Correlates of change in subjective well-being among the elderly.
This study examines two related issues concerning the subjective well-being of elderly adults: change over time and correlates of that change. Data come from a three-wave panel study of 401 elderly residents in St. Louis. Residualized change score regression analyses indicate: there is change in subjective well-being over 4-5 months and over 12 months; the 4-5 month and 12 month changes are remarkably similar; the effect of subjective well-being over time indicates regression to the mean; and, only socioeconomic status is a significant predictor of change in subjective well-being (net of the effects of subjective well-being itself). The implications of these results for our understanding of subjective well-being in the elderly are discussed, as are the policy implications of the positive effect of socioeconomic status on changes in the subjective well-being of the elderly.


Erratum: Withdrawal notice to 'WITHDRAWN: Specific protein-protein interactions limit the cutaneous iontophoretic transport of interferon beta-1B and a poly-ARG interferon beta-1B analogue' [International Journal of Pharmaceutics 589 (2020) 119913].
[This corrects the article DOI: 10.1016/j.ijpx.2020.100051.].


Collateral Capacity Assessment : Robustness and Interobserver Agreement of Two Grading Scales and Agreement with Quantitative Scoring.
Intracranial collateral capacity is conducive to imply parenchymal perfusion of affected territory after acute vessel occlusion. The Tan collateral score is commonly used to assess the intracranial collateral capacity; however, this score is coarsely grained and interobserver agreement is low, which reduces prognostic value and clinical utility. We introduce and evaluate an alternative extended Tan score based on the conventional Tan scale and assess the agreement with a quantitative score. We included 100 consecutive patients with a proven acute single large vessel occlusion of the proximal anterior circulation. Collaterals were graded with the conventional and extended Tan score and an automated quantitative score. The extended Tan score is a finer 6‑scale manual score based on the conventional 4‑point Tan scale. The quantitative score is calculated by an automatic software package (StrokeViewer). Interobserver agreement of the manual scores was assessed with the weighted kappa. The Spearman correlation coefficient was calculated to determine the agreement between the manual and automated collateral scores. The interobserver agreement was higher for the extended score than for the conventional score with a weighted kappa of 0.70 and 0.65, respectively. For the extended and conventional score, the Spearman correlation coefficient for the agreement with the automated score was 0.78 and 0.76, respectively. Because of the good interobserver agreement and good agreement with quantitative assessment, the extended collateral score is a strong candidate to improve prognostic value of collateral assessment and implementation in clinical practice.


Unconscious fearful body perception enhances discrimination of conscious anger expressions under continuous flash suppression.
The continuous flash suppression (CFS) paradigm is increasingly used to study unconscious visual perception. Our goal was to use CFS and to to compare the results with previous findings from patients with brain lesions, and studies of healthy participants. We used an emotion discrimination task and bilaterally presented whole-body postures expressing fear or anger, rendering the stimuli invisible in either one of the visual fields. We found that the CFS presentation did not yield the classical redundant target effect of response facilitation when the unconsciously seen stimuli had congruent emotions; instead we found a facilitation effect in reaction times by body stimuli of incongruent emotions, especially by the unconscious fearful body facilitating discrimination of conscious angry body. Our results with healthy participants showed similarities to hemianopia patients without blindsight, but not to blindsight or neglect patients, indicating that unconscious visual processing is not a single phenomenon, but is likely to involve multiple mechanisms, processes and brain regions. Further studies are necessary to validate the facilitation effect of fearful bodies on other tasks, and to study the neural substrates of this effect.


Developing a transcriptomic framework for testing testosterone-mediated handicap hypotheses.
Sexually selected traits are hypothesized to be honest signals of individual quality due to the costs associated with their maintenance, development, and/or production. Testosterone, a sex steroid associated with the development and/or production of sexually selected traits, has been proposed to enforce the honesty of sexually selected traits via its immunosuppressive effects (i.e., the Immunocompetence Handicap Hypothesis) and/or by influencing an individual's exposure/susceptibility to oxidative stress (i.e., the Oxidation Handicap Hypothesis). Previous work testing these hypotheses has primarily focused on physiological measurements of immunity or oxidative stress, but little is known about the molecular pathways by which testosterone could influence immunity and/or oxidative stress pathways. To further understand the transcriptomic consequences of experimentally elevated testosterone in the context of handicap hypotheses, we used previously published RNA-seq data from studies that measured the transcriptome of individuals treated with either a testosterone-filled or an empty (i.e., control) implant. Two studies encompassing three species of bird and three tissue types fit our selection criteria and we reanalyzed the data using weighted gene co-expression network analysis. Testosterone-treated individuals exhibited signatures of immunosuppression and our results describe the molecular pathways underlying this effect. We also provide some evidence to suggest that the transcriptomic signature of immunosuppression is evolutionarily conserved between the three species. While our results provide no evidence to suggest testosterone mediates handicaps via pathways associated with oxidative stress, they do support the hypothesis that testosterone enforces the honesty of sexually-selected traits by influencing an individual's immunocompetence. Overall, this study develops a framework for testing testosterone-mediated handicap hypotheses and provides guidelines for future integrative and comparative studies focused on the proximate mechanisms mediating sexually selected traits.


Investigation of early antibiotic use in pediatric patients with acute respiratory infections by high-performance liquid chromatography.
In this study, we developed and validated two reliable high-performance liquid chromatography (HPLC) methods for the qualitative detection of six oral β-lactams, which are commonly used in pediatric patients with acute respiratory infections (ARIs). Two distinct reverse-phase chromatographic separations of six β-lactams were obtained. Four β-lactams (cefadroxil, cephalexin, cefaclor and cefixime) in urine were separated using a gradient program with a mobile phase consisting of K2 HPO4 buffer (20 mm, pH 2.8) and acetonitrile on a LichroCART 250 × 4.6 mm, Purospher STAR C18 end-capped (5 μm) column. Two remained β-lactams (amoxicillin and cefuroxime) were analyzed using a gradient elution with the mobile phase containing K2 HPO4 buffer (20 mm, pH 3.0) and acetonitrile on a LichroCart® Purospher Star C8 end-capped column (5 μm, 125 × 4.6 mm). Good linearity within the range of 0.3-30 μg/ml for cefadroxil, cephalexin, cefaclor and cefixime, and 0.2-20 μg/ml for amoxicillin and cefuroxime, was attained. The precisions were <14%. The accuracies ranged from 85.87 to 102.8%. The two validated methods were then applied to determine these six antibiotics in 553 urine samples of pediatric patients with ARIs. As a result, 32.2% were positive with one or more of six tested β-lactams. Cefixime was the most commonly detected agent, accounting for 9.8% of enrolled patients.


The role of endothelin and endothelin antagonists in traumatic brain injury: a review of the literature.
To date, there is increasing evidence for the role of endothelins in the pathophysiological development of cerebral vasospasms associated with a variety of neurological diseases, e.g., stroke and subarachnoid hemorrhage. In contrast, only little is known regarding the role of endothelins in impaired cerebral hemodynamics after traumatic brain injury. Therapeutic work in blocking the endothelin system has led to the discovery of a number of antagonists potentially useful in restoring cerebral blood flow after traumatic brain injury, potentially reducing the detrimental effects of secondary brain injury. Therefore, the present work provides an overview of background topics such as structures and biosynthesis of endothelins, different types as well as potential mechanisms and sites of action. In addition, the role of age for the effects of endothelins on cerebral hemodynamics after traumatic brain injury is discussed. Description of data supporting the role of the endothelins play in a host of neurological deficits. Endothelin antagonists may be effective as novel treatments for various neuropathologies.


An integrated DEMATEL-MMDE-ISM approach for analyzing environmental sustainability indicators in MSMEs.
The Micro, Small and Medium Enterprises (MSMEs) face numerous environmental challenges encompassing resource and energy conservation; waste generation and disposal; water and air pollution; and so on. As a result, it becomes critical to implement policies, strategies, and technologies that can help in reducing the adverse impacts of manufacturing activities on the environment. In this context, the current study identified 15 critical environmental sustainability indicators to assess the impact of manufacturing activities on the environment by taking a case study of lock manufacturing MSMEs. To understand the interdependence among the selected indicators, the study further utilizes an integrated DEMATEL-MMDE-ISM approach to analyze the inputs of industry professionals. The results of the study highlighted that green product design, which facilitates the product to be disassembled, reused, or recycled and are free from hazardous materials, plays a significant role in enhancing the environmental sustainability of the concerned industry. Green product design significantly affects 12 other indicators out of 15 under consideration; thus, incorporating green practices in the design and development of a product leads to significant improvement in environmental sustainability. The study is expected to aid decision-makers (industry practitioners and academic researchers) to identify strategic areas in order to achieve higher environmental sustainability in manufacturing organizations.


Metavalent Bonding in Crystalline Solids: How Does It Collapse?
The chemical bond is one of the most powerful, yet much debated concepts in chemistry, explaining property trends in solids. Recently, a novel type of chemical bonding was identified in several higher chalcogenides, characterized by a unique property portfolio, unconventional bond breaking, and sharing of about one electron between adjacent atoms. This metavalent bond is a fundamental type of bonding in solids, besides covalent, ionic, and metallic bonding, raising the pertinent question as to whether there is a well-defined transition between metavalent and covalent bonds. Here, three different pseudo-binary lines, namely, GeTe1- x Sex , Sb2 Te3(1- x ) Se3 x , and Bi2-2 x Sb2 x Se3 , are studied, and a sudden change in several properties, including optical absorption ε2 (ω), optical dielectric constant ε∞ , Born effective charge Z*, electrical conductivity, as well as bond breaking behavior for a critical Se or Sb concentration, is evidenced. These findings provide a blueprint to experimentally explore the influence of metavalent bonding on attractive properties of phase-change materials and thermoelectrics. Particularly important is its impact on optical properties, which can be tailored by the amount of electrons shared between adjacent atoms. This correlation can be used to design optoelectronic materials and to explore systematic changes in chemical bonding with stoichiometry and atomic arrangement.


[A review of multiple sclerosis (1). Presentation of a case].
Multiple sclerosis is a major demyelinating disease of the central nervous system. It has a significant economic and social impact. Its etiology is unclear, although there are several hypotheses, such as infections or genetics. In its pathophysiology, it seems that immune activation attacks the myelin sheath, causing a progressive and irreversible axonal degeneration. The disease produces a variety of symptoms, and diagnosis requires fulfilling a number of criteria and the exclusion of other possible causes. The role of neuroimaging, especially MRI, is very important. Despite the availability of disease-modifying drugs, none of them are able to halt its progress, and the most useful drugs are those designed to alleviate the symptoms of outbreaks. Overall, multiple sclerosis requires a significant effort in research to clarify not only why and how it occurs, but also to develop of new measures to improve the life of affected patients.


The effect of short-term intensive insulin therapy on inflammatory cytokines in patients with newly diagnosed type 2 diabetes.
Diabetes mellitus was a chronic low-grade inflammatory disease and had increased circulating inflammatory cytokines and acute phase proteins. We aimed to identify the changes of inflammatory cytokines in newly diagnosed type 2 diabetic patients after short-term intensive insulin therapy using continuous subcutaneous insulin infusion (CSII). Thirty-three newly diagnosed type 2 diabetic patients were enrolled between September 2020 to December 2020. Expression of 40 inflammatory cytokines of the patients were tested with RayBiotech antibody array before and after 1 week of intensive insulin therapy of CSII. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was carried out to explore the signaling pathway involved in the therapy. Five inflammatory cytokines were downregulated significantly after 1 week of CSII therapy. They were interleukin-6 receptor (IL-6R), regulated upon activation normal T-cell expressed and secreted (RANTES), intercellular adhesion molecule-1 (ICAM-1), tissue inhibitor of metalloproteinase-1 (TIMP-1), and platelet-derived growth factor type BB (PDGF-BB) (p < 0.05 and foldchange <0.83). Among patients with baseline glycated hemoglobin (HbA1c) < 10%, three proinflammatory cytokines were decreased significantly after therapy: IL-6R, RANTES, and ICAM-1. As for the patients with baseline HbA1c ≥ 10%, eight inflammatory cytokines were inhibited significantly after the treatment, including ICAM-1, IL-6R, RANTES, TIMP-1, TIMP-2, macrophage inflammatory protein-1 beta (MIP-1β), PDGF-BB, and tumor necrosis factor receptor type II (TNF RII). No matter which subgroup of baseline HbA1c level was considered, the decreased cytokines after CSII therapy were significantly involved in TNF signaling pathway. Nuclear factor-kappa B (NF-κB) signaling pathway was mainly enriched in patients with baseline HbA1c ≥ 10%. A panel of 40 inflammatory cytokines, measured by protein microarray, were evaluated for 1 week of CSII treatment in newly diagnosed type 2 diabetic patients. After treatment, many proinflammatory cytokines decreased. In the higher baseline HbA1c subgroup, more proinflammatory cytokines improved. No matter which subgroup of HbA1c level was considered, IL-6R, RANTES, and ICAM-1, which were involved in TNF signaling pathway, decreased significantly after CSII therapy. This was the first report showing that the cytokines of IL-6R, TIMP-2, PDGF-BB, and TNF RII decreased after the CSII therapy.


Disparities in pediatric drug-resistant epilepsy care.
Epilepsy affects millions of children worldwide, with 20-40% experiencing drug-resistant epilepsy (DRE) who are recommended for epilepsy surgery evaluation and may benefit from surgical management. However, many patients live with DRE for multiple years prior to surgical epilepsy referral or treatment or are never referred at all. We aimed to describe factors associated with referral for epilepsy surgery in the USA, in order to identify disparities in DRE, characterize why they may exist, and recognize areas for improvement. Pediatric patients diagnosed with DRE between January 1, 2004 and December 31, 2020 were identified from the Pediatric Health Information System (PHIS) Database. Patients treated with antiseizure medications (ASMs) only, ASMs plus vagus nerve stimulation (VNS), and ASMs plus cranial epilepsy surgery were studied regarding access to epilepsy surgery and disparities in care. This study used chi-square tests to determine associations between treatment time and preoperative factors. Preoperative factors studied included epilepsy treatment type, age, sex, race/ethnicity, insurance type, geographic region, patient type, epilepsy type, and presence of pediatric complex chronic conditions (PCCCs). A total of 18,292 patients were identified; 10,240 treated with ASMs, 5019 treated with ASMs + VNS, and 3033 treated with ASMs + cranial epilepsy surgery. Sex was not found to significantly vary among groups. There was significant variation in age, census region, race/ethnicity, patient type, presence of PCCCs, diagnosis, and insurance (p < 0.001). Those treated surgically, either with VNS or cranial epilepsy surgery, were 2 years older than those medically treated. Additionally, those medically treated were less likely to be living in the Midwest (25.46%), identified as non-Hispanic white (51.78%), have a focal/partial epilepsy diagnosis (8.74%), and be privately insured (35.82%). We studied a large administrative US database examining variables associated with surgical epilepsy evaluation and management. We found significant variation in treatment associated with age, US census region, race/ethnicity, patient type, presence of PCCCs, diagnosis, and health insurance type. We believe that these disparities in care are related to access and social determinants of health, and we encourage focused outreach strategies to mitigate these disparities to broaden access and improve outcomes in children in the USA with DRE.


Vertebral fracture in postmenopausal Chinese women: a population-based study.
In a random sample of postmenopausal Chinese women, the prevalence of radiographic vertebral fractures increased from 13% between ages 50 and 59 to over 50% after age 80 years. A model with seven clinical risk factors predicted the probability of vertebral fractures as well with as without BMD and better than a model with only three risk factors. More than half an hour of outdoor activity per day might correlate with lower risk of vertebral fracture in this population. We aimed to describe the prevalence and develop a model for prediction of radiographic vertebral fractures in a large random sample of postmenopausal Chinese women. We enrolled 1760 women from an age-stratified random sample of postmenopausal women in Beijing, China. The presence of vertebral fracture was assessed by semi-quantitative grading of lateral thoracolumbar radiographs, risk factors by interview, bone mineral density (BMD) of the proximal femur and lumbar spine by dual x-ray absorptiometry (DXA), and markers of bone turnover from a fasting blood sample. Associations of these factors were analyzed in logistic models and discrimination by areas of receiver operating characteristics curves (AUC). The prevalence of vertebral fracture, ranged from 13.4% ages 50 to 59 years old to 58.1% at age 80 years or older. Older age, a history of non-vertebral fracture, lower femoral neck BMD T-score, body mass index (BMI), height loss, housework, and less than half an hour of outdoor activity were significantly associated with increased probability of having a vertebral fracture. A model with those seven factors had a similar AUC with or without BMD and performed better than a simple model with three factors. This study is from a true random sample of postmenopausal women in urban China with high response rate. The prevalence of vertebral fractures in postmenopausal women in Beijing increases from 13% under age 60 to over 50% by age 80 years. A model with seven clinical risk factors with or without BMD is better than simple models and may guide the use of spine x-rays to identify women with vertebral fractures. More than half an hour of outdoor activity might correlate with lower risk of vertebral fracture in this population.


Pharmacokinetics and bioequivalence study of two mosapride citrate formulations after single-dose administration in healthy Chinese male volunteers.
The pharmacokinetics and relative bioavailability/bioequivalence of two formulations of mosapride citrate (CAS 112885-42-4) were assessed in this study. The study was conducted in 20 healthy Chinese male volunteers according to an open, randomized, single-blind, 2-way crossover study design with a wash-out phase of 7 days. Blood samples for pharmacokinetic profiling were taken up to 12 h post-dose, and mosapride citrate plasma concentrations were determined by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Based on the plasma concentration-time data of each individual during two periods, pharmacokinetic parameters, Cmax, AUCo-t,, AUCo-infinity, and t1/2, were calculated by applying non-compartmental analysis. Pharmacokinetic data for test and reference formulations were analyzed statistically to test for bioequivalence of the two formulations. After oral administration, the values of Cmax, Tmax, t1/2, AUCo-t, AUCo-infinity for test and reference formulations were 68.48 +/- 22.95 and 70.69 +/- 23.78 ng/mL, 0.46 +/- 0.20 and 0.49 +/- 0.21 h, 2.30 +/- 0.30 and 2.24 +/- 0.28 h, 161.17 +/- 52.75 and 171.37 +/- 59.02 ng x h/mL, 165.76 +/- 54.34 and 175.77 +/- 60.54 ng x h/mL, respectively. Both primary target parameters, AUCo-infinity and AUCo-t, were tested parametrically by analysis of variance (ANOVA). Relative bioavailabilities were 95.3 +/- 11.3% for AUCo-infinity and 95.2 +/- 11.3% for AUo-t. Bioequivalence between test and reference formulations was demonstrated for both parameters, AUJCo-infinity and AUCo-t. The 90% confidence intervals of the T/R-ratios of logarithmically transformed data were in the generally accepted range of 80-125%. That means that the test formulation is bioequivalent to the reference formulation of mosapride citrate.


Efficacy of steroid therapy on adult patients with severe pneumonia.
Optimal management of steroid therapy for severe pneumonia is an urgent issue. One hundred forty-eight elderly patients enrolled in our study were treated for severe pneumonia in a university hospital in Tokyo from 1998 through 2002. Steroid drugs were given to 82 patients (55.4%), whereas 66 (44.6%) received no steroids. Based on this main division, retrospective analyses were performed with regard to patient characteristics, antimicrobial agents, use or nonuse of mechanical ventilators, and prognoses. Significant difference was not seen in age, sex, underlying disease, isolated pathogens, and artificial respirator between the steroid and nonsteroid groups. Partial pressure of oxygen in arterial blood/fraction of inspired oxygen (Pao(2)/Fio(2)) ratio was significantly lower in the steroid (227.2 +/- 96.9) compared with the nonsteroid group (271.6 +/- 86.4) (P < 0.01). Prognoses were evaluated 21 days after treatment initiation. Significant differences appeared: First, the average cure rate of patients who took steroids within 3 days after starting treatment was 62.7%, whereas the rate was 12.9% (P < 0.001) in those who did not take steroids earlier than the 4th day. The cure rate of the nonsteroid group was 39.3% (P < 0.001). Second, the total dose of steroids (methylprednisolone) given within 7 days was less in cured cases (774 +/- 749 mg) than in noncured cases (1,190 +/- 768 mg) (P < 0.05). In conclusion, steroids should be administered in the early stage after onset of pneumonia, and large doses of steroids becomes a compounding factor in the prognosis of pneumonia.


1α,25-Dihydroxyvitamin D₃ inhibits neutrophil recruitment in hamster model of acute lung injury.
The chemokine interleukin-8 (IL-8) is involved in the pathogenesis of acute lung injury (ALI). Although several studies have reported that 1α,25-dihydroxyvitamin D(3) (1α,25(OH)(2)D(3)) suppresses IL-8 production in vitro and in vivo, 1α,25(OH)(2)D(3) has not been demonstrated to be effective in an animal model of ALI. Here, we determined its effects of 1α,25(OH)(2)D(3) in a hamster model where ALI was induced by lipopolysaccharide (LPS) inhalation. 1α,25(OH)(2)D(3) inhibited neutrophil recruitment in the lung by approximately 40% without increasing plasma calcium concentration, while it did not inhibit monocyte recruitment. Our findings show that vitamin D(3) analogues may be suitable as novel anti-inflammatory agents for ALI.


Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the ENIGMA-Anxiety Working Group.
The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5-90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.


The fish-hook configuration of the distal ureter indicates bladder outlet obstruction due to benign prostatic hyperplasia.
The aim of this retrospective study was to evaluate in a historical series of patients whether morphological changes of the urinary tract imaged on intravenous urography (IVU) are associated with clinical or urodynamic data. During a 1-year period, every man 45 years or older with lower urinary tract symptoms suggestive of benign prostatic hyperplasia was systematically evaluated with multi-channel computer-urodynamic investigation and IVU. Men with urinary retention, known bladder stones or diverticula, severely impaired renal function, or allergy to iodine contrast media were excluded. Structural alterations of the urinary tract were correlated with clinical and urodynamic data using logistic regression analysis. Data on 203 consecutive patients were available for analysis. Multivariate analysis demonstrated that the "fish-hook" configuration of the distal ureter (also known as "hockey-stick", or "J-shaped" ureter) was the only sign significantly associated with benign prostatic obstruction (BPO) (odds-ratio 3.64; 95% confidence interval 1.69-7.83; P < 0.001). The sensitivity, specificity, positive and negative predictive values of the "fish-hook" ureter configuration sign to detect BPO was 53, 76, 61 and 70%, respectively. Bladder trabeculation, upper urinary tract dilatation, or bladder base elevation were not associated with BPO, detrusor overactivity, detrusor underactivity, bladder low-compliance or any clinical data. The "fish-hook" shape of the distal ureter(s) indicates BPO and may be a result of prostate median lobe enlargement.


FaxMatch: Multi-Curriculum Pseudo-Labeling for semi-supervised medical image classification.
Semi-supervised learning (SSL) can effectively use information from unlabeled data to improve model performance, which has great significance in medical imaging tasks. Pseudo-labeling is a classical SSL method that uses a model to predict unlabeled samples and selects the prediction with the highest confidence level as the pseudo-labels and then uses the generated pseudo-labels to train the model. Most of the current pseudo-label-based SSL algorithms use predefined fixed thresholds for all classes to select unlabeled data. However, data imbalance is a common problem in medical image tasks, where the use of fixed threshold to generate pseudo-labels ignores different classes of learning status and learning difficulties. The aim of this study is to develop an algorithm to solve this problem. In this work, we propose Multi-Curriculum Pseudo-Labeling (MCPL), which evaluates the learning status of the model for each class at each epoch and automatically adjusts the thresholds for each class. We apply MCPL to FixMatch and propose a new SSL framework for medical image classification, which we call the improved algorithm FaxMatch. To mitigate the impact of incorrect pseudo-labels on the model, we use label smoothing (LS) strategy to generate soft labels (SL) for pseudo-labels. We have conducted extensive experiments to evaluate our method on two public benchmark medical image classification datasets: the ISIC 2018 skin lesion analysis and COVID-CT datasets. Experimental results show that our method outperforms fully supervised baseline, which uses only labeled data to train the model. Moreover, our method also outperforms other state-of-the-art methods. We propose MCPL and construct a semi-supervised medical image classification framework to reduce the reliance of the model on a large number of labeled images and reduce the manual workload of labeling medical image data.


Microdamage: a cell transducing mechanism based on ruptured osteocyte processes.
As a result of underlying pathological diseases, such as osteoporosis, osteopenia, or due to altered loading after joint replacements, bones become more susceptible to microdamage accumulation than those of normal human beings, as are those of athletes who undertake strenuous exercise [Stromsoe, 2004. Fracture fixation problems in osteoporosis. Injury 35, 107-113]. Experimental evidence has linked bone adaptation to microdamage, and to increased cell activity. In this work, we investigated whether microcrack detection is related to rupturing of the cellular material itself due to crack face displacements. Using specific cell staining techniques, it was confirmed that relative crack displacements are capable of tearing cell processes between neighbouring osteocytes. No ruptured cell processes were found near the crack tip where the displacements are less. Rupturing of cell processes due to crack opening and shear displacement is a feasible new mechanism by which bone can detect and estimate the size of a microcrack. Ruptured cell processes may directly secrete passive and active components in the extracellular matrix, triggering a repair response.


Diagnostic utility of immunohistochemical analysis and Epstein-Barr virus-encoded small RNAs in situ hybridisation of cell block sections obtained using fine-needle aspiration in nasopharyngeal carcinoma with lymph node metastasis.
This study aimed to investigate the diagnostic utility of immunohistochemistry (IHC) analysis (FNA) and Epstein-Barr virus- (EBV) encoded small RNAs (EBERs) in situ hybridisation analyses of cell block (CB) sections obtained using fine needle aspiration in nasopharyngeal carcinoma (NPC) with lymph node metastasis. A total of 38 FNA biopsies were collected using a Youyi aspirator. The cytomorphology, CB-based histomorphology, IHC, and EBERs in situ hybridisation were observed and the sensitivity/final diagnostic rates were compared with those of simple smears and a combination of smears and CBs. The 38 cases of metastatic lymph nodes from NPC displayed the morphological characteristics of non-keratinising carcinoma in cell smears and CB sections. The tumour cells showed high expression of CK5/6, P63, Ki-67, and EBERs (94.7%, 36/38 cases) in the CB sections. The sensitivity and the final diagnostic rates were lowest with the simple cell smears (86.8%, 33/38 and 71.1%, 27/38 cases), moderate with the smears combined with CB sections (92.1%, 35/38 cases and 81.6%, 31/38 cases), and the highest with IHC and EBERs in situ hybridisation (94.7%, 36/38 and 94.7%, 36/38 cases). FNA has great value in the diagnosis of NPC with lymph node metastases, and using cell smears combined with IHC and EBERs in situ hybridisation of CB sections could help clinical doctors promptly identify the primary lesions.


Night-to-night variability of polygraphy in children with sleep disordered breathing symptoms.
Polygraphy (PG) can be used as an alternative test for the diagnosis of obstructive sleep apnea syndrome (OSAS) in children. Night-to-night variability of PG in children is not known. Our aim was to determine whether a single night PG was reliable for OSAS diagnosis in children with symptoms of sleep-disordered breathing (SDB). Otherwise healthy children who had been evaluated for symptoms of SDB were included. Two nocturnal PGs were performed 2-7 days apart. Demographic and clinical characteristics, Pediatric Sleep Questionnaire, and modified Epworth Sleepiness Scale were recorded. OSAS was diagnosed if obstructive apnea-hypopnea index was (oAHI) ⩾ 1/h and classified as mild (oAHI: 1-4.9/h), moderate (oAHI: 5-9.9/h), and severe (oAHI ⩾ 10/h). Forty-eight patients were included (37.5% female, age 10.8 ± 3.9 years) to the study. There were no significant differences in oAHI values and other respiratory parameters between the two PGs (p > 0.05). Thirty-nine children were diagnosed with OSAS if the highest oAHI over any single night was used for diagnosis. Thirty-three of the 39 children (84.6%) were diagnosed with OSAS with the first PG while 35 of 39 (89.7%) children were diagnosed with OSAS with the second PG. There was an agreement for identifying OSAS and its severity between the two PGs in our study even though there were few individual intra-subject differences in oAHI. There was no significant first-night effect for PG in this study which suggests that a single night PG is adequate for diagnosis of OSAS in children with SDB- related symptoms.


Cost-effectiveness analysis of the available pneumococcal conjugated vaccines for children under five years in Colombia.
Pneumococcal diseases in children under five years are common and preventable. In Colombia there are two pneumococcal conjugate vaccines (PCV) that have proved clinical efficacy. The aim was to estimate the cost-effectiveness of 13-valent PCV (PCV13) and 10-valent PCV (PCV10) in terms of prevention of Invasive Pneumococcal Diseases (IPD), radiologically-confirmed pneumonia, and their related mortality, as well as, acute otitis media (AOM) in a cohort of newborns in Colombia. We developed an analytical decision tree model with national data including the distribution of pneumococcal serotypes in Colombia between 2009 and 2013. A simulation of vaccination of 90% of newborns in Colombia took place with a time horizon of 5 years. The analysis was done from the Colombian health system perspective. Vaccines efficacy parameters were measured as life-years gained (LYG) and avoided morbidity by pneumococcal diseases; they were determined by a systematic review of literature. A health insurance company provided the costs. A probabilistic and a univariate sensitivity analysis for epidemiological, efficacy and cost parameters were done. After 5 years projection, PCV13 would prevent 437 deaths due to pneumococcal infections versus 321 that would be prevented by PCV10, compared to no vaccination. PCV13 would generate 25 396 LYG, and PCV10 would generate 18 708 LYG. Medical costs avoided would be US$ 19 479 395 for PCV13 and US$ 13 703 271 for PCV10. Compared to no vaccination, PCV13 and PCV10 were cost-effective, with an incremental cost-effectiveness ratio (ICER) of US$ 489.26 and US$ 813.41 per additional LYG, respectively; besides, PCV13 was dominant over PCV10 due to lower costs and better outcomes. PCV13 is a cost-saving strategy compared with PCV10, as part of a universal coverage vaccination program in Colombian children under one year. PCV13 is expected to lead to a greater decrement in infant mortality from pneumococcal diseases, and a higher cost saving by preventing more pneumococcal diseases compared with PCV10 in a 5 years projection.


Clinical, pathologic, and molecular features of amphicrine prostate cancer.
Amphicrine prostate carcinoma (AMPC) is a poorly defined subset of prostate cancer in which cells co-express luminal prostate epithelial and neuroendocrine markers. The optimal treatment strategy is unknown. We sought to further characterize the clinical, histomorphologic, and molecular characteristics of AMPC and to identify areas of potential future treatment investigations. We retrospectively identified 17 cases of AMPC at a single institution, defined as synaptophysin expression in >70% of cells and co-expression of androgen receptor (AR) signaling markers (either AR, PSA, or NKX3.1) in >50% of cells. Clinical and histologic features of AMPC cases as well as response to treatment and clinical outcomes were described. Five AMPC cases arose de novo in the absence of prior systemic treatment and behaved distinctly from cases that were treatment-emergent. In these de novo cases, despite expression of neuroendocrine markers, prognosis appeared more favorable than high-grade neuroendocrine carcinoma, with two (40%) patients with de novo metastatic disease, universal response to androgen deprivation therapy, and no deaths at a median follow-up of 12.3 months. Treatment-emergent AMPC arose a median of 41.1 months after androgen deprivation therapy initiation and was associated with poor response to therapy. We show that amphicrine prostate cancer is a unique entity and differs in clinical and molecular features from high-grade neuroendocrine carcinomas of the prostate. Our study highlights the need to recognize AMPC as a unique molecularly defined subgroup of prostate cancer.


[Opioids and driving ability].
Clinical observations of patients under oral opioid treatment suggest that the initially appearing central side effects such as sedation, dizziness or drowsiness decrease after a few weeks of treatment. However, it is still unclear whether long-term treatment with opioids impairs complex psychomotor functions such as driving a car. Twenty patients on stable dosages of oral opioids were examined using a driving simulator. The patients were regular car drivers and not older than 70 years. Additionally, every patient had to complete a questionnaire for mental condition and vigilance and the "d II" letter cancellation task. Control groups tested in the same way were: patients before an elective operation after taking benzodiazepines for sedation, volunteers after alcohol consumption (0.80 per thousand ), physicians on call with less than 4 h of sleep and healthy volunteers without any medication. Some of the patients treated with opioids reacted as fast as medication-free volunteers. There were no significant differences between the reaction times of older patients (>50 years) receiving opioids in comparison to the group of older healthy volunteers. The same result was obtained in the letter cancellation task. No differences could be seen between medication-free volunteers and patients receiving opioids with regard to tasks of visual or motor control skills. The volunteers under influence of alcohol and the patients under benzodiazepines had a considerable decrease in performance. Long-term therapy with opioids does not inevitably impair complex skills, but the decision to permit driving a car can only be made in the individual case. At the beginning of therapy with opioids the physician has to fulfil his duty to inform the patient of any possible dangers of treatment. From the medical point of view, driving must be prohibited until a stable opioid dosage is reached. Any changes in dosage (increase, reduction), change of the opioid and poor general condition independent of the opioid therapy must result in prohibition of car driving. Continuous control of the therapy with documentation is a duty of the physician. The written documentation should include the patients' physical and mental condition, side effects and the therapeutic result. From the medical point of view, driving can be possible when dosage treatment and general condition remain stable. In any case, the doctor has to remind the patient of the responsibility of critical self-examination. In doubt, special performance investigation should be taken into consideration.


For Francisco Varela: explorer of the phenomenal world.
Francisco Varela was an innovative thinker and researcher as well as a pioneer in the present dialog between science and Buddhism. In this essay, I will first speak briefly about some of Francisco's contributions to the world at large and then relate a few vivid moments from my own interactions with him.


Biodegradation of glutaraldehyde-tanned human umbilical vein grafts.
A retrospective analysis of the long-term behavior of 111 glutaraldehyde-tanned human umbilical vein (HUV) grafts implanted between September 1977 and December 1993 was conducted. A total of 81 patients, with a mean age of 68.7 years, received the grafts and were followed up for between 1 and 131 months. The 5-year primary cumulative patency rate for above-knee femoropopliteal bypass was 83.1%, whereas that of other bypasses was 60.9%. An aneurysm of the graft was defined as a physically apparent localized dilatation, with diffuse ectasia being excluded. There were 11 aneurysms found in 9 grafts, 2 of which arose at the factory-made suture lines. The accumulated incidence of aneurysms had reached 21.9% by the 6th year. One aneurysm compressed the graft and resulted in limb-threatening ischemia and another resulted in frank rupture. Moreover, reinforcement of the mesh could not prevent aneurysm development, the repair of which is mandatory due to the risk of rupture and acute thrombosis. The HUV grafts showed an acceptable patency rate in the above-knee location, but the incidence of aneurysm formation after 5 years was abnormally high. Thus, both the risks and benefits of HUV grafts must be taken into account when considering their clinical application.


Towards real-time intravascular endoscopic magnetic resonance imaging.
Fast, minimally invasive, high-resolution intravascular imaging is essential for identifying vascular pathological features and for developing novel diagnostic tools and treatments. Intravascular magnetic resonance imaging (MRI) with active internal probes offers high sensitivity to pathological features without ionizing radiation or the limited luminal views of conventional X-rays, but has been unable to provide a high-speed, high-resolution, endoscopic view. Herein, real-time MRI endoscopy is introduced for performing MRI from a viewpoint intrinsically locked to a miniature active, internal transmitter-receiver in a clinical 3.0-T MRI scanner. Real-time MRI endoscopy at up to 2 frames/s depicts vascular wall morphological features, atherosclerosis, and calcification at 80 to 300 μm resolution during probe advancement through diseased human iliac artery specimens and atherosclerotic rabbit aortas in vivo. MRI endoscopy offers the potential for fast, minimally invasive, transluminal, high-resolution imaging of vascular disease on a common clinical platform suitable for evaluating and targeting atherosclerosis in both experimental and clinical settings.


Neurological Manifestations of Influenza A (H1N1): Clinical Features, Intensive Care Needs, and Outcome.
To describe neurological manifestations in children with Influenza A (H1N1). This retrospective study was conducted in the Pediatric intensive care unit (PICU) and Pediatric Neurology unit of a tertiary care teaching hospital in North India involving children with PCR confirmed Influenza A (H1N1) with neurological manifestations during 2019 outbreak. Six children (5 females, 1 male) were enrolled. All presented with neurological symptoms (seizures and altered sensorium) accompanied with fever and respiratory symptoms with duration of illness of 2-7 d. The admission Glasgow Coma Scale ranged from 4 to 12. Only 2 cases showed cerebrospinal fluid pleocytosis. Neuroimaging was suggestive of diffuse cerebral edema, acute necrotizing encephalopathy of childhood, and acute disseminated encephalomyelitis. All were treated with Oseltamivir. Four cases had clinical features of raised intracranial pressure (ICP) and were managed in PICU, 3 of them needed mechanical ventilation, 3 needed vasoactive drugs, 3 received 3% saline infusion, 1 underwent invasive ICP monitoring, and 3 (cases 4, 5 and 6) received intravenous methylprednisolone (30 mg/kg) for 5 d. Total duration of hospital stay was 10-30 d. Case 2 expired due to refractory raised ICP. Among survivors, 3 children had residual neurological deficits and the remaining 2 had achieved premorbid condition. Influenza A (H1N1) can present with isolated or predominant neurological manifestations which can contribute to poor outcome. The authors suggest to rule out H1N1 in any child who presents with unexplained neurological manifestations during seasonal outbreaks of H1N1.


Lateral oblique incision for the Charnley low friction arthroplasty.
An oblique incision of the lateral exposure improves access to the acetabulum.


The photically evoked afterdischarge: a model for the study of drugs useful in the treatment of petit mal epilepsy.
Lightly restrained albino rats were administered dipropylacetic acid, trimethadione, diphenylhydantoin, saline, and a pentylenetetrazol challenge. The results were attributed to the locus of action of the anticonvulsants and strongly support the usefulness of the photically evoked after discharge as a model for the evaluation of thalamically active drugs, with particular reference to those useful in the control of petit mal epilepsy.


Improving outcomes in the treatment of locally-advanced NSCLC with gemcitabine.
Multiple approaches of combined modality therapy have emerged as potential treatments for improving unresectable, locoregionally advanced non-small-cell lung cancer (NSCLC). Several agents have been used either sequentially or concurrently in clinical trials of combined chemoradiotherapy. However, no specific regimen has been clearly defined, particularly with regard to the timing of chemotherapy (sequential and/or concurrent), the specific chemotherapeutic drugs, and the dose and intensity of the radiation therapy. Concurrent chemoradiotherapy demonstrates a survival advantage compared to sequential chemoradiotherapy. Initial data suggest that induction chemotherapy prior to concurrent chemoradiotherapy does not further improve survival. The potent radiosensitizer gemcitabine has been evaluated in combination chemotherapy with radiation therapy and appears to be a promising agent, although further trials are needed to define its optimal dose, toxicity and efficacy.


The effects of chemical and physical penetration enhancers on the percutaneous permeation of lidocaine through equine skin.
The effect of physical and chemical permeation enhancers on in vitro transdermal permeation of lidocaine was investigated in the horse.Therefore, the effect of six vehicles (phosphate-buffered saline (PBS), 50% ethanol, 50% propylene glycol, 50% isopropylalcohol, 50% isopropylalcohol/isopropylmyristate and 50% dimethylsulfoxide) was examined as well as the effect of microneedle pretreatment with different needle lengths on transdermal drug delivery of lidocaine.The skin was obtained from the thorax of six Warmblood horses and was stored up to two weeks at - 20°C. Franz-type diffusion cells were used to study the transdermal permeation through split skin (600 μm thickness). The amount of lidocaine in the receptor fluid was determined by UV-VIS high-performance liquid chromatography. All investigated vehicle supplementations diminished the transdermal flux of lidocaine through equine skin in comparison to pure PBS except dimethylsulfoxide, which resulted in comparable permeation rates to PBS. The maximum flux (Jmax) was 1.6-1.8 fold lower for lidocaine applied in 50% ethanol, propylene glycol, isopropylalcohol and isopropylalcohol/isopropylmyristate. A significant higher Jmax of lidocaine was observed when lidocaine was applied in PBS onto microneedle pretreated skin with similar permeation rates in both needle lengths. After 6 hours, 1.7 fold higher recovery rates were observed in the microneedle pretreated skin samples than in the untreated control samples. The lagtimes were reduced to 20-50% in the microneedle pretreated skin samples. Microneedles represent a promising tool for transdermal lidocaine application in the horse with a rapid systemic bioavailability.


Blood group isoantigens in human benign and malignant vascular tumors.
Paraffin material of 31 benign and malignant vascular tumors was investigated with respect to their blood group isoantigen (BG) content by the mixed cell agglutination reaction (MCAR). In capillary hemangioma, BG was found in endothelial cells as well as in solid buds. Benign hemangioendothelioma found in endothelial cells as well as in solid buds. Benign hemangioendothelioma found in children differed from that found in adults in that in juvenile cases only endothelial cells expressed BG whereas in adult cases BG isoantigenity was present in endothelial cells as well as in intercapillary cellular elements. In pericytomas only endothelial cells were BG positive, whereas the tumor cells lacked BG. Similar results were obtained with glomus tumors. All but one hemangiosarcoma were BG negative. In one case, however, which probably resembled a "true" malignant hemangioendothelioma (Stout and Lattes, 1967) the tumor cells contained BG in conspicuous amounts.


Impact of Sex on COVID-19 Media Exposure, Anxiety, Perceived Risk, and Severity in Middle-Aged and Older Adults.
To examine associations between COVID-19 media exposure and anxiety/perceived risk/severity and investigate their dependency on sex in middle-aged/older adults. Adults aged 50+ years completed online surveys: Coronavirus Anxiety Scale, COVID-19 media exposure, COVID-19 media dependency for health information, and COVID-19 perceived risk and severity. Multiple regressions examined independent and interactive (with sex) associations between COVID-19 media exposure/dependency and COVID-19 anxiety/perceived risk and severity. Analyses controlled for age, education, race, total medical conditions, and COVID-19 status. Higher COVID-19 media exposure was associated with higher COVID-19 anxiety among men (not women) and higher perceived risk/severity in both sexes. Higher COVID-19 media dependency was associated with higher COVID-19 anxiety and perceived risk/severity in both sexes. In middle-aged/older adults, the use/dependency of media for COVID-19 information may be linked to negative psychological health and increased COVID-19 perceived risk and severity. Men may be at increased risk of anxiety related to media exposure.


Behavioural evidence for central D-2 dopamine receptor agonistic effect by some 2-(fluorohydroxyphenyl)ethylamines.
The IP injection of 2-(4-fluoro-3-hydroxyphenyl)ethylamines. (FDA 24), N-n-propyl-N-(2-phenylethyl)-2-(3-fluoro-4-hydroxyphenyl)ethylamine (FDA 27F) and N-n-propyl-N-(2-phenylethyl)-2-(4-fluoro-3-hydroxyphenyl) ethylamine (FDA 40) into adult male rats induced the stretching and yawning (SY) syndrome, FDA 24 being the least active. Moreover, FDA 27F and FDA 40 potentiated penile erection (PE) with respect to controls. For both signs (PE and SY), FDA 40 was the most potent of the three compounds. These effects, which are considered typical signs of central D-2-dopamine (DA) receptor stimulation, were dose-related and significantly inhibited by pretreatment with the selective D-2 DA antagonist, sulpiride, but not by domperidone, which does not cross the hematoencephalic barrier. In previous binding studies, FDA 27F and FDA 40 showed high affinity and selectivity for D-2 DA receptors, while FDA 24 had a low affinity for both D-1 and D-2 DA receptors. The present data show that FDA 27F and FDA 40 cross the blood-brain barrier and exert an agonistic effect on the central D-2 DA receptors. These results also provide evidence of the value of PE and SY tests as sensitive tools for the study of DA-neurochemical mechanisms.


Retraction Note: Simulation and spatiotemporal pattern of air temperature and precipitation in Eastern Central Asia using RegCM.
This paper has been retracted.


Phosphorylation and inactivation of rabbit skeletal muscle glycogen synthase: distinction between kinase Fa-, phosphorylase kinase-, and glycogen synthase (casein) kinase-1-catalyzed reactions.
Rabbit skeletal muscle glycogen synthase was phosphorylated by kinase Fa, phosphorylase kinase, and cAMP-independent synthase (casein) kinase-1 to determine the differences among these kinase-catalyzed reactions. The stoichiometry of phosphate incorporation, the extent of inactivation, and the sites of phosphorylation were compared. Synthase (casein) kinase-1 catalyzes the highest level of synthase phosphorylation (4 mol/subunit) and inactivation (reduction of the activity ratio to below 0.05). The sites, defined by characteristic tryptic peptides, phosphorylated by synthase (casein) kinase-1 are distinguishable from those by kinase Fa and phosphorylase kinase. In addition, synthase (casein) kinase-1, unlike kinase Fa, does not activate ATP X Mg2+-dependent protein phosphatase. These results demonstrate that synthase (casein) kinase-1 is a distinct glycogen synthase kinase.


Use of blood colour for assessment of arterial oxygen saturation in immobilized impala (Aepyceros melampus).
To determine the relationship between arterial blood colour [as defined by the International Commission on Illumination (CIE) L∗a∗b∗ colour space] and haemoglobin oxygen saturation [functional saturation (SaO2) and fractional saturation (FO2Hb)], and if arterial blood colour can be used to predict arterial haemoglobin oxygen saturation. Descriptive study as an adjunct to two prospective randomized crossover studies. A group of 10 wild caught adult female impala (Aepyceros melampus) weighing 34.1 ± 5.2 kg (mean ± standard deviation). Impala were immobilized with potent opioids (0.09 mg kg-1 of etorphine or thiafentanil). A total of 163 arterial blood samples were collected anaerobically into heparinized syringes from arterial cannulae and analysed immediately using spectrocolourimetry and co-oximetry. Data were analysed by modelling the relationship between predicted arterial blood colour CIE L∗a∗b∗ components and SaO2 and FO2Hb. The models were then used to predict values for L∗, a∗ and b∗ to produce a colour palette for the range of SaO2 and FO2Hb used. The modified version of the Farnsworth-Munsell hue test was used to assess the subjective ordering of the resulting colour palette by 20 observers. The second-order polynomial (quadratic) model produced the best fit for all three arterial blood colour CIE L∗a∗b∗ components for both SaO2 and FO2Hb. The regression models were used to generate predicted arterial blood colour CIE L∗a∗b∗ components for the midpoint of each decile over a range of SaO2 and FO2Hb percentages (15% to 95%). The resulting colour palettes were correctly ordered by all observers in the SaO2 range of 45-95% saturation. An association between arterial blood colour (as defined by CIE L∗a∗b∗ components) and SaO2 and FO2Hb exists, and arterial blood colour can be used to give a clinically useful estimate of arterial haemoglobin oxygen saturation in impala.


Resistance to chemotherapeutic antimetabolites: a function of salvage pathway involvement and cellular response to DNA damage.
The inherent or acquired (induced) resistance of certain tumours to cytotoxic drug therapy is a major clinical problem. There are many categories of cytotoxic agent: the antimetabolites, e.g. methotrexate (MTX), N-phosphonacetyl-L-aspartate (PALA), 5-fluorouracil (5-FU), 6-mercaptopurine (6-TG), hydroxyurea (HU) and 1-beta-D-arabinofuranosylcytosine (AraC); the alkylating agents, e.g. the nitrogen mustards and nitrosoureas; the antibiotics, e.g. doxorubicin and mitomycin C; the plant alkaloids, e.g. vincristine and vinblastine; and miscellaneous compounds, such as cisplatin. There are also many mechanisms of drug resistance elucidated principally from in vitro studies. These include mutation of target genes, amplification of target and mutated genes, differences in repair capacity, altered drug transport and differences in nucleoside and nucleobase salvage pathways (Fox et al, 1991). The aim of the present review is to evaluate in detail the mechanisms of response of both normal and tumour cells to three chemotherapeutic antimetabolites, MTX, PALA and 5-FU, which are routinely used in the clinic either alone or in combination to treat some of the commonest solid tumours, e.g. breast, colon, gastric and head and neck. The normal and tumour cell response to these agents will be discussed in relation to the operation of the known alternative 'salvage pathways' of DNA synthesis and current theories of DNA damage response.


High correlation between Zika virus NS1 antibodies and neutralizing antibodies in selected serum samples from normal healthy Thais.
Despite the widespread presence of the mosquito transmitted Zika virus (ZIKV) over much of Southeast Asia, the number of reported cases remains low. One possibility is that residents in Southeast Asia are immunologically protected, although the nature of any such protection remains unclear. This study sought to investigate the presence of antibodies directed to ZIKV NS1 protein in a selected sub-set of samples from a well characterized cohort of serum samples from normal, healthy Thais that had been previously characterized for the presence of neutralizing antibodies to ZIKV, DENV 1-4, and JEV. Because of similarities in molecular weight between the flavivirus E and NS1 proteins, an immunoblot system was established in which the NS1 antigen was not denatured, allowing detection of the dimer form of NS1, distinctly clear from the migration position of the E and NS1 monomer proteins. The results showed that antibodies to ZIKV NS1 protein were only detected in samples with ZIKV neutralizing antibodies (27/30 samples), and no sample (0/30) with a ZIKV plaque reduction neutralization test (PRNT)90 < 20 showed evidence of anti-ZIKV NS1 antibodies. The high correlation between the presence of ZIKV NS1 antibodies and ZIKV PRNT suggests that immunological protection against ZIKV infection in Thailand arises from prior exposure to ZIKV, and not through cross neutralization.


Towards zero-waste airports: a case study of Istanbul Airport.
In this day and age, an important indicator of sustainable waste management is zero-waste index. Zero-waste approach is adopted by many organizations in different sectors. In this context, implementation of sustainable waste management at airports, which have become the most vibrant centers of the transportation sector in the globalizing world, is one of the important environmental issues. In this study, the activities carried out in the Istanbul airport in 2019-2020 within the scope of sustainable waste management were evaluated within the framework of zero-waste approach. For this purpose, waste characterizations for different zones in the airport have been presented. When the methods used in the disposal of the wastes were examined, it was seen that recycling (43-49%) and landfilling (50-57%) took the first place. The results of the study reveal that the pandemic restrictions implemented in 2020 have caused significant differences in the amount and composition of waste generated. The highest decrease in waste generation occurred in Zone A where terminal activities are located, with 76%. This change was also reflected in the zero-waste index determined depending on the waste management strategies applied, and the values calculated for 2019 and 2020 were found to be 0.35 and 0.26, respectively. The online version contains supplementary material available at 10.1007/s10163-021-01308-2.


An innovative fluorescent probe targeting IGF1R for breast cancer diagnosis.
Breast cancer is the most dangerous, among all malignant tumors that threaten women's lives and health. Surgical resection can effectively prolong the survival time of patients with early breast cancer. Insulin-like growth factor type 1 receptor (IGF1R) is a member of the large family of receptor tyrosine kinases, and it's significantly overexpressed in breast cancer cells, which make them ideal biomarkers for the diagnosis and surgery navigation of breast cancer. Herein, we developed a series of IGF1R-targeted probes (YQ-L) for fluorescent imaging in breast cancer based on the strategy of drug repositioning. YQ-L exhibited specific IGF1R binding both in vitro and in vivo, especially probe 5d exhibited higher tumor uptake with a high tumor/normal ratio in the MCF-7 tumor bearing mouse. The maximum T/N ratio of probe 5d was 4.9, which was about 3 times that of indocyanine green (ICG). Meanwhile, probe 5d displayed more favorable in vivo pharmacokinetic properties than that of ICG with less hepatic and intestinal uptake. Convenient preparation, excellent IGF1R specificity in breast cancer, rapid clearance from normal organs and good biosafety profiles of probe 5d warrant further investigations for clinical translation in detection and surgery navigation of breast cancer.


Type and token bigram frequencies for two-through nine-letter words and the prediction of anagram difficulty.
Recent research on anagram solution has produced two original findings. First, it has shown that a new bigram frequency measure called top rank, which is based on a comparison of summed bigram frequencies, is an important predictor of anagram difficulty. Second, it has suggested that the measures from a type count are better than token measures at predicting anagram difficulty. Testing these hypotheses has been difficult because the computation of the bigram statistics is difficult. We present a program that calculates bigram measures for two-to nine-letter words. We then show how the program can be used to compare the contribution of top rank and other bigram frequency measures derived from both a token and a type count. Contrary to previous research, we report that type measures are not better at predicting anagram solution times and that top rank is not the best predictor of anagram difficulty. Lastly we use this program to show that type bigram frequencies are not as good as token bigram frequencies at predicting word identification reaction time.


The role of obesity in kidney disease: recent findings and potential mechanisms.
Obesity epidemic is in rise in almost every industrialized country and continues to be a growing problem worldwide. In fact, obesity per se has been recognized as a chronic disease. Consequently, there has been a cascade of metabolic changes initiated by the markedly risen prevalence that contributes to the increased incidence of diabetes, hypertension, and cardiovascular disease. Moreover, obesity is also associated with an increased risk of chronic kidney disease (CKD). The majority of the studies indicate a direct relationship between body mass index (BMI) and CKD risk. Moreover, current evidence emphasized the fact that central obesity measurements, such as waist circumference, could be a better predictor of CKD progression and mortality than BMI. The detrimental effects of obesity on kidney outcome have been recognized in nondialysis-dependent (NDD)-CKD patients. However, survival in overweight or obese CKD patients undergoing maintenance hemodialysis is paradoxically opposed compared with the general population. This "reverse epidemiology," however, is valid mainly for the inflammated end-stage renal disease (ESRD) patients. In fact, renal transplant recipients with higher BMI have inferior patient and graft survival compared to patients with lower BMI. This review also provides perspectives concerning the mechanisms associated with obesity, such as the renin-angiotensin-aldosterone system (RAAS) activation, and the role of leptin, adiponectin, fetuin-A, and adipose tissue, as factors that contribute to the development of CKD. Prevention strategies for CKD patients are also discussed and should be considered by clinicians.


Sex differences in time to primary percutaneous coronary intervention and outcomes in patients presenting with ST-segment elevation myocardial infarction.
We assessed sex differences in treatment and outcomes in ST-segment elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PCI). Historically, delays to timely reperfusion and poorer outcomes have been described in women who suffer STEMI. However, whether these sex discrepancies still exist with contemporary STEMI treatment remains to be evaluated. Consecutive STEMI patients treated with primary PCI patients over a 10-year period (January 1, 2010 to December 31, 2019) from a tertiary referral center were assessed. Comparisons were performed between patient's sex. Primary outcomes were 30-day and 1-year mortality. Secondary outcomes were STEMI performance measures. Most patients (n = 950; 76%) were male. Females were on average older (66.8 vs. 61.4 years males; p < 0.001). Prehospital treatment delays did not differ between sexes (54 min [IQR: 44-65] females vs. 52 min [IQR: 43-62] males; p = 0.061). STEMI performance measures (door-to-balloon, first medical contact-to-balloon [FMCTB]) differed significantly with longer median durations in females and fewer females achieving FMCTB < 90 min (28% females vs. 39% males; p < 0.001). Women also experienced greater rates of initial radial arterial access failure (11.3% vs. 3.1%; p < 0.001). However, there were no significant sex differences in crude or adjusted mortality between sexes at 30-days (3.6% male vs. 5.1% female; p = 0.241, adjusted OR: 1.1, 95% CI: 0.5-2.2, p = 0.82) or at 1-year (4.8% male vs. 6.8% female; p = 0.190, adjusted OR: 1.0, (95% CI: 0.5-1.8; p = 0.96). Small discrepancies between sexes in measures of timely reperfusion for STEMI still exist. No significant sex differences were observed in either 30-day or 1-year mortality.


The Role of the "O.R. Personnel" for Operative Gynecologic Endoscopy
The role of the operating room personnel in gynecologic surgery has changed dramatically during the past decade. This change has been a result of the development of gynecologic endoscopy, and more importantly, due to the addition of the videocamera to the laparoscope and hysteroscope. The attachment of the videocamera to the laparoscope and hysteroscope during surgery so that everyone present can follow the procedure on the videomonitor and appropriately anticipate the surgeon's needs has created an entirely new involvement for operating room personnel. This has made the contribution by personnel so important that many hospitals have recognized the need for an "endoscopy team." The "endoscopy team" generally refers to the surgeon, surgical assistant, scrub nurse or technician, nurse circulator, and laser nurse. Our purpose is to outline in detail the responsibilities of the "endoscopy team" specific to the O.R. personnel involved in these procedures. It is essential for these members of the team to be aware of their role to enable them to provide the appropriate assistance before, during, and after surgery.


Constructive eHealth evaluation: lessons from evaluation of EHR development in 4 Danish hospitals.
Information and communication sources in the healthcare sector are replaced with new eHealth technologies. This has led to problems arising from the lack of awareness of the importance of end-user involvement in eHealth development and of the difficulties caused by using traditional summative evaluation methods. The Constructive eHealth evaluation method (CeHEM) provides a solution to these problems by offering an evaluation framework for supporting and facilitating end-user involvement during all phases of eHealth development. The aim of this paper is to support this process by sharing experiences of the eHealth evaluation method used in the introduction of electronic health records (EHR) in the North Denmark Region of Denmark. It is the first time the fully developed method and the experiences on using the CeHEM in all five phases of a full lifecycle framework is presented. A case study evaluation of the EHR development process in the North Denmark Region was conducted from 2004 to 2010. The population consisted of clinicians, IT professionals, administrators, and vendors. The study involved 4 hospitals in the region. Data were collected using questionnaires, observations, interviews, and insight gathered from relevant documents. The evaluation showed a need for a) Early involvement of clinicians, b) The best possible representation of clinicians, and c) Workload reduction for those involved. The consequences of not providing this were a lack of ownership of decisions and negative attitudes towards the clinical benefits related to these decisions. Further, the result disclosed that by following the above recommendations, and by providing feedback to the 4 actor groups, the physicians' involvement was improved. As a result they took ownership of decisions and gained a positive attitude to the clinical benefits. The CeHEM has proven successful in formative evaluation of EHR development and can point at important issues that need to be taken care of by management. The method provides a framework that takes care of feedback and learning during eHealth development. It can thus support successful eHealth development in a broader context while building on a well-known success factor: end-user involvement in eHealth development.


What does it mean to decriminalize marijuana? A cross-national empirical examination.
Although frequently discussed as a singular policy, there is tremendous variation in the laws and regulations surrounding so-called decriminalization policies adopted by Western countries, with many jurisdictions adopting depenalization policies rather than policies that actually change the criminal status of cannabis possession offences. This paper provides a discussion of the liberalization policies being adopted in Western countries, highlighting distinct elements about particular policies that are important for proper analysis and interpretation of the policies. It then discusses some of the environmental factors that also shape these policies, and hence influence their potential impact, using data from the U.S.A. as a particular example. The results clearly show that researchers should be careful conducting intra- or international comparisons of policies because important aspects of these policies are frequently ignored.


Tackling maternal mortality by improving technical efficiency in the production of primary health services: longitudinal evidence from the Mexican case.
Ensuring regular and timely access to efficient and quality health services reduces the risk of maternal mortality. Specifically, improving technical efficiency (TE) can result in improved health outcomes. To date, no studies in Mexico have explored the connection of TE with either the production of maternal health services at the primary-care level or the maternal-mortality ratio (MMR) in populations without social security coverage. The present study combined data envelopment analysis (DEA), longitudinal data and selection bias correction methods with the purpose of obtaining original evidence on the impact of TE on the MMR during the period 2008-2015. The results revealed that MMR fell 0.36% (P < 0.01) for every percentage point increase in TE at the jurisdictional level or elasticity TE-MMR. This effect proved lower in highly marginalized jurisdictions and disappeared entirely in those with low- or medium-marginalization levels. Our findings also highlighted the relevance of certain social and economic aspects in the attainment of TE by jurisdictions. This clearly demonstrates the need for comprehensive, cross-cutting policies capable of modifying the structural conditions that generate vulnerability in specific population groups. In other words, achieving an effective and sustainable reduction in the MMR requires, inter alia, that the Mexican government review and update two essential elements: the criteria behind resource allocation and distribution, and the control mechanisms currently in place for executing and ensuring accountability in these two functions.


[Ten years after the Bologna Declaration: reflections for the third reform of nursing education in Italy].
After 10 years from Bologna Declaration the Italian nursing education in undergoing its third major reform to harmonize nursing education: educational objectives, level of competences to be guaranteed at basic and post basic level. Although there are ample differences across European Countries, there is a trend toward the continuous elevation of the level of the nursing education.


Epidermal growth factor and amphiregulin up-regulate matrix metalloproteinase-9 (MMP-9) in human breast cancer cells.
The EGF family of proteins encompasses several polypeptides such as epidermal growth factor (EGF), transforming growth factor alpha (TGF alpha), amphiregulin (AR) and heregulin (HRG-beta 1). These polypeptides regulate proliferation in breast cancer cells through interaction with membrane receptors. It has been previously shown that high EGF receptor number correlates with aggressive behavior and increased metastasis in human breast cancer. In the present study, we investigated the association between EGF and EGF-like ligand-induced DNA synthesis and secretion of MMP-9 and MMP-2 in metastatic SKBR-3 and non-metastatic MCF-7 breast cancer cells. Exposure of SKBR-3 cells to EGF or AR induces expression of MMP-9 but has no effect on MMP-2 secretion. In contrast to EGF and AR, HRG had no effect on gelatinase induction. None of the EGF polypeptides had any effect on gelatinase induction in MCF-7 non-metastatic breast cancer cells. While a relatively specific inhibitor of EGF receptor tyrosine kinase, PD 153035, inhibited EGF-, AR- and HRG-induced cell proliferation, it had no effect on MMP-9 induced by EGF and AR. Experimental evidence suggests that signaling mechanisms for cell proliferation and MMP-9 induction are mediated by different pathways down-stream of EGF receptor autophosphorylation or that low levels of EGF-induced signal that escape inhibition are sufficient to induce MMP-9 but unable to support cell proliferation. In addition, our results suggest that EGF and AR may modulate invasion of metastatic breast cancer cells by increasing the expression of MMPs.


Changes in depressive symptoms of older adults in the Czech Republic.
It is unclear whether the rising burden of depression is due to its increasing prevalence or better detection. We aimed to study trends in depressive symptoms in older individuals from the Czech Republic. We used data from the Survey on Health, Aging and Retirement in Europe. Depressive symptoms, defined by 4 or more points on the EURO-D scale, alone or in combination with pharmacological treatment, were compared between participants in 2006/2007 (cohort 1) and in 2015 (cohort 2). Binary logistic regression assessed the association of cohort 2 with depressive symptoms, step-wise adjusting for sociodemographic and clinical covariates. The prevalence of depressive symptoms (defined by EURO-D) was 28% in cohort 1 and 22% in cohort 2 (p < 0.001). Cohort 2 was associated with lower odds of depressive symptoms, adjusting for all covariates (OR 0.77; 95% CI 0.63-0.94). Defined by EURO-D scale or pharmacological treatment, the prevalence was 30% in cohort 1 and 26% in cohort 2 (p < 0.001). Cohort 2 was associated with lower odds of depressive symptoms, adjusting for age and sex, but not in the fully adjusted model (OR 0.88; 95% CI 0.73-1.07). The difference in depressive symptoms between cohorts was associated in particular with increased length of education and higher household net worth. Information about pharmacological treatment has been reported inaccurately. The prevalence of depressive symptoms has decreased in older adults in the Czech Republic. Additional increase in education and socioeconomic resources of the population could further reduce the depressive symptoms in the population.


Ciprofloxacin at low levels disrupts colonization resistance of human fecal microflora growing in chemostats.
We studied the in vitro effects of a range of ciprofloxacin (CI) concentrations on the human intestinal flora's colonization resistance (CR) to Salmonella kedougou NCTC 12173. Four steady state microbial communities were established in chemostats using inocula from a single pool of human feces. Three chemostats were exposed to CI (0.1, 0.43 and 5 microg/mL, respectively); one served as a no-drug control. The CR of each community was tested by three successive daily challenges of 10(8) S. kedougou, each delivered in a 1 mL bolus. There was no colonization of the no-drug chemostat. Likewise, after exposure to only 0.1 microg/mL CI there was no loss of CR and S. kedougou did not colonize. Conversely, both the 0.43 and the 5 microg/mL-exposed floras suffered a loss of CR and these chemostats were colonized. S. kedougou overgrew faster and reached higher counts in the presence of 0.43 than it did in the presence of 5 microg/mL. One possible explanation is that CI had a dose-dependent effect on both the challenge strain and CR. Thus, at higher levels, even though CR was disrupted by CI, so too was the growth of the challenge strain. Since exposure to CI elicited a dose-dependent reduction in Escherichia coli counts [Reg. Pharmacol. Toxicol. 33 (2001) 276] our new data suggest that E. coli may contribute to the CR against salmonella. We further conclude that, even at fecal levels below those reached during therapy, CI may impact the human gut flora sufficiently to facilitate colonization by S. kedougou.


[Hallux valgus: results of the surgical management of hallux valgus].
The Authors purpose to analyse on the basis of a critical examination of the operated hallux valgus with 2 different surgical technics the causes of failure and to give more exact indications about choosing the right surgical system.


Phase I evaluation of spirogermanium and 5-fluorouracil in colorectal carcinoma.
We have conducted a phase I study to evaluate the toxicity and tolerance of a 5 day continuous infusion of spirogermanium and 5-fluorouracil, (5-FU). The 5-FU was administered via a peripheral vein at 1000 mg/M2/day for 5 days by continuous infusion. Simultaneously, spirogermanium was administered via an indwelling central venous catheter by continuous infusion for 5 days starting at 50 mg/M2/day and escalating to 250 mg/M2/day. Sixteen patients received a total of 54.5 courses of therapy. The most common and severe toxicity was neurotoxicity. Mild to moderate gastrointestinal toxicity also occurred. No significant hematologic toxicity occurred. Two partial responses occurred lasting 11 and 20.5 months, both at the 100 mg/M2/day level of spirogermanium. The recommended phase II dosages are 5-FU 1000 mg/M2/day and spirogermanium 200 mg/M2/day by 5 day continuous infusion with escalation of the spirogermanium in selected individuals. Patients on long term therapy should have close neurologic evaluation and follow up. Consideration should also be given to evaluating a group of patients at the 100 mg/M2/day level of spirogermanium due to the responses seen at this level.


Cryptococcal sepsis in small vessel vasculitis.
While meningoencephalitis due to cryptococcus is well known in immunocompromised patients, disseminated cryptococcosis and cryptococcemia is rare outside the setting of advanced HIV infection. We report a case of disseminated cryptococcosis occurring in a patient with Wegener's granulomatosis on immunosuppressive medications.


EGFR mutation testing practice in advanced non-small cell lung cancer.
Testing tumor samples for the presence of a mutation in the epithelial growth factor receptor (EGFR) gene is recommended for advanced non-squamous non-small cell lung cancer (NSCLC) patients. We aimed to collect data about common practice among Medical Oncologists treating lung cancer patients, regarding EGFR mutation testing in advanced NSCLC patients. An internet-based survey was conducted among members of the Israeli Society for Clinical Oncology and Radiotherapy involved in the treatment of lung cancer patients. 24 Oncologists participated in the survey. The participants encompass the Oncologists treating most of the lung cancer patients in Israel. 79% of them use EGFR testing routinely for all advanced NSCLC patients. Opinions were split regarding the preferable biopsy site for EGFR testing material. 60% of participants recommend waiting for EGFR test results prior to initiation of first-line therapy. EGFR testing is requested in Israel routinely by most treating Oncologists for all advanced NSCLC patients, regardless of histology. In most cases, systemic treatment is deferred until the results of this test are received.


Factorial invariance and norms of the 30-item shortened-version of the Revised Child Anxiety and Depression Scale (RCADS-30).
Anxiety and depressive disorders are among the most common mental disorders during childhood and adolescence. As the 30-item shortened version of the Revised Child Anxiety and Depression Scale (RCADS-30) exhibits excellent psychometric properties, it is one of the most commonly used scales for the initial detection and assessment of these symptoms in children and adolescents. This is because of the advantage of its brevity when compared to the 47-item version. The aim of this study was to analyse factorial invariance according to sex, age, and format used to administer the test, and to identify the RCADS-30 subscales. A sample of 3,708 Spanish children and adolescents aged between 7 and 18 years old (M = 12.0 years, SD = 2.8) participated in the study. The factorial structure of the RCADS-30 is invariant according to sex, age, and format used to administer the scale. The RCADS-30 exhibited excellent factorial invariance for the variables analysed, confirming its usability for different types of sample and administration formats.


Preliminary screening of plants used in South Africa as traditional herbal remedies during pregnancy and labour.
Agapanthus africanus, Pentanisia prunelloides and Gunnera perpensa are indigenous plants which are used in traditional herbal remedies during pregnancy and childbirth. A crude decoction of each plant was tested on isolated rat uterus and ileum for pharmacological activity. Agapanthus africanus and Pentanisia prunelloides exhibited direct smooth muscle activity on the uterus and ileum preparations, while Gunnera perpensa showed direct smooth muscle activity on the uterus only. All the plant extracts potentiated the initial response of the uterus to oxytocin but Pentanisia prunelloides reduced the maximum response of the uterus to oxytocin. The Agapanthus africanus and Pentanisia prunelloides extracts potentiated the initial response of the ileum to acetylcholine but all the plant extracts inhibited the maximum response of the ileum to acetycholine.


Enrichment and purification of peptide impurities using twin-column continuous chromatography.
N-Rich is a twin-column chromatography process that enriches target compounds relative to other components in a mixture, thereby facilitating their isolation and characterization. This study demonstrates the performance of N-Rich for isolation of Angiotensin II peptide impurities compared with standard analytical and preparative chromatography approaches. Peptides have diverse chemical properties and are produced using a wide range of methods, resulting in products with complex impurity profiles. The characterization of impurities for clinical development is essential but obtaining high purity samples in sufficient quantities is often a difficult task when using standard chromatographic techniques. In contrast, by using cyclic continuous chromatography with UV-based process control, N-Rich enables automatic on-column accumulation of target impurities while other compounds in the mixture are depleted. This has multiple advantages compared to standard techniques. Firstly, at the end of the cyclic accumulation phase the highly enriched target is eluted in one step with high purity and concentration. This means fewer fractions for analysis are generated and up-concentration steps are reduced. Secondly, the purification of target impurities using semi-preparative scale chromatography becomes viable, even if initial resolution is poor compared to analytical HPLC. This allows for very significant increases in productivity for purification of difficult to isolate impurities. This study demonstrates two N-Rich strategies: Example 1: Purification of µg quantities of multiple Angiotensin II impurities with a >9-fold increase in productivity compared to analytical HPLC. Example 2: Specific isolation of 1 mg of a critical impurity at 88% purity. 79-fold increase in productivity and a 69-fold reduction in solvent consumption compared to analytical HPLC.


A novel homozygous ISPD gene mutation causing phenotype variability in a consanguineous family.
Within the group of muscular dystrophies, dystroglycanopathies represent an important subgroup of recessively inherited disorders. Their severity varies from the relatively mild forms of adult-onset limb-girdle muscular dystrophy (LGMD), to the severe congenital muscular dystrophies (CMD) with cerebral and ocular involvement. We describe 2 consanguineous children of Pakistani origin, carrying a new homozygous missense mutation c.367G>A (p.Gly123Arg) in the ISPD gene. Mutations in this gene have been recently reported as a common cause of congenital and limb-girdle muscular dystrophy. Patient 1 is an 8-year-old female with an intermediate phenotype between CMD and early LGMD; patient 2 is a 20-month-old male and second cousin of patient 1, showing a CMD phenotype. Cognitive development, brain MRI, eye examination, electrocardiogram and echocardiogram were normal in both patients. To our knowledge, this is the first report on the co-occurrence of both a CMD/early LGMD intermediate phenotype and a CMD within the same family carrying a homozygous ISPD mutation.


An altered T cell repertoire in MECL-1-deficient mice.
Immunoproteasome subunits low-molecular mass polypeptide (LMP)2 and LMP7 affect Ag presentation by MHC class I molecules. In the present study, we investigated the function of the third immunosubunit LMP10/multicatalytic endopeptidase complex-like (MECL)-1 (beta2i) in MECL-1 gene-targeted mice. The number of CD8+ splenocytes in MECL-1-/- mice was 20% lower than in wild-type mice. Infection with lymphocytic choriomeningitis virus (LCMV) elicited a markedly reduced cytotoxic T cell (CTL) response to the LCMV epitopes GP276-286/Db and NP205-212/Kb in MECL-1-/- mice. The weak CTL response to GP276-286/Db was not due to an impaired generation of this epitope but was attributed to a decreased precursor frequency of GP276-286/Db-specific T cells. The expansion of TCR-Vbeta10+ T cells, which contain GP276-286/Db-specific cells, was reduced in LCMV-infected MECL-1-/- mice. Taken together, our data reveal an in vivo function of MECL-1 in codetermining the T cell repertoire for an antiviral CTL response.


Expression of basic fibroblast growth factor and its receptors by head and neck squamous carcinoma tumor and vascular endothelial cells.
Basic fibroblast growth factor (bFGF) is a potent angiogenic factor implicated in tumor growth and metastasis. To determine if bFGF and basic fibroblast growth factor receptor 1 (bFGFR1) and 2 (bFGFR2) are upregulated in head and neck squamous cell carcinoma (HNSCC), we measured the distribution and levels of each in HNSCC specimens and control specimens. Head and neck squamous cell carcinoma and control tissue specimens were analyzed qualitatively (40 patients, 10 controls) using immunohistochemistry, and quantitatively (26 patients, 8 controls) using immunoassays and graded immunohistochemistry. Control tissue consisted of palatal tissue obtained during uvulopalatopharyngoplasty (UPPP). Immunohistochemical analysis revealed that bFGF, bFGFR1, and bFGFR2 antigens were strongly associated with cancer and vascular endothelial cells in HNSCC. Control tissue had moderate staining of vascular endothelium and no stromal staining. Quantitative analysis of bFGF in tissue homogenates indicated that bFGF levels in cancer specimens were significantly elevated compared with control tissues (420.3 +/- 360.9 ng/mg total protein versus 49.2 +/- 48.7, respectively, P < or =0.05). When analyzed by clinical stage, bFGF levels were significantly higher in stage III patients as compared with stage IV patients (P < or =0.01). When immunohistochemistry results were correlated with clinical stage, bFGF (P < or =0.01), bFGFR1 (P < or =0.001), and bFGFR2 (P < or =0.0001) staining was significantly more intense in the cancer cells of stage III versus stage IV patients. Enhanced expression of bFGF and bFGF receptors by cancer and vascular endothelial cells is present in HNSCC, and may contribute to tumor growth and metastasis in HNSCC by mediating angiogenesis. Strategies aimed at decreasing the expression of bFGF and its receptors may be of therapeutic benefit in HNSCC, particularly at an early stage of disease.


The corneal biomechanical differences after wearing orthokeratology lenses and multifocal soft lenses in children: A self-control study.
To compare the changes in corneal biomechanics after orthokeratology (OK) lens and Defocus Incorporated Soft Contact (DISC) lens treatment. Of 28 myopic children were recruited, with one eye wearing OK lens and the other eye wearing DISC lens for one year, and the data after discontinued for 4 weeks were also collected. Major outcomes were corneal biomechanics and axial length (AL) elongation. Throughout the follow-up period, the DISC group had longer the first applanation (A1) time, larger A1 deformation amplitude, A1 deflection length (A1 DLL), and A1 deflection amplitude than the OK group. AL elongation was less in the OK group at each visit (all P < 0.05) but faster in the OK group than in the DISC group after discontinuation (P = 0.006). Moreover, AL elongation was related to baseline A1 time, A1 velocity and whole eye movement max in the DISC group, and in the OK group, was related to the baseline the second applanation (A2) DLL, A2 delta arc length and stiffness parameter A1 (all P < 0.05). The cornea was more deformable after wearing DISC lens than OK lens, and corneal biomechanical parameters were associated with AL elongation. Eyes showed less AL elongation during OK lens treatment while faster AL elongation after discontinuation than DISC lens. The baseline corneal biomechanics may help to predict AL elongation in myopic control strategies.


Effects of Ultra-Low Temperatures on the Mechanical Properties and Microstructure Evolution of a Ni-Co-Based Superalloy Thin Sheet during Micro-Tensile Deformation.
With the development of product miniaturization in aerospace, the nuclear industry, and other fields, Ni-Co-based superalloys with excellent overall properties have become key materials for micro components in these fields. In the microforming field, size effects significantly impact the mechanical properties and plastic deformation behavior of materials. In this paper, micro-tensile experiments at room temperature and an ultra-low temperature were carried out to study the effects of initial microstructure and deformation temperature on the deformation behavior of Ni-Co-based superalloy thin sheets. The results show that as the ratio of specimen thickness to grain size (t/d) decreased from 8.6 to 2.4, the tensile strength σb decreased from 1221 MPa to 1090 MPa, the yield strength σs decreased from 793 MPa to 622 MPa, and the elongation decreased from 0.26 to 0.21 at room temperature. When t/d decreased from 8.6 to 2.4, σb decreased from 1458 MPa to 1132 MPa, σs decreased from 917 MPa to 730 MPa, and the elongation decreased from 0.31 to 0.28 at ultra-low temperatures. When t/d decreased from 8.6 to 2.4, the surface roughness of the specimen increased from 0.769 to 0.890 at room temperature and increased from 0.648 to 0.809 at ultra-low temperatures. During the microplastic deformation process of Ni-Co-based superalloy thin sheets, the coupled effects of surface roughening caused by free surface grains and hindered dislocation movement induced by grain boundary resulted in strain localization, which caused fracture failure of Ni-Co-based superalloy thin sheets.


Metabolic control of the membrane fluidity in Bacillus subtilis during cold adaptation.
Membrane fluidity adaptation to the low growth temperature in Bacillus subtilis involves two distinct mechanisms: (1) long-term adaptation accomplished by increasing the ratio of anteiso- to iso-branched fatty acids and (2) rapid desaturation of fatty acid chains in existing phospholipids by induction of fatty acid desaturase after cold shock. In this work we studied the effect of medium composition on cold adaptation of membrane fluidity. Bacillus subtilis was cultivated at optimum (40 degrees C) and low (20 degrees C) temperatures in complex medium with glucose or in mineral medium with either glucose or glycerol. Cold adaptation was characterized by fatty acid analysis and by measuring the midpoint of phospholipid phase transition T(m) (differential scanning calorimetry) and membrane fluidity (DPH fluorescence polarization). Cells cultured and measured at 40 degrees C displayed the same membrane fluidity in all three media despite a markedly different fatty acid composition. The T(m) was surprisingly the highest in the case of a culture grown in complex medium. On the contrary, cultivation at 20 degrees C in the complex medium gave rise to the highest membrane fluidity with concomitant decrease of T(m) by 10.5 degrees C. In mineral media at 20 degrees C the corresponding changes of T(m) were almost negligible. After a temperature shift from 40 to 20 degrees C, the cultures from all three media displayed the same adaptive induction of fatty acid desaturase despite their different membrane fluidity values immediately after cold shock.


Clinical comparative effectiveness of acupuncture versus manual therapy treatment of lateral epicondylitis: feasibility randomized clinical trial.
Lateral epicondylitis (LE) is a challenging condition for clinicians, and research has yet not proven the superiority of one specific treatment approach. However, manual therapy (elbow mobilization) in addition to eccentric exercise has been found to be superior to exercise alone. As well, acupuncture is effective in short-term pain relief when compared with sham treatment, but there is little knowledge on the comparative effectiveness of manual therapy and acupuncture treatment of LE in terms of pain relief. The primary objective of this pilot trial was to assess the feasibility (retention and adherence rates) of performing a randomized controlled trial (RCT) to explore the clinical effectiveness of acupuncture and manual therapy treatment of LE. This pilot trial took place in an outpatient interdisciplinary institute of sports medicine and rehabilitation in Oslo, Norway. Thirty-six adults with clinically diagnosed LE were randomly allocated into one of three groups: eccentric exercise alone, eccentric exercise plus acupuncture, or eccentric exercise plus manual therapy for a 12-week treatment period. Primary outcomes were patient retention and adherence rates. Secondary outcomes included patient-reported pain (NRS), level of disability (Quick-DASH), and participant's satisfaction with treatment and global perceived effect. Nine (69%) patients in the acupuncture group completed the 1-year follow-up, compared to eight (67%) in the manual therapy group and five (45%) in exercise alone. Our goal was to demonstrate a retention rate above 80% to avoid serious threats to validity, but the result was lower than expected. The majority of participants (64%) in both treatment groups received only three-treatment sessions; the reasons included non-attendance or recovery from pain. Secondary outcomes support the rationale for conduction of an RCT. There were no adverse advents related to study participation. Based on differences in pain relief between groups, patient retention, and adherence rates, an RCT seems to be feasible to assess treatment effectiveness more precisely. In a future definitive trial, greater dropout may be reduced by maintaining contact with the participants in the exercise alone group throughout the intervention, and objective assessments might be considered. ClinicalTrials.gov, NCT02321696.