Development and Validation of a Fast Ultra-High Performance Liquid Chromatography-Fluorescent Method for the Quantification of Hydroxychloroquine and Its Metabolites in Patients With Lupus.
Hydroxychloroquine (HCQ) is approved for the treatment of systemic lupus erythematosus (SLE). Therapeutic drug monitoring of HCQ is necessary to detect nonadherence and to improve treatment efficacy in patients with SLE. Liquid chromatographic-tandem mass spectroscopy and high performance liquid chromatography (HPLC)-fluorescent methods are currently used to measure whole blood concentrations of HCQ and its 2 main metabolites desethylhydroxychloroquine and desethylchloroquine in patients with SLE. This study reports the development and validation of an ultra-HPLC (U-HPLC) method with fluorescence detection for the simultaneous quantification of HCQ and its metabolites in whole blood. After adding chloroquine (internal standard) to the samples, a single-step protein precipitation and a subsequent filtration were used for blood sample preparation. Analytes were separated under isocratic elution on a U-HPLC RP18 column with a total run time of 7 minutes. The mobile phase consisted of piperazine buffer (46.4 mM, pH = 9.8) and acetonitrile (68:32, vol/vol), which was delivered at a flow rate of 0.4 mL/min. Fluorescence excitation and emission wavelengths were 335 and 390 nm, respectively. Assay performance parameters were evaluated per FDA bioanalytical guidelines. The calibration curve was linear from 125 to 4000 ng/mL for HCQ. The lower limit of quantification was 10 ng/mL for all analytes. For HCQ, desethylchloroquine, and desethylhydroxychloroquine, accuracies and imprecisions ranged from -7.90% to 7.85% and 1.14% to 8.78%, respectively. A sensitive, accurate, and fast U-HPLC-fluorescent method was validated and successfully applied to quantify whole blood concentrations to perform therapeutic drug monitoring of HCQ in pediatric and adult lupus patients.


Ecotoxicity of arsenic contamination toward the soil enchytraeid Enchytraeus crypticus at different biological levels: Laboratory studies.
The ecotoxicity of arsenic (As) contamination toward small soil fauna living in soil pore water such as soil enchytraeids has rarely been studied but is important in the assessment of soil pollution. Here, the endpoints of As ecotoxicity to Enchytraeus crypticus were studied at three biological levels, i.e., individual (morphology and body tissue As concentrations), population (survival, reproduction and growth) and cell biochemistry (antioxidant enzymes CAT, POD and SOD and peroxidation malondialdehyde MDA). Contact filter paper tests without soil and single species tests with OECD artificial and field soils were conducted. Arsenic contamination resulted in severe morphological pathologies in E. crypticus and the symptoms and degree of damage increased gradually with increasing As concentration and exposure time up to 48 h. The abnormal morphological effects occurred before the impairment of fecundity. The population endpoints responded to the As concentration and the EC50 values increased in the following sequence: reproduction, juvenile body weight, adult body weight, juvenile length and adult length. Changes in biochemistry parameters were induced rapidly and changed with increasing As concentration and exposure time. The activity peak values of enzymes were 3-5 times higher and the activity maximum values of MDA were 1-3 time higher than their controls. The sensitivity of enzyme activities was generally much higher than that of MDA and CAT generally showed the highest enzyme activity. The results indicate that As contamination can be very harmful to soil enchytraeids and the endpoints of the ecotoxicity tests of soil enchytraeids can be used to complement existing soil As assessment systems or may be used alone for the assessment of soil As pollution.


Sonography of placental abnormalities: a pictorial review.
Often overlooked during routine ultrasound evaluation of a normal pregnancy, the placenta forms the biologic interface between the mother and fetus and is critical to fetal growth and development. Malformations in development, positioning, and vascularity can have profound implications for both maternal and fetal well-being. As such, a judicious inspection of the placenta is warranted as an integral part of every screening or emergent prenatal ultrasound. Herein, we present a pictorial review of a variety of placental pathologic conditions including abnormalities in positioning, adherence, vascularity, and hemorrhage as well as potential peri-placental masses and gestational trophoblastic disease, all of which are readily encountered in a busy emergency radiology practice.


Effect of counterions on the physical properties of l-arginine in frozen solutions and freeze-dried solids.
The objective of this study was to elucidate the physical properties of L-arginine and various counterion combinations in frozen aqueous solutions and in freeze-dried solids. L-Arginine remains amorphous in the highly concentrated non-ice phase in frozen solutions with a Tg (glass transition temperature of maximally freeze-concentrated solutes) of -41.4 degrees C. Some acids and salts (e.g., H3PO4, H2SO4, HNO3, and NaH2PO4) raised the Tg , whereas others (e.g., HCl, CH3COOH, HCOOH, Na2HPO4, and NaCl) had little effect or lowered the L-arginine Tg . Co-lyophilization with phosphoric acid also raised the glass transition temperature (Tg) of amorphous freeze-dried L-arginine solids. Arginine-H3PO4 combinations exhibited properties that led to either the stabilization or destabilization of a model protein (lactate dehydrogenase: LDH) during freeze-drying, depending on their concentration ratios. Fourier-transform infrared (FT-IR) and diffusion reflectance near-infrared (NIR) spectra indicated the presence of interactions between the amino and/or guanidyl groups of L-arginine and phosphate ions in the amorphous freeze-dried cakes. It was postulated that the interaction between L-arginine and the multivalent counterions, as well as an increase in hydrogen bonding network, reduced the mobility of molecules in the frozen solutions and freeze-dried solids.


Meroterpenoid enantiomers from Ganoderma sinensis.
Zizhines A-F (1-6), six pairs of new meroterpenoid enantiomers and a known meroterpenoid (7) were isolated from the fruiting bodies of Ganoderma sinensis. The structures and absolute configurations of the new substances were assigned by spectroscopic and computational methods. All the compounds apart from 7 were evaluated for their inhibition on extracellular matrix component (fibronectin) generation by using TGF-β1-induced rat kidney tubular epithelial cells. Although none of them was found to be active in these cells, the present findings add new facets for the chemistry of Ganoderma.


Scaleable purification of adenovirus vectors.
Adenovirus vectors currently are being evaluated in gene delivery studies ranging from prophylactic vaccination to therapeutic gene therapy. The quantity of purified virus required for these studies necessitate that purification methods must shift from classical density gradient ultracentrifugation to scaleable approaches. A methodology is described herein using batch centrifugation, tangential flow ultrafiltration, and chromatography to purify adenovirus particles at a scale of approximately 10(13) viral particles. This method has been demonstrated to easily scale an additional 40-fold. While purification of human adenovirus type 5 is exemplified, modifications are suggested for the purification of other serotypes.


Predicting diabetic nephropathy in type 2 diabetic patients using machine learning algorithms.
Global healthcare centers today are challenged by the dramatic increase in the prevalence of diabetes. Also, complications from diabetes are a major cause of deaths worldwide. One of the most frequent microvascular complications in diabetic patients is diabetic nephropathy (DN) which is the leading cause of death and end-stage renal disease (ESRD). Despite the different risk factors for DN identified in previous research, machine learning (ML) methods can help determine the importance of the predictors and prioritize them. The main focus of this investigation is on predicting the incidence of DN in type 2 diabetic mellitus (T2DM) patients using ML algorithms. Demographic information, laboratory results, and examinations on 6235 patients with T2DM covering a period of 10 years (2011-2020) were extracted from the electronic database of the Diabetes Clinic of the Imam Khomeini Hospital Complex (IKHC) in Iran. Recursive feature elimination using the cross-validation (RFECV) technique was then used with the three classification algorithms to select the important risk factors. Next, five ML algorithms were used to construct a predictive model for DN in T2DM patients. Finally, the results of the algorithms were evaluated according to the AUC criteria and the one with the best performance in terms of prediction and classification was selected. The 18 DN risk factors selected by RFECV were age, diabetes duration, BMI, SBP, hypertension, retinopathy, ALT, CVD, 2HPP, uric acid, HbA1c, waist-to-hip ratio, cholesterol, LDL, HDL, FBS, triglyceride, and serum insulin. Based on a 10-fold cross-validation, the best performance among the five classification algorithms was that of the random forest with 85% AUC. This investigation validates the known risk factors for DN and emphasizes the importance of controlling the blood pressure, weight, cholesterol, and blood sugar of T2DM patients. In addition, as an example of the application of ML approaches in medical predictions, the findings of this study demonstrate the advantages of using these techniques.


Metrizamide cisternography and computed tomography for the investigation of pituitary lesions.
Metrizamide cisternography and computed tomography (CT) have been performed on 22 patients suspected of having pituitary or suprasellar lesions, using a low dose of metrizamide. These patients would otherwise have been subjected to air encephalography. The technique is described and the results are presented. The lesions demonstrated included empty sellae and suprasellar extensions of pituitary tumours. We also identified those patients in whom there was no suprasellar extension of a pituitary tumour. The diagnostic information required was obtained in all cases by a combination of the two techniques and air encephalography was avoided in all but one case. The side effects were mild and no serious complications were encountered. We consider this combination of methods to be very useful for the investigation of pituitary lesions.


New Approaches to Regulatory Innovation Emerging During the Crucible of COVID-19 : In Responding to a Global Health Crisis, Industry is Discovering New, Efficient Ways of Meeting Objectives.
The urgency and impact of the ongoing COVID-19 pandemic are changing global drug development and regulatory processes. The need for speed to understand the virus and develop new vaccines, medicines, and therapies for patients has provided unprecedented learning opportunities and revealed how the pharmaceutical industry can improve upon traditional processes. To stay competitive while remaining compliant with agency regulations and guidance, companies need to implement new process/tools that allow for more flexible work models, consider expanding the use of decentralized/hybrid trials, and capitalize on the use of real-world evidence (RWE) and cloud-based data systems. In addition, regulatory agencies should retain the agility exhibited during current reviews of potential new therapies, applying this momentum to other areas of unmet medical need. Further, agencies should consider a globally acceptable application platform. This article, by the Pharmaceuticals' Head of Regulatory Affairs at Bayer AG, examines how impacts of the COVID-19 crisis will continue beyond the pandemic period to the benefit of patients, drug developers, regulators, clinicians, and caregivers.


Combinations of modifiable lifestyle behaviours in relation to colorectal cancer risk in Alberta's Tomorrow Project.
The objective of this study was to identify distinct clusters of individuals that exhibit unique patterns of modifiable lifestyle-related behaviours and to determine how these patterns are associated with the risk of developing colorectal cancer (CRC). The study consisted of 26,460 participants and 267 CRC cases from Alberta's Tomorrow Project. Exploratory latent class analysis of risk behaviours (obesity, physical inactivity, meat consumption, smoking, alcohol consumption, and fruit and vegetable consumption) and Cox proportional hazard models were utilized. Seven unique behavioural groups were identified, where the risk of CRC was 2.34 to 2.87 times greater for high risk groups compared to the low risk group. Sex-specific models identified higher risk groups among men (Hazard Ratios [HRs]: 3.15 to 3.89) than among women (HRs: 1.99 to 2.19). Targeting groups defined by clustering of behaviours could potentially lead to more effective prevention of CRC on a population level.


Combining geospatial analyses to optimize quality reference values of rare earth elements in soils.
High pedological and geological variability can trigger the formation of REE hotspots, causing a need to optimize the establishment of quality reference values (QRVs). Thus, we determined the background concentrations of REEs in the soils of an emerging Brazilian state and used a combination of Moran's I and indicator kriging to identify REE hotspots and determine QRVs. A total of 100 composite soil samples was collected at a 0.20 m depth to establish background concentrations, QRVs, and spatial distribution and to elaborate probability maps for REEs. The QRVs established for soils were the following (mg kg-1): La (27.21), Ce (57.26), Pr (10.49), Nd (24.29), Sm (4.75), Eu (0.90), Gd (4.22), Tb (0.82), Dy (1.54), Ho (0.38), Er (1.23), Yb (1.07), Lu (0.24), Y (10.65), and Sc (3.70). It was possible to draw attention to the Northwest and Southwest regions of the Rio Grande do Norte (RN) state, due to the formation of REE hotspots, indicated by Moran's I, and a high tendency to exceed the QRVs, confirmed by the indicator kriging. The high background concentrations and geochemical patterns for REEs showed that a single QRV for each REE and the entire state can neglect specific environmental characteristics and misrepresent the natural geochemistry of the soil. Thus, specific QRVs were established to optimize the monitoring of natural REE values by identifying hotspot areas. The criteria established here may be useful for other groups of potentially toxic elements, provided that observations meet the requirements of the spatial autocorrelation and kriging analyses. Graphical abstract.


Treatment of early caries lesions using biomimetic self-assembling peptides--a clinical safety trial.
We previously reported that a rationally designed biomimetic self-assembling peptide, P₁₁-4, nucleated hydroxyapatite de novo and was apparently capable of in situ enamel regeneration following infiltration into caries-like lesions. Our present aim was to determine the safety and potential clinical efficacy of a single application of P₁₁-4 on early enamel lesions. Fifteen healthy adults with Class V 'white spot' lesions received a single application of P₁₁-4. Adverse events and lesion appearances were recorded over 180 days. Patients treated with P₁₁-4 experienced a total of 11 adverse events during the study, of which two were possibly related to the protocol. Efficacy evaluation suggested that treatment with P₁₁-4 significantly decreased lesion size (p = 0.02) after 30 days and shifted the apparent progression of the lesions from 'arrested/progressing' to 'remineralising' (p <0.001). A highly significant improvement in the global impression of change was recorded at day 30 compared with baseline (p <0.001). The results suggest that treatment of early caries lesions with P₁₁-4 is safe, and that a single application is associated with significant enamel regeneration, presumably by promoting mineral deposition within the subsurface tissue.


P2X7 receptors regulate engulfing activity of non-stimulated resting astrocytes.
We previously demonstrated that P2X7 receptors (P2X7Rs) expressed by cultured mouse astrocytes were activated without any exogenous stimuli, but its roles in non-stimulated resting astrocytes remained unknown. It has been reported that astrocytes exhibit engulfing activity, and that the basal activity of P2X7Rs regulates the phagocytic activity of macrophages. In this study, therefore, we investigated whether P2X7Rs regulate the engulfing activity of mouse astrocytes. Uptake of non-opsonized beads by resting astrocytes derived from ddY-mouse cortex time-dependently increased, and the uptaken beads were detected in the intracellular space. The bead uptake was inhibited by cytochalasin D (CytD), an F-actin polymerization inhibitor, and agonists and antagonists of P2X7Rs apparently decreased the uptake. Spontaneous YO-PRO-1 uptake by ddY-mouse astrocytes was reduced by the agonists and antagonists of P2X7Rs, but not by CytD. Down-regulation of P2X7Rs using siRNA decreased the bead uptake by ddY-mouse astrocytes. In addition, compared to in the case of ddY-mouse astrocytes, SJL-mouse astrocytes exhibited higher YO-PRO-1 uptake activity, and their bead uptake was significantly greater. These findings suggest that resting astrocytes exhibit engulfing activity and that the activity is regulated, at least in part, by their P2X7Rs.


Detection of HBV-DNA in liver biopsy and serum: its significance in the selection of hepatitis B patients for antiviral therapy.
We have characterized the hepatitis B virus state in liver and serum of 38 HBsAg-positive chronic hepatitis patients (chronic active hepatitis (CAH), 19; chronic persistent hepatitis (CPH), 7; cirrhosis, 11; 'normal' carrier, 1) and 21 HBsAg-negative patients. Episomal HBV-DNA in liver, without detectable integrated HBV-DNA sequences, concomitant with HBV-DNA in serum was found in 19 HBeAg-positive patients (CAH, 16; CPH, 1; cirrhosis, 2). Integrated sequences were detected in 13 HBsAg-positive HBeAg-negative patients (CAH, 1; CPH, 5; cirrhosis, 7) and in 1 HBsAg-negative patient. Episomal HBV-DNA and integrated HBV-DNA sequences were observed simultaneously in 1 HBsAg-positive HBeAg-negative CPH patient and in 4 HBsAg-positive cirrhosis patients (2 HBeAg-positive, 2 HBeAg-negative). The presence of HBcAg immunofluorescence corresponded well with that of episomal HBV-DNA. Antiviral therapy is advised for HBsAg-positive chronic hepatitis patients with episomal HBV-DNA, irrespective of the presence of integrated sequences. Since the presence of episomal HBV-DNA in liver is not always accompanied by the presence of serum HBV-DNA, procedures for the selection and evaluation of patients for antiviral therapy should be extended by characterization of the HBV-DNA state in liver biopsies.


Photodynamic therapy using 5-aminolaevulinic acid for the treatment of dysplasia in Barrett's oesophagus.
5-Aminolaevulinic acid (ALA) is the naturally occurring metabolic precursor of an endogenously formed photosensitiser, protoporphyrin IX. It is used topically to treat benign and malignant skin disorders by a process called photodynamic therapy (PDT). Recently, data are emerging on its systemic use in the treatment of dysplasia in Barrett's oesophagus. To investigate the use of ALA-PDT for the treatment of dysplasia and early cancer in Barrett's oesophagus. A systematic literature review and synopsis is given. ALA is an attractive alternative to the currently approved photosensitiser (porfimer sodium) due to its oral route of administration, shorter generalised skin photosensitivity period and lower rate of stricture formation. The studies presented demonstrate that ALA-PDT is both safe and effective for the treatment of dysplasia and early cancer in Barrett's oesophagus.


Carbonate hydroxyapatite and silicon-substituted carbonate hydroxyapatite: synthesis, mechanical properties, and solubility evaluations.
The present study investigates the chemical composition, solubility, and physical and mechanical properties of carbonate hydroxyapatite (CO3Ap) and silicon-substituted carbonate hydroxyapatite (Si-CO3Ap) which have been prepared by a simple precipitation method. X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), X-ray fluorescence (XRF) spectroscopy, and inductively coupled plasma (ICP) techniques were used to characterize the formation of CO3Ap and Si-CO3Ap. The results revealed that the silicate (SiO4(4-)) and carbonate (CO3(2-)) ions competed to occupy the phosphate (PO4(3-)) site and also entered simultaneously into the hydroxyapatite structure. The Si-substituted CO3Ap reduced the powder crystallinity and promoted ion release which resulted in a better solubility compared to that of Si-free CO3Ap. The mean particle size of Si-CO3Ap was much finer than that of CO3Ap. At 750°C heat-treatment temperature, the diametral tensile strengths (DTS) of Si-CO3Ap and CO3Ap were about 10.8 ± 0.3 and 11.8 ± 0.4 MPa, respectively.


Seagrass ecosystem adjacent to mangroves store higher amount of organic carbon of Andaman and Nicobar Islands, Andaman Sea.
This study quantified the organic carbon (Corg) stocks in Thalassia hemprichii meadows that are (i) adjacent to mangroves (MG), and (ii) without mangroves (WMG), in tropical Andaman and Nicobar Islands (ANI) of India. In the top 10 cm of the sediment, Corg content was 1.8-fold higher at the MG sites than the WMG sites. The total Corg stocks (sediment + biomass) in the 144 ha of seagrass meadows at MG sites (988.74 ± 138.77 Mg C) was 1.9-fold higher than in 148 ha of WMG sites. Protection and management of T. hemprichii meadows of ANI can lead to emission avoidance of around 5447.33 (MG; 3595.12 + WMG: 1852.21) tons of CO2. The social cost of the carbon stocks in these T. hemprichii meadows is around US$ 0.30 and 0.16 million at the MG and WMG sites, respectively, showcasing the importance of ANI's seagrass ecosystems as nature-based solutions for climate change mitigation.


TRIM3 facilitates estrogen signaling and modulates breast cancer cell progression.
Breast cancer is the most common cancer in women worldwide. More than 70% of breast cancers are estrogen receptor (ER) alpha positive. Compared with ER alpha-negative breast cancer, which is more aggressive and has a shorter survival time, ER alpha-positive breast cancer could benefit from endocrine therapy. Selective estrogen receptor modulators, such as tamoxifen, are widely used in endocrine therapy. Approximately half of ER alpha-positive breast cancer patients will eventually develop endocrine resistance, making it a major clinical challenge in therapy. Thus, decoding the throughput of estrogen signaling, including the control of ER alpha expression and stability, is critical for the improvement of breast cancer therapeutics. TRIM3 and ER alpha protein expression levels were measured by western blotting, while the mRNA levels of ER alpha target genes were measured by RT-PCR. A CCK-8 assay was used to measure cell viability. RNA sequencing data were analyzed by Ingenuity Pathway Analysis. Identification of ER alpha signaling activity was accomplished with luciferase assays, RT-PCR and western blotting. Protein stability assays and ubiquitin assays were used to detect ER alpha protein degradation. Ubiquitin-based immunoprecipitation assays were used to detect the specific ubiquitination modification on the ER alpha protein. In our current study, we found that TRIM3, an E3 ligase, can promote ER alpha signaling activity and breast cancer progression. TRIM3 depletion inhibits breast cancer cell proliferation and migration, while unbiased RNA sequencing data indicated that TRIM3 is required for the activity of estrogen signaling on the -genome-wide scale. The immunoprecipitation assays indicated that TRIM3 associates with ER alpha and promotes its stability, possibly by inducing K63-linked polyubiquitination of ER alpha. In conclusion, our data implicate a nongenomic mechanism by which TRIM3 stabilizes the ER alpha protein to control ER alpha target gene expression linked to breast cancer progression. Our study provides a novel posttranslational mechanism in estrogen signaling. Modulation of TRIM3 expression or function could be an interesting approach for breast cancer treatment. Video abstract.


Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study.
We studied the influence of biochemical and virologic patterns and interferon on the outcome of anti-HBe positive chronic hepatitis B in 164 (103 treated) consecutive patients, followed-up prospectively for a mean of 6 years (21 months-12 years). Histology, biochemical and virologic profiles were characterized by monthly monitoring during the first 12 months of follow-up. Thereafter patients underwent blood and clinical controls every 4 and 6 months, respectively. Cirrhosis at follow-up histology or end stage complications of cirrhosis served as end points for the analysis of factors influencing disease progression in patients with baseline chronic hepatitis or cirrhosis, respectively. Disease progression was associated with older age (P<0.001), absence of previous HBeAg history (P=0.017) and higher serum HBV-DNA levels (P=0.009) (more frequently observed in unremitting disease profile, P=0.012) at multivariate analysis. Fluctuations of IgM anti-HBc levels (associated with disease exacerbations, P=0.045) correlated with end stage complications in cirrhotics (P=0.011). Disease improved in 14.6 and 1.6% of treated and untreated patients, respectively (P=0.015): interferon slowed disease progression (P<0.001). The outcome of anti-HBe positive chronic hepatitis B is worsened by older age and persistent viral replication or hepatitis exacerbations in chronic hepatitis or in cirrhotic patients, respectively. Interferon reduces by 2.5-folds disease progression.


Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease.
One hallmark of Alzheimer disease is the accumulation of amyloid beta-peptide in the brain and its deposition as plaques. Mice transgenic for an amyloid beta precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter (PDAPP mice), which overexpress one of the disease-linked mutant forms of the human amyloid precursor protein, show many of the pathological features of Alzheimer disease, including extensive deposition of extracellular amyloid plaques, astrocytosis and neuritic dystrophy. Active immunization of PDAPP mice with human amyloid beta-peptide reduces plaque burden and its associated pathologies. Several hypotheses have been proposed regarding the mechanism of this response. Here we report that peripheral administration of antibodies against amyloid beta-peptide, was sufficient to reduce amyloid burden. Despite their relatively modest serum levels, the passively administered antibodies were able to enter the central nervous system, decorate plaques and induce clearance of preexisting amyloid. When examined in an ex vivo assay with sections of PDAPP or Alzheimer disease brain tissue, antibodies against amyloid beta-peptide triggered microglial cells to clear plaques through Fc receptor-mediated phagocytosis and subsequent peptide degradation. These results indicate that antibodies can cross the blood-brain barrier to act directly in the central nervous system and should be considered as a therapeutic approach for the treatment of Alzheimer disease and other neurological disorders.


Triamcinolone Acetonide Produced by Bacillus velezensis YEBBR6 Exerts Antagonistic Activity Against Fusarium oxysporum f. sp. Cubense: A Computational Analysis.
Fusarium oxysporum f. sp. cubense is one of the most severe and threatening pathogens of bananas, causing "Panama wilt" worldwide. Confrontation assay of Foc antagonistic bacterial endophyte, Bacillus velezensis YEBBR6, with the Foc and GC-MS profiling of excised agar from the zone of inhibition, led to the unveiling of secondary metabolites produced by the endophyte. To refine the probable antifungal compounds among the numerous biomolecules formed during their di-trophic interaction with the pathogen, fungal protein targets were modeled, and docking studies (AutoDock Vina module of the PyRx 0.8 server) were done with all the compounds. Triamcinolone acetonide exhibited the most excellent affinity for the protein targets among the compounds studied. It had a maximum binding affinity of 11.2 kcal/mol for XRN2 (5' → 3'). Further, the protein-ligand complex formation kinetics was done through Molecular Dynamic Simulation studies. Graphs for the RMSD, RMSF, Rg, potential energy, and SASA were generated, and the values during the simulation period suggested the stability of the biomolecule as a complex with the protein. This indicated Triamcinolone acetonide's potential ability to act as a functional disrupter of the target protein and likely an antifungal molecule. Further, the biomolecule was tested for its activity against Foc by screening in the wet lab through the poisoned plate technique, and it was found to be fully inhibitory to the growth of the pathogen at 1000 ppm.


A multicomponent positive psychology group intervention for people with severe psychiatric conditions; a randomized clinical trial.
The aim of this study was to examine the efficacy and effectiveness of a theory-driven multicomponent positive psychology intervention to improve well-being for individuals with severe psychiatric conditions (SPCs) in comparison with treatment as usual (TAU). This intervention moves away from the traditional psychiatric perspectives that focused on symptoms and deficits, promoting a broader view of outcomes such as noncritical self-acceptance, strengths, and positive relationships with others, among other things. A two-arm randomized and outcome-blinded trial with pre-post and 6-month follow-up evaluations was conducted to assess the intervention. A total of 141 participants were allocated to either the experimental condition or the waiting list group receiving their TAU. A mixed-effect model was used to examine the efficacy of the intervention and a repeated-measures Student's t-test for the follow-up effectiveness analysis. The intervention protocol was highly acceptable for participants, showing very high participant satisfaction as well as good attendance and adherence rates. At the end of the group therapy, participants reported a significant improvement in self-acceptance and environmental mastery and, these changes were maintained in the follow-up assessment after 6 months. The results of this randomized control trial provide further evidence supporting that positive psychology approaches can be a powerful complementary strategy to promote more comprehensive psychiatric rehabilitation services for people with SPCs. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Parotid fat contents in healthy subjects evaluated with iterative decomposition with echo asymmetry and least squares fat-water separation.
To evaluate the effectiveness of three fat measurement methods for parotid glands in healthy subjects, with or without metallic dental implants. The institutional review board approved this study, with informed consent obtained from 114 volunteers undergoing magnetic resonance (MR) imaging at 1.5 T. Fat-saturated (FS) and non-fat-saturated (NFS) fast spin-echo T1-weighted imaging (T1 method), FS and NFS T2-weighted periodically rotated overlapping parallel lines with enhanced reconstruction fast spin-echo imaging (T2 method), and gradient-echo imaging with fat-water separation using iterative decomposition with echo asymmetry and least squares (IDEAL) method were used to derive parotid fat contents. Two raters examined the homogeneity of fat saturation to determine whether parotid fat quantification was successful, with the success rate in the 114 subjects recorded for each protocol. In subjects whose fat quantification was successful with all three imaging methods, linear regression was used to analyze the correlation between any pair of the three parotid fat content measurement methods. Success rates in parotid fat measurements by using T1, T2, and IDEAL methods were 87.7% (100 of 114), 87.7% (100 of 114), and 100% (114 of 114), respectively. The means of measured parotid fat contents revealed significant differences (P < .001) between any pair of the three measurement methods. The parotid fat contents measured with the three methods were significantly correlated with each other between any pair of combinations. The IDEAL method provided a high success rate for parotid fat measurements, even in subjects with metallic dental implants.


Is there a volume-quality relationship within the independent treatment centre sector? A longitudinal analysis.
The number of independent treatment centres (ITCs) has grown substantially. However, little is known as to whether the volume-quality relationship exists within this sector and whether other possible organisational factors mediate this relationship. The aim of this study is to gain a better understanding of such possible relationships. Data originate from the Dutch Health and Youth Care Inspectorate (IGJ) and the Dutch Patients Association. We used longitudinal data from 4 years (2014-2017) including three different quality measures: 1) composite of structural and process indicators, 2) postoperative infections, and 3) patient satisfaction. We measured volume by the number of invasive treatments. We adjusted for three important organisational characteristics: (1) size of workforce, (2) chain membership, and (3) ownership status. For statistical inference, random effects analysis was used. We also ran several robustness checks for the volume-quality relationship, including a fractional logit model. ITCs with higher volumes scored better on structure, process and outcome (i.e. postoperative infections) indicators compared to the low-volume ITCs - although only marginally on outcome. However, ITCs with higher volumes do not have higher patient satisfaction. There is a decreasing marginal effect of volume - in other words, an L-shaped curve. The effect of the intermediating structural factors on the volume-quality relationship (i.e. workforce size, chain membership and ownership status) is less clear. Our findings suggest that chain membership has a negative influence on patient satisfaction. Furthermore, for-profit providers scored better on the Net Promoter Score. Our study shows with some certainty that the quality of care in low-volume ITCs is lower than in high-volume ITCs as measured by structural, process and outcome (i.e. postoperative infection) indicators. However, the size of the effect of volume on postoperative infections is small, and at higher volumes the marginal benefits (in terms of lower postoperative infections) decrease. In addition, volume is not related to patient satisfaction. Furthermore, the association between the structural intermediating factors and quality are tenuous.


Acquired encephalopathy associated with carnitine deficiency after cefditoren pivoxil administration.
We describe a 47-year-old woman who presented with palinopsia and subacute altered mental change after cefditoren pivoxil administration. The patient showed characteristic clinical manifestations of hypocarnitinemia, which affected her state of consciousness and she had radiologic findings that revealed metabolic encephalopathy with cytotoxic edema in the right occipital area and intracranial hemorrhages in right occipital and left frontal areas. Follow-up imaging after oral carnitine supplementation demonstrated complete resolution of the bilateral frontal subcortical T2 high-intensity lesions. Carnitine deficiency due to cefditoren pivoxil treatment may present as metabolic encephalopathy in adults. This possibility should be considered with the differential diagnosis of encephalopathies, and carnitine levels should be checked in patients treated with cefditoren pivoxil.


Unravelling the Different Reaction Pathways for Low Temperature CO Oxidation on Pt/CeO2 and Pt/Al2O3 by Spatially Resolved Structure-Activity Correlations.
Spatially resolved operando HERFD-XANES (high energy resolution fluorescence detected X-ray absorption near edge structure) complemented by CO concentration gradient profiles along the catalyst bed (SpaciPro) was used to identify the dominant reaction paths for the low and high temperature CO oxidation on Pt/CeO2 and Pt/Al2O3. At low temperatures, features associated with CO adsorption on Pt were found for both catalysts. During the oxidation reaction light-off, the evolution of the spectral and catalytic profile diverged along the catalyst bed. The CO oxidation rate was high on Pt/CeO2 from the beginning of the catalyst bed with CO being adsorbed on Pt, whereas low CO conversion due to strong CO poisoning was found on Pt/Al2O3. This correlation of the CO concentration gradient with unique insight by HERFD-XANES gave direct proof of the crucial contribution of the Pt-CeO2 perimeter sites overcoming the CO self-inhibition effect at low temperatures.


Insect capture and growth of the insectivorous Drosera rotundifolia L.
Rates of insect capture increased with leaf area in the insectivorous plant Drosera rotundifolia, and growth of new leaves was related to insect capture. However, increased leaf growth was counterbalanced by leaf abscission which was in turn related to insect capture and leaf growth. Leaf loss equaled leaf growth in plants having natural rate of insect capture. A large proportion of the nitrogen gain from prey was stored in the hypocotyl; it was estimated from feeding experiments that about 24% to 30% of the nitrogen stored in the hypocotyl after winter originated from insect capture in the previous season. The effect of insect capture is discussed in relation to the life cycle of Drosera.


Risks of intestinal cancer in Crohn's disease.
This review describes the principal features of the three studies that have established clearly that patients in the U.S.A. or the U.K. who have long-standing (greater than 7 years) Crohn's colitis are at increased risk (up to 20-fold) of developing large bowel cancer. In addition, it emphasizes that there are no data on the extent of this risk in patients in other countries, and also that the magnitude of the risk of cancer of the small intestine in Crohn's disease is unknown. Despite the increased incidence of large bowel cancer in long-standing Crohn's colitis in the U.S.A. or the U.K., the total number of such patients is small, as is the number in which the colonic carcinoma will occur. However, careful supervision is advised for the small group at risk, despite the limitations of current methods for the early detection of cancer of the large intestine.


Daily update of motor predictions by physical activity.
Motor prediction, i.e., the ability to predict the sensory consequences of motor commands, is critical for adapted motor behavior. Like speed or force, the accuracy of motor prediction varies in a 24-hour basis. Although the prevailing view is that basic biological markers regulate this circadian modulation, behavioral factors such as physical activity, itself modulated by the alternation of night and day, can also regulate motor prediction. Here, we propose that physical activity updates motor prediction on a daily basis. We tested our hypothesis by up- and down-regulating physical activity via arm-immobilization and high-intensity training, respectively. Motor prediction was assessed by measuring the timing differences between actual and mental arm movements. Results show that although mental movement time was modulated during the day when the arm was unconstrained, it remained constant when the arm was immobilized. Additionally, increase of physical activity, via release from immobilization or intense bout of training, significantly reduced mental movement time. Finally, mental and actual times were similar in the afternoon in the unconstrained condition, indicating that predicted and actual movements match after sufficient amount of physical activity. Our study supports the view that physical activity calibrates motor predictions on a daily basis.


In vivo self-reactivity of mononuclear cells to T cells and macrophages exposed to HgCl2.
Mercuric chloride induces in Brown-Norway rats a polyclonal activation of B cells resulting in a lymphoproliferation and in the production of autoantibodies. Experiments were performed to test the role of cells modified by HgCl2 in the induction of B cell proliferation by using the popliteal lymph node assay. Spleen cells, T cells and peritoneal macrophages exposed in vivo or in vitro to HgCl2 induced a proliferation of T and B cells in the draining popliteal lymph node. Spleen cells from Lewis rats who received HgCl2 were ineffective. These data suggest that modified cells could trigger autologous lymphocyte subsets and be responsible for autoimmunity induced by HgCl2.


Doppler echocardiography.
We describe concepts important in the clinical application of continuous wave, pulsed wave, and color Doppler flow imaging. In the second half of this manuscript, the application of these tools in pediatric echocardiography is addressed.


[Auricular acupuncture in patients with detrusor overactivity: a pilot study].
Patients suffering from overactive bladder/detrusor overactivity (OAB/DO) seem to benefit from body acupuncture. The study was carried out to test if auricular acupuncture (AAP), which is supposed to show an immediate effect, can also cause urodynamic changes. The OAB/DO condition was verified by means of cystometry in 14 patients. These patients were subjected to bilateral AAP after cystometry, a second cystometry was performed 20-30 min later and data were analyzed using the Wilcoxon rank-sum test. None of the patients showed local or systemic complications but DO persisted in all patients and urge urinary incontinence (UUI) persisted in 85 % (11/13) of patients. Intravesical pressure decreased after AAP but without reaching statistical significance. In 22 % (2/9) of patients residual volume (RV) disappeared completely while 78 % (7/9) of patients showed significant reduction of RV. This study could not prove a significant influence of AAP on DO or UUI; therefore an immediate effect of AAP in patients suffering from OAB/DO seems to be unlikely. Further studies are necessary to evaluate the effect of repeated AAP sessions on urodynamic changes.


Efficacy of antimicrobial-impregnated silicone sections from penile implants in preventing device colonization in an animal model.
To assess, in an animal study, the efficacy of minocycline/rifampin-impregnated silicone sections of pump bulbs from penile implants in preventing device colonization by Staphylococcus aureus. Infection constitutes a very serious complication of penile implants. Minocycline/rifampin-impregnated and control silicone pump bulb sections from penile implants were each inoculated with about 10(3) to 10(4) colony-forming units of S. aureus. After 8 hours of incubation with bacteria at room temperature, the test devices were allowed to dry for 30 minutes, and then subcutaneously implanted in the backs of rabbits. Eleven rabbits each received a total of six devices. The wounds were sutured, and the rabbits were monitored daily, then killed at 2 days after surgery. In vitro zones of inhibition against S. aureus by the minocycline/rifampin-impregnated and control devices were also determined. All of the six tested antimicrobial-impregnated devices but none of the control devices produced zones of inhibition in vitro against S. aureus (mean zone of inhibition by antimicrobial-impregnated devices of 23 mm). The antimicrobial-impregnated devices retrieved from rabbits were sixfold less likely than were the control devices to be colonized with S. aureus (2 [6%] of 33 versus 11 [33%] of 33, respectively; P = 0.011). The results of this animal study indicate that minocycline/rifampin-impregnated pump bulb sections from penile implants provide antimicrobial activity in vitro against S. aureus and protect against staphylococcal colonization of devices implanted for 2 days in animals.


Idiopathic normal pressure hydrocephalus; treatment and outcome in the Region of Southern Denmark.
Idiopathic normal pressure hydrocephalus (iNPH) is a prevalent and cost-effective disease to treat. However, no gold standard exists to confidently select patients for shunt surgery. The aim of this study was to investigate how patients with suspected iNPH at our center responded to shunt surgery and to compare pre-surgical variables between shunt responders and non-responders. Preoperative baseline characteristics, MRI and/or CT scans were retrospectively obtained in 55 shunt-operated iNPH patients. Evan's index, third ventricle diameter, dilation of Sylvian fissures, tight high convexity, focal sulci, callosal angle, Rout value, MMSE score, CSF phosphorylated tau, CSF tau, and a combination of radiologic findings (DESH score) were compared according to whether or not patients expressed satisfactory response to shunt treatment at 1-month follow-up. Multiple logistic regression controlling for age and gender (α = 0.05) showed that tight high convexity, dilated Sylvian fissures, focal sulci, CSF tau, CSF phosphorylated tau, and DESH score correlated significantly with subjective shunt response at 1-month follow-up. In line with current literature, Shunt responders had lower levels of CSF tau and CSF phosphorylated tau compared to non-responders. While commonly used radiologic markers are of value, they can be aggregated into a score for better selection of shunt candidates.


Sociodemographic Drivers of Donor and Recipient Gender Disparities in Living Kidney Donation in Australia.
Females account for 60% of all living kidney donors worldwide. We defined the proportion of female to male donors for living donor kidney transplantation stratified by recipient gender, and explored the factors associated with female kidney donation. Data from the ANZDATA (Australian and New Zealand Dialysis and Transplantation) and ANZOD (Australian and New Zealand Organ Donor) registries (2002-2019) were used to identify the sociodemographic characteristics and their interactions associated with living donation from female donors. We derived the predicted probabilities from adjusted logistic models using marginal means. Of 3523 living donor pairs, 2203 (63%) recipients were male, and 2012 (57%) donors were female. Male recipients were more likely to receive kidneys from female donors than male donors. Donor and recipient sex association was modified by donor-recipient relationship (P < 0.01), with sensitivity analysis suggesting that spousal donor-recipient pairs drive this interaction. Older recipients residing in regional or remote areas were more likely to receive kidneys from female donors compared with those from major cities (aged ≥60 years: 0.67 [0.63-0.71] vs. aged <60 years: 0.57 [0.53-0.60]). Factors associated with female donation include recipient sex, with spousal donors contributing to the interaction between recipient gender and donor-recipient relationship. Recipient age and location of residence have interactive effects on the likelihood of living donor transplantation from female donors.


Sequence of stannous and sodium fluoride solutions to prevent enamel erosion.
Investigate the timing of stannous (SnF2) and sodium fluoride (NaF) application with and without salivary pellicle to prevent enamel erosion. Human buccal molar enamel samples (n=120, REC ref 12/LO/1836) were randomly assigned to three groups testing SnF2 and NaF basic fluoride formulation and commercial mouthrinses with and without the presence of human saliva. Samples were randomly allocated to 2 subgroups: immersion in either fluoride for 1 min either before or after citric acid immersion (0.3%, pH 3.2, 10 min), and the cycle repeated 5 times. For human saliva group, samples were immersed in 80 ml of natural saliva for 24 h prior to the experiment. Analysis was done using non-contacting profilometry and microhardness change. Data were not normal and were log transformed. A linear model tested statistical differences between the groups. SnF2 application before erosion statistically reduced step height compared to application after erosion for all groups (solutions: 6.5 μm (±1.2), 7.5 μm (±0.8); p=0.01, mouthrinses: 3.2 μm (±0.6), 4.2 μm (±0.7); p<0.0001, mouthrinses with saliva: 2.5 μm (±0.4), 3.1 μm (±0.6); p=0.002, before and after respectively). In contrast, application of NaF before erosion increased step height compared to application after, but this was only statistically significant for the saliva group (before: 5.6 μm (±0.3) and after: 4.9 μm (±0.3); p=0.023). Presence of saliva increased microhardness change (p<0.0001). Within this group, greatest microhardness change was observed when SnF2 was applied before erosion and when NaF was applied after erosion (SnF2: 156.6KHN (±32.8), 123KHN (±20.1); p=0.02. NaF: 119.5KHN (±33.5), 218KHN (±24.9), before, and after respectively). SnF2 reduced step height formation overall when compared to NaF, but particularly when applied before citric acid immersion. In contrast, NaF reduced step height when applied after citric acid immersion, but only in the presence of saliva. Stannous fluoride can be recommended over sodium fluoride to patients at risk of dental erosion and is optimally applied before erosion occurs. If sodium fluoride is to be used in the presence of saliva it is optimally applied after erosion has occurred.


Influence of enzymatic phospholipid cleavage on the permeability of the erythrocyte membrane. I. Transport of non-electrolytes via the lipid domain.
In order to further elucidate the influence of membrane lipids on transport via the lipid domain of the erythrocyte membrane, simple non-electrolyte diffusion was investigated by tracer flux measurements in whole cells after cleavage of up to 65% of phosphatidylcholine or sphingomyelin by phospholipase A2 from Naja naja, or by sphingomyelinase. A new type of labelled model non-electrolyte was used in this study, readily available by reacting a non-labelled thiol with a labelled alkylating SH-reagent. In spite of the marked enzymatic alterations of the membrane, which lead to the occurrence of large quantities of lysophosphatidylcholine and long chain fatty acids, or of ceramide, the permeability of the lipid domain remained unaffected. This finding is very surprising, since the physical properties of the lipid phase (microviscosity, structure of the membrane interface) are likely to be perturbed in the enzyme-treated membranes. Sphingomyelinase-treated cells undergo stomatocytic shape changes followed by deep invaginations of the membrane and finally endocytosis, while phospholipase A2-treated cells essentially maintain their normal shape.


Neonatal opiate withdrawal and rooming-in: a retrospective analysis of a single center experience.
To evaluate our treatment of neonatal abstinence syndrome (NAS), our experience with rooming-in of opiate-dependent mothers and to examine the influence of rooming-in on short term outcome of infants exposed to opiates in utero. Retrospective analysis of maternal and perinatal data of newborn infants with NAS treated between 2004 and 2011 in a level 3 academic children's hospital in a German metropolis. Therapy of NAS and duration of therapy, length of hospital stay and costs were considered in particular. Data of 77 newborns with NAS were analysed. 84.6% of infants were treated with tincture of opium (79.2% rooming-in, 88.7% no rooming-in). Infants with rooming-in (n=24) had a 17% shorter median duration of therapy [27.0 d (IQR 24.0-38.5), no rooming-in (n=53) 32.5 d (IQR 25.0-54.5)] and shorter median length of hospital stay [33.0 d (IQR 28.0-48.0), no rooming-in 41.5 d (IQR 30.3-54.5)]. Demographic data was comparable between newborns and mothers with or without rooming-in. Costs were median 13 457 € (IQR 8 967-17 494)/patient [rooming-in: 9 547 € (IQR 7 024-16 135), no rooming-in: 14 486 € (IQR 9 479-19 352)]. Rooming-in in NAS should be encouraged to shorten duration of therapy and length of hospital stay and thereby reduce costs. No major problems arose in the care of the infants with NAS when parents stayed with their infants but close monitoring of the newborn and strict instruction of parents are required.


[Study of inhibitory effect of extracts from Actinidia arguta on human carcinoma of esophagus cells].
To study the inhibitory effect of extracts from Actinidia arguta by n-butyl alcohol on human carcinoma of esophagus cells (Eca-109) and Its mechanism. MTT colonmetric assay was used to examine the growth inhibitory of concentration-effect (1 microg/ml, 10 microg/ml,100 microg/ml) and time-effect (24 h, 48 h, 72 h) of extracts from Actinidia arguta by n-butyl alcohol on Eca-109 cells. TUNEL test were performed to observe the apoptosis induced by the extracts (1 microg/ml, 10 microg/ml, 100 microg/ml) on Eca-109 cells. The inhibitory effect of the extracts on Eca-109 cells increased in a dose-time Manner and the highest rate of inhibition was 87.2%. The extracts could significantly induce apoptosis of Eca-109 cells, but in control group, apoptosis wasn't observed. The extracts from Actinidia arguta by n-butyl alcohol have good inhibitory effect on Eca-109 cells.


Comparison of the effects of the intestinal permeation enhancers, SNAC and sodium caprate (C10): Isolated rat intestinal mucosae and sacs.
SNAC and C10 are intestinal permeation enhancers (PEs) used in formulations of peptides for oral delivery in clinical trials. Our aims were to compare their: (i) mechanism of action in isolated rat intestinal mucosae mounted in Ussing chambers and in non-everted gut sacs, (ii) effects on mucosa integrity in those models and also in in situ intra-jejunal instillations and (iii) interactions with intestinal mucus. SNAC increased the apparent permeability coefficient (Papp) of the paracellular marker, FITC-dextran 4000 (FD4), across isolated rat gastric mucosae in concentration-dependent fashion, whereas C10 did not, while both reduced the transepithelial electrical resistance (TEER). In isolated jejunal and colonic mucosae, both agents increased the Papp of [14C]-mannitol and FD4 whereas C10 but not SNAC reduced TEER. 20 mM SNAC was required to achieve the efficacy of 10 mM C10 in jejunal and colonic mucosae. In isolated non-everted jejunal and colonics sacs, FD4 flux increases were observed in the presence of both PEs. Histology of mucosae revealed that both PEs induced minor epithelial damage to the mucosa at concentrations that increased fluxes. Jejunal tissue withstood epithelial damage in the following order: intra jejunal in situ instillations > jejunal sacs > isolated jejunal mucosae. Both PEs modulated viscoelastic properties of porcine jejunal mucus without altering rheological properties. In conclusion, SNAC and C10 are reasonably efficacious PEs in rat intestinal tissue with common overall mechanistic features. Their potency and toxic potential are low, in agreement with clinical trial data.


Intra- and inter-observer reproducibility of shoulder laxity tests: Comparison of the drawer, modified drawer and load and shift tests.
Conventional tests of shoulder laxity have been shown to have poor reliability due to the difficulty in palpating the subtle movements of the shoulder joint beneath the musculature. Modified drawer test that is performed while the soft tissues surrounding the shoulder are loosened has been proposed to facilitate glenohumeral joint movement and improve reliability. We hypothesised that the modified drawer test would have an improved intra- and inter-observer reproducibility in comparison to the drawer and load and shift tests. Correlation of shoulder laxity measured by these tests with generalized joint laxity was also assessed. Forty healthy volunteers underwent bilateral shoulder examination in the clinic using the three tests for anterior and posterior laxity assessment by a consultant shoulder surgeon and a resident. The examination was repeated three months later by the same examiners in the same cohort. Intra- and inter- observer reproducibility was calculated using Kappa values. The correlation of shoulder with generalized joint laxity was also investigated. The modified drawer test showed significantly improved intra-observer reproducibility compared to the drawer test, but not to the load and shift (κ = 0.173, -0.042, and 0.009, respectively). There were no significant differences in the inter-observer reproducibility between the three tests (κ = 0.054, 0.055, and 0.056, respectively). Moderate correlation was noted between shoulder and generalized joint laxity when modified drawer test was used (r = 0.417). The modified drawer test improves intra- but not inter- observer reproducibility compared to the drawer test. Shoulder laxity assessed by the modified test correlated to generalized joint laxity. The modified drawer test has an improved reproducibility and correlation to generalized joint laxity over the conventional tests.


Surface engineering of Al2O3 nanotubes by ureasolysis method for activating persulfate degradation of antibiotics.
Though ecofriendly, pure Al2O3 has never been used for activation of peroxodisulfate (PDS) to degrade pollutants. We report the fabrication of Al2O3 nanotubes by ureasolysis method for efficient activating PDS degradation of antibiotics. The fast ureasolysis in aqueous AlCl3 solution produces NH4Al(OH)2CO3 nanotubes, which are calcined to porous Al2O3 nanotubes, and the release of ammonia and carbon dioxide engineers the surface features of large surface area, numerous acidic-basic sites and suitable Zeta potentials. The synergy of these features facilitates the adsorption of the typical antibiotics ciprofloxacin and PDS activation, which is proved by experiment results and density functional theory simulation. The proposed Al2O3 nanotubes can catalyze 92-96% degradation of 10 ppm ciprofloxacin within 40 min, with chemical oxygen demand removal of 65-66% in aqueous, and 40-47% in whole including aqueous and catalysts. Ciprofloxacin at high concentration, other fluoroquinolones and tetracycline can also be effectively degraded. These data demonstrate the Al2O3 nanotubes prepared by the nature-inspired ureasolysis method has unique features and great potentials for antibiotics degradation.


Mechanism of ET(A)-receptor stimulation-induced increases in intracellular Ca2+ in SK-N-MC cells.
The mechanism underlying endothelin-1 (ET-1)-induced increases in intracellular Ca2+ concentrations in the human neuroblastoma cell-line SK-N-MC was investigated. ET-receptor agonists increased inositol phosphate (IP)-formation (assessed as accumulation of total [3H]-IPs in [3H]-myo-inositol prelabelled cells) and intracellular Ca2+ (assessed by the FURA-2 method) with an order of potency: ET-1 > sarafotoxin 6b (S6b)> ET-3 = S6c; the ETA-receptor antagonist BQ-123 inhibited both responses with apparent pKi-values of 8.3 and 8.6, respectively, while the ETB-receptor antagonist BQ-788 did not. Pretreatment of the cells with pertussis toxin (PTX, 500 ng ml(-1) overnight) reduced ET-1-induced Ca2+ increases by 46+/-5%, but rather enhanced ET-1-induced IP-formation. Chelation of extracellular Ca2+ by 5 mM EGTA did not affect ET-1-induced IP-formation. However, in the presence of 5 mM EGTA or SKF 96365, an inhibitor of receptor mediated Ca2+ influx (1.0-3.0 x 10(-5) M) ET-1-induced Ca2+ increases were inhibited in normal, but not in PTX-treated cells. [125I]-ET-1 binding studies as well as mRNA expression studies (by RT-PCR) detected only ETA-receptors whereas expression of ETB-receptor mRNA was marginal. ET-1 (10(-8) M) inhibited isoprenaline-evoked cyclic AMP increases; this was antagonized by BQ-123, not affected by BQ-788 and abolished by PTX-treatment. We conclude that SK-N-MC cells contain a homogeneous population of ETA-receptors that couple to IP-formation and inhibition of cyclic AMP formation. Stimulation of these ETA-receptors increases intracellular Ca2+ by at least two mechanisms: a PTX-insensitive IP-mediated Ca2+ mobilization from intracellular stores and a PTX-sensitive influx of extracellular Ca2+.


Laboratory tests on the impact of superabsorbent polymers on transformation and sorption of xenobiotics in soil taking 14C-imazalil as an example.
Due to water scarcity, the agricultural production in arid areas is dependent on a sustainable irrigation management. In order to optimize irrigation systems, the application of superabsorbent polymers (SAP) as soil amendments, frequently studied within the last years, may be an appropriate measure to enhance the water holding capacity and the plant-available water in poor arable soils. These persistent polymers are also able to reduce heavy metal and salt stress to crops by accumulating those inorganic compounds. However, the impact of SAP on fate and behavior of organic xenobiotics in soil is unknown. Therefore, transformation and sorption of the model substance 14C-imazalil were monitored without and with SAP amendment in silty sand and sand soil under laboratory conditions. Within the 100-d incubation period, the transformation of 14C-imazalil was not substantially affected by the SAP amendment even though the microbial activity increased considerably. In the silty sand soil, extractable residues dropped from 90% to 45% without and from 96% to 46% with SAP amendment. Non-extractable residues continuously increased up to 49% and 35% while mineralization reached 6% and 5%, respectively. In the sand soil, characterized by its lower microbial activity and lower organic carbon content, extractable residues merely dropped from 99% to 81% and from 100% to 85% while non-extractable residues increased from 2% to 14% and 1% to 10%, respectively. Mineralization was lower than 2%. The increased microbial activity, usually promoting transformation processes of xenobiotics, was compensated by the enhanced sorption in the amended soils revealed by the increase of soil/water distribution coefficients (Kd) of 26 to 42 L kg(-1) for the silty sand and 6 to 25 L kg(-1) for the sand, respectively.


TH1/TH2 cytokine profile of the immune response in limb component transplantation.
The purpose of this study was to define the cytokine secretion pattern during limb allograft rejection and to determine its correlation to differential tissue antigenicity of limb allograft components. Twenty-five C57Bl/6 mice (H-2Kb) were randomized to six groups. The experimental groups were recipients of vascularized Balb/c mice (H-2Kd) allografts consisting of skin, muscle, whole limb, or limb with the skin removed or nonvascularized nerve allografts. The unmodified rejection response was studied by histology, flow cytometry, and ELISPOT assay to quantify IFN-gamma (Th1) and IL-4 (Th2) production. The greatest Th1 response was seen in the recipients of allografts composed of skin (973.3 +/- 93 spots/million spleen cells; mean +/- SEM), followed by whole limb (961.3 +/- 86/million), nerve (613.3 +/- 245/million), limb with skin removed (483 +/- 246/million), and then muscle (460 +/- 234/million). Recipients of skin, whole limb, and nerve allografts had the highest IFN-gamma:IL-4 ratios, or greatest Th1 deviation, of 3.1 +/- 0.4, 3.0 +/- 0.2, and 2.9 +/- 0.6, respectively. These were significantly greater than those that received muscle (0.9 +/- 0.3) and limb allografts with skin removed (1.0 +/- 0.4) (p < 0.05). The skin component produced the greatest Th1 activation of the immune response and appears to be a critical component of the overall antigenicity of the whole limb allograft, as evidenced by the Th2 shift seen when the skin was removed. Muscle produced the least Th1 differentiation, with nerve being intermediate.


Evaluating Odisha's COVID-19 response: from quiet confidence to a slippery road.
Odisha is among handful of states that is at the forefront of India's fight against a rapidly growing COVID-19 pandemic. Even before the national lockdown was imposed by the Union government on March 24, Odisha was only state to have imposed partial lockdown in select districts. It was also first state that took proactive steps to ramp up its health care system particularly having a COVID-19 hospital with intensive care units (ICUs) on public-private partnership mode. Importantly, Odisha was among few states to have created a COVID-19 hospital at each district in record time. In addition, the state took many proactive measures including setting up a taskforce to oversee the COVID-19 response, put up a critical information and communication system with daily press briefings among others to stay on the top of pandemic management. But come May when the migrants rush unfolded, the state experienced steady surge in infections as the pandemic started spreading to relatively dense rural hinterlands. The migrant endowed districts like Ganjam became the epicentres of new spread and the state is struggling to rein on the growing pandemic. What led to the state losing its initial gains? How did the state manage it so ably in the initial period and what led to the surge? What are the unique features of Odisha's pandemic response? Is there an Odisha Model as claimed by several observers? (Patnaik et al. in The Wire, 2020) This paper endeavours to chronicle Odisha's response to COVID-19 in relations to policies and programmes initiatives and actors and dynamics shaping these responses? Key aim is to identify strengths and experience of the eastern state which has a long and credible record of fighting natural disasters.


Children's health and play in rural Nepal.
A study of morbidity and mortality in a peasant village in Nepal describes chronic malnutrition and endemic infectious disease. More than one-third of village children between the ages of 1 and 5 die. Those who survive apparently pursue a spontaneous strategy of maximizing their physical growth potential by minimizing the expenditure of energy in play. This raises the possibility that psychological, social and motor development is impaired. It is found, however, that while less time and energy is devoted to play, the pattern of play that does occur is similar to that of healthier peasant children in other times and places. It is therefore probable that maturational levels of attainment are not impaired, but it is urgent that this assumption be further investigated.


Redox regulation in stem-like cancer cells by CD44 variant isoforms.
Increasing evidence indicates that several types of solid tumor are hierarchically organized and sustained by a distinct population of cancer stem cells (CSCs). CSCs possess enhanced mechanisms of protection from stress induced by reactive oxygen species (ROS) that render them resistant to chemo- and radiotherapy. Expression of CD44, especially variant isoforms (CD44v) of this major CSC marker, contributes to ROS defense through upregulation of the synthesis of reduced glutathione (GSH), the primary intracellular antioxidant. CD44v interacts with and stabilizes xCT, a subunit of the cystine-glutamate transporter xc(-), and thereby promotes cystine uptake for GSH synthesis. Given that cancer cells are often exposed to high levels of ROS during tumor progression, the ability to avoid the consequences of such exposure is required for cancer cell survival and propagation in vivo. CSCs, in which defense against ROS is enhanced by CD44v are thus thought to drive tumor growth, chemoresistance and metastasis. Therapy targeted to the CD44v-xCT system may therefore impair the ROS defense ability of CSCs and thereby sensitize them to currently available treatments.


Impact of long-COVID on health-related quality of life in Japanese COVID-19 patients.
The empirical basis for a quantitative assessment of the disease burden imposed by long-COVID is currently scant. We aimed to inform the disease burden caused by long-COVID in Japan. We conducted a cross sectional self-report questionnaire survey. The questionnaire was mailed to 526 eligible patients, who were recovered from acute COVID-19 in April 2021. Answers were classified into two groups; participants who have no symptom and those who have any ongoing prolonged symptoms that lasted longer than four weeks at the time of the survey. We estimated the average treatment effect (ATE) of ongoing prolonged symptoms on EQ-VAS and EQ-5D-3L questionnaire using inverse probability weighting. In addition to symptom prolongation, we investigated whether other factors (including demography, lifestyle, and acute severity) were associated with low EQ-VAS and EQ-5D-3L values, by multivariable linear regression. 349 participants reported no symptoms and 108 reported any symptoms at the time of the survey. The participants who reported any symptoms showed a lower average value on the EQ-VAS (69.9 vs 82.8, respectively) and on the EQ-5D-3L (0.85 vs 0.96, respectively) than those reporting no symptoms considering the ATE of ongoing prolonged symptoms. The ATE of ongoing prolonged symptoms on EQ-VAS was - 12.9 [95% CI - 15.9 to - 9.8], and on the EQ-5D-3L it was - 0.11 [95% CI - 0.13 to - 0.09], implying prolonged symptoms have a negative impact on patients' EQ-VAS and EQ-5D-3L score. In multivariable linear regression, only having prolonged symptoms was associated with lower scores (- 11.7 [95% CI - 15.0 to - 8.5] for EQ-VAS and - 0.10 [95% CI - 0.13 to - 0.08] for EQ-5D-3L). Due to their long duration, long-COVID symptoms represent a substantial disease burden expressed in impact on health-related quality of life.


Rectal cancer surgery: does low volume imply worse outcome-a single surgeon experience.
The centralisation of rectal cancer management to high-volume oncology centres has translated to improved oncological and survival outcomes. We hypothesise that individual surgeon caseload, specialisation, and experience may be as significant in determining oncologic and postoperative outcomes in rectal cancer surgery. A prospectively maintained colorectal surgery database was reviewed for patients undergoing rectal cancer surgery between January 2004 and June 2020. Data studied included demographics, Dukes' and TNM staging, neoadjuvant treatment, preoperative risk assessment scores, postoperative complications, 30-day readmission rates, length of stay (LOS), and long-term survival. Primary outcome measures were 30-day mortality and long-term survival compared to national and international standards and best practice guidelines. In total, 87 patients were included (mean age: 66 years [range: 36-88]). The mean length of stay (LOS) was 16.5 days (SD 6.0). The median ICU LOS was 3 days (range 2-17). Overall, 30-day readmission rate was 16.4%. Twenty-four patients (26.4%) experienced ≥ 1 postoperative complication. The 30-day operative mortality rate was 3.45%. Overall 5-year survival rate was 66.6%. A significant correlation was observed between P-POSSUM scores and postoperative complications (p = 0.041), and all four variants of POSSUM, CR-POSSUM, and P-POSSUM scores and 30-day mortality. Despite improved outcomes seen with centralisation of rectal cancer services at an institutional level, surgeon caseload, experience, and specialisation is of similar importance in obtaining optimal outcomes within institutions.


Translating the essential drugs concept into the context of the year 2000.
The WHO Essential Drugs List (EDL) was first published in 1977. It must continue to be adapted to a changing world with new drugs, new indications and new diseases. Médecins sans Frontières is concerned that the eleventh list is outdated. The EDL should be stricter about its inclusion of first-line drugs and price should not be a criterion for excluding drugs from the list. Second-line drugs are complementary and their inclusion would in no way undermine the essential drugs concept. The EDL should be updated regularly and in a transparent manner, by an independent panel of experts chosen for their competence. Decisions regarding the inclusion of drugs in the list should be evidence-based, and the evidence should be available to the panel of experts long before their final sessions on updates to the EDL. The WHO not only has the challenge of defining a EDL that addresses today's epidemiological reality, but also a responsibility to assist countries in gaining access to these treatments.


Short-term effects of air pollution on hospitalization for acute lower respiratory infections in children: a time-series analysis study from Lanzhou, China.
Short-term exposure to air pollution is associated with acute lower respiratory infections (ALRI) in children. We investigated the relationship between hospitalization for ALRI in children and air pollutant concentrations from January 1, 2014 to December 31, 2020 in Lanzhou City. We collected data on air pollutant concentrations and children's hospitalization data during the study period. A time series regression analysis was used to assess the short-term effects of air pollutants on ALRI in children, and subgroup analyses and sensitivity analyses were performed. A total of 51,206 children with ALRI were studied, including 40,126 cases of pneumonia and 11,080 cases of bronchiolitis. The results of the study revealed that PM2.5, PM10, SO2 and NO2 were significantly associated with hospitalization for ALRI in children aged 0-14 years. For each 10 µg/m3 increase in air pollutant concentration in lag0-7, the relative risk of ALRI hospitalization in children due to PM2.5, PM10, SO2 and NO2 increased by 1.089 (95%CI:1.075, 1.103), 1.018 (95%CI:1.014, 1.021), 1.186 (95%CI:1.154. 1.219) and 1.149 (95%CI:1.130, 1.168), respectively. PM2.5, PM10, SO2 and NO2 short-term exposures were positively associated with ALRI, pneumonia and bronchiolitis hospitalizations in Lanzhou, China. Local governments should make efforts to improve urban ambient air quality conditions to reduce hospitalization rates for childhood respiratory diseases.


Mitophagy disorder mediates cardiac deterioration induced by severe hypoglycemia in diabetic mice.
Severe hypoglycemia is closely related to adverse cardiovascular outcomes in patients with diabetes; however, the specific mechanism remains unclear. We previously found that severe hypoglycemia aggravated myocardial injury and cardiac dysfunction in diabetic mice, and that the mechanism of damage was related to mitochondrial oxidative stress and dysfunction. Based on the key regulatory role of mitophagy in mitochondrial quality control, this study aimed to further explore whether the myocardial damage caused by severe hypoglycemia is related to insufficient mitophagy and to clarify their underlying regulatory relationship. After severe hypoglycemia, mitochondrial reactive oxygen species increased, mitochondrial membrane potential and ATP content decreased, and pathological mitochondrial damage was aggravated in the myocardium of diabetic mice. This was accompanied by decreased mitochondrial biosynthesis, increased fusion, and downregulated PTEN-induced kinase 1 (PINK1)/Parkin-dependent mitophagy. Treating diabetic mice with the mitophagy activator and polyphenol metabolite urolithin A activated PINK1/Parkin-dependent mitophagy, reduced myocardial oxidative stress and mitochondrial damage associated with severe hypoglycemia, improved mitochondrial function, alleviated myocardial damage, and ultimately improved cardiac function. Thus, we provide insight into the prevention and treatment of diabetic myocardial injury caused by hypoglycemia to reduce adverse cardiovascular outcomes in patients with diabetes.


Development of low blood glucose readings in nine non-diabetic patients treated with tumor necrosis factor-alpha inhibitors: a case series.
Treatment with various biological agents in disease states such as rheumatoid arthritis has been associated with multiple side effects. Whereas many of these are frequently reported in the literature, hypoglycemia, a possible side effect of tumor necrosis factor-alpha inhibitors, may be underpublicized. We report nine cases of non-diabetic Caucasian women who were between 29 and 68 years of age and who developed low glucose readings after treatment with tumor necrosis factor-alpha inhibitors. We provide a more detailed discussion of existing evidence of the role of tumor necrosis factor-alpha in the pathogenesis of inflammation and its impact on glycemic equilibrium. Physicians using tumor necrosis factor-alpha inhibitors in the treatment of various rheumatic and other autoimmune diseases should be aware of the potential for the development of glycemic disturbance in these patients. A further role of tumor necrosis factor-alpha inhibitors in the glycemic equilibrium warrants larger controlled trials in patients with and those without a history of diabetes.


Spray dried chitosan-EDTA superior microparticles as solid substrate for the oral delivery of amphotericin B.
The present investigation was aimed at synthesis of chitosan-EDTA superior microparticles (COECH) bearing high oil adsorbing and oil desorbing properties. These superior particles were prepared by thermal amide conjugation of COO(-) group of EDTA with NH2 group of chitosan employing spray-drying technique. The synthesis was optimized using 4(2) full factorial design. The particles showed high oil adsorbing capacity as well as oil desorbing capacity with enhanced dispersive components of surface free energy as compared to Aerosil 200. In addition, these COECH microparticles showed higher amphotericin B loading capacity, enhancement in the in vitro dissolution performance (12-fold) and produces nanoemulsion in the size range of 70-90 nm. Further, the results were in consonance with those observed during ex vivo performance. Thus, the findings revealed simple synthesis of COECH microparticles that showed superior properties of solid substrate for the development of amphotericin B nanoemulsion.


4,4'-Methyl-enebis[N-(2-hy-droxy-3-meth-oxy-benzyl-idene)-2,6-diiso-propyl-aniline].
In the V-shaped title Schiff base, C41H50N2O4, the planes of the benzene rings of the central di-phenyl-methane unit make a dihedral angle of 70.40 (5)°, whereas the planes of the neighbouring benzene and ortho-vanilin rings are twisted with respect to one another by dihedral angles of 75.76 (5) and 73.89 (6)°. The Schiff base displays intra-molecular O-H⋯N hydrogen bonds and weak inter-molecular C-H⋯O contacts.


Renal lineage cells as a source for renal regeneration.
The mammalian kidney is a highly complex organ, composed of various cell types within a unique structural framework. Nonetheless, in recent years, giant leaps in our understanding of nephrogenesis and the origin of new cells in the adult kidney have resulted in novel routes to regenerate damaged nephrons. While several strategies can be envisioned to achieve this aim, one common theme is the reliance on renal lineage cells, as extrarenal cells, such as bone marrow-derived cells, have been shown to be devoid of renal differentiation capacity. Herein, we will present the main motivation for the pursuit for cell-based therapies, which is the ever growing problem of chronic kidney disease (CKD), and discuss different strategies toward replenishing the damaged renal parenchyma. These include transplantation of fetal kidney grafts or fetal kidney stem cells, directed differentiation of pluripotent stem cells into kidney epithelia, establishment of renal progenitors from the adult kidney, and genetic reprogramming of mature kidney cells into a progenitor state. Taken together with novel techniques recapitulating the three-dimensional developmental environment, these advances are expected to take the field into a new era, bringing us closer than ever to the day when kidney stem cell-based therapy becomes a viable therapeutic option.


Increased high-frequency oscillations precede in vitro low-Mg seizures.
High-frequency oscillations (HFOs) in the range of > or = 80 Hz have been recorded in neocortical and hippocampal brain structures in vitro and in vivo and have been associated with physiologic and epileptiform neuronal population activity. Frequencies in the fast-ripple range (> 200 Hz) are believed to be exclusive to epileptiform activity and have been recorded in vitro, in vivo, and in epilepsy patients. Although the presence of HFOs is well characterized, their temporal evolution in the context of transition to seizure activity is not well understood. With an in vitro low-magnesium model of spontaneous seizures, we obtained extracellular field recordings (hippocampal regions CA1 and CA3) of interictal, preictal, and ictal activity. Recordings were subjected to power-frequency analysis, in time, by using a local multiscale Fourier transform. The power spectrum was computed continuously and was quantified for each epileptiform discharge into four frequency ranges spanning subripple, ripple, and two fast-ripple frequency bands. A statistically significant increasing trend was observed in the subripple (0-100 Hz), ripple (100-200 Hz), and fast-ripple 1 (200-300 Hz) frequency bands during the epoch corresponding to the transition to seizure (preictal to ictal). Temporal patterns of HFOs during epileptiform activity are indicative of dynamic changes in network behavior, and their characterization may offer insights into pathophysiologic processes underlying seizure initiation.


CT-functional diagnostics of the rotatory instability of upper cervical spine. 1. An experimental study on cadavers.
Twelve specimens of the upper cervical spine were functionally examined by using radiography, cineradiography and computerized tomographic (CT) scan. The range of rotation was measured from CT images after maximal rotations to both sides. The left alar ligament was then cut and the examination repeated. The alar and transverse ligaments could be differentiated on CT images in axial, sagittal, and coronal views. Rotation at occiput-atlas was 4.35 degrees to the right and 5.9 degrees to the left and at atlas-axis it was 31.4 degrees to the right and 33 degrees to the left. After one-sided lesion of the alar ligament, there was an overall increase of 10.8 degrees or 30% of original rotation to the opposite side, divided about equally between the occiput-atlas and the atlas-axis. It is concluded that a lesion (irreversible overstretching or rupture of alar ligaments) can result in rotatory hypermobility or instability of the upper cervical spine.


Novel Use of Nerve Branch to Sartorius as Donor for Intrapelvic Neurotization of the Sciatic Nerve and Its Contributions.
Sciatic nerve injuries are relatively infrequent but extremely disabling for the patient. As injury to this nerve is relatively infrequent, there is little about its repair in the literature, especially within the pelvis. Twelve adult embalmed cadavers (24 sides) underwent exposure of the anteromedial thigh, inguinal region, and pelvic cavity. The sartorius muscle was identified in the anterior thigh, and its nerve branches from the femoral nerve were isolated and traced proximally to the femoral nerve trunk. The isolated sartorius nerve branches were further traced to the pelvic part of the femoral nerve. Next, the lumbosacral plexus was dissected on the posterior aspect of the pelvis so that its constituent parts were seen and followed distally to also visualize the most proximal part of the sciatic nerve. The previously dissected nerve branches to sartorius were then transposed to these constituent parts, and the ability for a tension-free anastomosis between these 2 nerves was evaluated. The branches ranged in diameter from 1.89 to 3.1 mm (2.88 mm). The average length of the nerves was 17.3 cm. Transposition of these branches to all ventral rami of the lumbosacral plexus in the pelvis and proximal sciatic (intrapelvic) nerve was possible on all cadaveric sides. Our cadaveric study found that nerve branches to the sartorius muscle can be transposed intrapelvically to the lumbosacral plexus and could provide tension-free anastomoses for neurotization procedures in patients with nerve injury.


Video ambulatory EEG: A good alternative to inpatient video telemetry?
Video ambulatory EEG (V-AEEG) is a new technique which could add increased capacity for long term EEG monitoring to overstretched inpatient video telemetry (IPVT) services. We compare V-AEEG and IPVT for diagnostic efficacy, recording quality, patient acceptability and technologist time required. Forty-one V-AEEG and 64 IPVT adult patients were included. Patients were investigated to diagnose attacks or to obtain polysomnography (PSG) prior to multiple sleep latency test (MSLT). Number of attacks recorded, whether the diagnostic question was answered, quality of video and EEG recording and patients' preference for investigation at home or in hospital were noted. For V-AEEG patients, ease of procedure and extra technologist time required were recorded. Of patients investigated for diagnosis of attacks, 74% V-AEEG patients and 62% IPVT had typical attacks during the investigation. All PSGs were useful in interpreting the MSLTs. Diagnostic questions were answered by 73% V-AEEGs and 73% IPVTs. Quality of EEG and video recording was similar using V-AEEG and IPVT. Four patients had difficulty using V-AEEG equipment but diagnostic information was lost in only one. 5% of V-AEEG patients would have preferred hospital investigation but 45% of IPVT patients would have preferred home investigation. Extra technologist time for home visits (mean 2h) was required only for the first 7 patients. Video EEG recording quality and diagnostic efficacy from V-AEEG are similar to IPVT. V-AEEG is acceptable to most patients and does not require additional technical time. Hence, V-AEEG offers a convenient, economical alternative to IPVT.


Renal ischemic preconditioning: finally some good news for prevention of acute kidney injury.
Recent clinical trials of remote ischemic preconditioning offer hope that this well-validated experimental method of protecting tissues against ischemic injury will provide a more robust alternative to pharmaceutical prevention against cardiac and renal ischemic injury.


An alternative view of phospholipid phase behavior at the air-water interface. Microscope and film balance studies.
Pure-lipid films at the water interface have surface-pressures vs. area isotherms that are often interpreted as involving first-order phase transitions from a condensed region to a liquid-expanded region. Two phases are presumed to coexist in the intermediate part of the isotherm. We constructed a film balance that could be placed on the stage of an epifluorescence microscope. A dipalmitoyl phosphatidylcholine film containing a low concentration of a fluorescent lipid probe showed an inhomogeneous fluorescence distribution in the so-called liquid-expanded region of the isotherm. Only the intermediate and condensed regions could be prepared so as to be optically homogeneous below 25 degrees C. We investigated membrane flow and lateral lipid diffusion in the membrane on the trough. The isotherms and isochores were measured. The results require, at least, a modified description of the monolayer structure in various regions of the isotherms. The solid-condensed region corresponds to a gel phase of the lipids where there is no flow in the membrane, lateral diffusion is low, the compressibility is low, and the membrane is optically homogeneous. The "liquid-condensed/liquid-expanded" region appears to be a homogeneous membrane where lateral diffusion and membrane flow are both rapid. This is a region of high compressibility. The "liquid-expanded" region is not homogeneous as seen under the microscope, and the flow of the surface layer can be very fast.


Radical formation during the peroxidase catalyzed metabolism of carcinogens and xenobiotics: the reactivity of these radicals with GSH, DNA, and unsaturated lipid.
Radicals generated by the peroxidase catalyzed oxidation of a wide variety of substrates oxidize GSH, NADH, or arachidonate with accompanying oxygen activation. Substrates studied include carcinogens, drugs, or xenobiotics. The effectiveness of the various radicals is partly related to their one-electron oxidation potential. High redox potential radicals were particularly effective at oxidizing these biomolecules. Low redox potential radicals did not react with GSH, NADH, or arachidonate, but can directly activate oxygen to form hydroxyl radicals or undergo scission to carbon radicals. The hydroxyl and carbon radicals have a high redox potential and readily oxidize biomolecules. DNA strand breakage also occurs with some high redox potential radicals, but DNA did not react with low redox potential radicals. The extensive binding of xenobiotics to DNA in the peroxidase system was attributed to noncovalent binding by polymeric products or covalent binding by the two electron oxidation product (formed by radical dismutation or oxidation). The latter can cause alkali labile DNA strand breaks. GSH conjugate formation was also attributed to the two electron oxidation product. Radicals have been trapped in intact cells and oxygen activation or lipid peroxidation has been demonstrated but it is still not clear whether the associated GSH oxidation, DNA strand breakage and cytotoxicity is the result of direct action by radicals. Indirect enzymic mechanisms for free radical mediated DNA strand breakage and cytotoxicity are discussed.


Modulation of Radiation Doses and Chimeric Antigen Receptor T Cells: A Promising New Weapon in Solid Tumors-A Narrative Review.
Tumor behavior is determined by its interaction with the tumor microenvironment (TME). Chimeric antigen receptor (CART) cell therapy represents a new form of cellular immunotherapy (IT). Immune cells present a different sensitivity to radiation therapy (RT). RT can affect tumor cells both modifying the TME and inducing DNA damage, with different effects depending on the low and high doses delivered, and can favor the expression of CART cells. CART cells are patients' T cells genetically engineered to recognize surface structure and to eradicate cancer cells. High-dose radiation therapy (HDRT, >10-20 Gy/fractions) converts immunologically "cold" tumors into "hot" ones by inducing necrosis and massive inflammation and death. LDRT (low-dose radiation therapy, >5-10 Gy/fractions) increases the expansion of CART cells and leads to non-immunogenetic death. An innovative approach, defined as the LATTICE technique, combines a high dose in higher FDG- uptake areas and a low dose to the tumor periphery. The association of RT and immune checkpoint inhibitors increases tumor immunogenicity and immune response both in irradiated and non-irradiated sites. The aim of this narrative review is to clarify the knowledge, to date, on CART cell therapy and its possible association with radiation therapy in solid tumors.


Aging and atherosclerosis in human and nonhuman primates.
Atherosclerosis is a major age-related process and public health problem and its clinical manifestations (coronary heart disease [CHD] and cerebrovascular disease) continue to be responsible for approximately 50% of all deaths occurring annually. In addition, CHD is responsible for over 70 to 80% of deaths among men and women over 65 years old. As our population ages (35 million people over the age of 65 in the U.S. by the year 2030) and because of the increased morbidity and mortality associated with atherosclerosis, an understanding of the role of aging in the development of atherosclerosis is needed. Multiple risk factors such as smoking, gender, hypertension, and lipids contribute to the development of atherosclerosis. However, these risk factors in combination explain only about half of the individual variability in incidence of CHD, and it has been hypothesized that age-related conditions may play a role. To propectively evaluate the effects of age per se on atherosclerosis progression in humans would require observation over many years. Thus, animal models that are representative of both aging processes and atherosclerosis would be extremely valuable. As such, nonhuman primates have been used extensively in atherosclerosis research. However, studies that will specifically evaluate the role of aging per se in contributing to development of atherosclerosis in nonhuman primates have only recently been initiated. In this review, the contribution of nonhuman primates to atherosclerosis research will be discussed, as will the development of atherosclerosis in both human and nonhuman primates. In addition, a role for age-related conditions in atherosclerosis development in both human and nonhuman primates will be outlined.


Levels of tumor markers CEA/CA 19-9 in serum and peritoneal lavage predict postoperative recurrence in patients with pancreatic cancer.
This study aimed to clarify the usefulness of tumor markers from peritoneal lavage in selecting patients with a high risk of recurrence and predicting site-specific recurrence in patients with pancreatic cancer. The levels of serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 (sCEA/sCA 19-9) and paired peritoneal lavage CEA and CA 19-9 (pCEA/pCA 19-9) were measured in 90 patients with pancreatic cancer who underwent surgery. Using the cutoff values determined by maximally selected rank statistics for disease-free survival (DFS), the risk of recurrence and its patterns were evaluated in combination with different markers and different test specimens. In univariate and multivariate analysis, an elevated pCA 19-9 level (>1.3 U/mL) was an independent prognostic marker for both DFS (hazard ratio [HR], 2.391; P = .018) and overall survival (HR, 3.194; P = .033). Combination analyses contributed to further stratification of a very high risk of recurrence. Of the 58 patients with resectable pancreatic cancer who underwent curative resection, elevated pCA19-9 was also associated with inferior DFS and overall survival (OS). Patients with elevated pCA 19-9 levels were more likely to have an earlier onset of peritoneal recurrence than those with normal pCA 19-9 levels (P = .048, Gehan-Breslow-Wilcoxon test). pCA 19-9 is a reliable marker for predicting postoperative recurrence in patients with pancreatic cancer after surgery. Further risk stratification can be achieved by using combination assays. The combination of pCA 19-9 and sCA19-9 also serves as a predictor of recurrence site-specific recurrence.


Tempo of background sound and performance speed.
24 undergraduates performed a self-paced line tracing task. Fast music accelerated performance compared with slow music whereas the tempo of metronome tones did not affect performance.


Establishment and characterization of fibroblast cell lines from the skin of the Yangtze finless porpoise.
The Yangtze finless porpoise (Neophocaena phocaenoides asiaeorientalis), as the sole freshwater subspecies of N. phocaenoides, is endemic to the Yangtze River and its adjacent lakes. Its population has declined significantly over recent decades. In this study, we established a skin-derived finite fibroblast cell line of the Yangtze finless porpoise, named YFP-SF1, using primary cell culture methods, and an immortalized cell line, T-YFP-SF1, through co-transfection (GFP and SV40 T antigens) techniques. YFP-SF1 proliferated continuously with a minimum population doubling time of 31 h and exhibited age-dependent changes in growth rate. T-YFP-SF1 cells exhibited fibroblast morphology and were characterized by a shorter doubling time, higher attachment efficiencies, colony formation at a low seeding density, and growth in low serum concentrations. Anchorage independence and foci formation in the cell monolayer were observed from passage 36. The chromosome number of YFP-SF1 and T-YFP-SF1 remained stable at 2n = 44 in the early passages, and the viability of thawed cells remained above 90% after cryopreservation in liquid nitrogen. Taken together, we have established fibroblast cell lines of Yangtze finless porpoise for the first time, which might assist as an in vitro model for this endangered mammal.


Nuclear magnetic resonance and molecular modeling studies on O-beta-D-galactopyranosyl-(1----4)-O-beta-D-xylopyranosyl-(1----0)-L-se rine, a carbohydrate-protein linkage region fragment from connective tissue proteoglycans.
The solution conformation of O-beta-D-galactopyranosyl-(1----4)-O-beta-D-xylopyranosyl-(1----0)-L-ser ine (GXS), a carbohydrate-protein linkage region fragment from connective tissue proteoglycans, was investigated by two-dimensional NMR spectroscopy and molecular modeling calculations. Specifically, the 1H and 13C resonances were assigned by 2D-COSY and by 1H-13C heteronuclear correlation spectroscopy methods. 2D-NOESY was used to generate distance constraints between the galactose and xylose and between the xylose and serine residues. The 1H vicinal coupling constants for the sugars and the serine were also determined. A general molecular modeling methodology suitable for complex carbohydrates was developed. This methodology employed molecular dynamics and energy minimization procedures together with the application of inter-residue spatial constraints across the linkages derived from 2D-NOESY. The first step in this methodology is the generation of a wide variety of starting conformations that span the (phi, psi) space for each linkage. In the present study, nine such conformations were constructed for each linkage using the torsion angles phi and psi corresponding to the gauche+, gauche-, and trans configurations across each of the two bonds constituting the linkage. These conformations were subjected to a combined molecular dynamics/energy minimization refinement using the NOESY derived constraints as pseudoenergy functions. Families of conformations for the whole molecule were then constructed from the structures derived for each linkage. Characterization of GXS using this methodology identified a single family of conformations that are consistent with the solution phase NMR data on this molecule.


Mallet finger.
Mallet finger involves loss of continuity of the extensor tendon over the distal interphalangeal joint. This common hand injury results in a flexion deformity of the distal finger joint and may lead to an imbalance between flexion and extension forces more proximally in the digit. Mallet injuries can be classified into four types, based on skin integrity and the presence or absence of bony involvement. Although various treatment protocols have been proposed, splinting of the distal interphalangeal joint for 6 to 8 weeks has yielded good results while minimizing morbidity in the majority of patients. Surgical management may be considered for acute and chronic mallet lesions in patients who have failed nonsurgical treatment, are unable to work with the splint in position, or have a fracture involving more than one third of the joint surface.