separation between bound and unbound drug was done by ultrafiltration as well as equilibrium dialysis. The binding of thiopentone in human serum and in a physiological saline solution (PSS) with 45 g albumin per litre was 85% and remarkably constant over the concentration range between 4 and 80 micrograms/ml. At lower drug concentration the binding increases and was 87% at 0.4 micrograms/ml. The increase was more pronounced at pH 6 and 6.8 than at pH 7.4 while no increase was observed at pH 9.0. The percentage binding increases with increasing pH from approximate 75% at pH 6.0 to a maximum value of 95% at pH 9.0. This increase in binding with increasing pH might be explained by the simultaneous transition of N-albumin to B-albumin. The albumin binding was at a higher level after reduction of the temperature from 37 degrees C to 2 degrees C. The partition coefficient between olivaoil and PSS also showed an increase by this change in temperature. The very moderate changes in binding over long ranges of drug concentration made it difficult to obtain reliable expressions for thermodynamic parameters which could characterize the nature of the binding. It was suggested that the nature of the protein binding could be characterized best as a solution of the drug in hydrophobic areas of the albumin molecule. The average percentual binding on serum has been shown reduced in patients with deteriorated kidney and liver function and also in elderly subjects, in pregnant women and in newborns. The reduced binding may explain the increased values for total body clearance and for volumes of distribution found in patients with kidney failure.(ABSTRACT TRUNCATED AT 400 WORDS)


The art of the children of Terezin. A psychological study.
This study is an analysis of the content and symbolism inherent in the art of children who were imprisoned in the Terezin Concentration Camp during the Holocaust. Its purpose is to attempt to understand how they perceived and sought to cope with the conditions of their lives at the camp, and to assess the degree of psychic damage suffered by them. The major themes are food, family and freedom, intense feelings of claustrophobia, a sense of the fragility of one's physical existence and the lack of human value of the camp inmates. Impressive is the absence of evidence of serious mental illness and aggression. It may be inferred that these manifestations did not have survival value.


Erythropoietin activates SIRT1 to protect human cardiomyocytes against doxorubicin-induced mitochondrial dysfunction and toxicity.
The hormone erythropoietin (EPO) has been demonstrated to protect against chemotherapy drug doxorubicin (DOX)-induced cardiotoxicity, but the underlying mechanism remains obscure. We hypothesized that silent mating type information regulation 2 homolog 1 (SIRT1), an NAD+-dependent protein deacetylase that activates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), plays a crucial role in regulating mitochondrial function and mediating the beneficial effect of EPO. Our study in human cardiomyocyte AC16 cells showed that DOX-induced cytotoxicity and mitochondrial dysfunction, as manifested by decreased mitochondrial DNA (mtDNA) copy number, mitochondrial membrane potential, and increased mitochondrial superoxide accumulation, can be mitigated by EPO pretreatment. EPO was found to upregulate SIRT1 activity and protein expression to reverse DOX-induced acetylation of PGC-1α and suppression of a suite of PGC-1α-activated genes involved in mitochondrial function and biogenesis, such as nuclear respiratory factor-1 (NRF1), mitochondrial transcription factor A (TFAM), citrate synthase (CS), superoxide dismutase 2 (SOD2), cytochrome c oxidase IV (COXIV), and voltage-dependent anion channel (VDAC). Silencing of SIRT1 via small RNA interference sensitized AC16 cells to DOX-induced cytotoxicity and reduction in mtDNA copy number. Although with SIRT1 silenced, EPO could reverse to some extent DOX-induced mitochondrial superoxide accumulation, loss of mitochondrial membrane potential and ATP depletion, it failed to normalize protein expression of PGC-1α and its downstream genes. Taken together, our results indicated that EPO may activate SIRT1 to enhance mitochondrial function and protect against DOX-induced cardiotoxicity.


Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer.
Induction chemotherapy (IC) before radiotherapy lowers distant failure (DF) rates in locally advanced squamous cell carcinoma of the head and neck (SCCHN). The goal of this phase III trial was to determine whether IC before chemoradiotherapy (CRT) further improves survival compared with CRT alone in patients with N2 or N3 disease. Treatment-naive patients with nonmetastatic N2 or N3 SCCHN were randomly assigned to CRT alone (CRT arm; docetaxel, fluorouracil, and hydroxyurea plus radiotherapy 0.15 Gy twice per day every other week) versus two 21-day cycles of IC (docetaxel 75 mg/m(2) on day 1, cisplatin 75 mg/m(2) on day 1, and fluorouracil 750 mg/m(2) on days 1 to 5) followed by the same CRT regimen (IC + CRT arm). The primary end point was overall survival (OS). Secondary end points included DF-free survival, failure pattern, and recurrence-free survival (RFS). A total of 285 patients were randomly assigned. The most common grade 3 to 4 toxicities during IC were febrile neutropenia (11%) and mucositis (9%); during CRT (both arms combined), they were mucositis (49%), dermatitis (21%), and leukopenia (18%). Serious adverse events were more common in the IC arm (47% v 28%; P = .002). With a minimum follow-up of 30 months, there were no statistically significant differences in OS (hazard ratio, 0.91; 95% CI, 0.59 to 1.41), RFS, or DF-free survival. IC did not translate into improved OS compared with CRT alone. However, the study was underpowered because it did not meet the planned accrual target, and OS was higher than predicted in both arms. IC cannot be recommended routinely in patients with N2 or N3 locally advanced SCCHN.


A systematic review of healthcare applications for smartphones.
Advanced mobile communications and portable computation are now combined in handheld devices called "smartphones", which are also capable of running third-party software. The number of smartphone users is growing rapidly, including among healthcare professionals. The purpose of this study was to classify smartphone-based healthcare technologies as discussed in academic literature according to their functionalities, and summarize articles in each category. In April 2011, MEDLINE was searched to identify articles that discussed the design, development, evaluation, or use of smartphone-based software for healthcare professionals, medical or nursing students, or patients. A total of 55 articles discussing 83 applications were selected for this study from 2,894 articles initially obtained from the MEDLINE searches. A total of 83 applications were documented: 57 applications for healthcare professionals focusing on disease diagnosis (21), drug reference (6), medical calculators (8), literature search (6), clinical communication (3), Hospital Information System (HIS) client applications (4), medical training (2) and general healthcare applications (7); 11 applications for medical or nursing students focusing on medical education; and 15 applications for patients focusing on disease management with chronic illness (6), ENT-related (4), fall-related (3), and two other conditions (2). The disease diagnosis, drug reference, and medical calculator applications were reported as most useful by healthcare professionals and medical or nursing students. Many medical applications for smartphones have been developed and widely used by health professionals and patients. The use of smartphones is getting more attention in healthcare day by day. Medical applications make smartphones useful tools in the practice of evidence-based medicine at the point of care, in addition to their use in mobile clinical communication. Also, smartphones can play a very important role in patient education, disease self-management, and remote monitoring of patients.


Cardiac Potassium Channels: Physiological Insights for Targeted Therapy.
The development of novel drugs specifically directed at the ion channels underlying particular features of cardiac action potential (AP) initiation, recovery, and refractoriness would contribute to an optimized approach to antiarrhythmic therapy that minimizes potential cardiac and extracardiac toxicity. Of these, K+ channels contribute numerous and diverse currents with specific actions on different phases in the time course of AP repolarization. These features and their site-specific distribution make particular K+ channel types attractive therapeutic targets for the development of pharmacological agents attempting antiarrhythmic therapy in conditions such as atrial fibrillation. However, progress in the development of such temporally and spatially selective antiarrhythmic drugs against particular ion channels has been relatively limited, particularly in view of our incomplete understanding of the complex physiological roles and interactions of the various ionic currents. This review summarizes the physiological properties of the main cardiac potassium channels and the way in which they modulate cardiac electrical activity and then critiques a number of available potential antiarrhythmic drugs directed at them.


Daytime variation of perioperative myocardial injury in cardiac surgery and its prevention by Rev-Erbα antagonism: a single-centre propensity-matched cohort study and a randomised study.
On-pump cardiac surgery provokes a predictable perioperative myocardial ischaemia-reperfusion injury which is associated with poor clinical outcomes. We determined the occurrence of time-of-the-day variation in perioperative myocardial injury in patients undergoing aortic valve replacement and its molecular mechanisms. We studied the incidence of major adverse cardiac events in a prospective observational single-centre cohort study of patients with severe aortic stenosis and preserved left ventricular ejection fraction (>50%) who were referred to our cardiovascular surgery department at Lille University Hospital (Lille, France) for aortic valve replacement and underwent surgery in the morning or afternoon. Patients were matched into pairs by propensity score. We also did a randomised study, in which we evaluated perioperative myocardial injury and myocardial samples of patients randomly assigned (1:1) via permuted block randomisation (block size of eight) to undergo isolated aortic valve replacement surgery either in the morning or afternoon. We also evaluated human and rodent myocardium in ex-vivo hypoxia-reoxygenation models and did a transcriptomic analysis in myocardial samples from the randomised patients to identify the signalling pathway(s) involved. The primary objective of the study was to assess whether myocardial tolerance of ischaemia-reperfusion differed depending on the timing of aortic valve replacement surgery (morning vs afternoon), as measured by the occurrence of major adverse cardiovascular events (cardiovascular death, myocardial infarction, and admission to hospital for acute heart failure). The randomised study is registered with ClinicalTrials.gov, number NCT02812901. In the cohort study (n=596 patients in matched pairs who underwent either morning surgery [n=298] or afternoon surgery [n=298]), during the 500 days following aortic valve replacement, the incidence of major adverse cardiac events was lower in the afternoon surgery group than in the morning group: hazard ratio 0·50 (95% CI 0·32-0·77; p=0·0021). In the randomised study, 88 patients were randomly assigned to undergo surgery in the morning (n=44) or afternoon (n=44); perioperative myocardial injury assessed with the geometric mean of perioperative cardiac troponin T release was significantly lower in the afternoon group than in the morning group (estimated ratio of geometric means for afternoon to morning of 0·79 [95% CI 0·68-0·93; p=0·0045]). Ex-vivo analysis of human myocardium revealed an intrinsic morning-afternoon variation in hypoxia-reoxygenation tolerance, concomitant with transcriptional alterations in circadian gene expression with the nuclear receptor Rev-Erbα being highest in the morning. In a mouse Langendorff model of hypoxia-reoxygenation myocardial injury, Rev-Erbα gene deletion or antagonist treatment reduced injury at the time of sleep-to-wake transition, through an increase in the expression of the ischaemia-reperfusion injury modulator CDKN1a/p21. Perioperative myocardial injury is transcriptionally orchestrated by the circadian clock in patients undergoing aortic valve replacement, and Rev-Erbα antagonism seems to be a pharmacological strategy for cardioprotection. Afternoon surgery might provide perioperative myocardial protection and lead to improved patient outcomes compared with morning surgery. Fondation de France, Fédération Française de Cardiologie, EU-FP7-Eurhythdia, Agence Nationale pour la Recherche ANR-10-LABX-46, and CPER-Centre Transdisciplinaire de Recherche sur la Longévité.


Thyroid-stimulating hormone, prolactin, and growth hormone response to thyrotropin-releasing hormone in treated children with congenital hypothyroidism.
The purpose of the present study was to assess thyroid-stimulating hormone (TSH), prolactin, and growth hormone responses to TRH stimulation in 12 congenitally hypothyroid children adequately treated with L-thyroxine from the first weeks of life. Although clinically euthyroid, six of these children were found to have abnormally high basal serum TSH concentrations despite clinical euthyroidism. Serum triiodothyroxine and L-thyroxine concentrations were normal and did not differ whether the children had elevated or normal basal serum TSH. All six of the children with high basal TSH had an exaggerated TSH response to TRH and 4 of them also had an augmented prolactin response to TRH. The children with normal basal TSH concentrations had normal TSH and prolactin responses to TRH. An abnormal ("paradoxical") elevation of growth hormone concentration in response to TRH was found in four of seven children in a separate group of patients who had prolonged, untreated primary hypothyroidism, but such responses were not found in any of the adequately treated children. These findings suggest the following conclusions: 1) the phenomenon of high serum concentrations of TSH in conjunction with normal L-thyroxine and triiodothyronine levels (and clinical euthyroidism), is prevalent in congenital hypothyroid patients. 2) These patients have an exaggerated response of their pituitary thyrotroph and lactotroph cells to TRH, presumably caused by selective and relative resistance of these cells to the inhibitory effects of thyroid hormones. 3) Congenital hypothyroidism is not associated with abnormal somatotroph cell responses to TRH.


Expression of perforin in infiltrating cells in murine hearts with acute myocarditis caused by coxsackievirus B3.
Cell-mediated autoimmunity has been strongly implicated in the pathogenesis of viral myocarditis. Using a murine model of acute myocarditis caused by coxsackievirus B3, we analyzed the phenotypes and morphology of the infiltrating cells in the hearts by immunofluorescence and electron microscopy. We also examined the expression of a cytolytic factor, perforin, in the infiltrating cells by immunoperoxidase and in situ hybridization. We found that the dominant population of the infiltrating cells were asialo GM1 positive, were negative for T-cell markers, and had electron-dense cytoplasmic granules, which is consistent with a morphology of large granular lymphocytes. Perforin was found in the cytoplasmic granules of the infiltrating cells expressing perforin messenger RNA. These findings provide for the first time the direct evidence that the first wave of cell infiltration in hearts mainly consists of killer cells and strongly suggests that perforin plays, in part, an important role in myocardial cell damage involved in acute viral myocarditis. T-helper cells and cytotoxic T lymphocytes made up the second wave of cell infiltration. As we previously reported, the expression of major histocompatibility complex class I antigen on cardiac myocytes induced by the infiltrating cells, such as killer cells, may facilitate the interaction between cardiac myocytes and cytotoxic T lymphocytes, and may lead to further myocardial cell damage in a later phase.


Ultrafiltration of charge-stabilized dispersions at low salinity.
We present a comprehensive study of cross-flow ultrafiltration (UF) of charge-stabilized suspensions, under low-salinity conditions of electrostatically strongly repelling colloidal particles. The axially varying permeate flux, near-membrane concentration-polarization (CP) layer and osmotic pressure profiles are calculated using a macroscopic diffusion-advection boundary layer method, and are compared with filtration experiments on aqueous suspensions of charge-stabilized silica particles. The theoretical description based on the one-component macroion fluid model (OCM) accounts for the strong influence of surface-released counterions on the renormalized colloid charge and suspension osmotic compressibility, and for the influence of the colloidal hydrodynamic interactions and electric double layer repulsion on the concentration-dependent suspension viscosity η, and collective diffusion coefficient Dc. A strong electro-hydrodynamic enhancement of Dc and η, and likewise of the osmotic pressure, is predicted theoretically, as compared with their values for a hard-sphere suspension. We also point to the failure of generalized Stokes-Einstein relations describing reciprocal relations between Dc and η. According to our filtration model, Dc is of dominant influence, giving rise to an only weakly developed CP layer having practically no effect on the permeate flux. This prediction is quantitatively confirmed by our UF measurements of the permeate flux using an aqueous suspension of charged silica spheres as the feed system. The experimentally detected fouling for the largest considered transmembrane pressure values is shown not to be due to filter cake formation by crystallization or vitrification.


Tubular structures involved in movement of cowpea mosaic virus are also formed in infected cowpea protoplasts.
In cowpea plant cells infected with cowpea mosaic virus, tubular structures containing virus particles are formed in the plasmodesmata between adjacent cells; these structures are supposedly involved in cell-to-cell spread of the virus. Here we show that similar tubular structures are also formed in cowpea protoplasts, from which the cell wall and plasmodesmata are absent. Between 12 and 21 h post-inoculation, tubule formation starts in the periphery of the protoplast at the level of the plasma membrane. Upon assembly, the virus-containing tubule is enveloped by the plasma membrane and extends into the culture medium. This suggests that the tubule has functional polarity and makes it likely that a tubule 'grows' into a neighbouring cell in vivo. On average, 75% of infected protoplasts were shown to possess tubular structures extending from their surface. The tubule wall was 3 to 4 nm thick and they were up to 20 microns in length, as shown by fluorescent light microscopy and negative staining electron microscopy. By analogy to infected plant cells, both the viral 58K/48K movement and capsid proteins were located in these tubules, as determined by immunofluorescent staining and immunogold labelling using specific antisera against these proteins. These results demonstrate that the formation of tubules is not necessarily dependent on the presence of plasmodesmata or the cell wall, and that they are composed, at least in part, of virus-encoded components.


Challenges and cares to promote rational use of chloroquine and hydroxychloroquine in the management of coronavirus disease 2019 (COVID-19) pandemic: a timely review.
As a result of the 2019 coronavirus disease pandemic (COVID-19), there has been an urgent worldwide demand for treatments. Due to factors such as history of prescription for other infectious diseases, availability, and relatively low cost, the use of chloroquine (CQ) and hydroxychloroquine (HCQ) has been tested in vivo and in vitro for the ability to inhibit the causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, even though investigators noted the therapeutic potential of these drugs, it is important to consider the toxicological risks and necessary care for rational use of CQ and HCQ. This study provides information on the main toxicological and epidemiological aspects to be considered for prophylaxis or treatment of COVID-19 using CQ but mainly HCQ, which is a less toxic derivative than CQ, and was shown to produce better results in inhibiting proliferation of SARS-CoV-2 based upon preliminary tests.


Criticality of the geological copper family.
Because modern technology depends on reliable supplies of a wide variety of materials, and because of increasing concern about those supplies, a comprehensive methodology has been created to quantify the degree of criticality of the metals of the periodic table. In this paper, we apply this methodology to the elements of the geological copper family: Cu, As, Se, Ag, Te, and Au. These elements are technologically important, but show a substantial variation in different factors relating to their supply risk, vulnerability to supply restriction, and environmental implications. Assessments are made on corporate, national, and global levels for year 2008. Evaluations of each of the multiple indicators are presented and the results plotted in "criticality space", together with Monte Carlo simulation-derived "uncertainty cloud" estimates for each of the aggregated evaluations. For supply risk over both the medium term and long term, As is the highest risk of the six metals, with Se and Ag nearly as high. Gold has the most severe environmental implications ranking. Vulnerability to supply restriction (VSR) at the corporate level for an invented solar cell manufacturing firm shows Se, Te, and Cu as approximately equal, Cu has the highest VSR at the national level, and Cu and Au have the highest VSRs at the global level. Criticality vector magnitudes are greatest at the global level for As (and then Au and Ag) and at the national level for As and Au; at the corporate level, Se is highest with Te and Cu lower. An extension of this work, now in progress, will provide criticality estimates for several different development scenarios for the period 2010-2050.


'Well-leg' compartment syndrome associated with gynaecological surgery: a perioperative risk-reduction protocol and checklist.
'Well-leg' compartment syndrome (WLCS) is an uncommon, but potentially devastating, complication associated with prolonged patient positioning for abdomino-pelvic surgery. Gynaecologists, anaesthetists and the wider theatre team share a responsibility to minimise the risk of this highly morbid, and even fatal, postoperative complication. This article provides an overview of WLCS related to gynaecological surgery - raising awareness amongst gynaecologists and highlighting the time-critical nature of diagnosis and management. Given the potential litiginous nature of this complication, we also present a perioperative checklist and risk-reduction protocol to suggest a standardised approach to prevention and relevant documentation. TWEETABLE ABSTRACT: Gynaecologists share a responsibility to minimise the risk of postoperative 'well-leg' compartment syndrome.


Impact of sleep quality on cardiovascular outcomes in hemodialysis patients: results from the frequent hemodialysis network study.
Poor sleep quality is a common, persistent, and important problem to patients with end-stage renal disease (ESRD). This report examines whether sleep quality is associated with dialysis treatment factors and other modifiable clinical factors in a large group of hemodialysis (HD) patients. Cross-sectional analyses were conducted on baseline data collected from participants in the Frequent Hemodialysis Network trials. Sleep quality was measured using the Medical Outcomes Study Sleep Problems Index II (SPI II), a 9-item measure of sleep quality with higher scores reflecting poorer sleep quality. The participants had an age of 51.2 ± 13.6 years, 61% were male, 38% were black, and 42% had diabetes. Higher pre-dialysis serum phosphorus (per 0.5 mg/ml) (OR 0.91; 95% CI 0.85, 0.96) and depression (OR 0.16; 95% CI 0.10, 0.25) were independently associated with decrements in sleep quality. There was also a difference in time to recovery from dialysis for the fourth versus the first SPI II quartile (5.1 h; p < 0.0001). These findings underscore the link between sleep and daytime function and suggest that improving sleep may provide an opportunity to improve outcomes in ESRD. Whether sleep problems may be improved by reduction of serum phosphorus or treatment of depression in the HD population merits further investigation.


Replication of Zika Virus in Human Prostate Cells: A Potential Source of Sexually Transmitted Virus.
While Zika virus (ZIKV) is mainly transmitted by mosquitoes, numerous cases of sexual transmission have been reported during recent outbreaks. Little is known about which host cell types or entry factors aid in mediating this sexual transmission. In this study, we investigated ZIKV cell tropism by infecting 2 types of human prostate cells with 3 contemporary ZIKV isolates from persons infected in the Americas. We used real-time quantitative polymerase chain reaction and immunofluorescence analyses to measure infection and flow cytometry to detect entry factor expression. Here we show that ZIKV infects, replicates, and produces infectious virus in prostate stromal mesenchymal stem cells, epithelial cells, and organoids made with a combination of these cells. We also show that prostate cells express several well-characterized flavivirus attachment factors. In contrast, dengue virus does not infect or does not replicate in these prostate cells, although it is known to use similar receptors. Our results indicate that ZIKV favors infection of stromal cells more so than epithelial cells in organoids, possibly indicating a preference for stem cells in general. Overall, these results suggest that ZIKV replication occurs in the human prostate and can account for ZIKV secretion in semen, thus leading to sexual transmission.


Fetal hemodynamic response to aortic valvuloplasty and postnatal outcome: a European multicenter study.
Fetal aortic stenosis may progress to hypoplastic left heart syndrome. Fetal valvuloplasty (FV) has been proposed to improve left heart hemodynamics and maintain biventricular (BV) circulation. The aim of this study was to assess FV efficacy by comparing survival and postnatal circulation between fetuses that underwent FV and those that did not. This was a retrospective multicenter study of fetuses with aortic stenosis that underwent FV between 2005 and 2012, compared with contemporaneously enrolled natural history (NH) cases sharing similar characteristics at presentation but not undergoing FV. Main outcome measures were overall survival, BV-circulation survival and survival after birth. Secondary outcomes were hemodynamic change and left heart growth. A propensity score model was created including 54/67 FV and 60/147 NH fetuses. Analyses were performed using logistic, Cox or linear regression models with inverse probability of treatment weighting (IPTW) restricted to fetuses with a propensity score of 0.14-0.9, to create a final cohort for analysis of 42 FV and 29 NH cases. FV was technically successful in 59/67 fetuses at a median age of 26 (21-34) weeks. There were 7/72 (10%) procedure-related losses, and 22/53 (42%) FV babies were delivered at < 37 weeks. IPTW demonstrated improved survival of liveborn infants following FV (hazard ratio, 0.38; 95% CI, 0.23-0.64; P = 0.0001), after adjusting for circulation and postnatal surgical center. Similar proportions had BV circulation (36% for the FV cohort and 38% for the NH cohort) and survival was similar between final circulations. Successful FV cases showed improved hemodynamic response and less deterioration of left heart growth compared with NH cases (P ≤ 0.01). We report improvements in fetal hemodynamics and preservation of left heart growth following successful FV compared with NH. While the proportion of those achieving a BV circulation outcome was similar in both cohorts, FV survivors showed improved survival independent of final circulation to 10 years' follow-up. However, FV is associated with a 10% procedure-related loss and increased prematurity compared with the NH cohort, and therefore the risk-to-benefit ratio remains uncertain. We recommend a carefully designed trial incorporating appropriate and integrated fetal and postnatal management strategies to account for center-specific practices, so that the benefits achieved by fetal therapy vs surgical strategy can be demonstrated clearly. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.


Transmission of six ampeloviruses and two vitiviruses to grapevine by Phenacoccus aceris.
Grapevine leafroll disease is caused by grapevine leafroll-associated viruses (GLRaVs). These viruses are common in vineyards worldwide and often associated with vitiviruses that are involved in the rugose wood complex of grapevine. Ten mealybug species are known as vectors of one or several of these grapevine viruses, including the apple mealybug Phenacoccus aceris which is widespread in Holarctic regions and able to transmit Grapevine leafroll-associated virus-1 and -3 (GLRaV-1 and -3). Our aim was to characterize the transmission features of leafroll viruses by Phenacoccus aceris in order to better understand the contribution of this mealybug to leafroll epidemics. Results showed that Phenacoccus aceris is able to transmit GLRaV-1, -3, -4, -5, -6, and -9 to grapevine but not GLRaV-7. This is the first report of GLRaV-6 transmission by a mealybug. Also, for the first time it was shown that Phenacoccus aceris could vector vitiviruses Grapevine virus A (GVA) and Grapevine virus B (GVB). First instar nymphs were the most efficient stage in transmitting GLRaV-1, -3, and GVA. This research sheds light on the transmission biology of grapevine viruses by Phenacoccus aceris and represents a step forward to leafroll disease management.


Biomimetic strategy for constructing Clostridium thermocellum cellulosomal operons in Bacillus subtilis.
Enzymatic conversion of lignocellulosic biomass into soluble sugars is a major bottleneck in the plant biomass utilization. Several anaerobic organisms cope these issues via multiple-enzyme complex system so called 'cellulosome'. Hence, we proposed a "biomimic operon" concept for making an artificial cellulosome which can be used as a promising tool for the expression of cellulosomal enzymes in Bacillus subtilis. According to the proteomic analysis of Clostridium thermocellum ATCC27405 induced by Avicel or cellobiose, we selected eight highly expressed cellulosomal genes including a scaffoldin protein gene (cipA), a cell-surface anchor gene (sdbA), two exoglucanase genes (celK and celS), two endoglucanase genes (celA and celR), and two xylanase genes (xynC and xynZ). Arranging these eight genes in two different orders, we constructed two different polycistronic operons using the ordered gene assembly in Bacillus method. This is the first study to express the whole CipA along with cellulolytic enzymes in B. subtilis. Each operon was successfully expressed in B. subtilis RM125, and the protein complex assembly, cellulose-binding ability, thermostability, and cellulolytic activity were demonstrated. The operon with a higher xylanase activity showed greater saccharification on complex cellulosic substrates such as Napier grass than the other operon. In this study, a strategy for constructing an efficient cellulosome system was developed and two different artificial cellulosomal operons were constructed. Both operons could efficiently express the cellulosomal enzymes and exhibited cellulose saccharification. This strategy can be applied to different industries with cellulose-containing materials, such as papermaking, biofuel, agricultural compost, mushroom cultivation, and waste processing industries.


HIV/AIDS management in office practice. Antiretroviral therapy.
Treatment of HIV with nucleoside analog reverse transcriptase inhibitors (RTIs) and protease inhibitors forms the backbone of anti-HIV therapy. Non-nucleoside RTIs, immune modulators, and new entries in existing classes of pharmacologic agents hold promise for the future. Combination therapy with two, three, or more agents has become the standard of care, although additive toxicities often can be dose-limiting. Increases in the understanding of viral dynamics have introduced measures of systemic viral burden into clinical practice, and viral load considered in combination with CD4 lymphocyte numbers guides decisions about initiating and modifying antiviral therapy.


A Heuristic Force Model for Haptic Simulation of Nasogastric Tube Insertion Using Fuzzy Logic.
Nasogastric tube (NGT) placement is an essential clinical skill. The training is conventionally performed on rubber mannequins albeit practical limitations. Computer simulation with haptic feedback can potentially offer a more realistic and accessible training method. However, the complex interactions between the tube and the nasogastric passage make it difficult to model the haptic feedback during NGT placement. In this paper, a fuzzy-logic-based approach is proposed to directly transfer the experience of clinicians in NGT placement into the simulation system. Based on their perception of the varying tactile sensation and the conditions during NGT placement, the membership functions and fuzzy rules are defined to develop the force model. Forces created using the model are then combined with friction forces to drive the haptic device and render the insertion forces in real time. A prototype simulator is developed based on the proposed force model and the implementation details are presented. The usability of the prototype is also evaluated by clinical teachers. The proposed methodology has the potential for developing computerized NGT placement training methods for clinical education. It is also applicable for simulation systems involving complicated force interactions or computation-expensive models.


Conducting metallopolymers as precursors to fabricate palladium nanoparticle/polymer hybrids for oxygen reduction.
The novel conducting metallopolymer [N,N'-((2,2'-dimethyl)propyl)bis(5-(2,2'-bithiophene-5-yl)salcylideniminato-palladium(II)](n) prepared by electropolymerization provides a polymer matrix in which the palladium metal centers are evenly distributed. The metal centers embedded directly in the conducting metallopolymer backbone serve as seed points for size-controlled palladium nanoparticle (NP) growth of 3.8 to 4.9 nm NPs within the conducting metallopolymer film. The palladium NP/conducting metallopolymer hybrid material has demonstrated electrocatalytic behavior toward oxygen reduction with peak current densities around 400 μA/cm(2) in acidic aqueous conditions. These results demonstrate a promising new method for the production of electrocatalytically active hybrid materials.


YjjQ Represses Transcription of flhDC and Additional Loci in Escherichia coli.
The presumptive transcriptional regulator YjjQ has been identified as being virulence associated in avian pathogenic Escherichia coli (APEC). In this work, we characterize YjjQ as transcriptional repressor of the flhDC operon, encoding the master regulator of flagellar synthesis, and of additional loci. The latter include gfc (capsule 4 synthesis), ompC (outer membrane porin C), yfiRNB (regulated c-di-GMP synthesis), and loci of poorly defined function (ybhL and ymiA-yciX). We identify the YjjQ DNA-binding sites at the flhDC and gfc promoters and characterize a DNA-binding sequence motif present at all promoters found to be repressed by YjjQ. At the flhDC promoter, the YjjQ DNA-binding site overlaps the RcsA-RcsB DNA-binding site. RcsA-RcsB likewise represses the flhDC promoter, but the repression by YjjQ and that by RcsA-RcsB are independent of each other. These data suggest that YjjQ is an additional regulator involved in the complex control of flhDC at the level of transcription initiation. Furthermore, we show that YjjQ represses motility of the E. coli K-12 laboratory strain and of uropathogenic E. coli (UPEC) strains CFT073 and 536. Regulation of flhDC, yfiRNB, and additional loci by YjjQ may be features relevant for pathogenicity. Escherichia coli is a commensal and pathogenic bacterium causing intra- and extraintestinal infections in humans and farm animals. The pathogenicity of E. coli strains is determined by their particular genome content, which includes essential and associated virulence factors that control the cellular physiology in the host environment. However, the gene pools of commensal and pathogenic E. coli are not clearly differentiated, and the function of virulence-associated loci needs to be characterized. In this study, we characterize the function of yjjQ, encoding a transcription regulator that was identified as being virulence associated in avian pathogenic E. coli (APEC). We characterize YjjQ as transcriptional repressor of flagellar motility and of additional loci related to pathogenicity.


Blockade of connexin hemichannels with tonabersat protects against mild hypoxic ischemic brain injury in neonatal rats.
There is growing evidence that infants with mild hypoxic-ischemic (HI) encephalopathy have increased risk of brain injury and adverse neurodevelopmental outcomes. Currently, there is no approved treatment for these infants. It was previously shown that blocking connexin 43 hemichannels is neuroprotective in models of moderate to severe HI injury. However, it is yet to be established whether these channels play a role in the evolution of mild HI brain injury, and whether blocking these channels after mild HI is neuroprotective. HI was induced in postnatal day 10 rats of both sexes by right carotid artery ligation followed by 80 min of hypoxia in 8% oxygen. Pups receiving HI were randomised to receive intraperitoneal injections of either saline, vehicle (2-hydroxypropyl-beta-cyclodextrin polyethylene glycol-400), or tonabersat (2 mg/kg), at 60 min, 24 h, and 48 h after hypoxia. Seven days after HI, brains were harvested for measurement of volume loss and histological analysis. HI resulted in a significant reduction in hemispheric, hippocampal, and white matter volumes, which were significantly attenuated after treatment with tonabersat. HI was also associated with a significant reduction in numbers of neurons in the CA1 and CA3 hippocampal regions, a reduction in the numbers of oligodendrocytes in the corpus callosum, and an increase in the number of astrocytes in both regions, which were significantly attenuated by tonabersat treatment. There were no differences in rectal temperatures between tonabersat- and vehicle-treated rat pups. Blockade of connexin hemichannels with tonabersat significantly reduced mild HI injury in the hippocampus and white matter, without causing hypothermia.


[Doxazosin treatment of disorders of the voiding phase in benign prostatic hyperplasia].
To analyze the clinical and urodynamic efficacy of treatment with doxazosin during 6 months for voiding phase disorders in patients with BPH. A prospective clinical and urodynamic study (before and after treatment) was performed in 65 consecutive male patients with BPH, aged 54-79 years (mean 66.7), to evaluate the results of treatment with doxazosin 4 mg/day during 6 months. Clinical evaluation included patient history and the International Prostatic Symptom Score (IPSS) and urodynamic evaluation included uroflowmetry with post-void residual data and pressure-flow test. A static urethral pressure profile was associated with the urodynamic voiding study. The IPSS score improved significantly from 19.8 +/- 4.8 before treatment to 11.9 +/- 4.6 after treatment (p < 0.001). Urinary symptoms improved significantly more markedly after treatment (coeff. -0.45939) in patients with a lower IPSS score. The symptomatic improvement demonstrated by the IPSS did not correlate with the DRE or the transabdominal US prostatic volume. Mean maximum flow rate before treatment was 9.13 ml/sec and increased to 16.23 ml/sec after treatment (p < 0.01). Postvoid residual dropped from 21.7% to 12.5% (p < 0.01). In the pressure-flow test, foot-point PURR dropped significantly from 69 cms H2O to 45.9 cms H2O (p < 0.001). The PURR curvature diminished from 0.27416 to 0.15964 cms H2O (ml/sec2) (p < 0.01). A statistically significant improvement of the compressive (p < 0.001) and constrictive (p < 0.05) elements of lower urinary tract obstruction was observed. The urethral functional length of the urethral profile showed a significant reduction (pre-treatment: 5.56 cms; post-treatment 4.31 cms) (p < 0.05). A statistical correlation was found between the urethral functional length and the foot-point PURR post-treatment. Adrenergic blockade with doxazosin reduces both the compressive and constrictive elements of lower urinary tract obstruction in the voiding phase in patients with BPH, although no statistical correlation with the IPSS could be demonstrated.


Effects of administration of tri-iodothyronine on the response of cardiac and renal pyruvate dehydrogenase complex to starvation for 48 h.
Effects of administration of tri-iodothyronine (T3) on activities of cardiac and renal pyruvate dehydrogenase complex (active form, PDHa) were investigated. In fed rats, T3 treatment did not affect cardiac or renal PDHa activity, although blood non-esterified fatty acid and ketone-body concentrations were increased. Starvation (48 h) of both control and T3-treated rats resulted in similar increases in the steady-state concentrations of fatty acids and ketone bodies, but inactivation of cardiac and renal pyruvate dehydrogenase complex activities was diminished by T3 treatment. Inhibition of lipolysis increased renal and cardiac PDHa in control but not in T3-treated 48 h-starved rats, despite decreased fatty acid and ketone-body concentrations in both groups. The results suggest that hyperthyroidism influences the response of cardiac and renal PDHa activities to starvation through changes in the metabolism of lipid fuels in these tissues.


[Empirical analysis of expert social medicine assessment of disability based on the decision of the Federal social court].
Objective assessment of need for nursing care should be based on well defined criteria. In 1993, the Federal German Social Court ("Bundessozialgericht", BSG) has given criteria for identifying individuals in permanent need of very intensive nursing care ("Schwerpfledgebedürftige"), who qualified for benefits granted by the Germany statutory health insurance system at that time. The criteria were primarily based on the number of activities of daily living for which the applicants were in need of help. The criteria were largely, but not entirely, consistent with previously established criteria employed by the Medical Service of the Health Insurances ("Medizinischer Dienst der Krankenversicherung", MDK), who was responsible for the assessment. An analysis of 4185 examinations carried out by MDK in the region of Augsburg in 1991-1993 showed that the majority of judgments were in agreement with the criteria given by BSG. However, individuals with psychiatric disorders or symptoms were often rated by MDK as being in permanent need of very intensive nursing care even if BSG criteria were not fulfilled. Exclusive judgement of nursing dependency on the basis of single activities of daily living appears to be inadequate for this group of persons.


Phytoplasma effector SAP54 induces indeterminate leaf-like flower development in Arabidopsis plants.
Phytoplasmas are insect-transmitted bacterial plant pathogens that cause considerable damage to a diverse range of agricultural crops globally. Symptoms induced in infected plants suggest that these phytopathogens may modulate developmental processes within the plant host. We report herein that Aster Yellows phytoplasma strain Witches' Broom (AY-WB) readily infects the model plant Arabidopsis (Arabidopsis thaliana) ecotype Columbia, inducing symptoms that are characteristic of phytoplasma infection, such as the production of green leaf-like flowers (virescence and phyllody) and increased formation of stems and branches (witches' broom). We found that the majority of genes encoding secreted AY-WB proteins (SAPs), which are candidate effector proteins, are expressed in Arabidopsis and the AY-WB insect vector Macrosteles quadrilineatus (Hemiptera; Cicadellidae). To identify which of these effector proteins induce symptoms of phyllody and virescence, we individually expressed the effector genes in Arabidopsis. From this screen, we have identified a novel AY-WB effector protein, SAP54, that alters floral development, resulting in the production of leaf-like flowers that are similar to those produced by plants infected with this phytoplasma. This study offers novel insight into the effector profile of an insect-transmitted plant pathogen and reports to our knowledge the first example of a microbial pathogen effector protein that targets flower development in a host.


Mechanism of fibrosis in experimental tacrolimus nephrotoxicity.
The clinical use of tacrolimus (FK506) is limited by nephrotoxicity. The pathogenesis of fibrosis in chronic FK506 nephrotoxicity remains unknown. Because transforming growth factor (TGF)-beta plays a key role in the fibrogenesis of many diseases, including cyclosporine nephrotoxicity, we studied a salt-depleted rat model of chronic FK506 nephropathy in which clinically relevant FK506 blood levels are obtained and which shows similarities to the lesions described in patients receiving FK506. Pair-fed rats were treated with either FK506 (1 mg/kg/day s.c.) or an equivalent dose of vehicle and were killed at 7 or 28 days. Characteristic histologic changes of tubular injury, interstitial fibrosis, and arteriolopathy developed in FK506-treated rats at 28 days and were accompanied by worsening kidney function, decreased concentrating ability, and enzymuria. FK506-treated kidneys had a progressive increase in the expression of TGF-beta1 and matrix proteins (biglycan, tenascin, fibronectin, and type I collagen). This effect seems to be specific because the expression of type IV collagen, a basement membrane collagen, was not affected. Matrix deposition was present mostly in the tubulointerstitium and vessels in accordance with the FK506 chronic lesion. The expression of plasminogen activator inhibitor-1, a protease inhibitor influenced by TGF-beta, followed TGF-beta1 and matrix proteins, suggesting that the fibrosis of chronic FK506 nephropathy likely involves the dual action of TGF-beta1 on matrix deposition and degradation. Since both peripheral and tissue renin expression were elevated with FK506, the renin-angiotensin system may play a role in the pathogenesis of this condition.


Critical care bug team: a multidisciplinary team approach to reducing ventilator-associated pneumonia.
Ventilator-associated pneumonia rates in the medical-surgical intensive care unit first exceeded the 90th percentile in September 1997 and were significantly (P <.05) higher than National Nosocomial Infections Surveillance System pooled mean data. In January 1998, a multidisciplinary "Critical Care Bug Team" was developed by the Infection Control Committee to review 1997 National Nosocomial Infections Surveillance System data for four adult intensive care units in a 583-bed tertiary care hospital. Membership included clinical nurse specialists, a dietitian, a pharmacist, a respiratory therapist, an infection control professional, a research specialist, and a physician adviser. Having the team report directly to the hospital's Infection Control and Adult Critical Care Committees maximized support for recommendations and provided a direct link from patient care to hospital administration. By identifying issues, evaluating patient care processes, performing literature searches, and monitoring compliance, the team implemented numerous interventions, including policy and procedure changes, purchasing of equipment, and implementation of various education tools. Each member of the Critical Care Bug Team contributed to a synergized effort that may have produced the desired outcome of decreasing ventilator-associated pneumonia rates. Except for August 1998, ventilator-associated pneumonia rates have been below the 75th percentile since May 1998. This study illustrates the effectiveness of a multidisciplinary team approach devised to reduce and stabilize ventilator-associated pneumonia rates in a medical-surgical intensive care unit.


Oxidation of the carcinogens benzo [a] pyrene and benzo [a] anthracene to dihydrodiols by a bacterium.
A mutant strain of Beijerinckia, after growth with succinate plus biphenyl, contains an enzyme system that oxidizes benzo [a] pyrene and benzo [a] anthracene to mixtures of vicinal dihydrodiols. The major dihydrodiol formed from benzo [a] pyrene was identified as cis-9, 10-dihydroxy-9, 10-dihydrobenzo [a] pyrene by comparison with a synthetic sample. Benzo [a] anthracene was metabolized to four dihydrodiols, the major isomer being cis-1, 2-dihydroxy-1, 2-dihydroxy-1, 2-dihydrobenzo [a] anthracene.


Two overlapping regions within the N-terminal half of the herpes simplex virus 1 E3 ubiquitin ligase ICP0 facilitate the degradation and dissociation of PML and dissociation of Sp100 from ND10.
Herpes simplex virus 1 (HSV-1) establishes a lifelong latent infection in sensory neurons and can reactivate from latency under stress conditions. To promote lytic infection, the virus must interact with specific cellular factors to evade the host's antiviral defenses. The HSV-1 E3 ubiquitin ligase, infected cell protein 0 (ICP0), activates transcription of viral genes, in part, by mediating the degradation of certain cellular proteins that play a role in host antiviral mechanisms. One component of the cellular defenses that ICP0 disrupts is the suborganelle, nuclear domain 10 (ND10), by inducing the degradation and dissociation of the major organizer of ND10, a promyelocytic leukemia (PML) and ND10 constituent, Sp100. Because previously identified domains in ICP0 explain only partially how it directs the degradation and dissociation of PML and Sp100, we hypothesized that additional regions within ICP0 may contribute to these activities, which in turn facilitate efficient viral replication. To test this hypothesis, we used a series of ICP0 truncation mutants and examined PML protein levels and PML and Sp100 immunofluorescence staining in human embryonic lung cells. Our results demonstrate that two overlapping regions within the central N-terminal portion of ICP0 (residues 212 to 311) promoted the dissociation and degradation of PML and dissociation of Sp100 (residues 212 to 427). In conclusion, we have identified two additional regions in ICP0 involved in altering ND10 antiviral defenses in a cell culture model of HSV-1 infection.


DockTrina: docking triangular protein trimers.
In spite of the abundance of oligomeric proteins within a cell, the structural characterization of protein-protein interactions is still a challenging task. In particular, many of these interactions involve heteromeric complexes, which are relatively difficult to determine experimentally. Hence there is growing interest in using computational techniques to model such complexes. However, assembling large heteromeric complexes computationally is a highly combinatorial problem. Nonetheless the problem can be simplified greatly by considering interactions between protein trimers. After dimers and monomers, triangular trimers (i.e. trimers with pair-wise contacts between all three pairs of proteins) are the most frequently observed quaternary structural motifs according to the three-dimensional (3D) complex database. This article presents DockTrina, a novel protein docking method for modeling the 3D structures of nonsymmetrical triangular trimers. The method takes as input pair-wise contact predictions from a rigid body docking program. It then scans and scores all possible combinations of pairs of monomers using a very fast root mean square deviation test. Finally, it ranks the predictions using a scoring function which combines triples of pair-wise contact terms and a geometric clash penalty term. The overall approach takes less than 2 min per complex on a modern desktop computer. The method is tested and validated using a benchmark set of 220 bound and seven unbound protein trimer structures. DockTrina will be made available at http://nano-d.inrialpes.fr/software/docktrina.


Predictors of health promotion lifestyle among three ethnic groups of elderly rural women in Taiwan.
The purpose of this study was to examine the predictors of health promotion lifestyle (HPL) and examine the similarities and differences among three ethnic groups of elderly rural women in Taiwan. Pender's Health Promotion Model was used as the conceptual framework of this study. A convenience sample of 599 elderly rural women was recruited from three rural areas: Kao-Shu, San-Di-Men, and Ma-Chia. Ho-Lo, Hakka, and aboriginal people are the three main ethnic groups in these areas. Of the 599 elderly women, 391 completed all of the interview questions. Subjects ranged from 65 to 91 years old. All instruments used in this study have been evaluated for their content validity. The interrater reliability and alpha coefficient reliability of all instruments were greater than 0.70. A survey-interview method was used to collect data. Findings showed that the predictors of HPL have differences and similarities among elderly rural women from different ethnicities. In the group of elderly Ho-Lo women, age, education, living arrangements, and perceived barriers to health promotion lifestyle (PBaHPL) were significant predictors and they explained 41.9% of total variance in HPL. In the group of elderly Hakka women, education, number of chronic health problems, PBaHPL, and perceived benefits of health promotion lifestyle (PBeHPL) were significant predictors in explaining 53.9% of total variance in HPL. Finally, in the group of elderly aboriginal women, living arrangements, PBaHPL, and PBeHPL were significant predictors in explaining 70.0% of total variance in HPL. Community nurses can use their understanding of different ethnic groups to assess, identify, and use effective health promotion interventions for elderly rural women.


Neuroprotective effects and mechanism of cognitive-enhancing choline analogs JWB 1-84-1 and JAY 2-22-33 in neuronal culture and Caenorhabditis elegans.
Our previous work indicated that novel analogs of choline have cytoprotective effects in vitro that might be useful in neurodegenerative conditions such as Alzheimer's disease (AD). Furthermore, two lead compounds (JWB1-84-1 and JAY2-22-33) from a library of more than 50 improved cognitive performances in a transgenic mouse model of AD. The purpose of these experiments was to more specifically investigate the neuroprotective capabilities of these lead compounds both in vitro and in vivo. We used N2a cells which express a Swedish mutation in the amyloid precursor protein and presenilin 1 genes to investigate the effect of JWB1-84-1 and JAY2-22-33 on β-amyloid (Aβ) levels and found that both compounds significantly reduced Aβ levels. JWB1-84-1 and JAY2-22-33 also protected rat primary cortical neurons from Aβ toxicity. Subsequently, we utilized the nematode Caenorhabditis elegans (C. elegans) as an in vivo model organism to identify potential molecular targets of these compounds. In the C. elegans model of Aβ toxicity, human Aβ is expressed intracellularly in the body wall muscle. The expression and subsequent aggregation of Aβ in the muscle leads to progressive paralysis. We found that JAY2-22-33 (but not JWB1-84-1) significantly reduced Aβ toxicity by delaying paralysis and this protective effect required both the insulin signaling pathway and nicotinic acetylcholine receptors (nAChRs).


Long-term follow-up of a patient with achondroplasia treated with an orthodontic approach.
We successfully treated a patient with achondroplasia with conventional orthodontic techniques. It was followed by long-term retention. The patient, a 12-year-old boy, had chief complaints of occlusal disturbance and mandibular protrusion. He had been diagnosed with achondroplasia and had growth hormone treatment in his early teenage years. His facial profile was concave with a bulging forehead and a retrognathic maxilla. It was characterized by a skeletal Class III jaw-base relationship with a retropositioned maxilla. At the age of 12 years 9 months, maxillary protraction was initiated with a reverse headgear; for 2 years 6 months, the maxillomandibular growth was controlled. After the growth spurt, at the age of 15 years 6 months, leveling and alignment of both dental arches were started with preadjusted edgewise appliances. After 83 months of multibracket treatment, an acceptable occlusion with a Class I molar relationship and an adequate interincisal relationship was achieved, despite the simultaneous marked vertical growth of the mandible. The resultant occlusion was stable during a 6-year retention period, although considerable forward-downward mandibular growth was observed. Conclusively, our results indicated the necessity of long-term observation in this patient with achondroplasia, especially because of the persistent mandibular growth.


Nanomaterials in the aquatic environment: A European Union-United States perspective on the status of ecotoxicity testing, research priorities, and challenges ahead.
The European Union-United States Communities of Research were established in 2012 to provide a platform for scientists to develop a "shared repertoire of protocols and methods to overcome nanotechnology environmental health and safety (nanoEHS) research gaps and barriers" (www.us-eu.org/). Based on work within the Ecotoxicology Community of Research (2012-2015) the present Focus article provides an overview of the state of the art of nanomaterials (NMs) in the aquatic environment by addressing different research questions, with a focus on ecotoxicological test systems and the challenges faced when assessing NM hazards (e.g., uptake routes, bioaccumulation, toxicity, test protocols, and model organisms). The authors' recommendation is to place particular importance on studying the ecological effects of aged/weathered NMs, as-manufactured NMs, and NMs released from consumer products in addressing the following overarching research topics: 1) NM characterization and quantification in environmental and biological matrices; 2) NM transformation in the environment and consequences for bioavailability and toxicity; 3) alternative methods to assess exposure; 4) influence of exposure scenarios on bioavailability and toxicity; 5) development of more environmentally realistic bioassays; and 6) uptake, internal distribution, and depuration of NMs. Research addressing these key topics will reduce uncertainty in ecological risk assessment and support the sustainable development of nanotechnology.


Prostatic abscess rupture in three dogs.
Three dogs developed prostatic abscesses that subsequently ruptured. For various reasons, the dogs had been treated with glucocorticoids before abscess rupture. Immediately after the diagnosis was made, each dog was taken to surgery. Each dog developed septic shock. Two dogs died during surgery and one recovered. A glucose-insulin-potassium solution was used to treat septic shock in the dog that recovered. Few cases of ruptured prostatic abscesses have been reported. The purpose in the present study was to review the clinical signs, pathologic changes, and management of ruptured prostatic abscesses in 3 dogs.


Purification and characterization of two high-affinity (adenosine 3',5'-monophosphate)-binding proteins from yeast. Identification as multiple forms of glyceraldehyde-3-phosphate dehydrogenase.
Two high-affinity cAMP-binding proteins (I and II) have been purified to homogeneity from baker's yeast by a procedure avoiding proteolytic damage. These proteins have been identified as multiple forms of glyceraldehyde-3-phosphate dehydrogenase. The two cAMP-binding proteins are similar in affinities for cAMP, have identical elution volumes on gel filtration, and contain one type of subunit (Mr 37 500). The form II of glyceraldehyde-3-phosphate dehydrogenase is free of NAD+ and has a Kd of 1.3 X 10(-6) M with respect to cAMP. A marked concentration-dependent self-association of the subunits of the form-II protein was revealed by Yphantis sedimentation equilibrium studies. Significant monomer concentrations are present at total concentrations less than 0.02 mg/ml. Conventional sedimentation equilibrium analyses indicated a tetramer Mr of 170 000. The high-affinity binding of cAMP to glyceraldehyde-3-phosphate dehydrogenase may significantly reduce intracellular cAMP levels and is also discussed in relation to the nature of eukaryote cAMP-binding proteins with similar native or subunit Mr values which are at present functionally undefined.


Enjoying Each Other's Company: Gaining Other-Gender Friendships Promotes Positive Gender Attitudes Among Ethnically Diverse Children.
Gender segregation is ubiquitous and may lead to increased bias against other-gender peers. In this study, we examined whether individual differences in friendships with other-gender children reduce gender bias, and whether these patterns vary by gender or ethnicity. Using a 1-year longitudinal design (N = 408 second graders [Mage = 7.56 years] and fourth graders [Mage = 9.48 years]), we found that, across groups, gaining more other-gender friendships over the year led to (a) increased positive cognitive-based attitudes toward the other gender and (b) increased positive and decreased negative affect when with the other gender. We also tested the reverse pattern and found support for a bidirectional link. Girls and Latinx children often showed more gender bias than did boys and European American children. Implications for promoting positive relationships between girls and boys are discussed.


Mutagenicity test of cefodizime sodium.
The mutagenicity of cefodizime sodium (THR-221) was investigated by the reverse mutation test using seven bacterial strains (Salmonella typhimurium strains TA100, TA98, TA1535, TA1537 and TA1538, and Escherichia coli strains WP2 and WP2uvrA) and the chromosomal aberration test with cultured Chinese hamster lung (CHL) cells. The reverse mutation test was carried out in dose range from 0.0025 to 5.0 micrograms/plate in the absence and presence of mammalian metabolic activation system. Antibacterial effects were observed at concentrations more than 0.25 microgram/plate, and no significant increases in the number of revertants were observed at the dose levels where antibacterial effects were not detected. THR-221 caused no increases in the number of chromosomal aberrants at dose levels of 0.75, 1.5, 3.0 and 6.0 mg/ml in the absence and presence of the metabolic activation. These results indicate that THR-221 has no mutagenic activity.


Hydrophobic cryogels for DNA adsorption: effect of embedding of monosize microbeads into cryogel network on their adsorptive performances.
As alternative hydrophobic adsorbent for DNA adsorption, supermacroporous cryogel disks were synthesized via free radical polymerization. In this study, we have prepared two kinds of cryogel disks: (i) poly(2-hydroxyethyl methacrylate-N-methacryloyl-l-tryptophan) [p(HEMA-MATrp)] cryogel containing specific hydrophobic ligand MATrp; and (ii) monosize p(HEMA-MATrp) particles synthesized via suspension polymerization embedded into p(HEMA) cryogel structure to obtain p(HEMA-MATrp)/p(HEMA) composite cryogel disks. These cryogel disks containing hydrophobic functional group were characterized via swelling studies, Fourier transform infrared spectroscopy, elemental analysis, surface area measurements and scanning electron microscopy. DNA adsorption onto both p(HEMA-MATrp) cryogel and p(HEMA-MATrp)/p(HEMA) composite cryogels was investigated. Maximum adsorption of DNA on p(HEMA-MATrp) cryogel was found to be 15 mg/g polymer. Otherwise, p(HEMA-MATrp)/p(HEMA) composite cryogels significantly increased the DNA adsorption capacity to 38 mg/g polymer. Composite cryogels could be used repeatedly without significant loss on adsorption capacity after 10 repetitive adsorption-desorption cycles.


Multiplex Quantitative PCR Assays for the Detection and Quantification of the Six Major Non-O157 Escherichia coli Serogroups in Cattle Feces.
Shiga toxin-producing Escherichia coli (STEC) serogroups O26, O45, O103, O111, O121, and O145, called non-O157 STEC, are important foodborne pathogens. Cattle, a major reservoir, harbor the organisms in the hindgut and shed them in the feces. Although limited data exist on fecal shedding, concentrations of non-O157 STEC in feces have not been reported. The objectives of our study were (i) to develop and validate two multiplex quantitative PCR (mqPCR) assays, targeting O-antigen genes of O26, O103, and O111 (mqPCR-1) and O45, O121, and O145 (mqPCR-2); (ii) to utilize the two assays, together with a previously developed four-plex qPCR assay (mqPCR-3) targeting the O157 antigen and three virulence genes (stx1, stx2, and eae), to quantify seven serogroups and three virulence genes in cattle feces; and (iii) to compare the three mqPCR assays to a 10-plex conventional PCR (cPCR) targeting seven serogroups and three virulence genes and culture methods to detect seven E. coli serogroups in cattle feces. The two mqPCR assays (1 and 2) were shown to be specific to the target genes, and the detection limits were 4 and 2 log CFU/g of pure culture-spiked fecal samples, before and after enrichment, respectively. A total of 576 fecal samples collected from a feedlot were enriched in E. coli broth and were subjected to quantification (before enrichment) and detection (after enrichment). Of the 576 fecal samples subjected, before enrichment, to three mqPCR assays for quantification, 175 (30.4%) were quantifiable (≥4 log CFU/g) for at least one of the seven serogroups, with O157 being the most common serogroup. The three mqPCR assays detected higher proportions of postenriched fecal samples (P > 0.01) as positive for one or more serogroups compared with cPCR and culture methods. This is the first study to assess the applicability of qPCR assays to detect and quantify six non-O157 serogroups in cattle feces and to generate data on fecal concentration of the six serogroups.


How flower development genes were identified using forward genetic screens in Arabidopsis thaliana.
In the later part of the 1980s, the time was ripe for identifying genes controlling flower development. In that pregenomic era, the easiest way to do this was to induce random mutations in seeds by chemical mutagens (or irradiation) and to screen thousands of plants for those with phenotypes specifically defective in floral morphogenesis. Here, we discuss the results of premolecular screens for flower development mutants in Arabidopsis thaliana, carried out at Caltech and Monash University, emphasizing the usefulness of saturation mutagenesis, multiple alleles to identify full loss-of-function, conclusions based on multiple mutant analyses, and from screens for enhancer and suppressor modifiers of original mutant phenotypes. One outcome was a series of mutants that led to the ABC floral organ identity model (AP1, AP2, AP3, PI, and AG). In addition, genes controlling flower meristem identity (AP1, CAL, and LFY), floral meristem size (CLV1 and CLV3), development of individual floral organ types (CRC, SPT, and PTL), and inflorescence meristem properties (TFL1, PIN1, and PID) were defined. These occurrences formed targets for cloning that eventually helped lead to an understanding of transcriptional control of the identity of floral organs and flower meristems, signaling within meristems, and the role of auxin in initiating floral organogenesis. These findings in Arabidopsis are now being applied to investigate how orthologous and paralogous genes act in other flowering plants, allowing us to wander in the fertile fields of evo-devo.


A mouse homoeo box gene is expressed during embryogenesis and in adult kidney.
The homoeo box sequence of Drosophila is an element located in several genes that regulate segmentation and segment identity; it has homologues in the genomes of vertebrate species and a number of homoeo box-containing recombinant DNA clones have been isolated from Xenopus, man and mouse. In the present study we have isolated from a library of murine DNA a recombinant lambda clone (H24.1) which contains a sequence closely homologous to the homoeo box within the Drosophila Antennapedia (Antp) gene. The protein sequence of the homoeo domain is identical to that encoded by Hu-1, one of a the pair of closely linked homoeo boxes in the human genome. We have used a sensitive RNase protection assay to examine transcription of the H24.1 gene during mouse development, and in adult tissues. We report that the gene is transcribed from as early as 7.5 days post coitum (p.c.), with maximum expression at days 11.5 and 12.5 p.c. The transcript is enriched in embryonic spinal cord and brain at day 12.5 p.c., and in adult kidney.


Biochar-rhizosphere interactions - A review.
Biochar is a solid material of biological origin obtained from the biomass carbonization, designed as a mean to reduce greenhouse gases emission and carbon sequestration in soils for a long time. Biochar has a wide spectrum of practical utilization and is applied as a promising soil improver or fertilizer in agriculture, or as a medium for soil or water remediation. Preparations of biochar increase plant growth and yielding when applied into soil and also improve plant growth conditions, mainly bio, physical and chemical properties of soil. Its physical and chemical properties have influence on bacteria, fungi and invertebrates, both in field and laboratory conditions. Such effects on rhizosphere organisms are positive or negative depending on biochar raw material origin, charring conditions, frequency of applications, applications method and doses, but long terms effects are generally positive and are associated mainly with increased soil biota activity. However, a risk assessment of biochar applications is necessary to protect the food production and soil environment. This should be accomplished by biochar production and characterization, land use implementation, economic analysis, including life cycle assessment, and environmental impact assessment.


Opioid signaling in mast cells regulates injury responses associated with heterotopic ossification.
Previous studies found that neuron specific enolase promoter (Nse-BMP4) transgenic mice have increased expression of the nociceptive mediator, substance P and exaggerated local injury responses associated with heterotopic ossification (HO). It is of interest great to know the pain responses in these mice and how the opioid signaling is involved in the downstream events such as mast cell (MC) activation. This study utilized a transgenic mouse model of HO in which BMP4 is expressed under the control of the Nse-BMP4. The tactile sensitivity and the cold sensitivity of the mice were measured in a classic inflammatory pain model (carrageenan solution injected into the plantar surface of the left hind paw). The MC activation and the expression profiles of different components in the opioid signaling were demonstrated through routine histology and immunohistochemistry and Western blotting, in the superficial and deep muscle injury models. We found that the pain responses in these mice were paradoxically attenuated or unchanged, and we also found increased expression of both Methionine Enkephalin (Met-Enk), and the μ-opioid receptor (MOR). Met-Enk and MOR both co-localized within activated MCs in limb tissues. Further, Nse-BMP4;MOR(-/-) double mutant mice showed attenuated MC activation and had a significant reduction in HO formation in response to injuries. These observations suggest that opioid signaling may play a key role in MC activation and the downstream inflammatory responses associated with HO. In addition to providing insight into the role of MC activation and associated injury responses in HO, these findings suggest opioid signaling as a potential therapeutic target in HO and possibly others disorders involving MC activation.


A pathogenic relationship between a regulator of the actin cytoskeleton and serum response factor.
Cell hyperproliferation, inflammation, and angiogenesis are biological processes central to the pathogenesis of corneal disease, as well as other conditions including tumorigenesis and chronic inflammatory disorders. Due to the number of disease conditions that arise as a result of these abnormalities, identifying the molecular mechanisms underlying these processes is critical. The avascular and transparent cornea serves as a good in vivo model to study the pathogenesis of cell hyperproliferation, inflammation, and angiogenesis. Corneal disease 1 (Dstn(corn1)) mice are homozygous for a spontaneous null allele of the destrin (Dstn) gene, which is also known as actin depolymerizing factor (ADF). These mice exhibit abnormalities in the cornea including epithelial cell hyperproliferation, stromal inflammation, and neovascularization. We previously identified that the transcription factor, serum response factor (SRF) and a number of its target genes are upregulated in the cornea of these mice. In this study, we show that conditional ablation of Srf in the corneal epithelium of a diseased Dstn(corn1) cornea results in the rescue of the epithelial cell hyperproliferation, inflammation, and neovascularization phenotypes, delineating an epithelial cell-specific role for SRF in the development of all of these abnormalities. Our study also demonstrates that Dstn is genetically upstream of Srf and defines a new functional role for SRF as the master regulator of a hyperproliferative, inflammatory phenotype accompanied by neovascularization.


Structural determinants of long-term functional outcomes in young children with cystic fibrosis.
Accelerated lung function decline in individuals with cystic fibrosis (CF) starts in adolescence with respiratory complications being the most common cause of death in later life. Factors contributing to lung function decline are not well understood, in particular its relationship with structural lung disease in early childhood. Detection and management of structural lung disease could be an important step in improving outcomes in CF patients. Annual chest computed tomography (CT) scans were available from 2005 to 2016 as a part of the AREST CF cohort for children aged 3 months to 6 years. Annual spirometry measurements were available for 89.77% of the cohort (167 children aged 5-6 years) from age 5 to 15 years through outpatient clinics at Perth Children's Hospital (Perth, Australia) and The Royal Children's Hospital in Melbourne (Melbourne, Australia) (697 measurements, mean±sd age 9.3±2.1 years). Children with a total CT score above the median at age 5-6 years were more likely to have abnormal forced expiratory volume in 1 s (FEV1) (adjusted hazard ratio 2.67 (1.06-6.72), p=0.037) during the next 10 years compared to those below the median chest CT score. The extent of all structural abnormalities except bronchial wall thickening were associated with lower FEV1 Z-scores. Mucus plugging and trapped air were the most predictive sub-score (adjusted mean change -0.17 (-0.26 - -0.07) p<0.001 and -0.09 (-0.14 - -0.04) p<0.001, respectively). Chest CT identifies children at an early age who have adverse long-term outcomes. The prevention of structural lung damage should be a goal of early intervention and can be usefully assessed with chest CT. In an era of therapeutics that might alter disease trajectories, chest CT could provide an early readout of likely long-term success.


Diagnosis, treatment and long-term outcome of solitary fibrous tumours of the pleura.
Solitary fibrous tumours of the pleura (SFTP) are rare and can histologically be differentiated into benign and malignant forms. The aim of this study is to present new cases, and discuss up-to-date preoperative examinations, the role of video-assisted thoracic surgery and long-term outcome. Between 1993 and 2006, 27 SFTPs were diagnosed (14 females, mean age+/-SD, 62.3+/-9.6 years) at our institution. Medical records were reviewed, and follow-up was obtained by repeated examinations or contact with general practitioners. SFTPs were associated with symptoms in 63% of all cases. In the six patients in which positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) was performed preoperatively, malignant lesions were all found to be positive. Complete resection was achieved by video-assisted thoracic surgery in 15 and anterolateral thoracotomy in 12 patients. Mean hospital stay was shorter for patients operated by video-assisted thoracic surgery compared to thoracotomy, 4.5 (range 3-6) versus 7.5 (range 4-25) days, respectively (p<0.01). Histology revealed 17 benign and 10 malignant SFTP. Mean+/-SD tumour diameter of malignant SFTPs was larger than in benign forms, 11.9+/-7.1 versus 6.1+/-3.5 cm, respectively (p<0.01). Tumour recurrence was recognised in four patients with malignant SFTPs at a median time interval after surgery of 38 (range 6-122) months, two late deaths occurred resulting from tumour recurrences. SFTPs can be treated minimally invasively by video-assisted thoracic surgery with short hospital stay. Large SFTPs with increased FDG-uptake have a high likelihood for malignancy. Long-term follow-up is mandatory in malignant SFTPs because of late recurrences associated with death.


Regulation of chitinase synthesis in Trichoderma harzianum.
The production of chitinase by Trichoderma species is of interest in relation to their use in biocontrol and as a source of mycolytic enzymes. Fourteen isolates of the genus were screened to identify the most effective producer of chitinase. The best strain for chitinase was Trichoderma harzianum 39.1, and this was selected for study of the regulation of enzyme synthesis. Washed mycelium of T. harzianum 39.1 was incubated with a range of carbon sources. Chitinase synthesis was induced on chitin-containing medium, but repressed by glucose and N-acetylglucosamine. Production of the enzyme was optimal at a chitin concentration of 0.5%, at 28 degrees C, pH 6.0 and was independent of the age of the mycelium. The synthesis of chitinase was blocked by both 8-hydroxyquinoline and cycloheximide, inhibitors of RNA and protein synthesis, respectively. The mode of chitinase synthesis in this fungus is discussed.


Simulated Costs of the ASCO Patient-Centered Oncology Payment Model in Medicare Beneficiaries With Newly Diagnosed Advanced Ovarian Cancer.
Efforts to curb the rising costs of cancer care while improving quality include alternative payment models (APMs), which offer incentives to reduce avoidable spending and provide high-quality and cost-efficient care. The impact of proposed APMs has not been quantified in real-world practice. In this study, we evaluated ASCO's Patient-Centered Oncology Payment (PCOP) model in existing fee-for-service (FFS) Medicare beneficiaries to understand the magnitude of potential cost savings. SEER-Medicare data were used to identify women with advanced ovarian cancer diagnosed between 2000 and 2012 who either (1) underwent primary debulking surgery followed by chemotherapy or (2) received neoadjuvant chemotherapy followed by surgery. Medicare payments in each cohort were used to compare FFS and PCOP and to estimate the potential for cost savings across health care services received, including outpatient emergency department visits, hospitalizations, and imaging. Three thousand seven hundred seventy-seven primary debulking surgery and 866 neoadjuvant chemotherapy patients were included in the study, with mean total costs of $75,433 and $95,138 in 2016 US$, respectively Most costs were related to chemotherapy or hospitalization. Additional PCOP-related payments would be offset if hospitalizations could be reduced by 11.6% or imaging claims by 88%. APMs have the potential to reduce costs of current FFS reimbursement via either a large reduction in imaging or a modest reduction in hospitalizations during treatment of ovarian cancer. PCOP is a reasonable payment structure for oncologists if the additional payments can provide the necessary resources to invest in improved coordination of care.


Psychotropic medication exposure and age at onset of bipolar disorder in offspring of parents with bipolar disorder.
Exposure to psychotropic medications before the onset of bipolar disorder (BD) in children may have profound effects on the course of illness. Both antidepressant and stimulant exposure have been proposed to hasten the course of BD development, whereas mood stabilizers have been proposed as protective. We sought to describe psychotropic medication exposure in a cohort of children at risk for BD and retrospectively determine the effect of medication exposure on age at onset (AAO) of BD. Subjects were 106 children and adolescents who had at least 1 parent with BD. Of these, 63 had BD I or BD II and 43 had subsyndromal symptoms of BD. AAO was determined as nearest month of first manic or hypomanic episode. Past psychotropic medication exposure prior to AAO was determined through interview and chart review. Both groups had high rates of exposure to psychotropic medications. Antidepressant or stimulant exposure was not correlated with an earlier AAO of BD. However, mood stabilizer exposure was associated with a later AAO. Children with full or subsyndromal BD are frequently exposed to a variety of psychotropic medications before their first manic episode. Our findings do not support that early stimulant or antidepressant exposure leads to an earlier AAO of BD. However, early mood stabilizer exposure may be associated with delayed AAO. Longitudinal studies are needed to clarify these results.


[Radionuclide angiography (RNA) with 99mTc-DTPA to follow palliative embolization of renal cell carcinoma (author's transl)].
In 14 patients with renal cell carcinoma, not to be treated by nephrectomy, radionuclide angiography with 99mTc-DTPA (RNA) was employed before and after palliative tumor embolization. If RNA revealed remaining perfusion of the tumor, functional scintigraphy with 131J-hippurate was performed to detect and quantify residual function. Up to 16 months after embolization, 7 patients (50%) revealed neither residual perfusion nor function. In 5 patients (36%) remaining perfusion without functioning renal parenchyma and in 2 patients (14%) residual perfusion with additional function were found. In 4 cases (28%) a nuclear "tumor-halo" was imaged, describing a stripe of high radioactivity caused by capsular arteries surrounding the avascular tumor. RNA has proven to be a suitable non-invasive procedure for to blow-up of embolized renal cell carcinomas.


Filters with random transmittance for improving resolution in filter-array-based spectrometers.
In this paper, we introduce a method for improving the resolution of miniature spectrometers. Our method is based on using filters with random transmittance. Such filters sense fine details of an input signal spectrum, which, when combined with a signal processing algorithm, aid in improving resolution. We also propose an approach for designing filters with random transmittance using optical thin-film technology. We demonstrate that the improvement in resolution is 7-fold when using the filters with random transmittance over what was achieved in our previous work.


Definitions related to the use of pharmaceutical opioids: extramedical use, diversion, non-adherence and aberrant medication-related behaviours.
This paper (i) reviews the language used to describe and manage those patient practices that fall outside standard medical models of opioid treatment (for pain and opioid dependence), and (ii) proposes a consistent terminology that can be applied across multiple healthcare settings. Peer-reviewed and grey literature documenting empirical studies of (non-)adherence with opioid treatment, proposed definitions or other potentially important aspects of terminology were included in this review. There are international inconsistencies in the terminology used to describe the unintended consequences of opioid treatment, and the terms used often lack specificity. The terms 'hazardous use', 'extramedical use', 'opioid dependence', 'diversion', 'non-adherence' and 'aberrant behaviours' are defined. We advocate for consistent application of these terms in the context of opioid treatment, and propose that care is taken to describe individual practices and intentions. The increasing global attention on the use and diversion of pharmaceutical opioids warrants a discussion of current terms and definitions. Exaggerated concerns regarding 'addiction potential' may result in restrictions in the supply of opioids and the under-treatment of legitimate medical conditions. Researchers, clinicians, policy-makers and patients need to ensure greater care is given to terminology, including detailed descriptions of patient practices, the context in which they occur and severity of associated harm.


Place aversion induced by blockade of mu or activation of kappa opioid receptors in the dorsal periaqueductal gray matter.
Neural circuits in the dorsal periaqueductal grey matter (DPAG) play an important role in the integration of defensive behaviour. As considerable numbers of mu and kappa opioid receptors have been found in this region, we studied the effects of morphine, [3H]-[H-D-Phe-Cys-Tyr- D-Trp-Orn-Thr-Pen-Thr-NH2] (CTOP), a selective peptide antagonist for mu opioid receptors, U-50488H, a specific agonist for kappa opioid receptors, and nor-binaltorphimine (nor-BNI), a long-lasting selective antagonist for kappa opioid receptors, injected into the DPAG of rats submitted to the corral method, a conditioned place preference test. The behavioural testing apparatus was a circular open field consisting of four uniform quadrants that were equally preferred by the rats prior to drug treatments. For conditioning, rats received drug injections on three consecutive days and were placed into their assigned quadrant. Injection of 40 nmol of morphine into the DPAG produced place aversion effects, with reduced time spent in the drug-paired quadrant on the testing day. These place aversion effects were not inhibited by previous DPAG microinjection of CTOP (1 nmol) but were significantly reduced by prior systemic injections of nor-BNI (2 mg / kg). Microinjection of CTOP alone produced a clear decrease in the time spent in the treatment quadrant, whereas nor-BNI alone did not. Similarly, microinjection into the DPAG of the kappa agonist U-50488H (10 nmol) mimicked the effects of morphine, also producing place aversion for the drug-paired quadrant. These findings suggest that blockade of mu opioid receptors or activation of kappa opioid receptors in the DPAG may produce conditioned place aversion.


Diabetes aggravates periodontitis by limiting repair through enhanced inflammation.
Periodontitis is the most common lytic bone disease and one of the first clinical manifestations of diabetes. Diabetes increases the risk of periodontitis. The aim of the present study was to examine mechanisms by which diabetes aggravates periodontitis. Ligature-induced periodontitis was examined in Goto-Kakizaki rats with type 2 diabetes. A tumor necrosis factor (TNF)-specific-inhibitor, pegsunercept, was applied to diabetic rats after the onset of periodontal disease. Interferon-γ (IFN-γ), TNF-α, interleukin-1 β (IL-1β), fibroblast growth factor-2 (FGF-2), transforming growth factor beta-1 (TGFβ-1), bone morphogenetic protein-2 (BMP-2), and BMP-6 were measured by real-time RT-PCR, and histological sections were examined for leukocyte infiltration and several parameters related to bone resorption and formation. Inflammation was prolonged in diabetic rats and was reversed by the TNF inhibitor, which reduced cytokine mRNA levels, leukocyte infiltration, and osteoclasts. In contrast, new bone and osteoid formation and osteoblast numbers were increased significantly vs. untreated diabetic animals. TNF inhibition in diabetic animals also reduced apoptosis, increased proliferation of bone-lining cells, and increased mRNA levels of FGF-2, TGFβ-1, BMP-2, and BMP-6. Thus, diabetes prolongs inflammation and osteoclastogenesis in periodontitis and through TNF limits the normal reparative process by negatively modulating factors that regulate bone.


Ketogenic Diet Provides Neuroprotective Effects against Ischemic Stroke Neuronal Damages.
Ischemic stroke is a leading cause of death and disability in the world. Many mechanisms contribute in cell death in ischemic stroke. Ketogenic diet which has been successfully used in the drug-resistant epilepsy has been shown to be effective in many other neurologic disorders. The mechanisms underlying of its effects are not well studied, but it seems that its neuroprotective ability is mediated at least through alleviation of excitotoxicity, oxidative stress and apoptosis events. On the basis of these mechanisms, it is postulated that ketogenic diet could provide benefits to treatment of cerebral ischemic injuries.


UBE3A activates the NOTCH pathway and promotes esophageal cancer progression by degradation of ZNF185.
Background: Esophageal cancer is the sixth-most common fatal malignant tumor worldwide. Little is known regarding the genetic drivers that influence targeted therapy outcomes in patients with esophageal cancer. Exploring the pathogenesis of this lethal tumor could provide clues for developing appropriate therapeutic drugs. Ubiquitin-protein ligase E3A (UBE3A) reportedly promotes or suppresses various types of malignant tumors. However, the cancer-related role of UBE3A in esophageal cancer remains unclear. Methods: The relationship of UBE3A with the clinicopathological features of pancreatic tumors was bioinformatically investigated in the TCGA dataset. The protein levels of UBE3A and ZNF185 were assessed by Western blot and immunohistochemistry. The role of UBE3A and ZNF185 in esophageal cancer growth was assessed by MTS assays, colony formation assays, and experiments in mouse xenograft models. The interaction between UBE3A and ZNF185 was investigated by co-immunoprecipitation. The relationship between UBE3A, ZNF185, and NOTCH signaling pathway was explored by Western blot and quantitative real-time PCR. Results: We found that UBE3A was upregulated in patients with esophageal cancer and enhanced the cellular progression of esophageal cancer. Moreover, we found that UBE3A degraded ZNF185 in esophageal cancer. Additionally, ZNF185 suppressed the progression of esophageal cancer by inactivating the NOTCH pathway. Conclusions: These data demonstrated that aberrant expression of UBE3A led to enhanced progression of esophageal cancer through the ZNF185/NOTCH signaling axis. Therefore, UBE3A might be an ideal therapeutic candidate for esophageal cancer.


Ex vivo light dosimetry and Monte Carlo simulations for endobronchial photodynamic therapy.
The light distribution during photodynamic therapy of the bronchial tree has been estimated by measuring the fluence rate in ex vivo experiments on dissected pig bronchi. The trachea was illuminated (630 nm) with a cylindrical diffuser and the fluence rate was measured with a fibre optic isotropic probe. The experiment with the diffuser on the central axis was also simulated with Monte Carlo techniques using the optical properties that were determined with a double-integrating-sphere set-up. The results from ex vivo experiments and the Monte Carlo simulations were found to agree within the error of measurement (15%), indicating that the Monte Carlo technique can be used to estimate the light distribution for varying geometries and optical properties. The results showed that the light fluence rate in the mucosa of the tracheal tract may increase by a factor of six compared to the fluence rate in air (in the absence of tissue). This is due to the scattering properties of the tissue and the multiple reflections within the cavity. Further ex vivo experiments showed that the positioning of the diffuser is critical for the fluence rate in the lesion to be treated. When the position of the diffuser was changed from the central axis to near the lesion, the fluence rate in the mucosa increased significantly by several orders of magnitude as compared to the initial (central) illumination. The inter- and intraspecimen variations in this increase were large (+/- 35%) because of variations in optical and geometrical properties and light source positioning, respectively. These variations might cause under- or overdosage resulting in either insufficient tumour necrosis or excessive normal tissue damage.


Cytosine to thymine transitions from decay of cytosine-5-3H in bacteriophage S13.
Decay of cytosine-5-(3)H incorporated into bacteriophage S13 DNA causes a molectular rearrangement of the cytosine molecutle undergoing the decay. The molecular rearrangement produces a cytosine to thyimine coding change with at efficiency approaching one. Decay of either thymidine-(methyl)-(3)H or cytosine-6-(3)H is less than 1 percent as effective in calusing either cytosine to thymine or thymine to cytosine transitions.


Transvaginal Sonography Versus Cystoscopy for Detecting Urinary Bladder Invasion in Early Stage Cervical Cancer.
Cervical cancer is a major cause of mortality from cancer among women. In it's early stage pre operative staging with cystoscopy is a standard procedure for the detection of urinary bladder involvement. The present study was conducted with the aim to compare the efficacy of Transvaginal Sonography (TVS) and cystoscopy in diagnosing bladder involvement in early stage cervical cancer patients by confirming it intraoperatively and further by histopathologic examination. A prospective partially blinded study was conducted between March 2006 and September 2008 on 30 patients with early stage cervical cancer (Stage I and IIa) who were planned to undergo radical hysterectomy. Pre operatively, these patients underwent both TVS and cystoscopy to diagnose bladder involvement. Presence or absence of bladder involvement was then confirmed intra operatively and by histopathologic examination. In all the 30 patients studied, no bladder involvement was seen on cystoscopy where as TVS showed bladder involvement in three patients. Involvement of the bladder in these three patients was confirmed intra operatively and by histopathologic examination. Thus, in our study, TVS was 100% sensitive in detecting bladder involvement. TVS is highly sensitive in diagnosing bladder involvement in early stage cervical cancer and could potentially detect cases missed with a cystoscopy.


[Two children with unusual causes of torticollis: primitive neuroectodermal tumor and Grisel's syndrome].
Two children were presented with a torticollis. One, a 2-year-old girl, had a primitive neuroectodermal tumour of the cervical spinal cord which could not be radically removed surgically (the patient died three days later), the other, a 9-year-old boy, had the syndrome of Grisel. He was treated with antibiotics, head traction and atlantoaxial posterior spondylodesis. Acquired torticollis is a frequent innocent symptom in children with cervical lymphadenopathy following a respiratory tract infection. These cases demonstrate that additional investigation should not be delayed if relief of symptoms is not achieved very soon.


Molecular pain markers correlate with pH-sensitive MRI signal in a pig model of disc degeneration.
Intervertebral disc (IVD) degeneration is a leading cause of chronic low back pain that affects millions of people every year. Yet identification of the specific IVD causing this pain is based on qualitative visual interpretation rather than objective findings. One possible approach to diagnosing pain-associated IVD could be to identify acidic IVDs, as decreased pH within an IVD has been postulated to mediate discogenic pain. We hypothesized that quantitative chemical exchange saturation transfer (qCEST) MRI could detect pH changes in IVDs, and thence be used to diagnose pathologically painful IVDs objectively and noninvasively. To test this hypothesis, a surgical model of IVD degeneration in Yucatan minipigs was used. Direct measurement of pH inside the degenerated IVDs revealed a significant drop in pH after degeneration, which correlated with a significant increase in the qCEST signal. Gene analysis of harvested degenerated IVDs revealed significant upregulation of pain-, nerve- and inflammatory-related markers after IVD degeneration. A strong positive correlation was observed between the expression of pain markers and the increase in the qCEST signal. Collectively, these findings suggest that this approach might be used to identify which IVD is causing low back pain, thereby providing valuable guidance for pain and surgical management.