A strip liposome immunoassay for aflatoxin B1.
A technique has been developed for the preparation of aflatoxin B1 (AFB1)-tagged liposomes encapsulating a visible dye. These liposomes have several useful potential analytical applications, one of which is demonstrated. A simple plastic-backed nitrocellulose strip is the basis for an assay for detecting AFB1. Samples containing aflatoxin B1 are allowed to migrate by capillary action along the strip into a zone containing immobilized antibodies; then aflatoxin B1-tagged, dye-containing liposomes are allowed to migrate into the same area, filling any remaining antibody sites. The liposomes that bound to the antibody zone exhibit an intense purplish pink color whose optical density is inversely proportional to the aflatoxin concentration in the sample. The device is capable of detecting aflatoxin B1 at levels down to 20 ng and could serve as a rapid procedure for visual screening of agricultural and food samples for AFB1 or, with densitometry, as an inexpensive quantitative assay.


Effect of gene disruptions of the TCA cycle on production of succinic acid in Saccharomyces cerevisiae.
Succinate is the main taste component produced by yeasts during sake (Japanese rice wine) fermentation. The pathway leading to accumulation of succinate was examined in liquid culture in the presence of a high concentration (15%) of glucose under aerobic and anaerobic conditions using a series of Saccharomyces cerevisiae strains in which various genes that encode the expression of enzymes required in TCA cycle were disrupted. When cultured in YPD medium containing 15% glucose under aerobic conditions, the KGD1 (alpha-ketoglutarate dehydrogenase) gene disrupted mutant produced a lower level of succinate than the wild-type strain, while the SDH1 (succinate dehydrogenase) gene-disrupted mutant produced an increased level of succinate. On the other hand, the FUM1 (fumarase) gene disrupted mutant produced significantly higher levels of fumarate but did not form malate at all. These results indicate that succinate, fumarate and malate are mainly synthesized through the TCA cycle (oxidative direction) even in the presence of glucose at a concentration as high as 15%. When the growth condition was shifted from aerobic to anaerobic, the increased level of succinate in SDH1 disruptants was no longer observed, whereas the decreased level of succinate in the KGD1 diruptant was still observed. A double mutant of the two fumarate reductase isozyme genes (OSM1 and FRDS) showed a succinate productivity of 50% as compared to the parent when cells were incubated in glucose-buffered solution. These results indicate that succinate could be synthesized through two pathways, namely, alpha-ketoglutarate oxidation via the TCA cycle and fumarate reduction under anaerobic conditions.


Overexertion injuries in home health care workers and the need for ergonomics.
Home health care workers have high rates of back injuries and other musculoskeletal problems. This article addresses issues surrounding work-related overexertion injuries in home health care workers, including summaries of relevant research on workers in home settings as well as in traditional health care settings such as hospitals and nursing homes. The main work factors associated with these injuries are forceful exertions and awkward postures during patient- care tasks, especially while lifting and moving patients. Ergonomics-the design of work tasks to best accommodate natural human capabilities-is the most promising approach for preventing injuries, and for enhancing the comfort and safety of workers and patients.


Chemical and enzymatic oxidation of furosemide: formation of pyridinium salts.
Furosemide (Lasix) is frequently used in the treatment of cardiovascular and renal disease. Only one metabolite, furosemide glucuronide, has ever been identified. Oxidation of furosemide by cytochrome P450 has been demonstrated, but the metabolite(s) has never been identified. The oxidation of furosemide by dimethyldioxirane in acetone and by liver microsomal incubations was explored in this study. The first observable product from dimethyldioxirane oxidation was a ring-expanded enone resulting from an intramolecular condensation of the aldehyde group of the enonal, the secondary amine, and the carboxylic acid in a Mannich-like reaction. Keto-enol tautomerization and opening of the lactone gave a stable pyridinium salt. The pyridinium salt was also observed in the microsomal incubations of furosemide. The presence of an internal nucleophile in furosemide may have a significant effect on the toxicology and possibly the pharmacology of this furan.


[Anti-β2GPI antibody promotes release of inflammatory and pro-thrombosis molecules from arteries in apolipoprotein E-deficient mice].
Objective To investigate the roles of anti-beta 2 glycoprotein I antibodies (anti-β2GPI Ab) in the expressions of atherosclerosis(AS)-related inflammatory factors and pro-thrombosis molecules in apolipoprotein E-deficient (ApoE-/-) mice. Methods ApoE-/- mice were randomly divided into normal saline (NS) group, 100 μg anti-β2GPI Ab group, 100 μg homologous antibody (rabbit-IgG) group and 100 μg β2GPI/anti-β2GPI Ab complex group after silastic collars were placed around their carotid arteries by surgery. All mice were fed a high fat diet and corresponding stimuli were given through intraperitoneal injection at 7-day intervals. Six weeks later, the mice were executed. The blockage of carotid arteries of the operated side was observed by HE staining. The expressions of TLR4, tissue factor (TF) and von Willebrand factor (vWF) were detected by immunohistochemistry. The mRNA levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in aorta were tested by real-time quantitative PCR. Results HE staining showed that the blockage of carotid arteries in antibody group was the most obvious. The immunohistochemistry showed that the expressions of TLR4, TF and vWF in anti-β2GPI Ab group increased remarkably. Furthermore, the mRNA levels of IL-1β and TNF-α in anti-β2GPI Ab group were higher than those in the other groups. Conclusion The anti-β2GPI antibody promotes the formation of atherosclerotic plaques in mice by up-regulating the release of inflammatory cytokines IL-1β, TNF-α and thrombosis-related molecules TF, vWF and TLR4, ultimately enhancing the development of AS.


The Dixie Cup technique for salvaging limb length and preserving nerve continuity in the mangled lower extremity.
The mangled lower extremity posses a difficult problem for the reconstructive surgeon. We describe a novel technique for preserving limb length and maintaining nerve continuity in a severely injured lower extremity. This specific example of fixating the viable, sensate distal foot tissues onto the proximal tibia was vital in maintaining optimal limb length. This allowed for a more desirable level of amputation, preserved knee function, and provided well-vascularized, sensate soft tissue coverage.


Efficacy and safety of a standardised 500 unit dose of Dysport (clostridium botulinum toxin type A haemaglutinin complex) in a heterogeneous cervical dystonia population: results of a prospective, multicentre, randomised, double-blind, placebo-controlled, parallel group study.
Results from a dose-ranging study in a selected group of de novo patients with rotational cervical dystonia (CD) suggest that 500 units of Dysport (Clostridium botulinum toxin type A haemaglutinin complex) is the optimal starting dose. The present study aimed to confirm the efficacy and safety profile of this dose in a population of CD patients more representative of those seen in a typical dystonia clinic. A total of 68 patients with moderate to severe CD (Tsui score > or = 9) were randomly assigned to receive placebo or Dysport 500 units. Treatment was administered according to the clinical pattern of head deviation, using a standardised injection protocol. A total of 21 patients (11 Dysport, 10 placebo) had not previously received botulinum toxin type A (BtxA) injections, and 47 patients (24 Dysport, 23 placebo) had received BtxA more than 12 weeks previously. Assessments were performed at baseline and weeks 4, 8 and 16. Patients defined as non-responders at week 4 were re-treated in an open phase with 500 units of Dysport at week 6, and were followed up at week 10. Significant between-group differences in Tsui scores were present at weeks 4 (p=0.001) and 8 (p=0.002). Similarly, there were significant between-group differences (p < 0.001) in patient and investigator assessments of response in favour of Dysport at weeks 4 and 8. Also, more Dysport (49%) than placebo (33%) patients were pain-free at week 4 (p=0.02). Overall, 30/35 (86 %) Dysport patients and 14/33 (42%) placebo patients were classified as responders at week 4. Adverse events were reported by 15/35 Dysport patients and 9/33 placebo patients. Open phase treatment produced improvements in Tsui (p < 0.001) and pain scores (p=0.011), and 23/24 patients were classified as responders. Although individual dose titration and muscle selection is desirable, this study demonstrated that a dose of 500 units of Dysport injected into clinically identified neck muscles without electromyographic guidance is safe and effective in the treatment of patients with the major clinical types of cervical dystonia.


Kefir Grains Change Fatty Acid Profile of Milk during Fermentation and Storage.
Several studies have reported that lactic acid bacteria may increase the production of free fatty acids by lipolysis of milk fat, though no studies have been found in the literature showing the effect of kefir grains on the composition of fatty acids in milk. In this study the influence of kefir grains from different origins [Rio de Janeiro (AR), Viçosa (AV) e Lavras (AD)], different time of storage, and different fat content on the fatty acid content of cow milk after fermentation was investigated. Fatty acid composition was determined by gas chromatography. Values were considered significantly different when p<0.05. The highest palmitic acid content, which is antimutagenic compost, was seen in AV grain (36.6g/100g fatty acids), which may have contributed to increasing the antimutagenic potential in fermented milk. Higher monounsaturated fatty acid (25.8 g/100g fatty acids) and lower saturated fatty acid (72.7 g/100g fatty acids) contents were observed in AV, when compared to other grains, due to higher Δ9-desaturase activity (0.31) that improves the nutritional quality of lipids. Higher oleic acid (25.0 g/100g fatty acids) and monounsaturated fatty acid (28.2g/100g fatty acids) and lower saturated fatty acid (67.2g/100g fatty acids) contents were found in stored kefir relatively to fermented kefir leading to possible increase of antimutagenic and anticarcinogenic potential and improvement of nutritional quality of lipids in storage milk. Only high-lipidic matrix displayed increase polyunsaturated fatty acids after fermentation. These findings open up new areas of study related to optimizing desaturase activity during fermentation in order to obtaining a fermented product with higher nutritional lipid quality.


Harmonization of repetition time and scanner effects on estimates of brain hemodynamic response function.
Multisite contributions are essential to improve the reliability and statistical power of imaging studies but introduce a complexity because of different acquisition protocols and scanners. The hemodynamic response function (HRF) is the transform that relates neural activity to the measured blood oxygenation level-dependent (BOLD) signal in MRI and contains information about the latency, amplitude, and duration of neuronal activations. Acquisition variabilities, without adding harmonization techniques, can severely limit our ability to characterize spatial effects. To address this problem, we propose to study and remove variabilities of the sampling rate and scanners on estimates of the HRF. We computed the HRF using a blind deconvolution method in 547 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) across 62 sites and 18 scanners. The approach consists of studying the changes of the response according to repetition times (TR) and scanner models. We applied ComBAT, a statistical multi-site harmonization technique, to evaluate and reduce the scanner and repetition time effects and used the Wilcoxon rank sum test to assess the performance of the harmonization. Results show high scanner and repetition time variabilities (|d| ≥ 0.38, p = 4.5 × 10-5) across features, indicating that using harmonization is crucial in multi-site studies. ComBAT successfully removes the sampling effects and reduces the variance between scanners for 7 out of 10 of the HRF features (|d| ≤ 0.05, p = 0.0052). Scanners effects have been characterized on multi-site datasets, but the repetition time impact has been less studied. We showed that the use of different values of repetition time leads to changes in HRF behavior. Regression modeling changes in the HRF on the harmonized data are not significant (p = 0.0401) which does not allow to conclude how HRF changes with aging.


Superior Catalytic Activity of Electrochemically Reduced Graphene Oxide Supported Iron Phthalocyanines toward Oxygen Reduction Reaction.
Structure and surface properties of supporting materials are of great importance for the catalytic performance of the catalysts. Herein, we prepared the iron phthalocyanine (FePc) functionalized electrochemically reduced graphene oxide (ERGO) by the electrochemical reduction of FePc/GO. The resultant FePc/ERGO exhibits higher catalytic activity toward ORR than that of FePc/graphene. More importantly, the onset potential for ORR at FePc/ERGO positively shifts by 45 mV compared with commercial Pt/C in alkaline media. Besides, FePc/ERGO displays enhanced durability and selectivity toward ORR. The superior catalytic performance of FePc/ERGO for ORR are ascribed to the self-supported structure of ERGO, uniformly morphology and size of FePc nanoparticles.


Intermolecular interaction and solid state characterization of abietic acid/chitosan solid dispersions possessing antimicrobial and antioxidant properties.
The aim of this work was to prepare and characterize solid dispersions of abietic acid (AB) and chitosan (CS) to investigate how formulation of the mixture may help in the battle against microbial colonization in different areas, such as the biomedical field or the food industry. Solid dispersions were characterized by differential scanning calorimetry, infrared spectroscopy, Raman spectroscopy, polarized optical microscopy, zeta potential and size analysis. The data showed that the dispersion/solvent evaporation method formed solid dispersions in which abietic acid was molecularly dispersed in the carrier. A synergistic effect between the two components in terms of antioxidant and antimicrobial properties was found, especially in the formulations obtained with 1/1 AB/CS molar ratio. Interestingly, the aggregation state (amorphous/crystalline) of AB seemed to affect the antimicrobial activity of the formulation, suggesting increased bioactivity when the drug was in the amorphous state. These findings, together with the demonstrated biocompatibility of the formulations, seem to open promising perspectives for a successful application of the developed AB/CS formulations in the biomedical field or in the food industry.


The coordination of cyclic microtubule association/dissociation and tail swing of cytoplasmic dynein.
The dynein motor domain is composed of a tail, head, and stalk and is thought to generate a force to microtubules by swinging the tail against the head during its ATPase cycle. For this "power stroke," dynein has to coordinate the tail swing with microtubule association/dissociation at the tip of the stalk. Although a detailed picture of the former process is emerging, the latter process remains to be elucidated. By using the single-headed recombinant motor domain of Dictyostelium cytoplasmic dynein, we address the questions of how the interaction of the motor domain with a microtubule is modulated by ATPase steps, how the two mechanical cycles (the microtubule association/dissociation and tail swing) are coordinated, and which ATPase site among the multiple sites in the motor domain regulates the coordination. Based on steady-state and pre-steady-state measurements, we demonstrate that the two mechanical cycles proceed synchronously at most of the intermediate states in the ATPase cycle: the motor domain in the poststroke state binds strongly to the microtubule with a K(d) of approximately 0.2 microM, whereas most of the motor domains in the prestroke state bind weakly to the microtubule with a K(d) of >10 microM. However, our results suggest that the timings of the microtubule affinity change and tail swing are staggered at the recovery stroke step in which the tail swings from the poststroke to the prestroke position. The ATPase site in the AAA1 module of the motor domain was found to be responsible for the coordination of these two mechanical processes.


Outcomes of Vertical Split Conjunctival Autograft Using Fibrin Glue in Treatment of Primary Double-Headed Pterygia.
To evaluate the efficiency of pterygium excision with the vertical split conjunctival technique using fibrin glue in treatment of primary double-headed pterygia. 15 eyes of 15 patients with primary double-headed pterygia that underwent vertical split conjunctival autograft pterygium surgery were retrospectively reviewed. Recurrence was defined as fibrovascular proliferation over the limbus onto the cornea. The patients' mean age was 36.92 ± 10.8 years. At 12-month follow-up, recurrence was not seen in any cases. Regarding postoperative cosmetic grading, grade 1 (the appearance of the operated site is not different from the normal appearance) was found in 12 eyes (80%) and grade 2 (some fine episcleral vessels in the excised area extending up to but not beyond the limbus and without fibrous tissue) was found in 3 eyes (20%). None of the cases showed conjunctival scarring or fibrosis at the conjunctival donor area. Preoperative Sim K astigmatism at the central 3 mm and BCVA were 3.05 ± 1.5 diopters (D) and 0.64 ± 0.26 logMAR, which improved significantly to 1.15 ± 0.84 D and 0.26 ± 0.18 logMAR at 12-month follow-up postoperatively, respectively. Vertical split conjunctival autograft using fibrin glue is an effective technique with good cosmetic results and low to no recurrence for primary double-headed pterygia treatment. This trial is registered with NCT03507283.


Association of smoking with dsDNA autoantibody production in systemic lupus erythematosus.
To determine whether exposure to tobacco smoke is associated with double stranded DNA (dsDNA) seropositivity in patients with systemic lupus erythematosus (SLE). Medical record review was used to confirm the diagnosis of SLE and evaluate dsDNA antibody status. Smoking status at the time of autoantibody testing was assessed by patients' questionnaire responses. Multivariate regression analysis was used to determine whether exposure to tobacco smoke is associated with dsDNA seropositivity, while controlling for sex and age at SLE diagnosis. A significantly higher risk of dsDNA seropositivity in current smokers than never smokers (odds ratio (OR) = 4.0, 95% confidence interval (CI) 1.6 to 10.4) was shown by multivariate analysis. Current smokers were found to be at higher risk for dsDNA seropositivity than former smokers (OR = 3.0, 95% CI 1.3 to 7.1). The association between current smoking and dsDNA seropositivity remained significant after adjustment for sex, age at SLE diagnosis, amount smoked, age when smoking began, and the duration of smoking cessation (for former smokers). The association of smoking with dsDNA seropositivity provides insight into the potential mechanisms underlying autoantibody formation. This information may also serve as a possible point of intervention to prevent disease or target treatment.


[Effect of shenluotong decoction on renal interstitial fibrosis in rats with obstructive nephropathy].
To observe the effect of Shenluotong Decoction (SD) on serum levels of aldosterone, monocyte chemoattractant protein-1 (MCP-1), α-smooth muscle protein (α-SMA), and nuclear factor-KB (NF-κB) in obstructive nephropathy rats, and to explore the initial mechanism of SD for inhibiting renal interstitial fibrosis. Totally 48 healthy Wistar rats were randomly divided into the sham-operation group (n =12) and the model group (n =36). Renal interstitial fibrosis rat model was established by unilateral ureteral obstruction (UUO). After successful modeling, 36 rats were randomly divided into the model group, the Chinese medicine group, and the Western medicine group, 12 in each group. Eplerenone was added in the forage at the daily dose of 100 mg/kg for rats in the Western medicine group. Chinese medicine was added in the forage at the daily dose of 26 g/kg for rats in the Chinese medicine group. Equal volume of normal saline was administered to rats in the sham-operation group and the model group. All medication was performed once daily. The obstructive kidneys were extracted ten days after medication. The pathomorphological changes were observed. The contents of serum aldosterone and MCP-1, and the protein or mRNA expression of MCP-1, α-SMA, and NF-KB were detected. Compared with the sham-operation group, infiltration of a large amount of inflammatory cells and collagen deposition significantly increased, serum contents of aldosterone and MCP-1 obviously increased (P < 0.01), the expression of MCP-1 mRNA and protein were significantly up-regulated (P <0.01), the protein expression of α-SMA and NF-KB were significantly enhanced in the model group (P <0.01). Com- pared with the model group, infiltration of inflammatory cells and renal collagen deposition were attenua- ted in the Chinese medicine group and the Western medicine group, the serum MCP-1 level were reduced, and the mRNA and protein expression of MCP-1 were significantly down-regulated (P <0.01), the protein expression of α-SMA and NF-KB were obviously inhibited (P <0. 01). At the same time, serum aldosterone level was reduced in the Chinese medicine group (P <0.01). inflammatory lesions of the renal tissue could promote the progress of interstitial fibrosis in rats with obstructive nephropathy. SD could attenuate interstitial fibrosis through reducing serum contents of aldosterone and MCP-1, down-regulating MCP-1/ NF-KB, and inhibiting the expression of α-SMA.


[Phenotypic Trait Variation, Correlation and Path Analysis of Clerodendranthus spicatus].
To investigate the phenotypic trait variation range of Clerodendranthus spicatus, and to look for phenotypic traits closely related with its yield and quality, in order to provide reference for its breeding. Randomly labelled plants of Clerodendranthus spicatus, observed its phenotypic traits and analyzed by variation, principal component, correlation and path analysis. 13 phenotypic traits in the 15 germplasms of Clerodendranthus spicatus had great variations, the variations mainly distributed in yield, growth and genetic characteristics. Correlation and path analysis showed that, the plant dry weight had an extremely significantly positive correlation with fresh weight, and a positive correlation with stem height, stem diameter and root diameter. Plant fresh weight had a majorly direct contribution to the plant dry weight, stem height, stem diameter and root diameter also had a direct contribution to the plant dry weight. The other characters, including root length, branches, the number of leaf nodes, leaf number, leaf length, leaf width, fresh weight/dry weight ratio, rosmarinic acid content and ursolic acid content all had a negatively direct contribution to the plant dry weight. Rosmarinic acid content had a positive correlation with fresh weight, and a significantly positive correlation with fresh weight/dry weight ratio. Fresh weight had a majorly direct contribution to the rosmarinic acid content, stem height and stem diameter also had a direct contribution to the plant rosmarinic acid content. The other characters, including root length, root diameter, branches, the number of leaf nodes, leaf length, leaf width, dry weight, fresh weight/dry weight ratio, and ursolic acid content all had a negatively direct contribution to the rosmarinic acid content. The phenotypic traits of Clerodendranthus spicatus had rich variations on yield, growth and genetic characteristics. When choosing good germplasm, plant fresh weight, stem height, stem diameter and plant fresh weight/dry weight ratio having promoting effects on the plant dry weight and rosmarinic acid content should be considered comprehensively, and plant with vigorous growth, tall stem and more leaves can be choosed firstly.


Compounding Pharmacists Provide Customized Care.
Compounding is the creation of a pharmaceutical preparation by a licensed pharmacist to meet the unique needs of an individual patient when commercially available drugs do not meet those needs. For hundreds of years, compounding was the traditional practice of pharmacy. Today's advanced practice of compounding provides health care practitioners customized options for unique patients or for hard to treat conditions.


A migration-associated supergene reveals loss of biocomplexity in Atlantic cod.
Chromosome structural variation may underpin ecologically important intraspecific diversity by reducing recombination within supergenes containing linked, coadapted alleles. Here, we confirm that an ancient chromosomal rearrangement is strongly associated with migratory phenotype and individual genetic structure in Atlantic cod (Gadus morhua) across the Northwest Atlantic. We reconstruct trends in effective population size over the last century and reveal declines in effective population size matching onset of industrialized harvest (after 1950). We find different demographic trajectories between individuals homozygous for the chromosomal rearrangement relative to heterozygous or homozygous individuals for the noninverted haplotype, suggesting different selective histories across the past 150 years. These results illustrate how chromosomal structural diversity can mediate fine-scale genetic, phenotypic, and demographic variation in a highly connected marine species and show how overfishing may have led to loss of biocomplexity within Northern cod stock.


Tobacco Influence on Taste and Smell: Systematic Review of the Literature.
Introduction In Brazil, estimates show that 14.7% of the adult population smokes, and changes in smell and taste arising from tobacco consumption are largely present in this population, which is an aggravating factor to these dysfunctions. Objectives The objective of this study is to systematically review the findings in the literature about the influence of smoking on smell and taste. Data Synthesis Our research covered articles published from January 1980 to August 2014 in the following databases: MEDLINE (accessed through PubMed), LILACS, Cochrane Library, and SciELO. We conducted separate lines of research: one concerning smell and the other, taste. We analyzed all the articles that presented randomized controlled studies involving the relation between smoking and smell and taste. Articles that presented unclear methodologies and those whose main results did not target the smell or taste of the subjects were excluded. Titles and abstracts of the articles identified by the research strategy were evaluated by researchers. We included four studies, two of which were exclusively about smell: the first noted the relation between the perception of puff strength and nicotine content; the second did not find any differences in the thresholds and discriminative capacity between smokers and nonsmokers. One article considered only taste and supports the relation between smoking and flavor, another considered both sensory modalities and observes positive results toward the relation immediately after smoking cessation. Conclusion Three of the four studies presented positive results for the researched variables.


Aerosol and Contact Transmission Following Intranasal Infection of Mice with Japanese Encephalitis Virus.
The Japanese encephalitis virus (JEV), a causative agent of severe viral encephalitis in humans, has a biological cycle fluctuating between transmission in mosquitoes and avian species and amplification in pigs. Contact transmission of JEV was recently shown in pigs in the absence of arthropod vectors. Here, we show JEV transmission between infected and contact mice and further demonstrate that JEV transmission occurs between animals via aerosols, as both viral RNA and infectious JEV were detected in direct contact- and aerosol-exposed contact animals. The results of this study change our understanding of JEV transmission in densely populated regions and may help to explain JEV outbreaks without the presence of arthropod vectors.


Contribution of head movement to gaze command coding in monkey frontal cortex and superior colliculus.
Most of what we know about the neural control of gaze comes from experiments in head-fixed animals, but several "head-free" studies have suggested that fixing the head dramatically alters the apparent gaze command. We directly investigated this issue by quantitatively comparing head-fixed and head-free gaze trajectories evoked by electrically stimulating 52 sites in the superior colliculus (SC) of two monkeys and 23 sites in the supplementary eye fields (SEF) of two other monkeys. We found that head movements made a significant contribution to gaze shifts evoked from both neural structures. In the majority of the stimulated sites, average gaze amplitude was significantly larger and individual gaze trajectories were significantly less convergent in space with the head free to move. Our results are consistent with the hypothesis that head-fixed stimulation only reveals the oculomotor component of the gaze shift, not the true, planned goal of the movement. One implication of this finding is that when comparing stimulation data against popular gaze control models, freeing the head shifts the apparent coding of gaze away from a "spatial code" toward a simpler visual model in the SC and toward an eye-centered or fixed-vector model representation in the SEF.


Biochemical Investigations of Five Recombinantly Expressed Tyrosinases Reveal Two Novel Mechanisms Impacting Carbon Storage in Wetland Ecosystems.
Wetlands are globally distributed ecosystems characterized by predominantly anoxic soils, resulting from water-logging. Over the past millennia, low decomposition rates of organic matter led to the accumulation of 20-30% of the world's soil carbon pool in wetlands. Phenolic compounds are critically involved in stabilizing wetland carbon stores as they act as broad-scale inhibitors of hydrolytic enzymes. Tyrosinases are oxidoreductases capable of removing phenolic compounds in the presence of O2 by oxidizing them to the corresponding o-quinones. Herein, kinetic investigations (kcat and Km values) reveal that low-molecular-weight phenolic compounds naturally present within wetland ecosystems (including monophenols, diphenols, triphenols, and flavonoids) are accepted by five recombinantly expressed wetland tyrosinases (TYRs) as substrates. Investigations of the interactions between TYRs and wetland phenolics reveal two novel mechanisms that describe the global impact of TYRs on the wetland carbon cycle. First, it is shown that o-quinones (produced by TYRs from low-molecular-weight phenolic substrates) are capable of directly inactivating hydrolytic enzymes. Second, it is reported that o-quinones can interact with high-molecular-weight phenolic polymers (which inhibit hydrolytic enzymes) and remove them through precipitation. The balance between these two mechanisms will profoundly affect the fate of wetland carbon stocks, particularly in the wake of climate change.


Validation of a small-area model for estimation of smoking prevalence at a subnational level.
Small-area estimation methods are an alternative to direct survey-based estimates in cases where a survey's sample size does not suffice to ensure representativeness. Nevertheless, the information yielded by small-area estimation methods must be validated. The objective of this study was thus to validate a small-area model. The prevalence of smokers, ex-smokers, and never smokers by sex and age group (15-34, 35-54, 55-64, 65-74, ≥75 years) was calculated in two Spanish Autonomous Regions (ARs) by applying a weighted ratio estimator (direct estimator) to data from representative surveys. These estimates were compared against those obtained with a small-area model applied to another survey, specifically the Spanish National Health Survey, which did not guarantee representativeness for these two ARs by sex and age. To evaluate the concordance of the estimates, we calculated the intraclass correlation coefficient (ICC) and the 95% confidence intervals of the differences between estimates. To assess the precision of the estimates, the coefficients of variation were obtained. In all cases, the ICC was ≥0.87, indicating good concordance between the direct and small-area model estimates. Slightly more than eight in ten 95% confidence intervals for the differences between estimates included zero. In all cases, the coefficient of variation of the small-area model was <30%, indicating a good degree of precision in the estimates. The small-area model applied to national survey data yields valid estimates of smoking prevalence by sex and age group at the AR level. These models could thus be applied to a single year's data from a national survey, which does not guarantee regional representativeness, to characterize various risk factors in a population at a subnational level.


Realistic 3D computer model of the gerbil middle ear, featuring accurate morphology of bone and soft tissue structures.
In order to improve realism in middle ear (ME) finite-element modeling (FEM), comprehensive and precise morphological data are needed. To date, micro-scale X-ray computed tomography (μCT) recordings have been used as geometric input data for FEM models of the ME ossicles. Previously, attempts were made to obtain these data on ME soft tissue structures as well. However, due to low X-ray absorption of soft tissue, quality of these images is limited. Another popular approach is using histological sections as data for 3D models, delivering high in-plane resolution for the sections, but the technique is destructive in nature and registration of the sections is difficult. We combine data from high-resolution μCT recordings with data from high-resolution orthogonal-plane fluorescence optical-sectioning microscopy (OPFOS), both obtained on the same gerbil specimen. State-of-the-art μCT delivers high-resolution data on the 3D shape of ossicles and other ME bony structures, while the OPFOS setup generates data of unprecedented quality both on bone and soft tissue ME structures. Each of these techniques is tomographic and non-destructive and delivers sets of automatically aligned virtual sections. The datasets coming from different techniques need to be registered with respect to each other. By combining both datasets, we obtain a complete high-resolution morphological model of all functional components in the gerbil ME. The resulting 3D model can be readily imported in FEM software and is made freely available to the research community. In this paper, we discuss the methods used, present the resulting merged model, and discuss the morphological properties of the soft tissue structures, such as muscles and ligaments.


A Collection of Conserved Noncoding Sequences to Study Gene Regulation in Flowering Plants.
Transcription factors (TFs) regulate gene expression by binding cis-regulatory elements, of which the identification remains an ongoing challenge owing to the prevalence of large numbers of nonfunctional TF binding sites. Powerful comparative genomics methods, such as phylogenetic footprinting, can be used for the detection of conserved noncoding sequences (CNSs), which are functionally constrained and can greatly help in reducing the number of false-positive elements. In this study, we applied a phylogenetic footprinting approach for the identification of CNSs in 10 dicot plants, yielding 1,032,291 CNSs associated with 243,187 genes. To annotate CNSs with TF binding sites, we made use of binding site information for 642 TFs originating from 35 TF families in Arabidopsis (Arabidopsis thaliana). In three species, the identified CNSs were evaluated using TF chromatin immunoprecipitation sequencing data, resulting in significant overlap for the majority of data sets. To identify ultraconserved CNSs, we included genomes of additional plant families and identified 715 binding sites for 501 genes conserved in dicots, monocots, mosses, and green algae. Additionally, we found that genes that are part of conserved mini-regulons have a higher coherence in their expression profile than other divergent gene pairs. All identified CNSs were integrated in the PLAZA 3.0 Dicots comparative genomics platform (http://bioinformatics.psb.ugent.be/plaza/versions/plaza_v3_dicots/) together with new functionalities facilitating the exploration of conserved cis-regulatory elements and their associated genes. The availability of this data set in a user-friendly platform enables the exploration of functional noncoding DNA to study gene regulation in a variety of plant species, including crops.


Detection of influenza C virus by a real-time RT-PCR assay.
Influenza C virus can cause both upper and lower respiratory tract infections and has been reported to be prevalent in children. However, these infections have been under-diagnosed, and epidemiological data available are limited due to the lack of convenient detection assays. Design and validate a real-time reverse-transcriptase PCR (rt RT-PCR) assay for the detection of influenza C. Respiratory samples from two primary settings, namely, children who were hospitalized or seen in the emergency department, and respiratory outbreaks for which no other viral etiology was found were used for the detection of influenza C. The assay was sensitive and specific for the detection of influenza C. Eleven of 474 (2·32%) patients, all less than 10 years of age, were positive for influenza C. The strains clustered into two lineages, namely C/Kanagawa and C/Sao Paulo, based upon sequencing of the hemagglutinin-esterase gene. Epidemiological data showed that a higher proportion of influenza C infections occur in younger children and during the winter months. This is the first report of the detection of influenza C in Alberta, Canada, and suggests that the detection of this virus should be included in respiratory virus testing panels.


Nursing and theatre collaborate: an end-of-life simulation using forum theatre.
End-of-life care is an essential part of undergraduate nursing education. However, students may not have the opportunity to be exposed to an actual end-of-life situation during clinical rotations. A pilot project was implemented to evaluate the use of forum theatre to teach end-of-life care to undergraduate nursing students. A simulation used live actors, with theatre faculty and students playing the roles of a hospice patient, family members, and nursing students providing end-of-life care. Additional nursing students were participant observers. Using forum theatre methods, students identified important moments that occurred during the simulation and suggested alternative actions for those moments. The simulation was repeated using those alternatives and was evaluated by the students. Group debriefing was provided by nursing faculty with all students. A reflective journal entry was completed by all students. Project outcomes indicated that forum theatre was an effective teaching method for the topic of end-of-life care.


Psychiatric day programs: a descriptive analysis.
Partial hospitalization programs evolved as a result of a variety of financial, social and therapeutic circumstances. At present, these programs can take one of several different forms. Of these, the most common ones are the three day programs--day hospital, day treatment, and day care. In theory, each of the three would serve a distinct population, have a clearly defined structure, and be administered in a predictable manner. This article contrasts theory with practice and makes an analysis of the actual and potential effectiveness such as demographics and economics are presented. Recommendations for the present and future follow from projected long range shifts and trends.


Understanding dental CAD/CAM for restorations--dental milling machines from a mechanical engineering viewpoint. Part B: labside milling machines.
Nowadays, dental numerical controlled (NC) milling machines are available for dental laboratories (labside solution) and dental production centers. This article provides a mechanical engineering approach to NC milling machines to help dental technicians understand the involvement of technology in digital dentistry practice. The technical and economic criteria are described for four labside and two production center dental NC milling machines available on the market. The technical criteria are focused on the capacities of the embedded technologies of milling machines to mill prosthetic materials and various restoration shapes. The economic criteria are focused on investment cost and interoperability with third-party software. The clinical relevance of the technology is discussed through the accuracy and integrity of the restoration. It can be asserted that dental production center milling machines offer a wider range of materials and types of restoration shapes than labside solutions, while labside solutions offer a wider range than chairside solutions. The accuracy and integrity of restorations may be improved as a function of the embedded technologies provided. However, the more complex the technical solutions available, the more skilled the user must be. Investment cost and interoperability with third-party software increase according to the quality of the embedded technologies implemented. Each private dental practice may decide which fabrication option to use depending on the scope of the practice.


Current status and regulatory aspects of pesticides considered to be persistent organic pollutants (POPs) in Taiwan.
Organochlorine pesticides (OCPs) are capable of persisting in the environment, transporting between phase media and accumulating to high levels, implying that they could pose a risk of causing adverse effects to human health and the environment. Consequently, most OCPs are designated as persistent organic pollutants (POPs) and even as endocrine disrupting chemicals (EDCs). The objective of this paper was to review the current status of pesticide POPs in Taiwan, including aldrin, chlordane, chlordecone, DDT, dieldrin, endrin, heptachlor, hexachlorobenzene, α/β-hexachlorocyclohexanes, lindane, mirex, pentachloro-benzene, and toxaphene. The information about their environmental properties, banned use, carcinogenic toxicity and environmental levels, can be connected with the regulatory infrastructure, which has been established by the joint-venture of the central competent authorities (i.e., Environmental Protection Administration, Department of Health, Council of Agriculture, and Council of Labor Affairs). The significant progress to be reported is that the residual levels of these pesticide-POPs, ranging from trace amounts to a few ppb, have declined notably in recent years.


Novel applications for an established antimalarial drug: tumoricidal activity of quinacrine.
Quinacrine (QC), a synthetic antimalarial drug, was consistently used worldwide to combat malaria during the last century. Interestingly, later studies revealed that it also displays various additional properties, specifically antitumor activity. QC's antitumor activity occurs via a variety of pathways, including DNA intercalation, angiogenesis inhibition, signal transduction regulation, cell cycle arrest and autophagy induction. In combination with traditional therapies such as chemotherapy and radiotherapy, QC has also displayed synergistic effects against tumors, which may open promising therapeutic avenues. However, the breadth and complexity of its antitumor mechanisms have not yet been fully elucidated. In this review, we have systematically categorized QC's reported antitumor mechanisms from recent studies, to enable a deeper understanding of its antitumor activity.


Life-threatening posterior circumflex humeral artery injury secondary to fracture-dislocation of the proximal humerus.
Proximal humeral fractures account for 4% to 5% of all fractures, and most of these are minimally displaced and less prone to neurovascular injuries. This article presents a case of a 65-year-old man who injured the posterior circumflex humeral artery following a fracture dislocation of the proximal humerus leading to a life-threatening hemorrhagic complication during surgical fixation of the dislocated proximal humeral fracture. Preoperative vital signs were normal. Using the deltopectoral approach, the fracture site was exposed and the dislocated head was extracted. Blood pooled and overflowed the cavity at a brisk pace. Blood pressure dropped from 130/70 mm Hg to 90/45 mm Hg, and preoperative follow-up hemoglobin dropped to 4.8 g/dL. The axillary artery was explored and a ruptured posterior humeral circumflex artery was observed that was later ligated. In view of the damage to 1 of the circumflex humeral branches, primary hemiarthroplasty was performed. This article highlights the possibility of encountering life-threatening vascular injuries in highly displaced or dislocated 4-part proximal humeral fractures and the significance of obtaining the angiographic studies early in the course of management in such cases.


Symptom recognition and health care seeking among immigrants and native Swedish patients with heart failure.
It is not known what patient perceptions or beliefs lead to beneficial decisions or response patterns in symptom interpretation among heart failure (HF) patients, especially immigrants. The aim of this study was to explore and compare symptom recognition and health care seeking patterns among immigrants and native Swedes with HF. The study used a qualitative design. Semi-structured interviews were conducted with 42 patients with HF, of whom 21 were consecutively selected immigrants and 21 were randomly selected Swedish patients. The interviews were analysed using content analysis. A majority of the immigrant patients sought health care for symptoms and signs, such as breathing difficulties, fatigue and swelling. Twice as many immigrants as Swedes were unaware of "what the illness experience entailed" and which symptoms indicated worsening of HF. The symptoms that patients sought care for, were similar among immigrants and Swedes. However, when interpreting symptoms more immigrants were unaware of the connection between the symptoms/signs and their HF condition. More tailored educational interventions might improve recognition of worsening symptoms in immigrant patients with chronic heart failure.


Oncologists' Perspective on Dental Care Around the Treatment of Head and Neck Cancer: A Pattern of Practice Survey.
Patients with head and neck cancer are at risk of long-term dental complications. Proper dental assessment pre- and post-treatment can improve outcomes but is logistically challenging. We surveyed oncologists to better understand their perspectives surrounding dental care in this unique population. We surveyed oncologists at institutions associated with an ongoing national study of oral health after treatment of head and neck cancer. Seventeen questions were used to assess provider characteristics, patterns of practice, patterns of referral, barriers to referral, and willingness to apply fluoride varnish in the oncology clinic. Ninety-seven oncologists were invited from six institutions, of whom 40 (41%) responded. Surgeons represented 45% of the sample, followed by radiation oncologists (40%) and medical oncologists (15%). Both generalists and subspecialists were included. All practiced in a metropolitan area with an academic dental practice, and many felt that this improved access to care. Despite this, most oncologists thought that financial factors were a significant barrier to obtaining timely dental care. Most oncologists performed a dental assessment during visits. Oncologists felt qualified to identify the most significant complications of treatment, such as exposed bone, but felt underqualified to identify early changes in need of intervention. When asked if the oncology clinic could apply fluoride varnish during follow-ups, most stated that this seemed feasible but would require education and financial support. Oncologists often perform limited dental evaluations during their routine visits. Given the challenges associated with access to proper dental care for this population, these oncology visits may provide a window for preventative intervention.


Use of a thrombopoietin mimetic for chronic immune thrombocytopenic purpura in pregnancy.
Romiplostim, a thrombopoietin mimetic, is a novel therapeutic option for patients with chronic immune thrombocytopenic purpura. We report on the effects of romiplostim use throughout pregnancy. A 28-year-old primigravid woman with chronic immune thrombocytopenic purpura initiated a planned pregnancy on romiplostim. The second and third trimesters were marked by a cyclic pattern of thrombocytopenia requiring supplemental corticosteroids or intravenous immunoglobulin and resultant thrombocytosis. Increased romiplostim doses and daily corticosteroids stabilized the platelet count before induction of labor at 33 weeks of gestation. The newborn manifested intraventricular hemorrhage at birth, although no developmental delay was present on follow-up at 10 months of age. The decreased efficacy of romiplostim monotherapy is attributed to increased target-mediated drug disposition and the physiologic changes of pregnancy. Safety concerns still exist for the developmental effects of romiplostim on the fetus.


Voluntary upregulation of reflex cough is possible in healthy older adults and Parkinson's disease.
Cough is an airway-protective mechanism that serves to detect and forcefully eject aspirate material. Existing research has identified the ability of healthy young adults to suppress or modify cough motor output based on external cueing. However, no study has evaluated the ability of people with Parkinson's disease (PD) and healthy older adults (HOAs) to upregulate cough motor output. The goal of this study was to evaluate the ability of people with PD and healthy age-matched controls (HOAs) to upregulate reflex and voluntary cough function volitionally with verbal instruction and visual biofeedback of airflow targets. Sixteen participants with PD and twenty-eight HOAs (56-83 yr old) were recruited for this study. Experimental procedures used spirometry to evaluate 1) baseline reflex cough (evoked with capsaicin) and voluntary sequential cough and 2) reflex and voluntary cough with upregulation biofeedback. Cough airflow was recorded and repeated-measures ANOVA was used to analyze differences in cough airflow parameters. Cough peak expiratory airflow rate and cough expired volume were significantly greater in the cueing condition for both induced reflex (P < 0.001) and voluntary cough (P < 0.001) compared with baseline measures. This is the first study to demonstrate the ability of people with PD and HOAs to upregulate induced reflex and voluntary cough motor output volitionally. These results support the development of studies targeting improved cough effectiveness in patients with airway-protective deficits.NEW & NOTEWORTHY Aspiration pneumonia is a leading cause of death in Parkinson's disease (PD) and results from concurrent dysphagia and dystussia (cough dysfunction). This is the first study to demonstrate that people with PD and healthy age-matched controls can volitionally upregulate induced reflex and voluntary cough effectiveness when presented with novel cueing strategies. Thus targeting upregulation of cough effectiveness via biofeedback may be a viable way to enhance airway protection in people with PD.


Thermosensitive In Situ Gel Based on Solid Dispersion for Rectal Delivery of Ibuprofen.
The objective of this study was to develop a thermosensitive in situ gel based on solid dispersions (SDs) for rectal delivery of ibuprofen (IBU). Thermosensitive (poloxamer 407) and mucoadhesive (hydroxypropylmethyl cellulose E5 and sodium alginate) polymers were used to prepare the in situ gel and the sol-gel transition temperature (T sol-gel) and gel strength were optimized. The in vitro release performance and in vivo pharmacokinetic properties of the in situ gel after their rectal administration to rabbits were investigated. Compared with the solid suppository, the cumulative release of the IBU SDs loaded in situ gel was significantly increased. The in vivo pharmacokinetics indicated that in situ gel had a higher peak plasma concentration (C max) and area under the curve (AUC(0-∞)) in plasma than the solid suppositories. Histopathology results showed that the IBU in situ gel given at a dose of 15 mg/kg did not produce any irritation. In conclusion, this study suggested that the in situ gel could be an effective rectal formulation for IBU.


The critical shoulder angle is associated with osteoarthritis in the shoulder but not rotator cuff tears: a retrospective case-control study.
In 2013 Moor et al introduced the concept of the critical shoulder angle (CSA) and suggested that an abnormal CSA was a leading factor in development of rotator cuff tear (RCT) and osteoarthritis (OA) of the shoulder. This study assessed whether the CSA was associated with RCT and OA and tested the inter- and intrarater reliability of the CSA when measuring RCT and OA. The study was performed as a retrospective case-control study. The cases comprised 2 groups: 97 patients with RCT and 87 patients with OA. The controls were matched 3:1, by age and sex, from a population of 795 patients with humeral fractures. The CSA was measured as described by Moor et al. Analysis of the relation with CSA for RCT and OA was done by logistic regression. Models were fitted separately for RCT and OA and used the controls matched to the respective cases. Inter- and intrarater reliability was determined by measuring the intraclass correlation coefficient and minimal detectable change. The mean CSA was 33.9° in the RCT group and 33.6° in the matched control group. The odds ratio for developing RCT for people with a CSA above 35° was 1.12 (P = .63). The mean CSA in the OA group was 31.1° and in the matched control group 33.3°. The odds ratio for developing OA for people with a CSA below 30° was 2.25 (P = .002). The CSA measurements showed strong intra- and inter-rater reliability, with intraclass correlation coefficient values above 0.92 and minimal detectable change values below 0.4°. This study did not find any association between CSA and RCT but did show association between CSA and OA, with a 2.25 odds ratio of developing OA given the patient had a CSA below 30°. The results do not support the suggested praxis of shaving away the lateral border of the acromion to make the CSA smaller because it might increase the risk of developing OA without decreasing the risk of developing RCT. The CSA measurements showed excellent intra- and inter-rater reliability.


InDuo, a novel combined insulin injection and blood glucose monitoring device - effective and save as other devices, and patient preference.
Frequent blood glucose (BG) monitoring and insulin administration are necessary in intensive insulin regimes. A new integrated system, InDuo is a compact and portable combined insulin doser and BG monitor, designed to overcome some of the limitations of current insulin therapy. The aim of the study was to compare InDuo and a non-integrated system (HumaPen Ergo and Accu-Chek Sensor Meter) for efficacy and safety, and to evaluate patients preference. The trial design was a multicentre, randomised, 12-week, open-label, comparative, two period crossover. One hundred and ten patients with diabetes, treated with a basal bolus regime, were included. The subjects were assigned to use either InDuo or the non-integrated system. After six weeks of treatment, the subjects were transferred to the alternative system. To assess efficacy, fasting plasma glucose (FBG), 7-point blood glucose profile, serum fructosamine and HbA1c were measured. Serum fructosamine and FBG were measured at baseline and at six and 12 weeks; HbA1c was measured at baseline and week 12. Safety endpoints were number and severity of hypoglycaemic episodes, adverse events and adverse device effects. Patient preference was assessed by a comparative device questionnaire at 12 weeks. Analysis with an ANOVA mixed model showed no difference after each treatment between serum fructosamine or between FBG levels. HbA1c decreased during the trial from 7.5 % +/- 1.2 to 7.1 % +/- 0.8 at 12 weeks. The safety profiles were similar for both treatments for hypoglycaemic episodes. The incidence of adverse events was also similar. There were 10 adverse device effects reported: eight for the Innovo device in the InDuo, one for the InDuo device and one for the Accu-Chek Sensor Meter. The comparative device questionnaire at 12 weeks showed patients strongly preferred InDuo to HumaPen Ergo and Accu-Chek Sensor Meter (all p < 0.0001). Of those preferring InDuo, more than 60 % classified their choice as very or extremely strong. Both memory functions in InDuo(R) (i. e., for insulin dosage and for blood glucose readings) were used by more than 70 % of the patients. Treatment with the InDuo system was as effective and safe as treatment with the non-integrated system. Almost 75 % preferred using InDuo to the non-integrated HumanPen Ergo and Accu-Chek Sensor Meter.


Effect of a folate-binding protein on the plasma transport and tissue distribution of folic acid.
Folic acid (3H-pteroylglutamic acid or 75Se-selenofolate) administered free or bound to folate-binding protein (FABP) was rapidly cleared from the plasma but the plasma survival when bound to FABP was longer than unbound during the initial 5 min. 75Se-folate bound to FABP is more rapidly taken up by the liver than when administered as free 75-Se-folate. 125I-labeled FABP was rapidly cleared from the plasma (90% in 5 min). The rapid uptake of FABP, a sialoglycoprotein, was inhibited by the preadministration of desialyzed fetuin. Following the hepatic uptake of 75Se-folate/FABP, only free 75Se-folate was found in the bile. The total biliary secretion of 75Se-folate over 240 min was 63% when administered bound to FABP and 33% when administered as free 75Se-folate. The liver retained 33.5% of the 125I activity 5 min following the administration of 125I-FABP, while only 4.46% of the 125I activity was secreted into the bile over 180 min. This data suggests that FABP may play an important role in the enterohepatic circulation of folates by directing nonmethylated folates to the liver.


Localization and up-regulation of mucin (MUC2) gene expression in human nasal biopsies of patients with cystic fibrosis.
Using digoxigenin-UTP-labelled human HAM-1 (92 bp) or SMUC41 (850 bp) cRNA probes, the expression and localization of MUC2 gene transcripts were determined by in situ hybridization in human nasal tissues obtained as biopsies from 12 patients with cystic fibrosis (CF): all had been part of a gene therapy trial in which CFTR cDNA-liposome complexes had been delivered by topical application to eight and liposome alone to four as a placebo control. For comparison, there were nasal tissues taken at surgical resection from four non-CF subjects and a further four biopsies taken from normal healthy volunteer controls. Both SMUC41 and HAM-1 probes provided a strong signal. MUC2 mRNA transcripts were present in serous and mucous acini of submucosal glands, ciliated and basal cells of the surface epithelium, and occasional mononuclear inflammatory cells. The percentages (mean +/- SEM) of serous and mucous acini showing positivity for MUC2 gene expression in the four samples surgically resected from non-CF subjects were 25.4 +/- 5.6 and 26.7 +/- 3.3 per cent, respectively. Compared with the non-CF subjects, the mean percentage of acini showing MUC2 gene expression in the four placebo-treated CF subjects was significantly higher for serous (80.5 +/- 12.7 per cent; P < 0.05, t-test), but not for mucous acini (53.1 +/- 16.8 per cent; P = 0.38). In CF and non-CF groups, where present, MUC2 positivity was strongly expressed and constituted approximately 84 per cent of the cell area in serous acini, whereas it was less obvious and was confined to the perinuclear area of cells in mucous acini. A significantly greater proportion of the surface epithelium was positive for MUC2 mRNA transcripts in the CF subjects (89.0, +/- 1.4 per cent) than in the surgically resected tissues of the four non-CF subjects (19.4, +/- 4.0 per cent) (P = 0.02). In the eight CFTR-cDNA-treated subjects, there was an overall trend to reduction, but no statistically significant alteration of MUC2 gene expression. It is concluded that the MUC2 gene is expressed at three- to four-fold higher levels in CF nasal mucosa than in non-CF nasal tissue and that it is expressed in a variety of cells additional to submucosal mucus-secreting glands.


Effects of fluoxetine on electrically-induced spinal cord seizures in rats.
The effects of fluoxetine [an inhibitor of 5-hydroxytryptamine (5-HT) reuptake] on electrically-induced spinal cord seizures were determined by monitoring alterations in the total duration of seizure, as well as the durations of tonic flexion and extension. The capacity of fluoxetine to inhibit 5-HT reuptake in the spinal cord was confirmed by measurements of 5-hydroxyindoleacetic acid (5-HIAA) content. When given in a dose of 10 mg/kg, fluoxetine failed to produce an effect on spinal cord seizures or on 5-HIAA content. However, a dose of 20 mg/kg did significantly reduce 5-HIAA content although it did not alter seizure activity. These results further support our earlier suggestion that 5-HT containing neurons in the spinal cord do not modulate electrically-induced seizures.


Total composite graft replacement of the ascending aorta and aortic valve.
Ten patients (nine male and one female), ranging in age from 21 to 68 years, were operated on for total composite replacement of the ascending aorta and the aortic valve. Among them annulo-aortic ectasia was the most common indication (five patients), followed by annulo-aortic ectasia with aortic dissection (three patients), the aneurysm and aortic valve regurgitation associated with aortitis syndrome (one patient), and the syphilitic aneurysm and aortic valve regurgitation (one patient). In the first four patients, composite replacement was conducted according to the original procedure described by Bentall and DeBono (1986). The next six patients were treated according to the procedure modified by Cabrol et al. (1981). There were no operative deaths or complications during hospitalization. However, late complications occurred in two patients at 46 months and 15 months after surgery, respectively. Despite the repair on an urgent basis, one died of hepatic failure and the other died on the table with massive disruption. Eight late survivors remain in the New York Heart Association (NYHA) class 1 on an average of 4.3 years postoperatively. It is concluded that total replacement with a composite graft is feasible in all patients with low operative mortality, but this procedure needs a close follow-up because of the potential for anastomotic dehiscences.


Therapeutic and physical touch: physiological response to stressful stimuli.
Sixty female college students were exposed to a stressful stimulus and treated by therapeutic or physical touch. Groups were compared on levels of physiological response through electromyographic, skin conductance, and peripheral skin temperature measures. The hypotheses predicted that the therapeutic touch group would remain more relaxed than the physical touch group. None of the hypotheses were confirmed using a one-way analysis of covariance.


Congenital aglossia with situs inversus totalis--a case report.
Hypoglassia or aglossia is an uncommon anomaly, either of which may occur as an isolated finding or in association with other deformations, especially limb anomalies. Their genetic background is uncertain, and drug induced teratogen has not been clearly identified. We experienced a case of congenital aglossia with situs inversus in a female infant aged twelve days. Her initial complaints at admission were feeding difficulty and weight loss. In a review of literature, the association with situs inversus is very rare and only three cases have been reported until now.


Expression of biologically active human tumor necrosis factor-alpha in transgenic potato plant.
We report the successful insertion of the cDNA of human tumor necrosis factor-alpha (HuTNF-alpha) into the genome of potato plant species, Solanum tuberosum, using Agrobacterium tumefacience-mediated transformation. HuTNF-alpha is a known and essential cytokine mediating host defense against tumors and infectious diseases and an immunomodulating agent. To enhance the accumulation of foreign gene product expression in plant cells, the molecular design of the constructed HuTNF-alpha is presented. Transcription and translation of TNF-alpha in transformants were confirmed by Northern blot, RT-PCR, ELISA, and Western blot, respectively. Expression of the bioactive HuTNF-alpha in plant cells was confirmed by way of the cytotoxic effect of the extract obtained from the transformants against murine L929 cells. We think that the expression level of HuTNF-alpha (15 microg/g potato plant tissue) obtained in the present study may be sufficient to induce responses/effects similar to those generated by TNF-alpha in human milk administered orally. We believe that the TNF-alpha expressed in edible potato plants has tremendous potential for clinical use in the areas of medicine and veterinary science. Its usefulness and applicability, therefore, need to be fully explored.


Electron-electron momentum exchange in strong field double ionization.
We have investigated the momentum balance between the two electrons from strong field double ionization of argon at 780 nm and 1.9 x 10(14) W/cm(2). Experimental data show that perpendicular to the laser polarization direction the electrons emerge preferentially in opposite directions. Results of model calculations are found to agree well with the data and reveal a dominant role of the Coulomb correlation between the two outgoing electrons in this kinematical geometry. Differences between the experimental observations and the theoretical results for the ion momentum distribution indicate the importance of the further effects during the three-body breakup.


Multisystem inflammatory syndrome in children in Canada.
This article provides a summary of the epidemiology of multisystem inflammatory syndrome in children (MIS-C) cases reported nationally in Canada by provincial and territorial health authorities. Multisystem inflammatory syndrome in children is a post-viral inflammatory syndrome that temporally follows coronavirus disease 2019 (COVID-19). Symptoms may include fever, abdominal pain, vomiting, diarrhea, skin rash and other signs of inflammation. In Canada, MIS-C is rare, with 269 cases reported to the Public Health Agency of Canada between March 11, 2020 and October 2, 2021. One hundred forty-two (53%) of these cases were lab-confirmed COVID-19 cases or epidemiologically-linked with COVID-19 cases. Cases have been reported in infants as young as one week to youth as old as 18 years, with a median age of six years. Cases were more likely to occur in males than females (58% vs 42%, respectively; p=0.006). Almost all MIS-C cases (99%) required hospitalization and 36% required intensive care unit admission. No deaths have been reported to date. The time trend of MIS-C aligns with the incidence rate time trend of COVID-19 reported in children, with a two to six-week lag.


[Acute and chronic amiodarone effects on the dynamics of force-interval relationship in rat papillary muscle].
Effects of acute and chronic amiodarone treatment on the force-interval relationship were investigated in rat papillary muscle. It was found that both acute and chronic amiodarone treatment decreased the amplitude of extrasystoles. At the same time, only short-term administgration of amiodarone increased postextrasystols and post-rest potentiations of twitch force in rat myocardium. It is concluded that the acute and chronic amiodarone treatment suppress the excitability of cardiomyocytes, but only the chronic treatment increases the effective refractory period. The results suggest that the acute administration of amiodarone can influence the intracellular calcium homeostasis.


Resistance to oxidative stress is associated with metastasis in mucocutaneous leishmaniasis.
Mucocutaneous leishmaniasis (MCL) in South and Central America is characterized by the dissemination (metastasis) of Leishmania Viannia subgenus parasites from a cutaneous lesion to nasopharyngeal tissues. Little is known about the pathogenesis of MCL, especially with regard to the virulence of the parasites and the process of metastatic dissemination. We previously examined the functional relationship between cytoplasmic peroxiredoxin and metastatic phenotype using highly, infrequently, and nonmetastatic clones isolated from an L. (V.) guyanensis strain previously shown to be highly metastatic in golden hamsters. Distinct forms of cytoplasmic peroxiredoxin were identified and found to be associated with the metastatic phenotype. We report here that peroxidase activity in the presence of hydrogen peroxide and infectivity differs between metastatic and nonmetastatic L. (V.) guyanensis clones. After hydrogen peroxide treatment or heat shock, peroxiredoxin was detected preferentially as dimers in metastatic L. (V.) guyanensis clones and in L. (V.) panamensis strains from patients with MCL, compared with nonmetastatic parasites. These data provide evidence that resistance to the first microbicidal response of the host cell by Leishmania promastigotes is linked to peroxiredoxin conformation and may be relevant to intracellular survival and persistence, which are prerequisites for the development of metastatic disease.


Abnormality of Functional Connections in the Resting State Brains of Schizophrenics.
To explore the change of brain connectivity in schizophrenics (SCZ), the resting-state EEG source functional connections of SCZ and healthy control (HC) were investigated in this paper. Different band single-layer networks, multilayer networks, and improved multilayer networks were constructed and their topological attributes were extracted. The topological attributes of SCZ and HC were automatically distinguished using ensemble learning methods called Ensemble Learning based on Trees and Soft voting method, and the effectiveness of different network construction methods was compared based on the classification accuracy. The results showed that the classification accuracy was 89.38% for α band network, 82.5% for multilayer network, and 86.88% for improved multilayer network. Comparing patients with SCZ to those with Alzheimer's disease (AD), the classification accuracy of improved multilayer network was the highest, which was 88.12%. The power spectrum in the α band of SCZ was significantly lower than HC, whereas there was no significant difference between SCZ and AD. This indicated that the improved multilayer network can effectively distinguish SCZ and other groups not only when their power spectrum was significantly different. The results also suggested that the improved multilayer topological attributes were regarded as biological markers in the clinical diagnosis of patients with schizophrenia and even other mental disorders.


Self-harm behaviors (carving) in female adolescent drug abusers.
Deliberate self-lacerations by rebellious or delinquent adolescent girls, known by them as "carving," may be erroneously diagnosed as a suicide gesture. Carving is an important physical sign suggesting possible drug and alcohol abuse during adolescence. Eighty-five adolescent female patients in a long-term outpatient, self-payment, therapeutic community-type of adolescent drug treatment program, participated in a descriptive survey of "carving" behaviors. Forty-one girls (48%) admitted to deliberate cutting of their own wrists, arms, or other body parts without suicidal intent. Fifteen of the 85 girls (18%) cut themselves six or more times. Many girls had scarified their bodies with their boyfriends' initials as a visible means of demonstrating their affection and loyalty. They also carved rock group symbols or a Christian cross. Large and disfiguring scars were noted on 14 patients. The girls explained the behavior as a method of dealing with depressed affect, anger, emotional pain, or emptiness. Suicide attempts, usually by purposeful overdose of medication, had been made by 24 (59%) of 41 girls who carved themselves. Multiple suicide attempts were associated with habitual carving. Epidemics of carving, led by one or more angry, depressed, or lonely adolescents, may occur in closed facilities such as correctional institutions and drug abuse treatment facilities.


Inflammatory Bowel Disease: Future Therapies.
Current medical therapies for people with inflammatory bowel disease are not satisfactory, and it is unlikely that improvement of traditional drugs will have a major clinical impact. The immunopathogensis of Crohn's disease and ulcerative colitis are rapidly being deciphered, which is providing oppurtunities for radically innovative therapeutic approaches.


Inhibition of 7,12-dimethylbenz[a]anthracene-induced rat mammary tumor growth by aryl hydrocarbon receptor agonists.
The antitumorigenic activities of 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF), 8-methyl-1,3,6-trichlorodibenzofuran (8-MCDF) and 6-cyclohexyl-1,3,8-trichlorodibenzofuran (6-CHDF) were investigated in the 7,12-dimethylbenz[a]anthracene (DMBA) rat mammary tumor model. At doses of 5, 10 or 25 mg/kg/week, both 6-MCDF and 8-MCDF significantly inhibited mammary tumor growth and at the 5 mg/kg/week dose >50% growth inhibition was observed. In contrast, 6-CHDF was inactive at the 5 mg/kg/week dose and the structure-antitumorigenicity relationships (6-MCDF/8-MCDF > 6-CHDF) correlated with structure-antiestrogenicity (rat uterus) studies and the relative binding affinities of these compounds for the aryl hydrocarbon receptor (AhR). The antitumorigenic activity of 6-MCDF or 8-MCDF in the mammary was not accompanied by any significant changes in liver/body weight ratios, liver morphology or induction of hepatic CYP1A1-dependent activity which is one of the most sensitive indicators of exposure to AhR agonists. RT-PCR and Western blot analysis of mammary tumor mRNA and protein extracts, respectively, confirmed the presence of AhR suggesting that AhR-mediated signaling pathways are functional in rat mammary tumors. These results define a relatively non-toxic group of AhR agonists which exhibit potent antitumorigenic activity in the DMBA-induced rat mammary tumor model (<1 mg/kg/day), and therefore represent a new class of indirect-acting antiestrogens which have potential for clinical treatment of mammary cancer.


Differential cell surface antigen expression on metastatic variant lymphoma cell lines.
In the present investigation we have studied the cell surface antigenicity of a syngeneic murine metastatic lymphoma model system. This system is comprised of a highly malignant and metastatic RAW117-H10 subline and the less malignant/metastatic parental RAW117-P cell line. Using rabbit antisera raised against whole tumor cells we have been able to identify two major glycoprotein antigens which are differentially expressed on the cells. Although these antigens have a similar molecular weight (70 kD), they are antigenically distinct as determined by in vitro cytotoxicity assays. The levels of glycosylation on these glycoproteins were also found to be different. Increased expression of one of the antigenic components on the metastatic RAW117-H10 cells appeared to be associated with metastasis in this tumor model system.


Risk factors of delayed recovery from general anesthesia in patients undergoing radical biliary surgery: What can we prevent.
Delayed recovery (DR) is very commonly seen in the patients undergoing laparoscopic radical biliary surgery, we aimed to investigate the potential risk factors of DR in the patients undergoing radical biliary surgery, to provide evidences into the management of DR.Patients who underwent radical biliary surgery from January 1, 2018 to August 31, 2020 were identified. The clinical characteristics and treatment details of DR and no-DR patients were compared and analyzed. Multivariable logistic regression analyses were conducted to identify the potential influencing factors for DR in patients with laparoscopic radical biliary surgery.We included a total of 168 patients with laparoscopic radical biliary surgery, the incidence of postoperative DR was 25%. There were significant differences on the duration of surgery, duration of anesthesia, and use of intraoperative combined sevoflurane inhalation (all P < .05), and there were not significant differences on American Society of Anesthesiologists, New York Heart Association, tumor-lymph node- metastasis, and estimated blood loss between DR group and control group (all P > .05). Multivariable logistic regression analyses indicated that age ≥70 years (odd ratio [OR] 1.454, 95% confidence interval [CI] 1.146-1.904), body mass index ≥25 kg/m2 (OR 1.303, 95% CI 1.102-1.912), alcohol drinking (OR 2.041, 95% CI 1.336-3.085), smoking (OR 1.128, 95% CI 1.007-2.261), duration of surgery ≥220 minutes (OR 1.239, 95% CI 1.039-1.735), duration of anesthesia ≥230 minutes (OR 1.223, 95% CI 1.013-1.926), intraoperative combined sevoflurane inhalation (OR 1.207, 95% CI 1.008-1.764) were the independent risk factors for DR in patients with radical biliary surgery (all P < .05).It is clinically necessary to take early countermeasures against various risk factors to reduce the occurrence of DR, and to improve the prognosis of patients.


DNA topoisomerase II can drive changes in higher order chromosome architecture without enzymatically modifying DNA.
Topoisomerase II has been suggested to play a major role in chromosome organization based on its DNA decatenating activity and its ability to mediate direct binding interactions between DNA and nuclear matrix. However, this latter point remains controversial. Here we address the question of whether the chromatin binding activity of Topoisomerase II is sufficient to modify chromosome form using whole mammalian chromosomes in vitro. Intact chromosomes were microsurgically removed from living cells and disassembled by treatment with protease or heparin. When these disassembled chromosomes were incubated with recombinant human Topoisomerase II, the enzyme became incorporated into chromatin and reassembly resulted, leading to almost complete restoration of pre-existing chromosome shape and position within minutes. Chromosome reconstitution by Topoisomerase II was dose-dependent, saturable, and appeared to be controlled stoichiometrically, rather than enzymatically. Similar reassembly was observed in the absence of ATP and when a catalytically inactive thermosensitive Topoisomerase II mutant was used at the restrictive temperature. Chromosome recondensation also could be induced after the strand-passing activity of Topoisomerase II was blocked by treatment with an inhibitor of its catalytic activity, amsacrine. When a non-hydrolyzable beta,gamma-imido analog of ATP (AMP-PNP) was used to physiologically fix bound Topoisomerase II enzyme in a closed form around DNA, subsequent chromosome disassembly was prevented in the presence of high salt. These data suggest that Topoisomerase II may control higher order chromatin architecture through direct binding interactions, independently of its well-known catalytic activity.


TGF-beta1 modulates matrix metalloproteinase-13 expression in hepatic stellate cells by complex mechanisms involving p38MAPK, PI3-kinase, AKT, and p70S6k.
Transforming growth factor-beta1 (TGF-beta1), the main cytokine involved in liver fibrogenesis, induces expression of the type I collagen genes in hepatic stellate cells by a transcriptional mechanism, which is hydrogen peroxide and de novo protein synthesis dependent. Our recent studies have revealed that expression of type I collagen and matrix metalloproteinase-13 (MMP-13) mRNAs in hepatic stellate cells is reciprocally modulated. Because TGF-beta1 induces a transient elevation of alpha1(I) collagen mRNA, we investigated whether this cytokine was able to induce the expression of MMP-13 mRNA during the downfall of the alpha1(I) collagen mRNA. In the present study, we report that TGF-beta1 induces a rapid decline in steady-state levels of MMP-13 mRNA at the time that it induces the expression of alpha1(I) collagen mRNA. This change in MMP-13 mRNA expression occurs within the first 6 h postcytokine administration and is accompanied by a twofold increase in gene transcription and a fivefold decrease in mRNA half-life. This is followed by increased expression of MMP-13 mRNA, which reaches maximal values by 48 h. Our results also show that this TGF-beta1-mediated effect is de novo protein synthesis-dependent and requires the activity of p38MAPK, phosphatidylinositol 3-kinase, AKT, and p70(S6k). Altogether, our data suggest that regulation of MMP-13 by TGF-beta1 is a complex process involving transcriptional and posttranscriptional mechanisms.


Neurodegeneration, gliosis, and resolution of haemorrhage in neovascular age-related macular degeneration, a clinicopathologic correlation.
To analyse cellular and spatiotemporal factors of neurodegeneration and gliosis in a patient with submacular haemorrhage (SMH) secondary to type 1 macular neovascularization in neovascular age-related macular degeneration (nAMD). This is a case study and clinicopathologic correlation of an 84-year-old white man with nAMD treated with antiangiogenic drugs and photodynamic therapy during a 6-year follow-up. Eyes were recovered for histology 8.23 h after death. In vivo multimodal imaging including optical coherence tomography (OCT) and en face modalities was compared with ex vivo OCT and high-resolution histologic images, using a custom image registration procedure. SMH components were defined (intraretinal, subretinal, sub-retinal pigment epithelium (RPE), and dehemoglobinized blood). Neurodegenerative changes in each of these areas were described. One anonymous donor eye with haemorrhagic nAMD was also reviewed as a comparator. By in vivo OCT, progressive resolution of the haemorrhage and gradual transformation of sub-RPE fluid to fibrous hyperreflective tissue, progressive macular atrophy, and variation in external limiting membrane (ELM) visibility were observed. Histology showed intense photoreceptor loss with preservation and self-adhesion of macular Müller glia resulting in ELM condensation. The comparator eye exhibited shed cone inner segments among subretinal erythrocytes. This is the most detailed clinicopathologic correlation of nAMD with SMH resolution to date, and the first in the OCT era. Our results reveal profound macular neurodegeneration and gliosis, signified by condensed ELM, soon after haemorrhage begins. Intensified OCT reflectivity of the ELM, an important retinal barrier, has potential as a biomarker for severe photoreceptor loss and gliosis.


Individuation and discrimination in the classroom.
A negative tone pervades much of the literature on teacher discrimination in the classroom, and conjures up images of inequality, oppression, and racism. This paper differentiates between the negative forms of discrimination (responding prejudicially to children) and individuation (discerning differences among children and responding to individual needs). Focus is on the positive face of discrimination, as exemplified by three teachers who are highly "individuating" in their attitudes and behaviors towards children.


Antibiotic prescriptions in the paediatric population in the Lazio Region of Italy: association with children's and physician's characteristics.
Estimating prevalence rates for antibacterial use in 0-14 year old children in 2009 in Lazio (Italy). Antibiotic prescriptions has been selected as drugs belonging to the J01 main therapeutic of the Anatomical Therapeutic Chemical system. Prevalence data by sex and age were calculated. The proportion of children who underwent 1, 2 or ≥ 3 treatments was calculated. Relation between use of antibiotics and incidence of influenza cases was evaluated. The association of children's and physician's characteristics with prescription was assessed by multi-level Poisson regression model. 45% of children received one antibiotic with a peak in the 1-2 age. Penicillins combinations and beta-lactamase inhibitors were the most frequently prescribed group. Multilevel model highlighted prescription rate decreases with doctor's increasing age, if the doctor is a paediatrician and female. Contrarily, doctors with >900 patients present higher probability to prescribe antibiotics. The study highlights the variability in antibiotic use and the fact that several children's and primary care doctors' characteristics are associated with antibiotic prescription. Paper findings appear to be coherent with other Italian studies but prevalence rate is definitively higher comparing to other countries.


Urinary Extracellular Domain of Neurotrophin Receptor p75 as a Biomarker for Amyotrophic Lateral Sclerosis in a Chinese cohort.
To comprehensively assess whether p75ECD in urine could be a candidate biomarker for ALS evaluation. Urine samples were collected from 101 ALS patients, 108 patients with other neurological disease (OND) and 97 healthy controls. 61 ALS patients were followed up with clinical data including ALSFRS-r every 6 to 12 months, 23 ALS patients died and 17 ALS patients lost touch during follow up period. Enzyme-linked immunoassay was employed to determine urine p75ECD concentration. The ALSFRS-r was employed to assess the severity of ALS. The concentration of p75ECD in ALS was significantly higher than that of OND and CTRL (p < 0.001). Additionally, urine p75ECD concentrations in ALS-definite grade patients were significantly higher than that in ALS-probable grade and ALS-possible grade patients (p < 0.001). Higher urine p75ECD concentrations were correlated with increased clinical stage (p = 0.0309); urine p75ECD concentrations and ALSFRS-r were negatively correlated (p = 0.022); and urine p75ECD concentration in the fast-progressing ALS group was significantly higher than that in slow-progression (p = 0.0026). Our finding indicates that urine p75ECD concentration provides additional evidence for patients with clinically suspected ALS, and can be employed to evaluate ALS-severity.


[Intention to use and use of treatment due to psychological distress of patients in somatic rehabilitation].
Somatically ill patients in somatic rehabilitation often show comorbid psychological distress and mental disorders. In the framework of the implementation of a stepwise psychodiagnostic procedure, the present study investigated the intention to use and the use of treatment due to psychological distress. Cohort study with a 6-months follow-up in 5 orthopedic, cardiologic and oncologic inpatient rehabilitation clinics (n=1 374). Psychological distress, sociodemographic data, intention to use psychotherapeutic or psychiatric treatments and the use of health care offers due to psychological distress were assessed by means of questionnaires. Every third patient (34%) was psychologically distressed at the beginning of rehabilitation. A positive intention to use psychotherapeutic or psychiatric treatment was reported by 79% of the psychologically distressed patients. 6 months after the end of rehabilitation, 26% of the patients who were psychologically distressed at the beginning of rehabilitation, had received treatment for mental health reasons. Reasons for non-utilization of treatment included lack of subjective need (45%) and lack of interest in treatment despite a perceived need (30%). Further 25% were considering treatment or were seeking appropriate treatment. Psychologically distressed rehabilitation patients show a high intention to undergo treatment. However, they show a clearly diminished use of post-rehabilitative treatments due to mental health problems. Hence, the promotion of motivation as well as the management of treatment barriers for improving post-rehabilitative use in psychologically distressed rehabilitants are of particular importance.


[Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids].
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory disease of the central nervous system, mainly affecting the brain stem, cerebellum and spinal cord. The clinical picture includes gradually developing ataxia, double vision, dysarthria, pyramidal and cognitive impairment. Morphological examination reveals T-cell perivascular lymphocytic infiltration with CD4 lymphocytes predominance over CD8 lymphocytes. The cause of the disease is unknown. The article describes two patients (a 18-year-old woman and a 40-year-old man) with typical clinical and MRI manifestations of CLIPPERS, which was confirmed by brain biopsy in the female patient. The duration of follow-up was 3 and 7 years, respectively. Both patients survived an infection 2-3 weeks before the onset of disease that allows one to discuss its role in CLIPPERS pathogenesis. Both patients had a clear clinical and MRI responsiveness to steroids. In the female patient, steroids were replaced by intramuscular administration of the TNF-α blocker adalimumab. During 1,5 years of its use, there were no clinical relapses and pathological brain changes on MRI.


Infusion of sodium nitroprusside induces platelet dysfunction in vitro.
The effect of sodium nitroprusside (SNP) infusion on platelet function was prospectively evaluated in 29 patients undergoing cardiac surgical procedures requiring cardiopulmonary bypass. Any patient receiving preoperative medication known to interfere with platelet function was excluded from this study. Platelet function was evaluated by measurement of platelet aggregation with both adenosine diphosphate (ADP) and epinephrine-induced aggregation tests. Ten patients served as a control population receiving fentanyl anesthesia and no SNP. Nineteen patients received SNP, as clinically indicated, following the induction of anesthesia (and prior to cardiopulmonary bypass) to maintain a mean blood pressure of 80 mmHg. The infusion rate and total dose of SNP delivered was recorded for each patient. Infusion rates of SNP greater than or equal to 3 micrograms.kg.-1 min-1 resulted in a dose-related decrease in platelet aggregation (P less than 0.05). This reduction in platelet function was accompanied by a concomitant increase in bleeding time from 5.8 +/- 0.6 to 9.3 +/- 0.4 min in the patients receiving SNP (P less than 0.05). In addition, with the administration of a total dose of SNP greater than or equal to 16 mg, a significant reduction in platelet aggregation (P less than 0.05) was observed. Platelet aggregation studies and bleeding time performed in the control group (following the administration of fentanyl (30 micrograms/kg) did not reveal any deviation from baseline values. The results from this in vivo study support previous in vitro data demonstrating a detrimental effect upon platelet function following SNP infusion.


Thirty-day and one-year outcomes following transcatheter mitral valve edge-to-edge repair versus transapical mitral valve replacement in patients with left ventricular dysfunction.
A comparison of 30-day and 1-year clinical outcomes in patients with pre-existing left ventricular (LV) dysfunction undergoing transcatheter mitral valve edge-to-edge repair (TEER) or transcatheter transapical mitral valve replacement (TMVR) has not previously been reported. We aimed to compare 30-day and 1-year rates of all-cause and cardiovascular mortality as well as rehospitalisation for heart failure (HFH). All patients with severe (≥3+) symptomatic mitral regurgitation (MR) and an LV ejection fraction ≤50% who underwent TEER or TMVR over a 5-year period were evaluated. Ninety-six patients (50 TEER, age 80±9 years, 70% secondary MR and 46 TMVR, age 72±9 years, 91% secondary MR) were studied. Baseline demographic and transthoracic echocardiogram characteristics were well-matched, with the exception of age (TEER 80±9 vs TMVR 72±9; p=0.01). Successful device implantation occurred in 96% of TEER patients and 97.8% of TMVR patients. Ninety-two percent of TEER patients had ≤2+MR predischarge, whilst no TMVR patient had ≥1+MR (p<0.01). No significant difference in the combined endpoint of 30-day all-cause mortality or HFH was observed (p>0.05). At 1 year, freedom from all-cause mortality and HFH was 79.2% across the entire study population but was significantly higher in patients undergoing TEER (TEER: n=45 [90%] hazard ratio 11.26, 95% confidence interval [CI]: 10.59-11.93 vs TMVR: n=39 [67.4%] 95% CI: 10.09-11.33; p=0.008). Despite comparable rates of successful device implantation, MR reduction, and 30-day all-cause mortality/HFH, TEER patients had lower all-cause mortality and HFH rates at 1 year.


COVID-19 vaccination and thyroiditis.
At the end of 2019, the world began to fight the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus-2. Many vaccines have quickly been developed to control the epidemic, and with the widespread use of vaccines globally, several vaccine-related adverse events have been reported. This review mainly focused on COVID-19 vaccination-associated thyroiditis and summarized the current evidence regarding vaccine-induced subacute thyroiditis, silent thyroiditis, Graves' disease, and Graves' orbitopathy. The main clinical characteristics of each specific disease were outlined, and possible pathophysiological mechanisms were discussed. Finally, areas lacking evidence were specified, and a research agenda was proposed.


Association of serum IFN-λ3 with inflammatory and fibrosis markers in patients with chronic hepatitis C virus infection.
Hepatitis C virus (HCV) is one of the major causes of liver cancer. The single nucleotide polymorphisms within the IFNL3 gene, which encodes interferon (IFN)-λ(3), are strongly associated with the response to pegylated IFN-α (PEG-IFN-α) plus ribavirin (RBV) therapy in chronic hepatitis C (C-CH) patients. However, the roles of IFN-λ(3) in chronic HCV infection are still elusive. In this study, we aimed to identify clinical and immunological factors influencing IFN-λ(3) and evaluated whether serum IFN-λ(3) levels are involved or not involved in the response to PEG-IFN-α plus RBV therapy. We enrolled 119 C-CH patients with HCV genotype 1 infection who underwent 48 weeks of PEG-IFN-α plus RBV therapy. As controls, 23 healthy subjects and 56 patients with non-HCV viral hepatitis were examined. Serum IFN-λ(3) was quantified by chemiluminescence enzyme immunoassay, and 27 cytokines or chemokines were assayed by the multiplexed BioPlex system. Serum IFN-λ(3) levels were higher in C-CH patients or acute hepatitis E patients than in healthy volunteers. Such levels did not differ between the IFNL3 genotypes. In C-CH patients, serum IFN-λ(3) was positively correlated with aspartate aminotransferase, alanine aminotransferase, α-fetoprotein, histological activity, fibrosis index, IFN-γ-inducible protein 10, and platelet-derived growth factor. Multivariate analysis showed that IFNL3 single nucleotide polymorphisms, fibrosis score, and macrophage inflammatory protein 1α were involved in the sustained viral clearance in PEG-IFN-α plus RBV therapy; however, serum IFN-λ(3) levels were not involved. Serum IFN-λ(3) levels are increased in C-CH patients regardless of the IFNL3 genotype. IFN-λ(3) is a biomarker reflecting the activity and fibrosis of liver disease, but is not correlated with the responsiveness to PEG-IFN-α plus RBV therapy.


Pattern learning and the control of behaviour by all-inhibitory neural network hierarchies.
An all-inhibitory network which learns by selective disconnection of synapses is described. This is similar to an 'associative net'; however, it is simpler in that its neurons do not need to perform arithmetical operations, and the net does not require additional threshold modulating neurons in order to cope with input patterns which are incomplete, or of differing sizes. This fundamental simplicity permits a greater variety and density of connections. These can multiply the capacity of the nets to learn complex sequences of patterns without being saturated. An "all-connected" net is described which has the holograph-like capacity to reconstruct the whole of an input pattern from part patterns without involving delays or threshold devices. All of these inhibitory nets can construct themselves by means of simple random growth processes, without incurring any loss of learning capacity of holographic properties. Similarly, synapses can be allowed to potentiate with use, so that reaction times are progressively reduced by practice, without any reduction in the quality of the performance. Inhibitory connections between arrays can give patterns in one array control over the allocation of channels in which lower arrays store learned information. A description is given of a model, decentralised, inhibitory hierarchy consisting of inter-connected arrays which can learn to execute goal-directed TOTE-type programs of behaviour by means of a simple 'putting-through' procedure.


Alternatives to clopidogrel for acute coronary syndromes: Prasugrel or ticagrelor?
Clopidogrel is a mainstay in the treatment of patients with acute coronary syndromes or those receiving endovascular prostheses. However, its efficacy has been challenged in the recent past by studies suggesting variable individual responsiveness and by new, more potent competitors, such as prasugrel and ticagrelor. But what is the actual body of evidence in support of clopidogrel? Is there any dark side of the moon? What is the role of prasugrel, which has already been approved in Europe and in the United States? And what will be the future role of ticagrelor, when approved for routine clinical practice? We hereby concisely summarize the scope of this clinical choice, providing arguments in favor and against each of the three antiplatelet agents: clopidogrel, prasugrel, and ticagrelor.