Autoimmune hepatitis.
Autoimmune hepatitis (AIH) is an intermittently progressive liver disease characterized by hypergammaglobulinemia, autoantibodies, predominately periportal hepatitis, and a favorable response to corticosteroid therapy in most cases. There are no pathognomonic markers of autoimmune liver disease; rather, the diagnosis must be based on the presence of a constellation of characteristic clinical, laboratory, and histologic features in patients without other causes of such liver pathology. Although prednisone or prednisolone are the mainstays in initial therapy of AIH, azathioprine or other drugs with similar immunosuppressive mechanisms are of benefit for steroid-sparing effects or for use as monotherapy to maintain long-term remission. A fraction of patients meeting diagnostic criteria for AIH remains in long-term remission following withdrawal of immunosuppressive therapies, but in most patients, this disease represents a chronic condition requiring life-long monitoring and therapy.


Exogenous quinones directly inhibit the respiratory NADH dehydrogenase in Escherichia coli.
The ability of naphthoquinones to generate reactive oxygen species has been widely exploited in studies of oxidative stress. However, excess superoxide dismutase and catalase failed to protect Escherichia coli in rich medium against growth inhibition by plumbagin, indicating that its toxic effect was not due to the production of partially reduced oxygen species. Respiration failed immediately upon the addition of growth-inhibitory levels of plumbagin. Studies in vitro showed that plumbagin and other redox-active quinones intercept electrons from NADH dehydrogenase, the primary respiratory dehydrogenase in glucose-containing media. An excess of oxidative substrate, such as plumbagin, inactivates this enzyme, which appears to be redox-regulated. The resultant respiratory arrest is a cautionary example of metabolic dysfunction from redox-cycling drugs that cannot be attributed to superoxide or hydrogen peroxide.


Environmental change and the cost of philopatry: an example in the lesser snow goose.
The consequences of philopatric and dispersal behaviours under changing environmental conditions were examined using data from the colony of Lesser Snow Geese (Anser caerulescens caerulescens) breeding at La Pérouse Bay, Manitoba, Canada. In response to increased population size and decreased food abundance over time, increasing numbers of family groups have been dispersing from the traditional feeding areas. Goslings from dispersed broods were significantly heavier (7.3%), and had longer culmens (3.1%), head lengths (2.6%) and marginally longer tarsi (1.9%) on average than goslings that remained within La Pérouse Bay itself. These differences were consistent in each of 5 years. There was no evidence that the larger size of dispersed goslings was due to either a tendency for larger adults to disperse to alternative sites, or increased mortality of smaller goslings among dispersed broods. The most likely cause for the larger size of goslings from dispersed broods was the significantly greater per capita availability of the preferred salt-marsh forage species at non-traditional brood-rearing areas. The larger goslings in non-traditional feeding areas showed significantly higher firstyear survival, suggesting that the use of deteriorating traditional feeding areas may currently be maladaptive in this population.


Focal adhesion kinase and p53 signaling in cancer cells.
The progression of human cancer is characterized by a process of tumor cell motility, invasion, and metastasis to distant sites, requiring the cancer cells to be able to survive the apoptotic pressures of anchorage-independent conditions. One of the critical tyrosine kinases linked to these processes of tumor invasion and survival is the focal adhesion kinase (FAK). FAK was first isolated from human tumors, and FAK mRNA was found to be upregulated in invasive and metastatic human breast and colon cancer samples. Recently, the FAK promoter was cloned, and it has been found to contain p53-binding sites. p53 inhibits FAK transcription, and recent data show direct binding of FAK and p53 proteins in vitro and in vivo. The structure of FAK and p53, proteins interacting with FAK, and the role of FAK in tumorigenesis and FAK-p53-related therapy are reviewed. This review focuses on FAK signal transduction pathways, particularly on FAK and p53 signaling, revealing a new paradigm in cell biology, linking signaling from the extracellular matrix to the nucleus.


Mechanism of iron potentiation of hepatic uroporphyria: studies in cultured chick embryo liver cells.
Effects of iron were studied in cultured chick embryo liver cells to help elucidate the effect of hepatic iron in the human disease porphyria cutanea tarda and in toxic porphyria caused by chemicals. These cultures have proven useful because (a) phenobarbital and phenobarbital-like drugs induce a common form(s) of cytochrome P-450 (P-450-phenobarbital) in these cultures; (b) 20-methylcholanthrene and certain other polycyclic hydrocarbons induce a different form(s) (P-450-methylchol-anthrene), and (c) uroporphyria can be produced rapidly by exposure to suitable chemicals. In these cultures, treatment with iron alone did not produce porphyrin accumulation, and treatment with iron + 5-aminolevulinate caused accumulation of protoporphyrin, as did treatment with 5-aminolevulinate alone. However, treatment with phenobarbital-like drugs and iron, the latter at a concentration as low as 0.2 microM, led to accumulation of uro- and heptacarboxylporphyrins. Potentiation of uroporphyrin accumulation by iron began before there was a detectable synergistic increase in activity of 5-aminolevulinate synthase, the rate-controlling enzyme of heme synthesis. In contrast, treatment of cultures with 20-methylcholanthrene, in the presence or absence of iron, did not result in uroporphyrin accumulation or an increase in the activity of 5-aminolevulinate synthase. Uroporphyrinogen decarboxylase activity was unchanged by drug and iron treatments. Inhibitors of P-450-phenobarbital, SKF525A and piperonyl butoxide, as well as cadmium and cycloheximide prevented the porphyrin accumulation produced by glutethimide + iron, even though, except with cycloheximide, these substances further increased 5-aminolevulinate synthase activity. In vitro, uroporphyrin was oxidized autocatalytically by iron. In intact hepatocytes, even low concentrations of iron (0.2 to 20 microM), in the presence of a form of cytochrome P-450 induced by phenobarbital-like chemicals, produces uroporphyria primarily by enhancing uroporphyrinogen oxidation, not by inhibition of the decarboxylase. Induction of 5-aminolevulinate synthase amplifies the porphyrin overproduction.


Pediatricians' attitudes about collaborations with other community vaccinators in the delivery of seasonal influenza vaccine.
Achieving universal influenza vaccination among children may necessitate collaborative delivery involving both practices and community vaccinators. We assessed among pediatricians nationally their preferences regarding location of influenza vaccination for patient subgroups and their attitudes about collaborative delivery methods. The design/setting was a national survey conducted from July 2009 to October 2009. Participants included a representative sample of pediatricians from the American Academy of Pediatrics. The response rate was 79% (330 of 416). Physicians felt strongly that vaccination should occur in their practice for children with chronic conditions (52%) and healthy 6-24-month-old infants (48%), but few felt strongly about healthy 5-18-year-olds (17%). Most (78%) thought having multiple delivery sites increased vaccination rates, and 86% thought that influenza vaccine should be available at school. Physicians reported being very/somewhat willing to hold joint community clinics with public health entities (76%) and to suggest to patient subgroups that they receive vaccine at community sites, including public clinics or pharmacies (76%). The most frequently reported barriers to collaborative delivery with community sites or school-located delivery included concerns about the following: estimating the amount of vaccine to order if children are vaccinated elsewhere (community 56%; school 80%); transfer of vaccine records (community 57%; school 78%); and reluctance of families to go outside of the office (community 45%; school 74%). Most physicians are in favor of school-located or collaborative influenza vaccine delivery with community vaccinators, especially for healthy school-aged children. Collaborative approaches will require planning to ensure transfer of records, effective targeting of subgroups, and provisions to protect providers from being left with extra influenza supply.


B1 mapping using pre-learned subspaces for quantitative brain imaging.
To develop a machine learning-based method for estimation of both transmitter and receiver B1 fields desired for correction of the B1 inhomogeneity effects in quantitative brain imaging. A subspace model-based machine learning method was proposed for estimation of B1t and B1r fields. Probabilistic subspace models were used to capture scan-dependent variations in the B1 fields; the subspace basis and coefficient distributions were learned from pre-scanned training data. Estimation of the B1 fields for new experimental data was achieved by solving a linear optimization problem with prior distribution constraints. We evaluated the performance of the proposed method for B1 inhomogeneity correction in quantitative brain imaging scenarios, including T1 and proton density (PD) mapping from variable-flip-angle spoiled gradient-echo (SPGR) data as well as neurometabolic mapping from MRSI data, using phantom, healthy subject and brain tumor patient data. In both phantom and healthy subject data, the proposed method produced high-quality B1 maps. B1 correction on SPGR data using the estimated B1 maps produced significantly improved T1 and PD maps. In brain tumor patients, the proposed method produced more accurate and robust B1 estimation and correction results than conventional methods. The B1 maps were also applied to MRSI data from tumor patients and produced improved neurometabolite maps, with better separation between pathological and normal tissues. This work presents a novel method to estimate B1 variations using probabilistic subspace models and machine learning. The proposed method may make correction of B1 inhomogeneity effects more robust in practical applications.


Placental transport and embryonic utilization of essential metabolites in the rat at the teratogenic dose of cadmium.
Administration of Cd2+ to the 12-day pregnant rat caused a dose-dependent inhibition of placental 65Zn2+ transport. At 4 h after the injection of the teratogenic dose (1.25 mg Cd2+ per kg body weight), transport of 65Zn2+ to the embryo was inhibited by 75%. This inhibition decreased with time and at 48 h was no longer statistically significant. In contrast with Zn2+, the administration of Cd2+ did not affect the transport of sugar, amino acids and nucleic acid precursors from the maternal circulation to the embryo at any time. The incorporation of [14C]thymidine into embryonic DNA, however, was inhibited by about 50% at 4 h and by 75% at 20 h. By 48 h it returned to control levels. Incorporation of [14C]formate into DNA also was reduced. Inhibition of the incorporation of L-[14C]leucine into protein was apparent at 20 h, but not at 4 h, after the administration of Cd2+. Inhibition of DNA synthesis, which led to a significant reduction in embryonic DNA concentration at 20 h, was associated with a marked decrease in the activity in embryonic thymidine kinase. In extracts of embryos from Cd2+-treated dams, the activity of this enzyme was restored to the control level by the addition of 7.7 microM zinc acetate to the assay system. In vivo, the simultaneous injection of Zn2+ at a 2:1 atomic ratio with Cd2+ prevented the inhibition of thymidine incorporation into DNA. At the teratogenic dose, only about 16 ng Cd2+ per g wet weight is incorporated into the embryo. The inhibition of placental transport, particularly of Zn2+, therefore, may be of prime importance in the teratogenic response.


Pharmacokinetics of intravenously administered ketamine in the horse.
The metabolism and distribution of ketamine and its two major metabolites (norketamine and dehydronorketamine) was investigated in 10 horses undergoing airway surgery. Following premedication with xylazine (1.1 mg kg-1 intravenously) anaesthesia was induced by the rapid injection of ketamine at a dose of 2.2 mg kg-1 intravenously. Anaesthesia was maintained with halothane vaporized in oxygen and nitrous oxide (50:50). Serially collected blood samples were analysed by a sensitive gas liquid chromatographic technique. Plasma ketamine concentrations declined biexponentially with a rapid initial distribution phase (t1/2 2.89 +/- 0.25 minutes) being followed by a slower elimination phase (t1/2 65.84 +/- 3.46 minutes). Norketamine was found in the plasma of all the horses, but only at low concentrations while there was very little dehydronorketamine detected. It seems that recovery from ketamine anaesthesia in the horse depends mainly on rapid redistribution of the drug from the central compartment and this explains the abrupt recovery from ketamine anaesthesia often observed in the horse.


Chitosan based nanoparticles as protein carriers for efficient oral antigen delivery.
This study aimed to investigate the efficacy of nanoparticles based on chitosan as a vehicle for oral antigen delivery in fish vaccination. Carboxymethyl chitosan/chitosan nanoparticles (CMCS/CS-NPs) loaded extracellular products (ECPs) of Vibrio anguillarum were successfully developed by ionic gelation method. The prepared ECPs-loaded CMCS/CS-NPs were characterized for various parameters including morphology, particle size (312±7.18nm), zeta potential (+17.4±0.38mV), loading efficiency (57.8±2.54%) and stability under the simulated gastrointestinal (GI) tract conditions in turbot. The in vitro profile showed that the cumulative release of ECPs from nanoparticles was higher in pH 7.4 (58%) than in pH 2.0 (37%) and pH 4.5 (29%) after 48h. Fluorescein isothiocyanate-labeled bovine serum albumin (FITC-BSA) was used as model protein antigen and encapsulated in CMCS/CS-NPs for investigating the biodistribution of antigen after oral delivery to turbot in 24h. Oral immunization of ECPs-loaded CMCS/CS-NPs group in turbot showed elevated specific antibody and higher concentrations of lysozyme activity and complement activity in fish serum than ECPs solution. CMCS/CS-NPs loaded with ECPs could enhance both adaptive and innate immune responses than the group treated with ECPs solution and suggested to be a potential antigen delivery system.


Parental serum alkaline phosphatase activity as an auxiliary tool for prenatal diagnosis of hypophosphatasia.
The objective of this study is to clarify the usefulness of parental alkaline phosphatase (ALP) for prenatal diagnosis of hypophosphatasia (HPP). Maternal (m) and paternal (p) ALP values were measured in 77 cases from a multicenter cohort (fetal skeletal dysplasia forum in Japan) of cases with short limbs on ultrasonography during pregnancy. After birth, X-rays, cord blood ALP, and gene analysis were evaluated to achieve an exact diagnosis. The screening usefulness of ALP was examined retrospectively. Seventeen cases were eventually diagnosed as HPP and 60 as not HPP; the overall mean m-ALP and p-ALP (standard deviation) values were 133.4 (53) versus 197 (69) IU/L and 149.6 (71.8) versus 231 (61.4) IU/L (p < 0.001). Receiver operating characteristic curve analysis showed that the optimal m-ALP and p-ALP cutoff values were 123 and 165 IU/L, respectively. Presence of at least one of the m-ALP or p-ALP values abnormally low had a sensitivity, specificity, and positive predictive values of 82% (14/17), 93%, and 78%, respectively, for the diagnosis of HPP. Parental ALP measurement might be an auxiliary tool to hone in the prenatal diagnosis of fetal HPP. © 2017 John Wiley & Sons, Ltd.


Accountability in reminder-based adherence interventions: A review.
Interventions to elicit accountability capitalize on social behaviors to improve adherence but are distinct from reminders. However, little is known about the impact of accountability in reminder-based adherence interventions. Through a literature review, we aim to identify the frequency and effectiveness of accountability in reminder-based intervention studies. PubMed and PsycArticles were searched for reminder-based adherence studies. Articles were categorized as reminder-only or reminder with accountability studies. Studies were characterized by outcome measures, and differences between control and intervention groups were compared for studies that used electronic monitoring devices. 165 studies met the inclusion criteria; 154 used reminders without accountability (93%). 79 of the 154 reminder-only studies (51%) improved adherence in intervention groups compared to controls. Eleven of the 165 studies (6.6%) included an accountability aspect. The intervention group had better adherence than controls in 10 out of the 11 reminder with accountability studies (91%). Although distinct from reminders, accountability can be incorporated in reminder-based interventions. However, it is not commonly included in reminder-based interventions. It is important to consider accountability's effects on encouraging patient medication adherence. The addition of accountability interventions may further boost adherence, but few studies currently incorporate these types of interventions.


Capturing the post-exertional exacerbation of fatigue following physical and cognitive challenge in patients with chronic fatigue syndrome.
To design and validate an instrument to capture the characteristic post-exertional exacerbation of fatigue in patients with chronic fatigue syndrome (CFS). Firstly, patients with CFS (N=19) participated in five focus group discussions to jointly explore the nature of fatigue and dynamic changes after activity, and inform development of a self-report instrument - the Fatigue and Energy Scale (FES). The psychometric properties of the FES were then examined in two case-control challenge studies: a physically-demanding challenge (moderate-intensity aerobic exercise; N=10 patients), and a cognitively-demanding challenge (simulated driving; N=11 patients). Finally, ecological validity was evaluated by recording in association with tasks of daily living (N=9). Common descriptors for fatigue included 'exhaustion', 'tiredness', 'drained of energy', 'heaviness in the limbs', and 'foggy in the head'. Based on the qualitative data, fatigue was conceptualised as consisting of 'physical' and 'cognitive' dimensions. Analysis of the psychometric properties of the FES showed good sensitivity to the changing symptoms during a post-exertional exacerbation of fatigue following both physical exercise and driving simulation challenges, as well as tasks of daily living. The 'fatigue' experienced by patients with CFS covers both physical and cognitive components. The FES captured the phenomenon of a post-exertional exacerbation of fatigue commonly reported by patients with CFS. The characteristics of the symptom response to physical and cognitive challenges were similar. Both the FES and the challenge paradigms offer key tools to reliably investigate biological correlates of the dynamic changes in fatigue.


Neurons of the peripheral nervous system express thymidine phosphorylase.
Platelet-derived endothelial cell growth factor (PD-ECGF) is an angiogenic factor which recently has been shown to be identical to thymidine phosphorylase. We describe here, high levels of expression of PD-ECGF/thymidine phosphorylase in neurons of the peripheral nervous system (PNS) but very little in the central nervous system (CNS). Monoclonal and polyclonal antibodies were used for the staining of sections of dorsal root ganglia, sympathetic cervical ganglia and the enteric plexus as well as the brain and spinal cord. In addition, in situ hybridisation confirmed the results of immunohistochemistry. The possible role of thymidine phosphorylase in the PNS is discussed.


Daily serotonin rhythms in rat brain during postnatal development and aging.
Aging is characterized by progressive decline in most physiological functions. The age-related sleep disturbances have been attributed to disturbances of circadian function. Neurotransmitter serotonin plays important role in the photic and non-photic regulation of circadian rhythms and is a precursor of melatonin, an internal zeitgeber. To understand the age induced changes in the functional integrity of circadian system, we studied daily serotonin rhythms in brain by measuring serotonin levels at variable time points in wide range of age groups such as 15 days, 1, 2, 3 (adult), 4, 6, 9, 12, 18 and 24-months old male Wistar rats. Animals were maintained under light-dark conditions (LD 12:12), 2 weeks prior to experiment. We report here, mean serotonin levels over 24 h period in brain is highest at 3 months and daily serotonin rhythmicity reliably begins at 3 months and disintegrates at middle age and beyond. The age induced changes in daily serotonin rhythmicity in brain obtained in present study will be a step towards understanding age induced disorders of circadian function.


Conversion of methylallyl alcohol into C2-methyl-1,2-di-O-hexadecylglycerophosphocholine, a conformationally restricted phospholipid.
The synthesis of C2-methyl-1,2-di-O-hexadecylglycerophosphocholine from methylallyl alcohol is described and the 13C-NMR assignments of all glycerol backbone and headgroup resonances are provided. Bond rotations in the glycerol backbone of this diether phospholipid derivative are impeded by steric hindrance exerted by the methyl group. We discuss the utility of this conformationally restricted C2-alkyl phospholipid analog for study of the influence of conformational changes at the lipid-water interface of bilayers on the interactions between lipids and other membrane components.


The aggressive nature of the odontogenic keratocyst: is it a benign cystic neoplasm? Part 1. Clinical and early experimental evidence of aggressive behaviour.
In this, the first of three articles on the aggressive nature of the odontogenic keratocyst (OKC), there is a review of clinical and histological observations which indicated that this was an aggressive lesion with a predilection for recurrence unlike the majority of other jaw cysts. This led to the tentative suggestion that the OKC might be a benign neoplasm. Subsequently there were early laboratory investigations that compared proliferation rates of the OKC epithelium with other jaw cysts, comparative enzyme histochemistry to assess aspects of its metabolism and markers that would enable accurate presurgical diagnosis of this cyst. Comparative studies were also pursued on the walls of the OKC and other jaw cysts to identify factors that might influence the capacity of the OKC to resorb the bone surrounding it. The clinical and laboratory studies reviewed in this section provided cogent presumptive evidence of the distinctively aggressive nature of the OKC that led numbers of investigators to pursue immunocytochemical and genetic studies on this cyst. Parts 2 and 3 of this series review this work.


Electroejaculation of paraplegic males followed by pregnancies.
Semen obtained by electroejaculation was used to achieve pregnancies in the spouses of T5-6 and T4-5 paraplegics. Viable semen was recovered in both an antegrade and retrograde fashion. In both cases, the SPA test was positive. Semen recovered for AIH IUI was washed and swum up prior to insemination.


Tubeless versus standard PCNL in geriatric population.
Percutaneous nephrolithotomy (PCNL) is a standard, safe, and efficient method for large-volume renal calculi for all age groups. Nephrostomy tube constitutes an invaluable part of the nephrolithotomy operation. However, the nephrostomy tube has been recently replaced with ureteral catheter or double J-stent thanks to advances in urotechnology and operation equipment. The aim of the current article was to evaluate the safety and reliability of tubeless percutaneous nephrolithotomy in the geriatric population. Between January 2009 and September 2013, a total of 52 patients aged 65 years or elder with renal calculi bigger than 2cm underwent PCNL operation. The first group of 25 patients (48%) with a mean age of 70.0 years (std:±3,8) underwent tubeless PCNL whereas the second group consisting of 27 (52%) patients with a mean age of 71.3 years (std: ±4,0) underwent standard PCNL. The patients were randomly compared retrospectively in terms of burden of calculus, analgesic requirement, creatinine value, renal parenchymal thickness, Body-mass index (BMI), clavien score, length of hospitalization, and being calculus-free. The groups were found to be similar in age, BMI, and gender (P>.05). Burden of calculus, duration of operation, and rate of narcotic analgesic use were found to be statistically significantly higher in the group of Standard PCNL group than in the Tubeless PCNL group (P<.05). Length of hospital stay was 1.7 days in the group of tubeless PCNL and 2.6 days in the standard PCNL group (P<.05). No significant difference was found between the groups in terms of fall in hemoglobin, creatinine, values of parenchymal thickness, and clavien score, preoperative blood transfusion, previous SWL, location of calculi, number of access, and rate of success (P>.05). Burden of calculus was 900 mm2 (304-4232) in the standard PCNL group and 600mm(2) (220-2660) in the tubeless PCNL group with the difference being statistically significant (P=.014). Overall success was achieved in 96.0 and 96.3% of tubeless PCNL and standard PCNL patients after one session of PCNL, respectively. Tubeless percutaneous nephrolithotomy was found to be as safe and effective as standard PCNL in the geriatric population. It is recommended especially in this group of patients because of its advantages such as shorter length of hospitalization, less analgesic requirement, and earlier mobilization.


Generation of Fibroblasts Lacking the Sal-like 1 Gene by Using Transcription Activator-like Effector Nuclease-mediated Homologous Recombination.
The Sal-like 1 gene (Sall1) is essential for kidney development, and mutations in this gene result in abnormalities in the kidneys. Mice lacking Sall1 show agenesis or severe dysgenesis of the kidneys. In a recent study, blastocyst complementation was used to develop mice and pigs with exogenic organs. In the present study, transcription activator-like effector nuclease (TALEN)-mediated homologous recombination was used to produce Sall1-knockout porcine fibroblasts for developing knockout pigs. The vector targeting the Sall1 locus included a 5.5-kb 5' arm, 1.8-kb 3' arm, and a neomycin resistance gene as a positive selection marker. The knockout vector and TALEN were introduced into porcine fibroblasts by electroporation. Antibiotic selection was performed over 11 days by using 300 μg/mL G418. DNA of cells from G418-resistant colonies was amplified using polymerase chain reaction (PCR) to confirm the presence of fragments corresponding to the 3' and 5' arms of Sall1. Further, mono- and bi-allelic knockout cells were isolated and analyzed using PCR-restriction fragment length polymorphism. The results of our study indicated that TALEN-mediated homologous recombination induced bi-allelic knockout of the endogenous gene.


How to optimize rate control in clinical atrial fibrillation management.
Atrial fibrillation (AF) is the most common sustained arrhythmia seen in clinical practice, and accounts for most arrhythmia-related emergency room visits and hospital admissions. The present-day management of AF is centred on improving arrhythmia-related symptoms, exercise tolerance, and quality of life, and reducing the morbidity and mortality associated with AF (ie, the prevention of stroke or systemic thromboembolism and tachycardia-induced cardiomyopathy). The contemporary management of AF is centred on the apparently competing strategies of rate and rhythm control, which are more appropriately viewed as complementary. This contemporary review will discuss the rationale underpinning the rate control strategy, and focus on practical aspects of undertaking a rate control strategy.


The myth of "captive subjects" in hospital-based nursing research.
The completion of data collection in an environment rich with potential subjects can be very challenging. The experience is somewhat like being thirsty and being surrounded by salt water. The strategies presented here represent the application of a wide range of strategies from the literature, peer consultation, and research team problem solving. These specific strategies can be adapted to a wide range of types of clinical research and clinical settings. The entire research team found solving each problem and obstacle as it arose to be challenging and rewarding. Sharing the work load and problem solving among the research team was both productive and enjoyable.


CapsNet-MHC predicts peptide-MHC class I binding based on capsule neural networks.
The Major Histocompatibility Complex (MHC) binds to the derived peptides from pathogens to present them to killer T cells on the cell surface. Developing computational methods for accurate, fast, and explainable peptide-MHC binding prediction can facilitate immunotherapies and vaccine development. Various deep learning-based methods rely on separate feature extraction from the peptide and MHC sequences and ignore their pairwise binding information. This paper develops a capsule neural network-based method to efficiently capture the peptide-MHC complex features to predict the peptide-MHC class I binding. Various evaluations confirmed our method outperformance over the alternative methods, while it can provide accurate prediction over less available data. Moreover, for providing precise insights into the results, we explored the essential features that contributed to the prediction. Since the simulation results demonstrated consistency with the experimental studies, we concluded that our method can be utilized for the accurate, rapid, and interpretable peptide-MHC binding prediction to assist biological therapies.


Using the agile implementation model to reduce central line-associated bloodstream infections.
Central line-associated bloodstream infections (CLABSIs) are among the most common hospital-acquired infections and can lead to increased patient morbidity and mortality rates. Implementation of practice guidelines and recommended prevention bundles has historically been suboptimal, suggesting that improvements in implementation methods could further reductions in CLABSI rates. In this article, we describe the agile implementation methodology and present details of how it was successfully used to reduce CLABSI. We conducted an observational study of patients with central line catheters at 2 adult tertiary care hospitals in Indianapolis from January 2015 to June 2017. The intervention successfully reduced the CLABSI rate from 1.76 infections per 1,000 central line days to 1.24 (rate ratio = 0.70; P = .011). We also observed reductions in the rates of Clostridium difficile and surgical site infections, whereas catheter-associated urinary tract infections remained stable. Using the AI model, we were able to successfully implement evidence-based practices to reduce the rate of CLABSIs at our facility.


Reducing pain and discomfort associated with rubber dam clamp placement in children and adolescents: a systematic review and meta-analysis of effectiveness.
The application of rubber dams is a widely accepted method of tooth isolation in dental practice. Placement of the rubber dam clamp might be associated with levels of pain and discomfort, especially in younger patients. The purpose of the present systematic review is to evaluate the efficacy of the methods for reducing pain and discomfort associated with rubber dam clamp placement in children and adolescents. English-language literature from inception until September 6th, 2022 was searched in MEDLINE (via PubMed), SCOPUS, Web of Science, Cochrane, EMBASE, and ProQuest Dissertations & Theses Database Global for articles. Randomized controlled trials (RCTs) comparing methods of reducing the pain and/or discomfort associated with rubber dam clamp placement in children and adolescents were retrieved. Risk of bias assessment was performed using a Cochrane risk of bias-2 (RoB-2) risk assessment tool and the certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence profile. Studies were summarized and pooled estimates of pain intensity scores and incidence of pain were calculated. The meta-analysis was conducted in the following groups according to type of interventions (LA, audiovisual (AV) distraction, behavior management (BM), electronic dental anesthesia (EDA), mandibular infiltration, inferior alveolar nerve block (IANB), TA), outcome (intensity or incidence of pain), and assessment tool (face - legs - activity - cry - consolability (FLACC), color scale, sounds - motor - ocular changes, and faces pain scale (FPS)): (a) pain intensity using (LA + AV) vs (LA + BM), (b) pain intensity using EDA vs LA (c) presence or absence of pain using EDA vs LA (d) presence or absence of pain using mandibular infiltration vs IANB (e) Comparing pain intensity using TA vs placebo (f) Presence or absence of pain using TA vs placebo. Meta-analysis was conducted using StataMP software, version 17.0 (StataCorp, College Station, Texas). Restricted maximum-likelihood random effect model (REML), Mean difference (MD) with 95% confidence interval, and log odds ratio (OR) with 95% CI were calculated were calculated. Initially, 1452 articles were retrieved. Sixteen RCTs were finally included for reviewing and summarizing. Nine articles with a total of 867 patients were included for quantitative meta-analysis. The differences in pain intensity scores were not significant in any comparison groups (group a: [MD = -0.04 (95% CI = - 0.56, 0.47), P = 0.87, I2 = 0.00%], group b: [MD = 0.25 (95% CI = -0.08, 0.58), P = 0.14, I2 = 0.00%], group c [MD = -0.48 (95% CI = -1.41, 0.45), P = 0.31, I 2 = 0.00%], group d: [MD = -0.67 (95% CI = -3.17, 1.83), P = 0.60, I 2 = 0.00%], group e: [MD = -0.46 (95% CI = -l.08, 0.15), P = 0.14, I 2 = 90.67%], and group f: [MD = 0.61 (95% CI = -0.01, 1.23), P = 0.06, I 2 = 41.20%]. Eight studies were judged as having some concern for risk of bias and the remaining studies were considered as low risk for bias. The certainty of evidence was considered medium for all comparison groups. In the present meta-analysis, a considerable difference was obtained between the included studies regarding intervention methods and pain assessment tools and the analysis was performed in groups with small numbers of the studies. Owing to the mentioned variabilities and the small number of studies, the results of the analysis should be interpreted with caution. The indistinguishability of the manifestations of pain/discomfort from fear/anxiety, particularly in children, should also be considered while using the results of the present study. Within the limitations of the current study, no significant differences were found between the proposed methods for reducing pain and discomfort associated with rubber dam clamp placement in children and adolescents. A larger number of more homogenous studies regarding intervention methods and pain assessment tools need to be conducted in order to draw stronger conclusions. This study was registered in PROSPERO (ID number: CRD42021274835) and research deputy of Mashhad University of Medical Sciences with ID number 4000838 ( https://research.mums.ac.ir/ ).


Removal of obstructing blood clot from the lower airway: an alternative suction technique.
Clotted blood or organised thrombus in the lower airway may present clinicians with life-threatening airway obstruction or pulmonary collapse. An alternative suction technique is described, which applies suction directly to a tracheal tube.


Determination of the size of the Azotobacter vinelandii chromosome.
The chromosome of Azotobacter vinelandii UW was digested separately with the rape cutter restriction endonucleases SwaI (5'-ATTTAAAT), PmeI (5'GTTTAAAC) and PacI (5'-TTAATTAA) and the products were separated by pulsed-field gel electrophoresis. The size of the chromosome was determined to be approximately 4.5 megabase pairs (Mb) based on the sum of the sizes of the restriction fragments. This is almost the same as the size of the chromosome of Escherichia coli. The inability of the undigested DNA to enter the gel has led us to infer that the chromosome is circular.


Inhibition of TPA-induced cyclooxygenase-2 (COX-2) expression by apigenin through downregulation of Akt signal transduction in human keratinocytes.
Apigenin is a nonmutagenic bioflavonoid that has been shown to be an inhibitor of mouse skin carcinogenesis induced by the two-stage regimen of initiation and promotion with dimethylbenzanthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). These DMBA/TPA-induced squamous cell carcinomas overexpress cyclooxygenase-2 (COX-2). Cyclooxygenases are key enzymes required for prostaglandin (PG) synthesis, converting the arachidonic acid (AA) released by phospholipase A2 into prostaglandins. A large body of evidence indicates that the inducible form of cyclooxygenase, COX-2, is involved in tumor promotion and carcinogenesis in a wide variety of tissue types, including colon, breast, lung, and skin. In the present study, we have determined that apigenin inhibited the TPA-induced increase in COX-2 protein and mRNA in the human keratinocyte cell line; HaCaT. The induction of COX-2 elicited by TPA correlated with increased activation of Akt kinase and cell treatment with the PI3 kinase inhibitor, LY294002, blocked TPA induction of COX-2. In cells treated with TPA and apigenin, the inhibition of COX-2 expression correlated with inhibition of Akt kinase activation. Apigenin-mediated inhibition of TPA-induced COX-2 expression was reversed by transient transfection with constitutively active Akt (CA-Akt). Chemical inhibitors of MEK (PD98059), p38 (SB202190), but not JNK (SP600125) blocked TPA induction of COX-2 although apigenin did not inhibit TPA-mediated COX-2 expression through these pathways. The TPA-induced release of AA from HaCaT cells was also inhibited by cell treatment with apigenin. These data show that apigenin inhibits TPA-mediated COX-2 expression by blocking signal transduction of Akt and that apigenin also blocks AA release, which may contribute to its chemopreventive activity.


Silica particles settling characteristics and removal performances of oxide chemical mechanical polishing wastewater treated by electrocoagulation technology.
The purpose of this study was to explore the feasibility of removing silica particles and reducing turbidity from oxide chemical mechanical polishing (oxide-CMP) wastewater. Based on the dynamic characteristics of batch electrocoagulation, three operating stages (lag, reactive, and stabilizing) are proposed to identify the relationships among the zeta potential of the silica particles, solution turbidity, and the corresponding mean particle size of the silica. Experimental results show that the silica particles were destabilized and settled at the critical mean particle size, which was estimated to be above 520nm after 10min, and the corresponding turbidity removal mostly occurred during the reactive stage. Furthermore, the corresponding mean particle size varied from 520 to 1900nm as the treatment time progressed from 10 to 20min, which also occurred during the reactive stage. Several parameters, including different electrode pairs, electrolyte concentration, applied voltage, and the optimum condition of power input were investigated. Experimental results indicate that a Fe/Al electrode pair is the most efficient choice of the four electrode pair combinations in terms of energy consumption. The optimum electrolyte concentration and applied voltage were found to be 200ppm NaCl and 30V, respectively.


Multiple sclerosis health-related quality of life utility values from the UK MS register.
New interventions for multiple sclerosis (MS) commonly require a demonstration of cost-effectiveness using health-related quality of life (HRQoL) utility values. The EQ-5D is the utility measure approved for use in the UK NHS funding decision-making. There are also MS-specific utility measures - e.g., MS Impact Scale Eight Dimensions (MSIS-8D) and MSIS-8D-Patient (MSIS-8D-P). Provide EQ-5D, MSIS-8D and MSIS-8D-P utility values from a large UK MS cohort and investigate their association with demographic/clinical characteristics. UK MS Register data from 14,385 respondents (2011 to 2019) were analysed descriptively and using multivariable linear regression, with self-report Expanded Disability Status Scale (EDSS) scores. The EQ-5D and MSIS-8D were both sensitive to differences in demographic/clinical characteristics. An inconsistency found in previous studies whereby mean EQ-5D values were higher for an EDSS score of 4 rather than 3 was not observed. Similar utility values were observed between MS types at each EDSS score. Regression showed EDSS score and age were associated with utility values from all three measures. This study provides generic and MS-specific utility values for a large UK MS sample, with the potential for use in cost-effectiveness analyses of treatments for MS.


Proton pump inhibitor-induced gut dysbiosis and immunomodulation: current knowledge and potential restoration by probiotics.
Proton pump inhibitors (PPIs) are the most commonly prescribed drugs for the treatment of non-erosive reflux disease (NERD), ulcers associated with non-steroidal anti-inflammatory drugs (NSAIDs), esophagitis, peptic ulcer disease (PUD), Zollinger-Ellison syndrome (ZES), gastroesophageal reflux disease (GERD), non-ulcer dyspepsia, and Helicobacter pylori eradication therapy. The drugs have the effect of inhibiting acid production in the stomach. According to research, PPIs can affect the composition of gut microbiota and modulate the immune response. Recently, there has been a problem with the over-prescription of such drugs. Although PPIs do not have many side effects, their long-term use can contribute to small intestinal bacterial overgrowth (SIBO) or C. difficile and other intestinal infections. Probiotic supplementation during PPIs therapy may provide some hope in the reduction of emerging therapy side effects. This review aims to present the most important effects of long-term PPI use and provides critical insights into the role of probiotic intervention in PPI therapy.


Metabolic programming in chronically stimulated T cells: Lessons from cancer and viral infections.
T-cell metabolism is central to the shaping of a successful immune response. However, there are pathological situations where T cells are rendered dysfunctional and incapable of eliminating infected or transformed cells. Here, we review the current knowledge on T-cell metabolism and how persistent antigenic stimulation, in the form of cancer and chronic viral infection, modifies both metabolic and functional pathways in T cells.


Annual report of the Australian Gonococcal Surveillance Programme, 2005.
The Australian Gonococcal Surveillance Programme monitors the antibiotic susceptibility of Neisseria gonorrhoeae isolated in all States and Territories. In 2005 the in vitro susceptibility of 3,886 isolates of gonococci from public and private sector sources was determined by standardised methods. Different antibiotic susceptibility patterns were again seen in the various jurisdictions and regions. Resistance to the penicillins nationally was 29.5 per cent and, with the exception of the Northern Territory, ranged between 14 and 47 per cent. Quinolone resistance in gonococci increased with resistance to this agent found in all jurisdictions and in a larger proportion of strains and with higher minimal inhibitory concentrations (MICs). Nationally, 30.6 per cent of all isolates were ciprofloxacin-resistant and most of this resistance was at high MIC levels. All isolates remained sensitive to spectinomycin. Slightly more than one per cent of isolates showed some decreased susceptibility to ceftriaxone (MIC 0.06 mg/L or more). A high proportion of gonococci examined in larger urban centres were from male patients and rectal and pharyngeal isolates were common. In other centres and in rural Australia the male to female ratio of cases was lower, and most isolates were from the genital tract.


Further examination of the intermediate state in the denaturation of the tryptophan synthase alpha subunit. Evidence that the equilibrium denaturation intermediate is a molten globule.
To further characterize the intermediate state in the denaturation of tryptophan synthase alpha subunit from Escherichia coli, we have carried out differential scanning calorimetry in various concentrations of urea near pH 8.5. The heat capacity curve of the intermediate has no excess heat capacity nor any transition. This indicates that the intermediate is a thermodynamically denatured form. Although the intermediate retains significant CD signal in the far-uv region, the tertiary structure of the intermediate is disrupted as judged by the near-uv CD spectra and 1H NMR spectra in the aromatic region. This intermediate might be similar to a molten globule state. These results do not support our earlier proposal that the intermediate of the alpha subunit in the denaturation process retains an intact N-terminal domain, but that the C-terminal domain unfolds.


KappaAcc: A program for assessing the adequacy of kappa.
Categorical cutpoints used to assess the adequacy of various statistics-like small, medium, and large for correlation coefficients of .10, .30, and .50 (Cohen, Cohen, J. (1988). Statistical power analysis for the behavioral sciences (2nd ed.). Lawrence Erlbaum Associates.)-are as useful as they are arbitrary, but not all statistics are suitable candidates for categorical cutpoints. One such is kappa, a statistic that gauges inter-observer agreement corrected for chance (Cohen Educational and Psychological Measurement, 20(1), 37-46, Cohen, Educational and Psychological Measurement 20:37-46, 1960). Depending on circumstances, a specific value of kappa may be judged adequate in one case but not in another. Thus, no one value of kappa can be regarded as universally acceptable and the question for investigators should be, are observers accurate enough, not is kappa big enough. A principled way to assess whether a specific value of kappa is adequate is to estimate observer accuracy-how accurate would simulated observers need to be to have generated a specific value of kappa obtained by actual observers, given specific circumstances. Estimating observer accuracy based on a kappa table the user provides is what KappaAcc, the program described here, does.


Fluorimetric determination of biogenic 5-hydroxy- and 5-methoxyindoles by high-performance liquid chromatography using perchloric acid as post-column reagent.
A method for the determination of biogenic 5-hydroxy- and 5-methoxyindoles using high-performance liquid chromatography with fluorescence detection was developed. The specific fluorescence of these indoles induced by perchloric acid was utilized as the post-column detection system. The determination limits were 3 pmol for 5-hydroxy-L-tryptophan and 5 pmol for serotonin (5-HT) and 5-hydroxyindole-3-acetic acid (HIAA). The method was applied to the determination of 5-HT and HIAA in rat brain tissues using 5-hydroxygramine as the internal standard.


Regulation of calcium-sensing-receptor trafficking and cell-surface expression by GPCRs and RAMPs.
The calcium-sensing (CaS) receptor is a G-protein-coupled receptor (GPCR) that is of fundamental importance for extracellular calcium signalling and calcium homeostasis. The CaS receptor detects changes in free, ionized extracellular calcium concentration and initiates pathways that constantly re-adjust levels of circulating calcium. In addition, the CaS receptor is involved in processes such as stem-cell homing and regulation of neuronal-process outgrowth. To perform these functions, the CaS receptor must be appropriately targeted to the plasma membrane so that its large N-terminal calcium-sensing domain is positioned in the extracellular environment to detect dynamic changes in ionic calcium concentration. Here, we provide an overview of the molecular determinants controlling CaS receptor forward traffic and highlight the roles of CaS receptor interactors such as receptor-activity-modifying proteins and subunits of other class C GPCRs in this process.


Anastomotic leakage after resection and bypass for esophageal cancer: lessons learned from the past.
A retrospective study of anastomotic leakage has been undertaken in 730 patients who had resection or bypass for carcinoma of the esophagus during the period 1964-1982 at the Department of Surgery, University of Hong Kong, Queen Mary Hospital, Hong Kong. Partial or complete gangrene of the substitute loop also resulting in anastomotic disruptions were excluded from this series. Anastomotic leakage due to suture line failure occurred in 182 patients (24.9%). Two factors were found by multivariate analysis to influence leakage: the type of operation and the choice of organ used as substitute. Leakage occurred more than twice as often in bypass (42.7%) than in resection (18.3%). When the substitute used for reconstruction was viable, jejunum was associated with the lowest incidence of leakage followed by whole stomach, distal stomach, and colon in that order. The risk of leakage for any combination of the type of operation (resection or bypass) and substitute loop used was calculated. The probability of leakage was lowest when a resection was performed and jejunum was used as substitute. In view of the simplicity and relative safety of using the whole stomach, esophagectomy followed by gastric reconstruction is still the procedure of choice for the majority of patients. A bypass procedure using colon as substitute has the highest leakage rate. A low leakage rate should now be obtained, otherwise nonoperative therapy has a legitimate claim as the preferred alternative treatment modality.


Group-III nitride heteroepitaxial films approaching bulk-class quality.
III-nitride wide bandgap semiconductors are promising materials for modern optoelectronics and electronics. Their application has progressed greatly thanks to the continuous quality improvements of heteroepitaxial films grown on large-lattice-mismatched foreign substrates. But compared with bulk single crystals, there is still tremendous room for the further improvement of the material quality. Here we show a paradigm to achieve high-quality III-nitride heteroepitaxial films by the controllable discretization and coalescence of columns. By adopting nano-patterned AlN/sapphire templates with regular hexagonal holes, discrete AlN columns coalesce with uniform out-of-plane and in-plane orientations guaranteed by sapphire nitridation pretreatment and the ordered lateral growth of cleavage facets, which efficiently suppresses the regeneration of threading dislocations during coalescence. The density of dislocation etch pits in the AlN heteroepitaxial film reaches 3.3 × 104 cm-2, close to the present available AlN bulk single crystals. This study facilitates the growth of bulk-class quality III-nitride films featuring low cost and scalability.


Body mass index in children with newly diagnosed inflammatory bowel disease: observations from two multicenter North American inception cohorts.
To conduct a systematic review of children with newly diagnosed inflammatory bowel disease (IBD) from 2 prospective inception cohorts to examine body mass index (BMI) status at presentation. Clinical, demographic, and BMI data were obtained from 783 patients with newly diagnosed IBD. National Health and Nutrition Examination Survey data for 2748 healthy children were used as a control. Most children with Crohn's disease and ulcerative colitis had a BMI in the normative range (5%-84%). Low BMI (<5%) was seen in 22% to 24% of children with Crohn's disease and 7% to 9% of children with ulcerative colitis. Ten percent of children with Crohn's disease and 20% to 30% of children with ulcerative colitis had a BMI at diagnosis consistent with overweight or risk for overweight. Children with IBD are affected by current population trends toward overweight. A significant subgroup of children with newly diagnosed IBD has a BMI categorized as overweight or at risk for overweight. Clinicians should be aware of possible IBD diagnosis in the presence increased BMI.


New azafluorenones with cytotoxic and carbonic anhydrase inhibitory properties: 2-Aryl-4-(4-hydroxyphenyl)-5H-indeno[1,2-b]pyridin-5-ones.
New azafluorenones, 2-aryl-4-(4-hydroxyphenyl)-5H-indeno[1,2-b]pyridin-5-ones, were prepared to evaluate their cytotoxic/anticancer properties, also their inhibitory effects on hCA I and II isoenzymes. Aryl part was changed as [phenyl (H1), 4-methylphenyl (H2), 4-methoxyphenyl (H3), 4-fluorophenyl (H4), 4-bromophenyl (H5), 4-chlorophenyl (H6), 3-hydroxyphenyl (H7), and 4-hydroxyphenyl (H8)]. The structure of the synthesized compounds was characterized by 1H NMR, 13C NMR and HRMS spectra. Cytotoxicity results of the series pointed out that the compounds H6 (PSE: 28.0) and H5 (PSE: 27.3), with the highest potency selectivity expression (PSE) value, can be considered as leader compounds of the study in designing novel anticancer agents. Additionally, all azafluorenones synthesized showed a good inhibition profile towards hCA I and II isoenzymes in the range of 54.14-73.72 nM and 67.28-76.15 nM, respectively. The compounds H5 and H6 can be considered for further designs with their cytotoxic and CA inhibitory profiles.


[Sugar tumor of the lung--case report and review of the literature].
Clear cell tumors of the lung are commonly primary, clear-cell, bronchial carcinomas or metastasis of a renal cell carcinoma. Compared to this, pulmonary sugar tumor is a rare entity. A large intracellular content of glycogen and immunohistochemical procedures lead to diagnosis. The demonstration of the premelanosomal protein HMB-45 is considered as proof, but this is not airtight. We present a case of metachronic, benign, and HMB-45-negative sugar tumor of the lung after hypernephroma and give a review of the literature.


A case of silent rupture of an ectopic pregnancy.
Case report and review of literature. To report a case of a woman with paraplegia who had ruptured ectopic pregnancy but presented with minimal non-specific symptoms and no clinical signs. A trans-vaginal scan confirmed the diagnosis and an emergency laprotomy was performed to save the patient's life. Regional spinal injury unit in North West England. The diagnosis of ruptured ectopic in spinal cord injury woman can be difficult due to the lack of classical signs and symptoms. Awareness and constant vigilance is required to detect the early signs. Clinicians looking after such women should have sound knowledge of nervous system diseases and their pathophysiology. There should be a high index of suspicion when managing such cases and a prompt surgical treatment should be initiated.


The efficacy of in vivo administration of Apremilast on mesenchymal stem cells derived from psoriatic patients.
Psoriasis cellular hallmarks, such as the imbalance between Th1/Th17 and Th2 cytokines and the dysregulated expression of vascular endothelial growth factor (VEGF), inducible nitric oxide synthase, (iNOS) and indoleamine 2,3-dioxygenase (IDO), are all detectable in mesenchymal stem cells (MSCs) suggesting that psoriasis originates at mesenchymal level. In this scenario, MSCs may become the new therapeutic target and interest in the effects of traditionally used drugs, such as Apremilast, on MSCs has greatly increased. MSCs from control subjects (C-MSCs) and from psoriatic patients before (PsO MSCs T0) and after in vivo treatment with Apremilast (PsO-MSCs T12) were isolated and characterized; subsequently, the effects of Apremilast on VEGF, iNOS and IDO expression were evaluated by immunocytochemistry (ICC). The expression of VEGF, iNOS and IDO was also detected in skin sections by immunohistochemistry (IHC). The results indicate that in vivo administration of Apremilast is able to drive the altered profile of PsO-MSCs towards a more physiological pattern. In skin sections, the role of Apremilast is evident in reducing VEGF, iNOS and IDO expression. Apremilast treatment influences the expression of VEGF, iNOS and IDO not only by keratinocytes but also by MSCs, restoring their intrinsic profile and their natural anti-inflammatory action, and decreasing the auto-inflammatory process that underpins the development of psoriasis.


Cytology of myoepithelial carcinoma of the salivary gland.
Myoepithelial carcinoma, also know as malignant myoepithelioma, is rare in the salivary gland, and its cytologic features have rarely been reported. Four cases of myoepithelial carcinoma with cytology were retrieved from the archives of the Pathology Departments of two academic institutes. In three cases, the specimens were obtained by fine needle aspiration biopsy (FNA); the remaining case was a bench aspiration performed on the surgically resected specimen at the time of intra-operative consultation. The cytologic features were reviewed and correlated with the histology. The four patients with myoepithelial carcinoma (two men and two women) ranged in age from 48 to 64 years. Three cases arose from the parotid gland, and the remaining case was a recurrent tumor in the minor salivary glands of the hard palate. The aspirates of two cases consisted of predominantly spindle cells, one predominantly epithelioid/plasmacytoid cells, and one with a mixture of both spindle and epithelioid/plasmacytoid cells. Cellular pleomorphism was noted in two cases and mitotic figures in three cases. Two cases were cytologically diagnosed as malignant spindle cell neoplasm, not otherwise specified. The FNA of the recurrent tumor was diagnosed as consistent with the previous malignancy. The remaining case was interpreted as a pleomorphic adenoma with atypia. The cytologic features of myoepithelial carcinoma are diverse and may lack overt features of malignancy. Pathologists should be aware of this entity when evaluating cytologic specimen of salivary gland mass.


Clistopyga caramba sp. nov. (Hymenoptera: Ichneumonidae; Pimplinae), an astonishing example of mimicry in spider-attacking parasitoid wasps.
Clistopyga caramba sp. nov. Castillo & Sääksjärvi, collected from the tropical Andean-Amazonian interface in Peru, is described and illustrated. The new species is characterized by highly modified posterior metasomal tergites and a rare colour pattern of the metasoma. Two possible explanations for the bizarre metasomal morphology and colouration are proposed.


Mixed-lineage eosinophil/basophil crisis in MDS: a rare form of progression.
Basophilic crisis and eosinophilia are well recognized features of advanced chronic myeloid leukaemia. In other myeloid neoplasms, however, transformation with marked basophilia and eosinophilia is considered unusual. We examined the long-term follow-up of 322 patients with de novo myelodysplastic syndromes (MDS) to define the frequency of basophilic, eosinophilic and mixed lineage (basophilic and eosinophilic) transformation. Of all patients, only one developed mixed lineage crisis (>or= 20% basophils and >or= 20% eosinophils). In this patient, who initially suffered from chronic myelomonocytic leukaemia, basophils increased to 48% and eosinophils up to 31% at the time of progression. Mixed lineage crisis was not accompanied by an increase in blast cells or organomegaly. The presence of BCR/ABL and other relevant fusion gene products (FIP1L1/PDGFRA, AML1/ETO, PML/RAR alpha, CBF beta/MYH11) were excluded by PCR. Myelomastocytic transformation/myelomastocytic leukaemia and primary mast cell disease were excluded by histology, KIT mutation analysis, electron microscopy and immunophenotyping. Basophils were thus found to be CD123+, CD203c+, BB1+, KIT- cells, and to express a functional IgE-receptor. Among the other patients with MDS examined, 4(1.2%) were found to have marked basophilia (>or= 20%) and 7(2.1%) were found to have massive eosinophilia ( >or= 20%), whereas mixed-lineage crisis was detected in none of them. Mixed basophil/eosinophil crisis may develop in patients with MDS but is an extremely rare event.


[Nurse telephone support at home during chemotherapy].
An innovative scheme has been operational since 2013 at the Institut Claudius Regaud in Toulouse, aimed at patients undergoing chemotherapy. After an initial consultation, patients receive regular telephone support at home from expert nurses between treatments. The scheme helps to improve patient management and reinforce the community-hospital link.


Cluster headache and intercalated seizures in a young man: therapeutic effectiveness of flunarizine.
A young man suffering from both cluster headache and epilepsy is reported. Since the age of 37 he had recurrent generalized tonic-clonic seizures; one year later cluster headache attacks began. Neurological examination, standard laboratory tests and CT-scan were normal. The EEG showed medium-voltage sharp waves, not blocking upon eye opening, over the right parieto-temporal region. Flunarizine was added to his phenytoin therapy; it controlled both paroxysmal disorders. After six months, flunarizine was discontinued and during a one year follow-up the patient remained symptom-free. This calcium channel blocker can be regarded as an ideal drug in patients suffering from both cluster headache and epilepsy; it controls this headache syndrome and is a useful add-on to standard anti-convulsant therapy.


Preparation and molecular simulation of an environmentally friendly dust-fixing agent based on chitosan-gelatin.
In order to solve the hazard of coal mine dust, a dust-fixing agent (GC-TG-JFC) was prepared with gelatin, chitosan, octadecanol polyoxyethylene ether, and glutamine transaminase. The experimental conditions and the formulation were optimized by response surface method. The ratio of gelatin, chitosan, octadecanol polyoxyethylene ether, and glutamine transaminase was 0.405:0.211:0.095:0.286 and the dilution ratio was 1:30. The results of product performance test showed that the dust fixation rate could reach 99.95% when the wind speed was 9 m/s. The viscosity of the diluted solution was 42.5 mPa·s. The Forcite module in Materials studio software was used to analyze and calculate the radial distribution concentration, diffusion coefficient, and binding energy of the solution. The results showed that GC-TG-JFC migrated more water molecules to the surface of coal through the action of van der Waals force and hydrogen bond. In addition, the binding energy of water molecules increased and the diffusion coefficient decreased, which improved the binding ability of water molecules with coal. It could be found that GC-TG-JFC had good dust fixation performance by combining experiment and molecular dynamics method.


Continuous Meniscal Suture Technique of the Knee.
The menisci are fibroelastic structures interposed between the articular surfaces of the femur and tibia. They absorb impact and transmit load. Meniscal injury may compromise function and cause rapid joint degeneration, leading to the development of secondary osteoarthritis. Surgical treatment of meniscal injury is usually performed by arthroscopy, and meniscectomy or meniscal suture may be associated with such treatment. Meniscal suture should be considered when the injury compromises the proper functioning of the meniscus to recover its anatomy and function. Different meniscal suture techniques exist; the most widely used are the inside-out, outside-in, and all-inside techniques. The gold-standard repair technique is the inside-out technique. A drawback of this technique is the need to alternate between intra- and extra-articular structures for every stitch, which makes it even more laborious. We describe the continuous meniscal suture technique, also called "meniscal stitching," for a medial meniscal bucket-handle injury. This technique is performed from the inside out and allows the surgeon to perform multiple stitches with the same thread quickly and effectively. This surgical technique is performed using a single meniscal suture device that was developed by our group, called the "Meniscus 4 A-II" device.


Polarization properties and fractional-power analysis of coated and uncoated parallel-slab multireflection beam splitters.
The polarization properties of coated and uncoated parallel-slab multireflection beam splitters are investigated. In a recent study [Opt. Lett. 21, 1709 (1996)] it was shown that the parallel-slab beam splitter is a basic optical component of the parallel-slab division-of-amplitude photopolarimeter. The ellipsometric parameters and the fractional powers for multireflected components generated by this system are analyzed. Interesting new observations with respect to the polarization properties at the Brewster angle of incidence and the distribution of powers among the multireflected components are presented.


Diagnosis of TCM symptoms and analysis of risk factors of mild cognitive impairment in patients with type 2 diabetes mellitus.
To explore the diagnosis of traditional Chinese medicine (TCM) syndrome and analyze the risk factors of mild cognitive impairment (MCI) in patients with type 2 diabetes mellitus (T2DM). 141 T2DM patients, who were hospitalized in department of endocrinology of our hospital from February 2020 to December 2020, were chosen as research subjects. The patients were divided into an observation group (n=65, T2DM with MCI) and a control group (n=76, T2DM with normal cognitive function) according to the Montreal Cognitive Assessment (MoCA) score and diagnostic criteria of MCI. Pearson correlation analysis was used to study the correlation between MoCA score and influencing factors, and multiple logistic regression analyses were applied to analyze the risk factors of T2DM patients. Deficiency of kidney essence (34/65, 52.31%) and phlegm obstructing orifices (16/65, 2.62%) were common in T2DM patients with MCI. The observation group had apparently lower MoCA scores than the control group (23.46±3.12 points vs. 27.39±2.56 points, t=8.2150, P=0.0000). According to the results of multivariate logistic regression analysis, age, course of diabetes, homocysteine (HCY) and glycosylated hemoglobin (HbAlc) were the independent risk factors of MCI, and the education level was a protective factor. Mental deficiency and phlegm obstruction are common in T2DM patients complicated with MCI. The factors such as age, diabetes course, education degree, HCY and HbAlc are closely related to MCI. The occurrence of MCI in T2DM patients can be prevented by improving the education degree of patients, effective control of blood glucose and reduction of HCY level.


Designing an effective statewide tobacco control program--Oregon.
In this report, the author documents the first stages in the development and implementation of Oregon's tobacco control program. She briefly reviews the history of tobacco control coalitions in Oregon prior to the passage of Ballot Measure 44 and attributes much of the success to earlier coalition-building efforts.


National surveillance and the epidemiology of human Q fever in the United States, 1978-2004.
Although Q fever is considered enzootic in the United States, surveillance for human Q fever has been historically limited. From 1978 through 1999, 436 cases (average = 20 per year) of human Q fever were reported. After Q fever became nationally reportable in 1999, 255 human Q fever cases (average = 51 per year) were reported with illness onset during 2000 through 2004. The median age of cases was 51 years, and most cases were male (77%). The average annual incidence of Q fever was 0.28 cases per million persons, and was highest in persons 50-59 years of age (0.39 cases per million). State-specific incidence ranged from a high of 2.40 cases per million persons in Wyoming, to 0 cases in some states. Since Q fever became reportable, case reports have increased by more than 250%. Surveillance for Q fever is essential to establish the distribution and magnitude of disease and to complement U.S. bioterrorism preparedness activities.


From frugivore to folivore: Altitudinal variations in the diet and feeding ecology of the Bioko Island drill (Mandrillus leucophaeus poensis).
Variation in the quality and availability of food resources can greatly influence the ecology, behavior, and conservation of wild primates. We studied the influence of altitudinal differences in resource availability on diet in wild drill monkeys (Mandrillus leucophaeus poensis) on Bioko Island, Equatorial Guinea. We compared fecal samples (n = 234) collected across three consecutive dry seasons for drills living in lowland (0-300 m asl) forest with nearby (18 km distance) drills living in montane forest (500-1000 m asl) in the Gran Caldera Southern Highlands Scientific Reserve. Lowland forest drills had a frugivorous diet very similar to that reported from studies on nearby mainland drills (M. l. leucophaeus) and mandrills (M. sphinx), with fruits comprising 90% of their dried fecal samples. However drills living in montane forest had a more folivorous diet, with herbaceous pith, leaves and fungi comprising 74% of their dried fecal samples and fruit becoming a minor component (24%). Furthermore, a dietary preference index indicated that the differences in the proportion of fruit and fibrous vegetation in the diets of lowland compared to montane drills was not simply a result of relative availability. Montane drills were actively consuming a higher mass of the available fruits and fibrous vegetation, a condition reflected in the greater mass of their fresh feces. Our results demonstrate the unexpected flexibility and complexity of dietary choices of this endangered species in two adjacent habitat types, a comparison of considerable importance for many other limited-range species faced with habitat loss and climate change.


Management of cardiopulmonary resuscitation.
Since cardiopulmonary resuscitation was first described in 1960, it has become a standardized medical intervention. Separate guidelines have been developed for the neonatal and pediatric population, but none exist for the elderly population. This review will discuss recent available outcome data on resuscitation of the elderly and the known physiologic changes with aging that may affect decisions made during resuscitation.


A close relationship between microvilli and metabolic cooperation deficiency in embryonal carcinoma cells.
A revertant clone has been isolated from the metabolic cooperation-deficient embryonal carcinoma clone PT2md1. In PT2md1, its cooperation-competent parent, and its cooperation-competent revertant an inverse correlation has been demonstrated between cooperation competence and the incidence of microvilli. This demonstration, together with a similar correlation previously reported in an independently isolated series of cell lines, establishes a close causal relationship between the incidence of microvilli and communication deficiency.


Covariation bias in flight phobics.
Covariation estimates (CEs) between fear-relevant (FR) stimuli (slides of airplane crash sites) or fear-irrelevant (FI) stimuli (slides of airplanes in flight or mushrooms) and an aversive outcome (electrical shock) were examined in 15 flight phobics (high-fear participants) and 15 non-flight-phobic individuals (low-fear participants) by means of an illusory correlation experiment. In spite of a random relationship between all slide categories and outcome (illusory correlation), flight phobics exhibited a covariation bias and showed higher CEs for the contingency between FR slides and shocks than for the contingency between FI slides and shocks in a first experimental block. The CEs of flight phobics for FR slides and shocks was significantly higher than that of non-flight-phobic individuals, while high- and low-fear participants did not differ in their CEs for the other slide-shock combinations. However, even high-fear individuals were able to correct their initial covariation bias in subsequent illusory correlation blocks, presumably based on disconfirming situational information.


An in vivo and in vitro assessment of the anti-breast cancer activity of crude extract and fractions from Prunella vulgaris L.
Prunella vulgaris L.(P. vulgaris) is a perennial herb belonging to the Labiate family and widely distributed in China, Japan, Korea and Europe. Medical monographs and previous studies have shown that P. vulgaris has significant anti-breast cancer activity, and its use in breast treatment has a long history. However, systematically reports about the material basis and mechanism of P. vulgaris on anti-breast cancer activity are limited. In the present study, we first screened the best active fraction from the crude extract (PVE) and ethanol eluted fractions of P. vulgaris by using MDA-MB-231, MCF-7, 4T1 cell models in vitro and a 4T1-BALB/c transplanted tumour mouse breast cancer model in vivo. Furthermore, the anti-breast cancer mechanism of the best active fraction was investigated. The results demonstrated that PVE and ethanol fractions exhibited anti-breast cancer activity, especially with the 50% ethanol eluted fraction (PV50), which effectively regulated the 4T1 cell cycle, inhibited tumour cell proliferation, and promoted cancer cell apoptosis. In case of in vivo assays, PV50 inhibited tumour growth and lung metastasis, as well as inducing cell apoptosis by promoting damage of nuclear DNA and increasing expression of cleaved caspase-3. In addition, the chemical compositions of PV50 were analyzed by HPLC and UPLC-MS/MS, which were identified as flavonoids, moderately polar triterpenes, and a small amount of phenolic acid. The PV50 could be applied as natural sources against breast cancer in the pharmaceutical industry. These findings provide a basis for understanding the mechanism of the anti-breast cancer activity of P. vulgaris.


Wild Chimpanzees Show a Decrease in Pant Grunting over Their First 6 Years of Life.
Data from a large cross-sectional sample of wild chimpanzee mother-infant dyads yield evidence that young chimpanzees' pant grunting unfolds nonlinearly over the early developmental period. Though infants begin pant grunting early, and mothers' rates did not decrease, infant pant grunting declined as infants aged through infancy. Mother-infant dyadic pant grunting discordance therefore increased over infancy, with some discordance observed at even the earliest ages. In half of 90 observed instances involving infants ranging in age from 2 weeks to 69 months, only one member of the mother-infant dyad pant grunted; infants' pant grunting was not influenced by their mother's age, their position on their mother's body at the time of the greeting, or the dominance status of the male greeted. Male infants were more likely to pant grunt than female infants. We discuss the developmental trend in the context of infants' increasing independence, changing social motivations, and male-dominated social hierarchy.


Voltage-gated calcium channels and their auxiliary subunits: physiology and pathophysiology and pharmacology.
Voltage-gated calcium channels are essential players in many physiological processes in excitable cells. There are three main subdivisions of calcium channel, defined by the pore-forming α1 subunit, the CaV 1, CaV 2 and CaV 3 channels. For all the subtypes of voltage-gated calcium channel, their gating properties are key for the precise control of neurotransmitter release, muscle contraction and cell excitability, among many other processes. For the CaV 1 and CaV 2 channels, their ability to reach their required destinations in the cell membrane, their activation and the fine tuning of their biophysical properties are all dramatically influenced by the auxiliary subunits that associate with them. Furthermore, there are many diseases, both genetic and acquired, involving voltage-gated calcium channels. This review will provide a general introduction and then concentrate particularly on the role of auxiliary α2 δ subunits in both physiological and pathological processes involving calcium channels, and as a therapeutic target.


Combined analysis of two-year follow-up from two open-label randomized trials comparing efficacy of three nucleoside reverse transcriptase inhibitor backbones for previously untreated HIV-1 infection: OzCombo 1 and 2.
To compare inhibition of HIV replication, improvements in CD4+ T-cell counts, metabolic parameters, and body shape changes after 2 years of assigned therapy in OzCombo patients. Study participants were those who were recruited into the open-label OzCombo 1 (1996/1997) and OzCombo 2 (1997/1998) trials. Patients in OzCombo 1 were randomized to receive indinavir in combination with zidovudine+lamivudine (AZT+3TC; n = 35), stavudine (d4T)+3TC (n = 34), or d4T+didanosine (ddI) (n = 37). OzCombo 2 patients were randomized to the same nucleoside reverse transcriptase inhibitor (NRTI) backbones with nevirapine (n = 20, 22, 23, respectively). The mean time-weighted changes from baseline in CD4 T-cell count/mL, HIV RNA (log copies/mL plasma), and proportions with detectable viral load (<500 copies plasma HIV RNA/mL) between NRTI arms over 2 years were compared by formal meta-analysis. A cross-sectional study of metabolic and body shape complications was also undertaken. For the comparison of d4T+3TC and d4T+ddI to AZT+3TC, mean differences in time-weighted change from baseline in CD4 T-cell count/microL and log copies HIV RNA/mL adjusted for baseline CD4+ T-cell and HIV RNA counts were: -44 (p =.08) and -14 (p =.56) cells/microL and -0.1 (p =.40) and -0.1 (p =.6) copies/mL. Odds ratios for detectable viral load in the last study quarter were 0.6 (p =.44) and 1.0 (p =.95). The mean percent leg fat was lower in the d4T+3TC and d4T+ddI than the AZT+3TC arm (mean difference 5.1% [p =.07] and 7.6% [p =.02], respectively). For all regimens, virological control and immunological response were maintained over 2 years. Regimens containing d4T and particularly d4T+ddI were significantly associated with increased peripheral fat loss compared with AZT+3TC.


Extended gastrectomy: who benefits?
In the area of radical surgical treatment of gastric carcinoma, extended or multiorgan resection is--as is systematically extended lymph node dissection--becoming increasingly important. One indication for extended gastrectomy is intramural or transmural infiltration of neighboring organs or the gross presence of metastatic involvement of the lymph nodes associated with the celiac trunk, splenic artery, or splenic hilum. Because the mortality rate associated with extended gastrectomy is hardly any higher than that for nonextended gastrectomy, the indication for the former may be generously applied. The prognostically most unfavorable case is histologic evidence of transmural infiltration of neighboring organs (pT4). Multiorgan resection with improved systematic extension of lymph node dissection is of greatest benefit to patients with inflammatory adhesion of the stomach to neighboring organs or pN2 lymph node metastases. Intramural infiltration of the esophagus can be treated by including the thoracic part of the esophagus in the gastric resection done via an abdominothoracic approach, ensuring an appropriate margin of clearance, with no significant worsening of the prognosis.


Coupled effects of landscape structures and water chemistry on bacterioplankton communities at multi-spatial scales.
Bacterioplankton communities in rivers are strongly influenced by the surrounding landscape, yet the relationships between land use and bacterioplankton communities at multi-spatial scales and the mechanisms that shape bacterioplankton communities remain unclear. Here, we collected surface water samples from 14 tributaries of the Yuan River, a secondary tributary of the Yangtze River, which has been heavily impacted by human activities. We characterized the bacterioplankton communities by high-throughput sequencing techniques, and managed to identify the mechanisms governing bacterioplankton community assembly. The results showed that, in general, both landscape compositions and landscape configurations had significant effects on bacterial communities, and the effects were greater at the buffer scale than at the sub-basin scale. Additionally, there was no distinct distance-decay pattern for the effects of landscape structures on bacterial communities from the near-distance (100 m) to the long-distance (1000 m) buffer zones, with the maximal effects occurring in the 1000 m circular buffer (wet season) and 500 m riparian buffer (dry season) zone, respectively. Land use influenced the bacterioplankton community both directly through exogenous inputs (mass effect) and indirectly by affecting water chemistry (species sorting). Variance partitioning analyses showed that the total explanations of bacterial community variations by water chemistry and the intersections of water chemistry and land use (56.2% in wet season and 50.4% in dry season) were higher than that of land use alone (6.1% in wet season and 25.4% in dry season). These suggest that mass effects and species sorting jointly shaped bacterial community assembly, but that the effects of species sorting outweighed those of mass effects. Nevertheless, more biotic and abiotic factors need to be considered to better understand the microbial assembly mechanisms in anthropogenically influenced riverine ecosystems.


Identifying neuropathies through time series analysis of postural tests.
In physical therapy, postural tests are frequently used to diagnose neuropathies, particularly in diabetic individuals. This study aims to develop a method based on the analysis of time series that allows discriminating between healthy and diabetic subjects with or without a neuropathic condition. Do features obtained from time series corresponding to postural tests allow us to reliably discriminate between healthy, diabetic and neuropathic patients? In this study, 32 people participated in the healthy, diabetic, and neuropathic categories (11, 9, and 12, respectively). The data was collected by positioning each participant on a Wii Balanced Board platform, under 8 different conditions. The analyzed time series are sensed by devices that capture variations in the subject's center of pressure when subjected to a test on different conditions over a short period of time. The method proposed considers statistical techniques used for characterizing the time series combined with machine learning techniques to classify the individual's profile into one of the three categories mentioned. The classification is supported by an underlying probabilistic model, based on the characteristics of the time series, generating average curves for each class, which are then used by the classification methods. The empirical results include classification models for each class, obtaining a performance (F-score) over 98%. In addition, other models considering the particular conditions to which the subject is exposed during the test are developed, revealing that the conditions of eyes open and eyes closed show the highest levels of discrimination to classify participants into one of the three class categories. These results suggest a test protocol simplification and, at the same time, that the proposed method based on the analysis of the time series associated with the test used is highly predictive and may reliably complement or substitute a questionnaire-based diagnosis.


Identifying variants that contribute to linkage for dichotomous and quantitative traits in extended pedigrees.
Compared to genome-wide association analysis, linkage analysis is less influenced by allelic heterogeneity. The use of linkage information in large families should provide a great opportunity to identify less frequent variants. We perform a linkage scan for both dichotomous and quantitative traits in eight extended families. For the dichotomous trait, we identified one linkage region on chromosome 4q. For quantitative traits, we identified two regions on chromosomes 4q and 6p for Q1 and one region on chromosome 6q for Q2. To identify variants that contribute to these linkage signals, we performed standard association analysis in genomic regions of interest. We also screened less frequent variants in the linkage region based on the risk ratio and phenotypic distribution among carriers. Two rare variants at VEGFC and one common variant on chromosome 4q conferred the greatest risk for the dichotomous trait. We identified two rare variants on chromosomes 4q (VEGFC) and 6p (VEGFA) that explain 12.4% of the total phenotypic variance of trait Q1. We also identified four variants (including one at VNN3) on chromosome 6q that are able to drop the linkage LOD from 3.7 to 1.0. These results suggest that the use of classical linkage and association methods in large families can provide a useful approach to identifying variants that are responsible for diseases and complex traits in families.


The use of radioactive iodine in thyroid carcinoma.
The use of radioactive iodine (131I) for the treatment of primary carcinoma of the thyroid and as an alternative to a surgical thyroidectomy in the management of patients with metastatic disease is described. The rationale for using 131I to ablate normal thyroid tissue after a surgical thyroidectomy is considered in relation to the natural history of papillary and follicular tumours and in recognition of the results of such a policy in some recently reported series. It is concluded that 131I ablation is indicated in patients with follicular tumours: and in patients with papillary tumours if they are over the age of 40 or if the tumour contains a substantial follicular component. The management of patients undergoing post-operative 131I ablation is outlined and the possible complications of such treatment which include radiation thyroiditis, radiation sialitis, transient hyperthyroidism and oedema of the neck are described.


Psychosocial dysfunction of children and adolescents during the COVID-19 lockdown in Ecuador: a cross-sectional study.
Although the risk of morbidity and mortality of children and adolescents was lower during the COVID-19 pandemic, it appears that their mental health was strongly impacted. The goal of this study is to document psychological dysfunction among children and adolescents who underwent confinement due to COVID-19 in Ecuador. A cross-sectional, internet-based questionnaire. Ecuador. A total of 1077 caregivers of children and adolescents (4-16 years old). Caregivers responded to Pediatric Symptom Checklist-35 to assess psychosocial dysfunction. The prevalence of psychosocial dysfunction was 20.8%, with internalising symptoms being the most common (30.7%). The prevalence of psychosocial dysfunction was higher in children who had a poor family relationship during confinement (prevalence ratio (PR) 2.23; 95% CI 1.22 to 4.07), children who never helped with housework (PR 2.63; 95% CI 1.13 to 6.14) and those whose caregivers were worried about children's need for emotional therapy (PR 2.86; 95% CI 1.97 to 4.15). Never playing video games (PR 0.34; 95% CI 0.17 to 0.69) or playing video games infrequently (PR 0.39; 95% CI 0.20 to 0.79) was a protective factor for the psychosocial problems of children and adolescents. Our study demonstrates that children and adolescents have experienced a deterioration of mental health due to the pandemic. Family factors played an important role in the mental health of children during the lockdown. When a public crisis occurs, supportive mental health policies should be developed and implemented to promote children's psychological welfare.


Stratification of chemotherapy-treated stage III colorectal cancer patients using multiplexed imaging and single-cell analysis of T-cell populations.
Colorectal cancer (CRC) has one of the highest cancer incidences and mortality rates. In stage III, postoperative chemotherapy benefits <20% of patients, while more than 50% will develop distant metastases. Biomarkers for identification of patients at increased risk of disease recurrence following adjuvant chemotherapy are currently lacking. In this study, we assessed immune signatures in the tumor and tumor microenvironment (TME) using an in situ multiplexed immunofluorescence imaging and single-cell analysis technology (Cell DIVETM) and evaluated their correlations with patient outcomes. Tissue microarrays (TMAs) with up to three 1 mm diameter cores per patient were prepared from 117 stage III CRC patients treated with adjuvant fluoropyrimidine/oxaliplatin (FOLFOX) chemotherapy. Single sections underwent multiplexed immunofluorescence staining for immune cell markers (CD45, CD3, CD4, CD8, FOXP3, PD1) and tumor/cell segmentation markers (DAPI, pan-cytokeratin, AE1, NaKATPase, and S6). We used annotations and a probabilistic classification algorithm to build statistical models of immune cell types. Images were also qualitatively assessed independently by a Pathologist as 'high', 'moderate' or 'low', for stromal and total immune cell content. Excellent agreement was found between manual assessment and total automated scores (p < 0.0001). Moreover, compared to single markers, a multi-marker classification of regulatory T cells (Tregs: CD3+/CD4+FOXP3+/PD1-) was significantly associated with disease-free survival (DFS) and overall survival (OS) (p = 0.049 and 0.032) of FOLFOX-treated patients. Our results also showed that PD1- Tregs rather than PD1+ Tregs were associated with improved survival. These findings were supported by results from an independent FOLFOX-treated cohort of 191 stage III CRC patients, where higher PD1- Tregs were associated with an increase overall survival (p = 0.015) for CD3+/CD4+/FOXP3+/PD1-. Overall, compared to single markers, multi-marker classification provided more accurate quantitation of immune cell types with stronger correlations with outcomes.


Circadian Rhythms, Sleep, and Disorders of Aging.
Sleep-wake cycles are known to be disrupted in people with neurodegenerative disorders. These findings are now supported by data from animal models for some of these disorders, raising the question of whether the disrupted sleep/circadian regulation contributes to the loss of neural function. As circadian rhythms and sleep consolidation also break down with normal aging, changes in these may be part of what makes aging a risk factor for disorders like Alzheimer's disease (AD). Mechanisms underlying the connection between circadian/sleep dysregulation and neurodegeneration remain unclear, but several recent studies provide interesting possibilities. While mechanistic analysis is under way, it is worth considering treatment of circadian/sleep disruption as a means to alleviate symptoms of neurodegenerative disorders.


A concerted mechanism for berberine bridge enzyme.
Berberine bridge enzyme catalyzes the conversion of (S)-reticuline to (S)-scoulerine by formation of a carbon-carbon bond between the N-methyl group and the phenolic ring. We elucidated the structure of berberine bridge enzyme from Eschscholzia californica and determined the kinetic rates for three active site protein variants. Here we propose a catalytic mechanism combining base-catalyzed proton abstraction with concerted carbon-carbon coupling accompanied by hydride transfer from the N-methyl group to the N5 atom of the FAD cofactor.


Myocardial protection after whole body heat stress in the rabbit is dependent on metabolic substrate and is related to the amount of the inducible 70-kD heat stress protein.
The aims of this study were to examine the effects of whole body heat stress and subsequent stress protein induction on glycolytic metabolism, mitochondrial metabolism, and calcium handling within the heart. The effect of heat stress on glycolytic and mitochondrial pathways was examined by measuring contractile performance in the presence of glucose and pyruvate, respectively. Calcium handling was assessed using force-interval relationships. Right ventricular papillary muscles taken from heat-stressed and control rabbit hearts were superfused with Kreb's solution containing either glucose or pyruvate and rendered hypoxic for 30 min. After reoxygenation, the greatest recovery of contractile function occurred in the heat-stressed muscles with pyruvate as substrate; there was, however, no difference in the force-interval relationship between the groups. The degree of contractile recovery was related to the content of the inducible 70-kD but not the 65-kD, heat stress protein. This study suggests that heat stress enhances the ability of rabbit papillary muscle to use pyruvate, but not glucose, after reoxygenation, and that the differences seen in contractility may be secondary to induction of the 72-kD stress protein.


A pH-dependent macroglobulin gel.
Plasma from a patient with Waldenstrom's macroglobulinemia was observed to gel upon exposure to room air, yet to remain in solution indefinitely at 4 degrees C if sealed. Three studies were carried out which showed this change not to be due primarily to decreases in carbon dioxide tension or temperature, but to variations in the concentration of hydrogen ions within or just above physiologic levels. In purified material (IgM) a marked increase in viscosity occurred between pH 7.5 and 8.0, followed by precipitation between pH 8.0 and 9.7, and by reversible dissolution between pH 9.7 and 10.0. The analytical and clinical consequences of these solubility changes are discussed.


Spectator medicine at an international mega sports event: Rugby World Cup 2019 in Japan.
The Rugby World Cup (RWC) is one of the biggest international mega sports events in the world. This study was conducted to identify and evaluate the volume, nature, and severity of spectator medical care in the stadiums of 12 venues across Japan during RWC 2019. This was a retrospective review of medical records from spectator medical rooms of 45 official matches of RWC 2019 between September 20 and November 2, 2019. All patients in the stadium who visited the spectator medical room and were transferred to a hospital were included. The wet bulb globe temperature (WBGT) value at the kick-off time of each match, the number of visits to the spectator medical room, and the number of transfers to a hospital were reviewed and analyzed. The patient presentation rate (PPR) was calculated per 10,000 attendees. Severity categories were defined as mild or severe. Mild cases were considered non-life threatening requiring minimal medical intervention, and severe cases required transport to a hospital. The total number of visits to the spectator medical room was 449 with a PPR of 2.63. Most cases (91.5%) were mild in severity. The PPR was significantly higher for the matches held with a WBGT over 25 °C than for the matches under 21 °C (PPR 4.27 vs 2.04, p = 0.04). Thirty-eight cases were transferred to a hospital by ambulance; the PPR was 0.22. The most common reasons for transfer to the hospital were heat illness and fracture/dislocation, at a rate of 15.8% each. The incidence rate of cardiopulmonary arrest per 10,000 attendees was 0.0059 during RWC 2019. Preparation and provision of appropriate medical service for spectators is a key factor for mass-gathering events. During RWC 2019, the majority (91.5%) of patients who sought medical attention did so for minor complaints, which were easily assessed and managed. On the other hand, a higher WBGT situation contributes significantly to an increased PPR (< 21 versus > 25, 2.04 versus 4.27, p = 0.04). Careful medical preparation, management, and development of public education programs for higher WBGT situations will be required in the future for similar international mega sports events.


Transcriptional regulation of the human CYP46A1 brain-specific expression by Sp transcription factors.
Brain defective cholesterol homeostasis has been associated with neurologic diseases, such as Alzheimer's and Huntington's disease. The elimination of cholesterol from the brain involves its conversion into 24(S)-hydroxycholesterol by CYP46A1, and the efflux of this oxysterol across the blood-brain barrier. Herein, we identified the regulatory elements and factors involved the human CYP46A1 expression. Functional 5'deletion analysis mapped a region spanning from nucleotides -236/-64 that is indispensable for basal expression of this TATA-less gene. Treatment of SH-SY5Y cells with mithramycin A resulted in a significant reduction of promoter activity, suggesting a role of Sp family of transcription factors in CYP46A1 regulation. Combination of Sp1, Sp3, and Sp4 over-expression studies in Drosophila SL-2 cells, and systematic promoter mutagenesis identified Sp3 and Sp4 binding to four GC-boxes as required and sufficient for high levels of promoter activity. Moreover, Sp3 and Sp4 were demonstrated to be the major components of the protein-DNA complexes observed in primary rat cortical extracts. Our results suggest that the cell-type specific expression of Sp transcription factors - substitution of Sp1 by Sp4 in neurons - is responsible for the basal expression of the CYP46A1 gene. This study delineates for the first time the mechanisms underlying the human CYP46A1 transcription and thereby elucidates potential pathways underlying cholesterol homeostasis in the brain.