[Pitfalls and challenges of the preanalytical phase in hematology].
In the last few decades we have seen a significant decrease in the rates of analytical errors in clinical laboratories. The test performances have improved, new parameters have been introduced, as well as internal and external quality controls have been used for the monitoring of accuracy. Currently available evidence demonstrates that the pre- and post-analytical steps show higher error rates (up to 70 % of all errors) than the analytical phase. Recognition of the weak points of the preanalytical phase and search for appropriate solutions in case of discrepancies will finally help to lead to the correct therapeutic strategy. In order to avoid problems in the preanaytical phase in hematology it is very important to consider some essential issues. The patients must be identified in appropriate form, the blood collection for the requested tests must be made using the appropriate tubes in the specified sequence and the samples must be transported to the lab at the right temperature and on time to be analysed. In case of special tests additional information for the lab is very important for the interpretation of the results. In case of unexpected results the lab should contact the responsible physician in order to look for an adequate explanation for the abnormal findings. With help of several cases of the daily haematology routine we want to point out some preanalytical problems.


The type of ploidy of chrysanthemum is not black or white: a comparison of a molecular approach to published cytological methods.
Polyploidy is a widespread phenomenon among higher plants and a major factor shaping the structure and evolution of plant genomes. The important ornamental chrysanthemum (Chrysanthemum indicum hybrid) possesses a hexaploid genome with 54 chromosomes and was classified based on its evolutionary origin and cytological methods as an allopolyploid. However, it is questionable whether cytological methods are sufficient to determine the type of ploidy, and there are more informative methods available based on molecular marker analyses. Therefore, we collected segregation data for 406 dominant molecular marker alleles [327 amplified fragment length polymorphism (AFLPs), 65 single-strand conformation polymorphism (SSCPs) and 14 microsatellites (EST-SSRs)] in a biparental F1 population of 160 individuals. We analyzed these data for the characteristics that differ between allopolyploids and autopolyploids, including the segregation ratio of each marker, the ratio of single-dose (SD) to multi-dose (MD) markers, the ratio of SD markers in coupling to those in repulsion and the banding patterns of the SSRs. Whereas the analysis of the segregation ratio of each polymorphic marker indicated disomic (13 markers) as well as hexasomic (eight markers) inheritance, the ratio of SD markers in coupling to those in repulsion was 1:0, which is characteristic of autopolyploids. The observed ratio of SD to MD markers was 0.67:0.33 which is significantly different to the expected segregation for auto- and allohexaploids. Furthermore, the three EST-SSR alleles were inherited in all possible combinations and were not independent of each other, as expected for fixed heterozygosity in allopolyploids. Combining our results with published cytological data indicates that cultivated chrysanthemums should be classified as segmental allohexaploids.


[Influence of anatomical variations of the pancreatic artery on the surgical technic of segmental pancreas transplantation in dogs].
The surgical technique in clinical pancreas transplantation is still not standardized. Animal experimentation should allow a reproducible and reliable model by choosing the cervical region in dogs as the site of segmental grafting. A goal of the experiments was to determine the influence of preservation, operation technique, duct occlusion, immunosuppression, and gastrointestinal hormones (Somatostatin, Cyclosporin A). 50 grafts have been transplanted. It could be clearly demonstrated that in 54% the vascularization of the left lobe of the canine pancreas differs extremely from man. Successful results are to expect being aware of the anatomical variations. The varieties of the arterial blood supply indicate which technique has to be performed to avoid ischemic grafts due to inadequate preservation.


Efficacy of an ototoxic aminoglycoside (gentamicin) on the differentiation of the inner ear of cichlid fish.
Previous investigations revealed that the growth of fish inner ear otoliths depends on the amplitude and the direction of gravity, thus suggesting the existence of a (negative) feedback mechanism. In the course of these experiments, it was shown that altered gravity both affected otolith size (and thus the provision of the proteinacious matrix) as well as the incorporation of calcium. It is hitherto unknown, as of whether sensory hair cells are involved either in the regulation of otolith growth or in the provision of otolithic material (such as protein or inorganic components) or even both. The ototoxic aminoglycoside gentamicin (GM) damages hair cells in many vertebrates (and is therefore used for the treatment of Meniere's disease in humans). The present study was thus designed to determine as of whether vestibular sensory cells are needed for otolith growth by applying GM in order to induce a (functionally relevant) loss of these cells. Developing cichlid fish Oreochromis mossambicus were therefore immersed in 120 mg/l GM for 10 or 21 days. At the beginning and at the end of the experimental periods, the fish were incubated in the calcium-tracer alizarin complexone (AC). After the experiment, otoliths were dissected and the area grown during GM-exposure (i.e., the area enclosed by the two AC labellings) was determined planimetrically. The results showed that incubating the animals in a GM-solution had no effect on otolith growth, but the development of otolith asymmetry was affected. Ultrastructural examinations of the sensory hair cells revealed that they had obviously not been affected by GM-treatment (no degenerative morphological features observed). Overall, the present results suggest that hair cells are not affected by GM concerning their possible role in (general) otolith growth, but that these cells indeed might have transitionally been impaired by GM resulting in a decreased capacity of regulating otolith symmetry.


Advancement of microfluidic modulation spectroscopy as a highly sensitive protein characterization technique for the detection of small structural changes.
The higher order structure (HOS) of a protein is vital to its function and activity, making it a critical component in the development of protein-based therapeutics. Characterization of HOS can be performed using various biophysical techniques, but many of these methods have limitations such as low throughput, complicated workflow, narrow concentration range, and low sensitivity. Microfluidic Modulation Spectroscopy (MMS) is an emerging technology that addresses these limitations, offering high sensitivity and automated analysis for protein secondary structure. This study evaluates and compares the different well plate formats and scan modes of two MMS instruments. The newer Apollo system features a high throughput 96-well plate format and sweep scan mode that allows a 50% reduction in sample volume consumption and measurement time compared to the previous system. By measuring two proteins with drastically different secondary structures, the results demonstrated that the measurements were highly repeatable (>99% repeatability by area of overlap) regardless of the well plate formats or the scan modes. The limit of quantitation (LOQ) for determining structural impurity using the sweep scan mode was 3.2% and significantly better than that of FTIR at 23% from previous studies. This work highlighted the advancement of MMS as a highly sensitive technique to detect small changes of protein structures due to aggregation or misfolding.


Semi-embedded slot waveguide electro-optic modulator.
Electro-optic modulators are essential devices on silicon photonic chips in modern optical communication networks. This paper presents a compact, low-loss electro-optic modulator. The modulation efficiency is greatly improved by embedding the lower half of the slot waveguide into the buried oxide layer and inserting graphene at the junction. The interaction of graphene with an optical field in a waveguide is studied using the finite element method. The functions of phase modulation and absorption modulation are realized by changing the gate voltage to change the chemical potential of graphene. The semi-embedded slot waveguide optical modulator has a length of 50 µm. After simulation verification, it can be used as an electro-absorption modulator and can achieve a modulation depth of 26.38 dB and an insertion loss of 0.60 dB. When used as an electro-refractive modulator, it can be realized with a linear change of phase from zero to π; the total insertion loss is only 0.59 dB. The modulator has a modulation bandwidth of 79.6 GHz, and the energy consumption as electro-absorption and electro-refraction modulation are 0.51 and 1.92 pj/bit, respectively. Compared with common electro-optic modulators, the electro-optic modulator designed in this paper has a higher modulation effect and also takes into account the advantages of low insertion loss and low energy consumption. This research is helpful for the design of higher-performance optical communication network devices.


Pro-stimulatory role of methemoglobin in inflammation through hemin oxidation and polymerization.
Inflammation or vascular occlusion by parasitized red blood cell contributes to the pathogenesis of cerebral malaria. The current study aimed to characterize the role of major pro-oxidant factor methemoglobin present in the malaria culture supernatant contributing in inflammation during malaria. Heme and heme polymer stimulate macrophage to secrete large amount of reactive oxygen species into the external micro-environment. The addition of methemoglobin along with heme or heme polymer amplifies production of ROS from macrophages several folds. Methemoglobin mediated stimulatory effect is not due to release of iron, enhanced production of H2O2 or mutual interaction of reaction components. Spectroscopic studies show that methemoglobin accepts heme as a substrate and oxidizes it through a single electron transfer mechanism. Heme oxidation product is a heme polymer with similar chemical and structural properties to synthetic β-hematin. Phenyl N-t-butylnitrone inhibits heme polymerization (IC50=30 nM) and indicates the absolute necessity of heme oxidation and heme free radical generation for heme polymerization. Methemoglobin produced heme polymer is a potent pro-inflammatory factor to release ROS into external microenvironment. Interestingly, methemoglobin not only produces pro-inflammatory heme polymer, but it also amplifies the potential of heme or preformed heme polymer (haemozoin or β-hematin) to produce several folds high ROS production from macrophages. This study illustrates the pro-inflammatory effect of methemoglobin, the underlying novel mechanism by which this occurs and a possible clinical intervention. Based on the results, we recommend methemoglobin directed peroxidase inhibitors as an adjuvant therapy during malaria.


Cross-border impacts of the restriction of hazardous substances: a perspective based on Japanese solders.
Despite the relevance of the global economy, Regulatory Impact Assessments of the restriction of hazardous substances (RoHS) in the European Union (EU) are based only on domestic impacts. This paper explores the cross-border environmental impacts of the RoHS by focusing on the shifts to lead-free solders in Japan, which exports many electronics to the EU. The regulatory impacts are quantified by integrating a material flow analysis for metals constituting a solder with a scenario analysis with and without the RoHS. The results indicate that the EU regulation, the RoHS, has triggered shifts in Japan to lead-free solders, not only for electronics subject to this regulation, but for other products as well. We also find that the RoHS leads to a slow reduction in environmental emissions of the target, lead, but results in a rapid increase in the use of tin and silver in lead-free solders. This indicates the importance of assessing potential alternative substances, the use of which may increase as a result of adhering to the RoHS. The latter constitutes a negative impact because of recent concerns regarding resource criticality.


Primary health Centres' performance assessment measures in developing countries: review of the empirical literature.
It is universally accepted that primary healthcare is essential for achieving public health and that assessment of its performance is critical for continuous improvement. The World Health Organization's (WHO's) framework for performance assessment is a comprehensive global standard, but difficult to apply in developing countries because of financial and data constraints. This study aims to review the empirical literature on measures for Primary Health Centre (PHC) performance assessment in developing countries, and compare them for comprehensiveness with the aspects described by the WHO Framework. Research articles published in English scientific journals between January 1979 and October 2016 were reviewed systematically. The reporting quality of the article and the quality of the measures were assessed with instruments adapted for the purpose of this study. Data was categorized and described. Fifteen articles were included in the study out of 4359 articles reviewed. Nine articles used quantitative methods, one article used qualitative methods exclusively and five used mixed methods. Fourteen articles had a good description of the measurement properties. None of the articles presented validity tests of the measures but eleven articles presented measures that were well established. Mostly studies included components of personnel competencies (skilled/ non-skilled) and centre performance (patient satisfaction/cost /efficiency). In comparison to the WHO framework, the measures in the articles were limited in scope as they did not represent all service components of PHCs. Hence, PHC performance assessment should include system components along with relevant measures of personnel performance beyond knowledge of protocols. Existing measures for PHC performance assessment in developing countries need to be validated and concise measures for neglected aspects need to be developed.


Chiral Sulfur Nanosheets for Dual-Selective Inhibition of Gram-Positive Bacteria.
Elemental sulfur is the oldest known antimicrobial agent. However, conventional sulfur in the clinic suffers from poor aqueous solubility and limited antibacterial activity, greatly hindering its practical use. Herein, we report a reform strategy coupling dimension engineering with chirality transfer to convert conventional 3D sulfur particles into chiral 2D sulfur nanosheets (S-NSs), which exhibit 50-fold improvement of antibacterial capability and dual-selective inhibition against Gram-positive bacteria. Benefiting from the inherent selectivity of S-NSs and chirality selectivity from decorated d-histidine, the obtained chiral S-NSs are proven to precisely kill Gram-positive drug-resistant bacteria, while no obvious bacterial inhibition is observed for Gram-negative bacteria. Mechanism studies reveal that S-NSs produce numerous reactive oxygen specipoes and hydrogen sulfide after incubation with bacteria, thus causing bacterial membrane destruction, respiratory chain damage, and ATP production inhibition. Upon spraying chiral S-NSs dispersions onto MRSA-infected wounds, the skin healing process was greatly accelerated in 8 days due to metabolism inhibition and oxidative damage of bacteria, indicating the excellent treatment efficiency of MRSA-infected wounds. This work converts the traditional well-known sulfur into modern antibacterial agents with a superior Gram-selectivity bactericidal capability.


Heterogeneity of the induction of HLA-DR expression by human immune interferon on glioma cell lines and their clones.
The modulation of HLA-DR and HLA-A, -B, and -C by human recombinant immune interferon (IFN-gamma) was studied on 10 malignant glioma cell lines established in our laboratory, on 8 clones or subclones derived from these lines, and on a fetal astrocyte cell line. Comparative studies were performed with recombinant leukocyte interferon (IFN-alpha). The results not only confirmed the selective activity of IFN-gamma on the modulation of HLA-DR expression, as opposed to that of IFN-alpha, but also demonstrated a marked heterogeneity in the response of glioma cell lines and their clones to the two types of IFN tested. For example, all 3 clones of an inducible cell line could be modulated to express HLA-DR, whereas only 2 of 5 clones derived from a noninducible line were modulated. This heterogeneity did not seem to be due to the absence of the receptor for IFN-gamma on the surface of these cells, since almost all of the cell lines or clones tested (17 of 19) responded to IFN-gamma by the induction or enhancement of the expression for either HLA-DR or HLA-A, -B, and -C (or both). The heterogeneity of induction was also demonstrated between clones derived from a glioma line that did not express HLA-DR after IFN-gamma treatment. The production of HLA-DR by one of the clones was abundant enough to be confirmed by immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis.


A seven-year follow-up of intelligence test scores of foster grandparents.
After 7 years, a group of originally nonemployed poverty-level older people (over 60) who had been employed as foster grandparents were retested with the WAIS. Four WAIS subtests - Vocabulary Similarities, Digit Span, and Block Design - were employed. Of the original group of 39, complete data were available for 28; 18 of these were still working on the project, and the other 10 had dropped out. Dropouts as a group tested lower originally and also showed more deterioration in functional health ratings over time. For the total group of 32 foster grandparents, three subtest scores showed stability over the 7 years. Only Digit Span showed a statistically significant drop. Neither age nor the initial level of health or WAIS scores was related to test-score changes over time.


Interactions of phospholipase D and cytochrome P450 protein stability.
Previous studies have suggested a relationship between cytochrome P450 (P450) 3A (CYP3A) conformation and the phospholipid composition of the associated membrane. In this study, we utilized a novel microsomal incubation system that mimics many of the characteristics of CYP3A degradation pathway that have been observed in vivo and in cultured cells to study the effects of phospholipid composition on protein stability. We found that addition of phosphatidylcholine-specific phospholipase D (PLD) stabilized CYP3A in this system, but that phosphatidylinositol-specific phospholipase C (PLC) was without effect. Addition of phosphatidic acid also stabilized CYP3A protein in the microsomes. The use of 1,10-phenanthroline (phenanthroline), an inhibitor of PLD activity, decreased CYP3A stability in incubated microsomes. Similarly, 6-h treatment of primary cultures of rat hepatocytes with phenanthroline resulted in nearly complete loss of CYP3A protein. Treatment of rats with nicardipine or dimethylsulfoxide (DMSO), which have been shown to affect CYP3A stability, altered the phospholipid composition of hepatic microsomes. It did not appear, though, that the changes in phospholipid composition that resulted from these in vivo treatments accounted for the change in CYP3A stability observed in hepatic microsomes from these animals.


Expression of the Recombinant Human Interleukin-11 in Pichia pastoris.
Full length cDNA of human IL-11 was synthesized by DNA synthesizer. An expression plasmid, pGENYk, containing the recombinant DNA fragment, was linearized and transformed into Pichia pastoris. This recombinant gene was highly expressed in this yeast, and the expression product was purified by a three-step chromatography method. Analysis of the purified recombination protein with SDS-PAGE, Western blot and biological activities showed that the activity of the protein was the same as the Neumega expressed in E.coli.


In/ex copula ejaculatory activities of aqueous and methanolic extracts of Aframomum melegueta (Zingiberaceae) in sexually experienced male rat.
This study was undertaken to evaluate the effects of Aframomum melegueta on male rat ejaculation using in/ex copula techniques. For the in copula experiment, rats were orally treated with aqueous or methanolic extract (20 and 100 mg/kg) of A. melegueta for 14 days. Each rat was mated with a primed receptive female on days 0, 7 and 14 of treatment, and the ejaculatory latency and post-ejaculatory interval were measured. In the ex copula experiment, the electromyography of the bulbospongiosus muscles and intraseminal pressure were recorded in spinal rats after mechanical (urethral and penile) and pharmacological stimulations (intravenous injection of dopamine (5 mg/kg) and, aqueous or methanolic extract of A. melegueta, 2.5; 5; 10 and 20 mg/kg). Furthermore, the effect of dopamine on fictive ejaculation was monitored in rats orally pre-treated with A. melegueta extracts (20 and 100 mg/kg) for 7 or 14 days. Treatment with the aqueous or methanolic extract of A. melegueta significantly decreased the ejaculatory latency (p < .05) and post-ejaculatory interval (p < .01) after 14 days. In spinal rats, mechanical or pharmacological stimulations triggered fictive ejaculation. In animals orally pre-treated with A. melegueta extracts, the pro-ejaculatory effect of dopamine was more expressed. Present findings show that A. melegueta possesses pro-ejaculatory effects.


Cell culture process metabolomics together with multivariate data analysis tools opens new routes for bioprocess development and glycosylation prediction.
Multivariate latent variable methods have become a popular and versatile toolset to analyze bioprocess data in industry and academia. This work spans such applications from the evaluation of the role of the standard process variables and metabolites to the metabolomics level, that is, to the extensive number metabolic compounds detectable in the extracellular and intracellular domains. Given the substantial effort currently required for the measurement of the latter groups, a tailored methodology is presented that is capable of providing valuable process insights as well as predicting the glycosylation profile based on only four experiments measured over 12 cell culture days. An important result of the work is the possibility to accurately predict many of the glycan variables based on the information of three experiments. An additional finding is that such predictive models can be generated from the more accessible process and extracellular information only, that is, without including the more experimentally cumbersome intracellular data. With regards to the incorporation of omics data in the standard process analytics framework in the future, this works provides a comprehensive data analysis pathway which can efficiently support numerous bioprocessing tasks.


UBE2L3 promotes squamous cell carcinoma progression in the oral cavity and hypopharynx via activating the NF-κB signaling by increasing IκBα degradation.
Oral squamous cell carcinoma (OSCC) and hypopharyngeal squamous cell carcinoma (HSCC) are representative of head and neck squamous cell carcinoma (HNSCC) and the molecular pathogenesis has not been completely clarified. Ubiquitin-conjugating enzyme E2 L3 (UBE2L3) is the key member of the E2 family that encodes 153 amino acid residues. Previous studies demonstrate that UBE2L3 is aberrantly overexpressed in various types of human cancers, suggesting that UBE2L3 may function as an oncogene. However, its functional role and the potential mechanisms in the OSCC and HSCC remain unclear. In the present study, we found that UBE2L3 was significantly upregulated in clinical HNSCC samples and HNSCC cell lines, and patients with lower UBE2L3 expression have a higher survival rate. Two HNSCC cell lines FaDu (HSCC cells) and CAL-27 (OSCC cells) with moderate expression of UBE2L3 were selected for in vitro experiments. We proved that UBE2L3 overexpression was positively associated with cellular malignant phenotypes in vitro, including proliferation, invasion, migration, and tumor growth in vivo. Conversely, UBE2L3 suppression diametrically yielded opposing results. Our further study demonstrated that overexpression of UBE2L3 significantly activated the nuclear factor kappa B (NF-κB) signaling pathway through promoting NF-κB p65 nuclear translocation and the ubiquitination and degradation of IκBα protein. Additionally, UBE2L3 was proved to be targeted and negatively regulated by miR-378a-5p, and UBE2L3 overexpression reversed the effects of miR-378a-5p upregulation. Collectively, the present study indicates that UBE2L3 may promote OSCC and HSCC progression via activating the NF-κB signaling by increasing IκBα degradation, indicating that UBE2L3 may be a potential therapeutic target for the treatment of HNSCC.


Geometry unites synchrony, chimeras, and waves in nonlinear oscillator networks.
One of the simplest mathematical models in the study of nonlinear systems is the Kuramoto model, which describes synchronization in systems from swarms of insects to superconductors. We have recently found a connection between the original, real-valued nonlinear Kuramoto model and a corresponding complex-valued system that permits describing the system in terms of a linear operator and iterative update rule. We now use this description to investigate three major synchronization phenomena in Kuramoto networks (phase synchronization, chimera states, and traveling waves), not only in terms of steady state solutions but also in terms of transient dynamics and individual simulations. These results provide new mathematical insight into how sophisticated behaviors arise from connection patterns in nonlinear networked systems.


Analysis of Evaporation of Droplet Pairs by a Quasi-Steady-State Diffusion Model Coupled with the Evaporative Cooling Effect.
Multidroplet evaporation is a common phase-change phenomenon not only in nature but also in many industrial applications, including inkjet printing and spray cooling. The evaporation behavior of these droplets is strongly affected by the distance between neighboring droplets, and in particular, evaporation suppression occurs as the distance decreases. However, further quantitative information, such as the temperature and local evaporation flux, is limited because the analytical models of multidroplet evaporation only treat vapor diffusion, and the effect of the latent heat transfer through the liquid-vapor phase change is ignored. Here, we perform a numerical analysis of evaporating droplet pairs that linked vapor diffusion from the droplet surface and evaporative cooling. Heat transfer through the liquid and gas phases is also considered because the saturation pressure depends on the temperature. The results show an increase in the vapor concentration in the region between the two droplets. Consequently, the local evaporation flux in the proximate region significantly decreases with decreasing separation distance. This means that the latent heat transfer through the phase change is diminished, and an asymmetrical temperature distribution occurs in the liquid and gas phases. These numerical results provide quantitative information about the temperature and local evaporation flux of evaporating droplet pairs, and they will guide further investigation of multiple droplet evaporation.


Potential thresholds for genotoxic effects by micronucleus scoring.
The concept of thresholds in genotoxicity has been open for debate in the last decades. The micronucleus (MN) test contributed to a large extent in understanding the dose-response relationship for aneugens and clastogens. The threshold concept for aneuploidy is well accepted by the scientific community based on the data and for mechanistic reasons. The concept of threshold for clastogens is still challenging. Acceptance is based on a case-by-case basis together with thorough mechanistic understanding of the different steps from the mutagen-target interactions to MN formation for this class of genotoxicants. This review summarises the significant achievements in the assessment of threshold for genotoxins using the MN test and concludes with an overview of knowledge gaps and recommendations.


Tumor microenvironment dual-responsive core-shell nanoparticles with hyaluronic acid-shield for efficient co-delivery of doxorubicin and plasmid DNA.
As the tumor microenvironment (TME) develops, it is critical to take the alterations of pH value, reduction and various enzymes of the TME into consideration when constructing the desirable co-delivery systems. Herein, TME pH and enzyme dual-responsive core-shell nanoparticles were prepared for the efficient co-delivery of chemotherapy drug and plasmid DNA (pDNA). A novel pH-responsive, positively charged drug loading material, doxorubicin (DOX)-4-hydrazinobenzoic acid (HBA)-polyethyleneimine (PEI) conjugate (DOX-HBA-PEI, DHP), was synthesized to fabricate positively charged polyion complex inner core DHP/DNA nanoparticles (DDN). Hyaluronic acid (HA) was an enzyme-responsive shell which could protect the core and enhance the co-delivery efficiency through CD44-mediated endocytosis. The HA-shielded pH and enzyme dual-responsive nanoparticles (HDDN) were spherical with narrow distribution. The particle size of HDDN was 148.3±3.88 nm and the zeta potential was changed to negative (-18.1±2.03 mV), which led to decreased cytotoxicity. The cumulative release of DOX from DHP at pH 5.0 (66.4%) was higher than that at pH 7.4 (30.1%), which indicated the pH sensitivity of DHP. The transfection efficiency of HDDN in 10% serum was equal to that in the absence of serum, while the transfection of DDN was significantly decreased in the presence of 10% serum. Furthermore, cellular uptake studies and co-localization assay showed that HDDN were internalized effectively through CD44-mediated endocytosis in the tumor cells. The efficient co-delivery of DOX and pEGFP was confirmed by fluorescent image taken by laser confocal microscope. It can be concluded that TME dual-responsive HA-shielded core-shell nanoparticles could be considered as a promising platform for the co-delivery of chemotherapy drug and pDNA.


High-dose clonidine in a case of restless legs syndrome.
To describe a patient with idiopathic restless legs syndrome (RLS). A 37-year-old man developed severe symptoms of RLS. Treatment using combinations of levodopa, opioids, benzodiazepines, and baclofen provided only partial benefit or resulted in intolerable adverse effects. Higher dosages of clonidine than previously reported in the literature (0.9 mg/d in divided doses) were needed to completely relieve his RLS symptoms. The only prominent adverse effect was dry mouth. The RLS symptoms returned after subsequent reductions in the dosage. After the dosage of clonidine was again increased, complete relief of the symptoms was achieved again. After several months, clonidine was tapered to zero and the patient entered a period of spontaneous remission. When his symptoms returned four months after clonidine had been discontinued, clonidine therapy was restarted. Clonidine alleviated RLS symptoms in 30 of 41 patients reported in the literature, indicating that the adrenergic nervous system may play a role in RLS. High-dose clonidine appears to be useful in treating RLS when other therapies fail. However, well-controlled, polysomnographic studies are needed.


[Nucleic acid components in carbohydrate-rich food].
The content of nucleic acid components in numerous foods, especially carbohydrate-rich ones, has been investigated. The data obtained for bases (purines and pyrimidines) were calculated as nucleic-acid equivalents (RNA or DNA); the IMP content was calculated from the measured content of hypoxanthine. Not only did cultivated plants such as cereals and pulses show a high RNA-equivalent content but also vegetables such as spinach, leek, broccoli, Chinese cabbage and cauliflower. We found the same results in mushrooms including oyster, flat, button (whitecaps) and cep mushrooms. In many vegetarian instant meals, the addition of autolysed or hydrolysed yeast caused a large increase in the purine content. Most natural foods which contain resting cell tissue, such as grains of seed, have only high-molecular-mass nucleic acid components with different concentrations; however, growing cell tissue (e.g. soya-bean sprouts) show, as well as the nucleic acids, some lower-molecular-mass compounds.


Immunocytochemical localization of kallikrein in the rat exocrine pancreas.
The subcellular localization of kallikrein was studied in the rat pancreas using the immunocytochemical protein A-gold technique. Kallikrein was found at the level of the rough endoplasmic reticulum (RER), Golgi cisternae, condensing vacuoles, and zymogen granules of the pancreatic acinar cells as well as in the acinar lumen. The effect of various tissue processings on the immunocytochemical labeling of kallikrein was evaluated using pancreatic tissue fixed in glutaraldehyde and embedded in Epon, Lowicryl K4M, or glycol methacrylate (GMA). Compared to the results obtained with Epon, Lowicryl allowed improved resolution and specificity in the immunocytochemical labeling, while GMA retained greater amounts of kallikrein antigenicity leading to a higher intensity in the labeling; since it also gave a good ultrastructural preservation, GMA appeared to be the superior embedding medium for the localization of kallikrein. The quantitative evaluation of the labeling obtained under the three embedding conditions showed the presence of an increasing concentration gradient along the RER-Golgi-granule secretory pathway, suggesting that, like other pancreatic exocrine enzymes, kallikrein is synthesized in the RER, processed through the Golgi apparatus, and packed in the zymogen granules before being released into the acinar lumen.


The morphology of angle dysgenesis assessed by ultrasound biomicroscopy and its relationship with glaucoma severity and mutant genes in Axenfeld-Rieger syndrome.
Axenfeld-Rieger syndrome (ARS), a developmental disorder, involves anterior segment abnormalities and can lead to glaucoma. However, limited research has addressed the ultrasound biomicroscopy (UBM) characteristics of ARS. This study aimed to assess the anterior chamber angle features using UBM in ARS and determine their correlation with glaucoma severity and mutant genes. UBM examination was conducted for 42 patients diagnosed with ARS and glaucoma. The morphology of the anterior chamber angle was classified into 6 types (type A, pure high iris insertion; type B, posterior embryotoxon; type C, iris process; type D, trabecular-iris synechia; type E, peripheral iridocorneal adhesion; type F, goniodysgenesis). Candidate genes were sequenced with next-generation sequencing. Correlations of clinical characteristics with angle dysgenesis types and mutant genes were analyzed. Among the 42 patients recruited, 6 eyes were excluded for poor quality UBM images or lack of glaucoma development. The remaining 78 eyes were categorized into 6 groups according to their dominant type of anterior chamber angle (>2 quadrants). There were statistically significant differences in onset age of glaucoma (P<0.001), untreated intraocular pressure (IOP) (P=0.016), vertical cup to disc ratio (P=0.001), and age at surgery (P<0.001) among the groups. Eyes in the type C and D groups developed glaucoma and underwent surgery at an earlier age, while eyes in the type B, E, and F groups developed glaucoma at a relatively later age. Eyes in type A group developed glaucoma and underwent surgery at the latest age, and had the lowest untreated IOP compared to the other groups. Patients with FOXC1 defects were more likely to have angle type B, type C, and type D (accounting for 93.8% of the total), whereas patients with PITX2 defects were more likely to have angle type A, type E, and type F (accounting for 92.1% of the total). UBM is powerful for evaluating the anterior segment abnormalities in ARS. Combined with genetic testing results, the morphological classification helps to assess the severity of glaucoma.


Assigning cases to groups using taxometric results: an empirical comparison of classification techniques.
Determining whether individuals belong to different latent classes (taxa) or vary along one or more latent factors (dimensions) has implications for assessment. For example, no instrument can simultaneously maximize the efficiency of categorical and continuous measurement. Methods such as taxometric analysis can test the relative fit of taxonic and dimensional models, but it is not clear how best to assign individuals to groups using taxometric results. The present study compares the performance of two classification techniques-Bayes' theorem and a base-rate technique--across a wide range of data conditions. The base-rate technique achieves greater classification accuracy and a more even balance between sensitivity and specificity. In addition, the base-rate classification technique is easier to implement than Bayes' theorem and is more versatile in that it can be used when the context of assessment requires that cases be classified despite the absence of latent classes.


Beyond medical ethics: new directions for philosophy and medicine.
A unique relationship exists between physicians and philosophers -- one that expands on the constructive potential of the liaison between physicians and, for example, theologians, on the one hand, or, social workers on the other. This liaison should focus in the scientific aspects of medicine, not just the ethical aspects. Philosophers can provide physicians with a perspective on both the philosophy and the history of medicine through the ages -- a sense of how medicine has adapted to the social, cultural, and ethical needs of each period. This perspective, while emphasizing medicine as science, should not be limited to matters of methodology, or to criteria for distinguishing science from other intellectual pursuits, but should be concerned also with the history, sociology, and politics of science. Both physicians and philosophers stand to gain from a strengthening of their active liaison now as never before; but most of all, the public will be the beneficiary.


MICA and NLRP3 gene polymorphisms interact synergistically affecting the risk of ankylosing spondylitis.
Ankylosing spondylitis (AS) is an autoinflammatory disease that affects the sacroiliac joints, causing stiffness and pain in the back. MICA is a ligand of the NKG2D receptor, and an increase in its expression affects the immune response in various diseases. NLRP3 is a multiprotein complex that promotes the release of IL-1β, but its role in AS has been minimally explored. The objective of this study was to analyze the association and interaction of polymorphic variants of the MICA and NLRP3 genes in patients with AS. In this case-control study, patients with AS were included and compared with healthy controls of Mexican origin. The polymorphisms rs4349859 and rs116488202 of MICA and rs3806268 and rs10754558 of NLRP3 were genotyped using TaqMan probes. Associations were determined using logistic regression models, while interactions were analyzed by the multifactorial dimensionality reduction (MDR) method. A P value < 0.05 was considered statistically significant. The minor allele of rs4349859 (A) and rs116488202 (T) of MICA polymorphisms showed risk associations with AS (OR = 9.22, 95% CI = 4.26-20.0, P < 0.001; OR = 9.36, 95% CI = 4.17-21.0, P < 0.001), while the minor allele of the rs3806268 (A) polymorphism of NLRP3 was associated with protection (OR = 0.55, 95% CI = 0.33-0.91, P = 0.019). MDR analysis revealed synergistic interactions between the MICA and NLRP3 polymorphisms (P = 0.012). In addition, high- and low-risk genotypes were identified among these variants. The study findings suggest that the MICA rs4349859 A allele and rs116488202 T allele are associated with AS risk. An interaction between MICA and NLRP3 was observed which could increase the genetic risk in AS.


Analogy, explanation, and proof.
People are habitual explanation generators. At its most mundane, our propensity to explain allows us to infer that we should not drink milk that smells sour; at the other extreme, it allows us to establish facts (e.g., theorems in mathematical logic) whose truth was not even known prior to the existence of the explanation (proof). What do the cognitive operations underlying the inference that the milk is sour have in common with the proof that, say, the square root of two is irrational? Our ability to generate explanations bears striking similarities to our ability to make analogies. Both reflect a capacity to generate inferences and generalizations that go beyond the featural similarities between a novel problem and familiar problems in terms of which the novel problem may be understood. However, a notable difference between analogy-making and explanation-generation is that the former is a process in which a single source situation is used to reason about a single target, whereas the latter often requires the reasoner to integrate multiple sources of knowledge. This seemingly small difference poses a challenge to the task of marshaling our understanding of analogical reasoning to understanding explanation. We describe a model of explanation, derived from a model of analogy, adapted to permit systematic violations of this one-to-one mapping constraint. Simulation results demonstrate that the resulting model can generate explanations for novel explananda and that, like the explanations generated by human reasoners, these explanations vary in their coherence.


Sequence-specific m6A demethylation in RNA by FTO fused to RCas9.
N6-methyladenosine (m6A) is the most common internal modification in eukaryotic mRNA and associated with numerous cellular processes in health and disease. Up- and down-regulation of its "writer" or "eraser" proteins alter the global m6A level; however, modifying distinct m6A sites has remained elusive. We genetically fused the dioxygenase FTO responsible for m6A demethylation to RCas9 as an RNA-targeting module. The resulting RCas9-FTO retained demethylation activity and bound to RNA in a sequence-specific manner depending on the sgRNA and PAMmer. Using SCARLET analysis, we quantified the m6A level at a specific site and analyzed the effect of the PAM-to-m6A distance on activity. Sequence-specific demethylation by RCas9-FTO was tested on different RNA combinations and showed up to 15-fold sequence preference for target RNA compared to off-target RNA. Taken together, RCas9-FTO represents a new tool for sequence-specific demethylation of m6A in RNA that can be readily adapted to any given RNA sequence and opens the door to studying the function of distinct m6A sites.


Dexfenfluramine and feeding reward.
This review describes background experiments and new findings showing that dexfenfluramine inhibits self-stimulation of a lateral hypothalamic (LH) feeding-reward system. Earlier work suggested that self-stimulation excites a pathway to the ventral tegmental area (VTA), where the mesolimbic dopamine system is involved in self-administration of food and drugs. LH stimulation also excites taste neurons in the nucleus tractus solitarius (NTS). This helps explain why stimulation can induce feeding responses and also reward self-stimulation responses. Stimulation-induced feeding and self-stimulation are modulated by physiological signals that control an animal's appetite and body weight. An animal will self-stimulate at a slower rate after it has just eaten, or if it is overweight, or if it is given an anorectic dose of insulin. At the same time, responses to turn off automatic stimulation tend to increase. Paradoxically, racemic fenfluramine decreased both self-stimulation and stimulation-escape, which suggested overall lethargy, but new results show this can be avoided by using just the d isomer. Dexfenfluramine inhibited LH self-stimulation but not stimulation-escape. It also released serotonin in the LH, as shown by microdialysis. These results suggest that dexfenfluramine can release serotonin that has as one of its effects the inhibition of circuitry for feeding-reward.


[Immobilized lipase-catalyzed synthesis of biodiesel from crude cottonseed oil].
We investigated the transesterification of crude cottonseed oil with methyl acetate to biodiesel, by using Lipozyme TL IM and Novozym 435 as catalysts. Results showed that the biodiesel yield significantly increased with the addition of methanol into the reaction system, and the highest biodiesel yield of 91.83% was achieved with the optimum conditions as follows: n-hexane as solvent, molar ratio of methyl acetate to oil 9:1, 3% methanol based on the oil mass to inhibit the creation of acetic acid, 10% Lipozyme TL IM and 5% Novozym 435 as catalyst based on the oil mass, reaction temperature 55 degrees C and reaction time 8 h. Additionally, we explored the kinetics of lipase-catalyzed crude cottonseed oil to biodiesel, and proposed a kinetic model.


Duodenal gangliocytic paraganglioma with lymph node metastases: A case report and comparative review of 31 cases.
Gangliocytic paraganglioma (GP) is a rare tumor of uncertain origin most often located in the second portion of the duodenum. It is composed of three cellular components: Epithelioid endocrine cells, spindle-like/sustentacular cells, and ganglion-like cells. While this tumor most often behaves in a benign manner, cases with metastasis are reported. We describe the case of a 62-year-old male with a periampullary GP with metastases to two regional lymph nodes who was successfully treated with pancreaticoduodenectomy. Using PubMed, EMBASE, EBSCOhost MEDLINE and CINAHL, and Google Scholar, we searched the literature for cases of GP with regional lymph node metastasis and evaluated the varying presentations, diagnostic workup, and disease management of identified cases. Thirty-one cases of GP with metastasis were compiled (30 with at least lymph node metastases and one with only distant metastasis to bone), with age at diagnosis ranging from 16 to 74 years. Ratio of males to females was 19:12. The most common presenting symptoms were abdominal pain (55%) and gastrointestinal bleeding or sequelae (42%). Twenty-five patients underwent pancreaticoduodenectomy. Five patients were treated with local resection alone. One patient died secondary to metastatic disease, and one died secondary to perioperative decompensation. The remainder did well, with no evidence of disease at follow-up from the most recent procedure (except two in which residual disease was deliberately left behind). Of the 26 cases with sufficient histological description, 16 described a primary tumor that infiltrated deep to the submucosa, and 3 described lymphovascular invasion. Of the specific immunohistochemistry staining patterns studied, synaptophysin (SYN) stained all epithelioid endocrine cells (18/18). Neuron specific enolase (NSE) and SYN stained most ganglion-like cells (7/8 and 13/18 respectively), and S-100 stained all spindle-like/sustentacular cells (21/21). Our literature review of published cases of GP with lymph node metastasis underscores the excellent prognosis of GP regardless of specific treatment modality. We question the necessity of aggressive surgical intervention in select patients, and argue that local resection of the mass and metastasis may be adequate. We also emphasize the importance of pre-surgical assessment with imaging studies, as well as post-surgical follow-up surveillance for disease recurrence.


HPV related diseases in males: a heavy vaccine-preventable burden.
Human Papillomavirus (HPV) has a significant impact in male's health, as cause of clinical manifestations ranging from genital warts to several cancers of the anogenital and aero-digestive tract. HPV types which most frequently affect men are 6, 11, 16 and 18, included in the HPV quadrivalent vaccine, recently approved for use in males by Food and Drug Administration (FDA) and European Medicines Agency (EMA). Although several data about the safety and efficacy of quadrivalent vaccine are available, the implementation of proper immunization plans dedicate to male's population cannot ignore the knowledge of the characteristics of the disease in men, which in some aspects should be clarify, in particular clearance of type-specific HPV infections and transmission dynamics. Purpose of this review is to summarise the main information about the burden and the natural history of the HPV related disease in males.


Occupational therapist-led mindfulness-based stress reduction for older adults living with subjective cognitive decline or mild cognitive impairment in primary care: a feasibility randomised control trial protocol.
Community-dwelling older adults living with subjective cognitive decline or mild cognitive impairment may experience decreased efficiency in their overall functional performance. This decreased cognitive efficiency may result in anxiety, low mood, perceived stress and decreased emotional well-being and quality-of-life. These psychological symptoms may further exacerbate cognitive decline.Exploring non-pharmacological interventions such as mindfulness within primary care is vital in enabling individuals to develop strategies to manage cognitive impairment or psychological symptoms. Mindfulness-based stress reduction (MBSR) is an 8-week programme that is beneficial in alleviating psychological symptoms; however, its impact on perceived satisfaction on overall functional performance with this population has not been evaluated. The primary objective of this study is to explore the feasibility of conducting a randomised controlled trial of an occupational therapist-led MBSR programme within primary care. Convergent mixed-methods, randomised control feasibility trial with 40 participants from an interprofessional primary care team in Toronto, Ontario. Participants are randomised into the 8-week MBSR group or wait-list control will be compared at baseline, postintervention and 4weeks follow-up. The primary aim is to determine the feasibility of the intervention with this population and setting. The secondary aim is to examine perceived satisfaction with functional performance as measured by the Canadian Occupational Performance Measure. Secondary clinical outcomes include psychological symptoms. Investigators will analyse the quantitative and qualitative data strands separately. Descriptive statistics, focus group and interviews will then be merged and further analysed to best understand the feasibility and preliminary clinical outcomes from the study. The study is approved by Women's College Hospital (2017-0056-E), and Queen's University, Kingston, Ontario (6026418). The study will follow Standard Protocol Items: Recommendations for Interventional Trials. The results will be published in peer-reviewed academic journals and disseminated to patient organisations and media.Trial registration numberNCT03867474; Pre-results.


Microbial contribution to spoilage of African breadfruit (Artocarpus communis, Forst) during storage.
The contributions of microorganisms in the deterioration of African breadfruit during storage were investigated in this study. Matured fruits of the seedless variety of the African breadfruit (Artocarpus communis, Forst) were stored under different temperature conditions and morphological changes observed at 24-h intervals for 120 h. Spoilage of breadfruit was observed after 72 h with microbial growth. Although all the fruits in the different media deteriorated by the 72nd hour (this was revealed in morphology and confirmed by the proximate analysis which showed an increase in %crude protein in all the stored fruits), microbial growth was observed only in those fruits stored at room temperature and in water, and there was no significant microbial growth in fruits stored in refrigerator, freezer, and vinegar. A higher rate of deterioration (i.e., higher %crude protein) was observed in morphology of fruits which had microbial growth during storage (i.e., those stored in the room, under water, and refrigerator) than in those stored fruits with no significant microbial growth. The difference between the %crude protein in fruits where there is microbial growth and that of the fruits where there is no microbial growth (i.e., freezer and vinegar) proved to be significant (P ≤ 0.05). The study thus reveals that microorganisms play a substantial role in the spoilage of African breadfruit. A strain of the Aspergillus sp., two strains of the Penicillium sp., and a strain of the Molinia sp. were isolated as fungal spoilage organisms. Bacillus sp. and Pseudomonas sp. strains were isolated as bacteria spoilage organisms.


Microfiber-based, highly nonlinear graphene saturable absorber for formation of versatile structural soliton molecules in a fiber laser.
We reported on the generation of versatile soliton molecules in a fiber laser mode-locked by a microfiber-based graphene saturable absorber (GSA). By virtue of the highly nonlinear effect of the microfiber-based GSA, the soliton molecules could be easily observed. In addition to regular soliton molecules, it is found that the "soliton atoms" in molecules could exhibit different characteristics and show ultra-narrow pulse separations, which was termed as 'structural soliton molecule'. The pulse profiles of 'structural soliton molecules' were further reconstructed theoretically. The obtained results would give further insight towards understanding the dynamics of soliton molecules in fiber lasers.


Radiation, inflammation, and immune responses in cancer.
Chronic inflammation has emerged as one of the hallmarks of cancer. Inflammation also plays a pivotal role in modulating radiation responsiveness of tumors. As discussed in this review, ionizing radiation (IR) leads to activation of several transcription factors modulating the expression of numerous mediators in tumor cells and cells of the microenvironment promoting cancer development. Novel therapeutic approaches thus aim to interfere with the activity or expression of these factors, either in single-agent or combinatorial treatment or as supplements of the existing therapeutic concepts. Among them, NF-κB, STAT-3, and HIF-1 play a crucial role in radiation-induced inflammatory responses embedded in a complex inflammatory network. A great variety of classical or novel drugs including nutraceuticals such as plant phytochemicals have the capacity to interfere with the inflammatory network in cancer and are considered as putative radiosensitizers. Thus, targeting the inflammatory signaling pathways induced by IR offers the opportunity to improve the clinical outcome of radiation therapy by enhancing radiosensitivity and decreasing putative metabolic effects. Since inflammation and sex steroids also impact tumorigenesis, a therapeutic approach targeting glucocorticoid receptors and radiation-induced production of tumorigenic factors might be effective in sensitizing certain tumors to IR.


Comparison of fractional microneedling radiofrequency and bipolar radiofrequency on acne and acne scar and investigation of mechanism: comparative randomized controlled clinical trial.
Fractional microneedling radiofrequency (FMR) is one of the promising methods in acne treatment. Moreover, bipolar radiofrequency (BR) generates heat thereby which induces neocollagenosis. FMR may have the potential to be a safe and effective treatment for the patients both with acne and acne scar. This study was performed to compare the efficacy and safety of FMR and BR in acne and acne scar treatment. Furthermore, mechanism of the FMR treatment was investigated through skin tissues obtained from subjects. Twenty subjects with mild-to-moderate acne and acne scars were treated in a split-face manner with FMR and BR. Two sessions of treatment was done 4 weeks apart in a total 12-week prospective single-blind, randomized clinical trial. Clinical assessment and sebum measurement were carried out for the evaluation of efficacy and safety. Skin tissues were acquired for investigation of molecular changes. FMR was more effective for acne scar especially in icepick and boxcar scar compared to BR. Both inflammatory and non-inflammatory acne lesions decreased by 80 and 65 % in the FMR-treated side at the final visit of 12 weeks, respectively. FMR treatment resulted in significant reduction of sebum excretion. Both treatments showed no severe adverse effects other than erythema. The FMR showed superior efficacy in acne and acne scar compared with BR. Increased expression of TGFβ and collagen I and decreased expression of NF-κB, IL-8 are suggested to involve in the improvement of acne scar and acne lesion by FMR.


The Effect of Carbohydrate Restriction on Lipids, Lipoproteins, and Nuclear Magnetic Resonance-Based Metabolites: CALIBER, a Randomised Parallel Trial.
Low-carbohydrate high-fat (LCHF) diets can be just as effective as high-carbohydrate, lower-fat (HCLF) diets for improving cardiovascular disease risk markers. Few studies have compared the effects of the UK HCLF dietary guidelines with an LCHF diet on lipids and lipoprotein metabolism using high-throughput NMR spectroscopy. This study aimed to explore the effect of an ad libitum 8-week LCHF diet compared to an HCLF diet on lipids and lipoprotein metabolism and CVD risk factors. For 8 weeks, n = 16 adults were randomly assigned to follow either an LCHF (n = 8, <50 g CHO p/day) or an HCLF diet (n = 8). Fasted blood samples at weeks 0, 4, and 8 were collected and analysed for lipids, lipoprotein subclasses, and energy-related metabolism markers via NMR spectroscopy. The LCHF diet increased (p < 0.05) very small VLDL, IDL, and large HDL cholesterol levels, whereas the HCLF diet increased (p < 0.05) IDL and large LDL cholesterol levels. Following the LCHF diet alone, triglycerides in VLDL and HDL lipoproteins significantly (p < 0.05) decreased, and HDL phospholipids significantly (p < 0.05) increased. Furthermore, the LCHF diet significantly (p < 0.05) increased the large and small HDL particle concentrations compared to the HCLF diet. In conclusion, the LCHF diet may reduce CVD risk factors by reducing triglyceride-rich lipoproteins and improving HDL functionality.


Diffuse histiocytic lymphoma: the 20-year experience of an Australian teaching hospital.
There is a paucity of information regarding the natural history and treatment outcome of diffuse histiocytic lymphoma (DHL) in Australia. Case records from 80 patients treated for DHL at the Royal Adelaide Hospital between 1965 and 1985 were reviewed to determine treatment outcome and prognostic information. Pathological review of biopsy specimens confirmed the correct diagnosis in 78 patients. The Ann Arbor staging criteria were unsatisfactory for prognostic purposes. We identified three prognostic groups: Localised disease (82% five-year survival), Advanced disease marrow negative (36% five-year survival), and Advanced disease marrow positive (11% five-year survival). An elevated plasma lactate dehydrogenase (LDH) and calcium (Ca++) predicted a poorer outcome; no patient with a LDH greater than 500 IU achieved longterm survival (p less than 0.001). Survival was identical for patients reclassified histologically as intermediate grade or high grade (Working Formulation). Localised disease was associated with a good prognosis (82% five-year survival) regardless of treatment modality. The outcome of patients with advanced disease has markedly improved over the last two decades, particularly with the introduction of combination chemotherapy containing doxorubicin in 1974 (p less than 0.005). Using these regimens, complete remission was achieved in 65% of patients, with a 39% five-year survival.


Liver X Receptors Protect Dorsal Root Ganglia from Obesity-Induced Endoplasmic Reticulum Stress and Mechanical Allodynia.
Obesity is associated with many complications, including type 2 diabetes and painful neuropathy. There is no cure or prevention for obesity-induced pain, and the neurobiology underlying the onset of the disease is still obscure. In this study, we observe that western diet (WD)-fed mice developed early allodynia with an increase of ER stress markers in the sensory neurons of the dorsal root ganglia (DRG). Using cell-specific approaches, we demonstrate that neuronal liver X receptor (LXR) activation delays ER stress and allodynia in WD-fed mice. Our findings suggest that lipid-binding nuclear receptors expressed in the sensory neurons of the DRG play a role in the onset of obesity-induced hypersensitivity. The LXR and lipid-sensor pathways represent a research avenue to identify targets to prevent debilitating complications affecting the peripheral nerve system in obesity.


Exosomal long non-coding RNAs as biomarkers in human diseases.
The intensive study of extracellular vesicles was started about a decade ago revealing alterations of their amount and content to several cellular stimuli, highly depending on the releasing cell type. Exosomes, a type of extracellular vesicles, are released by every cell type and are present in most body fluids, what makes them attractive targets of biomarker research. Several studies have indicated that their content - including proteins and coding, as well as non-coding nucleic acids - could represent the disease state and serves as specific disease biomarkers. Out of these molecules, a special interest was gained by long non-coding RNAs (lncRNAs). Just as exosomes, lncRNAs are specific to their cell of origin and often specific to diseases, also found extracellularly, mainly contained in extracellular vesicles. Thus, recent efforts in biomarker research has turned to circulating exosomal lncRNAs, which might lead to the development of highly specific disease markers. Here we summarize the current knowledge on disease-associated exosomal long non-coding RNAs. The intensive studies in this area have revealed numerous potential targets for biomarkers, and highlighted the potential of their combination with other exosomal markers to represent a highly sensitive and specific diagnostic tool. However, we believe that additional functional data on both exosomes and lncRNAs are necessary for understanding their deregulation in diseases and developing their use as diagnostic approaches.


[Analysis of efficiency of human sleep by Pareto principle].
The results of system assessment efficiency of human night sleep which was registered on a large number of people without health problems, and data on the modeling of sleep structure by Pareto principle were showed. In contrast to the assessment of sleep efficiency, as the ratio of the duration of electrophysiological sleep to the total time of sleep, the introduced method increase adequacy assessment by taking into gender factor in the somnology and personalized medicine.


Resin Nanoceramic CAD/CAM Restoration of the Primary Molar: 3-Year Follow-Up Study.
This case report presents the clinical use of a resin nanoceramic CAD/CAM restoration of a primary second molar without successor in the form of a permanent second premolar tooth in a patient. Three-year follow-up of the case revealed that resin nanoceramic CAD/CAM restoration of the primary molar without successor achieved both aesthetics and function. Despite the high cost of treatment, this type of restoration should be considered if the retained tooth is expected to maintain functionality over the long term.


Peritoneal total protein transport assessed from peritoneal equilibration tests using different dialysate glucose concentrations.
The peritoneal equilibration test (PET) permits assessment of peritoneal protein transport, but this potential marker of outcome in peritoneal dialysis (PD) patients lacks adequate standardization. ♢ To assess various approaches for estimation of peritoneal protein transport in PD patients during 2.27% and 3.86% glucose-based PETs, and to uncover the demographic, clinical, and biochemical correlates of this phenomenon. ♢ We studied 90 PD patients who underwent 2.27% and 3.86% PETs in random order, and we used multivariate analysis to compare assessments of peritoneal protein transport in both tests, searching for correlations between D₂₄₀' - D₀' protein concentration (PETΔPConc), total peritoneal protein excretion (PET-PPE), or total protein clearance (PET-PC) on the one hand (the main study variables), and PET-derived markers of peritoneal function and selected demographic, clinical, and biochemical variables on the other. ♢ The PETΔPConc was higher during the 2.27% PET (mean: 45.2 mg/dL vs 37.0 mg/dL for the 3.86% test; p = 0.003); the PET-PPE and PET-PC were comparable (1121.8 mg vs 1168.9 mg, p = 0.52, and 17.1 mL vs 17.8 mL, p = 0.66, respectively). All three variables sustained a significant, yet moderate correlation (all r² values < 0.30) with the 24-hour PPE rate. Multivariate analysis identified dialysate-to-plasma ratio (D/P₂₄₀') of creatinine, end-to-initial dialysate ratio (D₂₄₀'/D₀') of glucose, current daily peritoneal glucose load, ultrafiltration during PET, systolic blood pressure, and previous cardiovascular events (3.86% test only) as independent predictors of protein transport during PET. ♢ Either PET-PPE or PET-PC seems preferable to PETΔPConc for characterization of peritoneal protein transport. Small-solute transport characteristics, ultrafiltration, and current peritoneal glucose load sustain independent correlations with peritoneal protein transport. The latter variable shows also a moderate association with markers of cardiovascular disease in PD patients.


Relationship Between Subclinical Hypothyroidism in Pregnancy and Hypertensive Disorder of Pregnancy: A Systematic Review and Meta-Analysis.
Studies have shown a high incidence of subclinical hypothyroidism in pregnancy, but the adverse pregnancy outcomes caused by it are not clear. Therefore, we conducted a systematic review and meta-analysis to evaluate the relationship between subclinical hypothyroidism in pregnancy and hypertensive disorders of pregnancy(HDP) to guide clinical practice. We searched the MEDLINE (PubMed), Cochrane Central, EMBASE, Web of Science, and SCOPUS databases and screened all studies evaluating the relationship between subclinical hypothyroidism in pregnancy and hypertensive disorders of pregnancy. Two researchers independently evaluated the quality of all eligible original studies using the Newcastle-Ottawa Scale (NOS). We also performed a meta-analysis using STATA15.1. Sensitivity analyses were also performed by examining the effects of individual studies as well as using different effect models and detecting any publication bias using the harbord test. Twenty-two studies were included in the final meta-analysis. Our results indicated that pregnant women with subclinical hypothyroidism had an increased risk of HDP (OR = 1.54(95% CI: 1.21-1.96) I²=67.1%), compared with euthyroidism. Subclinical hypothyroidism in pregnancy was not associated with hypertensive disorders of pregnancy at TSH diagnostic cut-off of less than 3.0 mIU/L (P = 0.077). Curiously, the risk of HDP increases when the TSH diagnostic cut-off value is higher or lower than 4 mIU/L. Although only 9 studies were above the threshold, the risk of developing HDP was still 1.69 times, which was highest in all subgroup analyses. This is consistent with the newly recommended diagnostic cut-off value of 4 mIU/L for TSH by the ATA. Our results consider that the risk of hypertensive disorder complicating pregnancy is increased regardless of the diagnosis of subclinical hypothyroidism at any stage of pregnancy. Unfortunately, there is insufficient evidence to support that patients can benefit from treatment with levothyroxine. The results of this meta-analysis indicate that subclinical hypothyroidism in pregnancy is associated with an increased risk of developing HDP, and this association exists regardless of the gestational period. However, the available evidence cannot support these patients receiving thyroxine intervention can benefit from it, so routine screening is only recommended for pregnant women with risk factors for hypothyroidism. Further research is needed to validate more scientific and rigorous clinical studies to clarify the relationship between subclinical hypothyroidism and HDP to improve patient prognosis. https://www.crd.york.ac.uk/prospero/, PROSPERO (CRD42021286405).


Safety and Efficacy of Radiofrequency Ablation and Epidural Steroid Injection for Management of Cervicogenic Headaches and Neck Pain: Meta-Analysis and Literature Review.
Dysfunction of the cervical spine and its anatomical features, mostly innervated by the C1, C2, and C3 spinal nerves, can result in a secondary headache known as cervicogenic headache (CHA), mainly characterized by unilateral pain. The usefulness of pharmaceutical medications and physical therapy is currently the subject of scant literature. Interventional pain management techniques can be applied when conservative treatment is unsuccessful. This study looks at radiofrequency ablation (RFA) and epidural steroid injection (ESI) to identify their safety and efficacy in managing patients with cervicogenic headaches and neck pain. Three databases - PubMed, Cochrane CENTRAL Library, and Embase were searched, and 110 studies were identified. Nine screening processes were included for review and meta-analysis. Statistical evaluation was conducted through STATA version 17 (College Station, TX: StataCorp LLC) and effect measures were reported through random effects model risk ratios. The main subject of focus included three following outcomes: incidences of pain relief, degree and duration of pain, and incidences of adverse effects. The findings showed both interventions relieved pain by a factor of >50%, demonstrating a relative effects risk ratio of 1.45 (-0.50, 3.39) for RFA: pain relief, 84.76 (82.82, 86.69) RFA: adverse effects, and 19.46 (18.80, 20.11) ESI: pain relief at 95% confidence interval. The efficacy of RFA and ESI differ. Both interventions are effective in the reduction of cervicogenic headache pain intensity. However, their complication rates and pain duration are considerably different. With ESI, the headaches can still recur weekly, demanding the use of oral analgesics to deal with them. On the other hand, RFA has a low complication rate. Improving guidance from imaging technologies, RFA has the potential to be the most effective interventional treatment.


Furylfuramide-induced hepatic necrosis in mice and its modification by phenobarbital.
Oral administration of furylfuramide (2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide), used as an antimicrobial food preservative until recently, caused centrolobular coagulation necrosis of the liver of the mouse (ddYS, male) in the degree corresponding to the doses. The recovery process after a single oral administration was characteristic: the necrotic cells were laden with calcium and replaced by foreign body granuloma accompanied by multinucleate giant cells. Complete healing ensued in about a month. Phenobarbital pretreatment reduced injurious effect of furylfuramide on the liver with preservation of the centrolobular region. In this case necrosis occurred in the intermediate zone in a ring-like shape. This indicates enhanced detoxication of furylfuramide by microsomal drug metabolizing enzyme(s) of the liver cells induced by phenobarbital.


Outcomes and satisfaction of two optional cadaveric dissection courses: A 3-year prospective study.
Teaching time dedicated to anatomy education has been reduced at many medical schools around the world, including Nova Medical School in Lisbon, Portugal. In order to minimize the effects of this reduction, the authors introduced two optional, semester-long cadaveric dissection courses for the first two years of the medical school curriculum. These courses were named Regional Anatomy I (RAI) and Regional Anatomy II (RAII). In RAI, students focus on dissecting the thorax, abdomen, pelvis, and perineum. In RAII, the focus shifts to the head, neck, back, and upper and lower limbs. This study prospectively analyzes students' academic achievement and perceptions within the context of these two, newly-introduced, cadaveric dissection courses. Students' satisfaction was assessed anonymously through a questionnaire that included items regarding students' perception of the usefulness of the courses for undergraduate teaching, as well as with regards to future professional activity. For each of the three academic years studied, the final score (1 to 20) in General Anatomy (GA), RAI, and RAII was on average 14.26 ± 1.89; 16.94 ± 1.02; 17.49 ± 1.01, respectively. The mean results were lower in GA than RAI or RAII (P < 0.001). Furthermore, students who undertook these courses ranked them highly with regards to consolidating their knowledge of anatomy, preparing for other undergraduate courses, and training for future clinical practice. These survey data, combined with data on participating students' academic achievement, lend strong support to the adoption of similar courses as complementary and compulsory disciplines in a modern medical curriculum. Anat Sci Educ 10: 127-136. © 2016 American Association of Anatomists.


Hip medial rotator action of gluteus medius in Japanese macaque (Macaca fuscata) and implications to adaptive significance for quadrupedal walking in primates.
The gluteus medius (GM) muscle in quadrupedal primates has long been thought to mainly act as a hip extensor. However, previous reports argue that it may be a prime hip medial rotator and functions to rotate the pelvis in the horizontal plane, suggesting the functional differentiation between the GM and other hip extensors as hamstrings. In this study, we aim to quantify the muscle actions of the GM and hamstrings using muscle moment arm lengths and discuss the functional differentiation among hip extensors. Muscle attachment sites of eight specimens of Japanese macaque (Macaca fuscata) were digitized, and musculoskeletal models were constructed. Flexor-extensor, abductor-adductor, and medial-lateral rotator moment arms were calculated as the models were moved following the experimentally acquired kinematic data during walking on a pole substrate. Using electromyography, we also recorded the pattern of muscle activation. The GM showed a larger medial rotator moment arm length than the extensor moment arm length when it was activated, suggesting this muscle acts mainly as a hip medial rotator rather than as a hip extensor. The medial rotator action of the GM in the early support phase may rotate the pelvis in the horizontal plane and function to help contralateral forelimb reaching as a previous study suggested and facilitate contralateral hindlimb swinging to place the foot near the ipsilateral forelimb's hand.


Shape optimization in steady blood flow: a numerical study of non-Newtonian effects.
We investigate the influence of the fluid constitutive model on the outcome of shape optimization tasks, motivated by optimal design problems in biomedical engineering. Our computations are based on the Navier-Stokes equations generalized to non-Newtonian fluid, with the modified Cross model employed to account for the shear-thinning behavior of blood. The generalized Newtonian treatment exhibits striking differences in the velocity field for smaller shear rates. We apply sensitivity-based optimization procedure to a flow through an idealized arterial graft. For this problem we study the influence of the inflow velocity, and thus the shear rate. Furthermore, we introduce an additional factor in the form of a geometric parameter, and study its effect on the optimal shape obtained.


Comparison of the effects of transarterial chemoembolization for advanced hepatocellular carcinoma between patients with and without extrahepatic metastases.
Sorafenib is a standard treatment for advanced hepatocellular carcinoma (HCC) (Barcelona Clinic Liver Cancer [BCLC] stage C). However, transarterial chemoembolization (TACE) has also been widely used as a treatment for patients with advanced HCC, even if they have extrahepatic metastases (EHM). The aim of this study was to determine the efficacy of TACE for advanced HCC patients with EHM upon initial diagnosis, as compared with those patients without EHM. This cohort study involved consecutive patients who underwent TACE as an initial treatment for advanced HCC. One hundred seventy-seven patients with EHM (the EHM group) and 205 with portal vein invasion without EHM (the non-EHM group) were included. A survival analysis was performed to compare overall survival between the two groups. The mean age was 54.5±9.9 years, and median follow-up duration was 13.1 months (range, 0.5-111.0). Overall survival was significantly shorter in the EHM group than the non-EHM group (median, 8.3 vs. 19.1 months; P<0.001). A multivariate analysis showed that the presence of EHM was an independent poor prognostic factor for shorter overall survival (adjusted hazard ratio, 1.74; 95% confidence interval, 1.39-2.17; P<0.001) after adjustment for Child-Pugh classification, intrahepatic tumor T classification, tumor response to TACE, and serum alpha-fetoprotein level. Patients administered TACE and systemic therapy demonstrated a better survival rate than those administered TACE alone in both the EHM (median, 13.5 vs. 7.2 months) and non-EHM groups (median, 27.9 vs. 18.2 months) (both, P<0.05). The prognosis of advanced HCC patients with EHM is significantly worse than those without EHM administered repeated TACE treatments, even if their tumor stage was similar to BCLC stage C. These results suggest that EHM presence means aggressive tumor biology and that BCLC stage C might be subclassified according to EHM presence.


Synthesis of some novel sulfur containing triazolothienopyrimidines and biscompounds as possible antitumor and radioprotective agents.
The syntheses of novel 1,2,4-triazolothienopyrimidine derivatives (4a,b), thiourea derivatives (5-8) and biscompounds having a thieno[2,3-d]pyrimidine nucleus (13-16) utilizing the 2-isothiocyanato derivatives 2a,b are reported. The structures of these compounds were confirmed by microanalysis, IR, 1H-NMR and mass spectrometry. Preliminary biological studies of some synthesized compounds showed promising antitumor and radioprotective activities.


Genetic Compositions of Broad bean wilt virus 2 Infecting Red Pepper in Korea.
The incidence of Broad bean wilt virus 2 (BBWV2) on red pepper was investigated using the samples obtained from 24 areas of 8 provinces in Korea. Two hundred and five samples (79%) out of 260 collected samples were found to be infected with BBWV2. While the single infection rate of BBWV2 was 21.5%, the co-infection rate of BBWV2 with Cucumber mosaic virus, Pepper mottle virus, Pepper mild mottle virus and/or Potato virus Y was 78.5%. To characterize the genetic diversity of BBWV2 Korean isolates, 7 isolates were fully sequenced and analyzed. Phylogenetic analyses revealed that BBWV2 isolates could be divided largely into two groups as Group I and Group II. Based on the partial sequence analyses, 153 selected BBWV2 isolates were subgrouped into GS-I (21.6%), GS-II (3.9%) and GS-III (56.9%). BBWV2 GS-III, which was predominant in Korea, appears to be a new combination between Group I RNA-1 and Group II RNA-2. Viral disease incidence of BBWV2 on red pepper was under 2% before 2004. However, the incidence was increased abruptly to 41.3% in 2005, 58.2% in 2006 and 79% in 2007. These rapid increases might be related with the emergence of new combinations between BBWV2 groups.


Fluorescent proteins as proteomic probes.
Protein complexes mediate the majority of cellular processes. Knowledge of the localization and composition of such complexes provides key insights into their functions. Although green fluorescent protein (GFP) has been widely applied for in vivo visualization of proteins, it has been relatively little used as a tool for the isolation of protein complexes. Here we describe the use of the standard GFP tag to both visualize proteins in living cells and capture their interactions via a simple immunoaffinity purification procedure. We applied this method to the analysis of a variety of endogenous protein complexes from different eukaryotic cells. We show that efficient isolations can be achieved in 5-60 min. This rapid purification helps preserve protein complexes close to their original state in the cell and minimizes nonspecific interactions. Given the wide use and availability of GFP-tagged protein reagents, the present method should greatly facilitate the elucidation of many cellular processes.


Effect of Statin Therapy on Fibrous Cap Thickness in Coronary Plaques Using Optical Coherence Tomography: A Systematic Review and Meta-Analysis.
We conducted a systematic review and meta-analysis to evaluate the effect of statin therapy on coronary fibrous cap thickness (FCT) as assessed by optical coherence tomography (OCT) and the relationship between FCT and traditional coronary risk factors. Increasing evidence has shown that statin therapy results in a marked increase in coronary FCT. However, the relationship between this increase in FCT and the lipid profile has not been clearly elucidated. A literature search of PubMed, Embase, the Cochrane Library, and Web of Science up to March 17, 2015 was performed. Studies providing data on FCT using OCT at baseline and follow-up in patients receiving statin therapy were included. Weighted mean difference (WMD) with a random-effects model was used. Six OCT studies were included. The FCT in coronary plaques was significantly increased after statin therapy (WMD: 58.79 μm, 95% CI 33.82-83.76 μm, P < 0.001). When compared with the placebo group, the increase in FCT was also greater in the statin group (WMD: 72.28 μm, 95% CI 44.97-99.58 μm, P < 0.001). Meta regression analysis demonstrated no significant correlations between the increase in FTC and the changes in total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels during follow-up. Similarly, there were no significant correlations between the increase in FCT and age, male gender, hypertension, diabetes, and smoking. Statin therapy induced a significant increase in coronary FCT evaluated by OCT. This increase in FCT was independent of traditional coronary risk factors including the lipid profile.


Eugenol and its association with levodopa in 6-hydroxydopamine-induced hemiparkinsonian rats: Behavioural and neurochemical alterations.
Parkinson's disease is a neurodegenerative disorder that affects the central nervous system and is mainly characterized by the loss of dopaminergic neurons and pro-oxidant mechanisms. Eugenol has been widely studied due to its anti-inflammatory and antioxidant activities, making it a promising neuroprotective agent. This study aimed to investigate the effects of eugenol and its combined action with levodopa in the 6-hydroxydopamine-induced Parkinson's disease model. Wistar rats were subjected to intrastriatal injection of 6-hydroxydopamine (21 μg) and then treated with eugenol (0.1, 1, or 10 mg/kg), levodopa (25 mg/kg) or their combination (eugenol 10 mg/kg + levodopa 12.5 mg/kg) orally for 14 days. On the 14th day, the animals were subjected to behavioural tests, and after euthanization and dissection of the brain areas, neurochemical analyses were performed. The results showed that eugenol reduced the oxidative stress and behavioural disturbances induced by 6-hydroxydopamine. The eugenol and levodopa combination was more effective in some behavioural parameters and body-weight gain in addition to promoting an increase in reduced glutathione levels compared to levodopa alone. Thus, the neuroprotective activity of eugenol was observed against motor and neurochemical disorders. Additionally, the eugenol and levodopa combination was promising when compared to conventional treatment.


Is there a weekend effect in spine surgery?: A systematic review and meta-analysis of postoperative outcomes.
The concept of a weekend effect is that patients admitted to hospitals on the weekend tend to have poorer outcomes compared to those admitted on a weekday. Whether there is a weekend effect among patients receiving spine surgery is not well described in the literature. We sought to perform a systematic review with meta-analysis to explore whether a weekend effect exists among patients experiencing spinal surgery. The Cochrane Library, PubMed, Embase, and MEDLINE electronic databases were searched for relevant articles. Meta-analyses were performed using functions available in the metafor package within the R software. We obtained adjusted odds ratios (OR) from included studies and pooled OR through an inverse variance method. A random-effects model was applied for meta-analysis and effect sizes were presented with their corresponding 95% confidence intervals (CI). Our search strategy identified 316 references from electronic databases and eventually 6 studies were included in the analysis. The pooled result of 5 studies reporting overall complication rate indicated significant increased risk of complications among the weekend admission group (OR, 1.35; 95% CI, 1.01 to 1.80). The pooled results of 3 studies demonstrated no difference in overall mortality rates between these 2 groups of patients (OR, 1.18; 95% CI, 0.67 to 1.97). In spinal surgical patients, the weekend effect significantly contributes to a higher complication rate. Knowledge of potential adverse events in patients admitted on weekends is necessary for spinal surgeons and caregivers to improve patient outcomes with spinal surgery.


Fluoroquinolone and Ovariectomy in the Bitch: Physiology of the Immune System as to CD56 and CD16 Expression.
Natural killer (NK) cells are innate lymphoid cells which act against a variety of pathogens and tumours. Phenotypically they are characterized by surface markers named cluster designation (CD) antigens. CD56 and CD16 are recognized as specific NK markers in the dogs as well as in humans. Surgical interventions suppress NK cells both in rats and humans. In this direction, it has been shown that an antibiotic regimen (amoxicillin, benzylpenicillin/dihydrostreptomycin, sulfametazine/sulfamerazine/ sulfathiazole, enrofloxacin, lincomycin/spectinomycin) administered only twice is effective in preventing infections after laparatomic ovariectomy, in the bitch. On these grounds, this research will show that the administration of a fluoroquinolone (5 mg/kg of enrofloxacin, Baytril®, Bayer, Milan, Italy) one hour before and at the end of ovariectomy is able to increase CD56 and CD16 expression levels. Moreover, the antibiotic administration modifies the relative expression levels of the two CD; thus suggesting that the fluoroquinolone employed enhances the activation of a specific subset of NK cells mainly involved in body recovering during the post operative period as already observed in humans.


Classification of obsessive-compulsive disorder from resting-state fMRI.
Obssesive-compulsive disorder (OCD) is a serious mental illness that affects the overall quality of the patients' daily lives. Accurate diagnosis of this disorder is a primary step towards effective treatment. Diagnosing OCD is a lengthy procedure that involves interviews, symptom rating scales and behavioral observation as well as the experience of a clinician. Discovering signal processing and network based biomarkers from functional magnetic resonance scans of patients may greatly assist the clinicians in their diagnostic assessments. In this paper, we explore the use of Pearson's correlation scores and network based features to predict if a subject has OCD. We extracted mean time series from 112 brain regions and decomposed them to 5-frequency bands. The mean time courses were used to calculate the Pearson's correlation matrix and network based features for each band. Minimum redundancy maximum relevance feature selection method is applied to the Pearson's correlation matrix and network based features from each frequency band to select the best features for the final predictor. A leave-one-out cross validation method is used for the final predictor performance. Our proposed methodology achieves 80% accuracy (23 out of 29 subjects classified correctly) with 81% sensitivity(13 out of 16 OCD subjects identified correctly) and 77% specificity (10 out of 13 controls identified correctly) using leave-one-out with in-fold feature ranking and selection. The most discriminating feature bands are 0.06-0.11 Hz for Pearson's correlation and 0.03-0.06 Hz for network based features. The high classification accuracy indicates the predictive power of the network features as well as carefully chosen Pearson's correlation values.


Derivatives of 3:4-xylidine and related compounds as inhibitors of influenza virus: relationships between chemical structure and biological activity.
A series of compounds, based primarily on 3:4-xylidine, was examined for inhibitory activity towards the growth of influenza virus in tissue culture. Marked dependence of inhibitory activity upon chemical structure was observed particularly when the 3:4-xylyl group was replaced by other simple aryl radicals. N-(2-Piperidinoethyl)-3:4-xylidine dihydrochloride, a typical compound combining high intrinsic inhibitory activity with no obvious toxicity towards the host tissues, did not inactivate the virus directly before its adsorption, did not interfere with adsorption of virus by the tissues, and did not inhibit the release of freshly synthesized virus by the tissues, but specifically depressed the synthesis of viral haemagglutinin to a greater extent than it depressed the synthesis of complement-fixing soluble antigen. The inhibition of growth of influenza virus caused by this compound in tissue culture was reversed by appropriate addition of 4:5-dimethyl-o-phenylenediamine, but not apparently by riboflavin or by vitamin B(12). The action of this substance, and, by inference, of related compounds, in inhibiting viral synthesis may be the result of depressed cytoplasmic protein synthesis.


Digital Design and Fabrication of Surgical Obturators Based Only on Preoperative Computed Tomography Data.
This article describes the digital fabrication of a surgical obturator (SO) using only computed tomography (CT) data from the tumor area. This procedure is a departure from the traditional method of making an impression and obtaining a patient cast prior to surgery to allow for SO fabrication. The present approach allows for a virtual resection based on the patient's CT image; the SO is digitally designed with animation software and fabricated by 3D printing. The SO is relined with a denture reliner at the time of surgery to complete the obturation of the maxillectomy defect.


Adrenal myelolipoma with translocation (3;21)(q25;p11).
Adrenal myelolipoma (ML) is a rare, benign, nonfunctioning tumor-like lesion composed of mature adipose tissue interspersed with bone marrow-like hematopoietic elements in various proportions. It occurs usually in adults and is frequently asymptomatic in about half of cases. The histogenesis of adrenal ML is not clear and this lesion has been found to be associated with endocrine disorders, other adrenal dysfunction and tumors, and hyperstimulation with adrenocorticotropic hormone. Specific chromosomal abnormalities, however, have not been observed in such cases. Herein, we report a typical case of adrenal ML found incidentally in a 26-year-old man. Conventional cytogenetic techniques demonstrated balanced translocation between bands 3q25 and 21p11 in 9 of 20 metaphases analyzed in cultured tumor cells. To the best of our knowledge, this is the first reported case of adrenal ML showing chromosomal abnormality. This finding would indicate that adrenal ML is a bona fide neoplasm and the possibility of derivation from misplaced hematopoietic cells may be alternatively taken into consideration in view of the similar genetic changes in hematopolietic neoplasms.


Adipose-Derived Regenerative Cell Transplantation for the Treatment of Hand Dysfunction in Systemic Sclerosis: A Randomized Clinical Trial.
Hand dysfunction is common in systemic sclerosis (SSc). We undertook this study to evaluate the capacity of autologous adipose-derived regenerative cells (ADRCs) to improve hand function in SSc patients. The Scleroderma Treatment with Celution Processed Adipose Derived Regenerative Cells Trial was a prospective, randomized, double-blind trial of ADRCs, in which ADRCs were obtained from patients with SSc by small-volume adipose tissue harvest, and the fingers of each patient were injected with ADRCs. The primary end point was change in hand function at 24 and 48 weeks, assessed using the Cochin Hand Function Scale (CHFS). One of the secondary end points included the change in Health Assessment Questionnaire disability index (HAQ DI) at 48 weeks. Separate prespecified analyses were performed for patients with diffuse cutaneous SSc (dcSSc) and those with limited cutaneous SSc (lcSSc). Eighty-eight patients were randomized to receive ADRCs (n = 48 [32 patients with dcSSc and 16 with lcSSc]) or placebo (n = 40 [19 patients with dcSSc and 21 with lcSSc]). Change in hand function according to CHFS score was numerically higher for the ADRC group compared to the placebo group but did not achieve statistical significance (mean ± SD improvement in the CHFS score at 48 weeks 11.0 ± 12.5 versus 8.9 ± 10.5; P = 0.299). For patients with dcSSc, the between-group difference in the CHFS at 48 weeks was 6.3 points (nominal P = 0.069). For the secondary end point, the dcSSc group exhibited a between-group difference of 0.17 points in the HAQ DI (nominal P = 0.044) at 48 weeks. Of the ADRC-treated patients with dcSSc, 52% reported improvement greater than the minimum clinically important difference for both CHFS and HAQ DI compared to 16% in the placebo group (nominal P = 0.016). Small-volume adipose tissue harvest and ADRC treatment were well tolerated. While the primary end point of this trial was not achieved, efficacy trends were observed in patients with dcSSc. Adipose tissue harvest and ADRC injection were demonstrated to be feasible. Further clinical trials of this intervention in the setting of dcSSc are warranted.


Liver function and dysfunction - a unique window into the physiological reach of ER stress and the unfolded protein response.
The unfolded protein response (UPR) improves endoplasmic reticulum (ER) protein folding in order to alleviate stress. Yet it is becoming increasingly clear that the UPR regulates processes well beyond those directly involved in protein folding, in some cases by mechanisms that fall outside the realm of canonical UPR signaling. These pathways are highly specific from one cell type to another, implying that ER stress signaling affects each tissue in a unique way. Perhaps nowhere is this more evident than in the liver, which-beyond being a highly secretory tissue-is a key regulator of peripheral metabolism and a uniquely proliferative organ upon damage. The liver provides a powerful model system for exploring how and why the UPR extends its reach into physiological processes that occur outside the ER, and how ER stress contributes to the many systemic diseases that involve liver dysfunction. This review will highlight the ways in which the study of ER stress in the liver has expanded the view of the UPR to a response that is a key guardian of cellular homeostasis outside of just the narrow realm of ER protein folding.


Determining the Targets of Fluopsin C Action on Gram-Negative and Gram-Positive Bacteria.
The antibiotic activity of metalloantibiotic compounds has been evaluated since the 90s, and many different modes of action were characterized. In the last decade, the effects of secondary metabolites produced by Pseudomonas aeruginosa LV strain, including a cupric compound identified as Fluopsin C, were tested against many pathogenic bacteria strains, proving their high antibiotic activity. In the present study, the bactericidal mechanisms of action of Fluopsin C and the semi-purified fraction F4A were elucidated. The results found in electron microscopy [scanning electron microscopy (SEM) and transmission electronic microscopy (TEM)] demonstrated that both Fluopsin C and F4A are affecting the cytoplasmatic membrane of Gram-positive and Gram-negative bacteria. These results were confirmed by fluorescence microscopy, where these bacteria presented permeabilization of their cytoplasmatic membranes after contact with the semi-purified fraction and pure compound. Using electronic and fluorescence microscopy, along with bacterial mutant strains with marked divisional septum, the membrane was defined as the primary target of Fluopsin C in the tested bacteria.


Bosnian refugees in the Scandinavian countries: a comparative perspective on immigration control in the 1990s.
"In all the Nordic countries, a change of direction in refugee policy has taken place in recent years, primarily for similar reasons to those in the rest of Western Europe. These changes have been sparked off by the situation in the former Yugoslavia, but should also be seen as reflecting something more.... The prospect of a continuing influx of refugee groups, and a corresponding strain on national budgets, creates a backdrop for new thinking in all countries. An interesting aspect of this issue in the Nordic region is that, despite being a fairly homogeneous area, these countries have chosen radically different points of departure for their approach to refugees from Bosnia-Herzegovina. The article identifies these different national strategies and analyses the subsequent tendency towards convergence of policies that has taken place along the way."