RBMS1 regulates lung cancer ferroptosis through translational control of SLC7A11.
Ferroptosis, an iron-dependent nonapoptotic cell death, is a highly regulated tumor suppressing process. However, functions and mechanisms of RNA-binding proteins in regulation of evasion of ferroptosis during lung cancer progression are still largely unknown. Here, we report that the RNA-binding protein RBMS1 participates in lung cancer development via mediating ferroptosis evasion. Through an shRNA-mediated systematic screen, we discovered that RBMS1 is a key ferroptosis regulator. Clinically, RBMS1 was elevated in lung cancer and its high expression was associated with reduced patient survival. Conversely, depletion of RBMS1 inhibited lung cancer progression both in vivo and in vitro. Mechanistically, RBMS1 interacted with the translation initiation factor eIF3d directly to bridge the 3'- and 5'-UTR of SLC7A11. RBMS1 ablation inhibited the translation of SLC7A11, reduced SLC7A11-mediated cystine uptake, and promoted ferroptosis. In a drug screen that targeted RBMS1, we further uncovered that nortriptyline hydrochloride decreased the level of RBMS1, thereby promoting ferroptosis. Importantly, RBMS1 depletion or inhibition by nortriptyline hydrochloride sensitized radioresistant lung cancer cells to radiotherapy. Our findings established RBMS1 as a translational regulator of ferroptosis and a prognostic factor with therapeutic potential and clinical value.


Catheter ablation of a difficult accessory pathway guided by coronary sinus venography and 3D electroanatomical mapping.
A 38-year-old man with history of unsuccessful catheter ablation of paraseptal accessory pathway (AP) and cardiac arrest was referred for reablation. Coronary sinus (CS) venography and detailed three-dimensional electroanatomical mapping demonstrated a large diverticulum near the CS ostium. A single radiofrequency ablation at the neck of the diverticulum eliminated conduction in the AP completely.


Impact of Open Dialogue about Complementary Alternative Medicine-A Phase II Randomized Controlled Trial.
Complementary alternative medicine (CAM) may reduce the symptom burden of side effects to antineoplastic treatment but also cause new side effects and non-adherence to conventional treatment. The aim of this RCT was to investigate the impact of open dialogue about complementary alternative medicine (OD-CAM) on cancer patients' safety, health and quality of life (QoL). Patients undergoing antineoplastic treatment were randomly assigned to standard care (SC) plus OD-CAM or SC alone. The primary endpoint was frequency of grade 3-4 adverse events (AE) eight weeks after enrollment. Secondary endpoints were frequency of grade 1-4 AE, QoL, psychological distress, perceived information, attitude towards and use of CAM 12 and 24 weeks after enrollment. Survival was analyzed post hoc. Fifty-seven patients were randomized to the OD-CAM group and fifty-five to the SC group. No significant difference in frequency of grade 3-4 AEs was shown. The same applied to grade 1-4 AEs and QoL, psychological distress and perceived information. A tendency towards better QoL, improved survival and a lower level of anxiety was found in the OD-CAM group. OD-CAM is not superior to SC in reducing the frequency of AEs in patients undergoing antineoplastic treatment. OD-CAM does not compromise patient safety; it may reduce psychological stress and improve QoL and overall survival.


Provider perspectives on the enabling environment required for skilled birth attendance: a qualitative study in western Nepal.
In Nepal, where difficult geography and an under-resourced health system contribute to poor health care access, the government has increased the number of trained skilled birth attendants (SBAs) and posted them in newly constructed birthing centres attached to peripheral health facilities that are available to women 24 h a day. This study describes their views on their enabling environment. Qualitative methods included semi-structured interviews with 22 SBAs within Palpa district, a hill district in the Western Region of Nepal; a focus group discussion with ten SBA trainees, and in-depth interviews with five key informants. Participants identified the essential components of an enabling environment as: relevant training; ongoing professional support; adequate infrastructure, equipment and drugs; and timely referral pathways. All SBAs who practised alone felt unable to manage obstetric complications because quality management of life-threatening complications requires the attention of more than one SBA. Maternal health guidelines should account for the provision of an enabling environment in addition to the deployment of SBAs. In Nepal, referral systems require strengthening, and the policy of posting SBAs alone, in remote clinics, needs to be reconsidered to achieve the goal of reducing maternal deaths through timely management of obstetric complications.


Biodiversity increased both productivity and its spatial stability in temperate forests in northeastern China.
Although the relationship between biodiversity and ecosystem functioning has been extensively studied, it remains unclear if the relationships of biodiversity with productivity and its spatial stability vary along productivity gradients in natural ecosystems. Based on a large dataset from 2324 permanent forest inventory plots across northeastern China, we examined the intensity of species richness (SR) and tree size diversity (Hd) effects on aboveground wood productivity (AWP) and its spatial stability among different productivity levels. Structural equation modeling was applied, integrating abiotic (climate and soil) and biotic (stand density) factors. Our results demonstrated that both SR and Hd positively affected AWP and its spatial stability, and the intensity of these positive effects decreased with increasing productivity. At low productivity levels, SR and Hd increased spatial stability by reducing spatial variability and increasing mean AWP. At high productivity levels, stability increased only through mean AWP increase. Moreover, temperature and stand density affected the AWP directly and indirectly via biodiversity, and the strength and direction of these effects varied among different productivity levels. We concluded that biodiversity could simultaneously enhance productivity and its spatial stability in temperate forests, and that the effect intensity was uniform along productivity gradients, which provided a new perspective on relationships within biodiversity-ecosystem functioning.


Colorimetric detection of urea nitrate: the missing link.
Traces of the improvised explosive urea nitrate can be characterized by a sensitive colorimetric reaction with p-dimethylaminocinnamalaldehyde (p-DMAC, UN-1 reagent). As recently shown, the dark red product has a structure of a protonated Schiff base. The unprotonated free base, previously postulated in the literature to be the colored product, was now prepared and fully characterized. It shows totally different spectroscopic properties from the dark red compound. Similarly, the analogous free base of the reaction between urea nitrate and the one-vinyl shorter reagent, p-dimethylaminobenzaldehyde, was synthesized and characterized. Similar differences between the free and protonated forms were observed. The protonated Schiff base spontaneously decomposes to the free base over time. This study provides the missing link in the elucidation of the colorimetric reaction between urea nitrate and UN-1. Both colored products show characteristics of typical acid-base indicators.


Superior Mesenteric Artery Blood Flow in Parenterally Fed Versus Enterally Fed Preterm Infants.
The aim of the study was to compare superior mesenteric artery (SMA) flow in premature infants with parenteral and enteral nutrition. A prospective study was conducted on 2 groups of preterm infants with gestational age of 280/7 to 366/7 weeks: group 1 did not qualify for early enteral feeds and received parenteral nutrition (PN), and group 2 received early enteral feeding. SMA peak systolic velocity (PSV), end diastolic velocity (EDV), and pulsatility index (PI) were measured using Doppler ultrasound before starting feeds at day 1 and at day 5. The study recruited 40 infants; 20 in each group. At baseline, PSV, EDV, and PI did not differ between groups. At day 5, enteral nutrition was associated with significant increases in PSV (91.53 ± 29.15 vs 65.49 ± 19.18, P = 0.003) and EDV (15.91 ± 7.01 vs 11.65 ± 5.58, P = 0.026) and a decrease in PI (1.28 ± 0.40 vs 2.48 ± 0.83, P < 0.001). Regression analysis to control for confounders showed enterally fed infants to have increased PSV (adjusted odds ratio [aOR] = 25.45; 95% confidence interval [CI]: 8.53-42.38, P = 0.004) and EDV (aOR 8.630; 95% CI: 2.987-14.273, P = 004) and decreased PI (aOR = -1.133; 95% CI: -1.603 to -0.664, P < 0.001). Infants in the PN group later developed more frequent feeding intolerance when compared with the enterally fed group (65% vs 15%, respectively, P < 0.001). In preterm neonates, early EF is associated with increased SMA blood flow, decreased vascular intestinal resistance, and less frequent incidence of feeding intolerance.


Immunologic patterns of regional lymph nodes in squamous cell carcinoma of the floor of the mouth. Prognostic significance.
Histologic specimens from 43 patients with squamous cell carcinoma of the floor of the mouth treated exclusively by surgery were studied with special attention paid to the reactivity of regional lymph nodes. The lymph nodes were classified into four microscopic patterns of immune response: lymphocyte predominance for sinus histiocytosis, germinal center predominance, unstimulated, and lymphocyte depletion. No nodes of the lymphocyte depletion pattern were found. Correlations were then made between the patterns and survival rate at 5 year follow-up. The results showed that those patients with lymph nodes that demonstrated lymphocyte predominance had a better survival rate than patients with germinal center predominance and the unstimulated patterns. These correlations were independent of stage and metastatic nodal status and the differences were statistically significant (p less than 0.5). Morphologic assessment of immunologic activity in lymph nodes that drain carcinoma of the floor of the mouth appears to be of significant prognostic value.


Differential effects on [35S]GTPgammaS binding using muscarinic agonists and antagonists in the gerbil brain.
In this work, we studied the in vitro G-protein activation induced by muscarinic agonists using [(35)S]guanylyl-5'-O-(gamma-thio)-triphosphate ([(35)S]GTPgammaS) autoradiographic methods to characterize the M(2) and M(4) muscarinic subtypes response. Thus, we describe a detailed characterization of the increases in [(35)S]GTPgammaS binding elicited by carbachol (Cch) and oxotremorine (OXO) (binding in the presence minus binding in the absence of agonist) throughout the gerbil brain (Meriones unguiculatus). For both agonists, the strongest stimulations were found in the superficial gray layer of the superior colliculus, the anteroventral and anteromedial thalamic nuclei, the anterior paraventricular thalamic nucleus, and the caudate-putamen. The comparative study using OXO and Cch suggested that OXO is able to detect differences in the response of structures enriched in M(4) muscarinic receptors, showing a lower potency to stimulate these brain areas. Furthermore, using increasing concentrations of selective M(2) (AF-DX 116) and M(1)/M(4) (pirenzepine) antagonists to inhibit specific Cch- or OXO-induced [(35)S]GTPgammaS binding, significant differences were observed in M(2)-enriched structures but not in M(4)-enriched ones such as the caudate-putamen. These data indicate that appropriate muscarinic agonist stimulation, together with selective inhibition of this effect using functional autoradiography, can be used as a tool to unravel the M(2)- and M(4)-muscarinic subtype-mediated response.


Low intensity pulsed ultrasound enhances fracture healing in both ovariectomy-induced osteoporotic and age-matched normal bones.
Low intensity pulsed ultrasound (LIPUS) was proven to enhance fracture healing effectively. Similar effect of LIPUS on accelerating the osteoporotic fracture healing was therefore hypothesized. The normal and osteoporotic fracture healings under this non-invasive biophysical intervention of LIPUS were compared and investigated. Closed femoral fracture procedures were performed on 120 Sprague-Dawley rats, in which 60 of them were ovariectomized (OVX). The rats were randomly assigned into four groups: sham OVX with treatment (Sham-T), sham OVX control (Sham-C), OVX with treatment (OVX-T) and OXV control (OVX-C). LIPUS treatment was 20 min a day, 5 days a week for durations of 2, 4, or 8 weeks. Results from weekly radiography, histomorphometry, micro-computed tomography and mechanical test showed both the treatment groups were with better healing responses than their control groups. Moreover, between the normal and the osteoporotic treatment groups, a significantly higher (p = 0.015) callus width (week 4), higher ratio of increment in bone volume to tissue volume ratio value (7.4% more), faster response of endochondral ossification and a higher stiffness measurement were observed in the osteoporotic treatment group. These comparable results on healing responses imply that LIPUS can be applied clinically to enhance both normal and osteoporotic fracture healing.


Probiotics Attenuate Myopathic Changes in Aging Rats via Activation of the Myogenic Stellate Cells.
Aging represents a complex biological process associated with decline in skeletal muscle functions. Aging impairs satellite cells that serve as muscle progenitor cells. Probiotic supplementation may have many beneficial effects via various mechanisms. We examined the possible effects of probiotics in stimulating the proliferation of myogenic stellate cells in aging rats. Twenty-four male albino Sprague-Dawley rats were classified equally into four groups: adult control, old control, adult + probiotics, and old + probiotics. Probiotics (Lactobacillus LB) were administered gavage at a dose of 1 ml (1 × 109 CFU/ml/day) for 4 weeks. A significant increase in the relative gastrocnemius weight ratio and improvement of contractile parameters was detected in the old + probiotics group (0.6 ± 0.01) compared to the old control group (0.47 ± 0.01; P < 0.001). Probiotics significantly upregulated the activities of GSH, while NO and MDA were markedly decreased compared to control groups (P ≤ 0.001). Also, probiotics increased the mRNA and protein expressions of myogenin and CD34 (P < 0.05) as determined by real-time PCR and immunohistochemistry. Moreover, the old + probiotics group showed apparent restoration of the connective tissue spaces, reflecting the all-beneficial effects of probiotics. Our findings indicated that probiotics attenuated myopathic changes in aging rats probably through activation of the myogenic stellate cells. Probiotics improved the muscle weight, function, antioxidant activity, and myogenic transcription factors of the skeletal muscle.


Precolumn diastereomerization and micellar electrokinetic chromatography on a plastic microchip: rapid chiral analysis of amino acids.
Precolumn derivatization and chiral separation of DL-amino acids based on diastereomerization have been performed on an integrated poly(dimethylsiloxane) microchip. Diastereomeric derivatives were formed in a microfabricated precolumn reactor by the reaction of amino acid enantiomers with o-phthaldialdehyde/2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranose (OPA/TATG), and separated by MEKC in an achiral environment without chiral selectors in the running buffer. Optimized precolumn reactions and chiral separations of amino acids were achieved within 2.5 min. Resolutions of diastereomers of OPA/TATG-amino acids were in the range of 2.5-6.1 at optimized separation conditions. Simultaneous separation of a mixture of five chiral amino acids was successfully performed in a single run in less than 100 s.


Increased resistance against cadmium toxicity by means of pretreatment with low cadmium/zinc concentrations in Bufo arenarum embryos.
A significantly increased resistance against cadmium toxicity in Bufo arenarum embryos was obtained by means of pretreatments with low cadmium/zinc concentrations, allowing embryos to tolerate lethal cadmium concentrations. Slight variations in the pretreatment schedule could result in significant differences within this acclimation phenomenon. The probable mechanisms of action of this protective effect are discussed.


Full-scale Randomized Trial Comparing Acceptance and Commitment Therapy Telephone-Delivered Coaching With Standard Telephone-Delivered Coaching Among Medicare/Uninsured Quitline Callers.
The aim of this study was to compare Acceptance and Commitment Therapy (ACT) telephone-delivered coaching with standard quitline (QL) telephone-delivered coaching. Medicare/uninsured adults (analyzable sample N = 1170) who smoked at least 10 cigarettes per day were recruited from Optum, a major US provider of QL services, in a two-arm stratified double-blind randomized trial with main outcome of self-reported missing = smoking 30-day point prevalence abstinence (PPA) at the 12-month follow-up. Participants were mean (SD) age 47.4 (12.7), 61% female, and 72% white race. Five sessions of telephone-delivered ACT or QL interventions were offered. Both arms included combined nicotine patch (4 weeks) and gum or lozenge (2 weeks). The 12-month follow-up data retention rate was 67.8%. ACT participants reported their treatment was more useful for quitting smoking (92.0% for ACT vs. 82.3% for QL; odds ratio [OR] = 2.48; 95% confidence interval [CI]: 1.53 to 4.00). Both arms had similar 12-month cessation outcomes (missing = smoking 30-day PPA: 24.6% for ACT vs. 28.8% for QL; OR =.81; 95% CI: 0.62 to 1.05) and the ACT arm trended toward greater reductions in number cigarettes smoked per day (-5.6 for ACT vs. -1.7 QL, among smokers; p = .075). ACT telephone-delivered coaching was more satisfying, engaging, and was as effective as standard QL telephone-delivered coaching. ACT may help those who fail to quit after standard coaching or who choose not to use nicotine replacement therapy. In a sample of Medicare and uninsured QL callers, a large randomized trial with long-term follow-up showed that ACT) telephone-delivered coaching was more satisfying, engaging, and was as effective as standard QL telephone-delivered coaching-which has followed the same behavior change approach since the 1990s. This newer model of coaching might be a welcome addition to QL services.


Bisphenol diglycidyl ethers and bisphenol A and their hydrolysis in drinking water.
Epoxy coatings are commonly used to protect the interior (and exterior) surfaces of water mains and storage tanks and can be used on the interior surfaces of water pipes in homes, hospitals, hotels, and other buildings. Common major components of epoxies include bisphenols, such as bisphenol A (BPA) or bisphenol F (BPF), and their reactive prepolymers, bisphenol A diglycidyl ether (BADGE) and bisphenol F diglycidyl ether (BFDGE), respectively. There currently are health concerns about the safety of BPA and BPF due to known estrogenic effects. Determination of key bisphenol leachates, development of a hydrolysis model, and identification of stable hydrolysis products will aid in assessment of human bisphenol exposure through ingestion of drinking water. Liquid chromatography/mass spectrometry (LC/MS/MS) was used for quantitation of key analytes, and a pseudo-first order kinetic approach was used for modeling. In fill-and-dump studies on epoxy-coated pipe specimens, BADGE and a BPA-like compound were identified as leachates. The BADGE hydrolysis model predicts BADGE half-lives at pH 7 and 15, 25, 35, and 40 °C to be 11, 4.6, 2.0, and 1.4 days respectively; the BFDGE half-life was 5 days at pH 7 and 25 °C. The two identified BADGE hydrolysis products are BADGE-H2O and BADGE 2H2O, with BADGE 2H2O being the final end product under the conditions studied.


Apoptosome-dependent myotube formation involves activation of caspase-3 in differentiating myoblasts.
Caspase-2, -9, and -3 are reported to control myoblast differentiation into myotubes. This had been previously explained by phosphatidylserine exposure on apoptotic myoblasts inducing differentiation in neighboring cells. Here we show for the first time that caspase-3 is activated in the myoblasts undergoing differentiation. Using RNAi, we also demonstrate that differentiation requires both cytochrome c and Apaf-1, and by using a new pharmacological approach, we show that apoptosome formation is required. We also show that Bid, whose cleavage links caspase-2 to the mitochondrial death pathway, was required for differentiation, and that the caspase cleavage product, tBid, was generated during differentiation. Taken together, these data suggest that myoblast differentiation requires caspase-2 activation of the mitochondrial death pathway, and that this occurs in the cells that differentiate. Our data also reveal a hierarchy of caspases in differentiation with caspase-2 upstream of apoptosome activation, and exerting a more profound control of differentiation, while caspases downstream of the apoptosome primarily control cell fusion.


Novel Ehrlichia and Hepatozoon genotypes in white-eared opossums (Didelphis albiventris) and associated ticks from Brazil.
White-eared opossums (Didelphis albiventris) are well adapted to anthropized areas. The increased contact with domestic animals and humans mediates the transmission of arthropod-borne pathogens. Despite the worldwide occurrence of tick-borne Anaplasmataceae and Hepatozoidae species in a variety of vertebrates, few studies reported serological evidence or molecular detection of theses agentes in marsupials. Up to now, while Ehrlichia/Anaplasma spp. have only been detected in marsupials from Brazil, Hepatozoon spp. have been reported in marsupials from Chile, Australia and Brazil. The present work aimed to investigate, using molecular techniques and blood smear analysis, the presence of Ehrlichia spp., Anaplasma spp., and Hepatozoon sp. in the blood and ticks collected from D. albiventris in urban forest fragments from midwestern Brazil. Between May and December 2017, 43 D. albiventris (27 males and 16 females) were captured for blood and tick collection in the city of Campo Grande, state of Mato Grosso do Sul, midwestern Brazil. Ticks (46 Amblyomma dubitatum nymphs and 24 Amblyomma spp. larvae) were collected from 14 out 43 (32.5%) of the white-eared opossums. Panoptic-stained blood smears were performed using peripheral blood (tail tip) of the captured opossums. DNA extracted from blood and tick samples were subjected to PCR/qPCR assays for Anaplasmataceae agents (rrs, gltA, groEL, sodB, and dsb genes, and 23S-5S intergenic region) and Hepatozoon spp. (18S rRNA gene), followed by Sanger sequencing, BLASTn and phylogenetic analyses. An inclusion resembling Ehrlichia morulae was found in a white-eared opossum's monocyte from a blood smear stained with Panoptic. Five (11.63% [5/43]) white-eared opossums' blood samples and 7 (25% [7/28]) tick samples (2 pools of Amblyomma spp. larvae and 5 pools of A. dubitatum nymphs) were positive for Anaplasmataceae via a PCR assay targeting the conserved rrs gene. Phylogenetic analysis based on the rrs gene positioned three sequences obtained from opossums and ticks together as a subclade within the Ehrlichia canis clade. However, all samples were negative in a qPCR assay specific for E. canis based on the dsb gene. Phylogenetic analyses positioned the gltA and 23S-5S ITS sequences obtained from opossums' blood samples in a separate clade from the other validated Ehrlichia species. One (2.3% [1/43]) opossum blood sample was positive for the 18S rRNA gene of Hepatozoon sp. The phylogenetic analysis positioned the Hepatozoon sp. sequence obtained from a D. albiventris specimen in a clade with a sequence previously detected in a black storm petrel (Oceanodroma melania) from Mexico. All the other sequences of Hepatozoon sp. previously detected in marsupials from Brazil were positioned in a separated clade. The present work showed the occurrence of putative novel genotypes of Ehrlichia sp. and Hepatozoon sp. in white-eared opossums and associated A. dubitatum ticks from midwestern Brazil.


An Eu(III) sensor based on N,N-diethyl-N-(4-hydroxy-6-methylpyridin-2-yl)guanidine.
A highly selective poly(vinyl chloride)-based membrane sensor produced by using N,N-diethyl-N-(4-hydroxy-6-methylpyridin-2-yl)guanidine (GD) as active material is described. The electrode displays Nernstian behavior over the concentration range 7.0 x 10(-5) - 1.0 x 10(-1) M. The detection limit of the electrode is 5.0 x 10(-5) M. The best performance was obtained with the membrane containing 30% PVC, 55% benzyl acetate, 5% GD and 10% oleic acid. The response of the sensor is pH-independent in the range of 3.0 - 7.0. The sensor possesses satisfactory reproducibility, fast response time (< 20 s), and specially excellent discriminating ability for Eu(III) ion with respect to the alkali, alkaline earth, transition and heavy metal ions. The membrane sensor was used as an indicator electrode in potentiometric titration of Eu(III) ion with EDTA. It was also applied in determination of fluoride ions in mouth wash preparations.


Metabolic fate in adult and pediatric population of steviol glycosides produced from stevia leaf extract by different production technologies.
More than 60 naturally occurring steviol glycosides in the Stevia rebaudiana Bertoni plant share a similar molecular structure with an aglycone steviol backbone conjugated with β- and α-glycosidic bonds to different sugar moieties. These glycosides are naturally produced in different quantities within the stevia leaf. Certain minor glycosides with superior sensory attributes, such as Reb D and Reb M, are found less than 0.1% in traditional stevia leaves. New technologies can now produce better tasting steviol glycosides by using enzymatic conversion of stevioside and Reb A, which are abundant in stevia leaf. Several regulatory authorities recently evaluated steviol glycosides produced by enzymatic conversion of stevia leaf extract and approved them safe for human consumption. Steviol glycosides undergo microbial hydrolysis in the colon to generate steviol, which is absorbed and metabolized into steviol glucuronide, and excreted primarily via human's urine. Previous studies have shown the hydrolysis of highly purified individual steviol glycosides extracted from stevia leaf are converted to steviol in the presence of colonic microbiota of adults. Since colonic microbiota of children may be different from adults, this study investigates the metabolic fate in the colonic microbiota of adults and children of the minor steviol glycosides produced by extraction and enzymatic conversion of major steviol glycosides from stevia leaf. Several in vitro incubation tests were conducted in human fecal homogenates collected from adult and pediatric populations with steviol glycoside test samples comprised of a complex stevia leaf extract, a blend of minor glycosides isolated from stevia extract and two mixtures of steviol glycosides produced by enzymatic conversion of Reb A to larger molecules by attaching glucose units via β- or α-glycosidic bonds. Results from these studies clearly demonstrate steviol glycosides produced by extraction from stevia leaf, or enzymatic conversion of stevia leaf extract, share the same metabolic fate in the human gut microbiota from adults and children. Considering a common metabolite structure and a shared metabolic fate in all ages, safety data for individual steviol glycosides can be used to support safety of all steviol glycosides produced by extraction and enzymatic conversion of stevia leaf extract.


[Latency values of 248 H reflexes in 124 normal subjects].
The Hoffmann reflex or H reflex is an electrical counterpart of the myotatic reflex. In normal adults is elicited with stimulating the tibial and the median nerves. It is useful as an adjunct study of neuroexamination and assesses the corresponding arc reflexes in their integrity. 248 H reflexes were studied stimulating the tibial nerve in 124 healthy subjects. The latency values were: minimum 23.6 ms; maximum 29.8 ms; mean value 27.6 ± 1.41 ms. This work explains the technique to obtain the H reflex and discusses the need for normalized values for each neurophysiology lab.


High-throughput screening of G protein-coupled receptor antagonists using a bioluminescence resonance energy transfer 1-based beta-arrestin2 recruitment assay.
In this study, the authors developed HEK293 cell lines that stably coexpressed optimal amounts of beta-arrestin2-Rluc and VENUS fusions of G protein-coupled receptors (GPCRs) belonging to both class A and class B receptors, which include receptors that interact transiently or stably with beta-arrestins. This allowed the use of a bioluminescence resonance energy transfer (BRET) 1- beta-arrestin2 translocation assay to quantify receptor activation or inhibition. One of the developed cell lines coexpressing CCR5-VENUS and beta-arrestin2- Renilla luciferase was then used for high-throughput screening (HTS) for antagonists of the chemokine receptor CCR5, the primary co-receptor for HIV. A total of 26,000 compounds were screened for inhibition of the agonist-promoted beta-arrestin2 recruitment to CCR5, and 12 compounds were found to specifically inhibit the agonist-induced beta-arrestin2 recruitment to CCR5. Three of the potential hits were further tested using other functional assays, and their abilities to inhibit CCR5 agonist-promoted signaling were confirmed. This is the 1st study describing a BRET1-beta-arrestin recruitment assay in stable mammalian cells and its successful application in HTS for GPCRs antagonists.


Penicillospirone from a marine isolate of Penicillium sp. (SF-5292) with anti-inflammatory activity.
Chemical investigation of the EtOAc extract of a marine-derived fungal isolate Penicillium sp. SF-5292 yielded a new polyketide-type metabolite, penicillospirone (1). The structure of 1 was determined by analysis of spectroscopic data such as 1D and 2D NMR spectra and MS data, and the final structure including absolute configuration was unambiguously established by single-crystal X-ray diffraction analysis. In the evaluation of its anti-inflammatory effects, 1 inhibited the overproduction of nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and BV2 microglia, and these inhibitory effects were correlated with the suppressive effect of 1 against overexpressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, 1 also inhibited the production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and IL-12. Overall, the anti-inflammatory effect of 1 was suggested to be mediated through the negative regulation of NF-κB pathway.


Endothelium-independent vasorelaxant effect of Asphodelus tenuifolius Cav. via inhibition of myosin light chain kinase activity in the porcine coronary artery.
Asphodelus tenuifolius Cav. (Asphodelaceae), a wild, terrestrial, annual stemless herb, is widely used in traditional medicine for the treatment of hypertension, diabetes, atherosclerosis and circulatory problems. A previous research study from our laboratory revealed that A. tenuifolius has beneficial effects in reducing blood pressure and improves aortic endothelial dysfunction in chronically glucose fed rats. Despite the fact that A. tenuifolius reduces blood pressure and improves endothelial function in vivo, there are no detailed studies about its possible mechanism of action. This study was designed to provide pharmacological basis and mechanism of action for the traditional use of A. tenuifolius in hypertension and circulatory problems. We explored the vasorelaxant effect of A. tenuifolius and its underlying vasorelaxation mechanism in porcine coronary artery rings. Aqueous methanolic crude extract of A. tenuifolius was prepared by maceration process and then activity guided fractionation was carried out by using different polarity based solvents. Phytochemical studies were carried out using LC-DAD-MS. Segments of porcine distal coronary artery were set up in a wire myograph for isometric force measurements. Extract/fractions of A. tenuifolius seeds were tested for vasodilator activity by measurement of changes in tone after pre-contraction with the thromboxane mimetic U46619 in the presence or absence of inhibitors of intracellular signaling cascades. Crude extract/fractions of A. tenuifolius produced dose dependent endothelium independent vasorelaxant response in coronary rings, whereas, the butanol fraction of A. tenuifolius (BS-AT) produced the largest relaxation response with 100% relaxation at 1 mg/ml, therefore the mechanism of relaxation of this fraction was determined. The relaxation to BS-AT was unaffected by removal of the endothelium, pre-contraction with KCl, or the presence of the non-selective potassium channel blocker tetraethylammonium, indicating that the relaxation was endothelium-independent, and does not involve activation of potassium channels. BS-AT (1 mg/ml) inhibited the contractile response to calcium,the L-type calcium channel activator BAY K8664,and ionomycin, indicating that it inhibits calcium-induced contractions. The relaxation response to BS-AT was attenuated in the absence of extracellular calcium. However, relaxations to BS-AT were also reduced after deletion of calcium from intracellular stores with cyclopiazonic acid. Incubation with 1 mg/ml BS-AT also inhibited phosphorylation of myosin light chains in homogenates of coronary artery. The butanol extract of Asphodelus tenuifolius produces a large endothelium-independent relaxation of the porcine coronary artery through inhibition of calcium-induced contractions. The effect appears to be downstream of calcium influx, possibly through inhibition of myosin light chain kinase. This study supports previous studies demonstrating that A. tenuifolius reduces blood pressure. Future studies will aim to determine the active compounds underlying this response.


Metabolite of 2,2',4',5-tetrabromobiphenyl, 3-methylsulphonyl-2,2',4',5-tetrabromobiphenyl, a potent inducer of CYP2B1/2 in rat.
1. 3-Methylsulphonyl- and 4-methylsulphonyl-2,2',4',5-tetrabromobiphenyls (3-MeSO(2)- and 4-MeSO(2)-TetraBrBs) were detected in the liver, lung, kidney, adipose tissue and faeces of the 2,2',4',5-tetrabromobiphenyl (TetraBrB)-dosed rat. 2. The administration of 0.05-2.0 micromol kg(-1) doses of 3-MeSO(2)-TetraBrB produced corrresponding increases in the hepatic concentration of the methyl sulphone metabolite, corresponding increases in the content of total cytochrome P450, and corresponding increases in the activities of 7-benzyloxy-, 7-ethoxy- and 7-pentoxyresorufin O-dealkylases. The inducing effects of the 3-MeSO(2)-TetraBrB (0.2 micromol kg(-1)), both on the content of total P450 and on the activities of the three alkoxyresorufin O-dealkylases, were higher than that of the parent TetraBrB (342 micromol kg(-1)). 3. The major phenobarbital (PB)-inducible forms of P450, CYP2B1, CYP2B2, CYP3A2 and CYP2C6, were substantially induced by 3-MeSO(2)-TetraBrB, but CYP1A1 and CYP1A2 were not. On the other hand, the activities of drug-metabolizing enzymes and the four PB-inducible forms of P450 were unchanged by 4-MeSO(2)-TetraBrB treatment. 4. The induction profiles of these enzymes and P450 forms in rat treated with 3-MeSO(2)-TetraBrB were similar to those treated with PB. 5. The inducing ability of 3-MeSO(2)-TetraBrB (0.5 micromol kg(-1)) both on the activities of the three alkoxyresorufin O-dealkylases and on the contents of four PB-inducible forms of P450 was roughly equal to that of PB (431 micromol kg(-1) twice at a 24-h interval) or 3-MeSO(2)-2,2',4',5-tetrachlorobiphenyl (1 micromol kg(-1)). It is noteworthy that the effects of 3-MeSO(2)-TetraBrB on the drug-metabolizing enzymes CYP2B1 and CYP2B2 were several thousand-fold higher than those of parent TetraBrB, while the effect of its isomeric 4-MeSO(2)-TetraBrB were not. 6. The extent of hepatic accumulation of the 3-MeSO(2) metabolite after the administration of TetraBrB (342 micromol kg(-1)) was almost the same as that after the administration of 3-MeSO(2)-TetraBrB (0.1-0.2 micromol kg(-1)). The relationship between the hepatic concentration of the 3-MeSO(2) metabolite and the extent of enzyme induction after the administration of TetraBrB or 3-MeSO(2)-TetraBrB suggests that 3-MeSO(2)-TetraBrB plays an important role in the induction of microsomal drug-metabolizing enzymes by TetraBrB.


Sema4D as a biomarker for Predicting rheumatoid arthritis disease activity.
The semaphorins are membrane or secreted proteins first identified in neural development. Semaphorin 4D (Sema4D) is the first family member found to have immune properties. We evaluated the potential of Sema4D as a marker for rheumatoid arthritis (RA) disease activity, singly and in combination with other known biomarkers including rheumatoid factor (RF) and C-reactive protein (CRP). Three hundred and eleven RA patients were enrolled. The patients were divided into three groups based on their disease activity in 28 joints (DAS28): mild, moderate, and severe. The healthy group included 40 healthy individuals. SerumSema4D was measured by quantitative ELISA and the specificity and sensitivity of biomarkers were evaluated by generating a receiver operating characteristic (ROC) curve to analyze their diagnostic accuracy. Serum Sema4D levels in the moderate and severe RA groups were elevated significantly above those of the controls (P < 0.01), while levels in the mild RA and control groups did not differ significantly (P > 0.05). The Sema4D cutoff threshold was 15.7 ng/ml when the DAS28 was applied as a reference. Compared to the erythrocyte sedimentation rate (ESR and CRP, Sema4D had the highest specificity (96.8%) and area under the curve (0.80) for diagnosing RA activity. The highest specificity (100%) for the biomarker combinations was obtained when Sema4D was combined with CRP and anti-CCP, the combination of the Sema4D combined with ESR and anti-CCP had the highest sensitivity (99.35%). According to this result, a new model for jointly calculating RA activity of Sema4D,anti-CCP and CRP was constructed. Meanwhile another model is established by using the method of multivariate analysis.Model comparison results showed the the multiple regression algorithm method fitted the patients' disease activity better. The serum Sema 4D level effectively reflects moderate to severe RA activity. Sema4D levels can be used together with conventional RA biomarkers to increase the diagnostic power of RA activity. The multiple regression algorithm method is promising in disease activity calculation.


Clinical implementation of MRI of joint arthroplasty.
The purpose of this article is to explain the basic physics of imaging patients with metal implants, explain conflicting information regarding MRI scanning of "MR Conditional" devices, and relate our experience of scanning total joint arthroplasty (TJA) at our institution. MRI near TJA is effective with appropriate imaging protocols and standardized safety precautions. Strict adherence to MR Conditional labeling may preclude broad use of MRI for TJA assessment.


A population-based study on the association between statin use and sudden sensorineural hearing loss.
No study has reported the relationship between statin use and sudden sensorineural hearing loss (SSNHL). In this study, we examined the association between statin use and SSNHL using a population-based dataset. A case-control study. Taiwan. The study sample was selected from the Taiwan Longitudinal Health Insurance Database. We identified 1263 subjects aged ≥40 years with SSNHL and 6315 sex-, age-, hypertension-, and coronary heart disease-matched controls. We used conditional logistic regression to compute the odds ratio (OR) for having been a previous statin user between cases and controls. Furthermore, we performed conditional logistic regression to explore the relationship of regular and irregular statin users with SSNHL. There was a significant difference in the prevalence of statin use between cases and controls (27.2% vs 21.3%, respectively; P < .001). The OR of statin use before the index date for cases was 1.36 (95% confidence interval [CI], 1.18-1.57) compared to controls after taking gender, age group, hypertension, coronary heart disease, diabetes, renal disease, and hyperlipidemia into consideration. Furthermore, compared to controls, the adjusted ORs of regular and irregular statin use for cases were 1.30 (95% CI, 1.11-1.52) and 1.49 (95% CI, 1.11-1.93), respectively, compared to controls. This study found that SSNHL was significantly associated with previous statin use.


Morphometric features on enhanced depth imaging optical coherence tomography scans in idiopathic posterior uveitis or panuveitis.
Enhanced depth imaging (EDI) optical coherence tomography (OCT) has emerged as a novel tool for qualitative and quantitative choroidal assessment in posterior uveitis. The objective of this study was to investigate the role of EDI-OCT to assess the choroidal and retinal changes in posterior uveitis. In this retrospective study, EDI-OCT scans of patients with idiopathic posterior uveitis or panuveitis were reviewed. Morphological features from retina and choroid from the OCT scans were assessed and compared to the fellow normal eyes. Follow-up assessment was performed at 6-month follow-up. Nineteen patients with idiopathic posterior or panuveitis were included in the study. Choroidal examination using EDI-OCT scans showed areas of focal hypo-reflective and discrete hyper-reflective foci in one-third patients. Macular edema, disruption of the ellipsoid zone (generalized and discrete), outer retinal hyper-reflective foci, and intraretinal and subretinal fluid were observed. The index study reports qualitative OCT-derived parameters as possible tools in monitoring disease progression in uveitis.


Risk of adverse pathology at prostatectomy in the era of MRI and targeted biopsies; rethinking active surveillance for intermediate risk prostate cancer patients.
Men with intermediate risk (IR) prostate cancer (CaP) are often excluded from active surveillance (AS) due to higher rates of adverse pathology (AP). We determined our rate of AP in men who underwent multiparametric MRI (MpMRI) with combined biopsy (CB) consisting of targeted biopsy (TB) and systematic biopsy (SB) prior to radical prostatectomy (RP). A retrospective review was conducted of men with Gleason Grade Group (GG) 2 disease who underwent RP after SB alone or after preoperative MRI with CB. AP was defined as either pathologic stage T3a (AP ≥ T3a) or pathologic stage T3b (AP ≥ T3b) and/or GG upgrading. Rates of AP were determined for both groups and those who fit the National Comprehensive Cancer Network (NCCN) definition of favorable IR (FIR) or the low volume IR (LVIR) criteria. Multivariable logistic regression was used to determine predictive factors. The overall rate of AP ≥ T3b was 21.2% in the SB group vs. 8.6% in the MRI with CB group, P = 0.006. This rate was lowered to 6.8% and 5.6% when men met the definition of NCCN FIR or LVIR, respectively. Suspicion for extraprostatic extension (EPE) (OR 7.65, 95% CI 1.77-33.09, P = 0.006) and positive cores of GG 2 on SB (OR 1.43, 95% CI 1.05-1.96, P = 0.023) were significant for predicting AP ≥ T3b. Rates of AP at RP after MRI with CB are lower than studies prior to the adoption of this technology, suggesting that more men with IR disease may be considered for AS. However, increasing cores positive on SB and MRI findings suggestive of EPE remain unsafe.


Outcomes of a Therapeutic Fly-Fishing Program for Veterans with Combat-Related Disabilities: A Community-Based Rehabilitation Initiative.
The purpose of this study was to examine the outcomes of a therapeutic fly-fishing program for veterans with combat-related disabilities. A total of 40 veterans participated in the 4-day therapeutic fly-fishing program and this study. The outcomes examined included reducing symptoms of posttraumatic stress (PTS), depression, perceived stress, functional impairment (i.e., work, relationships, physical, and everyday life), increasing self-determination, and leisure satisfaction. Each research participant completed pretest, posttest, and 3-month follow-up questionnaires. Repeated measures MANOVA and ANOVA were conducted to examine the differences between the three time points on each outcomes. The results indicated significant decreases from the pretest to posttest for symptoms of PTS, depression, perceived stress, and functional impairment, and an increase in leisure satisfaction from pretest to 3-month follow-up. These results highlight the use of therapeutic recreation programming for veterans with disabilities as a holistic approach to treatment and recovery.


Eye position and head size in the Chinese population: a comparison of the Chinese from Hong Kong with the Chinese from Guangdong Province.
Measurements obtained in this study include facial and head dimensions. From our findings, it would appear that the Chinese population in Hong Kong have not become different in the two or three generations that separate them from those living in Guangdong province of China.


Synthesis and properties of triazole-linked RNA.
RNA oligonucleotides having triazole linkages between uridine and adenosine nucleosides have been prepared and studied using spectroscopic techniques. UV melting and CD showed that triazole strongly destabilized RNA duplex (7-14°C per modification). NMR data suggested that, despite relative flexibility around the modified linkage, all base pairs were formed.


What patients want to know, and what we actually tell them: The ABIDE project.
We studied to what degree and at whose initiative 25 informational topics, formerly identified as important, are discussed in diagnostic consultations. Audio recordings of clinician-patient consultations of 71 patients and 32 clinicians, collected in eight Dutch memory clinics, were independently content-coded by two coders. The coding scheme encompassed 25 informational topics. Approximately half (Mdn = 12) of the 25 topics were discussed per patient during the diagnostic process, with a higher frequency among individuals receiving a dementia diagnosis (Mdn = 14) compared to others (Mdn = 11). Individual topics ranged from being discussed with 2/71 (3%) to 70/71 (99%) of patients. Patients and/or care partners rarely initiated topic discussion (10%). When they did, they often enquired about one of the least frequently addressed topics. Most patients received information on approximately half of the important informational topics. Providing the topic list to patients and care partners beforehand could allow consultation preparation and stimulate participation.


The Importance of Animal Models in Biomedical Research: Current Insights and Applications.
Animal research is considered a key element in advance of biomedical science. Although its use is controversial and raises ethical challenges, the contribution of animal models in medicine is essential for understanding the physiopathology and novel treatment alternatives for several animal and human diseases. Current pandemics' pathology, such as the 2019 Coronavirus disease, has been studied in primate, rodent, and porcine models to recognize infection routes and develop therapeutic protocols. Worldwide issues such as diabetes, obesity, neurological disorders, pain, rehabilitation medicine, and surgical techniques require studying the process in different animal species before testing them on humans. Due to their relevance, this article aims to discuss the importance of animal models in diverse lines of biomedical research by analyzing the contributions of the various species utilized in science over the past five years about key topics concerning human and animal health.


G.L. Amidon, H. Lennernas, V.P. Shah, and J.R. Crison. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability, Pharm Res 12, 413-420, 1995--backstory of BCS.
The Biopharmaceutics Classification System (BCS) has become widely accepted today in the academic, industrial, and regulatory world. While the initial application of the BCS was to regulatory science bioequivalence (BE) issues and related implications, it has come to be utilized widely by the pharmaceutical industry in drug discovery and development as well. This brief manuscript will relate the story of the BCS development. While much of the ground work for the BCS goes back to the pharmacokinetic and drug absorption research by Gordon Amidon (GLA) in the 1970s and 1980s, the realization of the need for a classification or categorization of drug and drug products for setting dissolution standards became apparent to GLA during his 1990-1991 sabbatical year at the FDA. Initiated at the invitation of the then CEDR director, Dr. Carl Peck, to become a visiting scientist at the FDA, the goal was to promote regulatory research at the FDA, in my case, in biopharmaceutics, and to develop a science-based system to simplify regulatory requirements.


A self-control classroom for hyperactive children.
In this study we investigated the effectiveness of a package of self-control procedures in a classroom with six hyperactive boys ages 7 to 10. A within-subjects reversal design was used. Measures of on-task behavior and class misbehavior, as well as measures of activity level, were recorded. Results indicated that the self-control package was effective in improving misbehavior and attention to tasks during the individual seat work but not during group instruction. Activity level was not affected by the treatment. Changes in the schedule of self-monitoring for the boys in the class produced an increase in variability and some deterioration in their behavior. Those boys of lower mental age seemed most affected by the schedule shift.


Mid-trimester residual cervical length and the risk of preterm birth in pregnancies after abdominal radical trachelectomy: a retrospective analysis.
To investigate the association between mid-trimester residual cervical length (CL) and the risk of preterm birth in pregnancies after abdominal radical trachelectomy (RT). Retrospective cohort study. University hospital. A total of 33 deliveries after 22 weeks' gestation in 30 women who underwent abdominal RT including prophylactic cervical cerclage and perinatal care between January 2002 and May 2016. The association between mid-trimester residual CL (the distance between the cerclage and the external cervical os) and gestational age at delivery was investigated. Receiver-operating characteristics (ROC) curve analysis was performed to estimate the optimal cut-off values of the mid-trimester residual CL for the prediction of preterm birth. Preterm birth before 34 weeks' gestation. Mid-trimester residual CL showed a significant correlation with gestational age at delivery (r = 0.36, P < 0.05). There was a significant difference in residual CL between women who did and those who did not give birth before 34 weeks (P < 0.05). Mid-trimester residual CL < 13 mm was a good predictor of birth before 34 weeks, with a sensitivity of 67%, specificity of 75%, positive predictive value of 55% and negative predictive value of 86% (area under ROC curve, 0.75). Mid-trimester residual CL is significantly correlated with gestational age at delivery. Residual CL assessment could be used to reassure physicians and women that there is only a small chance of preterm birth in pregnancies after abdominal RT. Mid-trimester residual cervical length is a good predictor of preterm birth after radical trachelectomy.


NanoTox: Development of a Parsimonious In Silico Model for Toxicity Assessment of Metal-Oxide Nanoparticles Using Physicochemical Features.
Metal-oxide nanoparticles find widespread applications in mundane life today, and cost-effective evaluation of their cytotoxicity and ecotoxicity is essential for sustainable progress. Machine learning models use existing experimental data and learn quantitative feature-toxicity relationships to yield predictive models. In this work, we adopted a principled approach to this problem by formulating a novel feature space based on intrinsic and extrinsic physicochemical properties, including periodic table properties but exclusive of in vitro characteristics such as cell line, cell type, and assay method. An optimal hypothesis space was developed by applying variance inflation analysis to the correlation structure of the features. Consequent to a stratified train-test split, the training dataset was balanced for the toxic outcomes and a mapping was then achieved from the normalized feature space to the toxicity class using various hyperparameter-tuned machine learning models, namely, logistic regression, random forest, support vector machines, and neural networks. Evaluation on an unseen test set yielded >96% balanced accuracy for the random forest, and neural network with one-hidden-layer models. The obtained cytotoxicity models are parsimonious, with intelligible inputs, and an embedded applicability check. Interpretability investigations of the models identified the key predictor variables of metal-oxide nanoparticle cytotoxicity. Our models could be applied on new, untested oxides, using a majority-voting ensemble classifier, NanoTox, that incorporates the best of the above models. NanoTox is the first open-source nanotoxicology pipeline, freely available under the GNU General Public License (https://github.com/NanoTox).


Multi-Institutional Prospective Validation of Prognostic mRNA Signatures in Early Stage Squamous Lung Cancer (Alliance).
Surgical resection is curative for some patients with early lung squamous cell carcinoma. Staging and clinical factors do not adequately predict recurrence risk. We sought to validate the discriminative performance of proposed prognostic gene expression signatures at a level of rigor sufficient to support clinical use. The two-stage validation used independent core laboratories, objective quality control standards, locked test parameters, and large multi-institutional specimen and data sets. The first stage validation confirmed a signature's ability to stratify patient survival. The second-stage validation determined which signature(s) optimally improved risk discrimination when added to baseline clinical predictors. Participants were prospectively enrolled in institutional (cohort I) or cooperative group (cohort II) biospecimen and data collection protocols. All cases underwent a central review of clinical, pathologic, and biospecimen parameters using objective criteria to determine final inclusion (cohort I: n = 249; cohort II: n = 234). Primary selection required that a signature significantly predict a 3-year survival after surgical resection in cohort I. Signatures meeting this criterion were further tested in cohort II, comparing risk prediction using baseline risk factors alone versus in combination with the signature. Male sex, advanced age, and higher stage were associated with shorter survival in cohort I and established a baseline clinical model. Of the three signatures validated in cohort I, one signature was validated in cohort II and statistically significantly enhanced the prognosis relative to the baseline model (C-index difference 0.122; p < 0.05). These results represent the first rigorous validation of a test appropriate to direct adjuvant treatment or clinical trials for patients with lung squamous cell carcinoma.


Impact of Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography on the Therapeutic Decision of Prostate Carcinoma Primary Staging: A Retrospective Analysis at the Brazilian National Public Health System.
Prostate cancer (PCa) is the most common malignant tumor in males and conventional imaging does not provide accurate primary staging. Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) presents superior performance and strongly affects therapeutic choice. The aim of this study was to evaluate the impact of PSMA PET, compared with conventional imaging methods, on the therapeutic approach in primary staging scenarios in patients with PCa treated at the Brazilian National Public Health System. Overall, 35 patients diagnosed with PCa were evaluated using PSMA after conventional staging imaging with multiparametric magnetic resonance (MMR) and/or total abdominal computed tomography (CT) scan and bone scintigraphy (BS). The PCa extension identified by PET was compared with conventional imaging; staging changes and the management impact were then determined. PET comparison with conventional imaging, staging, and decision-making changes was analyzed using descriptive statistics. PET revealed local disease (LD) in 15 (42.9%) patients, seminal vesicle invasion (SVI) in 5 (14.3%) patients, pelvic nodal impairment (PNI) in 7 (20%) patients, pelvic and distant nodes in 3 (8.6%) patients, pelvic nodes and bone metastasis in 4 (11.4%) patients, and pelvic and distant nodes and bone metastasis in 1 (2.8%) patient. Staging changes were observed in 60% of patients, with downstaging predominance (76.2%). Volume increase was identified in 11 (31.4%) patients (only 4 related to upstaging, 36.4%). The board changed management decisions for 60% of the patients. The main limitations of this study were the sample size and its retrospective nature. PSMA findings changed the management decisions in more than half of the patients, which made the majority eligible for locoregional treatment and avoided unnecessary procedures in the systemic disease scenario.


Association of circulating adipokine concentrations with indices of adiposity and sex in healthy, adult client owned cats.
Both diabetes mellitus (DM) and obesity are common in cats. The adipokines leptin, adiponectin, resistin and omentin are thought to have important roles in human obesity and glucose homeostasis; however, their functions in the pathophysiology of feline diabetes mellitus and obesity are poorly understood. We determined whether sexual dimorphism exists for circulating concentrations of these adipokines, whether they are associated with adiposity, and whether they correlate with basic indices of insulin sensitivity in cats. Healthy, client-owned male and female cats that were either ideal weight or obese were recruited into the study. Fasting blood glucose, fructosamine, cholesterol, triglycerides, insulin and plasma concentrations of adipokines were evaluated. Obese cats had greater serum concentrations of glucose and triglycerides than ideal weight cats, but fructosamine and cholesterol concentrations did not differ between groups. Body weight and body mass index were greater in male than female cats, but circulating metabolite cocentrations were similar between sexes of both the ideal weight and obese groups. Plasma concentrations of insulin and leptin were greater in obese than ideal weight cats, with reciprocal reduction in adiponectin concentrations in obese cats; there were no sex differences in these hormones. Interestingly, plasma omentin concentrations were greater in male than female cats but with no differences between obese and ideal weight states. Together our findings suggest that rather than gender, body weight and adiposity are more important determinants of circulating concentrations of the adipokines leptin and adiponectin. On the contrary, the adipokine omentin is not affected by body weight or adiposity but instead exhibits sexual dimorphism in cats.


The efficacy and safety of bisphosphonate analogs for treatment of osteoporosis after spinal cord injury: a systematic review and meta-analysis of randomized controlled trials.
Bisphosphonates can inhibit osteoclast-mediated bone resorption, prevent bone loss, and reduce the risk of osteoporotic fractures. Our meta-analysis of studies shows that early bisphosphonate administration after SCI was safe and beneficial to the BMD of the total hip and lumbar spine at 12 months. Rapid bone loss in the early stages of spinal cord injury (SCI) leads to an increased risk of osteoporotic fracture. A meta-analysis was conducted to assess the efficacy and safety of bisphosphonates for the treatment of osteoporosis after SCI. A literature search of the PubMed, EMBASE, Cochrane Library, and Web of Science databases identified nine randomized controlled trials with 206 individuals. This meta-analysis was performed using a random-effects model. The primary outcome was the percent change in bone mineral density (BMD) of the total hip, distal femur, and lumbar spine from baseline to 12 months. Bone turnover markers were secondary outcomes. The incidences of adverse events were assessed in order to evaluate safety. There were significant differences in BMD of the total hip and lumbar spine or serum C-terminal telopeptide between the bisphosphonate and control groups but no difference in adverse events. The percent change in BMD of the distal femur and serum type 1 procollagen N-terminal peptide from baseline to 12 months was not superior in the treatment groups. Osteoclast-mediated bone resorption was inhibited by bisphosphonate administration. Subgroup analyses of participants treated with zoledronate at different sites revealed a beneficial effect on BMD of the total hip and lumbar spine but not the distal femur. Early bisphosphonate administration after SCI was safe and beneficial to the BMD of the total hip and lumbar spine at 12 months.


Rheological and kinetic study of the ultrasonic degradation of xanthan gum in aqueous solutions.
The effectiveness of ultrasound to degrade the molecular weight of xanthan gum in aqueous solutions was investigated for sonication times up to 60 min at 20 °C and for polymer concentrations up to 0.1g/dl. The Huggins equation was found to be applicable to the intrinsic viscosity of xanthan gum prior to sonication, while a truncated form was found to be adequate for estimating the intrinsic viscosity of the degraded xanthan. To better understand the influence of salting-in and salting-out salts (classified on the basis of the Hofmeister series) on degradation, xanthan-gum solutions were pre-mixed with 0.1, 10(-2), 10(-3), or 10(-4)M NaCl or Na2SO4, prior to ultrasonication. A kinetic model was developed and successfully applied to quantify and predict the degradation rates and efficiency. The various reaction rate constants and reaction orders were found to correlate with the different salt species and concentrations used, suggesting that salting-in and salting-out salts could increase or inhibit ultrasonic degradation by adjusting the molecular conformation of the xanthan.


A technique for postembolectomy streptokinase infusion.
Despite successful arterial thromboembolectomy, some extremities may have progressive ischemic necrosis due to persistent arterial occlusion. Streptokinase infusion can be valuable in this situation. We have developed a clinically applicable technique that is of value in lysing residual thrombi.


Daily users compared to less frequent users find vape as or more satisfying and less dangerous than cigarettes, and are likelier to use non-cig-alike vaping products.
We assessed the roles of perceived satisfaction and perceived danger and vaping-product-type as correlates of more frequent use of vaping products. In a baseline assessment of a longitudinal study of US Army Reserve/National Guard Soldiers and their partners (New York State, USA, 2014-2016), participants were asked about current use of vaping products (e-cigarettes) and perceived satisfaction and danger in comparison to cigarettes as well as type of product used. Fisher-exact tests and multiple ordinal logistic regressions were used. In multivariable and univariate models, more perceived satisfaction, less perceived danger, and use of non-cig-alike products were associated with more frequent use of vaping products (ps < 0.05, two-tailed). For self-selected, more frequent adult users, e-cigs can be at least as satisfying as cigarettes and often more satisfying and are perceived as less dangerous than cigarettes. Non-cig-alike products were more likely in daily users. Some concern that e-cigs are a gateway to cigarettes arises from assuming that e-cigs may not be as reinforcing and pleasurable as cigarettes. These results indicate that accurate perception of comparative risk and use of more effective-nicotine delivery product can produce for some users a highly-satisfying alternative to cigarettes.


Correction to 'Integration of single-cell datasets reveals novel transcriptomic signatures of β-cells in human type 2 diabetes'.
[This corrects the article DOI: 10.1093/nargab/lqaa097.].


Epithelium derived interleukin 15 regulates intraepithelial lymphocyte Th1 cytokine production, cytotoxicity, and survival in coeliac disease.
Epithelium derived interleukin (IL)-15 signalling via IL-15Ralpha is critical for the development, activation, and survival of intraepithelial lymphocytes (IEL). We aimed to better understand the IL-15 driven effects on IEL underlying mucosal damage and lymphomagenesis in coeliac disease (CD). Enterocytes, IEL, and lamina propria mononuclear cells (LPMC) were isolated from 46 patients with uncomplicated CD (25 untreated and 21 treated) and 22 controls. IL-15 and IL-15Ralpha expression were determined by immunoblotting. Secretion of IL-15, interferon gamma (IFN-gamma), tumour necrosis factor alpha (TNF-alpha), and granzyme B into cell culture supernatants was assessed by ELISA. The ability of IL-15 to regulate IEL proliferation, perforin/granzyme dependent cytotoxicity, and apoptosis was tested by adding different combinations of IL-15, IL-15 blocking antibody, or chloroquine to IEL cultured alone or with Caco-2 cells as target. IL-15 mucosal levels were also determined by ELISA in five patients with complicated CD (two ulcerative jejunoileites, one refractory sprue, and two enteropathy associated T cell lymphomas) tested for T cell receptor gamma chain clonality. IL-15 was overexpressed in untreated CD enterocytes and LPMC, and in the mucosa of complicated CD patients and uncomplicated untreated CD patients, where its levels correlated with the degree of mucosal damage. Enterocytes from untreated, but not treated, CD patients and controls secreted IL-15. Untreated CD IEL, characterised by higher IL-15Ralpha expression, showed increased proliferation, production of IFN-gamma and TNF-alpha, and perforin/granzyme dependent cytotoxicity, and a decreased propensity to apoptosis in response to IL-15. Our findings suggest that IL-15 plays a crucial role in the generation of epithelial damage in active CD. Its promotion of IEL survival in CD may predispose to the emergence of T cell clonal proliferations. Blocking IL-15, by suppressing uncontrolled IEL activation and survival, has the potential to provide new therapeutic tools to prevent tissue damage and lymphomagenesis in CD.


Binary dance rhythm or Quaternary dance rhythm which has the greatest effect on non-motor symptoms of individuals with Parkinson's disease?
This study aimed to compare the effect of a binary and quaternary rhythm protocol on cognition, mental activity, daily life, and quality of life among individuals with Parkinson's Disease. A two-arm randomized clinical trial with 31 individuals diagnosed with Parkinson's disease, who were allocated to the binary group or quaternary group. Both groups underwent a 12-week intervention. The following variables were analyzed: personal and clinical information; MoCA; UPDRSI and II; PDQ-39. Both intervention groups improved cognition, mental activity, activities of daily living, and quality of life. In addition, there were intergroup differences in total UPDRSII, writing, and hygiene where the quaternary group was superior to the binary group. It concludes that the binary and quaternary rhythm positively influenced and presented similar effects on the complementary treatment of individuals with Parkinson's disease on the studied variables. Thus, it is believed that both interventions are possible and feasible for the health professionals involved in the area.


Selection for inferior limited macular translocation on the basis of distance from the fovea to the inferior edge of the subfoveal choroidal neovascularization.
To assess the visual outcome of inferior limited macular translocation in eyes selected based on the distance from the fovea to the inferior edge of the subfoveal choroidal neovascularization. Interventional case series. We performed inferior limited macular translocation in 12 consecutive eyes (12 patients) with age-related macular degeneration or polypoidal choroidal vasculopathy, in which the choroidal neovascularization did not extend for more than half of one disk diameter inferior to the fovea. In all eyes, the choroidal neovascularization was moved to an extrafoveal location. In seven of the 12 eyes, postoperative vision was 20/40 or better. The visual acuity improved by 2 or more lines in 11 eyes. Selection for inferior limited macular translocation on the basis of distance from the fovea to the inferior edge of the choroidal neovascularization may be associated with a greater likelihood of visual acuity improvement.


The organization of an integrated basic medical science curriculum at a new medical school, Nottingham.
The detailed organization of an integrated medical sciences curriculum from its initial planning to the final stage of "automatic" administration are described. Although some reduction in departmental autonomy results, this is outweighed by the advantages of a timetable and curriculum prepared, planned and carried out in a cooperative manner. Flexibility and scope for controlled change and experiment are retained.


REINVENT: ERS International survey on REstrictive thoracic diseases IN long term home noninvasive VENTilation.
Little is known about the current use of long-term home noninvasive ventilation (LTHNIV) in restrictive thoracic diseases, including chest wall disorders and neuromuscular disorders (NMD). This study aimed to capture the pattern of LTHNIV in patients with restrictive thoracic diseases via a web-based international survey. The survey involved European Respiratory Society (ERS) Assembly 2.02 (NIV-dedicated group), from October to December 2019. 166 (22.2%) out of 748 members from 41 countries responded; 80% were physicians, of whom 43% worked in a respiratory intermediate intensive care unit. The ratio of NMD to chest wall disorders was 5:1, with amyotrophic lateral sclerosis the most frequent indication within NMD (78%). The main reason to initiate LTHNIV was diurnal hypercapnia (71%). Quality of life/sleep was the most important goal to achieve. In 25% of cases, clinicians based their choice of the ventilator on patients' feedback. Among NIV modes, spontaneous-timed pressure support ventilation (ST-PSV) was the most frequently prescribed for day- and night-time. Mouthpieces were the preferred daytime NIV interface, whereas oro-nasal masks the first choice overnight. Heated humidification was frequently added to LTHNIV (72%). Single-limb circuits with intentional leaks (79%) were the most frequently prescribed. Follow-up was most often provided in an outpatient setting. This ERS survey illustrates physicians' practices of LTHNIV in patients with restrictive thoracic diseases. NMD and, specifically, amyotrophic lateral sclerosis were the main indications for LTHNIV. NIV was started mostly because of diurnal hypoventilation with a primary goal of patient-centred benefits. Bi-level ST-PSV and oro-nasal masks were more likely to be chosen for providing NIV. LTHNIV efficacy was assessed mainly in an outpatient setting.


State of the art. Primary biliary cirrhosis and the immune system.
The immunologic features of diseases associated with primary biliary cirrhosis (PBC) such as Sjörgren's syndrome, scleroderma, rheumatoid arthritis and others are reviewed. Immunologic abnormalities involving both humoral and cell mediated immunity have been found in PBC. The morphologic and immunologic data have been used to propose a pathogenetic mechanism for PBC. Recent studies of penicillamine indicate that the drug may influence liver copper content and the deposition of immune complexes.


1H-nmr studies on the structure of a new thionin from barley endosperm.
A new thionin from barley, omega-hordothionin, has been shown to exist in aqueous solution as a mixture of two different isoforms in a 3:2 ratio, as revealed by a complete analysis of its two-dimensional 1H-nmr spectra. The conformational heterogeneity arises from cis-trans isomerism about the Phe 12-Pro 13 peptide bond, where the major form corresponds to the cis conformation. The complete assignment of chemical shifts and nuclear Overhauser effects (NOEs) of the two isoforms allows a detailed comparative analysis of their conformational properties, even though a complete calculation of their solution structures is not possible because of a somewhat limited number of NOE constraints. Structures for the two isomers could be modeled, however, on the basis of the high structural homology between omega-hordothionin and related gamma-thionins, and under the conditions of satisfying all observed experimental data. The two isoforms adopt practically identical global folds and the structural changes imposed by cis-trans isomerization are confined to the region proximal to Pro 13. The cis-trans isomerism occurs in a conserved loop connecting the first beta-strand of the triple-stranded antiparallel beta-sheet and the alpha-helix. A comparative analysis of the sequences of this loop in the different thionins suggests that the cis-trans equilibrium about the X-Pro peptide bond depends on the size of the side chain of X (X = Gly in gamma-thionins and Phe in omega-thionin). The structural homology of this new thionin with gamma-thionins as well as with some scorpion toxins and insect defensins suggests that these proteins may share a common mode of functional activity.


Autofluorescence bronchoscopy and endobronchial ultrasound: a practical review.
Endobronchial ultrasound (EBUS) and autofluorescence bronchoscopy (AFB) are the two technologies to have the largest impact on diagnostic bronchoscopy in the last forty years. The AFB utilizes inherent tissue properties to identify preinvasive lesions of the central airways. The EBUS can accurately define airway invasion versus compression from tumors, guide transbronchial needle aspiration of hilar and mediastinal lymph nodes, and predict, based on ultrasound morphology, whether peripheral nodules are benign or malignant. It is also extremely useful for determining the proximal and distal extent of tumors in and around the airway, and aid in surgical planning. This article will review the principles and clinical applications of these two technologies.


Comparing conventional and high sensitivity troponin T measurements in identifying adverse cardiac events in patients admitted to an Asian emergency department chest pain observation unit.
High sensitive cardiac troponin assays can be used for prediction of major adverse cardiac events (MACE) in patients with chest pain. We included patients with symptoms suggestive of acute coronary syndrome in the emergency department observation unit. We compared the accuracy of conventional troponin T (cTnT) with high sensitive troponin T (hsTnT) at various ranges, as well as the utility of hsTnT and cTnT in prediction of 30-day and 1-year MACE. 1023 patients were included (68.1% male, median age 56 years). There were 2712 hsTnT and cTnT values compared. hsTnT had a higher AUC than cTnT for 30-day and 1-year MACE. The optimal cut-off of 0-hour hsTnT for 30-day (PPV 34%, NPV 96.6%) and 1-year MACE (PPV 40.2%, NPV 94.2%) was 16 ng/L.For 844 patients who had values for both 0 and 2 h hsTnT, we proposed a rule-out cut-off of 0 and 2 h hsTnT < 16 ng/L (NPV 97.0%, 95%CI 95.5-98.1%) and a rule-in cut-off of 0 and 2 h hsTnT ≥ 26 ng/L (PPV 58.8%, 95%CI 40.7%-75.4%) for 30-day MACE. Negative 0-2 h delta-hsTnT had poor predictive discriminant capabilities on 30-day (PPV 8.2%) and 1-year MACE (PPV 12.3%). The cut off values of hsTnT used in the 0 and 2-hour algorithm to rule-out (16 ng/L) and rule-in MACE (26 ng/L) are in the range that previous cTnT assays are unable to measure accurately. Risk scores can be used to further improve NPV of the rule-out group. A fall in hsTnT level acutely is not predictive of MACE.


Low-frequency ultrasound irradiation increases blood-tumor barrier permeability by transcellular pathway in a rat glioma model.
Low-frequency ultrasound (LFU) irradiation under certain acoustic intensity can increase blood-brain barrier permeability non-invasively and reversibly. The aim of this study was to find out the effect of LFU irradiation on blood-tumor barrier (BTB) permeability in rat C6 glioma model and the possible mechanism. In this research, Evans blue and H&E staining were used to evaluate the optimal parameter of LFU to open the BTB without damaging the normal brain tissue. Transmission electron microscopy was used to observe the changes of the number of pinocytotic vesicles in cerebral or glioma microvascular endothelial cells. The phosphorylation of tyrosine kinase Src, caveolin-1, and caveolin-2 was detected by western blot. The distribution and expressing levels of caveolae proteins, caveolin-1 and caveolin-2, were detected by immunohistochemical and immunofluorescent staining, RT-PCR, and western blot. Our research data showed that, in rat C6 glioma model, LFU irradiation at a frequency of 1 MHz, a power of 12 mW, and exposure time of 20 s induced the increase of BTB permeability temporally, which reached a peak at 1.5 h, then decreased and restored to normal level at 12 h after LFU irradiation. In the glioma microvascular endothelial cells of rat glioma model, LFU irradiation induced a significant increase of the pinocytotic vesicles' density. The phosphorylation of Src, caveolin-1, and caveolin-2 began to increase at 0.5 h and reached a maximum at 1 h. Immunohistochemical and immunofluorescent staining showed that caveolin-1 and caveolin-2 were co-localized in the glioma microvascular endothelial cells and glioma cells. The mRNA and protein expression levels of caveolin-1 and caveolin-2 were up-regulated, reached the peak value at 1.5 h, and re-normalized at 12 h after LFU irradiation. These results demonstrated that LFU irradiation increased BTB permeability by promoting transcellular transport in glioma microvascular endothelial cells. The phosphorylation of tyrosine kinase Src, caveolin-1, caveolin-2 and up-regulation of caveolin-1 and caveolin-2 were involved in LFU-induced caveolae-mediated endocytosis.


SARS-CoV-2 inactivated vaccine (Vero cells) shows good safety in repeated administration toxicity test of Sprague Dawley rats.
The outbreak of COVID-19 has posed a serious threat to global public health. Vaccination may be the most effective way to prevent and control the spread of the virus. The safety of vaccines is the focus of preclinical research, and the repeated dose toxicity test is the key safety test to evaluate the vaccine before clinical trials. The purpose of this study was (i) to observe the toxicity and severity of an inactivated SARS-CoV-2 vaccine (Vero cells) in rodent Sprague Dawley rats after multiple intramuscular injections under the premise of Good Laboratory Practice principles and (ii) to provide a basis for the formulation of a clinical trial scheme. The results showed that all animals in the experimental group were in good condition, no regular changes related to the vaccine were found in the detection of various toxicological indexes, and no noticeable stimulating reaction related to the vaccine was found in the injected local tissues. The neutralizing antibodies in the low- and high-dose vaccine groups began to appear 14 days after the last administration. In the negative control group, no neutralizing antibodies were observed from the administration period to the recovery period. Therefore, the repeated administration toxicity test of the inactivated SARS-CoV-2 vaccine (Vero cells) in Sprague Dawley rats showed no obvious toxic reaction. It was preliminarily confirmed that the vaccine can stimulate production of neutralizing antibodies and is safe in Sprague Dawley rats.


[Cell lineage, determination and regulation in the female genital disc ofDrosophila melanogaster].
1. Under certain experimental conditions medially halved genital discs ofDrosophila melanogaster will form a complete, symmetrically duplicated genital apparatus. Female genital discs of heterozygous larvae were treated with X-rays at different developmental stages so that somatic crossingover (mitotic recombination) was induced which leads to genetically marked single cells. In the course of proliferation the homozygous cell will give rise to a clone which can be detected on the metamorphosed genital structures as a patch of marked bristles. This system was used to establish the cell lineagein situ and to investigate the mechanism of regulation in medially halved genital discs. 2. Marked clones on the genital apparatusin situ were restricted to either the vaginal or the anal plates, and to the left or to the right side of the symmetrical plates. Genital discs, irradiated between 3 and 60 h after egg laying gave rise to mosaic anal plates on which the marked clone frequently extended over the dorsal and ventral plates of one side. The results indicate that the female genital disc consists of two separate anlagen on each side as early as the time of blastoderm formation or shortly afterwards (3 h after egg laying): one anlage for the vaginal plate on each side, and a common anlage for the dorsal and ventral anal plates of each side. Dorsal and ventral anal plates share a common cell-pool at least up to the late second instar. 3. Medially halved genital discs in which marked clones had been induced were cultured in adult hosts and four days later transplanted back into larvae. Such fragments differentiated into symmetrical genital apparatuses which on the "new" side exhibited fewer but larger mosaics than on the "old" side. Clonally related bristles on the "new" side of the symmetrically duplicated genital apparatus occupied either only the vaginal or only the anal plates, and frequently extended over the dorsal and ventral halves of the anal plates. The results of the transplantation experiments indicate i) that the duplication of the genital structures is initiated from a limited zone of proliferation which forms separated blastemas for anal and vaginal plates, and ii) that the "new" halves of the dorsal and ventral anal plates arise from a common cell-pool. 4. In some developmental stages X-rays caused an enlargement of the anal plates and an increase in the bristle number on the anal and vaginal plates.


Cerium oxide nanoparticle delivery of microRNA-146a for local treatment of acute lung injury.
Acute respiratory distress syndrome (ARDS) is a devastating pulmonary disease with significant in-hospital mortality and is the leading cause of death in COVID-19 patients. Excessive leukocyte recruitment, unregulated inflammation, and resultant fibrosis contribute to poor ARDS outcomes. Nanoparticle technology with cerium oxide nanoparticles (CNP) offers a mechanism by which unstable therapeutics such as the anti-inflammatory microRNA-146a can be locally delivered to the injured lung without systemic uptake. In this study, we evaluated the potential of the radical scavenging CNP conjugated to microRNA-146a (termed CNP-miR146a) in preventing acute lung injury (ALI) following exposure to bleomycin. We have found that intratracheal delivery of CNP-miR146a increases pulmonary levels of miR146a without systemic increases, and prevents ALI by altering leukocyte recruitment, reducing inflammation and oxidative stress, and decreasing collagen deposition, ultimately improving pulmonary biomechanics.


Molecular mechanism of acute ammonia toxicity: role of NMDA receptors.
Acute administration of large doses of ammonia leads to the rapid death of animals. This article reviews the role of excessive activation of N-methyl-D-aspartate (NMDA) receptors in the mediation of ammonia-induced mortality. The studies reviewed here show that acute intoxication with large doses of ammonia leads to the activation of NMDA receptors in brain in vivo. Moreover, excessive activation of NMDA receptors is responsible for ammonia-induced death of animals, which is prevented by different antagonists of NMDA receptors. This article also reviews the studies showing that activation of NMDA receptors is also responsible for the following effects of acute ammonia intoxication: (1) depletion of brain ATP, which, in turn, leads to release of glutamate; (2) activation of calcineurin and dephosphorylation and activation of Na+/K+-ATPase in brain, thus increasing ATP consumption; (3) impairment of mitochondrial function and calcium homeostasis at different levels, thus decreasing ATP synthesis; (4) activation of calpain that degrades the microtubule-associated protein MAP-2, thus altering the microtubular network; (5) increased formation of nitric oxide (NO) formation, which, in turn, reduces the activity of glutamine synthetase, thus reducing the elimination of ammonia in brain.


Learning Curve and Associated Prognosis of Minimally Invasive McKeown Esophagectomy.
The implementation of McKeown minimally invasive esophagectomy (MIE) is associated with a steep learning curve. However, there is no consensus on the number of cases required before effective and safe McKeown MIE can be achieved. Data on consecutive patients with esophageal carcinoma who underwent esophagectomy performed by a single surgeon in the Department of Thoracic Surgery at Daping Hospital in Chongqing, China from September 2009 to June 2019 were collected. The cumulative sum learning curve was plotted on the basis of the learning associated parameters. Propensity score matching was used to reduce selection bias from confounding factors. The Kaplan-Meier method was used to assess the survival differences. The learning curve was divided into the ascending period (cases 1-197), the plateau period (198-314), and the descending period (315-onward). After 197 cases, significant improvements in operative time (300 minutes vs 210minutes; P < .001), retrieved lymph nodes (17 vs 20; P = .004), hospital length of stay (18 days vs 13 days; P = .001), major postoperative complications (38.6% vs 32.5%; P < .001), vocal cord palsy (6.1% vs 0.9%; P = .04), and pulmonary complications (31.5% vs 17.1%; P = .005) were observed. In addition, after 314 cases, significant decreases in blood loss (200 mL vs 100 mL; P < .001), anastomotic leak (24.8% vs 14.8%; P = .02), and chylothorax (4.3% vs 0%; P = .001) were observed. After propensity score matching, the overall and disease-free survival rates were significantly improved during the experienced period (P = .02 and .03, respectively). The initial learning phase of McKeown MIE consisted of 197 procedures in 51 months. Moreover, the surgeon's experience did have a direct impact on the long-term outcomes in patients with esophageal carcinoma.


New CT response criteria in non-small cell lung cancer: proposal and application in EGFR tyrosine kinase inhibitor therapy.
We aimed to devise new CT response criteria (new response criteria, NRC) in patients with non-small cell lung cancer (NSCLC) and to evaluate the efficacy of the criteria for stratifying patient responses and predicting patient survival compared to that of the traditional size-based criteria RECIST version 1.1. Our institutional review board approved this study with a waiver of informed consent. We enrolled 80 NSCLC patients as an experimental arm and treated them with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs). Two blinded, independent radiologists assessed CT images for tumor response using the NRC, which were also validated in a separate arm (75 NSCLC patients). Tumor responses evaluated by RECIST 1.1 and the new criteria were compared from each other and correlated with patient survival. For statistical analyses, Kaplan-Meier method and kappa statistics were used. In the experimental arm (n=80), interobserver agreements for the assessment of patient response were excellent for both RECIST and NRC. Sixteen RECIST nonresponding patients achieved a designation of partial response according to NRC. In the validation arm (n=75), patients of optimal response (partial response) with the new criteria had median overall survival of 18.4 months compared with 8.5 months in patients with poor response (P=.04). However, RECIST failed to show survival difference between the two response groups. In NSCLC patients treated with EGFR-TKIs, new CT criteria reflecting additional morphological characteristics of target lesions are reproducible and have statistically significant association with overall survival.


Can paracetamol lower stress and anxiety by blunting emotions during and after computer guided dental implant surgeries? Findings from a randomized crossover clinical trial.
Dental implants insertion can be a major factor in stress and anxiety. The aim was to evaluate the paracetamol ability to lower stress and anxiety when compared with ibuprofen during and after computer guided implant surgery utilizing CAD/CAM surgical template and a computer vision system for assessment. Thirty patients were enrolled in a crossover study design having bilateral missing lower molars. Patients were randomized into 2 equal groups with the first assigned for dental implant insertion in the lower molar area on one side with the administration of paracetamol (with 7-day follow-up) followed by 2-week washout period, then another implant was inserted on the contra-lateral side with ibuprofen. The second group received the same drugs but in reversed order. Salivary cortisol level was used to measure anxiety and a computer vision system was used to measure swelling. Visual-Analogue-Scale pain score from 0-to-100 was also utilized. Only 29 patients completed the study. Stress and anxiety was found to be significantly lower in paracetamol group (4.1 ± 1.08 ng/mL and 6.2 ± 0.94 ng/mL for paracetamol/ibuprofen respectively). Pain score was 13.1 ± 1.1 and 12.9 ± 2.3 in paracetamol/ibuprofen groups respectively with no significant differences. Swelling showed significant difference favoring the paracetamol group (0.91 ± 0.41 and 0.61 ± 0.31 for paracetamol/ibuprofen respectively). Paracetamol is effective in reducing stress by minimizing anxiety and blunting emotions of "fear-from-pain" so that pain is no longer perceived as much. However, paracetamol lacks the ability to control swelling at implant site. Computer guided flapless-implant surgery with immediate loading can be recommended for fearful patients.


Prostanoid release from ex vivo perfused canine arteries and veins: effects of prolonged perfusion, intermittent perfusion, as well as exposure to exogenous arachidonic acid, thrombin and bradykinin.
Regulation of prostanoid release from ex vivo perfused vessel segments is not fully understood. A series of perfusion experiments were performed with canine arteries and veins to define certain regulatory phenomena. Arteries were perfused with pulsatile flow of 90 ml/min at a pressure of 100 mmHg, and veins with nonpulsatile flow of 90 ml/min at a pressure of 7 mmHg. Segments were perfused with Hanks' balanced salt solution for five 15-min periods with the perfusate exchanged after each study period. With onset of perfusion, there was an initial burst of prostacyclin release to 127 +/- 40 pg/mm2, declining to 32 +/- 10 pg/mm2 after 60 minutes (p less than 0.005). If perfusion continued for 5.5 hours, there was a stable release period between 1 and 3 hours, followed by a very slow decline. At that time addition of arachidonic acid (AA) increased prostacyclin release six-fold (p less than 0.01). Vessels perfused for 1 hour and then rested for another hour, responded to reperfusion at the second onset of flow with a two-fold increase in prostacyclin release (p less than 0.01). Vessels perfused with thrombin, bradykinin or AA (either added to each perfusate or only to the last perfusate) exhibited greater prostacyclin release than did control segments. Release of thromboxane steadily declined with time in all parts of the study, and only increased with the addition of AA to the perfusate.(ABSTRACT TRUNCATED AT 250 WORDS)


Characterization of Wear Particles Generated from CoCrMo Alloy under Sliding Wear Conditions.
Biological effects of wear products (particles and metal ions) generated by metal-on-metal (MoM) hip replacements made of CoCrMo alloy remain a major cause of concern. Periprosthetic osteolysis, potential hypersensitivity response and pseudotumour formation are possible reactions that can lead to early revisions. To accurately analyse the biological response to wear particles from MoM implants, the exact nature of these particles needs to be characterized. Most previous studies used energy-dispersive X-ray spectroscopy (EDS) analysis for characterization. The present study used energy filtered transmission electron microscopy (TEM) and electron diffraction pattern analysis to allow for a more precise determination of the chemical composition and to gain knowledge of the crystalline structure of the wear particles.Particles were retrieved from two different test rigs: a reciprocating sliding wear tribometer (CoCrMo cylinder vs. bar) and a hip simulator according to ISO 14242-1 (CoCrMo head vs. CoCrMo cup). All tests were conducted in bovine serum. Particles were retrieved from the test medium using a previously published enzymatic digestion protocol.Particles isolated from tribometer samples had a size of 100 - 500 nm. Diffraction pattern analysis clearly revealed the lattice structure of strain induced hcp ε-martensite. Hip simulator samples revealed numerous particles of 15 - 30 nm and 30 - 80 nm size. Most of the larger particles appeared to be only partially oxidized and exhibited cobalt locally. The smallest particles were Cr(2)O(3) with no trace of cobalt. It optically appeared that these Cr(2)O(3) particles were flaking off the surface of larger particles that depicted a very high intensity of oxygen, as well as chromium, and only background noise of cobalt. The particle size difference between the two test rigs is likely related to the conditions of the two tribosystems, in particular the difference in the sample geometry and in the type of sliding (reciprocating vs. multidirectional).Results suggest that there may be a critical particle size at which chromium oxidation and cobalt ionization is accelerated. Since earlier studies have shown that wear particles are covered by organic residue which may act as a passive layer inhibiting further oxidation, it would suggest that this organic layer may be removed during the particle isolation process, resulting in a change of the particle chemical composition due to their pyrophoric properties. However, prior to being isolated from the serum lubricant, particles remain within the contact area of head and cup as a third-body. It is therefore possible that during that time, particles may undergo significant transformation and changes in chemical composition in the contact area of the head and cup within the tribological interface due to mechanical interaction with surface asperities.


Hepatobiliary complications of hematopoietic cell transplantation, 40 years on.
Liver problems caused by infection, cholestasis and sinusoidal liver injury in the months following HCT have become less frequent because of preventive and pre-emptive strategies. When patients develop jaundice after transplant, the time to search for treatable causes is early in the course of jaundice, as the risk of mortality rises steeply with small increments of serum bilirubin above normal. Chronic hepatitis C, persistent GVHD, cirrhosis and hepatocellular carcinoma are significant liver problems in the longest-lived survivors of HCT.


A personalized method for estimating centre of mass location of the whole body based on differentiation of tissues of a multi-divided trunk.
There are several methods for obtaining location of the centre of mass of the whole body. They are based on cadaver data, using volume and density of body parts, using radiation and image techniques. Some researchers treated the trunk as a one part only, while others divided the trunk into few parts. In addition some researchers divided the trunk with planes perpendicular to the longitudinal trunk's axis, although the best approach is to obtain trunk parts as anatomical and functional elements. This procedure was used by Dempster and Erdmann. The latter elaborated personalized estimating of inertial quantities of the trunk, while Clauser et al. gave similar approach for extremities. The aim of the investigation was to merge both indirect methods in order to obtain accurate location of the centre of mass of the whole body. As a reference location a direct method based on reaction board procedure, i.e. with a body lying on a board supported on a scale was used. The location of the centre of mass using Clauser's and Erdmann's method appeared almost identical with the location obtained with a direct method. This approach can be used for several situations, especially for people of different morphology, for the bent trunk, and for asymmetrical movements.