2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline reduces glial loss and acute white matter pathology after experimental spinal cord contusion.
Focal microinjection of 2, 3-dihyro-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), an antagonist of the AMPA/kainate subclass of glutamate receptors, reduces neurological deficits and tissue loss after spinal cord injury. Dose-dependent sparing of white matter is seen at 1 month after injury that is correlated to the dose-related reduction in chronic functional deficits. To determine whether NBQX exerts an acute effect on white matter pathology, female, adult Spague Dawley rats were subjected to a standardized weight drop contusion at T-8 (10 gm x 2.5 cm) and NBQX (15 nmol) or vehicle (VEH) solution focally injected into the injury site 15 min later. At 4 and 24 hr, tissue from the injury epicenter was processed for light and electron microscopy, and the histopathology of ventromedial white matter was compared. The axonal injury index, a quantitative representation of axoplasmic and myelinic pathologies, was significantly lower in the NBQX group at 4 hr (2.7 +/- 0.24, mean +/- SE) and 24 hr (1.4 +/- 0.19) than in VEH controls (3.8 +/- 0.33 and 2.1 +/- 0.20, respectively). Counts of glial cell nuclei indicated a loss of at least 60% at 4 and 24 hr after injury in the VEH group compared with uninjured controls. NBQX treatment reduced this glial loss by half. Immunohistochemistry revealed that the spared glia were primarily oligodendrocytes. Thus, the chronic effects of NBQX in reducing white matter loss after spinal cord injury appear to be attributable to the reduction of acute pathology and may be mediated through the protection of glia, particularly oligodendrocytes.


Role of anti-polyethylene glycol (PEG) antibodies in the allergic reactions to PEG-containing Covid-19 vaccines: Evidence for immunogenicity of PEG.
A small fraction of recipients who receive polyethylene-glycol (PEG)-containing COVID-19 mRNA-LNP vaccines (Comirnaty and Spikevax) develop hypersensitivity reactions (HSRs) or anaphylaxis. A causal role of anti-PEG antibodies (Abs) has been proposed, but not yet been proven in humans.We used ELISA for serial measurements of SARS-CoV-2 neutralizing Ab (anti-S) and anti-PEG IgG/IgM Ab levels before and after the first and subsequent booster vaccinations with mRNA-LNP vaccines in a total of 291 blood donors. The HSRs in 15 subjects were graded and correlated with anti-PEG IgG/IgM, just as the anti-S and anti-PEG Ab levels with each other. The impacts of gender, allergy, mastocytosis and use of cosmetics were also analyzed. Serial testing of two or more plasma samples showed substantial individual variation of anti-S Ab levels after repeated vaccinations, just as the levels of anti-PEG IgG and IgM, which were over baseline in 98-99 % of unvaccinated individuals. About 3-4 % of subjects in the strongly left-skewed distribution had 15-45-fold higher values than the median, referred to as anti-PEG Ab supercarriers. Both vaccines caused significant rises of anti-PEG IgG/IgM with >10-fold rises in about ∼10 % of Comirnaty, and all Spikevax recipients. The anti-PEG IgG and/or IgM levels in the 15 vaccine reactors (3 anaphylaxis) were significantly higher compared to nonreactors. Serial testing of plasma showed significant correlation between the booster injection-induced rises of anti-S and anti-PEG IgGs, suggesting coupled anti-S and anti-PEG immunogenicity.Conclusions: The small percentage of people who have extremelevels of anti-PEG Ab in their blood may be at increased risk for HSRs/anaphylaxis to PEGylated vaccines and other PEGylated injectables. This risk might be further increased by the anti-PEG immunogenicity of these vaccines. Screening for anti-PEG Ab "supercarriers" may help predicting reactors and thus preventing these adverse phenomena.


Carbon dot induces tolerance to arsenic by regulating arsenic uptake, reactive oxygen species detoxification and defense-related gene expression in Cicer arietinum L.
The scientific and technological applications of one of the nanomaterials viz.; carbon dot (C-dots), having extraordinary properties, is becoming an emerging and ongoing research area in recent times. In the present study, we have evaluated the effectiveness of C-dots in reducing arsenic (As) toxicity by analyzing physiological, biochemical and molecular parameters in Cicer arietinum L. The results revealed that As decreased the germination rate, growth, biomass, and membrane stability of the cell to a significant extent. Further, As was taken up by the growing seeds which eventually caused cell death. Levels of reactive oxygen species (ROS), stress markers (malondialdehyde), activities of defensive enzymes (glutathione-S-transferase and pyrroline-5-carboxylate synthetase) and non-enzymatic antioxidant contents (proline and glutathione) were increased under As stress. Moreover, As treatment resulted in the up-regulation of expressions of NADPH oxidase and defense-related genes in Cicer arietinum L. However, application of C-dots along with As improved the germination and growth of Cicer arietinum L. Exogenous application of C-dots, enhanced the expressions of defense-related genes and, contents of proline and glutathione, thereby causing considerable reductions in ROS, and malondialdehyde levels. Overall, this study suggests the possible involvement of C-dots in lowering the toxic effects of As on biomass by reducing As uptake and, inducing the activities/gene expressions and contents of enzymatic and non-enzymatic antioxidants.


K-ras activation in non-small cell lung cancer in the dog.
To investigate the role of K-ras mutations in canine non-small cell lung cancer, we first determined the nucleotide sequence of the normal canine K-ras gene and then examined 21 canine lung tumors for activating K-ras mutations. Canine K-ras was analyzed by direct sequencing of polymerase chain reaction products generated with oligonucleotide primers derived from the human K-ras sequence. Four nucleotide differences were found between the canine and human K-ras sequence from position 5 to 211. The deduced amino acid sequence of the canine gene was identical to that of the human. Activated K-ras alleles were detected in 5 of the 21 canine lung tumors examined. The activating lesions were point mutations, predominantly in codon 12. Of the 14 adenocarcinomas examined, 2 (14%) had K-ras mutations. Two of 5 (40%) adenosquamous carcinomas and the only large cell carcinoma also contained activated alleles. The overall frequency of K-ras point mutation in non-small cell lung cancer (25%) is similar to that reported in human non-small cell lung cancer. We conclude that K-ras activation by point mutation is associated with, but not necessary for, non-small cell lung cancer development in the dog.


The fate of autologous fascia lata grafts in dogs.
The fate of tricuspid fascia lata valves and intracardiac grafts was studied morphologically, histologically, and biochemically in dogs. Severe degenerative changes occurring by 21 days were largely correlated with graft thickening due to gross endothelialization. A primary event in graft alteration was an initial loss of the indigenous fibroblast population as detected both microscopically and by autoradiography after pulse labeling with 14C-Nethylmaleimide. Using different isotopic labeling procedures, both the in vivo and in vitro graft degradation patterns demonstrated that a second early eft degradation was correlated in vivo with endothelialization and collagenase secretion by invasive cells.


Taking stock of business strategy and environment (sustainable development): evidence of disparities in research efforts and knowledge gaps - a bibliometric review.
Despite a spike in publications on business strategies focused on environmental awareness subjects in recent years, business-environment nexus research has recently been criticized for failing to address urgent issues like climate change. Therefore, we endeavored to do a trend analysis to find knowledge gaps in business studies related to the interaction between businesses, the environment, and society using bibliometric. Our study reveals that the area of business sustainability has evolved over the past decade from an internal conquest to include external indices like the environment, such as the debate over the relative merits of social and economic performance and the greening of management. Our findings point to three (3) main conclusions. (1) Many corporations see the urgency of green practices and have distinctive organizational sustainability and business strategies for environmental crises. (2) Business strategy and environment research are concentrated within developed countries to the neglect of developing countries. (3).The literature on business sustainability has not yet given much attention to the managerial implications and effects of climate change. Therefore, scholars must test and develop business-environmental nexuses to aid in sustainable production and consumption improvement.


Identification of monoclonal antibody variants involved in aggregate formation - Part 1: Charge variants.
Biopharmaceutical products contain conformational and chemical variants, that are typically well characterized regarding identity and activity. However, little is known about their self-interaction propensity and tendency to unfold, which are critical characteristics for drug stability and safety. This study aimed to separate and compare charge variants of a monoclonal antibody (mAb) and to identify aggregation prone species. We show a semi-preparative cation exchange method, that we developed to separate the individual acidic and basic variants from the naïve mAb. Additionally, we demonstrate, that the yield and purity of the fractionated charge species, extracted by that method, were sufficient for subsequent analysis of aggregate content, conformation stability and self-interaction. Our analysis revealed a differently behaving acidic variant and confirmed its increased aggregation propensity by molecular modeling. During a stability study, the potentially aggregation prone charge variant posed a limited risk to the drug substance (DS). We are the first to look at the stability of single charge variants of biopharmaceuticals, and thus present manufacturers and regulatory authorities with a method to enhance drug safety.


Responsive shape-shifting nanoarchitectonics and its application in tumor diagnosis and therapy.
Nanodrug delivery system has a great application in the treatment of solid tumors by virtue of EPR effect, though its success in clinics is still limited by its poor extravasation, small intratumoral accumulation, and weak tumor penetration. The shape of nanoparticles (NPs) greatly affects their circulation time, flow behavior, intratumoral amassing, cell internalization as well as tumor tissue penetration. Generally, short nanorods and 100-200 nm spherical nanocarriers possess nice circulation behaviors, nanorods and nanofibers with a large aspect ratio (AR) cumulate well at tumor sites, and tiny nanospheres/disks (< 50 nm) and short nanorods with a low AR achieve a favorable tumor tissue penetration. The AR and surface evenness of NPs also tune their cell contact, cell ingestion, and drug accumulation at tumor sites. Therefore, adopting stimulus-responsive shape-switching (namely, shape-shifting nanoarchitectonics) can not only ensure a good circulation and extravasation for NPs, but also and more importantly, promote their amassing, retention, and penetration in tumor tissues to maximize therapeutic efficacy. Here we review the recently developed shape-switching nanoarchitectonics of antitumoral NPs based on stimulus-responsiveness, demonstrate how successful they are in tumor shrinking and elimination, and provide new ideas for the optimization of anticancer nanotherapeutics.


In vitro chondrogenic differentiation of human mesenchymal stem cells in collagen microspheres: influence of cell seeding density and collagen concentration.
Given the inadequacies of existing repair strategies for cartilage injuries, tissue engineering approach using biomaterials and stem cells offers new hope for better treatments. Recently, we have fabricated injectable collagen-human mesenchymal stem cell (hMSC) microspheres using microencapsulation. Apart from providing a protective matrix for cell delivery, the collagen microspheres may also act as a bio-mimetic matrix facilitating the functional remodeling of hMSCs. In this study, whether the encapsulated hMSCs can be pre-differentiated into chondrogenic phenotype prior to implantation has been investigated. The effects of cell seeding density and collagen concentration on the chondrogenic differentiation potential of hMSCs have been studied. An in vivo implantation study has also been conducted. Fabrication of cartilage-like tissue micro-masses was demonstrated by positive immunohistochemical staining for cartilage-specific extracellular matrix components including type II collagen and aggrecan. The meshwork of collagen fibers was remodeled into a highly ordered microstructure, characterized by thick and parallel bundles, upon differentiation. Higher cell seeding density and higher collagen concentration favored the chondrogenic differentiation of hMSCs, yielding increased matrix production and mechanical strength of the micro-masses. These micro-masses were also demonstrated to integrate well with the host tissue in NOD/SCID mice.


The Italian Research Group for Gastric Cancer (GIRCG) guidelines for gastric cancer staging and treatment: 2015.
This article reports the guidelines for gastric cancer staging and treatment developed by the GIRCG, and contains comprehensive indications for clinical management, including radiological, endoscopic, surgical, pathological, and oncological paths.


Growth energetics in relation to temperature of the larvae of Rhopaea verreauxi (Coleoptera: Scarabaeidae).
Instantaneous energy budgets were constructed at a range of constant temperatures (7.5°-27.5°C) for the larval stages of the scarabaeid Rhopaea verreauxi. It was found that as larvae increased in size the temperature optima/maxima for the components of the energy budget shifted to lower temperatures. Also, as larvae increased in size the instantaneous assimilation efficiency (A/C) decreased and the temperature range over which energy could be assimilated narrowed. Within this narrowing range, temperature was found to have an increasingly greater influence upon A/C. This was attributed to its influence upon the post-consumption energetics processes rather than upon consumption itself. The instantaneous net production efficiency (P/A) also decreased with increasing body size. Also, the temperature range over which assimilated energy could be partitioned to growth production became narrower as body size increased. These findings are discussed in relation to those of other energy budget studies. Some comment is made on the importance of temperature acclimation in studies such as this, and on the relation of energetics conversion efficiencies to ectothermy and endothermy and to trophic status. It was concluded that in terms of instantaneous conversion efficiences R. verreauxi could be described as a typical ectothermic herbivore, a moderately efficient converter.


Flash-Induced High-Throughput Porous Graphene via Synergistic Photo-Effects for Electromagnetic Interference Shielding.
Porous 2D materials with high conductivity and large surface area have been proposed for potential electromagnetic interference (EMI) shielding materials in future mobility and wearable applications to prevent signal noise, transmission inaccuracy, system malfunction, and health hazards. Here, we report on the synthesis of lightweight and flexible flash-induced porous graphene (FPG) with excellent EMI shielding performance. The broad spectrum of pulsed flashlight induces photo-chemical and photo-thermal reactions in polyimide films, forming 5 × 10 cm2-size porous graphene with a hollow pillar structure in a few milliseconds. The resulting material demonstrated low density (0.0354 g cm-3) and outstanding absolute EMI shielding effectiveness of 1.12 × 105 dB cm2 g-1. The FPG was characterized via thorough material analyses, and its mechanical durability and flexibility were confirmed by a bending cycle test. Finally, the FPG was utilized in drone and wearable applications, showing effective EMI shielding performance for internal/external EMI in a drone radar system and reducing the specific absorption rate in the human body.


The interaction of biological factors with mechanical signals in bone adaptation: recent developments.
Mechanotransduction in bone is fundamental to proper skeletal development. Deficiencies in signaling mechanisms that transduce physical forces to effector cells can have severe consequences for skeletal integrity. Therefore, a solid understanding of the cellular and molecular components of mechanotransduction is crucial for correcting skeletal modeling and remodeling errors and designing effective therapies. In recent years, progress has been made on many fronts regarding our understanding of bone cell mechanotransduction, including subcellular localization of mechanosensitive components in bone cells, the discovery of mechanosensitive G-protein-coupled receptors, identification of new ion channels and larger pores (eg, hemichannels) involved in physical signal transduction, and cell adhesion proteins, among others. These and other recent mechanisms are reviewed to provide a synthesis of recent experimental findings, in the larger context of whole bone adaptation.


Repeatability and reproducibility of retinal thickness measurements with spectral-domain optical coherence tomography using different scan parameters.
To evaluate repeatability (test-retest) and reproducibility of retinal thickness measurements using spectral-domain optical coherence tomography with different densities of A-scans per B-scan and different frames per B-scan for real-time averaging. Twelve healthy subjects were analyzed by spectral-domain optical coherence tomography. Raster lines analysis with 19 B-scans over the examined area centered on the macula was performed. Images were acquired both in standard-density (768 A-scans/B-scan) and high-density (1,536 A-scans/B-scan) modalities. Moreover, images were acquired using 2 and 20 frames/B-scan for real-time averaging. Each analysis was repeated twice to test for repeatability. Intersession repeatability was good for all studied analysis protocols, with Lin concordance correlation coefficient values ranging between 0.88 and 1.00. Reproducibility assessment showed consistent retinal thickness measurements using variable scan density, with Bland-Altman limits of agreement of -6 μm to 6 μm in the central area. Reproducibility assessment showed consistent retinal thickness measurements using different number of frames used in the real-time averaging process, with Bland-Altman limits of agreement of -8 μm to 4 μm in the central area. Spectral-domain optical coherence tomography is a very reliable tool for central retinal thickness assessment. Changes in the number of A-scans/B-scan and in frames used for real-time averaging do not affect repeatability and reproducibility.


Evaluation of deep convolutional neural networks for automatic classification of common maternal fetal ultrasound planes.
The goal of this study was to evaluate the maturity of current Deep Learning classification techniques for their application in a real maternal-fetal clinical environment. A large dataset of routinely acquired maternal-fetal screening ultrasound images (which will be made publicly available) was collected from two different hospitals by several operators and ultrasound machines. All images were manually labeled by an expert maternal fetal clinician. Images were divided into 6 classes: four of the most widely used fetal anatomical planes (Abdomen, Brain, Femur and Thorax), the mother's cervix (widely used for prematurity screening) and a general category to include any other less common image plane. Fetal brain images were further categorized into the 3 most common fetal brain planes (Trans-thalamic, Trans-cerebellum, Trans-ventricular) to judge fine grain categorization performance. The final dataset is comprised of over 12,400 images from 1,792 patients, making it the largest ultrasound dataset to date. We then evaluated a wide variety of state-of-the-art deep Convolutional Neural Networks on this dataset and analyzed results in depth, comparing the computational models to research technicians, which are the ones currently performing the task daily. Results indicate for the first time that computational models have similar performance compared to humans when classifying common planes in human fetal examination. However, the dataset leaves the door open on future research to further improve results, especially on fine-grained plane categorization.


Demonstration of Isthmocele Surgical Repair.
To describe the surgical treatment of a uterine isthmocele. Demonstration of the laparoscopic technique with narrated video footage. Cesarean section rate has been increasing despite the World Health Organization's recommendation of a maximum 15%, with some countries reaching rates as high as 50%. The choice of delivery method is a complex topic based on physical and psychologic health, social and cultural context, and quality of maternity care. With the increasing number of cesarean sections, a new entity was recognized, the isthmocele [1]. A uterine isthmocele is a dilatation of the uterine cesarean scar and functions as a reservoir collecting blood during menstruation. Isthmocele prevalence ranges from 19% to 84%[2]. The most frequent complaint relates to intermittent postmenstrual bleeding (30%). Isthmocele can be a cause of infertility and pelvic pain [3]. Interstitial pregnancy is a known complication with a mortality rate up to 2.5%. The diagnosis can be made by transvaginal ultrasound and/or magnetic resonance imaging but also by hysteroscopy or hysterosalpingography. Treatment can be done by controlling the symptoms with oral combined contraceptive (decreasing metrorrhagia) or with surgical correction improving symptoms and/or fertility [4-7]. Isthmocele correction seems to improve secondary infertility in patients in whom a fertility workup did not find other cause [8,9]. Surgical approach can be done by vaginal route with hysteroscopy; abdominal route with laparoscopy, robotic or laparotomy; or through a combine procedure with both routes. Hysterectomy is the definitive treatment, but for those who want to preserve fertility, isthmocele correction can be offered. For laparoscopic surgery, several ways have been described to detect the isthmocele such as Foley catheter, hysteroscopy, methylene blue, and Hegar probe. When we do laparoscopy, we prefer concomitant use of hysteroscopy. There is a trending opinion that patients with a smaller isthmocele could be treated hysteroscopically (2.5 mm according to Jeremy et al [10] and 3.0 mm described by Marotta et al [11]). The goal of hysteroscopy correction is to remove the inflammatory infiltration in the endocervix, cutting the superior and inferior edges of the defect enabling normal blood evacuation of the uterus. By contrast, those with a larger isthmocele (with <2.5-3.0-mm residual myometrium) and a risk of perforation during hysteroscopy could be better treated by laparoscopy. This is especially important in patients interested in pregnancy because of the risk of uterine perforation [12]. There is still no strong evidence that hysteroscopic correction leads to an increased number of uterine ruptures compared with laparoscopy, but myometrium thickness seems to be greater after laparoscopic correction. Myometrium thickness is an independent risk factor for uterine rupture [13], and therefore, laparoscopic correction is preferred over hysteroscopic in women with a pregnancy desire. Finally, after surgical correction of an isthmocele, we recommend a 6-month interval before attempting pregnancy. Laparoscopic treatment is important in women who are symptomatic, have thin endometrium, and desire a pregnancy. Key strategies are (1) dissection of the vesicouterine pouch laterally to avoid entering the bladder wall; (2) transillumination with hysteroscopy; (3) cut with cold scissors avoiding thermal damage of remaining myometrium; and (4) suture with figure 8 in multiple layers. No evidence of using a specific suture is available. Surgical treatment of a uterine isthmocele is a good option in women who are symptomatic and infertile. Laparoscopic treatment guided by hysteroscopy is a good option if residual myometrium is <3 mm.


The effect of educational brochures on follow-up compliance in women with abnormal Papanicolaou smears.
To determine whether women with abnormal Papanicolaou smears who received educational brochures at the initial booking for colposcopy were more likely to complete recommended treatment and follow-up after 18-24 months than were those who did not receive the brochures. One hundred eight women participated in an earlier randomized study of the effect of educational brochures on emotional distress and knowledge about abnormal Papanicolaou smears. Their medical records were reviewed 18-24 months later for completed treatment and follow-up compliance. Women who received the brochure had more completed treatment and follow-up compliance (75.4%) than did those who did not receive the brochure (45.8%). The difference in compliance was 30% (99% confidence interval [CI] 6-54%, P = .002). There were no significant differences in age, education, marital status, or levels of emotional distress between subjects with complete and incomplete follow-up. Knowledge of the recommended number of follow-up visits was greater in women who completed follow-up (difference in frequency 30.4%; 99% CI 7-54%, P = .002). All women with completed treatment and follow-up who had received the brochure found it helpful. Given the high patient acceptability and demonstrated effectiveness in improving completed treatment and follow-up compliance, educational brochures should routinely accompany, or immediately follow, notification about abnormal Papanicolaou smears.


Enhanced gastric IL-18 mRNA expression in Helicobacter pylori-infected children is associated with macrophage infiltration, IL-8, and IL-1 beta mRNA expression.
To investigate IL-18 mRNA expression in the gastric mucosa in Helicobacter pylori-infected children and its association with macrophage infiltration, IL-8, and IL-1 beta mRNA expression. From 39 children, blood samples were taken for IL-1 beta gene polymorphism analysis and antral biopsies were obtained for histology (including macrophage immunostaining), culture and semiquantitative analysis of IL-18, IL-8, IL-1 beta, and CD14 mRNA expression by reverse transcription-PCR (RT-PCR). RT-PCR was used for H. pylori ureA and cagA mRNA detection in gastric tissue. H. pylori-infected patients had significantly higher IL-18, IL-8, and IL-1 beta transcript levels and macrophage numbers in the antral mucosa than H. pylori-negative children. IL-1 beta-511/31 gene polymorphism had no impact on gastric IL-1 beta mRNA levels. IL-18 mRNA expression correlated with mRNA expression of IL-8 and IL-1 beta, and transcript levels of all three cytokines were associated with macrophage infiltration and CD14 mRNA expression in the gastric tissue. Significant correlation was also observed between macrophage numbers and histological parameters of gastritis. These results suggest that interleukin(IL)-18 and macrophages may have an important function in gastric inflammatory response to H. pylori infection in children. IL-18, and possibly CD14 receptor signalling pathway, may be involved in macrophage activation and subsequent IL-8 and IL-1 beta release.


Pfeiffer syndrome: systemic and ocular implications.
In 1964, Pfeiffer described a three-generation family in which eight individuals had a syndrome consisting of craniosynostosis, broad thumbs and great toes, and partial syndactyly of the hands and feet. Pfeiffer syndrome affects males and females equally, and is most commonly a result of de novo mutations, but can be inherited in an autosomal dominant fashion. Pfeiffer syndrome is considered Type V of the five acrocephalosyndactly syndromes (ACS), a group of rare genetic diseases that involve premature closure of the cranial sutures. Cohen, in 1993, further described Pfeiffer syndrome and it's various expression patterns by creating three subgroups of the syndrome. While Pfeiffer syndrome is clearly a rare disorder, affecting 15 of every 1 million births, there has been a series of publications reviewing the difficult differential diagnosis among Pfeiffer types and between the other acrocephalosyndactly syndromes. While these publications individually focus on a variety of specific systemic and ocular implications of the syndrome, together they encompass the scope of the syndrome. Since Pfeiffer syndrome mainly affects the craniofacial regions, the eye care professional plays an essential role in diagnosis and management. What follows are guidelines to aid in the diagnosis, ophthalmic and functional testing, and management of this disorder.


Genes encoding both subunits of phycoerythrocyanin, a light-harvesting biliprotein from the cyanobacterium Mastigocladus laminosus.
Phycocyanin (PC) and phycoerythrocyanin (PEC) are light-harvesting components of the phycobilisome (PbS) from the cyanobacterium Mastigocladus laminosus. These two biliproteins are closely related, and show a particularly high degree of sequence homology in the C-terminal part of their beta-subunits. A 198-bp gene fragment encoding this region of PC from M. laminosus was therefore used as a heterologous hybridization probe to identify the genes coding for PEC from the same organism. A 1.7-kb HindIII fragment was cloned and its sequence determined. Three open reading frames (ORFs) were found on this fragment. The gene coding for the beta-subunit of PEC (pecB) was followed downstream by the alpha-subunit encoding gene (pecA). This gene arrangement had also been found in the PC-encoding (cpc) gene pair from M. laminosus, and is conserved in cpc genes from other organisms. This finding is compatible with a model of evolution of the cpc and pec gene pairs as the product of gene duplication of an ancestral beta- and alpha-subunit-encoding pair. A third ORF starts downstream from pecA. It codes for the 34.5-kDa linker protein, which forms complexes with PEC with a 1:6 stoichiometry in the PbS. Biliprotein- and linker protein-encoding genes are frequently clustered, and this provides mechanisms for the production of the different stoichiometric amounts of these gene products required in the PbS and for coregulation by environmental factors.


Snapshots of wintertime urban aerosol characteristics: Local sources emphasized in ultrafine particle number and lung deposited surface area.
Urban air fine particles are a major health-relating problem. However, it is not well understood how the health-relevant features of fine particles should be monitored. Limitations of PM2.5 (mass concentration of sub 2.5 μm particles), which is commonly used in the health effect estimations, have been recognized and, e.g., World Health Organization (WHO) has released good practice statements for particle number (PN) and black carbon (BC) concentrations (2021). In this study, a characterization of urban wintertime aerosol was done in three environments: a detached housing area with residential wood combustion, traffic-influenced streets in a city centre and near an airport. The particle characteristics varied significantly between the locations, resulting different average particle sizes causing lung deposited surface area (LDSA). Near the airport, departing planes had a major contribution on PN, and most particles were smaller than 10 nm, similarly as in the city centre. The high hourly mean PN (>20 000 1/cm3) stated in the WHO's good practices was clearly exceeded near the airport and in the city centre, even though traffic rates were reduced due to a SARS-CoV-2-related partial lockdown. In the residential area, wood combustion increased both BC and PM2.5, but also PN of sub 10 and 23 nm particles. The high concentrations of sub 10 nm particles in all the locations show the importance of the chosen lower size limit of PN measurement, e.g., WHO states that the lower limit should be 10 nm or smaller. Furthermore, due to ultrafine particle emissions, LDSA per unit PM2.5 was 1.4 and 2.4 times higher near the airport than in the city centre and the residential area, respectively, indicating that health effects of PM2.5 depend on urban environment as well as conditions, and emphasizing the importance of PN monitoring in terms of health effects related to local pollution sources.


A computer feedback system for clinical research.
This paper presents a computerized data base management and information retrieval system for a heroin addiction research clinic, which has potential application for any type of clinical research. It describes data input checking programs, file structures, and output programs. The system contains several interesting features: built-in feedback error detection and correction; patient month matrix formatting and data compression; and a virtual blocking system to reduce the size of the files.


Alterations of Cortisol and Melatonin Production by the Theca Interna Cells of Porcine Cystic Ovarian Follicles.
(1) Background: Cortisol and melatonin (MT) act in regulating follicular development. We hypothesized that abnormal levels of cortisol, MT, and steroids in theca interna cells might be involved in the development of follicular cysts in sows. (2) Methods: To test this hypothesis, we measured the mRNA levels of enzymes involved in steroid hormone synthesis, the glucocorticoid receptor (GR), and melatonin receptors (MTRs) in theca interna cells of cystic and normal porcine follicles. (3) Results: The concentrations of estradiol, progesterone, and cortisol were greater in cystic follicles than in control ones (p = 0.034, p = 0.020, p = 0.000), but the concentration of MT was significantly lower (p = 0.045). The levels of GR, 11β-HSD1, and 11β-HSD2 were higher in cystic follicles than in control l follicles. MT types 1 and 2 were significantly lower in cystic follicles (p < 0.05). The mRNA expression levels of genes encoding the steroid hormone synthesis enzymes, steroidogenic acute regulatory protein (StAR), recombinant cytochrome P45011A1 (CYP11A1), and 3β-hydroxysteroid dehydrogenase (3β-HSD) in theca interna cells of cystic follicles were significantly higher than in control follicles. Thus, there was disruption of hormone secretion in the fluid of cystic follicles in sows. (4) Conclusions: The levels of steroid hormones, cortisol and MT are disrupted in porcine cystic follicles.


Endotoxins inhibit endocytotic catabolism of low-density lipoproteins in Hep G2 cells.
The effects of endotoxins on the uptake and degradation of low-density lipoproteins in Hep G2, a well-differentiated human hepatoma cell line, were studied. The results showed that incubation of Hep G2 cells with 125I-labeled low-density lipoprotein in the presence of endotoxins caused decreased uptake and degradation of 125I-labeled low-density lipoprotein. The inhibitory effects of endotoxins on the uptake and degradation of 125I-labeled low-density lipoprotein were dose and time dependent. With a monoclonal low-density lipoprotein receptor antibody, it was found that endotoxins interfered with both low-density lipoprotein receptor-mediated and non-low-density lipoprotein receptor-mediated uptake. If, however, the cells were pretreated with endotoxins for 1 or 24 hr and then incubated with new medium without endotoxins, no inhibitory effect on the subsequent uptake and degradation of 125I-labeled low-density lipoprotein occurred. Endotoxins had no toxic effects on Hep G2 cells as judged by [3H]thymidine incorporation and by determination of cell growth. Also, endotoxins did not under our experimental conditions induce oxidative modification of low-density lipoprotein. Furthermore, reisolated low-density lipoprotein that had previously been incubated with endotoxin was catabolized to a lower extent by Hep G2 cells than was control low-density lipoprotein. We speculate that the inhibitory effect of endotoxins on cellular low-density lipoprotein catabolism is due to the formation of endotoxin-low-density lipoprotein complexes, which interfere with the binding of low-density lipoprotein to the cell surface.


Radiological clerkships as a critical curriculum component in radiology education.
The aim of this research was to explore the perceived value of clinical clerkships in the radiology curriculum as well as the impact of radiology clerkship on students' beliefs about the profession of radiology as a whole and as a career. This study is a sequel to a previous survey in which student perceptions about radiology curriculum components were investigated. The present study focuses on a further analysis of a subsection in this study, based on 14 statements about radiology clerkship and two statements about radiology as a career. Perceived usefulness of the aspects of radiology clerkship as "radiology examination", "skills development" and "diagnosis focus" were awarded the highest scores. The predict value of the subscale "radiology examination" on the level of performance was very high (adjusted R(2)=0.19, p<.001). Students expressed highly favorable evaluation of clerkship as a learning environment to learn to order and to interpret imaging studies as well as an unique possibility to attend various radiological examinations and to access to specific radiology software systems, as well as to get a better view on radiology and to improve image interpretation skills. This positive attitude towards clerkship is closely tied to students' beliefs about the profession of radiology as a whole. These aspects of dedicated radiology clerkship are crucial for effective and high-quality education as well as for the choice of radiology as a career.


Implication of Interleukin (IL)-18 in the pathogenesis of chronic obstructive pulmonary disease (COPD).
Interleukin (IL)-18 is a pro-inflammatory cytokine that was firstly described as an interferon (IFN)-γ-inducing factor. Similar to IL-1β, IL-18 is synthesized as an inactive precursor requiring processing by caspase-1 into an active cytokine. The platform for activating caspase-1 is known as the inflammasome, a multiple protein complex. Macrophages and dendritic cells are the primary sources for the release of active IL-18, whereas the inactive precursor remains in the intracellular compartment of mesenchymal cells. Finally, the IL-18 precursor is released from dying cells and processed extracellularly. IL-18 has crucial host defense and antitumor activities, and gene therapy to increase IL-18 levels in tissues protects experimental animals from infection and tumor growth and metastasis. Moreover, multiple studies in experimental animal models have shown that IL-18 over-expression results to emphysematous lesions in mice. The published data prompt to the hypothesis that IL-18 induces a broad spectrum of COPD-like inflammatory and remodeling responses in the murine lung and also induces a mixed type 1, type 2, and type 17 cytokine responses. The majority of studies identify IL-18 as a potential target for future COPD therapeutics to limit both the destructive and remodeling processes occurring in COPD lungs.


Evaluation of the bronchial stump following pulmonary resection.
Bronchoscopic and conventional bronchographic examinations are reliable methods to evaluate the integrity of a sutured bronchial stump. However, sometimes the critical condition of the patient makes these diagnostic procedures impractical. We present here a simpler method to achieve this purpose. This requires minimal invasiveness, no disturbance to the therapeutic support, and no transportation of the patient.


Expression levels of hsc70 and hsp60 are developmentally regulated during B-cell maturation and not associated to childhood c-ALL at presentation or relapse.
Heat shock proteins are potent regulators of apoptosis, and so they may also be involved in normal cellular differentiation and cancerogenesis. We used quantitative two-dimensional gel electrophoresis for determining whether either the constitutive chaperonic heat shock cognate protein 70 (hsc70) or heat shock protein 60 (hsp60) contribute to B-cell differentiation and leukemogenesis. We compared the expression of these hsps in normal peripheral blood (PB) CD19+ B-cells, in pediatric bone marrow (BM) CD19+ CD10+ B-cell precursors (BCPs) from normal donors, and in BCPs from common acute lymphoblastic leukemia (c-ALL) patients at diagnosis and at relapse. We found that the mean levels of hsc70 in c-ALL BCPs at initial presentation and at relapse failed to differ significantly. Likewise, they failed to differ significantly from the level in high-expressing normal BM BCPs or from that in low-expressing PB B-cells. Mean levels of hsp60 expression in c-ALL BCPs at initial presentation and at relapse were similar and not distinguishable from that in normal BM BCPs, however, elevated (by a factor of 2-3) compared with that in PB B-cells. Hsc70 and Hsp60 expressions were increased (by a factor of 2 of mean levels) in populations of normal BM BCPs as compared with populations of PB B-cells. Thus, no abnormal levels of hsc70 and hsp60 were detectable in populations of pediatric c-ALL BCPs neither at diagnosis nor at relapse. In contrast, our data were in support of developmentally regulated levels of hsc70 and hsp60 expression during B-cell ontogenesis.


Sustained oxidative stress inhibits NF-kappaB activation partially via inactivating the proteasome.
NF-kappaB is a family of important transcription factors involved in many cellular functions, such as cell survival, proliferation, and stress responses. Many studies indicate that NF-kappaB is a stress-sensitive transcription factor and its activation is regulated by reactive oxygen species. In previous studies, we and others demonstrated that this transcription factor can be activated by transient oxidative stress. However, the effects of sustained oxidative stress on NF-kappaB activation are not clear. The objective of this study was to determine the effects of sustained oxidative stress on NF-kappaB activation and to elucidate the signaling events affected by sustained oxidative stress. Human lens epithelial cells (HLEC) that were subjected to 4 h of continuous influx of hydrogen peroxide were used to investigate the effects of sustained oxidative stress on NF-kappaB activation. The data showed that, unlike transient oxidative stress, sustained exposure of HLEC to physiologically relevant levels of H(2)O(2) (50-100 microM for 4 h) did not induce the degradation of I-kappaB and activation of NF-kappaB, but attenuated TNFalpha-induced degradation of I-kappaB and activation of NF-kappaB. Sustained exposure of HLEC to these levels of H(2)O(2) also inactivated proteasome activity by 50-80%. Consistent with the role of the proteasome in degradation of I-kappaB and activation of NF-kappaB, treatment of HLEC with proteasome inhibitors also attenuated TNFalpha-induced I-kappaB degradation and NF-kappaB activation. The data also indicate that activation of NF-kappaB is essential for the cells to recover from oxidative stress. Inhibiting NF-kappaB activation during recovery from transient oxidative stress significantly reduced the cell viability. Together, these data indicate that sustained oxidative stress may inactivate the proteasome and subsequently inhibit NF-kappaB activation by impeding the degradation of I-kappaB. The oxidative inactivation of the proteasome and subsequent impairment of NF-kappaB activation may contribute to the death of lens epithelial cells, a common feature associated with cataract.


Clozapine administration ameliorates disrupted long-range synchrony in a neurodevelopmental animal model of schizophrenia.
The abnormal synchronisation of neural networks may underlie some of the deficits observed in schizophrenia. Abnormal synchronisation can be induced in animal models. We investigated whether acute clozapine treatment might function therapeutically by ameliorating the deficit in theta frequency coherence between the prefrontal cortex and the hippocampus that is induced in rats exposed to maternal immune activation (MIA)--a risk-factor for schizophrenia. Clozapine treatment increased synchrony levels to that of control animals in a dose-dependent manner. Clozapine's effect on synchrony may in part be mediated through increases in local synchrony that occurred in prefrontal cortex but not hippocampus.


Kinetics genetics: Incorporating the concept of genomic balance into an understanding of quantitative traits.
While most mutations are recessive, variants that affect quantitative traits are largely semi-dominant in their action making hybrids between divergent genotypes intermediate. In parallel, changes in chromosomal dosage (aneuploidy) for multiple regions of the genome modulate quantitative characters. We have previously argued that these observations are a reflection of a common process, originating from the more or less subtle effects of changes in dosage on the action of multi-subunit regulatory machineries. Kinetic analyses that vary the amount of one subunit of a complex while holding others constant do not always predict a linear response for the production of the whole. Indeed, in many instances, strong non-linear effects are expected. Here, we advocate that these kinetic observations and predictions should be incorporated into quantitative genetics thought.


Osteotomy for laminoplasty without soft tissue penetration, performed using a harmonic bone scalpel: instrumentation and technique.
Laminoplasty in the case of intramedullary spinal tumor requires care to avoid neurologic injury. The harmonic bone scalpel provides a method of laminoplasty that can be done safely and quickly for this and other indications. Five cases are presented, each of which required operative intervention, namely laminoplasty. The pathologies presented are one cervical intramedullary tumor, one thoracic intramedullary spinal mass, one lumbar extramedullary intradural tumor, and two cases of multiple lower brachial plexus nerve root avulsions requiring dorsal root entry zone (DREZ) lesion. These five patients underwent laminoplasty for either tumor resection or DREZ lesion. The laminotomies were performed using the BoneScalpel™ (Misonix Inc., Farmingdale, NY, USA), which is a harmonic bone scalpel instrument. This obviated the need to place any instrument under the intact lamina. Kerrison punches and various instruments were still used, but for purposes other than the bony removal of the laminoplasty. These cases demonstrate that the BoneScalpel™ can be used to facilitate the laminar cuts while still allowing a safe and effective operation, even in cases as delicate as an intramedullary thoracic spinal cord tumor. The mechanism of action of the harmonic bone scalpel allows osteotomies without cutting or penetrating soft tissue and also leaves minimal bony defect.


Symptomatic Upper Extremity Deep Venous Thrombosis After Laser Lead Extraction.
Laser lead extraction is a well-established method for removing unwanted leads with low morbidity and mortality. In this small series of cases, we documented our experience with venous thrombosis after laser lead extraction. Retrospective data of patients who underwent laser lead extraction with postoperative axillo-subclavian vein thrombosis between May 2010 and January 2020 were analyzed. Demographic, operative, clinical, and follow-up characteristics of those patients were collected from our medical database. Six patients underwent percutaneous laser lead extraction. Mean age of the patients was 64±7 years. And four of them were male. A total of 11 leads with a mean age of 92±43.8 months were extracted. Patients presented with painful arm swelling postoperatively. Laser lead extraction may lead to symptomatic upper extremity deep venous occlusion.


Clinical and Hemodynamic Results After Conversion from Single to Biventricular Circulation After Fetal Aortic Stenosis Intervention.
At our institution a multidisciplinary team has performed fetal aortic valvuloplasty (FAV) for severe aortic stenosis with evolving hypoplastic left heart syndrome with high technical success rates. Measurement of postnatal success has been biventricular circulation (BC). Postnatal survival for patients after FAV who achieved a BC appears encouraging. However, there are limited late clinical and hemodynamic outcomes in this cohort and there is concern for diastolic dysfunction. We reviewed all patients with FAV at our institution who initially underwent single ventricle palliation and subsequently BC, as this is likely the subset at high-risk for poor outcomes. Clinical, imaging, and surgical data were collected. Two of 7 patients (29%) died within 16 months of BC, and 1 patient has been listed for transplant. Diastolic dysfunction was common and progressive with median left ventricular end diastolic pressure of 12 mm Hg before BC, and increasing to 22 mm Hg for survivors at last follow-up. Left ventricular size was adequate with all patients reaching a left ventricular end diastolic volume (LVEDV) z score in the normal or elevated range. Presence and severity of residual valve lesions decreased over time secondary to a median of 6 interventions (range 3 to 10), either surgical or cath-based, performed for these 7 patients during the study period. In conclusion, clinical outcomes are concerning for this high-risk group. Diastolic dysfunction is persistent and progressive despite anatomic interventions and adequate left ventricular growth. The main contributing factor to poor outcomes may be intrinsic myocardial dysfunction and primordial pathology. Achievement of a BC after FAV may not be an appropriate measure of success.


The soluble glucocorticoid-induced tumor necrosis factor receptor causes cell cycle arrest and apoptosis in murine macrophages.
In order to clarify the mechanism by which soluble GITR (sGITR) inhibits the survival of murine macrophages we examined its effect on the macrophage cell cycle. Soluble GITR induced G1 phase arrest followed by apoptosis. It also reduced the expression of cyclins D2 and A, and of cdk4, resulting in reduced cdk2 and cdk4 activities. These findings suggest that sGITR arrests division of the macrophages in G1 by lowering the activities of cdk2 and cdk4, and that this leads to apoptosis.


Endocardial mapping of ventricular tachycardia in the intact human ventricle: evidence for reentrant mechanisms.
A balloon array of 112 electrodes was used to obtain simultaneous recordings of endocardial electrograms during intraoperative mapping studies of ventricular tachycardia. Introduction of the balloon through a left atriotomy and across the mitral valve allowed endocardial activation maps to be obtained in the intact left ventricle. Of 20 patients with coronary artery disease studied in this way, suggestive evidence of endocardial reentry was found in 6. Three separate reentrant mechanisms were observed. In two patients, a single broad wave front of continuous recirculating activation reminiscent of a vortex was initiated by the formation of a functional arc of block in response to premature stimuli. In five patients, premature stimuli again produced a functional arc of block, which was circumvented by two opposing wave fronts that united on the distal side. Retrograde penetration by a narrow isthmus of slow conduction through the block initiated the tachycardia, whose activation sequence was consistent with figure eight reentry. In one patient, premature stimuli produced a region of delayed potentials. Critical timing of these resulted in microreentry in an adjacent circumscribed site, which formed the site of origin of the ensuing tachycardia. The microreentrant signals were not detected by standard unipolar recordings, but were seen on simultaneously recorded high gain electrograms. In 14 patients, although mapping identified a site of origin, the activation patterns showed either radial spread or incomplete circles. Detection of reentrant mechanisms during intraoperative mapping required high density electrode arrays and refined high gain recordings. An intact ventricle may facilitate intraoperative initiation of tachycardia.


Highly bright and stable CsPbBr3 perovskite nanocrystals with amphiphilic polymer binding based dual-readout lateral flow immunoassay for detection of carcinoembryonic antigen.
Rapid and highly sensitive detection of tumor marker (TM) is critical for the early diagnosis and treatment of cancers. Herein, utilizing highly bright and water-stable CsPbBr3 perovskite nanocrystals (NCs) capped with amphiphilic polymer ligand of octylamine-modified polyacrylic acid (OPA) and gold nanoparticles (AuNPs) as reporters, a lateral flow immunoassay (LFIA) strip is developed for fluorescence and colorimetric dual-mode detection of carcinoembryonic antigen (CEA). The prepared CsPbBr3 NCs capped by an amphiphilic polymeric of OPA ligand showed high stability and bright fluorescence. Moreover, the AuNPs immunoprobes were captured with CEA antigen and quench the green fluorescence of CsPbBr3/OPA NCs on the T line due to the inner filter effect (IFE). Therefore, CEA could be quantitative analyzed by the dual-readout of fluorescence and colorimetric signal. The detection limits of CEA can reach as low as 0.023 ng/mL and 0.027 ng/mL for the fluorescence and colorimetric mode, respectively. Good specificity and reproducibility were also demonstrated for this method. Finally, the CsPbBr3/OPA NCs-based LFIA showed good accuracy in detection of CEA level from clinical serum samples. This work firstly enables the application of CsPbBr3 perovskite NCs in a LFIA, displaying great potential in point-of-care clinical diagnosis.


Presence of immunoreactive beta-endorphin in normal human plasma: a concomitant release of beta-endorphin with adrenocorticotropin after metyrapone administration.
To elucidate whether or not beta-endorphin exists in plasma of normal subjects, plasma extracts obtained before and after metyrapone administration were subjected to gel exclusion chromatography, and fractions obtained were assayed by a sensitive radioimmunoassay for beta-endorphin. The basal plasma level of beta-endorphin was 5.8 +/- 1.1 pg/ml (mean +/- SE, n = 5), which rose significantly to the level of 48.9 +/- 3.8 pg/ml after a single oral dose (30 mg/kg of body wt) of metyrapone administration (P less than 0.001). Plasma ACTH levels also increased from the mean basal level of 73 +/- 4 pg/ml to 269 +/- 41 pg/ml after metyrapone administration. These results indicate that beta-endorphin, distinct from beta-lipotropin, exists in normal human plasma and that it is released from the pituitary concomitantly with ACTH.


Inferior vena cava duplication and deep venous thrombosis: case report and review of literature.
Duplications of the inferior vena cava (IVC) are seen with an incidence of 0.2% to 3.0%. Duplications causing symptoms are rare, with only six reported cases of IVC duplication associated with a deep venous thrombosis. We present a 78-year-old caucasian woman with an IVC duplication who developed a deep venous thrombosis. The etiologies of IVC duplication include failure of anastomosis between the primitive cardinal veins and failure of regression of the left supracardinal vein. When asymptomatic, treatment includes observation, placing filters in both systems, or coil-embolization of the duplicated segment plus placing a filter in the right IVC. For our patient, we chose to coil-embolize the communication to the duplicated segment as well as place a filter in the main right IVC system.


Atypical fibrous histiocytoma with myxoid stroma: a rare lesion arising from dura mater of the brain.
Intracranial fibrohistiocytic tumors are rare. This report is concerned with a 24-year-old white male who had an 8 month history of intermittent visual disturbance. Craniotomy revealed a large, completely intradural lesion on the floor of the left anterior cranial fossa without involvement of the leptomeninges or brain parenchyma. Gross and microscopic examination revealed that the fibrogenic portion of the tumor was composed of spindle shaped neoplastic cells arranged in storiform pattern, a hallmark of fibrohistiocytic tumor. In contrast to three previously reported cases of "fibrous xanthomas" involving the leptomeninges and superficial cortex of the brain, the present lesion is clearly originated from mesenchymal stem cell of the dura. The other distinct gross and microscopic feature was the presence of myxoid component which constituted about 40% of the entire lesion. The myxoid component had not been observed in previous 5 reported cases of intracranial fibrohistiocytic lesions. Since there was cellular pleomorphism with extremely rare mitosis, it was felt that the lesion be best designated as atypical fibrous histiocytoma with myxoid stroma.


Vasoactive drugs, microvascular permeability, and hemorrhagic pancreatitis in cats.
We investigated the mechanisms by which 16,16-dimethyl prostaglandin E2 and histamine induced pancreatic hemorrhage in an experimental model of acute pancreatitis in cats. In normal animals, when large molecular weight dextran molecules were infused into the systematic circulation, they were recovered in secretin-stimulated pancreatic juice in low concentrations. Both 16,16-dimethyl prostaglandin E2 (in a dose that increased splenic artery blood flow and microvascular permeability) and histamine (in a dose that increased permeability only) increased the amount of dextran recovered in pancreatic juice. Isoproterenol, in a dose that produced the same increase in blood flow as 16,16-dimethyl prostaglandin E2 but which did not increase microvascular permeability, did not alter the amount of dextran recovered. This suggested that the increase in dextran output after 16,16-dimethyl prostaglandin E2 was primarily due to the increase in microvascular permeability caused by the drug. In other experiments, a combination of H1- and H2-receptor antagonists (mepyramine and cimetidine) protected against the development of pancreatic hemorrhage in both the prostaglandin- and histamine-treated animals. Indomethacin (a cyclooxygenase inhibitor) protected against the development of hemorrhage in the histamine-treated animals. Our results support the hypothesis that changes in microvascular permeability may be important in the pathogenesis of parenchymal hemorrhage in this model.


Effect of nisoldipine and olmesartan on endothelium-dependent vasodilation in essential hypertensive patients.
To investigate whether nisoldipine and olmesartan improve endothelial function, decrease asymmetric dimethylarginine (ADMA) and alleviate the inflammatory and oxidative process. Fifty-five essential hypertensive patients were randomized to receive nisoldipine or olmesartan for 8 weeks according to a parallel-group, active-controlled, single blind study, and 28 matched normotensive subjects served as healthy controls. Flow-mediated dilation (FMD), and plasma levels of nitric oxide (NO), endothelin-1 (ET-1), high-sensitive C-reactive protein (hs-CRP), 8-isoprostane (also named 8-isoPGF2α), and ADMA were determined. At baseline, the plasma levels of ADMA, ET-1, hs-CRP, and 8-isoPGF2α were markedly higher in patients with essential hypertension than in normotensive subjects (P < 0.05). A significant positive correlation was observed between plasma levels of ET-1 and ADMA in patients with essential hypertension, but not in normotensive subjects. The NO plasma concentrations were significantly lower in patients with essential hypertension than in normotensive subjects. Furthermore, hypertensive subjects demonstrated significantly lower FMD than healthy control (P < 0.05). Nisoldipine and olmesartan significantly and similarly reduced blood pressure in patients with essential hypertension (P < 0.001). At the end of the 8-week treatment, plasma ADMA and ET-1 levels were decreased significantly (P < 0.01). FMD increased significantly in nisoldipine or olmesartan-treated patients (P < 0.05). A significant decrease in plasma hs-CRP contents was observed in patients receiving nisoldipine (P < 0.05). The findings demonstrate that nisoldipine and olmesartan both improve FMD in patients with essential hypertension. This may be associated with decreased circulating levels of CRP, ET-1, and ADMA.


Functional (psychogenic) movement disorders - Clinical presentations.
Functional or psychogenic movement disorders are common and disabling, and sometime difficult to diagnose. The history and physical exam can give positive features that will support the diagnosis, which should not be based solely on exclusion. Some clues in the history are sudden onset, intermittent time course, variability of manifestation over time, childhood trauma, history of other somatic symptom and secondary gain. Anxiety and depression are common, but not necessarily more than the general population. On examination, distraction and suggestibility may be present. There are specific signs that should be looked for with different types of movements. For example, with tremor, change in frequency over time and entrainment are common features. With myoclonus, the movements might be complex in type with long latencies to stimulus induced jerks. Gait disorders show good balance despite claims to the contrary. Functional dystonia still remains a challenging diagnosis in many circumstances, although fixed dystonia is one sign more likely to be functional.


Work in Progress: Immigrant Health Care from the Vantage of Cancer Testing and Screening.
This letter offers a perspective from cancer testing and screening on the improvements in immigrant insurance coverage and care charted in Bustamante et al.'s April 2019 article in JOIH on "Health Care Access and Utilization Among U.S. Immigrants Before and After the Affordable Care Act." Supportive evidence for their data may be found in complementary literature drawing from both the National Health Interview Survey the authors use and the Medical Expenditure Panel Survey, while post-ACA surveys and state level information suggest disparities remain for lawfully present and undocumented immigrants ineligible for Medicaid and unable to secure insurance to pay medical costs. Existent options for cancer services are discussed. Further relevant reform depends on voter awareness and collaborative efforts between consumer advocates and legislators.


Targeting Mitochondrial COX-2 Enhances Chemosensitivity via Drp1-Dependent Remodeling of Mitochondrial Dynamics in Hepatocellular Carcinoma.
Mitochondria are highly dynamic organelles and undergo constant fission and fusion, which are both essential for the maintenance of cell physiological functions. Dysregulation of dynamin-related protein 1 (Drp1)-dependent mitochondrial dynamics is associated with tumorigenesis and the chemotherapeutic response in hepatocellular carcinoma (HCC). The enzyme cyclooxygenase-2 (COX-2) is overexpressed in most cancer types and correlates with a poor prognosis. However, the roles played by the translocation of mitochondrial COX-2 (mito-COX-2) and the interaction between mito-COX-2 and Drp1 in chemotherapeutic responses remain to be elucidated in the context of HCC. Bioinformatics analysis, paired HCC patient specimens, xenograft nude mice, immunofluorescence, transmission electron microscopy, molecular docking, CRISPR/Cas9 gene editing, proximity ligation assay, cytoplasmic and mitochondrial fractions, mitochondrial immunoprecipitation assay, and flow cytometry analysis were performed to evaluate the underlying mechanism of how mito-COX-2 and p-Drp1Ser616 interaction regulates the chemotherapeutic response via mitochondrial dynamics in vitro and in vivo. We found that COX-2 and Drp1 were frequently upregulated and confer a poor prognosis in HCC. We also found that the proportion of mito-COX-2 and p-Drp1Ser616 was increased in HCC cell lines. In vitro, we demonstrated that the enhanced mitochondrial translocation of COX-2 promotes its interaction with p-Drp1Ser616 via PTEN-induced putative kinase 1 (PINK1)-mediated Drp1 phosphorylation activation. This increase was associated with higher colony formation, cell proliferation, and mitochondrial fission. These findings were confirmed by knocking down COX-2 in HCC cells using CRISPR/Cas9 technology. Furthermore, inhibition of Drp1 using pharmacologic inhibitors (Mdivi-1) or RNA interference (siDNM1L) decreased mito-COX-2/p-Drp1Ser616 interaction-mediated mitochondrial fission, and increased apoptosis in HCC cells treated with platinum drugs. Moreover, inhibiting mito-COX-2 acetylation with the natural phytochemical resveratrol resulted in reducing cell proliferation and mitochondrial fission, occurring through upregulation of mitochondrial deacetylase sirtuin 3 (SIRT3), which, in turn, increased the chemosensitivity of HCC to platinum drugs in vitro and in vivo. Our results suggest that targeting interventions to PINK1-mediated mito-COX-2/p-Drp1Ser616-dependent mitochondrial dynamics increases the chemosensitivity of HCC and might help us to understand how to use the SIRT3-modulated mito-COX-2/p-Drp1Ser616 signaling axis to develop an effective clinical intervention in hepatocarcinogenesis.


Weight change and body composition in patients with Parkinson's disease.
To compare reports of weight loss and actual measures of body composition to predict nutritional risk in patients with Parkinson's disease and matched control subjects. Patients and control subjects were asked to record prior changes in weight and activity. Body composition was then compared in both groups using percentage ideal body weight (IBW), body mass index (BMI), triceps skinfold (TSF) thickness, midarm muscle circumference, and percentage body fat (BF) as determined by bioelectrical impedance. Fifty-one free-living patients with Parkinson's disease and 49 matched control subjects were recruited from the neurology clinic and the surrounding area. We anticipated that reported weight loss would be greater and actual measures of body composition would show greater nutritional risk in the patients with Parkinson's disease. chi 2 Analysis was used to determine differences in the ratio of patients and control subjects who lost weight. Paired t tests were used to compare amount of weight change and measures of body composition. Correlations were performed among measures of weight change, body composition, and associated disease factors. Patients with Parkinson's disease were four times more likely to report weight loss greater than 10 lb than the matched control subjects (odds ratio > 4.2). Patients reported a mean (+/- standard deviation) weight loss of 7.2 +/- 2.9 lb and control subjects reported a mean weight gain of 2.1 +/- 1.6 lb (P < .01). Percentage IBW (P < .02), BMI (P < .009), TSF thickness (P < .005), and percentage BF (P < .022) were lower in patients. Significant correlations (P < .01) were found between reported weight change and percentage IBW, BMI, TSF, percentage BF, and stage of the disease. CONCLUSIONS/APPLICATION: Patients with Parkinson's disease appear to be at greater nutritional risk than a matched population. Simple screening and assessment tools can be used to detect nutritional risk.


Pyrene acts as a cocarcinogen with the carcinogens benzo[a]pyrene, beta-propiolactone and radiation in the induction of malignant transformation in cultured mouse fibroblasts; soybean extract containing the Bowman-Birk inhibitor acts as an anticarcinogen.
Pyrene was found to act as a cocarcinogen in the induction of transformation of cultured Balb/c3T3 cells by three different types of carcinogens: a direct acting chemical carcinogen, beta-propiolactone, a chemical carcinogen requiring metabolic activation, benzo[a]pyrene, and a physical carcinogen (60Co) gamma radiation. Since pyrene enhanced transformation in vitro by approximately the same amount for all the carcinogens tested, these results suggest that the carcinogenic action of pyrene is not related to carcinogen metabolism or uptake in vitro. An extract of soybeans containing the Bowman-Birk protease inhibitor was shown to reduce transformation induced by beta-propiolactone, benzo[a]pyrene and gamma-rays, both with and without the cocarcinogenic effect of pyrene, to background levels; the magnitude of the reduction in transformation by the protease inhibitor preparation was unrelated to the concentration of carcinogen. Neither the mechanism for the cocarcinogenic action of pyrene not the anticarcinogenic effect of the soybean extract is known, but several hypotheses are discussed.


Levels of metals in blood samples from Mallards (Anas platyrhynchos) from urban areas in Poland.
In this paper we present the studies conducted on blood samples taken from Mallards (Anas platyrhynchos). Birds were captured for ringing purposes (n = 43) in two small and two big towns (including highly urbanized areas). For comparison samples of blood from birds shot on fish ponds were used (n = 26). Based on the body mass all sampled individuals can be assessed as being in good condition. Levels of cadmium (Cd), chromium (Cr), copper (Cu), iron (Fe), nickel (Ni), lead (Pb) and zinc (Zn) in blood samples were measured with AAS. Concentrations of metals did not differ statistically between sexes and made up a following order: Fe > Zn > Cu > Cr ≈ Ni > Pb > Cd. Mallards from towns revealed lower concentrations of Zn and Cu but higher concentration of Fe. There was no difference in exposition to Pb between birds from towns and fish ponds.


Resource partitioning among forest owls in the River of No Return Wilderness, Idaho.
We studied resource partitioning among the forest owls in the River of No Return Wilderness, Idaho, during the winter and spring of 1980 and 1981. The owl assemblage consisted of five abundant species: pygmy (Glaucidium gnoma), saw-whet (Aegolius acadicus), boreal (A. funereus), western screech (Otus kennicottii), and great-horned (Bubo virginianus). Long-eared (Asio otus) and flammulated (O. flammeolus) owls were rarely observed. Information from the literature supplemented our data to describe the pattern of resource partitioning. Stepwise discriminant function analysis and multivariate analysis of variance revealed differences in macrohabitat and microhabitat. The saw-whet, boreal, western screech, and great-horned owls all preferred mammalian prey but exhibited habitat differences. They also differed in activity periods and food habits. The pygmy owl, a food and habitat generalist, foraged diurnally more than the other species and took a higher proportion of brids. The flammulated owl used areas within the territories of other owl species but specialized on forest insects. The observed pattern of resource use was interpreted to result from environmental factors, morphological limitations and interspecific competition. Differences in food and activity time, we suggest, result from environmental factors and differences in owl morphology, while present-day interspecific competition may be important in shaping habitat use. Experiments will be necessary to determine the causal factors responsible for segregation among the forest owls.


Domestic activities and walking in the elderly: evaluation from a 30-hour heart rate recording.
The physical activity pattern among 43 subjects (25 women, 18 men) from the Intervention Study of Elderly in Gothenburg (IVEG) has been evaluated by means of heart rate monitoring, rating of perceived exertion and recording activities over a 30-hour period. These subjects had previously been interviewed about their activity pattern, including the duration of their daily walks. In 91% of the participants the average heart rate was below 100 beats/min during walking. Considerable individual variations were noted in the duration of domestic activities and of walks. Using heart rate levels equal to or above the average heart rate during walking as a criterion, it was found that 68% of the women, but only 17% of the men, spent more time on domestic activities than on walking. Nonetheless, it is suggested that in addition to walking, domestic activities, owing to their duration, are important in maintaining physical fitness in the elderly, especially among women. This should be taken into account when physical activity is being classified (to avoid bias in favour of men). A modified version of a previously published six-grade scale for the classification of physical activity has been suggested.


Ultrastructure of the mucus-negative vacuolated cells in the metaplastic pyloric gland of the human stomach.
Mucus-negative vacuolated cells, often with apical cilia, were found in the metaplastic pyloric gland of the human stomach. These vacuoles were not stained by various mucus stains, but contained neutral fat. Electron microscopic observation revealed that the ciliated cells had prominent autophagosomes in the supranuclear region and sometimes had large vacuoles. These vacuoles were limited by a unit membrane and had electron-lucent contents consisting of small amounts of lipid droplets and lamellar bodies. The non-mucus vacuolated cells might correspond to the mature ciliated cells in which cystic degeneration of the autophagosomes occurred after digestion by lysosomal enzymes.


Non-O157 Shiga toxin-producing Escherichia coli-A poorly appreciated enteric pathogen: Systematic review.
Non-O157 strains of Shiga toxin-producing Escherichia coli (STEC) are more common causes of acute diarrhea than the better-known O157 strains and have the potential for large outbreaks. This systematic review of the literature identified 129 serogroups as well as 262 different O and H antigen combinations of STEC in cases of epidemic and sporadic disease worldwide. Excluding the results from a single large outbreak of STEC O104:H4 in Germany and France in 2011, the reported frequency of dysenteric illness in patients was 26% (119 of 464) for epidemic disease and 25% (646 of 2588) for sporadic cases. Hemolytic uremic syndrome was identified in 14% of epidemic disease cases and 9% of sporadic illness cases. With the increasing use of PCR-based diagnostics, STEC strain identification may not be possible. Rapid diagnostics are needed for STEC infections to aid the clinician while allowing epidemiologists the opportunity to identify outbreaks and to trace the source of infection.


Quantification of dopaminergic neurotransmission SPECT studies with 123I-labelled radioligands. A comparison between different imaging systems and data acquisition protocols using Monte Carlo simulation.
(123)I-labelled radioligands are commonly used for single-photon emission computed tomography (SPECT) imaging of the dopaminergic system to study the dopamine transporter binding. The aim of this work was to compare the quantitative capabilities of two different SPECT systems through Monte Carlo (MC) simulation. The SimSET MC code was employed to generate simulated projections of a numerical phantom for two gamma cameras equipped with a parallel and a fan-beam collimator, respectively. A fully 3D iterative reconstruction algorithm was used to compensate for attenuation, the spatially variant point spread function (PSF) and scatter. A post-reconstruction partial volume effect (PVE) compensation was also developed. For both systems, the correction for all degradations and PVE compensation resulted in recovery factors of the theoretical specific uptake ratio (SUR) close to 100%. For a SUR value of 4, the recovered SUR for the parallel imaging system was 33% for a reconstruction without corrections (OSEM), 45% for a reconstruction with attenuation correction (OSEM-A), 56% for a 3D reconstruction with attenuation and PSF corrections (OSEM-AP), 68% for OSEM-AP with scatter correction (OSEM-APS) and 97% for OSEM-APS plus PVE compensation (OSEM-APSV). For the fan-beam imaging system, the recovered SUR was 41% without corrections, 55% for OSEM-A, 65% for OSEM-AP, 75% for OSEM-APS and 102% for OSEM-APSV. Our findings indicate that the correction for degradations increases the quantification accuracy, with PVE compensation playing a major role in the SUR quantification. The proposed methodology allows us to reach similar SUR values for different SPECT systems, thereby allowing a reliable standardisation in multicentric studies.


Towards realization of longer life.
The current demographic situation in the world is characterized by an increase in average life expectancy, low birth rate, as well as an increase in the number of older and senior people, which is why our epoch is referred to as «the age of ageing». [...].


Cerebral glucose utilization: comparison of [14C]deoxyglucose and [6-14C]glucose quantitative autoradiography.
The [14C]deoxyglucose [Sokoloff et al., J. Neurochem. 28, 897-916 (1977)] and [6-14C]glucose [Hawkins et al., Am. J. Physiol. 248, C170-C176 (1985)] quantitative autoradiographic methods were used to measure regional brain glucose utilization in awake rats. The spatial resolution and qualitative appearance of the autoradiograms were similar. In resting animals, there was no significant difference between the two methods among 18 gray and three white matter structures over a fourfold range in glucose utilization rates (coefficient of correlation = 0.97). In rats given increasing frequencies of photoflash visual stimulation, the two methods gave different results for glucose utilization within visual pathways. The linearity of the metabolic response was studied in the superior colliculus using an on-off checkerboard stimulus between 0 and 33 Hz. The greatest increment in activity occurred between 0 and 4 Hz stimulation with both methods, probably representing recruitment of neuronal elements into activity. Above 4 Hz, there was a progressive increase in labeling with [14C]deoxyglucose up to 1.7 times control at 33 Hz. With [6-14C]-glucose, there was no further increment in change above a 30% increase seen at 4 Hz. Measurement of tissue glucose revealed no drop in the visually stimulated structures compared to control. We interpret these results to indicate that, with increasing rates of physiological activity, the products of deoxyglucose metabolism accumulate progressively, but the products of glucose metabolism are removed from brain in 10 min.


Effects of acetylcholine and cyclic GMP on input resistance of cortical neurons in awake cats.
The effects on input resistance (Rm) of extracellular iontophoresis of acetylcholine (ACh) and of intracellular iontophoresis of cyclic GMP (cGMP) were studied in neurons of the coronal-pericruciate cortex of awake cats. Control studies were also conducted including iontophoresis of saline extracellularly and 5'-GMP intracellularly. (1) Substantial increases in Rm occurred in approximately half the neurons given ACh or cGMP. (2) In the absence of associated repetitive spike discharge induced by intracellular injection of depolarizing current pulses during iontophoretic applications, the increases in Rm were transient occurring in less than 30 sec and lasting 4--5 min. (3) With associated current-induced spike discharge, the increases in Rm persisted for as long as the neurons could be held -- up to 1.5 h maximally. (4) Rm was not increased if saline was substituted for ACh, if 5'-GMP was substituted for cGMP, or if the neuron was only discharged repeatedly. (5) The magnitude and time course of both transient and persistent increases in Rm were comparable between cells given ACh or cGMP and whether action potentials and resting potentials were greater than or equal to 40 mV (average 47 mV)* or were less.


Severe rhabdomyolysis with hypoglycemia in an adult patient with carnitine palmitoyltransferase II deficiency.
Carnitine palmitoyltransferase II (CPT2) deficiency is an inherited disorder associated with rhabdomyolysis. The adult form of CPT2 deficiency is usually "benign", characterized by episodes of rhabdomyolysis without extramuscular manifestations and with a good outcome, while the infantile type characteristically presents with severe metabolic symptoms such as hypoketotic hypoglycemia. We present here a case of severe rhabdomyolysis with acute renal failure and hypoglycemia in an adult patient with CPT2 deficiency.


Effect of β3-adrenergic receptor gene polymorphism and lifestyle on overweight Japanese rural residents: A cross-sectional study.
The β3-adrenergic receptor (ADRB3) gene polymorphism has been implicated in obesity. Therefore, the contribution of ADRB3 Trp64Arg polymorphism to obesity-related indicators was investigated, taking into account the lifestyle-related factors in a Japanese rural population. A total of 600 Japanese adults aged ≥40 years in a population-based cohort study were analyzed. The ADRB3 polymorphism was determined using peripheral blood samples. Associations between genotype and body mass index (BMI), waist circumference (WC), and body fat (BF) percentage were examined, adjusting for lifestyle-related factors, including daily nutrient intake. The frequency of Arg64 allele carriers was 36%. There was no significant difference in BMI, WC, or BF between the groups with or without the Trp64Arg polymorphism. Multivariable logistic regression analysis showed that the Trp64Arg polymorphism was not associated with these three indicators, but lifestyle factors including physical inactivity, higher energy and sodium consumption, and less animal protein intake were significantly related to increased WC and BF percentages. The Trp64Arg polymorphism of ADRB3 gene did not contribute to increased BMI, WC, or BF. However, lifestyle-related factors impacted these indicators in middle-aged and older Japanese individuals living in rural areas.


Women's and physicians' utilities for health outcomes in estrogen replacement therapy.
Estrogen replacement therapy (ERT) prevents fractures and relieves vasomotor symptoms, but it increases the risk of endometrial cancer. Previous studies and national prescribing patterns show that physicians are conservative in their approach to this therapy. The authors interviewed physicians and perimenopausal women to assess their utilities for the various health outcomes of estrogen replacement therapy. On all outcomes, physicians rated illness episodes followed by recovery as being closer to perfect health than did perimenopausal women. Physicians, in judging which outcomes were most important to women, estimated relief of symptoms above fracture prevention, whereas women rated fracture prevention above symptom relief. These results emphasize the need to assess patients' utilities directly, particularly when utilities for the outcome of a particular therapy may influence the choice of a therapeutic regimen.


Calcium transport by permeabilised rabbit small intestinal epithelial cells.
Intestinal epithelial cells isolated from rabbit small intestine and whose plasma membrane had been rendered highly permeable were used to study the role of intracellular structures in Ca2+ buffering. Monitoring free Ca2+ with a selective electrode revealed that the cells could reduce Ca2+ concentration in the medium to a level of 3.6 X 10(-7) M independently, within a certain range, of the initial Ca2+ concentration or amount of cells used. Ca2+ buffering by permeabilised enterocytes was Mg2+- and ATP-dependent and was abolished in the presence of the Ca2+ ionophore A23187. The rapidity of Ca2+ buffering, but not the final Ca2+ level attained, was reduced in the combined presence of the mitochondrial inhibitors azide and oligomycin or in the presence of ruthenium red. Buffering of Ca2+ was abolished in the presence of vanadate, although some uptake was still observed. Complete blocking occurred in the presence of both vanadate and mitochondrial inhibitors. Measurement of initial rates of uptake with radioactive calcium revealed that mitochondrial uptake plays a role at relatively high Ca concentrations but that at the presumably physiological levels most of the uptake is into a non-mitochondrial compartment. Non-differentiated crypt cells seemed to handle intracellular Ca2+ in a similar way as mature villus cells, although they appeared to buffer at a level about 2 X 10(-7) M lower.


Ionizing radiation enhances the engraftment of transplanted in vitro-derived multipotent astrocytic stem cells.
The subependymal zone (SEZ) is a region of persistent neurogenesis in the adult mammalian brain containing a neural stem cell (NSC) pool that continuously generates migratory neuroblasts that travel in chains through the rostral migratory stream (RMS) to the olfactory bulb (OB), where they differentiate and functionally integrate into existing neural circuitry. NSCs can be isolated from the SEZ and cultured to generate either neurospheres (NSs) or multipotent astrocytic stem cells (MASCs), with both possessing the stem cell characteristics of multipotency and self-renewal. NSs and MASCs home to the SEZ after transplantation into the lateral ventricle (LV) and contribute to neuroblast migration, with minimal engraftment into the OB observed in the adult mouse. Recent studies have compared the relatively uncharacterized NSC with the more established hematopoietic stem cell (HSC) in an effort to determine the level of stemness possessed by the NSC. Depletion of native HSCs in the bone marrow by lethal irradiation (LI) is necessary to maximize functional engraftment of donor HSCs. Our data show that the NSC pool and neuroblasts in the SEZ can be significantly and permanently depleted by exposure to LI. Attenuation of donor-derived migratory neuroblast engraftment into the OB is observed after transplantation of gfp+ MASCs into the LV of LI animals, whereas engraftment is significantly enhanced after transplantation into animals exposed to sublethal levels of ionizing radiation. By increasing receptiveness of the NSC niche through depletion of indigenous cells, the adult SEZ-RMS-OB can be used as a model to further characterize the NSC.


Quantitative evaluation of functional capacity during isoniazid therapy in Huntington's disease.
Eleven patients with Huntington's disease were treated with high doses of isoniazid. In addition to clinical assessment, the functional capacity was evaluated quantitatively. The symptoms of four of the patients showed a marked improvement and their functional capacity increased. The condition of one patient with the rigid form (Westphal's variant) deteriorated, and the remaining six patients showed no change. Patients with prominent mental disturbances appeared to respond best to isoniazid therapy.


Corrigendum: Evaluation and management of systemic corticosteroids-induced ocular hypertension in children with non-Hodgkin lymphoma.
[This corrects the article DOI: 10.3389/fped.2022.982224.].


Expanding the phenotypic spectrum of lipomatosis of the sciatic nerve: Early-onset colonic diverticular disease.
Lipomatosis of nerve (LN) is a complex peripheral nerve disorder characterized by fibrofatty nerve enlargement. MRI of this pathology is pathognomonic and obviates a diagnostic biopsy. Mutation in PIK3CA has been associated with LN cases with nerve-territory overgrowth which may occur in some cases. We evaluate an association of LN of the sciatic nerve and early-onset colonic diverticular disease and discuss the potential pathogenesis. Our institutional database was searched for LN cases. Available information of identified cases was reviewed, and cases with a confirmed diagnosis of LN affecting the lumbosacral plexus and/or sciatic nerve; available MRI of the affected nerve(s); and diverticular disease occurring in the area supplied by the nerve(s) affected by LN were further analyzed. PIK3CA mutation testing was performed on available tissue samples. We identified 10 LN cases of lumbosacral plexus and/or sciatic nerve. Of these, three fulfilled our inclusion criteria. All three patients had concomitant colonic diverticular disease, diagnosed at a relatively young age. MRI studies of these cases showed LN involvement of the sacral nerves innervating the sigmoid colon. All three also had abnormal diagnostic workup including various GI tests and evidence of associated nerve-territory overgrowth. Colonic tissue samples for PIK3CA mutation were negative. While the pathogenesis of the colonic diverticular disease is increasingly recognized as being multifactorial, our observations are consistent with the potential role of autonomic nervous system dysfunction affecting either the pelvic floor musculature, or the colon itself (or both) in a subset of patients with early-onset diverticular disease.


Negative regulation of Sirtuin 1 by AMP-activated protein kinase promotes metformin-induced senescence in hepatocellular carcinoma xenografts.
Increasing evidence suggests that therapy-induced senescence (TIS), a novel therapeutic approach in which low doses of therapeutic drugs or radiation are used to induce senescence, suppresses tumor development. Our previous in vitro studies have demonstrated that a low dose of metformin promoted hepatoma cell senescence instead of apoptosis via activation of AMP-activated protein kinase (AMPK) and inactivation of Sirtuin 1 (SIRT1) deacetylase activity. However, the intricate relationship between AMPK and SIRT1, and how they cooperate to induce senescence remains elusive. We showed here that persistent exposure to a low concentration of metformin led to AMPK activation in a mouse xenograft model of human hepatocellular carcinoma (HCC), resulting in senescence. Intriguingly, AMPK counter-regulated SIRT1 via direct phosphorylation in metformin-mediated senescence in hepatoma cells. Taken together, these findings suggest that a low dose of metformin could potentially be used as a TIS-inducing therapeutic drug for HCC, and that this occurs by inducing senescence of HCC cells via the AMPK-SIRT1 pathway.


Digital Technology, Health and Well-Being and the Covid-19 Pandemic: It's Time to Call Forward Informal Carers from the Back of the Queue.
To describe the current challenges of family caregivers during and beyond the COVID-19 pandemic, the need for future digital innovations including involvement from professional nursing roles. Review of recent literature from PubMed and relevant health and care reports. The COVID-19 pandemic has caused monumental disruption to health care delivery and care. Caregivers face unprecedented levels of uncertainty: both for the people they care for and for their own health and well-being. Given that many carers face poor health and well-being, there is a significant risk that health inequalities will be increased by this pandemic, particularly for high-risk groups. Innovations including those supported and delivered by digital health could make a significant difference but careful planning and implementation is a necessity for widespread implementation. Carers need to be championed in the years ahead to ensure they do not become left at the "back of the queue" for health and well-being equity. This situation has been exacerbated by the COVID-19 pandemic. Disruptive change to health and social care is now required where digital health solutions hold considerable promise, yet to be fully realized.


Attributes of excellent attending-physician role models.
Although effective role models are important in medical education, little is known about the characteristics of physicians who serve as excellent clinical role models. We therefore conducted a case-control study to identify attributes that distinguish such physicians from their colleagues. We asked members of the internal-medicine house staff at four teaching hospitals to name physicians whom they considered to be excellent role models. A total of 165 physicians named by one or more house-staff members were classified as excellent role models (these served as the case physicians in our study). A questionnaire was sent to them as well as to 246 physicians who had residency-level teaching responsibilities but who were not named (controls). Of these 411 physicians, 341 (83 percent) completed questionnaires while unaware of their case-control status. Of the 341 attending physicians who responded, 144 (42 percent) had been identified as excellent role models. Having greater assigned teaching responsibilities was strongly associated with being identified as an excellent role model. In the multivariate analysis, five attributes were independently associated with being named as an excellent role model: spending more than 25 percent of one's time teaching (odds ratio, 5.12; 95 percent confidence interval, 1.81 to 14.47), spending 25 or more hours per week teaching and conducting rounds when serving as an attending physician (odds ratio, 2.48; 95 percent confidence interval, 1.15 to 5.37), stressing the importance of the doctor-patient relationship in one's teaching (odds ratio, 2.58; 95 percent confidence interval, 1.03 to 6.43), teaching the psychosocial aspects of medicine (odds ratio, 2.31; 95 percent confidence interval, 1.23 to 4.35), and having served as a chief resident (odds ratio, 2.07; 95 percent confidence interval, 1.07 to 3.98). These data suggest that many of the attributes associated with being an excellent role model are related to skills that can be acquired and to modifiable behavior.


Novel thiophene Chalcones-Coumarin as acetylcholinesterase inhibitors: Design, synthesis, biological evaluation, molecular docking, ADMET prediction and molecular dynamics simulation.
A series of around eight novel chalcone based coumarin derivatives (23a-h) was designed, subjected to in-silico ADMET prediction, synthesized, characterized by IR, NMR, Mass analytical techniques and evaluated as acetylcholinesterase (AChE) inhibitor for the treatment of Alzheimer's disease (AD). The results of predicted ADMET study demonstrated the drug-likeness properties of the titled compounds with developmental challenges in lipophilicity and solubility parameters. The in vitro assessment of the synthesized compounds revealed that all of them showed significant activity (IC50 ranging from 0.42 to 1.296 µM) towards AChE compared to the standard drug, galantamine (IC50 = 1.142 ± 0.027 µM). Among these, compound 23e displayed the most potent inhibitory activity with IC50 value of 0.42 ± 0.019 µM. Cytotoxicity of all compounds was tested on normal human hepatic (THLE-2) cell lines at three different concentrations using the MTT assay, in which none of the compound showed significant toxicity at the highest concentration of 1000 µg/ml compared to the control group. Based on the docking study against AChE, the most active derivative 23e was orientated towards the active site and occupied both catalytic anionic site (CAS) and peripheral anionic site (PAS) of the target enzyme. In-silico studies revealed tested showed better inhibition activity of AChE compared to Butyrylcholinesterase (BuChE). Molecular dynamics simulation explored the stability and dynamic behavior of 23e- AChE complex.


Clinical factors associated with positive corneal culture in suspected microbial keratitis.
Determine demographic and clinical characteristics associated with positive culture in suspected microbial keratitis. Retrospective audit of patients that had corneal scrapings between October 1999-September 2004 at Princess Alexandra Hospital. Clinical information was gathered from medical records, smear and culture results from the local microbiology database. Univariate and multivariate analyses of variables associated with positive cultures and calculation of population attributable risk percentage (PAR). Univariate analysis showed that positive cultures were associated with patients over 60 years (81% vs 55%; p < 0.001), presenting visual acuity (VA) of 6/24 or worse (74% vs 57%; p = 0.012) or contact lens-related keratitis (CLK 77% vs 62%; p = 0.08). Analysis of patients' clinical presentation showed that positive culture was associated with a central epithelial defect (74% vs 57%; p = 0.012), anterior chamber reaction of 2 + cells or worse (73% vs 56%; p = 0.03), an epithelial defect of 2 mm or more in diameter (71% vs 50%; p = 0.006) or no prior treatment with antibiotics (68% vs 56%; p = 0.053). Multivariate analysis showed the independent variables associated with positive cultures were VA of 6/24 or worse on presentation, contact lens-related keratitis, age greater than 60 years, an anterior chamber reaction of 2 + cells or worse and no prior treatment with antibiotics. The factor with the highest attributable risk (PAR%) for a positive corneal scraping was VA of 6/24 or worse on presentation (21%). In this series positive cultures were associated with poor presenting VA contact lens keratitis (CLK), older age, anterior chamber reaction and no prior treatment with antibiotics.


Carbohydrate changes during growth and fruiting in Pleurotus ostreatus.
The carbohydrate distribution in mushrooms is reported changing greatly in its different regions during growth and fruiting. In this study, the carbohydrate distribution in the compost and fruiting bodies of Pleurotus ostreatus was analysed. Sugar, polyol, polysaccharide, and chitin content during different growth phases and in different regions of the mushroom were determined. Results indicate that trehalose, mannitol, and glucose were first accumulated in the compost and then decreased during differentiation and growth of fruiting bodies. Meanwhile, trehalose, mannitol, and glucose also accumulated in the fruiting bodies and primarily distributed in the stipe, base, and pileus region, respectively. Polysaccharides mainly accumulated within the pileus and stipe regions, and chitin was mainly observed in the base region. These findings provide insights into carbohydrate function and utilisation during mushroom growth.


Aceclofenac-loaded unsaturated esterified alginate/gellan gum microspheres: in vitro and in vivo assessment.
Aceclofenac-loaded alginate/gellan gum microspheres for prolonged aceclofenac release were prepared through maleic anhydride-induced unsaturated esterification. The drug entrapment efficiency of these microspheres was found 39.30 ± 1.28% to 98.46 ± 0.40% and their average particle sizes were 270-490 μm. These microspheres were characterized by FTIR, DSC, P-XRD and SEM analysis. The in vitro dissolution indicated prolonged sustained release of aceclofenac over 6h, which also followed the Korsmeyer-Peppas model (R(2)=0.9571-0.9952). The microspheres prepared through 3% (w/v) maleic anhydride-induced esterification exhibited comparatively slower drug-release. Most of the microspheres were followed Fickian diffusion mechanism except the microspheres containing higher gellan gum content, which followed anomalous (non-Fickian) diffusion. The in vivo results showed sustained systemic absorption of aceclofenac in rabbits and excellent anti-inflammatory activity in carrageenan-induced rats after oral administration over prolonged period.