The coordination of upper and lower arm rotation.
We tested the hypothesis that the upper and lower arm act as a coordinative structure coupled through a higher order control system. Five healthy participants moved their hand between two targets in ten conditions via internal/external rotation of the shoulder. In eight conditions, the task required concurrent rotation of the lower arm (180 degrees pronation/supination). Movements were stereotypical within a condition but plotting the upper and lower arm angle against each other produced an asymmetrical pattern. With internal rotation, the upper arm reached peak angular velocity slower than the lower arm but this was reversed with external rotation. In two conditions, participants were asked to move faster and slower than their normal speed. The peak speed, time to peak speed and duration were predictable for the different tasks. Internal and external asymmetries decreased with faster movements. In addition a decrease in upper arm amplitude (from 90 degrees to 30 degrees) removed the asymmetry. The asymmetry was unaffected by initial posture but was exaggerated when external rotation was paired with pronation rather than supination, and internal rotation combined with supination (versus pronation). However, the presence of the same fundamental pattern suggests that the asymmetry is not due to biomechanical factors but might arise because of the difficulties involved in visually monitoring the hand when it is close to the body. The results support the idea that functional coupling can occur between upper and lower arm rotations and thus provides further evidence for a higher order control system which is responsible for coordination of arm segment movement.


Revisiting the Term "Compassionate Use" and Leadership of the World Health Organization in Resolving Confusion in the Age of COVID-19 and Beyond.
We discuss the term "compassionate use" (CU) as an example of terminology having a huge impact on drug regulation. CU is used in many confusing situations, and its meaning varies significantly. We ethically affirm the necessity of CU. We insist that CU should be properly placed in exceptional status. The regulation of CUs is much more lenient than that of clinical trials because of the difference in the purpose. Whether consciously or unconsciously, abuse results in confusion and is never acceptable. The World Health Organization (WHO) proposed not to use the previous term CU but to replace it with another one. WHO also proposed the term MEURI (monitored emergency use of unregistered and experimental interventions). However, this was extremely incomplete, and WHO used the term CU subsequently. The main purpose of the proposal needs to be thoroughly implemented. In the context of the COVID-19 pandemic and beyond, expectations regarding WHO's role and leadership in global health issues are rising. We hope that WHO will play a major role in promoting research ethics preparedness while discontinuing the use of confusing terms such as CU and will develop alternative terms and their content. We discuss the evaluation of MEURI, the Japanese version of CU, and appropriate and inappropriate terminology related to the therapeutic use of unapproved drugs. We also discuss the expected appearance of CU including its name. It is appropriate to target group/cohort patients and unapproved drugs in the late stage of development. It is also important to solve the problem of incentives for CUs of pharmaceutical companies that are rushing to obtain marketing approval. The UK's Early Access to Medicine Scheme has provided many suggestions. We believe that our opinion can contribute to WHO's efforts to resolve the confusion and promote research ethics preparedness in health emergencies.


Donor-derived spermatogenesis following stem cell transplantation in sterile NANOS2 knockout males.
Spermatogonial stem cell transplantation (SSCT) is an experimental technique for transfer of germline between donor and recipient males that could be used as a tool for biomedical research, preservation of endangered species, and dissemination of desirable genetics in food animal populations. To fully realize these potentials, recipient males must be devoid of endogenous germline but possess normal testicular architecture and somatic cell function capable of supporting allogeneic donor stem cell engraftment and regeneration of spermatogenesis. Here we show that male mice, pigs, goats, and cattle harboring knockout alleles of the NANOS2 gene generated by CRISPR-Cas9 editing have testes that are germline ablated but otherwise structurally normal. In adult pigs and goats, SSCT with allogeneic donor stem cells led to sustained donor-derived spermatogenesis. With prepubertal mice, allogeneic SSCT resulted in attainment of natural fertility. Collectively, these advancements represent a major step toward realizing the enormous potential of surrogate sires as a tool for dissemination and regeneration of germplasm in all mammalian species.


Perioperative epidural analgesia in children undergoing major abdominal tumor surgery--a single center experience.
The purpose of this study was to assess the use of continuous epidural analgesia in pediatric patients undergoing major abdominal tumor surgery. Children undergoing major abdominal tumor surgery at our institution between 2008 and 2012 (n=40) received continuous epidural analgesia via an epidural catheter. Surgical trauma scores, pain scores, and clinical data of the children were compared to a pair-matched historical control group operated on between 2002 and 2007 without epidural analgesia. Pain levels in the study group on day 1 and 3 after surgery were lower compared to the control group. The differences did, however, not reach statistical significance (p=0.15 and 0.09). Children in the study group received significantly fewer additional doses of piritramide or morphine (45% versus 82%, p<0.001). Despite significantly higher surgical trauma scores in the study group (p=0.018), there were no statistical differences regarding clinical parameters, such as mechanical ventilation time, time on intensive care unit, and total hospital stay. There were no catheter-related complications. Continuous epidural analgesia is beneficial for children undergoing complex abdominal tumor surgery with regard to pain levels, postoperative recovery, and general clinical course. Expertise of the managing team, a careful patient selection, and a continuous quality assessment are essential for success.


Density of motility-related charge in the outer hair cell of the guinea pig is inversely related to best frequency.
Whole cell voltage clamp and freeze fracture were used to study the electrophysiological and ultrastructural correlates of the outer hair cell (OHC) lateral membrane molecular motors. We find that specific voltage-dependent capacitance, which derives from motility-related charge movement, increases as cell length decreases. This increasing non-linear charge density predicts a corresponding increase in sensor-motor density. However, while OHC lateral membrane particle density increases, a quantitative correspondence is absent. Thus, the presumed equivalence of particle and motor is questionable. The data more importantly indicate that whereas the voltage driving OHC motility, i.e. the receptor potential, may decrease with frequency due to the OHC's low-pass membrane filter, the electrical energy (Q x V) supplied to the lateral membrane will tend to remain stable. This conservation of energy delivery is likely crucial for the function of the cochlear amplifier at high frequencies.


Swarming behaviour associated with group cohesion in tree-dwelling bats.
Group living of social species increases the individual survival rate and enhances optimal exploitation of resources within their environment. Groups of cryptic tree-dwelling bats perform frequent roost switching on relatively long distances, whereas groups are temporarily disintegrated during foraging that precedes moving into new roost. In this study, we attempted to elucidate a mechanism in which group members can select new roost from a large set of potential roosting sites without disintegration of the whole group. Exploring the activity at the front of the tree hollows, recorded by automatic infrared monitors, we found that the swarming activity of Leisler's bats was performed during the whole night and was concentrated before the civil twilight at occupied roosts. A generalized linear model revealed significant positive association between the group size and swarming activity while season had negative but smaller effect. As bats swarmed the whole night also at sites that were less occupied or even unoccupied, we suggest that members of a bat colony selected new roost from a potentially larger set of available roosting sites. Thus, we propose a possible signalling role of swarming as a threshold behaviour that ensures group cohesion during roost switching.


Artificial intelligence based prediction models for individuals at risk of multiple diabetic complications: A systematic review of the literature.
The aim of this review is to examine the effectiveness of artificial intelligence in predicting multimorbid diabetes-related complications. In diabetic patients, several complications are often present, which have a significant impact on the quality of life; therefore, it is crucial to predict the level of risk for diabetes and its complications. International databases PubMed, CINAHL, MEDLINE and Scopus were searched using the terms artificial intelligence, diabetes mellitus and prediction of complications to identify studies on the effectiveness of artificial intelligence for predicting multimorbid diabetes-related complications. The results were organized by outcomes to allow more efficient comparison. Based on the inclusion/exclusion criteria, 11 articles were included in the final analysis. The most frequently predicted complications were diabetic neuropathy (n = 7). Authors included from two to a maximum of 14 complications. The most commonly used prediction models were penalized regression, random forest and Naïve Bayes model neural network. The use of artificial intelligence can predict the risks of diabetes complications with greater precision based on available multidimensional datasets and provides an important tool for nurses working in preventive health care. Using artificial intelligence contributes to a better quality of care, better autonomy of patients in diabetes management and reduction of complications, costs of medical care and mortality.


Inhibitory effect of plain and functionalized graphene nanoplateles on hen egg white lysozyme fibrillation.
Protein fibrillation is a phenomenon associated with misfolding and the production of highly ordered nanofibrils, which may cause serious degenerative diseases such as Parkinson's disease, Alzheimer's disease, and type 2 diabetes. Upon contact with biological fluids, the nanomaterials are immediately covered by proteins and interact with them. In this study, the effects of Graphene NanoPlateles (Plain-GNPs) and their modified forms with a carboxyl group (GNPs -COOH) and an amine group (GNPs -NH2) are evaluated on the fibrillation process of Hen Egg White Lysozyme (HEWL). The fibrillation process of HEWL was studied using thioflavin-T, Circular Dichroism spectrometry, and Atomic Force Microscopy. Plain-GNPs significantly decreased the fibrillation process at different stages, including nucleation, exponential fibrillation phases, and end-mature fibril products. However, GNPs-COOH and GNPs-NH2 affected the final fluorescence of ThT. The species formed in the presence of Plain-GNPs showed less toxicity in SH-SY5Y cells, which could be applicable for therapeutic purposes.


Increased serum levels of fractalkine and mobilisation of CD34+CD45- endothelial progenitor cells in systemic sclerosis.
The disruption of endothelial homeostasis is a major determinant in the pathogenesis of systemic sclerosis (SSc) and is reflected by soluble and cellular markers of activation, injury and repair. We aimed to provide a combined assessment of endothelial markers to delineate specific profiles associated with SSc disease and its severity. We conducted an observational, single-centre study comprising 45 patients with SSc and 41 healthy control subjects. Flow cytometry was used to quantify circulating endothelial microparticles (EMPs) and CD34+ progenitor cell subsets. Colony-forming unit-endothelial cells (CFU-ECs) were counted by culture assay. Circulating endothelial cells were enumerated using anti-CD146-based immunomagnetic separation. Blood levels of endothelin-1, vascular endothelial growth factor (VEGF) and soluble fractalkine (s-Fractalkine) were evaluated by enzyme-linked immunosorbent assay. Disease-associated markers were identified using univariate, correlation and multivariate analyses. Enhanced numbers of EMPs, CFU-ECs and non-haematopoietic CD34+CD45- endothelial progenitor cells (EPCs) were observed in patients with SSc. Patients with SSc also displayed higher serum levels of VEGF, endothelin-1 and s-Fractalkine. s-Fractalkine levels positively correlated with CD34+CD45- EPC numbers. EMPs, s-Fractalkine and endothelin-1 were independent factors associated with SSc. Patients with high CD34+CD45- EPC numbers had lower forced vital capacity values. Elevated s-Fractalkine levels were associated with disease severity, a higher frequency of pulmonary fibrosis and altered carbon monoxide diffusion. This study identifies the mobilisation of CD34+CD45- EPCs and high levels of s-Fractalkine as specific features of SSc-associated vascular activation and disease severity. This signature may provide novel insights linking endothelial inflammation and defective repair processes in the pathogenesis of SSc.


Economic interests cloud hazard reductions in the European regulation of substances of very high concern.
Here we investigate how the conflicts between hazard reduction and economic interests have shaped the regulation of substances of very high concern (SVHCs) under the Authorization program of the European chemical regulation Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH). Since regulation starts with listing SVHCs on the Candidate List, we analyze the relative importance of toxicological properties, economic motivations, and available scientific knowledge on the probability of inclusion on the Candidate List. We find that the most important factor in whether a substance is listed is whether it is being produced in, or imported into, the European Economic Area (EEA), with the regulators less likely to place a substance on the list if it is currently being produced or imported in the EEA. This evidence suggests that regulators have listed chemicals of secondary importance leading to lesser than anticipated hazard reductions, either because production and imports had already ceased before the listing, or because the compound has never been produced or imported in the EEA at all.


Effects of paclitaxel in combination with ionizing radiation on angiogenesis in the chick embryo chorioallantoic membrane. A radiobiological study.
To investigate the combined effects of paclitaxel and single or fractionated doses of ionizing radiation on the angiogenesis process, using as a model the chick embryo choriallantoic membrane (CAM). Experiments were performed on 9-day CAM, when membranes were irradiated with various single or fractionated doses of X-rays, either alone or in combination with paclitaxel (6.4 micro g/disk). Single doses of irradiation (5, 10, or 15 Gy) produced a significant antiangiogenic effect, which was not dose-dependent. Fractionated doses of X-rays (two doses of 2.5, 5, or 7.5 Gy, each 12 h apart) exerted a dose-dependent reduction of the vascular density index. Paclitaxel was not shown to provoke radiosensitization in this model, i. e., to inhibit angiogenesis of the 9-day CAM. These data confirm that the CAM system can be conveniently and properly used for radiobiological studies and indicate that paclitaxel in combination with ionizing radiation does not inhibit further angiogenesis in the system used.


The accuracy of transcutaneous bilirubin to identify hyperbilirubinemia in jaundiced neonates.
To compare transcutaneous bilirubin (TcB) to total serum bilirubin (TSB) in jaundiced neonates by using a JM-103 bilirubinometer. We conducted a retrospective study in jaundiced infants ≥35 weeks' gestation. Infants' and maternal information, TcB measurements, and TSB levels were collected. The correlation and consistency between TcB and TSB were analyzed by Pearson's correlation analysis and the Bland-Altman plot. Multivariate regression analysis was used to identify characteristics associated with the difference between TcB and TSB, underestimation by TcB and overestimation by TcB. A total of 787 paired samples were collected. There was a strong correlation between TcB and TSB with a Pearson correlation coefficient of 0.708 (p < .001). In preterm infants, outpatients and infants with high TSB levels, the TcB measurements were less precise. The TcB-TSB difference was significantly associated with gender, maternal hypertension disease, ABO hemolytic disease, and outpatient setting (p < .05). Only the outpatient setting had statistical significance in the underestimation of TSB ≥2 mg/dL. Generally, TcB by a JM-103 bilirubinometer had a good correlation and consistency with the TSB values. However, small for gestational age, postnatal age of hour, ABO hemolytic disease, and outpatient setting may lead to inconsistencies between the TcB and TSB.


Whole-body counter surveys of over 2700 babies and small children in and around Fukushima Prefecture 33 to 49 months after the Fukushima Daiichi NPP accident.
BABYSCAN, a whole-body counter (WBC) for small children was developed in 2013, and units have been installed at three hospitals in Fukushima Prefecture. Between December, 2013 and March, 2015, 2707 children between the ages of 0 and 11 have been scanned, and none had detectable levels of radioactive cesium. The minimum detectable activities (MDAs) for (137)Cs were ≤ 3.5 Bq kg(-1) for ages 0-1, decreasing to ≤ 2 Bq kg(-1) for ages 10-11. Including the (134)Cs contribution, these translate to a maximum committed effective dose of ∼ 16 µSv y(-1) even for newborn babies, and therefore the internal exposure risks can be considered negligibly small.Analysis of the questionnaire filled out by the parents of the scanned children regarding their families' food and water consumption revealed that the majority of children residing in the town of Miharu regularly consume local or home-grown rice and vegetables, while in Minamisoma, a majority avoid tap water and produce from Fukushima. The data show, however, no correlation between consumption of locally produced food and water and the children's body burdens.


RhoA/ROCK pathway inhibitor ameliorates erectile dysfunction induced by radiation therapy in rats.
Prostate cancer (PCa) treatment with radiation therapy (RT) has an excellent cure rate. However, Radiation-induced Erectile Dysfunction (RiED) is a common and irreversible toxicity impacting quality of life, and there is no FDA approved specific drug for RiED. We previously showed that prostate RT increased RhoA/ROCK signaling in the cavernous nerve (CN) and penile tissues, which may lead to RiED in rats. In this study, we investigated whether RhoA/ROCK pathway inhibition by a specific inhibitor called Hydroxyfasudil (HF) can improve RiED in our well-established rat model. Male Sprague-Dawley rats were randomized to the following groups: sham-RT, HF-only, RT-only, and RT + HF. Rats were either exposed to a single dose of 25 Gy prostate-confined RT or a sham procedure. 10 mg/kg HF or normal saline was injected intraperitoneally. Erectile function was evaluated by intracavernosal pressure (ICP) and mean arterial pressure (MAP) measurements at week 14 post-RT. Cavernous nerve (CN) injury was evaluated by transmission electron microscopy (TEM), and penile tissue fibrosis by Masson trichrome staining (MT). We have found that the HF treatment prior to RT showed significant (p < 0.001) improvement in ICP/MAP ratio, area under the curve, and maximum ICP value, compared to RT-alone rats. Furthermore, RT + HF treated rats exhibited increased CN myelination and decreased axonal atrophy, comparted to RT-only. HF treatment showed significantly decreased penile tissue fibrosis (p < 0.05) compared to RT-alone treated rats. Our results provide the first preclinical evidence that targeting RhoA/ROCK pathway by HF may provide a novel therapeutic option for the treatment of RiED.


Acute kidney injury and renal replacement therapy in COVID-19 patients: A systematic review and meta-analysis.
Reported rates of acute kidney injury (AKI) have varied significantly among studies of coronavirus disease 2019 (COVID-19) published to date. The present meta-analysis was conducted to gain clarity regarding AKI incidence and renal replacement therapy (RRT) use in COVID-19 patients. The PubMed, Embase, Web of Science, medRxiv, and bioRxiv databases were systematically searched for COVID-19-related case reports published through 25 July 2020. Pooled analyses were conducted using R. The pooled incidence of AKI in 51 studies including 21,531 patients was 12.3% (95% CI 9.5-15.6%), with higher rates of 38.9% in 290 transplant patients (95% CI 27.3-51.9%), 39.0% in 565 ICU patients (95% CI 23.2-57.6%) and 42.0% among 1745 deceased patients (95% CI 30.3-54.7%). RRT usage was reported in 39 studies of 17,664 patients, with an overall pooled use of 5.4% (95% CI 4.0-7.1%), with higher rates of 15.6% in 117 transplant patients (95%CI 9.9-23.8%) and 16.3% in 776 ICU patients (95% CI 11.1-23.3%). AKI and RRT use among COVID-19 patients represent a major public health concern, and early and appropriate intervention should be called upon to improve the prognosis of patients suffering from AKI.


Probing a functional role of Glu87 and Trp89 in the lid of Humicola lanuginosa lipase through transesterification reactions in organic solvent.
To reveal the functional role of Glu87 and Trp89 in the lid of Humicola lanuginosa lipase, site-directed mutagenesis at Glu87 and Trp89 was carried out. The catalytic performance of wild-type and mutated lipases was studied in transesterification reactions in cyclohexane at a controlled water activity. Two different acyl donors were used in the investigation: tributyrin, a natural substrate for a lipase, and vinyl butyrate, an activated ester suitable for fast and efficient lipase-catalyzed transformations in preparative organic synthesis. As acyl acceptor 1-heptanol was used. The Glu87Ala mutation decreased the Vmax,app value with tributyrin and vinyl butyrate by a factor of 1.5 and 2, respectively. The Km,app for tributyrin was not affected by the Glu87Ala mutation, but the Km,app for vinyl butyrate increased twofold compared to the wild-type lipase. Changing Trp89 into a Phe residue afforded an enzyme with a 2.7- and 2-fold decreased Vmax,app with the substrates tributyrin and vinyl butyrate, respectively, compared to the wild-type lipase. No significant effects on the Km,app values for tributyrin or vinyl butyrate were seen as a result of the Trp89Phe mutation. However, the introduction of a Glu residue at position 89 in the lid increased the Km,app for tributyrin and vinyl butyrate by a factor of > 5 and 2, respectively. The Trp89Glu mutated lipase could not be saturated with tributyrin within the experimental conditions (0-680 mM) studied here. With vinyl butyrate as a substrate the Vmax,app was only 6% of that obtained with wild-type enzyme.


Isolation and characterization of a rat brain triakontatetraneuropeptide, a posttranslational product of diazepam binding inhibitor: specific action at the Ro 5-4864 recognition site.
This report describes the purification and characterization from rat brain of triakontatetraneuropeptide (TTN, DBI 17-50), a major biologically active processing product of diazepam binding inhibitor (DBI). Brain TTN was purified by immunoaffinity chromatography with polyclonal octadecaneuropeptide, DBI 33-50) antibodies coupled to CNBr-Sepharose 4B followed by two reverse-phase HPLC steps. The amino acid sequence of the purified peptide is: Thr-Gln-Pro-Thr-Asp-Glu-Glu-Met-Leu-Phe-Ile-Tyr-Ser-His-Phe-Lys-Gln-Ala-Thr-Val - Gly-Asp-Val-Asn-Thr-Asp-Arg-Pro-Gly-Leu-Leu-Asp-Leu-Lys. Synthetic TTN injected intracerebroventricularly into rats induces a proconflict activity (IC50 0.8 nmol/rat) that is prevented by the specific "peripheral" benzodiazepine (BZ) receptor antagonist isoquinoline carboxamide, PK 11195, but not by the "central" BZ receptor antagonist imidazobenzodiazepine, flumazenil. TTN displaces [3H]Ro 5-4864 from synaptic membranes of olfactory bulb with a Ki of approximately 5 microM. TTN also enhances picrotoxinin inhibition of gamma-aminobutyric acid (GABA)-stimulated [3H]flunitrazepam binding. These data suggest that TTN, a natural DBI processing product acting at "Ro 5-4864 preferring" BZ binding site subtypes, might function as a putative neuromodulator of specific GABAA receptor-mediated effects.


Microleakage of five dentin bonding systems.
Class V preparations were placed in the buccal surfaces of 60 extracted human teeth such that approximately half of the preparations were above the CEJ and half below. The teeth were restored with Gluma/Pekalux, Tenure/Perfection, Scotchbond 2/Silux Plus, XR bond/Herculite XR, and Optec/Pentrafil 2 according to manufacturers' instructions. The sixth set of teeth was restored with a combination of XRbond/Silux Plus. The teeth were thermocycled and stained in silver nitrate. They were then scored for dye penetration. Scotchbond 2 showed the least dye penetration but not statistically less than the XR bond/Silus Plus combination. XR bond/Silux Plus showed significantly less dye penetration than XR bond/Herculite XR.


Endoscopic rendez-vous reconstruction of complete biliary obstruction.
Complete biliary strictures normally require surgical intervention. We describe an alternative, minimally invasive endoscopic/percutaneous rendez-vous technique for the reconstruction of complete benign biliary strictures. Complete biliary strictures were reconstructed in four patients using a rendez-vous percutaneous-endoscopic or percutaneous-percutaneous route guided by fluoroscopic and visual (transillumination) control. All four patients were treated successfully and safely with the rendez-vous technique. Complications were caused by the preliminary creation, dilatation and maturation of the percutaneous tract. This technique may offer a good alternative to surgical bilio-enteric anastomosis in experienced hands. The long term course of the patients treated remains to be seen.


Analysis of relative bacterial activity and lactate dehydrogenase gene expression of caries-associated bacteria in a site-specific natural biofilm: an ex vivo study.
Detecting bacterial activity is considered a promising approach to monitor shifts from symbiosis to dysbiosis in oral microbiome. The present study aimed at investigating both the relative bacterial activity and the lactate dehydrogenase (ldh) gene expression of caries-associated bacteria in a site-specific natural biofilm. Sixty subjects (age, mean ± SE: 30.1 ± 1.4) were allocated to two groups: caries-free subjects (CF) or caries-active subjects (CA). CF presented one sound surface (CFS, n = 30). CA presented two donor sites: a cavitated caries lesion (CAC, n = 30) and a sound reference surface (CAS, n = 30). Real-time quantitative PCR (q-PCR) on species or genus level and total bacteria was performed targeting the 16S gene, the 16S rRNA, the ldh gene, and the ldh mRNA (increasing 16S ribosomal RNA copy numbers can function as an indicator of increased energy metabolism). As the 16S rRNA abundance represents the number of ribosomes, while the 16S gene abundance represents the number of genomes, the quotient of the relative abundances functions as a measure for the relative bacterial activity (%). Both lactobacilli and S. mutans showed the highest relative bacterial activity in CAC ((mean ± SE) 218 ± 60% and 61 ± 16%, respectively) and the lowest values for both sound reference surfaces (69 ± 48%; 8 ± 3%). Significant differences were found between CAC and CAS as well as between CAC and CFS for both lactobacilli and S. mutans (p < 0.05). The ldh gene expression of lactobacilli and S. mutans only showed moderate values in CAC (1.90E+03 ± 2.11E+03; 2.08E+04 ± 4.44E+04 transcripts/μl) and CFS (2.04E+03 ± 2.74E+03; 8.16E+03 ± 6.64E+03 transcripts/μl); consequently no significant differences were detected. Caries-associated bacteria (lactobacilli and S. mutans) showed the highest relative bacterial activity in plaque of cavitated lesions, the lowest in sound surfaces, allowing the detection of a significant activity shift in health and disease for caries-active patients. However, no significant differences in ldh gene expression could be determined.


MRI of optic nerve and postchiasmal visual pathways and visual evoked potentials in secondary progressive multiple sclerosis.
We studied the relationship between abnormalities shown by MRI and functional disturbances in the visual pathway as assessed by the visual evoked potential (VEP) in 25 patients with established multiple sclerosis (MS); only 4 of whom had a history of acute optic neuritis. Optic nerve MRI was abnormal in 19 (76%) and is thus useful in detecting subclinical disease. Optic nerve total lesion length and area on the STIR sequence was found to correlate significantly with prolongation of the VEP latency. This may reflect a predominantly demyelinating rather than inflammatory origin for the signal change in the optic nerve.


Ultrastructural detection of RNA: complementarity of high-resolution autoradiography and of RNAase-gold method.
The recently developed RNAase-gold cytochemical method and the more classical high-resolution autoradiography following incorporation of tritiated uridine, were applied for the localization of RNA molecules in thin sections of isolated liver cells cultured under control conditions or submitted to drugs known to alter the distribution of nuclear RNA. The similar pattern of labeling obtained with both techniques under the three experimental conditions studied (control, treatments with CdCl2, or actinomycin D), together with the results obtained after RNAase digestion, are a good indication of the high specificity and sensitivity of the RNAase-gold method and provide a demonstration of the complementarity of these two methods for the study of the ultrastructural distribution of nuclear RNA.


Comparative economic and environmental assessment of four beech wood based biorefinery concepts.
The aim of this study was to analyze four conceptual beech wood based biorefineries generated during process design in terms of environmental and economic criteria. Biorefinery 1 annually converts 400,000 dry metric tons of beech wood into the primary products 41,600t/yr polymer-grade ethylene and 58,520tDM/yr organosolv lignin and the fuels 90,800tDM/yr hydrolysis lignin and 38,400t/yr biomethane. Biorefinery 2 is extended by the product of 58,400t/yr liquid "food-grade" carbon dioxide. Biorefinery 3 produces 69,600t/yr anhydrous ethanol instead of ethylene. Compared to biorefinery 3, biorefinery 4 additionally provides carbon dioxide as product. Biorefinery 3 and 4 seem most promising, since under basic assumptions both criteria, (i) economic effectiveness and (ii) reduction of potential environmental impacts, can be fulfilled. All four alternatives may reduce potential environmental impacts compared to reference systems using the ReCiPe methodology. Economic feasibilities of the analyzed biorefineries are highly sensitive.


Ultrasonic assessment of fetal colon by comparing ratios of colon circumference to abdominal circumference in normal pregnancy and two abnormal cases. A preliminary study.
Fetal gastrointestinal malformations occur with an incidence of approximately 6/1,000 births and can often be diagnosed in utero by ultrasound. Antenatal knowledge of these abnormalities can potentially decrease fetal and neonatal morbidity and mortality because the appropriate preparations can be made in advance of delivery. Changes in ultrasonic images of the fetal colon were measured by comparing ratios of colon circumference to abdominal circumference in 136 normal pregnancies. Normal values of these parameters are given for gestational age. Two abnormal case reports are included to exemplify the clinical applications.


Worldwide variability in physical inactivity a 51-country survey.
Physical inactivity is an important risk factor for chronic diseases, but for many (mainly developing) countries, no prevalence data have ever been published. To present data on the prevalence of physical inactivity for 51 countries and for different age groups and settings across these countries. Data analysis (conducted in 2007) included data from 212,021 adult participants whose questionnaires were culled from 259,526 adult observations from 51 countries participating in the World Health Survey (2002-2003). The validated International Physical Activity Questionnaire (IPAQ) was used to assess days and duration of vigorous, moderate, and walking activities during the last 7 days. Country prevalence of physical inactivity ranged from 1.6% (Comoros) to 51.7% (Mauritania) for men and from 3.8% (Comoros) to 71.2% (Mauritania) for women. Physical inactivity was generally high for older age groups and lower in rural as compared to urban areas. Overall, about 15% of men and 20% of women from the 51 countries analyzed here (most of which are developing countries) are at risk for chronic diseases due to physical inactivity. There were substantial variations across countries and settings. The baseline information on the magnitude of the problem of physical inactivity provided by this study can help countries and health policymakers to set up interventions addressing the global chronic disease epidemic.


Concussion history and postconcussion neurocognitive performance and symptoms in collegiate athletes.
Athletes are at an inherent risk for sustaining concussions. Research examining the long-term consequences of sport-related concussion has been inconsistent in demonstrating lingering neurocognitive decrements that may be associated with a previous history of concussion. To determine the relationship between concussion history and postconcussion neurocognitive performance and symptoms in collegiate athletes. Repeated-measures design. Multi-center analysis of collegiate athletes. Fifty-seven concussed collegiate athletes (36 without concussion history, 21 with a history of 2 or more concussions). All subjects were administered an Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) neurocognitive test battery, which measures verbal memory, visual memory, reaction time, and visual processing speed and 22 concussion symptoms. Subjects who sustained a concussion were administered 2 follow-up tests at days 1 and 5 postinjury. Independent variables were history of concussion (no history of concussion, 2 or more concussions) and time (baseline, day 1 postconcussion, or day 5 postconcussion). A within-subjects effect (time) on ImPACT performance (P < .001), a between-subjects multivariate effect of group (P < .001), and a group-by-time interaction (P = .034) were noted. Athletes with a concussion history performed significantly worse on verbal memory (P = .01) and reaction time (P = .023) at day 5 postconcussion compared with athletes who did not report a previous concussion. No significant group differences were seen at day 5 postinjury on visual memory (P = .167), processing speed (P = .179), or total concussion symptoms (P = .87). Concussed collegiate athletes with a history of 2 or more concussions took longer to recover verbal memory and reaction time than athletes without a history of concussion.


Plasma ZO-1 proteins predict the severity and outcome of sepsis: A prospective observational study.
We determined whether plasma concentrations of ZO-1 proteins may be used a predictor of sepsis severity and 30-day mortality. A total of 143 patients with sepsis and 30 healthy controls were enrolled. Plasma ZO-1 proteins concentrations were measured. Various methods, including area under the curves (AUCs), Kaplan-Meier curve, Cox regression, net reclassification improvement (NRI) and integrated discrimination improvement (IDI), were carried out to determine the value of ZO-1 in predicting 30-day mortality. Plasma ZO-1 concentrations in patients with sepsis and septic shock were significantly higher than those in healthy controls and were associated with the number of organ failures. ZO-1 concentrations also correlated with APACHE II or SOFA score and predicted 30-day mortality in sepsis patients with an AUC of 0.754. Multivariable regression analyses showed that a ZO-1 concentration ≥2.60 ng/ml remained a significant predictor of 30-day mortality in sepsis patients. Kaplan-Meier survival plots showed that patients with ZO-1 concentrations <2.60 ng/ml had a clear survival benefit. Adding ZO-1 to the SOFA score significantly improved its prognostic accuracy. Plasma ZO-1 proteins appear to be a valuable prognostic biomarker for the severity of sepsis and a predictor of 30-day mortality for patients with sepsis.


Use of a decision aid did not decrease decisional conflict in patients with carpal tunnel syndrome.
Although a model for shared decision-making is important for patient-centered care, decisional conflict can emerge when patients participate in the decision-making. A decision aid is proposed to provide information and to involve patients more comfortably in the decision-making process. We aimed to determine whether a decision aid helps patients with carpal tunnel syndrome (CTS) experience less decisional conflict regarding their decision-making for surgery. Eighty patients with CTS were randomized into two groups. The test group was given a decision aid in addition to regular information and the control group regular information only. The decision aid consisted of a 6-min videoclip that explains diagnosis and information regarding surgery for CTS with other treatment options. We evaluated patients' decisional conflict regarding surgery, knowledge about CTS, and symptom severity as measured by the Disabilities of Arm, Shoulder, and Hand (DASH) Questionnaire. There was no difference in the decisional conflict scale (DCS) between both groups (p = 0.76). The test group had significantly better knowledge than the control group (p = 0.04). There was no correlation between the knowledge score and the DCS (p = 0.76). However, less severe symptoms were correlated with greater decisional conflict (r = -0.29, p = 0.02). We found that a decision aid does not reduce decisional conflict in patients with CTS, although it can help them be better informed. This study suggests that although a decision-aid is effective for patient education, doctor-patient communication should be more emphasized for patients with less severe symptoms, as they can have greater decisional conflict. SNUBH Registry 1510/317-003 Registered November 13, 2015.


Cerebral granular cell tumor.
Intracerebral granular cell tumors (GCTs) are a rare finding. We report here on a case of cerebral GCT in a 47-year-old man who suffered with severe headache. The tumor appeared as a relatively well-defined, enhancing mass at the periventricular white matter of the left occipital lobe of the brain. Histologically, the tumor was entirely composed of granular cells. Some of the tumor cells showed peripherally accentuated cytoplasmic granules with central clearing, which produced a unique "targetoid" appearance. The granular cells of the current case were positive for neuron-specific enolase (NSE), S-100 protein, GFAP, vimentin, CD 68, lysozyme, and alpha-1-antitrypsin. These wide immunoexpressions were not observed for the previously reported cerebral GCTs. Interestingly, this case showed "targetoid" or "reversed targetoid" immunoreactive patterns in NSE, CD68, GFAP, and vimentin. Despite these wide immunoexpressions and the lack of any association with astrocytoma, the histogenesis of cerebral GCTs is still suggested to be of a glial origin, based on the tumor location, the GFAP positivity and the ultrastructural findings, of which the latter showed intermediate filaments, and these are reminiscent of neoplastic astrocytes.


A new designed π conjugated molecule for stable single walled carbon nanotube dispersion in aqueous medium.
A molecule with a π conjugated backbone built from aromatic thiophene and dialkoxyphenylene units and substituted imidazolium groups (TPO) is designed to obtain ultra-stable single walled carbon nanotube (SWCNT) dispersion in aqueous medium. The proposed mechanism of non-covalent interaction is accompanied by individualization of SWCNT and comprises of dominant nondisruptive π-π and cation-π interaction between them and the TPO conjugated oligomer. The individualization of SWCNT and dispersibility and stability of the ultra-stable suspensions were estimated using high resolution transmission electron microscopy, UV-Visible-NIR absorption spectroscopy, Raman spectroscopy, photoluminescence and zeta potential measurement. Nuclear magnetic resonance data provides direct evidence toward possible cation-π interaction.


Early cardiovascular remodelling in Fabry disease.
Fabry disease (FD) is a rare X-linked genetic disorder caused by the deficiency or absent activity of lysosomal α-galactosidase A. Cardiovascular remodelling is a hallmark of FD. The present study aimed to comprehensively evaluate the cardiac, vascular and microvascular status in a population of patients with genetic mutations for FD without left ventricular hypertrophy (LVH). This study includes subjects carrying genetic mutations for FD (Fabry disease mutation-carrier, FDMC) without LVH (n = 19). A group of control subjects (n = 19) matched for age, sex, body mass index and cardiovascular risk factors were also included. All subjects underwent echocardiography, carotid ultrasound scan, endothelial flow-mediated dilatation (FMD) and nailfold capillaroscopy (NFC) assessment. When compared to the subjects in the control group, FDMC patients showed significantly lower mean values of systolic myocardial velocity (7.33 ± 1.28 vs. 10.08 ± 1.63 cm/s, p < 0.0001), longitudinal systolic strain (-18.07 ± 1.72 vs. -21.15 ± 2.22%, p < 0.0001), significantly higher E/E' mean values (7.15 ± 1.54 vs. 5.98 ± 1.27, p = 0.016) and intima-media thickness mean values (0.80 ± 0.20 vs. 0.61 ± 0.19 mm, p = 0.005), significantly lower FMD (8.3 ± 4.6 vs. 12.2 ± 5.0%, p = 0.02), more atypical capillaries and irregular NFC architecture in FDMC than control subjects (52.6 vs. 0%, p < 0.0001; 78.9 vs. 36.8%, p = 0.02 respectively). FD progressively involves cardiac, macrovascular and microvascular systems in an early stage. These features are present even in asymptomatic mutation carriers without LVH.


[Epiretinal membranes].
Idiopathic epiretinal membranes represent a common condition, and are present in approximately 10% of people over the age of 70 years. They are idiopathic in 80% of cases, or may be secondary to various conditions such as a prior retinal detachment, or vascular or inflammatory retinal diseases. The main symptoms are visual loss and metamorphopsia. The diagnosis of epiretinal membrane is currently facilitated by OCT, which provides prognostic and therapeutic decision-making assistance. Surgery for epiretinal membranes is currently well codified through sutureless vitrectomy and dyes. Dissection of the membrane (with or without associated peeling of the internal limiting membrane) ensures good anatomical and functional results, while being relatively minimally invasive.


Impact of Full-Field Digital Mammography Versus Film-Screen Mammography in Population Screening: A Meta-Analysis.
Breast screening programs replaced film mammography with digital mammography, and the effects of this practice shift in population screening on health outcomes can be measured through examination of cancer detection and interval cancer rates. A systematic review and random effects meta-analysis were undertaken. Seven databases were searched for publications that compared film with digital mammography within the same population of asymptomatic women and reported cancer detection and/or interval cancer rates. The analysis included 24 studies with 16 583 743 screening examinations (10 968 843 film and 5 614 900 digital). The pooled difference in the cancer detection rate showed an increase of 0.51 per 1000 screens (95% confidence interval [CI] = 0.19 to 0.83), greater relative increase for ductal carcinoma in situ (25.2%, 95% CI = 17.4% to 33.5%) than invasive (4%, 95% CI = -3% to 13%), and a recall rate increase of 6.95 (95% CI = 3.47 to 10.42) per 1000 screens after the transition from film to digital mammography. Seven studies (80.8% of screens) reported interval cancers: the pooled difference showed no change in the interval cancer rate with -0.02 per 1000 screens (95% CI = -0.06 to 0.03). Restricting analysis to studies at low risk of bias resulted in findings consistent with the overall pooled results for all outcomes. The increase in cancer detection following the practice shift to digital mammography did not translate into a reduction in the interval cancer rate. Recall rates were increased. These results suggest the transition from film to digital mammography did not result in health benefits for screened women. This analysis reinforces the need to carefully evaluate effects of future changes in technology, such as tomosynthesis, to ensure new technology leads to improved health outcomes and beyond technical gains.


Drug Design Targeting T-Cell Factor-Driven Epithelial-Mesenchymal Transition as a Therapeutic Strategy for Colorectal Cancer.
Metastasis is the cause of 90% of mortality in cancer patients. For metastatic colorectal cancer (mCRC), the standard-of-care drug therapies only palliate the symptoms but are ineffective, evidenced by a low survival rate of ∼11%. T-cell factor (TCF) transcription is a major driving force in CRC, and we have characterized it to be a master regulator of epithelial-mesenchymal transition (EMT). EMT transforms relatively benign epithelial tumor cells into quasi-mesenchymal or mesenchymal cells that possess cancer stem cell properties, promoting multidrug resistance and metastasis. We have identified topoisomerase IIα (TOP2A) as a DNA-binding factor required for TCF-transcription. Herein, we describe the design, synthesis, biological evaluation, and in vitro and in vivo pharmacokinetic analysis of TOP2A ATP-competitive inhibitors that prevent TCF-transcription and modulate or reverse EMT in mCRC. Unlike TOP2A poisons, ATP-competitive inhibitors do not damage DNA, potentially limiting adverse effects. This work demonstrates a new therapeutic strategy targeting TOP2A for the treatment of mCRC and potentially other types of cancers.


Efficient bio-deodorization of aniline vapor in a biotrickling filter: metabolic mineralization and bacterial community analysis.
A biotrickling filter inoculated with commercial mixed microorganisms B350 was employed to treat N-containing odorous vapor - aniline. Results indicated no aniline could be detected when empty bed residence time (EBRT) was larger than 110s at inlet concentration of 0.30 g m(-3). The variation of inlet concentration did not change removal efficiencies when concentration is less than 0.21 g m(-3) at fixed EBRT 110s. Biodegradation mechanism of aniline was tentatively proposed based on identified intermediates and predicted biodegradation pathway as well as final mineralized products. Aniline was firstly biodegraded to catechol, and then to levulinic acid and subsequently to succinic acid. Finally, about 62% aniline carbon was completely mineralized to CO(2), while about 91% aniline nitrogen was converted into ammonia and nitrate. Bacterial community in biotrickling filter was found that at least seven bands microbes were identified for high efficiencies of bioreactor at stable state. In all, biotrickling filter seeded with B350 would be a better choice for the purification odorous gas containing high concentration aniline.


Coffee and serum lipids: findings from the Olivetti Heart Study.
The relationship between coffee consumption and blood lipids was analyzed in a sample of 900 male workers of southern Italy participating in the Olivetti Heart Study. In the univariate analysis, coffee drinkers (n = 856) had higher values for body mass index (P < or = 0.05) and number of cigarettes smoked per day (P < or = 0.001) and lower levels of serum high-density-lipoprotein cholesterol (P < or = 0.05), compared to noncoffee drinkers (n = 44). In addition, coffee consumption (cups/d) was positively related to serum triglyceride levels (r = 0.105, P < or = 0.01) and cigarette smoking (r = 0.491, P < or = 0.01), and was inversely related to age (r = -0.122, P < or = 0.01). After multivariate adjustment, coffee consumption remained significantly related to age, cigarette smoking, and body mass index (data not shown). After stratification for smoking status, a significant positive linear trend between coffee consumption and serum total cholesterol was observed only in smokers. No significant trend was observed for serum triglycerides and high-density-lipoprotein cholesterol with coffee intake according to smoking status. This finding suggests that the relationship between coffee consumption and serum total cholesterol may change with the smoking status.


Exploiting effectors of Rac GTPase.
Targeting a specific arm of signaling pathways is of great interest. In this issue of Chemistry & Biology, Bosco et al. exploit the interactive interface between Rac GTPase and its effector p67(phox) to specifically inhibit reactive oxygen species production without perturbing other Rac-mediated cellular processes.


Sebaceous gland hyperplasia of the vulva.
Sebaceous gland hyperplasia is a common condition of the face in elderly patients. We report a case of sebaceous gland hyperplasia on the vulva. A 19-year-old woman presented with a polypoid tumor on her left labium majus of which the greatest diameter was 2.5 cm, covered by normal appearing skin. Histologic examination revealed a sebaceous gland hyperplasia. Immunohistochemical techniques showed high expression of androgen receptors on sebaceous cells. Clinical and gross features of the two documented cases of sebaceous gland hyperplasia on the vulva are different from those of typical lesions on the face. Histologic study of a vulvar biopsy is required to reach a specific diagnosis of this hamartomatous benign condition.


Neurohypophysial responses to emotional stress after deafferentation of sino-aortic baroreceptors in rats.
In an attempt to test the possibility that sino-aortic baroreceptors may mediate the previously reported stress response in hypothalamic magnocellular neurosecretory cell activity in rats, effects of deafferentation of sino-aortic baroreceptors on plasma levels of vasopressin and oxytocin after fear-related emotional stress were studied in male rats 28-33 days after the surgery. An alpha 1-adrenergic receptor agonist, phenylephrine (1 mg/kg) injected i.p. under anesthesia increased arterial blood pressure in the rats that had received surgical operation of sino-aortic denervation (SAD) and in the rats of sham-operation control (SHAM). Reflex bradycardia after phenylephrine occurred in the SHAM but not in the SAD group. These results indicate that afferent signals originating from sino-aortic baroreceptors were effectively blocked by the SAD surgery. In the similarly prepared SAD group, plasma level of vasopressin was decreased and plasma level of oxytocin was increased significantly to the same extent as in the SHAM group after low-frequency shocks (0.05 Hz, 5 min) or environmental cue signals previously paired with shocks. It is therefore suggested that afferent neural signals originating from sino-aortic baroreceptors are not primarily involved in the suppressive vasopressin or the facilitatory oxytocin response to fear-related emotional stress in rats.


Hoquet diabolique: intractable hiccups as a manifestation of multiple sclerosis.
In three patients, intractable hiccups occurred as part of the symptomatology of multiple sclerosis. In one patient intractable hiccups were the presenting complaint, and in another patient exacerbations of symptoms were almost always heralded by intractable hiccups. Intractable hiccups occur in a variety of diseases, including many that affect the brainstem and cervical cord, but have not been reported in multiple sclerosis. The hiccup may be a "primitive" gastrointestinal reflex that is disinhibited by lesions such as multiple sclerosis plaques. Carbamazepine was successful in arresting the hiccups in one of the cases presented.


Arsenic and antimony determination in non- and biodegradable materials by hydride generation capacitively coupled plasma microtorch optical emission spectrometry.
A sensitive method using a miniature analytical system with a capacitively coupled plasma microtorch (25 W, 13.56 MHz, 0.4 l min(-1) Ar) was developed and evaluated for the determination of As and Sb in recyclable plastics and biodegradable materials by hydride generation optical emission spectrometry. Given their toxicity, As and Sb should be subject to monitoring in such materials despite not being included within the scope of Restriction of Hazardous Substances Directive. The advantages of the proposed approach are better detection limits and lower analysis cost relative to conventional systems based on inductively coupled plasma optical emission and flame atomic absorption spectrometry with/without derivatization. Samples were subjected to acidic microwave-assisted digestion in a nitric-sulfuric acid mixture. Chemical hydride generation with 0.5% NaBH4 after the prereduction of As(V) and Sb(V) with 0.3% L-cysteine in 0.01 mol l(-1) HCl (10 min contact time at 90±5°C) was used. Under the optimal hydride generation conditions and analytical system operation the detection limits (mg kg(-1)) were 0.5 (As) and 0.1 (Sb), whereas the precision was 0.4-7.1% for 10.2-46.2 mg kg(-1) As and 0.4-3.2% for 7.1-156 mg kg(-1) Sb. Analysis of two polyethylene CRMs revealed recoveries of 101±2% As and 100±1% Sb.


Anomalous non-equilibrium response in black phosphorus to sub-gap mid-infrared excitation.
The competition between the electron-hole Coulomb attraction and the 3D dielectric screening dictates the optical properties of layered semiconductors. In low-dimensional materials, the equilibrium dielectric environment can be significantly altered by the ultrafast excitation of photo-carriers, leading to renormalized band gap and exciton binding energies. Recently, black phosphorus emerged as a 2D material with strongly layer-dependent electronic properties. Here, we resolve the response of bulk black phosphorus to mid-infrared pulses tuned across the band gap. We find that, while above-gap excitation leads to a broadband light-induced transparency, sub-gap pulses drive an anomalous response, peaked at the single-layer exciton resonance. With the support of DFT calculations, we tentatively ascribe this experimental evidence to a non-adiabatic modification of the screening environment. Our work heralds the non-adiabatic optical manipulation of the electronic properties of 2D materials, which is of great relevance for the engineering of versatile van der Waals materials.


Expression of a phosphorylated form of ATF4 in lung and non-small cell lung cancer tissues.
ATF4 is a member of the cAMP-responsive element-binding protein family of basic zipper-containing proteins, a family of transcription factors phosphorylated at serines residues by protein kinase A. The family has been proved to be able to stimulate the transcription of the genes containing CRE elements. Elevated ATF4 expression was detected in some tumors including breast carcinoma compared to their corresponding nontumor tissues. p-ATF4 (ser 245), a phosphorylated form of ATF4 protein at serine 245 site, was believed to be an active type of this protein. However, its expression and clinical significance in malignant tumors including non-small cell lung cancer were not reported up to date. In the current study, we investigate the expression of p-ATF4 (ser 245) in non-small cell lung cancer using tissue microarray and immunohistochemistry. p-ATF4 (ser 245) immunostaining was detected in nucleus and cytoplasm in cancer cells and normal lung epithelial cells. Compared to bronchial epithelium and submucosal glands (total positive rate, 14.6% (12/82)), there was increased expression of p-ATF4 (ser 245) in non-small cell lung cancer cells (total positive rate, 42.7% (35/82)) (p < 0.05). In addition, increased expression of p-ATF4 (ser 245) was associated with lymph node metastasis and advanced TNM stages (III and IV) in non-small cell lung cancer (p < 0.05). Immunofluorescent staining confirmed nuclear and cytoplasmic expression of p-ATF4 (ser 245) in lung and cancer tissues, and also in non-small cell lung cancer cell lines including NCI-H157 and LTE cells. These results indicate that increased expression of p-ATF4 (ser 245) may contribute to cancer development of non-small cell lung cancer and may be a potential cancer marker.


Aircraft noise and cardiovascular morbidity and mortality near Heathrow Airport: A case-crossover study.
Aircraft noise causes annoyance and sleep disturbance and there is some evidence of associations between long-term exposures and cardiovascular disease (CVD). We investigated short-term associations between previous day aircraft noise and cardiovascular events in a population of 6.3 million residing near Heathrow Airport using a case-crossover design and exposure data for different times of day and night. We included all recorded hospitalisations (n = 442,442) and deaths (n = 49,443) in 2014-2018 due to CVD. Conditional logistic regression was used to estimate the ORs and adjusted for NO2 concentration, temperature, and holidays. We estimated an increase in risk for 10 dB increment in noise during the previous evening (Leve OR = 1.007, 95% CI 0.999-1.015), particularly from 22:00-23:00 h (OR = 1.007, 95% CI 1.000-1.013), and the early morning hours 04:30-06:00 h (OR = 1.012, 95% CI 1.002-1.021) for all CVD admissions, but no significant associations with day-time noise. There was effect modification by age-sex, ethnicity, deprivation, and season, and some suggestion that high noise variability at night was associated with higher risks. Our findings are consistent with proposed mechanisms for short-term impacts of aircraft noise at night on CVD from experimental studies, including sleep disturbance, increases in blood pressure and stress hormone levels and impaired endothelial function.


Fine root growth and demographic responses to nutrient patches in four old-field plant species.
Proliferation of roots in a nutrient patch can occur either as a result of an increase in root length (morphological response) or by a change in root birth or death rates (demographic responses). In this study we attempted to distinguish between these two mechanisms of response to nutrient patches and to compare the responses of four old-field plant species (two annuals, two perennials). For all four species combined, there were significant increases in root numbers and root length in fertilized patches. Root proliferation in fertilized patches was largely due to increased birth (=branching) rates of new roots. However, there was also a significant increase in root death rates in the fertilized patches which reduced the magnitude of the increase in net root numbers. Plots for individual species suggested they differed in the magnitude and timing of root proliferation in fertilized patches due to differences in root birth and death rates. However, because of the limited sample size in this study, there was only a marginally significant difference among species in root birth rates, and no difference in death rates. Further studies are currently underway to better quantify species differences in the demographic mechanism, as well as magnitude, of response to nutrient patches and if this would affect the ability to exploit small-scale heterogeneity in soil resources.


Cytochrome b558, a component of the phagocyte NADPH oxidase, is a flavoprotein.
Cytochrome b558 is the only membrane component of the phagocyte O2(-)-producing NADPH oxidase. The O2- production by the oxidase reconstituted in vitro with the crude membrane fraction is enhanced several-fold by addition of FAD, whereas that with the partially purified cytochrome is completely dependent on exogenous FAD, suggesting that FAD acts through the membrane component, cytochrome b558. The alignments of the amino acid sequence of the large subunit of the cytochrome (gp91-phox) with those of previously characterized flavoproteins reveal that the middle and C-terminal portions of gp91-phox are likely to be FAD- and NADPH-binding domains, respectively. Cytochrome b558, thus, appears to be a flavoprotein with an NADPH-binding site, of the NADPH oxidase.


The significance of cerebral atrophy for the symptomatology of Parkinson's disease.
Hitherto published results on the impact of brain atrophy on the neurological and psychopathological sympion of this problem without risk of complications. We investigated 173 parkinsonian patients (89 men, 84 women) aged 37--83 years. Besides CT in all patients a standardized neurological and psychopathological investigation was carried out, including psychological tests, intelligence, personality structure, fine motor performance and visual reaction times. The investigations revealed pronounced correlations between CT-findings and more severe clinical symptomatology and a corresponding impairment in daily activities in the levodopa-treated and particularly in the untreated group, above all when there was a combination of cortical atrophy and ventricular enlargement. The same was true for fine motor performance and simple and complex reaction times. These functions were more impaired in patients with brain atrophy, irrespective of its localisation, whether cortical atrophy or ventricular enlargement. In contrast, no statistically significant relationship between the different parameters of brain atrophy and intelligence could be found. Considering cortical atrophy as a specific sign in Parkinson's disease -- our results are in favour of this assumption -- and ventricular enlargement more related to increasing age, parkinsonism is influenced by extranigral lesions inherent in the disease and dependent on increasing age.


Risk factors of primary and recurrent fractures in postmenopausal osteoporotic Chinese patients: A retrospective analysis study.
As postmenopausal osteoporotic fractures can cause higher rates of disability and mortality in women; it is essential to analyze the factors associated with primary and recurrent fractures in postmenopausal osteoporosis (PMOP) patients. Retrospective analysis of 2478 PMOP patients aged ≥ 50 years who attended the Shanghai General Hospital from January 2007 to December 2016, including 1239 patients with no fractures and 1239 patients with histories of fractures (1008 in the primary fracture group and 231 in the re-fracture group). All patients' basic clinical data, serum biochemical and bone metabolic markers, bone mineral density (BMD), and other indicators were recorded uniformly. Comparing the differences between the clinical characteristics of patients with primary and recurrent fractures, as well as the differences in the clinical characteristics of patients with primary and recurrent fractures in combination with different diseases, further analyses the risk factors for primary and recurrent fractures in PMOP patients. SPSS.26 was used for statistical analysis. Compared to the unfractured group, the fractured group was older and had lower height and bone mineral density (all P < 0.01), with the re-fractured group having lower BMD at each key site than the primary fracture group (all P < 0.01). Analysis of the combined disease subgroups showed that serum BGP levels were lower in the primary and re-fracture patients with diabetes than in the non-diabetic subgroup (P < 0.05), and serum CTX levels were lower in the re-fracture group with diabetes than in the primary fracture group with diabetes (P < 0.05). Patients with recurrent fractures with cardio-vascular diseases had lower BMD than the subgroup without cardio-vascular diseases (P < 0.05) and also had lower BMD than the group with primary fractures with cardio-vascular diseases (P < 0.05). Multiple logistic regression analysis showed that advanced age, overweight, low lumbar spine and total hip BMD were risk factors for primary and recurrent fractures; and comorbid chronic liver and kidney diseases were risk factors for primary fractures. PMOP patients with advanced age, overweight, low bone mineral density, and comorbid chronic liver and kidney diseases are at greater risk of fractures and require early intervention to reduce fractures occurrence. Moreover, those who are elderly, overweight, and have low bone density should also be aware of the risk of re-fractures.


Non-compliance in asthmatic children: a study of theophylline levels in a pediatric emergency room population.
Sub-therapeutic theophylline levels due to patient (parent) non-compliance is a significant cause of outpatient treatment failure in childhood asthma. In a study of 50 known asthmatic children with acute asthmatic episodes, 98% had sub-therapeutic theophylline levels less than 10 mcg/ml with 75.5% due to inadequate patient (parent) compliance.


Correction to: An Interdisciplinary Definition of Pornography: Results from a Global Delphi Panel.
Two members of the Delphi panel who completed a tranche of the survey.


Early harvesting of the vascularized pedicled nasoseptal flap during endoscopic skull base surgery.
The vascularized pedicled nasoseptal flap (PNSF) represents a successful option for reconstruction of large skull base defects after expanded endoscopic endonasal approaches (EEA). This vascularized flap can be harvested early or late in the operation depending on the anticipation of high-flow CSF leaks. Each harvesting technique (early vs. late) is associated with different advantages and disadvantages. In this study, we evaluate our experience with early harvesting of the PNSF for repair of large skull base defects after EEA. A retrospective review was performed at a tertiary care medical center on patients who underwent early PNSF harvesting during reconstruction of intraoperative high-flow CSF leaks after EEA between December 2008 and March 2012. Demographic data, repair materials, surgical approach, and incidence of PNSF usage were collected. Eighty-seven patients meeting the inclusion criteria were identified. In 86 procedures (98.9%), the PNSF harvested at the beginning of the operation was used. In 1 case (1.1%), the PNSF was not used because a high-flow intraoperative CSF leak was not encountered. This patient had recurrence of intradural disease 8months later, and the previously elevated PNSF was subsequent used after tumor resection. Based on our data, a high-flow CSF leak and need for a PNSF can be accurately anticipated in patients undergoing EEA for skull base lesions. Because of the advantages of early harvesting of the PNSF and the high preoperative predictive value of CSF leak anticipations, this technique represents a feasible harvesting practice for EEA surgeries.


Clinical complications with implants and implant prostheses.
The purpose of this article is to identify the types of complications that have been reported in conjunction with endosseous root form implants and associated implant prostheses. A Medline and an extensive hand search were performed on English-language publications beginning in 1981. The searches focused on publications that contained clinical data regarding success/failure/complications. The complications were divided into the following 6 categories: surgical, implant loss, bone loss, peri-implant soft tissue, mechanical, and esthetic/phonetic. The raw data were combined from multiple studies and means calculated to identify trends noted in the incidences of complications. The most common implant complications (those with a greater than a 15% incidence) were loosening of the overdenture retentive mechanism (33%), implant loss in irradiated maxillae (25%), hemorrhage-related complications (24%), resin veneer fracture with fixed partial dentures (22%), implant loss with maxillary overdentures (21%), overdentures needing to be relined (19%), implant loss in type IV bone (16%), and overdenture clip/attachment fracture (16%). It was not possible to calculate an overall complications incidence for implant prostheses because there were not multiple clinical studies that simultaneously evaluated all or most of the categories of complications. Although the implant data had to be obtained from different studies, they do indicate a trend toward a greater incidence of complications with implant prostheses than single crowns, fixed partial dentures, all-ceramic crowns, resin-bonded prostheses, and posts and cores.


NP-40 reduces contamination by endogenous biotinylated carboxylases during purification of biotin tagged nuclear proteins.
We describe here a simple procedure for greatly reducing contamination of nuclear extracts by naturally biotinylated cytoplasmic carboxylases, which represent a major source of non-specific background when employing BirA-mediated biotinylation tagging for the purification and characterization of nuclear protein complexes by mass spectrometry. We show that the use of 0.5% of the non-ionic detergent Nonidet-40 (NP-40) during cell lysis and nuclei isolation is sufficient to practically eliminate contamination of nuclear extracts by carboxylases and to greatly reduce background signals in downstream mass spectrometric analyses.


The induction of chromosomal abnormalities by inhalational anaesthetics.
When Vicia faba root tips are exposed for 2 h to clinically useful concentrations of halothane or methoxyflurane in air, or to halothane in 80% nitrous oxide/20% oxygen, there is a transient increase in mitotic index and then abnormal interphase cells are produced in proportion to the anaesthetic concentrations. After exposure there is a period of mitotic inhibition during which the cells become partially synchronised. When colchicine-metaphase cells collected 28 h after exposure are compared with controls and with metaphases collected only 4 h after exposure, they show a significant increase in the incidence of aneuploidy, tetraploidy and the results of chromosome breakage. It is suggested that all the abnormalities seen can be accounted for by the effects of the anaesthetics on spindle movements, and that at the concentrations used the anaesthetics have no mutagenic effects on chromosomes in interphase.


Direct mass spectrometry approaches to characterize polyphenol composition of complex samples.
Lower molecular weight polyphenols including proanthocyanidin oligomers can be analyzed after HPLC separation on either reversed-phase or normal phase columns. However, these techniques are time consuming and can have poor resolution as polymer chain length and structural diversity increase. The detection of higher molecular weight compounds, as well as the determination of molecular weight distributions, remain major challenges in polyphenol analysis. Approaches based on direct mass spectrometry (MS) analysis that are proposed to help overcome these problems are reviewed. Thus, direct flow injection electrospray ionization mass spectrometry analysis can be used to establish polyphenol fingerprints of complex extracts such as in wine. This technique enabled discrimination of samples on the basis of their phenolic (i.e. anthocyanin, phenolic acid and flavan-3-ol) compositions, but larger oligomers and polymers were poorly detectable. Detection of higher molecular weight proanthocyanidins was also restricted with matrix-assisted laser desorption ionization (MALDI) MS, suggesting that they are difficult to desorb as gas-phase ions. The mass distribution of polymeric fractions could, however, be determined by analyzing the mass distributions of bovine serum albumin/proanthocyanidin complexes using MALDI-TOF-MS.


Role of Preincisional Peritonsillar Infiltration of Bupivacaine in Postoperative Pain Relief in Tonsillectomy Patients.
Tonsillectomy is one of the most common surgical procedures carried out in ENT since ancient time, is associated with several morbidities in which the pain and bleeding being the commonest and can cause considerable delay in starting oral intake and discharge from the hospital. Different methods have been used to reduce posttonsillectomy pain including use of opioids, sucralfate and local anaesthetics. Local anaesthetics in the form of pre-incisional or post-incisional peritonsillar infiltration and also topical post-incisional spray or packing are some of the most effective methods for post-tonsillectomy pain management. In our hospital, a study was carried out for preincisional peritonsillar infiltration of 0.5% bupivacaine in tonsillectomy patients for post operative pain relief. Written informed valid consent was taken, all routine investigations were done. Pre anaesthetic check up was done and bupivacaine test dose was given, none of the patients showed allergic reactions. Our study showed that this is effective method of controlling post operative pain. Patients receiving bupivacaine showed lower pain scores 6 h post operatively. The mean pain scores for Bupivacaine group were 2.85, 5.52 and 7.04 versus 5.04, 7.04 and 7.61 in saline group at 2, 4, and 6 h post operatively (t value significant). Pre incisional peritonsillar infiltration of 0.5% bupivacaine significantly reduces postoperative pain till 6 h, thereby reducing the need of analgesics intraoperatively and post operatively. Oral intake was also earlier without any adverse effects in our study.


Behavior of PAHs from sewage sludge incinerators in Korea.
Although production of sewage sludge increases every year, its proper treatment has only been recently raised as a new issue, as current landfill and ocean dumping arrangements are expected to become increasingly difficult to manage in the future. The Korean Ministry of Environment plans to diversify its processing facilities and expand its processing systems by 2011, with the purpose of processing all sludge produced in Korea. According to this plan, incineration (including incineration of municipal wastes) will process 30% of the entire sewage sludge throughout the country in 2011. This study reviews the characteristics of PAH, which is one of the organic substances found in sewage sludge during the incinerating process. The total amount of PAH produced from sewage sludge incineration was found to be 6.103 mg/kg on average, and investigation performed on 16 PAHs of inlets and outlets of the air control devices at five full-scale incineration facilities showed that concentrations of the PAHs on the inlet and on the outlet ranged from 3.926 to 925.748 microg/m(3) and from 1.153 to 189.449 microg/m(3), respectively. In the case of the incineration facility fed with municipal waste (95%) and sewage sludge (5%), the total of the PAH emissions concentration was higher than that found at the incineration facilities used exclusively to treat sewage. The combustion of waste vinyl and plastics contained in municipal waste fed into the facility might contribute to the high levels of PAHs in the stack gas. However more investigation is needed on the production mechanism of PAHs at different operating conditions of the incineration facilities, such as the types of waste, and other relevant factors.


Reward, attention and the dorsal noradrenergic bundle.
The resistance to extinction seen after lesion to the dorsal noradrenergic bundle has been suggested to arise from a deficit in internal inhibition or a 'perseverative' type of deficit. This hypothesis is tested by examining the ability of 6-hydroxydopamine-treated animals to inhibit a previously developed preference for saccharine solution as a result of poisoning with lithium chloride. Unimpaired taste aversion is found, arguing against a deficit in the ability to inhibit a prepotent response. An alternative explanation of the dorsal bundle extinction effect (DBEE), that of alterations in attention, is tested by acquisition and reversal of a successive light-dark discrimination. Both acquisition and reversal are severely impaired, suggesting that the treated animals have difficulty in attending to a specific stimulus in the environment when this is required in order to structure behaviour appropriately, and thus being consistent with a role for the dorsal bundle in the control of attentional processes.


Evaluation of a programming algorithm for the third tachycardia zone in a fourth-generation implantable cardioverter-defibrillator.
The clinical efficacy of electrical algorithms for termination of slow ventricular tachycardia (VT) and ventricular fibrillation (VF) in implantable cardioverter-defibrillators (ICDs) is well established. Such algorithms have not been equally well defined for fast VT reversion. We report the testing of a prospectively designed algorithm for ICDs to treat fast VT that is inherently less responsive to antitachycardia pacing than slow VT. Fourth-generation ICD devices were programmed to three prospectively defined tachycardia detection zones as follows: cycle lengths < or = 260 ms for VF, 270-330 ms for fast VT, and > 330 ms for slow VT. The initial selected therapy for the VF zone was a high-energy biphasic shock (> 15 J), while a 3- or 5-J biphasic shock was usually administered for fast VT, and antitachycardia pacing was initially attempted for slow VT. Initial therapy was followed by backup therapy with high-energy shocks. Twenty-eight patients, 24 of whom were males, all with organic heart disease, with a mean age of 65 +/- 9 years, received either a Medtronic 7219D (23 patients), 7219C (2 patients), 7218SP1 (2 patients), or 7218C (1 patient) ICD with a nonthoracotomy lead system. The defibrillation threshold was 10 +/- 5 J. At predischarge electrophysiologic testing, a single 3- or 5-J shock terminated all episodes of fast VT tested. During a follow-up of 18 +/- 9 months, there were four nonarrhythmic deaths. Fourteen patients (50%) had a total of 21 VF, 44 fast VT, and 202 slow VT episodes. Twenty-three of 24 (96%) VF, 33 of 39 (84%) fast VT, and 193 of 202 (95.5%) slow VT episodes were terminated with the first delivered therapy in each therapy algorithm (p = NS). The overall efficacy of the entire electrical therapy algorithm was 100% for VF, 100% for fast VT, and 98% for slow VT episodes (p = NS). No patient experienced syncope or presyncope during fast VT or VF in this study. We conclude that a third detection and therapy zone can be successfully programmed in ICDs to define a range of fast VT episodes that can be effectively terminated with lower energy cardioversion shocks with comparable success and freedom from arrhythmic symptoms to electrical therapies used for slow VT and VF.


Thermal perceptions and skin temperatures during continuous and intermittent ventilation of the torso throughout and after exercise in the heat.
This study tested the hypothesis that intermittent cooling in air-perfused vests (APV) will not only maintain thermal balance but, due to cyclical activations of cutaneous thermoreceptors, also enhance thermal perceptions. Ten physically active males completed four conditions where they exercised (walking: 5 km h(-1), 2 % gradient) in a hot environment (~34.0 °C, 50 % RH) for 72 min, followed by a 33-min period of rest. They wore an APV throughout. The four conditions differed in respect to the profile of ambient air that was perfused through the APV: continuous perfusion (CP); intermittent perfusion of 6 min ON/OFF periods (IPonoff); a steady increase and decrease in flow rate in equal increments (IPramp); and an initial step-increase in the flow rate followed by an incremental decrease to zero flow rate (IPtriang). Whole body and torso thermal comfort (TC, TTC), whole body and torso temperature sensation (TS, TTS), whole body and torso skin temperature ([Formula: see text], [Formula: see text]), local relative humidity ([Formula: see text]) and rectal temperature (T re) were measured. There were no significant differences in T re, absolute whole body and local [Formula: see text], TC, TTC and TS between the cooling profiles. However, TTS was cooler in CP and IPramp than IPonoff and IPtriang. Even though intermittent cooling did not significantly enhance thermal perceptions in CP, a trend existed for TC (P = 0.063) to become less favourable over time. To reduce the power consumption and extend the battery life of an APV, it is recommended that an intermittent cooling profile should be adopted.


Proposal to replace the illegitimate genus name Prescottia Jones et al. 2013 with the genus name Prescottella gen. nov. and to replace the illegitimate combination Prescottia equi Jones et al. 2013 with Prescottella equi comb. nov.
Recently we proposed that Rhodococcus equi (Magnusson 1923) Goodfellow and Alderson 1977 be transferred to a novel genus, Prescottia, as Prescottia equi comb. nov. However, in accordance with Principle 2 and Rule 51b(4) of the Bacteriological Code (1990 Revision), the bacterial genus name Prescottia Jones et al. 2013 is deemed illegitimate as this name has been used previously for a plant genus within the family Orchidaceae. Consequently, a new genus name, Prescottella gen. nov. is proposed for the bacterial taxon and a new combination Prescottella equi comb. nov. is proposed for the type species.


Efficacy and Tolerability of Lacosamide for Focal Epileptic Patients: Study from Epilepsy Clinic in Makkah.
Lacosamide is characterized by its novel dual mode of action on account of its structural components; its molecule contains a functional amino acid that selectively and slowly promotes the inactivation of voltage-gated sodium channels. This study aims to assess the effectiveness and tolerability of Lacosamide with respect to its use in the treatment of focal epileptic patients. This retrospective cohort study used data collected from the clinical notes or diaries of all epileptic patients who were treated in King Abdullah Medical City during the time period from 2014 to 2019. The multivariate Generalized Estimating Equation (GEE) repeated measure logistic regression analysis was used to assess the odds of having an improvised seizure rate. Majority of the focal epileptic patients (57.9%) were diagnosed with temporal epilepsy, while 26.3% patients had frontal epileptic lesion/diagnoses. Majority of the patients (54.4%) had received a combination of old and new treatment. Out of the seven patients who reported side effects, 57.14% experienced dizziness and headache, tremors (n = 1), loss of balance (n = 1) and increased seizure with abnormal vision acuity and psychosis (n = 1). 84.2% patients experienced reduced median seizure frequency in 12-month period. However, on the basis of clinical characteristics, no significant difference was observed in the seizure control rate. No statistically significant differences were observed between male and female patients with respect to their average improvement rate across the four time points. Lacosamide is an effective and well tolerable drug for patients with focal epilepsy.


Optimizing the ICA-based removal of ocular EEG artifacts from free viewing experiments.
Combining EEG with eye-tracking is a promising approach to study neural correlates of natural vision, but the resulting recordings are also heavily contaminated by activity of the eye balls, eye lids, and extraocular muscles. While Independent Component Analysis (ICA) is commonly used to suppress these ocular artifacts, its performance under free viewing conditions has not been systematically evaluated and many published reports contain residual artifacts. Here I evaluated and optimized ICA-based correction for two tasks with unconstrained eye movements: visual search in images and sentence reading. In a first step, four parameters of the ICA pipeline were varied orthogonally: the (1) high-pass and (2) low-pass filter applied to the training data, (3) the proportion of training data containing myogenic saccadic spike potentials (SP), and (4) the threshold for eye tracker-based component rejection. In a second step, the eye-tracker was used to objectively quantify the correction quality of each ICA solution, both in terms of undercorrection (residual artifacts) and overcorrection (removal of neurogenic activity). As a benchmark, results were compared to those obtained with an alternative spatial filter, Multiple Source Eye Correction (MSEC). With commonly used settings, Infomax ICA not only left artifacts in the data, but also distorted neurogenic activity during eye movement-free intervals. However, correction results could be strongly improved by training the ICA on optimally filtered data in which SPs were massively overweighted. With optimized procedures, ICA removed virtually all artifacts, including the SP and its associated spectral broadband artifact from both viewing paradigms, with little distortion of neural activity. It also outperformed MSEC in terms of SP correction. Matlab code is provided.


Influence of carboxylic ion-pairing reagents on retention of peptides in thin-layer chromatography systems with C18 silica-based adsorbents.
One of the main problems related to chromatography of peptides concerns adverse interactions of their strong basic groups with free silanol groups of the silica based stationary phase. Influence of type and concentration of ion-pairing regents on peptide retention in reversed-phase high-performance liquid chromatography (RP-HPLC) systems has been discussed before. Here we present influence of these mobile phase additives on retention of some peptide standards in high-performance thin-layer chromatography (HPTLC) systems with C18 silica-based adsorbents. We prove, that due to different characteristic of adsorbents used in both techniques (RP HPLC and HPTLC), influence of ion-pairing reagents on retention of basic and/or amphoteric compounds also may be quite different. C18 silica-based HPTLC adsorbents provide more complex mechanism of retention and should be rather considered as mixed-mode adsorbents.


Decrease of hemostatic cardiovascular risk factors by aggressive vs. conventional atorvastatin treatment in patients with Type 2 diabetes mellitus.
Patients with Type 2 diabetes mellitus have increased levels of hemostatic risk variables for cardiovascular disease, such as fibrinogen, von Willebrand factor (VWF), factor (F)VIIa, d-dimer and plasminogen activator inhibitor-1 (PAI-1). To evaluate the effect of aggressive vs. standard dose atorvastatin on hemostatic cardiovascular risk factors in patients with Type 2 diabetes mellitus. The effect of 30 weeks of treatment with atorvastatin 10 and 80 mg on hemostatic cardiovascular risk factors was assessed in a randomized double-blind placebo-controlled trial on 217 patients with Type 2 diabetes mellitus and dyslipidemia. Atorvastatin 10 and 80 mg dose-dependently reduced d-dimer (7.4% and 8.5%, respectively, P for trend = 0.004) and PAI-1 antigen levels (9.0% and 18%, respectively, P for trend = 0.021). Levels of fibrinogen, VWF, tissue-type plasminogen activator and FVIIa were not influenced by atorvastatin. In conclusion, in patients with Type 2 diabetes mellitus, atorvastatin dose-dependently improved the levels of the hemostatic risk variables d-dimer and PAI-1.


Determination of muscarinic agonist potencies at M1 and M2 muscarinic receptors in a modified pithed rat preparation.
The agonistic potencies of (+/-)muscarine, (+/-)cis-2-methyl-5- [(dimethylamino)methyl]-1,3-oxathiolane methiodide (cis-oxathiolane) and its two enantiomers were determined at muscarinic M1 and M2 receptors in the pithed rat. In non-pretreated animals, i.v. administration of these agents produced bradycardic effects mediated by cardiac M2 receptors followed by increases in heart rate mediated by M1 receptors in sympathetic ganglia. As these responses have been shown to partly overlap, "true" M1 and M2 potencies were determined after selective blockade of M1 and M2 receptors by pirenzepine and methoctramine, respectively. A similar rank order of agonist potencies was obtained at M1 and M2 receptors: (+)cis-oxathiolane greater than (+/-)cis-oxathiolane greater than (+/-)muscarine greater than (-)cis-oxathiolane. At both receptor subtypes, (+)cis-oxathiolane was considerably more potent (ca. 30-fold) than its corresponding (-) enantiomer indicating that the agonist binding sites of the two receptor subtypes may have similar stereochemical properties. While (+/-)muscarine showed similar potencies at M1 and M2 receptors, racemic cis-oxathiolane and its two enantiomers showed a slight selectivity (3-7 fold) for M1 receptors indicating the potential usefulness of these compounds in the development of selective M1 receptor agonists.


Effect of oral contraceptive used by technician on sensitivity of progesterone radioimmunoassay.
Gonadotropin and steroid radioimmunoassays (RIAs) have been run in our laboratory for the past 6 years. Recently, the progesterone RIA was unpredictable when performed by one technician. After checking the mechanics and reagents, it was discovered that the technician had changed from Ortho Novum 1 + 50 to Ovral about the time the RIA became erratic. Standard curves of progesterone RIAs performed while the technician was taking either Ortho Novum 1 + 50 or Ovral, or on no contraceptive are reported. The data suggest that a probably exhaled metabolic product of norgestrel, the synthetic progestin in Ovral, interferes with the progesterone RIA and indicate an additional variable investigators must eliminate in performing RIAs.


Advanced glycation endproducts inhibit prostacyclin production and induce plasminogen activator inhibitor-1 in human microvascular endothelial cells.
Several thrombogenic abnormalities are associated with diabetes. To investigate the underlying molecular mechanisms, we examined the effects of advanced glycation endproducts (AGE), non-enzymatically glycated protein derivatives, on the production of prostacyclin (PGI2), an anti-thrombogenic prostanoid, and of plasminogen activator inhibitor-1 (PAI-1), a fast-acting serine protease inhibitor of fibrinolysis, in human microvascular endothelial cells (EC). Firstly, AGE-bovine serum albumin (BSA) but not non-glycated BSA, was found to considerably decrease the production of PGI2 to about two-thirds of the control value. Secondly, quantitative reverse transcription-polymerase chain reaction showed that AGE-BSA increased the EC levels of mRNA coding for PAI-1, this being associated with a concomitant increase in the immunoreactive PAI-1 contents and the anti-fibrinolytic activity. Thirdly, the effects of AGE on PGI2 and PAI-1 syntheses in EC were found to be mediated by a receptor for AGE (RAGE) because antisense DNA against RAGE mRNA could reverse the AGE effects. Further, it was found that AGE decreased the intracellular cyclic AMP concentrations in EC and that cyclic AMP agonists such as dibutyryl cyclic AMP, forskolin and PGI2 analogue reduced the AGE-stimulated PAI-1 production, suggesting the involvement of cyclic AMP in the AGE-signalling pathway. The results thus suggest that AGE have the ability to cause platelet aggregation and fibrin stabilization, resulting in a predisposition to thrombogenesis and thereby contributing to the development and progression of diabetic vascular complications.


Reprogramming cell fates towards novel cancer immunotherapies.
Recent advances in our understanding of host immune and cancer cells interactions have made immunotherapy a prominent choice in cancer treatment. Despite such promise, cell-based immunotherapies remain inapplicable to many patients due to severe limitations in the availability and quality of immune cells isolated from donors. Reprogramming technologies that facilitate the engineering of cell types of interest, are emerging as a putative solution to such challenges. Here we focus on the recent progress being made in reprogramming technologies with respect to the immune system and their potential for clinical applications.


Ferrofluid-based dispersive solid phase extraction of palladium.
A new mode of dispersive solid phase extraction based on ferrofluid has been developed. In this method, an appropriate amount of ferrofluid is injected rapidly into the aqueous sample by a syringe. Since the sorbent is highly dispersed in the aqueous phase, extraction can be achieved within a few seconds. The ferrofluid can be attracted by a magnet and no centrifugation step is needed for phase separation. Palladium was used as a model compound in the development and evaluation of the extraction procedure in combination with flame atomic absorption spectrometry. The experimental parameters (pH, DDTC concentration, type and concentration of eluent, the amount of adsorbent, extraction time, and the effect of interfering ions) were investigated in detail. Under the optimized conditions, the calibration graph was linear over the range of 1-100 μg L(-1) and relative standard deviation of 3.3% at 0.1 μg mL(-1) was obtained (n=7). The limit of detection and enrichment factor (EF) was obtained to be 0.35 μg L(-1) and 267, respectively. The maximum adsorption capacity of the adsorbent at optimum conditions was found to be 24.6 mg g(-1) for Pd(II). The method was validated using certified reference material, and has been applied for the determination of trace Pd(II) in actual samples with satisfactory results.


Endothelial microvesicles induced by physiological cyclic stretch inhibit ICAM1-Dependent leukocyte adhesion.
Physiological cyclic stretch (CS), caused by artery deformation following blood pressure, plays important roles in the homeostasis of endothelial cells (ECs). Here, we detected the effect of physiological CS on endothelial microvesicles (EMVs) and their roles in leukocyte recruitment to ECs, which is a crucial event in EC inflammation. The results showed compared with the static treatment, pretreatment of 5%-CS-derived EMVs with ECs significantly decreased the adherence level of leukocytes. Comparative proteomic analysis revealed 373 proteins differentially expressed between static-derived and 5%-CS-derived EMVs, in which 314 proteins were uniquely identified in static-derived EMVs, 34 proteins uniquely in 5%-CS-derived EMVs, and 25 proteins showed obvious differences. Based on the proteomic data, Ingenuity Pathways Analysis predicted intercellular adhesion molecule 1 (ICAM1) in EMVs might be the potential molecule involved in EC-leukocyte adhesion. Western blot and flow cytometry analyses confirmed the significant decrease of ICAM1 in 5%-CS-derived EMVs, which subsequently inhibited the phosphorylation of VE-cadherin at Tyr731 in target ECs. Moreover, leukocyte adhesion was obviously decreased after pretreatment with ICAM1 neutralizing antibody. Our present research suggested that physiological stretch changes the components of EMVs, which in turn inhibits leukocyte adhesion. ICAM1 expressed on CS-induced EMVs may play an important role in maintaining EC homeostasis.


Improving Surgical Excellence: Can Coaching Surgeons Improve Patient Engagement?
Non-technical skills complement technical skills in surgeons to provide best possible care for patients. The former is essential to promote patient engagement. Coaching has been introduced to surgeons as a method to improve non-technical skills. We aimed to investigate the impact of coaching for surgeons on patient engagement in the outpatient consultation setting. This was a single-centre cohort study conducted in South Australia. Consultant surgeons, suitable coaches, and patients were recruited. Coaches underwent further training by a human factors psychologist on being an effective coach. Outpatient consultations were recorded in an audio-visual format and analysed by investigators. Patient talking time, mutual eye gaze between surgeon and patient, and number of questions asked by the patient were measured as outcomes for patient engagement. 182 patients, 12 surgeons, and 4 coaches participated in the study. Each surgeon underwent 3 coaching sessions, 5 to 6 weeks apart. There were 62 pre-coaching patient consultations, 63 patient consultations after one coaching session, and 57 patient consultations after two coaching sessions. The mean talking time of the patient increased significantly after a single coaching session (P < 0.05) without making significant difference to the total consultation time (p = 0.76). Coaching sessions did not have a significant effect on mutual eye gaze or mean number of questions asked by the patient. Coaching of non-technical skills for surgeons appears to objectively improve patient engagement during the outpatient consultation. This would suggest that tailored coaching programs should be developed and delivered to surgeons to improve care delivery.