Herbal Prescription SH003 Alleviates Docetaxel-Induced Neuropathic Pain in C57BL/6 Mice.
Docetaxel-based therapy has been applied to kill cancers including lung and breast cancers but frequently causes peripheral neuropathy such as mechanical allodynia. Lack of effective drugs for chemotherapy-induced peripheral neuropathy (CIPN) treatment leads us to find novel drugs. Here, we investigated whether and how novel anticancer herbal prescription SH003 alleviates mechanical allodynia in mouse model of docetaxel-induced neuropathic pain. Docetaxel-induced mechanical allodynia was evaluated using von Frey filaments. Nerve damage and degeneration in paw skin of mice were investigated by immunofluorescence staining. Neuroinflammation markers in bloodstream, lumbar (L4-L6) spinal cord, and sciatic nerves were examined by ELISA or western blot analysis. Docetaxel (15.277 mg/kg) was intravenously injected into the tail vein of C57BL/6 mice, and mechanical allodynia was followed up. SH003 (557.569 mg/kg) was orally administered at least 60 min before the mechanical allodynia test, and von Frey test was performed twice. Docetaxel injection induced mechanical allodynia, and SH003 administration restored withdrawal threshold. Meanwhile, degeneration of intraepidermal nerve fibers (IENF) was observed in docetaxel-treated mice, but SH003 treatment suppressed it. Moreover, docetaxel injection increased levels of TNF-α and IL-6 in plasma and expressions of phospho-NF-κB and phospho-STAT3 in both of lumbar spinal cord and sciatic nerves, while SH003 treatment inhibited those changes. Taken together, it is worth noting that TNF-α and IL-6 in plasma and phospho-NF-κB and phospho-STAT3 in spinal cord and sciatic nerves are putative biomarkers of docetaxel-induced peripheral neuropathy (DIPN) in mouse models. In addition, we suggest that SH003 would be beneficial for alleviation of docetaxel-induced neuropathic pain.


Effects and Safety of the Tripterygium Glycoside Adjuvant Methotrexate Therapy in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis.
This study aimed to systematically review the efficacy and clinical safety of different courses and doses of tripterygium glycoside (TG) adjuvant methotrexate (MTX) therapy in the treatment of rheumatoid arthritis (RA). Randomized controlled trials (RCTs) of TG adjuvant MTX therapy in patients with RA were retrieved from SinoMed, China Network Knowledge Infrastructure, WanFang Data, PubMed, Cochrane Library, and Embase from inception to September 30, 2021. The effects and clinical safety evaluations were conducted using RevMan 5.3 software. A total of 9 RCTs and 892 patients with RA were included in this study. In the meta-analysis, a total of 463 and 429 patients were enrolled into the TG adjuvant MTX therapy group and MTX monotherapy group, respectively. In comparison with MTX monotherapy, the results of the analyzed effects showed that the TG adjuvant MTX therapy can achieve 20%, 50%, and 70% improvements in American College of Rheumatology (ACR) criteria ACR20, ACR50, and ACR70 at P = 0.005, P = 0.0001, and P = 0.004, respectively. Simultaneously, the efficacy of the TG adjuvant MTX therapy was improved at either 30 or 60 mg/day over a six-month course compared to MTX monotherapy (P < 0.0001). There was no statistical difference in the effects between the doses of 30 and 60 mg/day after three months (P = 0.82). TG adjuvant MTX also reduced the expression rate of the swollen joint count, tender joint count, erythrocyte sedimentation rate, rheumatoid factor, and C-reactive protein in subgroup analyses with different courses and doses. In terms of hepatic adverse effects (P = 0.28), leukopenia (P = 0.78), gastrointestinal adverse effects (P = 0.17), cutaneous adverse effects (P = 0.94), and irregular menstruation adverse effects (P = 0.29), there was no statistically significant difference with TG adjuvant MTX therapy and MTX monotherapy with different courses and doses. TG adjuvant MTX therapy is more effective than MTX monotherapy and is a safe strategy for RA treatment in doses of 30 or 60 mg/day over a treatment course of six months. However, high-quality multicenter RCT studies with large sample sizes are still needed to confirm the effects and clinical safety of different courses and doses of TG adjuvant MTX therapy.


Location of phosphotyrosine-containing proteins by immunocytochemistry in the rat forebrain corresponds to the distribution of the insulin receptor.
Cellular regulation by certain growth factor receptors and protooncogene products involves tyrosine kinase activity with the resultant tyrosine phosphorylation of protein substrates. In the present report we describe the distribution of phosphotyrosine-containing material detected by immunocytochemistry (ICC) in the rat forebrain. Specificity of the affinity-purified antibody against phosphotyrosine used in the ICC technique was demonstrated by the ability of phosphotyrosine and p-nitrophenyl phosphate but not phosphoserine, phosphothreonine, or L-tyrosine to inhibit the immunostaining reaction. With ICC, relatively high amounts of phosphotyrosine-positive material were observed in neurons in specific structures that included the supraoptic, paraventricular, and arcuate nuclei; the median eminence; medial habenula; subfornical organ; and piriform cortex. Moderate to high amounts were present in the cerebral cortical layers II-IV and in the pyramidal cell layer of the hippocampus. Small to moderate amounts were detected in a few other locations. Glial elements showed minimal staining. Other areas of the rat forebrain failed to react with this antibody. Importantly, the distribution of the areas positive for phosphotyrosine agreed to a remarkable extent with the distribution of the brain insulin receptor, which itself has tyrosine kinase activity. These findings suggest a relationship between the insulin receptor and the increased phosphotyrosine content of these neurons and support the concept that the brain insulin receptor is active in vivo.


Blurring the germline: Genome editing and transgenerational epigenetic inheritance.
Sperm, eggs and embryos are made up of more than genes, and there are indications that changes to non-genetic structures in these elements of the germline can also be inherited. It is, therefore, a mistake to treat phrases like 'germline inheritance' and 'genetic inheritance' as simple synonyms, and bioethical discussion should expand its focus beyond alterations to the genome when considering the ethics of germline modification. Moreover, additional research on non-genetic inheritance draws attention to a variety of means whereby differences can be inherited in offspring generations that do not rely on differences in germline structures. Research on these diverse forms of inheritance challenges the notion that there is some special form of ethical concern that falls on germline interventions in general, and on interventions to the nuclear genome within the germline in particular.


Post harvest wound infection and patient's perception: comparative study between radial artery and saphenous vein harvest sites.
Despite renewed clinical interest in radial artery grafts (RA) for coronary artery bypass grafting, there is a paucity of controlled prospective data on its efficacy. We report on the rate of harvest related complications from a randomized radial artery study. Two hundred eighty nine patients were divided into two groups. Group 1 received RA grafts (n=154 patients) and Group 2 (n=135 patients) received saphenous vein grafts (SVG). Postoperative wound problems were assessed using a questionnaire. Postoperative harvest site infections were also carefully documented. In group 1, 6 of 154 (3.9%) patients had harvest site wound infections. Five of them improved by antibiotic therapy alone. In group 2, 24 of 135 (17.8%) patients had harvest site wound infections (p=0.001 vs. group 1). Fifteen of these patients needed redressing due to discharge from the wound. One hundred forty-nine patients (96.7%) in group 1 answered that their hand function was normal on the questionnaire. Concerns and discomfort about the arm scars in the group 1 were of a similar value of 5.2% (8/154), respectively. In group 2, the incidence of those about the leg were 7.4% (10/135) and 11.9% (16/135), respectively. Although there was no significant difference in concerns about the scar, discomfort was significantly higher in group 2 compared with group 1 (p=0.0139). RA harvest is associated with fewer wound infections and scar discomfort than SVG harvest. Radial artery harvest is almost acceptable in terms of a patient's perception. However, there are still patients who have some symptoms in the forearm after RA harvest. Long-term follow-up is necessary for patient's hand function.


Characterization of the role of LtgB, a putative lytic transglycosylase in Neisseria gonorrhoeae.
Neisseria gonorrhoeae releases monomeric peptidoglycan (PG) fragments during growth. These PG fragments affect pathogenesis-related phenotypes including induction of inflammatory cytokines and killing of ciliated fallopian tube cells. Although the biological activities of these molecules have been established in multiple systems, the genes and gene products responsible for their production in N. gonorrhoeae have not been determined. The authors previously identified genes for three lytic transglycosylase homologues (ltgA, ltgB and ltgC) in the N. gonorrhoeae genome sequence. Mutation of ltgA was found to affect PG fragment release, and mutation of ltgC affected cell separation. In this study the effects of complete deletion or point mutations in ltgB were characterized. Point mutations were introduced by a combination of insertion-duplication mutagenesis and positive and negative selection, thereby generating selectable marker-less mutations. The ltgB deletion mutant had normal growth characteristics and was not affected in PG fragment release. When expressed in Escherichia coli, gonococcal LtgB was able to substitute for lambda endolysin to cause cell lysis. Mutation of the predicted catalytic-site glutamic acid residue did not decrease lysis in this system. However, mutation of a nearby glutamic acid residue eliminated lysis activity.


Cardiovascular disease risk in patients receiving organ transplantation: a national cohort study.
Although organ transplantation is the definitive treatment for end-stage organ failure, the post-transplant outcomes can be substantially influenced by cardiovascular complications. A national cohort study was performed to estimate risks of cardiovascular diseases in those with heart, lung, kidney, and liver transplantation. This cohort study consisted of 5978 solid organ transplantations identified using the Taiwan National Health Insurance Database. Cardiovascular and mortality risks in transplant recipients were evaluated using standardized incidence ratios, excess absolute risks, and standardized mortality ratios as compared to those in the general population. In heart, kidney, and liver recipients, the standardized incidence ratios of overall cardiovascular diseases were 9.41 (7.75-11.44), 3.32 (2.29-3.77), and 1.4 (1.15-1.7) and the overall standardized mortality ratios were 5.23 (4.54-6.03), 1.48 (1.34-1.63), and 3.95 (3.64-4.28), respectively. Except for heart organ recipients who were at highest risk for coronary artery disease with a standardized incidence ratio of 13.12 (10.57-16.29), kidney and liver organ recipients had a ninefold increased risk in developing deep vein thrombosis post-transplant. In conclusion, solid organ transplant patients are at risk of cardiovascular disease, in particular, deep vein thrombosis, which may warrant early identification of high-risk patients in addition to prompt and adequate thromboprophylaxis perioperatively.


Employing shells to eliminate concentration quenching in photonic upconversion nanostructure.
It is generally accepted that a lanthanide ions based upconversion material follows an activator low doping strategy (normally <3 mol%), because of the restriction of the harmful concentration quenching effect. Here, we demonstrate that this limitation can be broken in nanostructures. Simply by using an inert shell coating strategy, the concentration quenching effect for the activator (Er3+) could be eliminated and highly efficient upconversion luminescence realized in the activator fully doped nanostructure, e.g. NaErF4@NaYF4. More importantly, this novel nanostructure achieves some long-cherished desires, such as multiple-band co-excitation (∼800 nm, ∼980 nm and ∼1530 nm) and monochromic red emission. Proof-of-concept experiments are presented of the potential benefit of this structure in solar cells and anti-counterfeiting. This nanostructure offers new possibilities in realizing high upconversion emission and novel functionalities of lanthanide based nanomaterials.


Genetic Diversity and Structure of Populations of Annona crassiflora Mart. of Brazilian Savanna and Its Association with Chemical Variability.
Annona crassiflora Mart. is a native tree from Brazilian savanna. Isoquinoline alkaloids are characteristic of species of Annonaceae. This work aimed to assess the magnitude of genetic diversity among different populations of A. crassiflora using AFLP markers, and verify the existence of any correlation between the AFLP data and previous reported alkaloid composition. A. crassiflora from eight populations in the states of São Paulo, Goiás, Minas Gerais, and Distrito Federal were analyzed. The data suggest a low, moderate, and high level of genetic diversity from different populations of A. crassiflora. Concentration of alkaloids was significantly correlated with AFLP data, suggesting interaction between chemical and molecular markers in A. crassiflora. The data of association between the chemical and genetic differentiation of A. crassiflora may be useful to establish cultivation areas allowing the definition of strategies to preserve their genetic diversity with an interest in specific chemotypes for genetic improvement programs focused on sustainable utilization of this specie.


Effect of residual water and microwave heating on the half-life of the reagents and reactive intermediates in peptide synthesis.
Precise microwave heating has changed the way many small molecules are being synthesized and, currently, the field of solid-phase peptide synthesis is undergoing dramatic changes owing to the use of microwave heating. To fully reap the benefits of precise microwave heating for the formation of amide bonds in peptide synthesis, it is important to understand the kinetics of formation and break-down of activated esters and their N-acylation of the nascent peptide chain at elevated temperatures. Herein, we present systematic studies of, first, the rate of formation of activated esters by NMR spectroscopy and, second, their N-acylation during peptide synthesis. A study of the amount of residual water in the solvents revealed a significant effect on electrophilic reagents and intermediates. This observation was expanded into a general study of microwave heating in peptide synthesis.


Prevalance of gestational diabetes mellitus in patients with gestational transient thyrotoxicosis.
To investigate prevalence of gestational diabetes mellitus (GDM) in patients with gestational transient thyroxicosis (GTT). Fifty two patients with GTT and 100 age matched healthy pregnant women were included. Fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), LDL-cholesterol, HDL-cholesterol, triglyceride, thyrotrophin (TSH) and thyroid hormones were measured at thyrotoxic state in GTT patients and at 6-12th weeks of pregnancy in control group. Oral glucose tolerance test (OGTT) with 100 g glucose was performed and laboratory parameters were re-evaluated at 24-28th weeks of pregnancy in all subjects. Mean age of patients with GTT was 28.46 ± 5.45 and control group was 27.78 ± 3.75(p = 0.085). Patients with GTT had significantly higher HbA1c, LDL-cholesterol and HDL-cholesterol at 6-12th weeks of pregnancy (p < 0.01, p < 0.01 and p = 0.034, respectively). TSH was negatively correlated with HbA1c and LDL-cholesterol in thyrotoxic state in GTT patients (r = -0.393, p < 0.001 and r = -0.293, p < 0.001, respectively). OGTT showed GDM in 7 (13.5%) GTT patients and 4 (4%) healthy pregnants (p = 0.047). HbA1c, LDL-cholesterol and HDL-cholesterol were higher in GTT patients compared to healthy pregnants also at 24-28th weeks of pregnancy (p < 0.001, p < 0.001 and p = 0.024). Although GTT is known to be a transient state that can resolve spontaneously, it might have negative effect on carbohydrate metabolism like other causes of hyperthyroidism.


Preoperative inflammatory status as a predictor of primary patency after femoropopliteal stent implantation.
The purpose of this study was to evaluate the impact of preoperative inflammatory status, as determined by complete blood count test parameters, on 12- and 24-month patency of femoropopliteal stenting for peripheral arterial disease. We retrospectively analyzed baseline clinical and angiographic data among 138 patients (median age, 73 years; 46% female) from 2005 to 2014 at our institution with preoperative complete blood count test values and information of patency for at least 12 months after first-time femoropopliteal stenting. Patients were stratified into tertiles on the basis of preoperative blood counts to evaluate associations with in-stent restenosis (ISR) leading to loss of primary patency, defined by a Doppler velocity ratio ≥2.5:1, computed tomography angiography demonstrating ≥50% luminal narrowing within the stent, or reintervention. Univariate analysis determined that the 81 patients (59%) who experienced ISR within 12 months had significantly higher preoperative white blood cell (WBC), platelet, neutrophil, and lymphocyte counts than the 57 patients (41%) whose stents remained patent for longer than 12 months (8.7 vs 6.7 [P < .001], 246 vs 184 [P < .001], 5.7 vs 4.7 [P = .001], and 1.8 vs 1.2 [P = .004], respectively). Compared with patients in the lower WBC tertile (n = 45) who had a median patency of 19.4 months, those in the upper WBC tertile (n = 44) had a median patency of only 7.0 months and a 3.3-fold increased risk for ISR after adjusting for age, sex, lesion type, TransAtlantic Inter-Society Consensus II score, tibial vessel runoff, antiplatelet therapy, presence of diabetes, critical limb ischemia, adjunct procedures, hyperlipidemia, and end-stage renal disease in multivariate analysis (P < .001). Compared with patients in the lower platelet tertile (n = 45) who had a median patency of 16.9 months, those in the upper platelet tertile (n = 47) had a median patency of 7.1 months and a 2.7-fold increased adjusted risk (P = .001). Compared with patients in the lower neutrophil tertile (n = 33) who had a median patency of 14.3 months, those in the upper neutrophil tertile (n = 33) had a median patency of 6.2 months and a 3.2-fold increased adjusted risk (P = .001). After adjusting for covariates, patients divided into tertiles by lymphocyte counts exhibited no significant differences for ISR. Routine preoperative tests that determine baseline inflammatory status may provide strong clinical utility in assessing potential risk stratification of patients for ISR after femoropopliteal stenting. Circulating WBCs, platelets, and neutrophils may be important inflammatory mediators of ISR.


Comparison of health-related quality of life and exercise capacity according to stages in patients with non-small cell lung cancer.
The aim of this study is to compare the exercise capacity and health-related quality of life parameters according to stages of patients with non-small cell lung cancer (NSCLC). Fifty-two patients (who are able to ambulate independently) with stage I-II (group early-stage, n= 17) and stage IIIA-IV NSCLC (group advanced-stage, n= 35) were included. Exercise capacity (six minute walking test), strength of the peripheral muscle (Back and Leg Dynamometer), performance status (Karnofsky performance status scale), health-related quality of life- HRQOL (European Organization for Research and Treatment of Cancer Quality of life measure and Short Form-36 Health Survey), depression and anxiety (Hospital Anxiety and Depression Scale) were evaluated. No difference was found in age, body mass index, respiratory symptoms and the distribution of disease cell types between two groups (p> 0.05). In advanced-stage group, pulmonary function test values, peripheral muscle strength, walking distance and health-related quality of life scores especially the categories of functional capacity and pain were established significantly lower compared to early-stage group (p ≤ 0.05). Depression and anxiety levels were confirmed to be similar between groups (p> 0.05). The exercise capacity of patients with advanced-stage NSCLC is lower due to reduced pulmonary functions and peripheral muscle strength compared to patients with early-stage NSCLC. Therefore, we can conclude that reduced exercise capacity negatively impacts functional categories of health related quality of life of patients with advanced-stage NSCLC.


A frequency-adjustable electromagnet for hyperthermia measurements on magnetic nanoparticles.
We describe a low-cost and simple setup for hyperthermia measurements on colloidal solutions of magnetic nanoparticles (ferrofluids) with a frequency-adjustable magnetic field in the range of 5-500 kHz produced by an electromagnet. By optimizing the general conception and each component (nature of the wires, design of the electromagnet, etc.), a highly efficient setup is obtained. For instance, in a useful gap of 1.1 cm, a magnetic field of 4.8 mT is generated at 100 and 500 kHz with output powers of 3.4 and 75 W, respectively. A maximum magnetic field of 30 mT is obtained at 100 kHz. The temperature of the colloidal solution is measured using optical fiber sensors. To remove contributions due to heating of the electromagnet, a differential measurement is used. In this configuration the sensitivity is better than 1.5 mW at 100 kHz and 19.3 mT. This setup allows one to measure weak heating powers on highly diluted colloidal solutions. The hyperthermia characteristics of a solution of Fe nanoparticles are described, where both the magnetic field and the frequency dependence of heating power have been measured.


Behavioral effects of somatostatin microinjected into caudate putamen.
The present study examined the behavioral responses to bilateral microinjections of somatostatin (SRIF) into caudate putamen of male Wistar rats. SRIF locally administered at doses of 10, 50 and 100 ng/side dose-dependently affected locomotor activity, as reflected in both horizontal and vertical movements. SRIF modulated locomotor activity in a biphasic manner, exerting an inhibitory and a facilitatory effect. In the elevated plus-maze experiments, SRIF at doses of 50 and 100 ng/side microinjected bilaterally into caudate putamen decreased only the total number of entries in the open and closed maze arms, confirming the suppressing effect of SRIF on locomotion at the first 5 min.


Monitoring of cerebral blood flow and metabolism in traumatic brain injury.
The aim of the present study was to investigate the course of cerebral blood flow (CBF) and metabolism in traumatic brain injury (TBI) patients and to specifically characterize the changes in lactate and glucose indices in the acute post-traumatic period with regard to neurological condition and functional outcome. For this purpose, 55 consecutive TBI patients (mean age 37 +/- 17 years, mean GCS 6.8 +/- 3.2) were prospectively and daily evaluated. Global CBF, cerebral metabolic rates of oxygen (CMRO2), glucose (CMRGlc), and lactate (CMRLct) were calculated using arterial jugular differences. In all patients, CBF was moderately decreased during the first 24 h in comparison with normal subjects although this relative oligemia was more pronounced in patients with poor outcome (p = 0.0007). Both CMRO2 and CMRGlc were significantly depressed and correlated to outcome (p < 0.0001, p = 0.0088). CMRLct analysis revealed positive values (lactate uptake) during the first 48 h, especially in patients with favorable outcome. Both CMRO2 and CMRLct correlated with GCS (p = 0.0001, p = 0.0205). CMRLct levels showed an opposite correlation with CBF in patients with favorable and poor outcome. In the former group, correlation analysis exhibited a negative slope with evidence for increasing lactate uptake associated with lower CBF values (r = -0.1940, p = 0.0242). On the contrary, in patients with adverse outcome, CMRLct values demonstrated a weak though opposite correlation with CBF (r = 0.0942, p = 0.2733). The present data emphasize the clinical significance of monitoring of cerebral blood flow and metabolism in TBI and provide evidence for metabolic coupling between astrocytes and neurons.


Ejection Fraction Estimation from Echocardiograms Using Optimal Left Ventricle Feature Extraction Based on Clinical Methods.
Echocardiography is one of the imaging systems most often utilized for assessing heart anatomy and function. Left ventricle ejection fraction (LVEF) is an important clinical variable assessed from echocardiography via the measurement of left ventricle (LV) parameters. Significant inter-observer and intra-observer variability is seen when LVEF is quantified by cardiologists using huge echocardiography data. Machine learning algorithms have the capability to analyze such extensive datasets and identify intricate patterns of structure and function of the heart that highly skilled observers might overlook, hence paving the way for computer-assisted diagnostics in this field. In this study, LV segmentation is performed on echocardiogram data followed by feature extraction from the left ventricle based on clinical methods. The extracted features are then subjected to analysis using both neural networks and traditional machine learning algorithms to estimate the LVEF. The results indicate that employing machine learning techniques on the extracted features from the left ventricle leads to higher accuracy than the utilization of Simpson's method for estimating the LVEF. The evaluations are performed on a publicly available echocardiogram dataset, EchoNet-Dynamic. The best results are obtained when DeepLab, a convolutional neural network architecture, is used for LV segmentation along with Long Short-Term Memory Networks (LSTM) for the regression of LVEF, obtaining a dice similarity coefficient of 0.92 and a mean absolute error of 5.736%.


A segment of the MHC class II beta chain plays a critical role in targeting class II molecules to the endocytic pathway.
The ability of MHC class II molecules to sort into the endocytic pathway has generally been attributed to the invariant chain glycoprotein. In this paper, we present evidence suggesting that lumenal sequences in the MHC class II molecule itself control the post-Golgi entry of class II into endosomes. Single amino acid changes have been introduced into a highly conserved region of the class II beta chain (amino acids 80-83). Mutant class II beta chain genes and wild-type alpha chain genes have been transfected into cells that lack both class II and invariant chain expression. Immunofluorescent staining of transfected cells indicates that single amino acid changes in this region of beta can positively or negatively modulate expression of class II in endocytic vesicles independently of invariant chain. Mutation at residue 80 leads to prominent localization in vesicular structures typical of late endocytic compartments, while a change at position 82 leads to arrest in the Golgi. These data argue in favor of the possibility that MHC class II molecules bear a sorting signal that allows access to MHC class II molecules into the endocytic pathway of antigen presenting cells.


Dynamical low-noise microwave source for cold-atom experiments.
The generation and manipulation of ultracold atomic ensembles in the quantum regime require the application of dynamically controllable microwave fields with ultra-low noise performance. Here, we present a low-phase-noise microwave source with two independently controllable output paths. Both paths generate frequencies in the range of 6.835 GHz ± 25 MHz for hyperfine transitions in 87Rb. The presented microwave source combines two commercially available frequency synthesizers: an ultra-low-noise oscillator at 7 GHz and a direct digital synthesizer for radio frequencies. We demonstrate a low integrated phase noise of 480 µrad in the range of 10 Hz to 100 kHz and fast updates of frequency, amplitude, and phase in sub-µs time scales. The highly dynamic control enables the generation of shaped pulse forms and the deployment of composite pulses to suppress the influence of various noise sources.


1-Methyl-3-hydroxy-pyridin-2-one complexes of near infra-red emitting lanthanides: efficient sensitization of Yb(III) and Nd(III) in aqueous solution.
The synthesis, X-ray structure, solution stability, and photophysical properties of several trivalent lanthanide complexes of Yb(III) and Nd(III) using both tetradentate and octadentate ligand design strategies and incorporating the 1-methyl-3-hydroxy-pyridin-2-one (Me-3,2-HOPO) chelate group are reported. Both the Yb(III) and Nd(III) complexes have emission bands in the Near Infra-Red (NIR) region, and this luminescence is retained in aqueous solution (Phi(tot)(Yb) approximately 0.09-0.22%).Furthermore, the complexes demonstrate very high stability (pYb approximately 18.8-21.9) in aqueous solution, making them good candidates for further development as probes for NIR imaging. Analysis of the low temperature (77 K) photophysical measurements for a model Gd(III) complex were used to gain an insight into the electronic structure, and were found to agree well with corresponding time-dependent density functional theory (TD-DFT) calculations at the B3LYP/6-311G++(d,p) level of theory for a simplified model monovalent sodium complex.


European primary forest database v2.0.
Primary forests, defined here as forests where the signs of human impacts, if any, are strongly blurred due to decades without forest management, are scarce in Europe and continue to disappear. Despite these losses, we know little about where these forests occur. Here, we present a comprehensive geodatabase and map of Europe's known primary forests. Our geodatabase harmonizes 48 different, mostly field-based datasets of primary forests, and contains 18,411 individual patches (41.1 Mha) spread across 33 countries. When available, we provide information on each patch (name, location, naturalness, extent and dominant tree species) and the surrounding landscape (biogeographical regions, protection status, potential natural vegetation, current forest extent). Using Landsat satellite-image time series (1985-2018) we checked each patch for possible disturbance events since primary forests were identified, resulting in 94% of patches free of significant disturbances in the last 30 years. Although knowledge gaps remain, ours is the most comprehensive dataset on primary forests in Europe, and will be useful for ecological studies, and conservation planning to safeguard these unique forests.


Fatal influenza myocarditis with incessant ventricular tachycardia.
Influenza myocarditis is an underappreciated and severe complication of influenza infection, estimated to be present in about 10% of all influenza cases. We present a case of a woman who precipitously died of fulminant influenza myocarditis and then review the historical data, literature and expert recommendations for suspecting and managing influenza myocarditis.


Self-trapping of strong electromagnetic beams in relativistic plasmas.
Interaction of an intense electromagnetic (em) beam with a relativistic electron-positron (e-p) plasma is investigated. It is shown that the thermal pressure brings about a fundamental change in the dynamics-localized, high amplitude, em field structures, not accessible to a cold (but relativistic) plasma, can now be formed under well-defined conditions. The possibilities of trapping em beams in self-guiding regimes to form stable two-dimensional solitonic structures in a pure e-p plasma are worked out.


Redundant roles of Bradyrhizobium oligotrophicum Cu-type (NirK) and cd1-type (NirS) nitrite reductase genes under denitrifying conditions.
Reduction of nitrite to nitric oxide gas by respiratory nitrite reductases (NiRs) is the key step of denitrification. Denitrifiers are strictly divided into two functional groups based on whether they possess the copper-containing nitrite reductase (CuNiR) encoded by nirK or the cytochrome cd1 nitrite reductase (cdNiR) encoded by nirS. Recently, some organisms carrying both nirK and nirS genes have been found. Bradyrhizobium oligotrophicum S58 is a nitrogen-fixing oligotrophic bacterium that carries a set of genes for complete denitrification of nitrate to dinitrogen, including nirK and nirS genes. We show that denitrification in S58 is functional under low-oxygen conditions (anaerobiosis and microaerobiosis), but not under aerobiosis. Under denitrifying conditions, the ΔnirK and ΔnirS single S58 mutants grew normally and their NiR activity was not affected. However, the ΔnirKS double mutant grew more slowly, presumably because the impaired NiR activity resulted in nitrite accumulation in the medium. These results suggest a redundant role for nirK and nirS genes in B. oligotrophicum S58 denitrification. In addition, we found that the nirS gene product, but not that of nirK, maintains swimming motility of S58 under aerobic and low-oxygen conditions in the presence of nitrate.


Incorporating covariates in skewed functional data models.
We introduce a class of covariate-adjusted skewed functional models (cSFM) designed for functional data exhibiting location-dependent marginal distributions. We propose a semi-parametric copula model for the pointwise marginal distributions, which are allowed to depend on covariates, and the functional dependence, which is assumed covariate invariant. The proposed cSFM framework provides a unifying platform for pointwise quantile estimation and trajectory prediction. We consider a computationally feasible procedure that handles densely as well as sparsely observed functional data. The methods are examined numerically using simulations and is applied to a new tractography study of multiple sclerosis. Furthermore, the methodology is implemented in the R package cSFM, which is publicly available on CRAN.


Experimental hydrosyringomyelia, ischemic myelopathy, and syringomyelia.
The authors found that cavities in the spinal cord of dogs appearing after the intracisternal administration of kaolin are not due to ischemic softening, but rather to distention and subsequent rupture of the central canal. Ischemic lesions could be produced and were found to have a quite different histopathology; this supports the hydrodynamic hypothesis of cavitary myelopathy following adhesive arachnoiditis, probably as a compensatory mechanism to the associated hydrocephalus. The similarities to human syringomyelia are discussed.


Recurrent renal cell cancer: 10 years or more after nephrectomy.
Localized renal cell carcinoma (RCC) responds well to surgery. Patients often question how long they have to be on surveillance after their surgery. Several follow-up patterns have been described in the literature. Until 2009, no published established Canadian guidelines existed to assist Canadian health-care practitioners in the surveillance of these patients. We present 3 cases of RCC that recurred 10 years or longer after the initial nephrectomy. These cases emphasize the need for careful long-term follow-up, as recommended in the Canadian Urological Association guidelines. We also discuss the optimism of prolonged disease survival in the era of novel therapeutic agents that target angiogenesis.


Overproduction of human immunodeficiency virus type I reverse transcriptase in Escherichia coli and purification of the enzyme.
Overexpression of the reverse transcriptase was designed in E. coli. For a high level of expression, HIV protein was expressed as a protein fusion with beta-galactosidase. When the proviral DNA fragment covering the 3' half of the gag gene and the entire pol gene was ligated to the 3' end of the lacZ gene to fuse the truncated gag to lacZ in frame, a small quantity of reverse transcriptase was produced, indicating that frameshifting and post-translational processing have occurred. Much more reverse transcriptase was produced when the entire pol region was directly fused to the lacZ gene. From a one liter culture of bacteria, 1 mg of highly purified reverse transcriptase consisting of approximately equimolar amounts of two species (p64 and p51) was obtained. These proteins had identical N-termini consistent with the deduced amino acid sequence and therefore, might be correctly processed from the fusion protein in E. coli by the protease encoded by the pol region. The purified reverse transcriptase was enzymatically as active as the enzyme purified from the virus particles, and immunoreactive to the sera of HIV carriers with high sensitivity and specificity.


Conditional inactivation of glucocorticoid receptor gene in dopamine-beta-hydroxylase cells impairs chromaffin cell survival.
Glucocorticoid hormones (GCs) have been thought to determine the fate of chromaffin cells from sympathoadrenal progenitor cells. The analysis of mice carrying a germ line deletion of the glucocorticoid receptor (GR) gene has challenged these previous results because the embryonic development of adrenal chromaffin cells is largely unaltered. In the present study, we have analyzed the role of GC-dependent signaling in the postnatal development of adrenal chromaffin cells by conditional inactivation of the GR gene in cells expressing dopamine-beta-hydroxylase, an enzyme required for the synthesis of noradrenaline and adrenaline. These mutant mice are viable, allowing to study whether in the absence of GC signaling further development of the adrenal medulla is affected. Our analysis shows that the loss of GR leads not only to the loss of phenylethanolamine-N-methyl-transferase expression and, therefore, to inhibition of adrenaline synthesis, but also to a dramatic reduction in the number of adrenal chromaffin cells. We provide evidence that increased apoptotic cell death is the main consequence of GR loss. These findings define the essential role of GCs for survival of chromaffin cells and underscore the specific requirement of GCs for adrenergic chromaffin cell differentiation and maintenance.


Complementary surface-enhanced resonance Raman spectroscopic biodetection of mixed protein solutions by chitosan- and silica-coated plasmon-tuned silver nanoparticles.
Silver nanoparticles with identical plasmonic properties but different surface functionalities are synthesized and tested as chemically selective surface-enhanced resonance Raman (SERR) amplifiers in a two-component protein solution. The surface plasmon resonances of the particles are tuned to 413 nm to match the molecular resonance of protein heme cofactors. Biocompatible functionalization of the nanoparticles with a thin film of chitosan yields selective SERR enhancement of the anionic protein cytochrome b(5), whereas functionalization with SiO(2) amplifies only the spectra of the cationic protein cytochrome c. As a result, subsequent addition of the two differently functionalized particles yields complementary information on the same mixed protein sample solution. Finally, the applicability of chitosan-coated Ag nanoparticles for protein separation was tested by in situ resonance Raman spectroscopy.


Regulation of carbon metabolism in the mollicutes and its relation to virulence.
The mollicutes are cell wall-less bacteria that live in close association with their eukaryotic hosts. Their genomes are strongly reduced and so are their metabolic capabilities. A survey of the available genome sequences reveals that the mollicutes are capable of utilizing sugars as source of carbon and energy via glycolysis. The pentose phosphate pathway is incomplete in these bacteria, and genes encoding enzymes of the tricarboxylic acid cycle are absent from the genomes. Sugars are transported by the phosphotransferase system. As in related bacteria, the phosphotransferase system does also seem to play a regulatory role in the mollicutes as can be concluded from the functionality of the regulatory HPr kinase/phosphorylase. In Mycoplasma pneumoniae, the activity of HPr kinase is triggered in the presence of glycerol. This carbon source may be important for the mollicutes since it is available in epithelial tissues and its metabolism results in the formation of hydrogen peroxide, the major virulence factor of several mollicutes. In plant-pathogenic mollicutes such as Spiroplasma citri, the regulation of carbon metabolism is crucial in the adaptation to life in plant tissues or the insect vectors. Thus, carbon metabolism seems to be intimately linked to pathogenicity in the mollicutes.


Cholesterol embolisation. A lethal complication of instrumentation of an aneurysmal aorta: a case report.
A case of cholesterol embolisation (CE) following instrumentation of an aneurysmal aorta is presented. The patient developed myalgias, livedo reticularis in the buttocks, suprapubic area and legs, that progressed to patchy gangrene and renal failure. Maximum conservative management including heparin, iloprost and haemodialysis was ineffective, in keeping with previous reports that there is no known therapy for CE. The aetiology, presentation, treatment and prognosis of this condition is discussed. With the ever increasing use of endovascular treatment of abdominal aortic aneurysms, this complication may be more frequently encountered.


Evaluation of Brassicas in grazing systems for sheep: I. Quality of forage and animal performance.
Four years of grazing trials were conducted with Brassica forages to evaluate their chemical composition and effect on ADG of fattening lambs and breeding ewes in late fall. Brassicas tested included kales (Brassica oleracea L. var. acephala DC), turnips (B. rapa L.), and a chinese cabbage hybrid (B. rapa L. x B. pekinensis [Lour.] Rupr.). Daily gains of lambs varied widely among years (19 to 330 g/d); ADG on Brassicas were, however, generally higher than on stockpiled Kentucky 31 tall fescue (Festuca arundinacea Schreb.) or orchardgrass (Dactylis glomerata L.)-red clover (Trifolium pratense L.) pastures grazed at the same time. In 1 yr, dietary supplementation of lambs grazing a hybrid turnip (Forage Star) with iodine and copper oxide needles improved (P < .05) ADG; however, there was no effect on gains in two later years. In 2 yr, lambs showed higher ADG on Tyfon chinese cabbage hybrid (241 and 330 g/d) than on Forage Star turnip (197 and 275 g/d) or stockpiled grass-clover (135 and 233 g/d), but yield of Tyfon was lower. Indications that supplementary hay improved ADG of lambs and ewes were not confirmed in the final year, in which hay increased (P < .05) ADG of lambs in the first 3 wk of grazing Brassicas but decreased gains later. Thyroid weights were increased (P < .01) consistently in all trials on Brassicas, but enlargement was modest and not related to ADG. Brassica forages provided high yields (5.6 to 10.5 t/ha) of DM in the late fall to early winter period, with high carrying capacity for sheep but large variability in ADG.


Understanding and controlling filamentous growth of fungal cell factories: novel tools and opportunities for targeted morphology engineering.
Filamentous fungal cell factories are efficient producers of platform chemicals, proteins, enzymes and natural products. Stirred-tank bioreactors up to a scale of several hundred m³ are commonly used for their cultivation. Fungal hyphae self-assemble into various cellular macromorphologies ranging from dispersed mycelia, loose clumps, to compact pellets. Development of these macromorphologies is so far unpredictable but strongly impacts productivities of fungal bioprocesses. Depending on the strain and the desired product, the morphological forms vary, but no strain- or product-related correlations currently exist to improve process understanding of fungal production systems. However, novel genomic, genetic, metabolic, imaging and modelling tools have recently been established that will provide fundamental new insights into filamentous fungal growth and how it is balanced with product formation. In this primer, these tools will be highlighted and their revolutionary impact on rational morphology engineering and bioprocess control will be discussed.


Contact-mediated acceleration of migration of melanoma B16 cells depends on extracellular calcium ions.
The escape of malignant cells from primary tumour and their active migration to the surrounding tissues are among the most important steps in the metastatic process. During migration, tumour cells interact with neighbouring neoplastic and normal cells and such interactions may affect their motile activity. We investigated the effect of extracellular calcium ions on migration of mouse melanoma B16 cells stimulated by homotypic cell-to-cell contacts. It was found that the decreasing of extracellular Ca2+ influx into B16 cells by lowering Ca2+ concentration in culture medium, or by the application of 0.5 mM La3+ (non-selective inorganic Ca2+ channels blocker), reduced the contact-mediated acceleration of migration of melanoma cells but only slightly affected the basal motile activity of non-stimulated single, separated cells moving without contacts with neighbouring ones in sparse culture. Since it was suggested that contact-mediated acceleration of migration of melanoma B16 cells may be controlled by mechanosensitive and/or voltage-gated ion channels, the presented data support the concept that these channels may affect cell migration by regulation of extracellular Ca2+ influx into stimulated cell.


Hand orientation in hand paddle swimming.
The aim of this research was to study the effect of hand paddles on the pitch, the sweepback angles and other stroke kinematic characteristics of the hand during front crawl swimming. Ten female competitive swimmers swam without and with small (116 cm (2)) and large (268 cm (2)) paddles. Four cameras (60 Hz) were used to record the underwater strokes and the digitizing was undertaken using the Ariel Performance Analysis System. When the size of the paddles increased, the stroke length, the mean swimming velocity and the total duration of the stroke were significantly increased (p < 0.05), while the average velocity of the hand during the pull and the push phases were significantly decreased (p < 0.05). The stroke rate was decreased significantly (p < 0.05) only when using large paddles. The relative duration of the separate phases of the stroke, the magnitude of the medial-lateral displacements and the pitch and sweepback angles of the hand were not modified, indicating that the use of hand paddles did not caused significant alterations in the orientation and the movement of the hand during the underwater stroke in front crawl swimming.


Intra-articular inclusions of the cervical synovial joints.
Two hundred and ten cervical synovial joints from 15 adult vertebral columns were studied by dissection to determine the form, dispositions and prevalence of intra-articular inclusions. Three types of inclusions were found. Fat pads occurred regularly in the atlanto-occipital joints but rarely in the zygapophysial joints. Capsular rims occurred occasionally at all levels. Fibro-adipose meniscoid occurred regularly in the atlanto-axial and zygapophysial joints. The function of fibroadipose meniscoids seems to be to protect the articular cartilages in gliding joints that subluxate during normal movement. Arguments are raised that these structures may act as a nidus for intra-articular fibrosis, and that meniscus extrapment may be a mechanism for torticollis.


The relationship between nuclear DNA content and leaf strategy in seed plants.
Species' 2C-values (mass of DNA in G(1) phase 2n nuclei) vary by at least four orders of magnitude among seed plants. The 2C-value has been shown to be co-ordinated with a number of other species traits, and with environmental variables. A prediction that species 2C-values are negatively related to leaf life span (LL) and leaf mass per area (LMA) is tested. These leaf traits are components of a major dimension of ecological variation among plant species. Flow cytometry was used to measure the 2C-values for 41 Australian seed plant species, 40 of which were new to the literature. Where possible, LL and LMA data from the global literature were combined with 2C-values from our data set and online C-value databases. Across all species, weak positive relationships were found between 2C-values and both LL and LMA; however, these did not reflect the relationships within either angiosperms or gymnosperms. Across 59 angiosperm species, there were weak negative relationships between 2C-values and both LL (r2 = 0.13, P = 0.005) and LMA (r2 = 0.15, P = 0.002). These relationships were the result of shifts to longer LL and greater LMA in woody compared with herbaceous growth forms, with no relationships present within growth forms. It was not possible to explain a positive relationship between 2C-values and LMA (r2 = 0.30, P = 0.024) across 17 gymnosperm species. The 2C-value was not related to LL or LMA either across species within orders (except for LMA among Pinales), or as radiation divergences in a model phylogeny. Gymnosperms appear to vary along a spectrum different from angiosperms. Among angiosperms, weak negative cross-species relationships were associated with growth form differences, and traced to a few divergences deep in the model phylogeny. These results suggest that among angiosperms, nuclear DNA content and leaf strategy are unrelated.


A quantitative study of pituitary colloid in the bat Myotis lucifugus lucifugus in relation to age, sex, and season.
Extracellular colloid accumulations were examined in pituitary glands of adult and juvenile, male and female, little brown bats, Myotis lucifugus lucifugus (Chiroptera: Vespertilionidae), collected at various times during the annual reproductive cycle. Round or ovoid periodic acid-Schiff-reactive accumulations of colloid were scattered throughout the pars distalis, pars intermedia, and pars tuberalis. These accumulations were surrounded by processes of agranular "follicular" cells. The proportion of the volume of the pars distalis occupied by colloid (volume fraction) exhibited considerable variation among animals, ranging from 0.00 to 3.18% in the total sample of bats. Pituitaries of juvenile males, yearling males, and nonparous females contained significantly less colloid than those of parous females and adult males. The mean volume fraction for each of these groups suggested that colloid content increased progressively from birth through sexual maturity in this animal. In addition, the frequency distribution of colloid content measurements made in parous females and adult males provided indirect evidence that colloid continues to accumulate throughout life. No sexual dimorphism in colloid content was observed before or after sexual maturity, and colloid content did not fluctuate in relation to the annual reproductive cycle of either males or females.


[Increasing activity of Rhizopus chinensis CCTCC M201021 lipase by directed evolution-error prone PCR].
Directed evolution strategy (error-prone PCR) was conducted to improve the activity of lipase from Rhizopus chinensis CCTCC M201021. Through two rounds of ep-PCR and pNPP top agar screening, two optimum mutant strains 1-11 and 2-28 were obtained with 2 and 4 fold of enzyme activity higher than that of parent strain, respectively. DNA sequencing of mutant lipase 2-28 revealed four amino acid substitutions: A129S, K161R, A230T, K322R. According to the simulated protein structure of Rhizopus chinensis lipase, A129S, K161R, A230T were located on the surface of the protein. A230T substitution improved the stability of the alpha-helix loop. K322R, near the catalytic center of lipase, located at a loop, formed a salt-bridge with a nearby aspartic acid (negative charged). Electrostatic force pulled the loop to the opposite direction of the substrate channel and made it easier for substrate to enter the lipase catalytic domain. Purified lipase was characterized and the result showed that Km of 2-28 lipase decreased by 10% compared with Km of the parent lipase, and Kcat was 2.75 fold improved than that of the original lipase.


Testosterone, 17 beta-hydroxy-5 alpha-androstan-3-one and 4-androstene-3, 17-dione in the plasma of male and female grey squirrels (Sciurus carolinensis).
Extracts of squirrel plasma have been chromatographed on partition columns (using a hydrophilic stationary phase) at atmospheric pressure (Celite support) and a reversed phase system at high pressure (HPLC). Both methods effectively separated testosterone, 17 beta-hydroxy-5 alpha-androstan-3-one (DHT) and 4-androstene-3,17-dione; they gave elution patterns that differed considerably. Chromatographic mobility of the three androgens on the two systems was identical with that of fractions of squirrel plasma extracts that gave responses measured by appropriate androgen radioimmunoassays; good evidence for the occurrence of these androgens in squirrel plasma is thus provided. Plasma testosterone levels were 300 pmol/l in juvenile males, 800-7000 pmol/l in sexually-active males but undetectable (less than 50 pmol/l) in sexually-regressed males. Plasma DHT levels were also high in sexually-active males, but undetectable in other males except for one regressed individual. Plasma androstenedione was higher in juvenile males than in adult males, in which it was similar whether or not they were sexually regressed. Plasma testosterone and DHT, unlike androstenedione, were totally dependent on the presence of the testes. In females testosterone and DHT were undetectable in plasma but androstenedione levels were high, especially at oestrus. Androstenedione was dependent on the presence of the ovaries.


Metabolic phenotypes in primary unknown metastatic carcinoma.
The purpose of this study is to evaluate expression of metabolism-related proteins in primary unknown metastatic carcinoma (PUMC) and associated implications for treatment. A tissue microarray containing 77 cases of PUMC was constructed and immunohistochemical staining was used to evaluate expression of the following proteins: Glycolysis-related: Glut-1, carbonic anhydrase (CA) IX, and monocarboxylate transporter (MCT) 4; Glutaminolysis-related: glutaminase1 (GLS1), glutamate dehydrogenase (GDH), and amino acid transporter-2 (ASCT2); and Mitochondrial-related: ATP synthase, succinate dehydrogenase (SDH)A, and SDHB. The association between immunohistochemical staining results and clinicopathologic parameters was evaluated. The expression of metabolism-related proteins was different depending on the histologic subtype. Compared to other subtypes, squamous cell carcinomas (SQ) expressed more Glut-1 (p = 0.028), while adenocarcinomas (AD) expressed more SDHB in the stroma (p = 0.025). The expression of metabolism-related proteins was also different depending on the clinical subtypes. Glut-1 was expressed most in the nodal type and the least in carcinomatosis type, when compared to other subtypes (p = 0.021). The metabolic phenotypes also showed other trends: when the stroma showed no glutaminolysis, the tumor mostly invaded lymph node, bone, and brain, while the tumor invaded regions other than lymph node, bone, and brain when the stroma showed glutaminolysis (p = 0.003). When the stroma showed the mitochondrial metabolic type, the histologic subtype was mainly AD, but the non-mitochondrial type was associated more with SQ (P = 0.049). For PUMC, the expression of metabolism-related proteins, such as Glut-1 and SDHB, differs in the tumor or stroma depending on the clinical and histologic tumor subtype.


A phase 2 study of moderate dose interleukin-2 and granulocyte-macrophage colony-stimulating factor in patients with metastatic or unresectable renal cell carcinoma.
Interleukin-2 (IL-2) has been shown to produce durable complete remission in patients with renal cell carcinoma (RCC). A phase 2 study was conducted to evaluate the potential therapeutic synergy as well as the toxic side effects of the concurrent administration of IL-2 and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced stage disease. Twenty-one patients with unresectable or metastatic RCC having an Eastern Oncology Cooperative Group performance status of 0 or 1 were enrolled. Six patients had received prior immunotherapy with interferon (IFN)-alpha, IFN-gamma, and IL-12, whereas the remaining 15 subjects were previously untreated. Thirteen patients were assigned to a moderate-dose bolus of IL-2 at 72,000 IU/kg every 8 hours on days 1 through 5 and days 15 through 19, whereas 8 patients were given IL-2 as an intravenous continuous infusion at a dose of 5 MU/m2/d on days 1 through 5 and days 15 through 19. Subcutaneous GM-CSF at 125 microg/d on days 1 through 21 was administered concomitantly with IL-2. The median number of IL-2 bolus doses was 23 of a scheduled 28 (85%), whereas with the continuous infusion, 93% of planned IL-2 was given. All patients received 100% of GM-CSF doses. There were no complete or partial responses in this study. Of 13 patients treated in the bolus IL-2 arm, 10 had systemic progression of disease at 4 to 8 weeks, 1 developed metastasis in the brain at 4 weeks, and 2 had stable disease for 4 and 17 months. Among the 8 subjects treated with continuous infusion IL-2, 3 progressed with brain lesions at 3 to 8 weeks and 5 had stable disease at 6+, 7, 8+, 15+, and 17+ months. The median survival for the whole group was 10 months, with a range of 0.5 to 40+ months. There were no regimen-related deaths, and most of the observed toxicities were grade 1 and 2. Serious toxicities (grade 3 and 4) included anemia, atrial fibrillation, oliguria, abnormal liver function, and neurologic events like agitation or confusion. The combination of recombinant IL-2 and GM-CSF administered in the designed schedule and doses was not effective in patients with metastatic RCC and may even interfere with the therapeutic potential of moderate-dose IL-2 and increase its adverse events.


Listening to people to cure people: the LpCp - tool, an instrument to evaluate hospital humanization.
In the healthcare environment, nowadays, only a few among the available evaluation systems pay enough attention to certain social sustainability aspects. Among these, humanization plays a key role in an environment, like hospitals, where the mental and physical well-being of patients and healthcare operators is crucial. Our research project, known as 'SustHealth', is focused on the deficiencies of the evaluation methodology and aims at developing an assessment system related to a questionnaire-based investigation capable of revealing the most influential conditions and dynamics in people's hospital experience, while also recommending areas in hospitals where efforts can be made to sustain improvement strategies. The humanization of healthcare structures began with a significant investigation to assess all the major evaluation tools in both hospitals - to better understand the physical and emotional interactions in the structure-user ratio - and other areas. This helped understand the strengths and criticalities of the systems that were examined. This first step also allowed to shed light on the most important aspects to keep in mind when developing an evaluation system. During the operational steps an all-new LpCp - tool (Listening to people to Cure people) was created, which includes a questionnaire-based investigation and processing software, and its application for beta-testing in a 600-bed hospital in Milan. The LpCp - tool proved to be effective and capable of finding the deficiencies and potential in the examined hospital. Considering different themes through alternative viewpoints (staff, patients/visitors, technicians, etc.), the tool has allowed underlining different perceptions of the same place and also provided sound information to guide healthcare management in taking informed decisions about specific problems or users. Former interesting results show an inadequate appraisal about e.g. on-site facilities or recreational activities and a lack of perception on existing services by users (e.g. translation, P.R.). The LpCp - tool was presented to other healthcare centres in Milan for wider-scale testing. Therefore, the LpCp - tool will hopefully increase healthcare companies' responsiveness towards improving comfort and humanization levels in hospitals. Sometimes all that is needed are small and inexpensive actions that often improve a hospital user's experience, and often important services are not used due to a lack of communication and information.


Omental infarction in childhood.
We present a case of right-sided omental infarction in a child documented with ultrasound and multislice computed tomography and confirmed by surgery and pathologic examination. Omental infarction is a rare cause of right-sided acute abdominal pain in a child. Differential diagnosis includes appendicitis. With different imaging modalities a diagnosis can be made and avoid unnecessary appendectomy.


Maternal dyslipidaemic diet induces sex-specific alterations in intestinal function and lipid metabolism in rat offspring.
This study investigated the effects of a maternal dyslipidaemic (DLP) diet on lipid metabolism, microbial counts in faeces and hepatic and intestinal morphology in rat offspring with respect to sex during different phases of life. Wistar rats (dams) were fed a control (CTL) or DLP during gestation and lactation. After weaning, CTL and DLP offspring were fed a standard diet. The effects of a maternal DLP on body composition, biochemical parameters, faecal microbiota and intestinal and hepatic histomorphometric characteristics in rat offspring were evaluated at 30 and 90 d of age. The DLP diet during gestation and lactation caused lower birth weight and a greater weight gain percentage at the end of the 90-d period in both male and female offspring. Female pups from DLP dams had higher liver fat levels compared with CTL (P≤0·001) at 90 d of age. Males from DLP dams had greater visceral fat weight and lower Lactobacillus spp. faecal counts at 90 d of age (P≤0·001) as well as lower faecal fat excretion (P≤0·05) and Bacteroides spp. faecal counts (P≤0·001) at 30 d of age when compared with pups from CTL dams. However, both dams and DLP pups showed damage to intestinal villi. A maternal DLP alters intestinal function and lipid metabolism in a sex-specific manner and is a potential predisposing factor for health complications in offspring from the juvenile period to the adult period.


Spinal neural fibrolipoma: A case report and review of the literature.
Neural fibrolipoma is characterized by infiltration of the epineurium by adipose and fibrous tissue. Intradural spinal cases are extremely rare. We report an unusual case of spinal neural fibrolipoma. A 31-year-old pregnant woman presented due to weakness of right leg (muscle strength 2/5). Magnetic resonance (MR) evaluation of the spine revealed an extramedullary intradural mass at the T1-T4 level. MR findings were suggesting a dermoid cyst or a lipoma. Subtotal surgical excision of the tumor was done. Histopathological examination showed enlarged nerve bundles infiltrated by fibroadipose tissue. Thus, the diagnosis of neural fibrolipoma was established. One month after surgery, lumbar MR showed residual tumor tissue, but successful decompression of the spinal cord. Six months after surgery, the neurological examination, muscle strength 4/5 evaluated. Neural fibrolipoma is characterized by infiltration of the epineurium by adipose and fibrous tissue. The tissue grows between and around nerve bundles thereby causing enlargement of the affected nerve. Neural fibrolipoma is a benign lesion with no effective therapy. Surgical excision usually causes severe damage of the involved nerve. Although spinal cases are extremely rare, it should be included in the differential diagnosis of extramedullary intradural masses.


Adsorption of an endoglucanase from the hyperthermophilic Pyrococcus furiosus on hydrophobic (polystyrene) and hydrophilic (silica) surfaces increases protein heat stability.
The interaction of an endoglucanase from the hyperthermophilic microorganism Pyrococcus furiosus with two types of surfaces, that is, hydrophobic polystyrene and hydrophilic silica, was investigated, and the adsorption isotherms were determined. The adsorbed hyperthermostable enzyme did not undergo loss of biological activity. A model was proposed for the mechanism of interaction of the enzyme with the surface based on the shape of the adsorption isotherm, the morphological characteristics of the enzyme, and the thermodynamic parameters of the system. The enzyme was irreversibly immobilized at the solid/liquid interface even at high temperatures, and most interestingly, it acquired further heat stabilization upon adsorption. The denaturation temperature increased from 108 degrees C in solution to 116 degrees C upon adsorption on hydrophilic silica particles. Adsorption on the hydrophobic polystyrene surface even shifted the denaturation temperature to 135 degrees C, the most extreme experimentally determined protein denaturation temperature ever reported. Maintenance of the biological function particularly at high temperatures is important for the development of solid substrate immobilized enzymes for applications in biocatalysis and biotechnology. This also presents an additional stabilization mechanism employed by nature where the extracellular hyperthermostable enzyme remains folded and active at the extreme temperatures of its natural environment by adsorption on the surface of rocks and other materials appearing in the surroundings of the microorganism.


An evaluation of peptide-bond isosteres.
Peptide-bond isosteres can enable a deep interrogation of the structure and function of a peptide or protein by amplifying or attenuating particular chemical properties. In this Minireview, the electronic, structural, and conformational attributes of four such isosteres-thioamides, esters, alkenes, and fluoroalkenes-are examined in detail. In particular, the ability of these isosteres to partake in noncovalent interactions is compared with that of the peptide bond. The consequential perturbations provide a useful tool for chemical biologists to reveal new structure-function relationships, and to endow peptides and proteins with desirable attributes.


[Pathological and virological studies of the liver tissues from the patients with sporadic hepatitis E].
To study the pathological feature, viral distribution and replication in the liver tissue of sporadic hepatitis E(HE), and to explore the mechanism of the liver injury induced by hepatitis E virus(HEV). The total bioptic liver tissues (n=54) were obtained from the patients with sporadic hepatitis E, including the clinical acute stage (n=20), the convalescent stage (n=16), and the chronic hepatitis B (CHB) overlapped with HEV infection recently (n=18). The pathological changes in the liver tissues were observed under the light and the electron microscope. HEV RNA was detected by in situ hybridization, and Kupffer cells were marked with immunohistochemistry. The HE liver tissues showed the pathological features in the clinical acute stage, presenting frequently with feathery degeneration of hepatocytes (100%), cholangiolar cholestasis (75.0%), and double nuclei and multinuclei hepatocytes (65.0%). The apoptotic body of hepatocyte was larger and irregular, and the proliferation of Kupffer cells was prominent. HEV RNA was distributed in hepatocyte cytoplasm near the nuclei. The positive rate of HEV RNA in acute stage was evidently higher than that in convalescent stage (100% vs 12.5%,P < 0.001), and the HEV RNA positive hepatocytes and the viral copies in acute stage were also more than in convalescent stage, in which the liver tissues were becoming normal. The liver tissue changes of the CBH overlapped with HEV infection were more severe compared with the single CHB. Sporadic HE had histopathological characteristics. HEV infection and replication in hepatocytes occurred mainly during clinical acute stage and regressed in convalescent stage, which suggested sporadic acute HE may have a good result. The immune-mediated liver injury by lymphocytes might be a main pathogenesis of HE,but the liver injury induced directly by HEV might not be excluded.


Implementation of a youth-adult partnership model in youth mental health systems research: Challenges and successes.
By integrating Youth-Adult Partnerships (Y-APs) in organizational decision making and programming in health-care settings, youth can be engaged in decisions that affect them in a way that draws on their unique skills and expertise. Despite challenges, Y-APs can have many benefits for youth and adults alike, as well as for the programmes and initiatives that they undertake together. This article describes the development, implementation and success of a Y-AP initiative at the McCain Centre at the Centre for Addiction and Mental Health, a large urban hospital. The McCain Y-AP implementation model was developed based on the existing literature, guided by the team's progressive experience. The development and implementation procedure is described, with indicators of the model's success and recommendations for organizations interested integrating youth engagement. The McCain Y-AP has integrated youth into a wide range of mental health and substance use-related initiatives, including research projects, conferences and educational presentations. The model of youth engagement is flexible to include varying degrees of involvement, allowing youth to contribute in ways that fit their availability, interest and skills. Youth satisfaction has been strong and both the youth and adult partners have learned from the experience. Through the McCain Y-AP initiative, youth engagement has helped advance numerous initiatives in a variety of ways. Flexible engagement, multifaceted mentorship, reciprocal learning and authentic decision making have led to a successful partnership that has provided opportunities for growth for all those involved. Health-care organizations interested in engaging youth can learn from the McCain Y-AP experience to guide their engagement initiatives and maximize success.


Involvement of Rab28 in NF-κB nuclear transport in endothelial cells.
Our previous proteomic analysis revealed the expression of Rab28 in arteries of rats. However, the function of Rab28 in mammalian cells, and its role in vessels are still unknown. Coarctation of abdominal aorta above left kidney artery in rat was used as hypertensive animal model. FX-4000 cyclic strain loading system was used to mimic the mechanical condition on vascular cells during hypertension in vitro. Immunofluorescence and co-immunoprecipitation (Co-IP) were used to identify distribution and interaction of Rab28 and nuclear factor kappa B (NF-κB). Rab28 expression was significantly increased in carotid arteries of hypertensive rats. High cyclic strain induced Rab28 expression of endothelial cells (ECs) through a paracrine control of vascular smooth muscles cells (VSMCs), which at least partly via angiotensin II (Ang II). Rab28 knockdown decreased proliferation of ECs, while increased apoptosis and migration. Immunofluorescence revealed that Ang II stimulated the co-translocation of Rab28 and NF-κB from cytoplasm into nucleus. Knockdown of Rab28 attenuated NF-κB activation. Co-IP of NF-κB p65 and Rab28 indicated their interaction. Our results revealed that Rab28, as a novel regulator of NF-κB nuclear transport, might participate in the disturbance of EC homeostasis.


Sense of self: voices of separation and connection in women who have experienced abuse.
The findings of qualitative studies with women who have experienced abuse by an intimate partner suggest that a woman's sense of self is a central feature in her decision to leave the abusive relationship. This qualitative study was undertaken, in part, to listen to how women describe themselves, specifically explicating voices of relational connection and disconnection within the narratives. This paper presents the findings of interviews with 18 rural women from culturally diverse backgrounds who had been or were currently in abusive relationships. The women were asked to respond to the question "How would you describe yourself to yourself?" The responses were read using the interpretive method of reading narratives for self and moral voice. The theory of moral development was used to frame the inquiry. The experiences of self that emerged from the narratives are presented as progressively relational voices of separation and connection. The relationship between these voices and moral development is discussed, as are implications for nursing practice and for future research.


MicroRNA-23a downregulates the expression of interferon regulatory factor-1 in hepatocellular carcinoma cells.
Interferon regulatory factor-1 (IRF-1) is a tumor-suppressor gene induced by interferon-γ (IFNγ) and plays an important role in the cell death of hepatocellular carcinoma (HCC). HCC tumors evade death in part by downregulating IRF-1 expression, yet the molecular mechanisms accounting for IRF-1 suppression in HCC have not yet been characterized. Previous studies have shown that microRNA-23a (miR-23a) can suppress apoptosis by targeting IRF-1. Therefore, we hypothesized that miR-23a promotes HCC growth by downregulating IRF-1. For the in vivo studies, 7 cases of resected HCC and adjacent liver samples were analyzed. For the in vitro studies, IRF-1 mRNA and protein were examined in HepG2 and Huh-7 HCC cells after IFNγ stimulation by real-time PCR and western blotting, respectively. To determine the role of miR-23a in regulating IRF-1, HepG2 cells were transfected with an miR-23a mimic or inhibitor, and IRF-1 expression was examined. Binding of miR-23a was assessed by cloning the 528-bp human IRF-1 3'-untranslated region (3'UTR) into luciferase reporter plasmid pMIR-IRF-1-3'UTR. The results showed that IRF-1 mRNA expression was downregulated in the human HCC tumor tissues compared to that in the adjacent background liver tissues. IFNγ-induced IRF-1 protein was less in the HepG2 tumor cells compared to that in the primary human hepatocytes. miR-23a expression was inversely correlated with IRF-1, and addition of the miR-23a inhibitor increased basal IRF-1 mRNA and protein. Likewise, the miR-23a mimic downregulated IFNγ-induced IRF-1 protein expression, while the miR-23a inhibitor increased IRF-1. Furthermore, the miR-23a mimic repressed IRF-1-3'UTR reporter activity, while the miR-23a inhibitor increased the reporter activity. These results demonstrated that IRF-1 expression is downregulated in human HCC tumors compared to that noted in the background liver. miR-23a downregulates the expression of IRF-1 in HCC cells, and the IRF-1 3'UTR has an miR‑23a binding site that binds miR-23a and decreases reporter activity. These findings suggest that the targeting of IRF-1 by miR-23a may be the molecular basis for IRF-1 downregulation in HCC and provide new insight into the regulation of HCC by miRNAs.


Forensic norms of female and male Lebanese adults.
Patients born to Lebanese parents and grandparents, visiting two private practice orthodontic clinics, with normal occlusion and no need for any kind of orthodontic treatment during a six month period and satisfying inclusion criteria, were asked permission to include their lateral cephalometric radiographs in this study. Sixty three individuals met the inclusion criteria. Sixteen cephalometric measurements were taken (seven linear and nine angular) were analyzed on each radiograph. Measurements were compared between genders using student's t-test. The study population included 31 females and 32 males with a mean (±SD) of 21.6 (±4.0) and 21.3 (±3.9) years for males and females respectively. Men had significantly larger skeletal linear measurements: the mandibular base menton to gonion (Me-Go) (p=0.027), the total mandibular length of condylon to gnathion (Co-Gn) (p=0.009) and significantly larger angular measurements: sella to nasion to subspinal point (S-N-SS) (p=0.006), and sella to nasion to supramental point (S-N-Spm) (p=0.009). The results of this study demonstrated that male skeletal linear and angular measurements are significantly larger in Lebanese adult males compared to Lebanese adult females.


Intracardiac Metastatic Sarcoma.
Even though intracardiac sarcoma metastases are rare, they have been previously reported in the literature. We report the case of a 60-year-old man who had a synovial sarcoma with metastasis in the right ventricle. These findings were associated with the presence of a new cardiac murmur and severe thrombocytopenia. The treatment with systemic chemotherapy resulted in a normalization of the patient's hematologic profile and in a reduction of the intracardiac mass. The patient subsequently underwent intracardiac tumor resection.


Binocular advantage for prehension movements performed in visually enriched environments requiring visual search.
The purpose of this study was to examine the role of binocular vision during a prehension task performed in a visually enriched environment where the target object was surrounded by distractors/obstacles. Fifteen adults reached and grasped for a cylindrical peg while eye movements and upper limb kinematics were recorded. The complexity of the visual environment was manipulated by varying the number of distractors and by varying the saliency of the target. Gaze behavior (i.e., the latency of the primary gaze shift and frequency of gaze shifts prior to reach initiation) was comparable between viewing conditions. In contrast, a binocular advantage was evident in performance accuracy. Specifically, participants picked up the wrong object twice as often during monocular viewing when the complexity of the environment increased. Reach performance was more efficient during binocular viewing, which was demonstrated by shorter reach reaction time and overall movement time. Reaching movements during the approach phase had higher peak velocity during binocular viewing. During monocular viewing reach trajectories exhibited a direction bias during the acceleration phase, which was leftward during left eye viewing and rightward during right eye viewing. This bias can be explained by the presence of esophoria in the covered eye. The grasping interval was also extended by ~20% during monocular viewing; however, the duration of the return phase after the target was picked up was comparable across viewing conditions. In conclusion, binocular vision provides important input for planning and execution of prehension movements in visually enriched environments. Binocular advantage was evident, regardless of set size or target saliency, indicating that adults plan their movements more cautiously during monocular viewing, even in relatively simple environments with a highly salient target. Nevertheless, in visually-normal adults monocular input provides sufficient information to engage in online control to correct the initial errors in movement planning.


Low-cost urchin-like silicon-based anode with superior conductivity for lithium storage applications.
Poor rate and cycling performance are the most critical drawbacks for Si-based anodes on account of their inferior conductivity and colossal volumetric expansion during lithiation/delithiation. Here we report the fabrication of structurally-integrated urchin-like Si anode, which provides prominent structural stability and distinguished electron and ion transmission pathways for lithium storage. The inexpensive solid Si waste from organosilane industry after acid-washed and further ball-milling serves as the pristine Si-source in this work. Carbon nanotubes (CNTs) are in-situ grown outside Si microparticles, resulting in an urchin-like structure (Si/CNTs). The optimized Si/CNTs presents ascendant invertible capacity and rate performance, achieving up to 920 mAh g-1 beyond 100 cycles at 100 mA g -1, and a capacity of 606.2 mAh g-1 at 1 A g -1 after long cycling for 1000 cycles. The proposed scalable synthesis can be adopted to advance the performance of other electrode materials with inferior conductivity and enormous volume expansions during cycling.


AMG 151 (ARRY-403), a novel glucokinase activator, decreases fasting and postprandial glycaemia in patients with type 2 diabetes.
Phase I studies have shown that AMG 151 activates glucokinase, a key enzyme in glucose homeostasis. The present randomized, placebo-controlled phase IIa study evaluated the dose-effect relationship of the glucokinase activator AMG 151 relative to placebo on fasting plasma glucose (FPG) in 236 patients (33-35 patients per arm) with type 2 diabetes treated with metformin. Patients received oral AMG 151 at 50, 100 or 200 mg twice daily, AMG 151 at 100, 200 or 400 mg once daily or matching placebo for 28 days. A significant linear dose-effect trend was observed with the twice-daily regimen (p = 0.004) for change in FPG to day 28. No trend was observed with the once-daily regimen. A higher incidence of hypoglycaemia and hypertriglyceridaemia was observed with AMG 151 administration. AMG 151 significantly reduced FPG when administered twice daily but not when administered once daily in patients with type 2 diabetes treated with metformin.


Transferred wrinkled Al2O3 for highly stretchable and transparent graphene-carbon nanotube transistors.
Despite recent progress in producing transparent and bendable thin-film transistors using graphene and carbon nanotubes, the development of stretchable devices remains limited either by fragile inorganic oxides or polymer dielectrics with high leakage current. Here we report the fabrication of highly stretchable and transparent field-effect transistors combining graphene/single-walled carbon nanotube (SWCNT) electrodes and a SWCNT-network channel with a geometrically wrinkled inorganic dielectric layer. The wrinkled Al2O3 layer contained effective built-in air gaps with a small gate leakage current of 10(-13) A. The resulting devices exhibited an excellent on/off ratio of ~10(5), a high mobility of ~40 cm(2) V(-1) s(-1) and a low operating voltage of less than 1 V. Importantly, because of the wrinkled dielectric layer, the transistors retained performance under strains as high as 20% without appreciable leakage current increases or physical degradation. No significant performance loss was observed after stretching and releasing the devices for over 1,000 times. The sustainability and performance advances demonstrated here are promising for the adoption of stretchable electronics in a wide variety of future applications.


The History, Symptoms, Causes, Risk Factors, Types, Diagnosis, Treatments, and Prevention of Gout, Part 2.
Gout, a common and complex form of inflammatory arthritis, is characterized by abnormally elevated levels of uric acid in the blood. The most current estimate from the Centers for Disease Control and Prevention shows an increase from 52.5 million to 54.4 million people in the U.S. have arthritis or one of the rheumatic diseases. There are over 100 rheumatic diseases and conditions. In the U.S., the most common types of arthritis or rheumatic diseases are osteoarthritis, gout, fibromyalgia, and rheumatoid arthritis, in that order according to prevalence. This article focuses on gout. Gout can be effectively treated and managed with a combination of medication (manufactured and/or compounded) and self-management strategies. Part 1 of this 2-part article provided the definition of gout and a brief history of gout. Part 2 continues the discussion of gout and includes examples of compounded formulations used in the treatment of gout.


Patient Education for Consumer-Mediated HIE. A Pilot Randomized Controlled Trial of the Department of Veterans Affairs Blue Button.
Consumer-mediated health information exchange (HIE) is one of the three types of HIE designated by the Office of the National Coordinator. HIE is intended to improve the quality of care while reducing cost, yet empirical support for this claim is mixed. Future research should identify the contexts whereby HIE is most effective. This study was conducted as a pilot two-arm randomized controlled trial. In the intervention arm, 27 veterans were taught how to generate a Continuity of Care Document (CCD) within the Blue Button feature of their VA patient portal and were then asked to share it with their community non-VA provider. In the attention control condition, 25 Veterans were taught how to look up health information on the Internet. The impact of this training on the next non-VA medical visit was examined. Nineteen (90%) veterans in the intervention arm shared their CCD with their non-VA provider as compared with 2 (17%) in the attention control arm (p<0.001). Both veterans and non-VA providers indicated high satisfaction with the CCD. Comparison of medical records between the VA and non-VA providers did not indicate improved medication reconciliation (p=0.72). If veterans shared their CCD prior to their non-VA providers ordering laboratory tests, the number of duplicate laboratories was significantly reduced (p=0.02). In this pilot randomized controlled trial, training 52 veterans to share their CCD was feasible and accepted by both patients and providers. Sharing this document appeared to reduce duplicate laboratory draws, but did not have an impact on documented medication list concordance.


Diagnosis, treatment and genetic analysis of an elderly patient with Gaucher's disease characterized by marked multiple bone destruction.
Gaucher's disease is a rare autosomal recessive genetic disease. Due to the decrease or lack of glucocerebrosidase (GBA) activity in lysosome caused by the mutation of GBA gene, its substrate glucocerebroside is detained in lysosome, resulting in clinical manifestations of liver, spleen, kidney, bone, hematopoietic system and even nervous system involvement. Here, we report a case of elderly patient presenting marked multiple bone destruction, with childhood medical history of splenectomy and "osteomyelitis". The patient has a significantly enlarged liver, accompanied by anemia, thrombocytopenia and osteopenia. Laboratory studies show this patient has low blood GBA activity and high glucosyl sphingosine level and increased chitotriosidase activity. Genetic testing revealed a homozygous missense variant NM_001005741.2 c.770A>G (p.Asp257Gly) in the patient's GBA gene. After 6 months of enzyme replacement therapy, the patient's platelets returned to normal, anemia improved, and liver volume decreased. Further detections show that the mother and brothers of the patient have heterozygous mutations at this locus, which is consistent with Mendelian inheritance law. Although this variant has not been reported in literatures or database, both clinical manifestations, characteristics of enzymology and biomarkers, and the effect of enzyme replacement therapy support the diagnosis of Gaucher's disease. The Asp257Gly variant is therefore assessed as a clinical pathogenic variant. This study expands the spectrum of the GBA gene variants. The diagnosis and treatment process of this case also provide reference for the early identification, diagnosis and early treatment of this kind of patients.


Long-Term Effects of TCM Yangqing Kangxian Formula on Bleomycin-Induced Pulmonary Fibrosis in Rats via Regulating Nuclear Factor-κB Signaling.
We aimed to evaluate the therapeutic effects and long-term effects of YKF and dissect the potential mechanisms. IPF rats were given YKF, prednisone, or pirfenidone, respectively, from day 1 to day 42, followed by a 28-day nonintervention interval through day 70. Forced vital capacity (FVC), histopathology, hydroxyproline (HYP) contents, lung coefficient, blood inflammatory cell populations, inflammatory cytokine levels of the lung tissues, and the expression of proteins involved in nuclear factor- (NF-) κB signaling pathway were evaluated on days 7, 14, 28, 42, and 70. HYP contents, Ashcroft scores, lung coefficient, and pulmonary fibrosis blood cell populations increased significantly in IPF rats, while FVC declined. All the above-mentioned parameters were improved in treatment groups from day 7 up to day 70, especially in YKF group. The mRNA and protein expressions of tumor necrosis factor- (TNF-) α significantly decreased, while interferon- (IFN-) γ significantly increased, and phosphorylations of cytoplasm inhibitor of nuclear factor kappa-B kinase β (IKKβ), inhibitor of nuclear factor kappa-B α (IκBα), and NF-κB were obviously downregulated in YKF group from day 7 to day 70. YKF has beneficial protective and long-term effects on pulmonary fibrosis by anti-inflammatory response and alleviating fibrosis.


Arterial baroreflex control of the sinus node during dobutamine exercise stress testing.
The contributions of increases in circulating catecholamines, changes in central command, and muscle afferents on baroreflex control of the sinus node during exercise are unclear. We used a dobutamine infusion to induce hemodynamic changes comparable to those of moderate physical exercise in the absence of changes in central command and muscle afferents in 13 healthy subjects. Dobutamine (up to 9 microg/kg body weight per minute) increased systolic blood pressure, shortened the RR interval, increased systolic blood pressure variability, but blunted RR interval variability (P<0.05 versus placebo). Consequently, dobutamine decreased the coherence between variations in systolic blood pressure and RR interval and decreased arterial baroreflex sensitivity from 12+/-2 to 3+/-1 ms/mm Hg (P<0.01). The largest increases in systolic blood pressure with dobutamine were paralleled by the greatest impairments in arterial baroreflex sensitivity (0. 50<r<0.56, P<0.01). The chronotropic effects of dobutamine prevented a reflex bradycardia in response to the blood pressure increase. However, less predominant low-frequency oscillations in systolic blood pressure (P<0.0001) suggested preserved sympathetic withdrawal in response to the blood pressure increase induced by dobutamine. In conclusion, this study revealed that a shift in the operating point of the arterial baroreceptors and the chronotropic effects of adrenergic stimulation impair baroreflex control of the sinus node during dobutamine exercise stress testing. Baroreflex control of the sinus node is not reset when hemodynamic characteristics of exercise are reproduced in the absence of modifications in central command and muscles afferents.


Use of the AO femoral distractor in revision total hip arthroplasty.
Use of the femoral distractor in trauma settings is well documented in the orthopedic literature. Use of the device extends into adult reconstructive surgery; surgeons use this distractor as an aid in performing difficult revision total hip arthroplasties (THAs). Patients with associated soft-tissue contractures secondary to subacute or chronic dislocation of a THA may present a clinical picture that might make consideration of simple open reduction only a remote possibility. Patients with long-standing Girdlestone resection arthroplasty usually present with soft-tissue deficiencies that render the hip unstable (unless it is at maximal length), or these patients have severe contractures that make reduction difficult after all components are implanted. We present a distractor technique for reduction of prosthetic components in such clinical situations. The femoral distractor is easily applied, and, because of its mechanical effectiveness, it can assist in reducing the "irreducible" hip.


Bilateral transient visual loss and meningeal irritation signs following retrobulbar anesthesia.
A 62-year-old man underwent an uneventful cataract surgery in the left eye following retrobulbar anesthesia. Fifteen minutes after the surgery, the patient had visual loss in his right (unoperated) eye, headache, dizziness, nausea, and vomiting. The bandage on the left (operated) eye was removed and the initial ophthalmic examination revealed bilateral dilated pupils with absence of light perception. His fundus examination and vital signs were unremarkable. Immediately, a computerized tomography (CT) was performed to scan both orbit and brain. The orbit CT revealed air bubbles within the left optic nerve sheath, which confirmed inadvertent injection and administration of anesthetic medications into the optic nerve sheath. Within three hours, meningeal irritation signs recovered spontaneously and visual acuity improved to 20/20 in the right eye and 20/40 in the left eye.


Tranexamic acid versus fractional carbon dioxide laser in post-acne hyperpigmentation.
Post-acne hyperpigmentation is a common undesirable sequela of acne vulgaris that causes distress for many patients. This study's objective was to compare the efficacy of both low-power/low-density fractional carbon dioxide (CO2 ) laser and tranexamic acid (TXA) microinjection on post-acne hyperpigmentation. Twenty-five post-acne hyperpigmentation patients (resistant to regular treatment for more than 6 months) were enrolled in this randomized split-face study. One side of the face was randomly assigned to low-power fractional CO2 laser every 4 weeks, and the other side was assigned to TXA intradermal-microinjection every 2 weeks for 3 months. Efficacy was evaluated using digital photography, dermoscopy, post-acne hyperpigmentation index (PAHPI), melanin index (MI), and erythema index (EI) at baseline and 4 weeks after the last session. Both fractional CO2 laser and TXA microinjection treatment sides showed a significant reduction in the PAHPI and MI (p < 0.001). There was statistically significant difference with better percentage of improvement regarding total dermoscopic score on the fractional CO2 laser side than the TXA microinjections side (p < 0.009). Both fractional CO2 laser and TXA microinjection are effective and safe treatment options for post-acne hyperpigmentation with potential superiority of fractional CO2 laser. We also believe that dermoscopy could be helpful tool for assessment of pigmentation depth in patients on treatment by analyzing the color pattern. ClinicalTrials.govID: NCT03765021.


Common bile duct injury after laparoscopic cholecystectomy: report of two cases.
With a few exceptions, laparoscopic cholecystectomy has rapidly supplanted open cholecystectomy as the operation of choice for symptomatic cholelithiasis. The risk of bile duct injury using the laparoscopic technique is almost twice that of the open technique (0% to 1% vs 0% to 0.5%). There appears to be a direct correlation between the number of cases an individual surgeon performs and the frequency of bile duct injury. The nature of bile duct injuries following the laparoscopic technique tends to be more serious than those seen following the open procedure. In addition, more than 50% of bile duct injuries go undetected at the time of operation. A number of technical steps can be taken to help prevent bile duct injuries when using the laparoscopic technique. This article reports two such cases to alert the surgeon that a high index of suspicion must always be maintained concerning the possibility of bile duct injury following laparoscopic cholecystectomy.


Reply to "Comment on 'Validity of path thermodynamic description of reactive systems: Microscopic simulations' ".
The Comment's author argues that a correct description of reactive systems should incorporate an explicit interaction with reservoirs, leading to a unified system-reservoir entity. However, this proposition has two major flaws. First, as we will emphasize, this entity inherently follows a thermodynamic equilibrium distribution. In the Comment, no indication is provided on how to maintain such a system-reservoir entity in a nonequilibrium state. Second, contrary to the author's claim, the inclusion of a system-reservoir interaction in the traditional stochastic modeling of reactive systems does not automatically alter the limited applicability of path thermodynamics to problematic reactive systems. We will provide a simple demonstration to illustrate that certain elementary reactions may not involve any changes in reservoir components, which seem to have been overlooked by the author.


[Free perforation in Crohn's disease].
Free perforation in abdominal cavity in patients with Crohn's disease is a rare entity as attested from the data reported in the literature. It is a very dangerous event and requires a surgical urgency management. The Authors reported two cases of free perforation, in patients with Crohn' disease, undergoing surgical operation in urgency. Analyzing pathogenesis, difficulty in diagnosis making and therapeutic choices, they underline that CT is very useful in the diagnosis, while resection of the perforated intestinal tract represent the best surgical treatment.


[Conservative cholelitholysis in the calculus-congested gallbladder].
Daily administration of 500 mg ursodeoxycholic acid and chenodeoxycholic acid (divided into two doses, morning and evening, corresponding to 8.5 mg per kg body-weight and substance), all concrements in the gall-bladder were dissolved over a period of 14 months in a 60-year-old man for whom surgical treatment was contra-indicated because of severe coronary heart disease. This case illustrates that, in the face of a high operative risk, the attempt to dissolve stones in the gall-bladder by drugs is justified.