Quantitative Calorimetric Studies of the Chiral Nematic Mesophase in Aqueous Cellulose Nanocrystal Suspensions.
Aqueous suspensions of cellulose nanocrystals (CNCs) can spontaneously form a chiral nematic mesophase at a critical concentration (c*). Unfortunately, no current analytical technique permits rapid detection of c*. Herein, we introduce a facile and accurate approach to assess c* rapidly (<2 h) from a small sample volume and compare our results with those obtained by conventional methods. Our strategy employs isothermal titration calorimetry (ITC) to measure the heat associated with interactions in the suspension, which can identify the onset of mesophase formation as the heat signature is sensitive to the suspension viscosity and thus capable of detecting small changes in the suspension environment. We measure c* for CNC samples differing in surface charge and aspect ratio, and find that both lower aspect ratios and higher surface charges increase c*. Our ITC results reveal the role of CNC interactions prior to the visual observation of mesophase formation and elucidate mesomorphic effects related to nanocrystals and their suspensions.


Molecular studies on genetic integrity of open-pollinating species rye (Secale cereale L.) after long-term genebank maintenance.
The genetic integrity of six accessions represented by 14 sub-populations of the open-pollinating species rye ( Secale cereale L.) was investigated. Seeds available from a herbarium collection (first regeneration) and from the cold store (most recent regeneration) were multiplied two to fourteen times and fingerprinted using microsatellite markers. Four accessions had significantly different allele frequencies. These were multiplied seven to thirteen times. Nearly 50% of the alleles discovered in the original samples were not found in the material present in the cold store. However alleles were detected in the most recently propagated sub-populations, that were not observed in the investigated plants of the original one. The change in allele frequencies is a continuous process. Reasons for the occurrence of genetic changes and consequences for managing open pollinating species maintained in ex situ genebanks are discussed.


Grandparenting and subjective well-being in China: The moderating effects of residential location, gender, age, and income.
Grandparenting is a social determinant of older adults' subjective well-being (SWB) worldwide, and is receiving increasing scholarly attention. Grandparenting is particularly prevalent in China because of the increasing number of women in the labor force, shortages of daycare services, and intergenerational bonds. Based on three waves (2011, 2013, and 2015) of the China Health and Retirement Longitudinal Study (n = 14,846), we used pooled ordinary least squares (POLS) regression to examine the association between grandparenting and Chinese older adults' SWB and the moderating effects of residential location (rural/urban), gender, age, and income. We measured SWB by four outcomes: self-rated health, life satisfaction, depressive symptoms, and cognitive function. Our findings indicate that intensive grandparenting is positively associated with older adults' life satisfaction. Older adults providing a low-to-high intensity of grandparenting have better cognitive function than non-caregivers. Among caregivers, a moderate level of grandparenting is associated with better cognitive function. Residential location, age, and income are significant moderators. For example, high-intensity grandparenting is positively associated with rural grandparents' but not urban grandparents' life satisfaction. Although younger grandparents have better self-rated health, higher life satisfaction, and fewer depressive symptoms than their older counterparts if they provide grandparenting care, grandparenting is more beneficial for older grandparents' cognitive function. Both low and high intensities of grandparenting are positively related to self-rated health and cognitive function for grandparents with lower incomes. Overall, the findings of this study indicate how grandparenting is related to the SWB of older people in China in different social groups and of people living in different locations.


Studies with antisera against peripheral nervous system myelin and myelin basic proteins. II. Immunohistochemical studies in cultures of rat dorsal root ganglion neurons and Schwann cells.
Antiserum against rat peripheral nervous system (PNS) myelin contained immunoglobulins which bound preferentially to the extracellular surfaces of myelin-related Schwann cells in intact cultures of dorsal root ganglion (DRG) neurons and Schwann cells, while antiserum against basic protein (BP) from central nervous system myelin or the PNS basic protein P2 did not. We demonstrate the presence of PNS myelin proteins P1 (identical to BP) and P2 by immunoperoxidase techniques in DRG cultures that had been treated to disrupt cellular membranes. These observations suggest that P1 and P2 are not exposed on the extracellular surfaces of myelin-related Schwann cells in culture. The results also support the hypothesis concerning the possible mechanisms by which anti-PNS myelin serum demyelinates DRG cultures, while anti-BP serum and anti-P2 serum do not.


Drug-Eluting Bead, Irinotecan Therapy of Unresectable Intrahepatic Cholangiocarcinoma (DELTIC) with Concomitant Systemic Gemcitabine and Cisplatin.
Unresectable intrahepatic cholangiocarcinoma (ICC) carries a poor prognosis, and currently there are moderately established chemotherapeutic [gemcitabine/cisplatin (Gem/Cis)] treatments to prolong survival. The purpose of this study was to assess the efficacy of irinotecan drug-eluting beads (DEBIRI) therapy by transarterial infusion in combination with systemic therapy in unresectable ICC. This is a prospective, multicenter, open-label, randomized phase II study (Clin Trials: NCT01648023-DELTIC trial) of patients with ICC randomly assigned to Gem/Cis with DEBIRI or Gem/Cis alone. The primary endpoint was response rate. The intention-to-treat population comprised 48 patients: 24 treated with Gem/Cis and DEBIRI and 22 with Gem/Cis alone (2 screen failures). The two groups were similar with respect to the extent of liver involvement (35% versus 38%) and presence of extrahepatic disease (29% versus 14%, p = 0.12). Median numbers of chemotherapy cycles were similar (6 versus 6), as were rates of grade 3/4 adverse events (34% for the Gem/Cis-DEBIRI group versus 36% for the Gem/Cis group). The overall response rate was significantly greater in the Gem/Cis-DEBIRI arm versus the Gem/Cis arm at 2 (p < 0.04), 4 (p < 0.03), and 6 months (p < 0.05). There was significantly more downsizing to resection/ablation in the Gem/Cis-DEBIRI arm versus the Gem/Cis arm (25% versus 8%, p < 005), and there was improved median progression-free survival [31.9 (95% CI 8.5-75.3) months versus 10.1 (95% CI 5.3-13.5) months, p = 0.028] and improved overall survival [33.7 (95% CI 13.5-54.5) months versus 12.6 (95% CI 8.7-33.4) months, p = 0.048]. Combination Gem/Cis with DEBIRI is safe, and leads to significant improvement in downsizing to resection, improved progression-free survival, and overall survival.


Elucidating the influence of praziquantel nanosuspensions on the in vivo metabolism of Taenia crassiceps cysticerci.
The aim of this work was to develop nanosuspensions of praziquantel (PZQ) and to evaluate their influence on the energetic metabolism of cysticerci inoculated in BALB/c mice. We analyzed metabolic alterations of glycolytic pathways and the tricarboxylic acid cycle in the parasite. The nanosuspensions were prepared by precipitation and polyvinyl alcohol (PVA), poloxamer 188 (P188) and poloxamer 407 (P407) were used as stabilizers. Nanosuspension prepared with PVA had a particle size of 100nm, while P188- and P407-based nanosuspensions had particle sizes of 74nm and 285nm, respectively. The zeta potential was -8.1, -8.6, and -13.2 for the formulations stabilized with PVA, P188 and P407, respectively. Treatments of T. crassiceps cysticerci-infected mice resulted in an increase in glycolysis organic acids, and enhanced the partial reversion of the tricarboxylic acid cycle, the urea cycle and the production of ketonic bodies in the parasites when compared to the groups treated with conventional PZQ. These data suggest that PZQ nanosuspensions greatly modified the energetic metabolism of cysticerci in vivo. Moreover, the remarkable metabolic alterations produced by the stabilizers indicate that further studies on nanoformulations are required to find potentially suitable nanomedicines.


A case series and review of Poncet's disease, and the utility of current diagnostic criteria.
Poncet's disease is a well recognized form of reactive arthritis in the presence of extra-articular tuberculosis. There are very limited case reports even from countries where tuberculosis is common and there are no accepted diagnostic criteria for Poncet's disease. In the present study we are describing clinical features of Poncet's disease from a tuberculosis-endemic region along with a proposal of a new diagnostic criteria. All patients diagnosed as having Poncet's disease were included. The clinical details, demographic features, pattern of joint involvement, investigation findings, treatment details and clinical outcomes were recorded on a structured pro forma. Twenty-three patients with Poncet's disease were identified during the study period. Thirteen patients had oligoarthritis and the rest had polyarthritis with ankle joint involvement being most common. The duration of joint symptoms varied from 3 days to 6 years. All patients had non-erosive and non-deforming arthritis. Systemic symptoms were absent in 48% of patients. Mantoux was positive in most cases (81%). Tuberculosis was extrapulmonary in most cases, lymph node tuberculosis being most common. All patients had complete resolution of joint symptoms with anti-tubercular treatment. All the factors contributing to eventual diagnosis of Poncet's disease were carefully analyzed and diagnostic criteria are proposed. In the proposed criteria, there are two essential, two major and three minor criteria. According to these criteria 19 patients had definite and three had probable Poncet's disease. The most common presentation of Poncet's is in the form of oligoarthritis. The proposed criteria can be used for diagnosing Poncet's disease.


A model for the variability of interspike intervals during sustained firing of a retinal neuron.
The statistics of the variability of interspike intervals of ganglion cells in the retina of goldfish are modeled by assuming the noise in an integrate-and-fire mechanism is proportional to the reciprocal of a normally distributed variable. This model meets the constraint that the coefficient of variation of the interspike. This does not change when the mean firing rate of the neuron changes. Alternative sources of variability of interspike intervals are discussed.


Animal experimental study on repairing alveolar clefts by using rectilinear distraction osteogenesis.
The aim of this study was to evaluate the clinical applicability of rectilinear distraction osteogenesis for repairing alveolar cleft models. Alveolar process distraction surgery to produce bilateral clefts was performed on six adult cats. In our study, the left side with the distraction device was the experimental side, and the other side without a distraction device was the control side. After a 6-day latent period, animals underwent gradual distraction at a rate of 0.6mm per day (distraction was performed twice each day, at a rate of 0.3mm each time), until the tissue on the two sides of the cleft touched, then the distraction strength was maintained for 2 days. Two cats were sacrificed at 2 weeks, 6 weeks and 10 weeks postoperatively. Gross anatomical, histological and radiographical analyses were performed after the animals were sacrificed. In addition, the arch width was measured both before setting the distraction device and after distraction was complete. Two weeks after the distraction was complete, the soft tissue of the two sides of the cleft region on the experimental side touched, and it began to coalesce. The extremities of the two sides of the cleft region on all the experimental sides drew close to each other, but there was no bony conjunction. New bone formation appeared in the distraction region. The arch width at the front of the maxillary bone on the distraction side after distraction was smaller than before distraction. The alveolar cleft could be closed by rectilinear distraction osteogenesis. Two sides of the cleft touched each other and only soft tissue coalesced, but we did not observe bone coalescing. This phenomenon suggested that it might be difficult to achieve complete bony repair by rectilinear distraction osteogenesis. However, rectilinear distraction osteogenesis can minimise the size of the alveolar cleft and make bone grafting advisable for those patients who are not suitable for bone grafting before distraction osteogenesis.


Epidemiology of infections in women.
This article describes the epidemiologic profiles of sexually transmitted infections seen in US women. We present a brief description of the infectious agent, describe the epidemiology of the infection among women in terms of race/ethnicity and age (if those data are available), and present what is known about the behavioral risk factors associated with acquisition.


Left ventricular dysfunction after acute intracranial hypertension is associated with increased hydroxyl free radical production, cardiac ryanodine hyperphosphorylation, and troponin I degradation.
In addition to generating free radicals, stress-induced activation of the sympathetic nervous system results in hyperphosphorylation of the cardiac ryanodine receptor (RyR2)/calcium (Ca2+) release channel on the sarcoplasmic reticulum, causing leaky channels. These events may contribute to cytosolic Ca2+ overload and activation of Ca2+-dependent cytotoxic processes. Because myocardial dysfunction associated with intracranial hypertension is catecholamine mediated, we sought to determine in a rat model if hemodynamic changes are associated with an increase in oxidative stress, hyperphosphorylation of RyR2, and degradation of myofilament protein cardiac troponin I (TnI). In halothane-anesthetized rats treated with saline, dimethyl sulfoxide (DMSO), or the synthetic calpain inhibitor calpeptin (3,500 microg), a subdural balloon catheter was inflated to induce intracranial hypertension. Hearts were excised, and RyR2 phosphorylation status and TnI degradation was determined with Western blot analysis. In separate experiments, treated rats were challenged with increasing doses of dobutamine 30 minutes after subdural balloon inflation. Elevating the intracranial pressure resulted in an increase in plasma catecholamines, as well as in 3,4-dihydroxybenzoic acid (DHBA), an indirect marker of HO. radical production, and left ventricular dysfunction in rats treated with saline or DMSO. There was evidence of hyperphosphorylation of RyR2 and TnI degradation (27 kD immunoreactive band). Calpeptin treatment improved left ventricular function; however, this had no effect on the phosphorylation status of RyR2 or TnI degradation levels. In addition, the myocardial responsiveness to dobutamine was augmented in rats with depressed myocardial function. The present findings demonstrate that hemodynamic instability after intracranial hypertension is associated with oxidative stress and post-translational changes to RyR2 and TnI degradation. Despite this, the myocardial responsiveness to beta1 adrenergic stimulation is preserved in rats with depressed myocardial function.


A critical assessment of the Wilhelmy method in studying lung surfactants.
1. The surface properties of over 250 films of diplamitoyl lecithin (DPL) and Tween 20 on distilled water have been investigated using two different surface balances simultaneously, the Wilhelmy balance, popular in physiological studies, and the Du Nuoy ring method whose readings are independent of contact angle. 2. Using concentrations of DPL ranging from 0.08 to 1.90 microgram cm-2 on a Langmuir trough where the pool area was cycled from 100 to 27.5% of maximum, the Wilhelmy balance registered virtually the same force per wetted perimeter as the ring method for both pure water and Tween 20, but appreciably lower values for DPL over the whole cycle. 3. The above differences can be explained on the basis of a significant (45-70 degrees) contact angle, a surface property also demonstrated photographically and by direct measurement. 4. Contact angle was shown to vary with pool area, a relationship exhibiting hysteresis. 5. This study indicates that the Wilhelmy balance has been an unfortunate choice of instrument for studying DPL films whose surface tensions are appreciably higher than previously estimated.


Influence of saline solution on hydration behavior of β-dicalcium silicate in comparison with biphasic calcium phosphate/hydroxyapatite bio-ceramics.
The influence of using saline solution as mixing and curing liquid on some characteristics of β-dicalcium silicate (β-C2S) and biphasic compound tri-calcium phosphate/hydroxyapatite (TCP/HAp) bio-ceramics was investigated. β-C2S (27-30 nm) was prepared by solid state reaction at 1450°C, while biphasic compound TCP/HAp (7-15 nm) was synthesized from an aqueous solution of Ca(NO3)2·4H2O and (NH4)2HPO4·12H2O by chemical precipitation method. Setting times, compressive strength, pH values, X-ray diffraction analysis, infrared spectroscopy, scanning electron microscopy (SEM) were investigated. The evaluation of cytotoxicity of both calcium silicate and biphasic compounds to human gingival fibroblasts was carried out. The use of saline solution as mixing and immersing liquid shortened the setting time for the two bio-cements. TCP/HAp did not show any mechanical strength but β-C2S showed good strength values. Both synthesized compounds showed a moderate cytotoxicity and both materials were effective in a no significant way.


DeepRT: Predicting compounds presence in pathway modules and classifying into module classes using deep neural networks based on molecular properties.
Metabolic pathways play a crucial role in understanding the biochemistry of organisms. In metabolic pathways, modules refer to clusters of interconnected reactions or sub-networks representing specific functional units or biological processes within the overall pathway. In pathway modules, compounds are major elements and refer to the various molecules that participate in the biochemical reactions within the pathway modules. These molecules can include substrates, intermediates and final products. Determining the presence relation of compounds and pathway modules is essential for synthesizing new molecules and predicting hidden reactions. To date, several computational methods have been proposed to address this problem. However, all methods only predict the metabolic pathways and their types, not the pathway modules. To address this issue, we proposed a novel deep learning model, DeepRT that integrates message passing neural networks (MPNNs) and transformer encoder. This combination allows DeepRT to effectively extract global and local structure information from the molecular graph. The model is designed to perform two tasks: first, determining the present relation of the compound with the pathway module, and second, predicting the relation of query compound and module classes. The proposed DeepRT model evaluated on a dataset comprising compounds and pathway modules, and it outperforms existing approaches.


[Studies on the effects of intravenous administration of glucose, fructose, invertose and sorbitol on various blood constituents of blood plasma (monosaccharides, insulin, lactate, pyruvate and free fatty acids as well as glutamate-oxaloacetate transaminase) in the horse].
Horses were examined for the behaviour of various blood constituents prior to and following infusions of solutions of glucose, fructose, invertose, and sorbitol. Infusion of 0.5 g/kg live weight glucose to six horses was followed by half-life variation between eleven and 23 minutes. Subsequent infusion of invertose to the same animals usually caused prolongation of glucose half-life. Half-life values were between 17 and 33 minutes for fructose and between 21 and 80 minutes for glucose. Infusion of 0.5 g/kg live weight fructose to two horses was followed by half-life values between 17 and 18 minutes, while the half-life values of sugar alcohol were 16, 16, 27, and 29 minutes in four horses who had received sorbitol. Sugar or sorbitol infusion was not followed by substantive change of lactate and pyruvate concentrations in the blood or free fatty acids in the blood plasma or GOT activity. The rise of insulin in the blood plasma was differentiated. Invertose and sorbitol solutions, consequently, can be recommended for application to horses.


Developmental changes in Asn-linked neutral oligosaccharides in murine cerebrum.
The changes in Asn-linked oligosaccharide composition in the murine cerebrum during development have been examined by high-performance liquid chromatography (HPLC) and electrospray ionization mass spectrometry (ESI-MS). The oligosaccharides, obtained from murine cerebrum in several developmental stages, were separated by HPLC on anion-exchange and reverse-phase columns. We found that two Asn-linked oligosaccharides, designated oligosaccharide I and oligosaccharide II, had their expression changed during postnatal development. Whereas oligosaccharide I was reduced during brain development, oligosaccharide II was increased. The structures of oligosaccharides I and II were analyzed by ESI-MS and sequential exoglycosidase digestions. Judging from the molecular and fragment ions in each oligosaccharide, the oligosaccharide I was composed of 5Hex+2HexNAc+ABOE (MW 1467.2) and the oligosaccharide II was 3Hex+4HexNAc+DoHex+ABOE (MW 1695.2). The results of sequential exoglycosidase digestion indicated that the oligosaccharide I was an oligomannose type saccharide and the oligosaccharide II was a biantennary complex type saccharide including fucose. The proposed structures are shown below. These results offer an important clue to the role of Asn-linked oligosaccharides associated with development of the central nervous system.


The prospects and promise of chimeric antigen receptor immunotherapy in multiple myeloma.
Despite encouraging therapeutic advances, multiple myeloma (MM) remains an incurable malignancy. The exciting results of chimaeric antigen receptor (CAR)-based immunotherapy in CD19(+) B-cell malignancies have spurred a great interest in extending the use of the CAR technology to other cancers, including MM. Availability of a specific, tumour-restricted antigen is crucial for the design of successful antibody-based CAR therapy. However, in MM, as in other malignancies, the relative dearth of such antigens-targets represents the main obstacle for the wider pre-clinical development and clinical application of the CAR technology. Here we provide an overview of the current progress and future promises of CAR technology in MM therapy. We highlight that, owing to its complexity, phenotypic and functional heterogeneity and the impact of the microenvironment, MM poses several challenges for CAR-based therapeutic approaches. Nevertheless, for the same reasons, MM can serve as a paradigm for better understanding, optimization and overall improvement of the CAR technology for the benefit of cancer and myeloma patients.


Effect of grain morphology on the degradation behavior of Mg-4 wt% Zn alloy in Hank's solution.
The degradation behavior of Mg-4 wt% Zn alloy with three different microstructures was examined in Hank's solution at 37 °C by electrochemical measurements and immersion tests in this study. The results show that the sample with cellular structure exhibits a more positive corrosion potential, lower corrosion current density, larger impedance and more protective film than samples with columnar dendritic and equiaxed dendritic structure. The higher corrosion resistance is attributed to the preferred orientation, eliminating susceptible grain boundaries and reduced secondary phases.


Gingival enlargement and resolution during and after orthodontic treatment.
Gingival enlargement (GE) is a condition that commonly develops during orthodontic treatment. Thirty adolescent subjects with clinically significant GE were analyzed at pre-orthodontic treatment (T1), when the appliances were removed (T2), and 3 to 12 months after (T3). The mean GE decreased from T2 to T3, but was significantly higher on T3 than T1 (p<.05). It may be concluded that complete resolution of GE developed during orthodontic treatment is not always attained after removal of the fixed appliances.


SLAMF8 expression predicts the efficacy of anti-PD1 immunotherapy in gastrointestinal cancers.
Epstein-Barr virus (EBV) infection is associated with a better response to anti-PD1 immunotherapy. We hypothesised that genetic alterations induced by EBV infection are responsible for the activation of key immune responses and hence are predictive of anti-PD1 efficacy. With transcriptome data of gastric cancer (GC), we explored differentially expressed genes (DEGs) specific for EBV infection and performed coexpression network analysis using the DEGs to identify the consistent coexpression genes (CCGs) between EBV-positive and EBV-negative GC tissues. We selected the tag genes of the CCGs and validated them using RNA sequencing and immunohistochemistry. We established murine models and collected tissues from clinical patients to test the value of SLAMF8 in predicting anti-PD1 treatment. The location and expression of SLAMF8 were characterised by multiplex immunofluorescence and quantitative PCR. Moreover, exogenous overexpression and RNA-sequencing analysis were used to test the potential function of SLAMF8. We identified 290 CCGs and validated the tag gene SLAMF8 in transcriptome data of gastrointestinal cancer (GI). We observed that the T-cell activation pathway was significantly enriched in high-expression SLAMF8 GI cancers. Higher SLAMF8 expression was positively associated with CD8 expression and a better response to anti-PD1 treatment. We further observed dynamically increased expression of SLAMF8 in murine models relatively sensitive to anti-PD1 treatment. SLAMF8 was mainly expressed on the surface of macrophages. Exogenous overexpression of SLAMF8 in macrophages resulted in enrichment of positive regulation of multiple immune-related pathways. Higher SLAMF8 expression may predict better anti-PD1 immunotherapy efficacy in GI cancer.


Zinc/Aluminium⁻Quinclorac Layered Nanocomposite Modified Multi-Walled Carbon Nanotube Paste Electrode for Electrochemical Determination of Bisphenol A.
This paper presents the application of zinc/aluminium-layered double hydroxide-quinclorac (Zn/Al-LDH-QC) as a modifier of multiwalled carbon nanotubes (MWCNT) paste electrode for the determination of bisphenol A (BPA). The Zn/Al-LDH-QC/MWCNT morphology was examined by a transmission electron microscope and a scanning electron microscope. Electrochemical impedance spectroscopy was utilized to investigate the electrode interfacial properties. The electrochemical responses of the modified electrode towards BPA were thoroughly evaluated by using square-wave voltammetry technique. The electrode demonstrated three linear plots of BPA concentrations from 3.0 × 10-8⁻7.0 × 10-7 M (R² = 0.9876), 1.0 × 10-6⁻1.0 × 10-5 M (R² = 0.9836) and 3.0 × 10-5⁻3.0 × 10-4 M (R² = 0.9827) with a limit of detection of 4.4 × 10-9 M. The electrode also demonstrated good reproducibility and stability up to one month. The presence of several metal ions and organic did not affect the electrochemical response of BPA. The electrode is also applicable for BPA determination in baby bottle and mineral water samples with a range of recovery between 98.22% and 101.02%.


[Cytogenetic monitoring of the Usmansky and Hrenovskoy autochtonic pine stands].
The data on the cytogenetic monitoring of the Usmansky and Khrenovskoy autochthonic pine stands (Voronezh Region) allow their status to be rated satisfactory. The indices of the mitotic and nucleolar activity as well as of abnormal mitosis were within the normal variation range for Scotch pine. However, the occurrence of micronuclei (less than 1%) points to pathological processes starting in the stands, which necessitates urgent measures for the conservation of the Usmansky and Khrenovskoy Forests as valuable gene sources.


Recombinant adeno-associated viral vector reference standards.
Reference standard materials (RSMs) exist for a variety of biologics including vaccines but are not readily available for gene therapy vectors. To date, a recombinant adeno-associated virus serotype 2 RSM (rAAV2 RSM) has been produced and characterized and was made available to the scientific community in 2010. In addition, a rAAV8 RSM has been produced and will be characterized in the coming months. The use of these reference materials by members of the gene therapy field facilitates the calibration of individual laboratory vector-specific internal standards and the eventual comparison of preclinical and clinical data based on common dosage units. Normalization of data to determine therapeutic dose ranges of rAAV vectors for each particular tissue target and disease indication is important information that can enhance the safety and protection of patients.


Recent advances in the role of interleukin-6 in health and disease.
Interleukin-6 (IL-6) is a pleotropic cytokine, and in this review, we highlight recent studies focusing on the role of IL-6 in health and disease. IL-6 is known as an exercise-inducible myokine, and in rodents it was identified that a lactate-dependent increase in protease activity mediates IL-6 release from skeletal muscle, which acts in both an autocrine and paracrine roles. In humans, a series of publications observed that blocking IL-6 during exercise training prevented beneficial adaptations, such as reductions in visceral and epicardial fat mass. Independent of exercise, IL-6 impacts postprandial physiology, as demonstrated by a slowing of gastric emptying rate and improving glucose homeostasis. Finally, an engineered cytokine harnessing the biology of IL-6, termed IC7Fc, was found to have beneficial impacts on numerous health outcomes. Together, these recent advances indicate that IL-6 has a multifaceted, and perhaps beneficial, role in health and disease.


Risk factors associated with linezolid-nonsusceptible enterococcal infections.
Linezolid is one of few treatment options available for vancomycin-resistant enterococci. The present study investigated risk factors for linezolid-nonsusceptible enterococci using a case-control study of 15 cases and 60 control patients. Previous hospitalization, admission to a medical service, comorbidity, and linezolid and sulfonamide therapy were identified as risk factors.


Ten-year review of hypospadias surgery from a single centre.
Hypospadias is more common than cleft lip and palate. However, in comparison to the latter, few units have dedicated any team to its correction. Hence, urologists, paediatric surgeons, plastic surgeons, general surgeons and paediatric urologists keep trying various methods of correcting this deformity. That more than 350 procedures have been described for the correction of one anomaly speaks volumes of dissatisfaction with the results. We describe our humble experience with this anomaly over a period of 10 years during which time we were able to treat 1415 cases. However, this paper only describes results of 1206 patients. We use universally only one technique for hypospadias repair and perform this in two stages. This technique has been described by many but lately popularized by Aivar Bracka from UK. Our overall fistula rate has been 3.8% though most of the fistulae occurred in the earlier period. Other complications included repeated UTI (3%) and hair growth in the urethra (0.2%).


RNAi Screening: Automated High-Throughput Liquid RNAi Screening in Caenorhabditis elegans.
RNAi is a powerful reverse genetics tool that has revolutionized genetic studies in model organisms. The bacteriovorous nematode Caenorhabditis elegans can be genetically manipulated by feeding it an Escherichia coli strain that expresses a double-stranded RNA (dsRNA) corresponding to a C. elegans gene, which leads to systemic silencing of the gene. This unit describes protocols for performing an automated high-throughput RNAi screen utilizing a full-genome C. elegans RNAi library. The protocols employ liquid-handling robotics and 96-well plates. © 2018 by John Wiley & Sons, Inc.


Age related differences in left and right hand skill and in visuo-spatial performance: their possible relationships to the hypothesis that the right hemisphere ages more rapidly than the left.
Young and old right handed people were disproportionately worse with their left hand when speed was stressed but showed no especial difficulty when accuracy of performance was emphasised. Both groups of people were also tested on the AH4 test of cognitive abilities. As frequently reported by Rabbitt, the old were disproportionately worse on the visuo-spatial part than on the verbal part compared with the young, even though both parts required "fluid" abilities and even though both were given under time constraints. There was no correlation amongst the elderly people between speed stressed deficits in their left hand performance and their deficits on the visuo-spatial part of the AH4. Both fine control of the left hand and fingers and visuo-spatial performance are likely to be mediated by the right cerebral hemisphere and the implications of these results for a variety of possible views about selective aging of the right hemisphere are discussed.


Mites, rodents, and pathogens: A global review for a multi-species interaction in disease ecology.
More than ever, there is a need to understand how pathogens, vectors and hosts occur temporally and spatially to predict the occurrence of zoonotic outbreaks. Related to this, mites of the Mesostigmata and Trombidiformes orders have the potential to transmit several diseases, yet their information of occurrence, distribution and zoonotic accompanying agents have not been systematically organized. We conducted a systematic review using a combination of words through the Sysrev platform, as well as literature searches in specialised databases to identify global patterns of infections, trends in mite-rodent-pathogen research and existing knowledge gaps. The inclusion criterion was the detection of pathogens in mites, either by molecular or serological techniques or by direct observation under the microscope, which rendered 125 papers. Most works have been carried out in Asia, mainly around the transmission of Orientia tsutsugamushi. Interestingly, co-infections, i.e., the presence of more than one pathogen in an individual, are common in other Acari groups such as ticks. Moreover, this is not the case for Trombidiformes and Mesostigmata as only 4.7 percent of the articles reviewed detected more than one pathogen in these mites. It is important to include a multi-host, multi-vector and multi-pathogen approaches to understand complex systems in disease ecology. A synergy between mite taxonomists, physicians and veterinarians, decision-makers, governmental organisations, and society is needed to address the emergence of mite-borne new or neglected diseases.


Ghrelin activation and neuropeptide Y elevation in response to medium chain triglyceride administration in anorexia nervosa patients.
Ghrelin, a peptide found in the stomach, increases appetite and fat-free mass while suppressing energy expenditure. Ghrelin requires modification by medium-chain triglycerides (MCTs) to exert its physiological effects. In this study, we investigated ghrelin activation and the resulting physiological changes following MCT administration. Thirty participants were selected from among inpatients diagnosed with anorexia nervosa (AN). The patients were randomly divided into three groups by the MCT content of their nutritional supplement: (1) 'MCT high' (>6 g/day), (2) 'MCT moderate' (1-6 g/day), and (3) 'MCT low' (<1 g/day). Physical factors such as body weight and composition, as well as levels of nutrition-related serum factors such as acylated (active form) and desacyl (inactive form) ghrelin, leptin, growth hormone, insulin-like growth factor, and neuropeptide Y (NPY) were measured at weeks 0, 2, 4, and 6 of the treatment protocol. Significantly higher ghrelin activation was found in the 'MCT high' than in the 'MCT low' group (P < 0.05). The amount of consumed MCT had a curvilinear relationship with the active ghrelin level (P = 0.00). NPY levels in the 'MCT high' group were significantly more elevated than in the 'MCT low' group (P < 0.05). MCT administration did not significantly affect the remaining factors. This study clearly demonstrated that MCT activates ghrelin and increases NPY, suggesting that nutritional supplementation with MCT may be effective for the treatment of AN patients in an emaciated state.


Macromolecular characterization of muscle membranes. Endogenous membrane kinase and phosphorylated protein substrate from normal and denervated muscle.
Light density membranes derived from the "microsomal" fraction of rat skeletal muscle contained an endogenous protein kinase which catalyzed the phosphorylation of an endogenous membrane substrate. No other membrane fraction contained any significant protein kinase activity. The optimal specific activity of the enzyme in these membranes was 350 pmol/mg/min. The endogenous muscle membrane protein kinase required magnesium, was stimulated by micromolar concentrations of calcium, had a pH optimum between 7.0 and 7.5, and demonstrated a K-m for ATP of 2.6 times 10 minus 5 M. The enzyme was markedly heat labile and demonstrated a linear Arrhenius plot with an apparent energy of activation of 12,100 cal/mol. There was no stimulation by cyclic nucleotides; and neither monovalent cations nor various neurotransmitters exerted any effect. It is presently unclear where the membranes exhibiting protein phosphorylation are localized within the muscle fiber. Enzyme markers suggest that these membranes are not derived from sarcolemma or sarcoplasmic reticulum but may originate in transverse tubules. The membrane phosphorylation was largely confined to a polypeptide with an apparent molecular weight of 28,000. Phosphorylation could also be detected in a lower molecular weight substrate as well as two polypeptides with apparent molecular weights of 95,000 and 56,000. The M-r-28,000 endogenous protein kinase substrate was isolated by preparative gel electrophoresis in sodium dodecyl sulfate. High voltage electrophoresis of a partial acid hydrolysate of the phosphorylated M-r-28,000 substrate identified the phosphate bond to be that of phosphoserine. The amino acid composition of the substrate was neither strongly acidic nor basic. It had a high content of glycine, glutamic acid, serine, and lysine. Hydrophobic residues constituted only 45% of the total composition. Following muscle denervation for 10 days, there was a significant decrease in the amount of the M-r-28,000 polypeptide as well as the extent of phosphorylation.


Secondary synovial chondromatosis of the subacromial subdeltoid bursa with coexisting glenohumeral osteoarthritis: Case report.
Synovial chondromatosis of the shoulder joint is uncommon; this condition usually affects the knee joint and the hip joint. Lesions of multiple chondral nodules form in the synovium and are usually found within the joint capsule. Treatment of synovial chondromatosis consists of loose body removal and synovectomy. In synovial chondromatosis of the shoulder, arthroscopic loose body removal and synovectomy have been reported with good outcomes. Arthroplasty can be a treatment option when osteoarthritis co-occurs at the affected joint. Since incidence of glenohumeral joint osteoarthritis is low compared to osteoarthritis of the knee or hip joints, reports of shoulder synovial chondromatosis treated with arthroplasty are scarce. A 79-year-old woman presented with right shoulder pain with loss of motion for several years without a history of trauma. Degenerative changes in the humeral head and glenoid were noted and multiple loose bodies were found in the subdeltoid bursa, and the subacromial bursa. The pathology of loose bodies showed degenerated cartilage tissue and some bony components. Characteristic concentric rings of calcification were observed, indicative of secondary synovial chondromatosis. The diagnosis was secondary synovial chondromatosis of the subacromial subdeltoid bursa with coexisting glenohumeral osteoarthritis. The patient was treated with loose body removal, extensive synovectomy, bursectomy and reverse total shoulder arthroplasty. Visual analog scale for shoulder pain, range of motion of shoulder joint had improved demonstrating a good short-term outcome and there was no radiographic evidence of disease recurrence. In synovial chondromatosis of the shoulder, loose bodies may form in the bursa. In combination with degenerative osteoarthritis of the glenohumeral joint, arthroplasty is a viable option.


Incorporation of specific amino acids as markers of cell differentiation.
Incorporation of different amino acids into the proteins of wheat embryo has been found to be not uniform during the various stages of seed germination. It is suggested that incorporation maxima of appropriate amino acids can be used as markers of switching of specific protein synthesis during embryo development. Such markers have been found suitable for defining the functional activity of preformed messenger RNA.


The application of dual energy X-ray soil screening in forensic archaeology.
The need to forensically search soil for small artefacts at a burial site or traces of evidence in a deposition site is a common task shared by investigators and forensic archaeologists. In forensic casework, the importance of finding small pieces of evidence, such as personal effects or ballistic fragments, cannot be overstated as it can assist in the positive identification of the deceased, give an insight into the manner and cause of death, and identify any perpetrators. The soil search methods known as wet and dry sieving, are cumbersome, time-consuming and have limited success for some soil types. This often leads to the decision not to search, resulting in missed opportunities to identify potential evidence. The primary aim of this study was to investigate if a dual energy X-ray baggage scanner could be used to search for items of potential forensic interest in soil. A trial was conducted using a Smiths Detection ScanTrailer 100100 V-2is mobile X-ray inspection system to establish if it could be used to detect organic, inorganic, and metallic items located within soil. The soil type and natural variables such as water and organic content were adjusted to simulate different environments. The baggage scanner was found to provide a quick and easy way to detect items contained within various soil types, particularly in a sand rich matrix. It is estimated that using this method to search 1 m3 of soil, when broken down into samples that are < 13 cm in depth, would take around one hour to complete, compared with 100 to 150 person-hours by manual sieving. This is believed to be the first use of dual energy X-ray technology for this purpose and shows the potential for further research and use of this method in forensic archaeology.


Printed temperature sensor array for high-resolution thermal mapping.
Fully-printed temperature sensor arrays-based on a flexible substrate and featuring a high spatial-temperature resolution-are immensely advantageous across a host of disciplines. These range from healthcare, quality and environmental monitoring to emerging technologies, such as artificial skins in soft robotics. Other noteworthy applications extend to the fields of power electronics and microelectronics, particularly thermal management for multi-core processor chips. However, the scope of temperature sensors is currently hindered by costly and complex manufacturing processes. Meanwhile, printed versions are rife with challenges pertaining to array size and sensor density. In this paper, we present a passive matrix sensor design consisting of two separate silver electrodes that sandwich one layer of sensing material, composed of poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS). This results in appreciably high sensor densities of 100 sensor pixels per cm[Formula: see text] for spatial-temperature readings, while a small array size is maintained. Thus, a major impediment to the expansive application of these sensors is efficiently resolved. To realize fast and accurate interpretation of the sensor data, a neural network (NN) is trained and employed for temperature predictions. This successfully accounts for potential crosstalk between adjacent sensors. The spatial-temperature resolution is investigated with a specially-printed silver micro-heater structure. Ultimately, a fairly high spatial temperature prediction accuracy of 1.22 °C is attained.


Clinical experience with gossypol in non-Chinese men: a follow-up.
Gossypol monoacetic acid was administered to 12 Brazilian volunteers. The initial dose was 20 mg daily for 4 months. The dose was then reduced to 60 mg weekly (20 mg three times weekly). A significant reduction in sperm motility was detected in all subjects. An increase in the number of immature cells in the ejaculate was also detected in all subjects. Severe oligospermia or azoospermia developed in all subjects at the end of the loading phase. Two years following discontinuation, 3 men were still azoospermic. Only 1 man who was azoospermic 2 years after discontinuation had a late (3 years) recovery. Two of the 3 men who were subjected to high spermatic vein ligation because of varicocele remained azoospermic 2 years after the operation. The third patient, who did not have the operation, also remained azoospermic. Of the 9 patients who recovered, 3 had fathered children during the last 2 years.


G-proteins and phospholipase activation in endothelial cells.
ATP stimulates arachidonic acid release and prostaglandin biosynthesis (most likely via phospholipase A2 (PLA2) activation) and phospholipase C (PLC) activation in cultured rabbit coronary microvessel endothelial cells. Pertussis toxin pretreatment inhibits ATP stimulated prostaglandin release, but not ATP stimulated phosphatidylinositol turnover. In contrast, activation of G-proteins with GTP tau S or AlF4- stimulates both prostaglandin synthesis and PLC. These observations suggest that PLC activation by ATP involves a G-protein(s) that is not ADP-ribosylated by pertussis toxin and further, that ATP activation of prostaglandin biosynthesis appears to involve a different, pertussis toxin sensitive, G-protein.


An in vivo insight to the toxicological profile of various organotellurides.
In this study we have examined the in vivo toxic effects of various organochalcogens on hepatic, renal, glycemic and lipid profile. Diorganotellurium dichloride phosphonate (C1) at all tested doses did not modify serum alanine aminotransferase (ALT) activity in mice. While, 2-butyltellurium furan (C2) and dinaphthalene ditelluride (C3) at a dose of 0.75 and 0.125 mmol/kg caused an increase in aspartate aminotransferase (AST) and ALT activities. Our data showed that C1 caused an increase in urea content at different doses while treatment with C2 and C3 did not modify urea content. Treatment with C2 caused a significant alteration in serum glucose and fructosamine levels which explains the possible toxicity of these compounds. No significant changes were observed for cholesterol and triglycerides levels. These results suggest that organochalcogen compounds presented liver and renal toxicity and also altered glycemic profile which may leads to various clinical complications.


Enterovirus 71 encephalomyelitis and Japanese encephalitis can be distinguished by topographic distribution of inflammation and specific intraneuronal detection of viral antigen and RNA.
To investigate if two important epidemic viral encephalitis in children, Enterovirus 71 (EV71) encephalomyelitis and Japanese encephalitis (JE) whose clinical and pathological features may be nonspecific and overlapping, could be distinguished. Tissue sections from the central nervous system of infected cases were examined by light microscopy, immunohistochemistry and in situ hybridization. All 13 cases of EV71 encephalomyelitis collected from Asia and France invariably showed stereotyped distribution of inflammation in the spinal cord, brainstem, hypothalamus, cerebellar dentate nucleus and, to a lesser extent, cerebral cortex and meninges. Anterior pons, corpus striatum, thalamus, temporal lobe, hippocampus and cerebellar cortex were always uninflamed. In contrast, the eight JE cases studied showed inflammation involving most neuronal areas of the central nervous system, including the areas that were uninflamed in EV71 encephalomyelitis. Lesions in both infections were nonspecific, consisting of perivascular and parenchymal infiltration by inflammatory cells, oedematous/necrolytic areas, microglial nodules and neuronophagia. Viral inclusions were absent. Immunohistochemistry and in situ hybridization assays were useful to identify the causative virus, localizing viral antigens and RNA, respectively, almost exclusively to neurones. The stereotyped distribution of inflammatory lesions in EV71 encephalomyelitis appears to be very useful to help distinguish it from JE.


Promises and challenges of fluorescence cystoscopy.
Fluorescence based photodynamic diagnostic (PDD) techniques have been developed to improve detection and treatment of non-muscle invasive bladder cancer. The goal of this article is to evaluate the promises and challenges of blue light cystoscopy. The literature was reviewed regarding articles pertaining to fluorescent cystoscopy and blue light cystoscopy (BLC). Blue light cystoscopy improves detection of bladder cancer tumors especially CIS. Randomized trials have demonstrated a reduction of recurrences. BLC has been demonstrated to be safe and effective in treatment of NMIBC of varying risk. The main obstacle to BLC will be adoption by urologists. Purchase cost of capital equipment may impact usage especially if adopted for outpatient clinics. BLC has been demonstrated to be safe and effective in treatment of NMIBC of varying risk. The reduction of recurrences and yet unproven but potential reduction in progression should be viewed favorably by urologists and patients. The main obstacle to BLC will be adoption by urologists who can put pressure on hospitals to acquire the capital equipment and who will seek the training to become proficient in using the technology. Patient demand for the technology may also help increase availability. Finally, the companies involved with BLC need to support trials that will demonstrate reduction in progression and that will answer the practical issues regarding usage in proximity to BCG and repeated usage.


Reducing children's pain and distress towards flu vaccinations: a novel and effective application of humanoid robotics.
Millions of children in North America receive an annual flu vaccination, many of whom are at risk of experiencing severe distress. Millions of children also use technologically advanced devices such as computers and cell phones. Based on this familiarity, we introduced another sophisticated device - a humanoid robot - to interact with children during their vaccination. We hypothesized that these children would experience less pain and distress than children who did not have this interaction. This was a randomized controlled study in which 57 children (30 male; age, mean±SD: 6.87±1.34 years) were randomly assigned to a vaccination session with a nurse who used standard administration procedures, or with a robot who was programmed to use cognitive-behavioral strategies with them while a nurse administered the vaccination. Measures of pain and distress were completed by children, parents, nurses, and researchers. Multivariate analyses of variance indicated that interaction with a robot during flu vaccination resulted in significantly less pain and distress in children according to parent, child, nurse, and researcher ratings with effect sizes in the moderate to high range (Cohen's d=0.49-0.90). This is the first study to examine the effectiveness of child-robot interaction for reducing children's pain and distress during a medical procedure. All measures of reduction were significant. These findings suggest that further research on robotics at the bedside is warranted to determine how they can effectively help children manage painful medical procedures.


Aerosol dilution as a new sample introduction strategy for microwave-induced plasma optical emission spectrometry.
A new sample introduction method using aerosol dilution for microwave-induced plasma optical emission spectrometry (MIP OES) is presented. Signal emissions from N2+ and OH species were monitored for plasma diagnostics and quantity of solvent plasma load (QSPL). The N2+/OH signal intensity ratio demonstrated that aerosol dilution is a desolvation process which can reduce the QSPL, increasing plasma energy. Efficiency of the system was observed with solutions containing the easily ionizable element (EIE) Na, without important alteration of the plasma physics at concentrations up to 5 g L-1. Atomic and ionic lines of Cr, Mn, V and Zn in saline solutions proved to have distinct variations. Despite the lower amount of analyte introduced, the LOQs of these elements were similar to the ones obtained from conventional nebulization. The analysis of two CRMs (fertilizer, NIST 695 and tomato leaves, NIST 1573a) resulted in percentage recoveries within 90-130%. Aerosol dilution in MIP OES (AD-MIP OES) brings increased robustness to the technique, once complex matrices can be introduced with the advantage of suppressing matrix interferences. Additionally, the sample is less prone to dilution error, and costs are saved due to increased life span of consumables since less sample matrix is introduced in the plasma.


Enhanced inhibition of Aspergillus niger on sedge (Lepironia articulata) treated with heat-cured lime oil.
This study aimed to examine heat curing effect (30-100°C) on antifungal activities of lime oil and its components (limonene, p-cymene, β-pinene and α-pinene) at concentrations ranging from 100 to 300 μl ml(-1) against Aspergillus niger in microbiological medium and to optimize heat curing of lime oil for efficient mould control on sedge (Lepironia articulata). Broth dilution method was employed to determine lime oil minimum inhibitory concentration, which was at 90 μl ml(-1) with heat curing at 70°C. Limonene, a main component of lime oil, was an agent responsible for temperature dependencies of lime oil activities observed. Response surface methodology was used to construct the mathematical model describing a time period of zero mould growth on sedge as functions of heat curing temperature and lime oil concentration. Heat curing of 90 μl ml(-1) lime oil at 70°C extended a period of zero mould growth on sedge to 18 weeks under moist conditions. Heat curing at 70°C best enhanced antifungal activity of lime oil against A. niger both in medium and on sedge. Heat curing of lime oil has potential to be used to enhance the antifungal safety of sedge products.


The interaction of platinum complexes with nucleosomes investigated with fluorescent probes.
The fluorescent probes, N,-(3-pyrene)maleimide, which is specific for histone H3, and terbium (Tb3+), which is specific for guanine single-stranded residues in DNA, are used to investigate the interaction of platinum complexes (cis- and trans-dichlorodiammineplatinum(II)) with rat liver and calf thymus nucleosomes. At low concentrations of the drug, lower than most of those reported previously in studies investigating the interaction of the drugs with isolated DNA, N-(3-pyrene)maleimide studies show that profound modifications occur near or in the cysteinyl binding site of histone H3. H3 dimer formation appears to be the cause of the change induced by trans-DDP; however, the effects observed with the cis-isomer do not seem to be correlated with dimer formation. At short incubation times, Tb3+ fluorescence shows small changes in DNA conformation, but they are slight when compared to the effect observed with proteins at the same length of incubation. SDS-polyacrylamide gels indicate some changes in protein composition, and agarose gels display a decrease in ethidium bromide staining of the cis-treated DNA. The results suggest that the protein portion, predominantly histone H3, as well as DNA are targets for the platinum derivatives in the nucleosome.


WITHDRAWN: Minocycline hydrochloride combined with invisible and fixed orthodontic treatment improves periodontal health in periodontitis patients by reducing microRNA-146a levels.
This article has been withdrawn at the request of the authors. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.


Effects of different energy density low-level laser therapies for temporomandibular joint disorders patients: a systematic review and network meta-analysis of parallel randomized controlled trials.
To compare the effects of different energy density LLLT on TMD patients' pain reduction. Reviewers searched RCTs published in Embase, PubMed and The Cochrane Library before 1 April 2020. Reviewers included parallelRCTs that compared the effects of LLLT with placebo or different energy density LLLT for TMD patients' pain reduction. Reviewers did network meta-analysis and evaluated the quality of evidence using the GRADE process. From 352 studies, reviewers included 16 RCTs. Immediately after treatment, the d1 laser therapy (energy density ranging from 0 to 10 J/cm2) ranked first. The d1 laser therapy showed more pain reduction than placebo ( MD = 2.49, 95% CI ranging from 1.28 to 3.71). The quality of "d1 vs p" comparison was assessed as "moderate" quality. A month after treatment, the d1 laser therapy also performed better than placebo (MD = 1.69, 95%CI = [-0.78, 4.16]). The quality of secondary outcome was assessed as "low" quality. For clinical application, d1 laser therapy (energy density ranging from 0 to 10 J/cm2) is recommended for short-term pain management of TMD patients (moderate quality evidence). A month after treatment, the d1 laser therapy also performed better than placebo and other laser groups but the result didn't reach the point of statistical significance (low quality evidence). PROSPERO-CRD42018118313.


Intrathecal drug delivery in the management of chronic pain.
Targeted intrathecal drug delivery (TIDD) has the objective of bringing the drug(s) close to the receptors influencing pain modulation, and thus reducing the dose and the side effects. Intrathecal drug delivery knew its real start with the development of permanent implantation of intrathecal and epidural catheters, combined with internal or external ports, reservoirs, and programmable pumps. TIDD is a valuable treatment for patients with cancer suffering refractory pain. Patients suffering noncancer-related pain should only be considered for TIDD when all other options have been tested, including spinal cord stimulation. Only two drugs are approved by the US Food and Drug Administration for TIDD administration for chronic pain: morphine and ziconotide as monotherapy. In pain management, off-label use of medication and combination therapy is often reported. The specific action of the intrathecal drugs, the efficacy and safety, is described, as well as the modalities for trialing intrathecal drug delivery and the implantation methods.


Isolation and identification of active compounds from Drimys winteri barks.
The barks of Drimys winteri are used in folk medicine as a remedy to treat several diseases, including dolorous processes. Previous pre-clinical experiments carried out in our laboratories revealed that the hydroalcoholic extract of this plant showed anti-allergenic, anti-inflammatory and antinociceptive properties. Such promising results led us to determine the analgesic compounds present in D. winteri. Through conventional chromatographic procedures with fractions of CH2Cl2 and EtOAc obtained from methanolic extract, it was found that polygodial (1), 1-beta-(p-methoxycynnamyl) polygodial (2), taxifolin (3) and astilbin (4), are the main components of these fractions. Compounds 1 and 2 exhibited marked antinociceptive action by intraperitoneal and oral routes against acetic acid-induced abdominal constrictions in mice, suggesting that they are responsible, at least partially, for the antinociceptive effects of this plant. In addition, both compounds were notably more potent than aspirin and acetaminophen, two well-known drugs used here as comparison.


Quantitative and qualitative features of acute phase-adverse events following SARS-CoV-2 vaccination in a large sample of people with multiple sclerosis.
Few data are available on adverse events (AE) associated to vaccines in persons with multiple sclerosis (pwMS). to study the incidence of acute phase AE (AP-AE) related to SARS-CoV-2 mRNA vaccines in pwMS compared to a control group, and to analyze the association between AP-AE and disease modifying treatments (DMT). This was a cross-sectional study on 438 PwMS and 481 age- and sex-matched subjects not affected by dysimmune diseases that underwent two doses of SARS-CoV-2 mRNA BNT162b2 vaccine (Pfizer/BioNtech). Two hundred and twenty five (51.4%) pwMS complained of ≥1 AP-AE after the first dose, 269 (61.4%) after the second dose. A logistic regression analysis revealed that only pwMS on Fingolimod and Ocrelizumab did not show a higher risk of developing AP-AE. The likelihood to present with ≥1 AP-AE, after correcting for age and sex, was significantly higher in pwMS than controls. This study reports qualitative and quantitative features of AP-AE associated with the first and second doses of SARS-CoV-2 vaccine in a large sample of pwMS. The only risk factor identified for developing AP-AE is female gender. AntiCD-20 monoclonal antibodies and S1P inhibitors are associated with a lower risk of AP-AE occurrence.


Photoinduced Reversible Bending and Guest Molecule Release of Azobenzene-Containing Polydiacetylene Nanotubes.
Creation of hollow, one-dimensional nanomaterials has gained great recent attention in the chemical and material sciences. In a study aimed at discovering new functional materials of this type, we observed that an amphiphilic diacetylene (DA) derivative, containing an azobenzene moiety and an oligo-ethylene group, self-assembles to form nanotubes and undergoes photopolymerization to form hollow polydiacetylene (PDA) nanotubes with a uniform wall thickness and diameter. The azobenzene-PDA nanotubes are photoresponsive in that on-and-off UV-irradiation leads to a reversible morphological change between straight and bent forms in association with E-Z photoisomerization of the azobenzene group. Owing to the UV-induced structural change feature, the new DA and PDA nanotubes serve as a controlled release material. Accordingly, fluorescent rhodamine B encapsulated inside the nanotubes are effectively released by using repeated on-off UV irradiation. Furthermore, photo-release of rhodamine B was shown to occur in an artemia (brine shrimp).


Neutrophil extracellular chromatin traps connect innate immune response to autoimmunity.
Autoantibodies to DNA and histones (chromatin) are the defining antigen specificity in systemic lupus erythematosus (SLE) and related musculoskeletal disorders but the mechanisms responsible for their induction remain mysterious. That situation rapidly changed once neutrophil extracellular chromatin traps (NETs) were discovered and observed to play a conserved role in innate immune responses to a broad variety of microbial pathogens. At the center of an infectious process, neutrophils exert various antimicrobial defenses, including the release of nuclear chromatin into the extracellular space. The externalized NETs, a complex meshwork of nuclear chromatin and antimicrobial proteins, serve to immobilize and degrade microbial pathogens. Here, we critically evaluate the evidence supporting NETs versus apoptotic bodies as a source for nuclear antigens in autoimmunity. We also discuss the possibility that NET chromatin forms an essential component of immune deposits in the pathogenesis of glomerulonephritis in SLE and other autoimmune immune complex diseases.


Irrelevant speech, changing state, and order information.
The changing state effect is the finding that a stream of irrelevant sounds that change more (e.g., different digits in random order) disrupts memory more than a stream of irrelevant sounds that change less (e.g., a single digit repeated over and over). According to the Object-Oriented Episodic Record (O-OER) model, the changing state effect will be observed only in memory tasks that have an order component or which induce serial rehearsal or serial processing. In contrast, other accounts-including the Feature Model, the Primacy Model, and various attentional theories-predict that the changing state effect should be observable when there is no order component. Experiment 1 first demonstrated that the irrelevant stimuli created for the current experiments produced a changing state effect in immediate serial recall in both on-campus and online samples. Then, three experiments assessed whether a changing state effect is observable in a surprise 2AFC recognition test. Experiment 2 replicated Stokes and Arnell (2012, Memory & Cognition, 40, 918-931), who found that although irrelevant sounds reduce performance on a surprise recognition test of words presented previously in a lexical decision task, they do not produce a changing state effect. Experiments 3 and 4 used two different encoding tasks (pleasantness and frequency judgment) and also found no changing state effect. The results support the prediction of the O-OER model and provide additional evidence against the other accounts.


Human plasma protein binding of the angiotensin II receptor antagonist losartan potassium (DuP 753/MK 954) and its pharmacologically active metabolite EXP3174.
The in vitro protein binding characteristics of the prototypical angiotensin II receptor antagonist losartan potassium (DuP 753/MK 954) and its pharmacologically active metabolite EXP3174 were determined by ultrafiltration with plasma from naive donors, volunteers dosed with losartan, and purified human plasma proteins. The binding of losartan was high, with a percent unbound (free) of 1.4 +/- 0.2% to 1.2 +/- 0.1% at concentrations ranging from 0.5 to 5.0 micrograms/mL; that is, approximately 98.6 to 98.8% bound. EXP3174 was more highly bound than losartan (P < .05) with 0.2 +/- 0.0% free at concentrations ranging from 0.1 to 10.0 micrograms/mL; or, greater than 99.7% bound. The binding in the plasma from volunteers given oral losartan was similar to that determined with plasma from naive donors, with 1.5 +/- 0.3 versus 1.4 +/- 0.1% free for losartan, and 0.5 +/- 0.1 versus 0.4 +/- 0.0% for EXP3174, respectively. This extensive plasma binding of both acidic compounds occurs primarily to albumin, with negligible binding to the alpha 1-acid glycoprotein. Although highly bound, neither losartan nor EXP3174 were displaced in vitro by pharmacologically relevant concentrations of non-steroidal antiinflammatory drugs (NSAIDs), warfarin, or diazepam; however, suprapharmacologic concentrations of the NSAIDs increased the free fraction of both compounds. These data show that the angiotensin II receptor antagonists losartan and EXP3174 are highly bound to plasma albumin in humans, although clinically significant drug interactions due to displacement from binding sites are unlikely.(ABSTRACT TRUNCATED AT 250 WORDS)


[Cancer of the cervix uteri in pregnancy: surgical treatment with conservation of the ovaries. Clinical case].
Authors report the case of 32 years old pregnant woman, who at the VI month of pregnancy developed an invasive carcinoma of the cervix uteri. It is hypothesized that surgical therapy according to Weirtheim-Meigs, without bilateral ovariectomy, consent the conservation of the reproductive function in the young women thought the development of the artificial insemination technics.


Small intestinal stromal tumors with skeinoid fibers in neurofibromatosis: report of four cases with ultrastructural study of skeinoid fibers from paraffin blocks.
Small intestinal stromal tumors (SIST) with skeinoid fibers (SF) are reported in four patients with neurofibromatosis. SF appeared as intercellular eosinophilic globules that stained positively on periodic acid-Schiff stain and bluish on Masson trichrome stain, like those reported previously. Electron microscopic confirmation of SF was carried out on tissue retrieved from paraffin blocks, which revealed diagnostic ultrastructural features of SF. The association of SIST with SF and neurofibromatosis enhances the diagnostic value of SF as a marker of neurogenic spindle cell tumors. This study also underscores the importance of electron microscopy for differentiation of SF from pseudoskeinoid structures, which may mimic SF on light microscopic examination.


The social life of the dead: The role of post-mortem examinations in medical student socialisation.
Dissection has held a privileged position in medical education although the professional values it inculcates have been subject to intense debate. Claims vary from it generating a dehumanising level of emotional detachment, to promotion of rational and dispassionate decision-making, even to being a positive vehicle for ethical education. Social scientists have positioned dissection as a critical experience in the emotional socialisation of medical students. However, curricular revision has provoked debate about the style and quantity of anatomy teaching thus threatening this 'rite of passage' of medical students. Consequently, some UK medical schools do not employ dissection at all. In its place, observation of post-mortem examinations - a long established, if underutilised, practice - has re-emerged in an attempt to recoup aspects of anatomical knowledge that are arguably lost when dissection is omitted. Bodies for post-mortem examinations and bodies for dissection, however, have striking differences, meaning that post-mortem examinations and dissection cannot be considered comparable opportunities to learn anatomy. In this article, we explore the distinctions between dissection and post-mortem examinations. In particular, we focus on the absence of a discourse of consent, concerns about bodily integrity, how the body's shifting ontology, between object and person, disrupts students' attempts to distance themselves, and how the observation of post-mortem examinations features in the emotional socialisation of medical students.


Congenital giant hairy nevus: implications for treatment.
Congenital giant hairy nevi represent a special group of melanocytic lesions which generally cover large areas of the body surface. Giant hairy nevi assume special significance because of their predisposition to malignant transformation. Adequate treatment of this lesion involves complete surgical excision as early in the child's life as possible.


Complications and hospitalization costs in patients with hypothyroidism following total hip arthroplasty.
Hypothyroidism is a common disease in the US population. The impact of hypothyroidism on perioperative complications of total hip arthroplasty is poorly understood. To examine risk factors and hospitalization costs in patients with hypothyroidism after total hip arthroplasty (THA) using a large-scale sample national database. A case-control study was performed based on the national inpatient sample database from 2005 to 2014. With the use of propensity scores, patients with hypothyroidism were matched in a 1:1 ratio to those without hypothyroidism by age, gender, race, Elixhauser Comorbidity Index (ECI), and insurance type. Patient demographics, postoperative complications, length of stay (LOS), and hospital costs were compared between matched cohorts. Short-term complication rates after THA were compared using multivariate logistic analysis. The proportion of patients with hypothyroidism receiving THA was 12.97%. Linear regression analysis yielded that patients with hypothyroidism receiving THA were more likely to have postoperative acute anemia (odds ratio = 1.15; 95% confidence interval = 1.12-1.18) and higher mean hospital costs compared to the non-hypothyroid cohort. This present study demonstrates that hypothyroid patients undergoing THA have a higher risk of short-term complications. Furthermore, it significantly increased the total cost of hospitalization, which deserves more attention from orthopedic surgeons.


Prevalence, consequences of female genital mutilation among asylum seekers in Ile-de-France and socio-demographic characteristics
Female Genital Mutilation (FGM) is an intervention on the female genital organs for non-medical reasons. In France, asylum is possible for girls at risk of FGM in their country of origin. The procedure includes a forensic examination of the child. To describe the prevalence of FGM and the sociodemographic characteristics of girls and their mothers examined at the Department of Forensic Medicine of Paris. Between 2018 and 2021, 2422 family interviews were conducted. The mothers were mainly from Côte d'Ivoire, Mali, and Guinea Conakry. A FGM was found in 84.4% of the 1838 women examined, mostly of type IIb. The mothers reported immediate complications (21.2%: hemorrhage, pain) and long-term complications (31.8%: sexual disorders, obstetrical complications) due to these FGM. The families often included several children, and 3307 girls were examined. They were mostly born in France (72.0%). An FGM was identified in 61 of these girls (1.8%, mostly type IIb); it was already known by the family in half of the cases. Three of these girls were born in Europe. FGM is a public health problem on a global scale, but also in France due to migratory pathways. This descriptive study carried out an initial medical assessment of FSM in female asylum seekers examined at the Department of Forensic Medicine of Paris, and difficulties in the diagnosis of FSM. Other studies are useful to corroborate and compare our results.


Prevalence and subtype distribution of early-onset dementia in Japan.
People living with early-onset dementia (EOD) have specific social needs. Epidemiological studies are needed to obtain current information and provide appropriate service planning. This study aimed to clarify the current prevalence and subtype distribution of EOD, as well as the services frequently used by individuals with EOD. A multisite, population-based, two-step study was conducted. Questionnaires were sent to 26 416 candidate facilities in 12 areas with a target population of 11 630 322 to inquire whether any individuals with EOD had sought services or stayed during the last 12 months (step 1). When "yes" responses were received, additional questionnaires were sent to the facilities both to complete and to distribute to the target individuals with EOD to obtain more detailed information, including the dementia subtype (step 2). In step 1, valid responses were obtained from 16 848 facilities (63.8%), and 4077 cases were identified. In step 2, detailed information was obtained for 1614 cases (39.6%) from the facilities and 530 cases (13.0%) from the individuals. The national EOD prevalence rate was estimated to be 50.9/100 000 population at risk (95% confidence interval: 43.9-57.9; age range, 18-64 years). The number of individuals with EOD was estimated to be 35 700 as of 2018. Alzheimer-type dementia (52.6%) was the most frequent subtype, followed by vascular dementia (17.1%), frontotemporal dementia (9.4%), dementia due to traumatic brain injury (4.2%), dementia with Lewy bodies/Parkinson's disease dementia (4.1%), and dementia due to alcohol-related disorders (2.8%). Individuals with EOD were most frequently identified at medical centers for dementia. The prevalence rate estimated in this study was comparable to those in previous studies in Japan. However, the subtype distribution differed, with Alzheimer-type dementia being the most prominent. Based on the case identification frequencies, medical centers for dementia are expected to continue to function as the primary special health service by providing quality diagnosis and post-diagnostic support for individuals with EOD.


A concise synthesis of marine natural product (-)-15-oxopuupehenol from (+)-sclarelide.
A step-economical synthesis of (-)-15-oxopuupehenol from cheap and readily available (+)-sclarelide is achieved with 20.3% overall yield in 9 steps. The key features of this synthetic mythology include a palladium catalyzed tandem carbine migratory insertion reaction to construct the key skeleton, a DDQ-mediated isomerization/oxidation of allyl alcohol to afford α, β-unsaturated ketone, and a NaOH-induced intramolecular Michael addition followed by acetonide deprotection to give (-)-15-oxopuupehenol.


Fluctuations in prey availability and food limitation for a terrestrial salamander.
A Virginia population of the forest-dwelling salamander Plethodon cinereus was repeatedly sampled over four years to determine volume and number of prey ingested under varying conditions of moisture and temperature. The proportion of the population on a daily negative energy budget was estimated by comparing actual foraging success with laboratory determined values of energetic requirements at various temperatures.Prey became "limited" in availability during rainless periods, apparently because salamanders were not able to forage in dry leaf litter. Foraging success increased with increasing rainfall. Food was a "limiting" resource for a majority of the population on most sampling days, as determined by energy budget analysis. While ambient moisture regulated food availability, ambient temperature set the metabolic requirements and assimilation efficiencies for the population. Consequently, food was more limiting on dry, warm days and less so on wet, cool days. These data support the hypothesis that intraspecific competition frequently occurs for a food resource that is periodically limited in availability.


Nefiracetam ameliorates associative learning impairment in the scopolamine-injected older rabbit.
The cognition-enhancing drug, nefiracetam, is in Phase III clinical trials to treat memory impairment in Alzheimer's disease (AD). Nefiracetam ameliorates acquisition of delay eyeblink classical conditioning in older rabbits, a form of associative learning with striking behavioral and neurobiological similarities in rabbits and humans. In both species, delay eyeblink conditioning engages the septo-hippocampal cholinergic system and is disrupted when the cholinergic system is antagonized. Delay eyeblink classical conditioning is impaired in normal aging and severely disrupted in AD. To test further the efficacy of nefiracetam in an animal model that mimics some of the neurobiological and behavioral effects present in AD, we tested 56 older rabbits assigned to 7 treatment groups in the 750 ms delay eyeblink conditioning procedure. Older rabbits were injected with 1.5 mg/kg scopolamine to simulate disruption of the cholinergic system in AD. Three doses of nefiracetam (5, 10, or 15 mg/kg) were also injected in older rabbits receiving 1.5 mg/kg scopolamine. Control groups were treated with 1.5 mg/kg scopolamine + vehicle, vehicle alone, or explicitly unpaired presentations of conditioning stimuli and vehicle or 1.5 mg/kg scopolamine + 15 mg/kg nefiracetam. Rabbits injected with 1.5 mg/kg scopolamine alone were impaired, but a dose of 15 mg/kg nefiracetam reversed significantly the behavioral impairment. Nefiracetam had ameliorating effects on a task impaired in AD in an animal model of AD: older rabbits with cholinergic system antagonism.


Sigma-2 ligands induce tumour cell death by multiple signalling pathways.
The sigma-2 receptor has been identified as a biomarker of proliferating cells in solid tumours. In the present study, we studied the mechanisms of sigma-2 ligand-induced cell death in the mouse breast cancer cell line EMT-6 and the human melanoma cell line MDA-MB-435. EMT-6 and MDA-MB-435 cells were treated with sigma-2 ligands. The modulation of multiple signaling pathways of cell death was evaluated. Three sigma-2 ligands (WC-26, SV119 and RHM-138) induced DNA fragmentation, caspase-3 activation and PARP-1 cleavage. The caspase inhibitor Z-VAD-FMK partially blocked DNA fragmentation and cytotoxicity caused by these compounds. These data suggest that sigma-2 ligand-induced apoptosis and caspase activation are partially responsible for the cell death. WC-26 and siramesine induced formation of vacuoles in the cells. WC-26, SV119, RHM-138 and siramesine increased the synthesis and processing of microtubule-associated protein light chain 3, an autophagosome marker, and decreased the expression levels of the downstream effectors of mammalian target of rapamycin (mTOR), p70S6K and 4EBP1, suggesting that sigma-2 ligands induce autophagy, probably by inhibition of the mTOR pathway. All four sigma-2 ligands decreased the expression of cyclin D1 in a time-dependent manner. In addition, WC-26 and SV119 mainly decreased cyclin B1, E2 and phosphorylation of retinoblastoma protein (pRb); RHM-138 mainly decreased cyclin E2; and 10 μM siramesine mainly decreased cyclin B1 and pRb. These data suggest that sigma-2 ligands also impair cell-cycle progression in multiple phases of the cell cycle. Sigma-2 ligands induce cell death by multiple signalling pathways.


Preparation and solid-state characterization of ball milled saquinavir mesylate for solubility enhancement.
Saquinavir is an anti-retroviral drug with very low oral bioavailability (e.g. 0.7-4.0%) due to its affinity toward efflux transporters (P-gp) and metabolic enzymes (CYP3A4). The aim of this study was to characterize the effects of high-energy ball milling on saquinavir solid-state characteristics and aqueous solubility for the design of effective buccal drug delivery systems. The solubility of saquinavir mesylate was evaluated in simulated saliva before and after milling for 1, 3, 15, 30, 50, and 60 h. To elucidate changes in crystallinity and long-range structure in the drug, analyses of the milled powders were performed using XRD, ATR-IR, DSC/TGA, BET surface area, EDX and SEM. In addition, the effects of milling time on saquinavir solubility were statistically correlated using repeated measures ANOVA. Results of this study indicate that the milling of saquinavir mesylate produces nanoporous particles with unique surface structures, thermal properties, and increased aqueous solubility. Optimal milling time occurred at 3h and corresponded to a 9-fold solubility enhancement in simulated saliva. Thermal analysis revealed only a slight decrease in melting point (T(m)) from 242 °C to 236 °C after 60 h milling. XRD diffractograms indicate a gradual crystalline-to-amorphous transition with some residual crystallinity remaining after 60 h milling time. Unstable polymorphic structures appeared between 15 and 30 h which were converted to more stable isomorphs at 60 h. Aggregate formation also seems to occur after 15 h but no metal contamination of the drug was observed during the milling process as determined by EDX analysis. In conclusion, high-energy ball milling may be a method of choice for improving the solubility of saquinavir and facilitating novel drug formulations design.


Life-history traits of the lizard Sceloporus undulatus from two populations raised in a common laboratory environment.
Hatchling Sceloporus undulatus elongatus from Washington Co., Utah and S. u. garmani from Woods Co., Oklahoma were raised to maturity and reproduction under identical laboratory conditions with ad libitum food availability. Growth, allometry, age and size of maturity, clutch size and egg mass were compared among lab-raised cohorts from the two populations, among lab-raised and field-caught animals (including their field-caught mothers) and, for growth, with values obtained by previously published field studies on the same or nearby populations. For all traits population differences observed in previous field studies and current field samples resulted from both a plastic response to proximate environmental conditions and intrinsic (possibly genetic) difference. The most plastic traits were growth and age of maturity. Cohorts from both populations expressed the ability to mature in less than 6 months in the laboratory but only the S.u. garmani express early maturity in the field. Allometric differences generated during growth in the lab were not observed in field samples but may reflect an adaptive physiological difference. The least plastic trait was egg mass. The only trait for which the rank order of the difference in the field was reversed in the lab was growth rate. S.u. elongatus grew significantly faster than S.u. garmani in the lab but much slower in the field. The tendency of S.u. garmani females to breed at minimum size of maturity may be greater than that of S.u. elongatus.


Hypomethylation mediated by decreased DNMTs involves in the activation of proto-oncogene MPL in TK6 cells treated with hydroquinone.
Hydroquinone (HQ), one of the most important metabolites derived from benzene, is known to be associated with acute myelogenous leukemia (AML) risk, however, its carcinogenic mechanism remains unclear. In this study, the epigenetic mechanism of HQ exposure was investigated. We characterized the epigenomic response of TK6 cells to HQ exposure, and examined the mRNA expression of DNA methyltransferases (DNMTs) including DNMT1, DNMT3a and DNMT3b, methyl-CpG-binding domain protein 2 (MBD2) and six proto-oncogenes (MPL, RAF1, MYB, MYC, ERBB2 and BRAF). Compared to the control cells, HQ exposure (2.5, 5.0, 10.0 and 20.0 μM for 48 h) resulted in the decrease of DNMTs and MBD2 expression, the global hypomethylation and increase of MPL at mRNA level. Meanwhile, most of these changes were in dose-dependent manner. Moreover, inhibition of DNMTs induced by 5-aza-2'-deoxycytidine (5-AZA), an identified DNMT inhibitor, caused more induction of MPL expression at mRNA level compared to the HQ (10.0 μM) pre-treated group. Furthermore, treatment of HQ potentially led to MPL itself hypomethylation (10.0 and 20.0 μM reduced by 47% and 44%, respectively), further revealing that the activation of proto-oncogene MPL was related to hypomethylation in its DNA sequences. In conclusion, hypomethylation, including global and specific hypomethylation, might be involved in the activation of MPL, and the hypomethylation could be induced by decreased DNMTs in TK6 cells exposed to HQ.


Staphylococcus aureus bloodstream infection: Secular changes associated with the implementation of a de novo clinical infectious diseases service in a Canadian population.
To investigate the epidemiology of Staphylococcus aureus bloodstream infections (BSI) in a mixed rural to small city population and examine secular changes associated with the implementation of a regional clinical infectious diseases program. Population-based surveillance for incident S. aureus BSI was conducted in the western interior of British Columbia, Canada between April 2010 and March 2020. An infectious diseases service was progressively implemented starting in 2013. 581 incident S. aureus BSI were identified. There was an increasing incidence during the study and the overall age- and gender-adjusted annual rate was 32.9 per 100,000 population. Implementation of the infectious diseases program was associated with an increase in rates of blood culture sampling, documentation of persistent bacteremia, use of transthoracic and transesophageal echocardiography, and a reduction in cases of relapsed BSI. Infectious diseases consultation was independently associated with a reduced risk for death (odds ratio 0.5; 95% CI 0.3-0.9). Although the implementation of a clinical infectious diseases service was associated with changes in management and improved outcome, S. aureus BSI still causes a major burden of illness.


Rapid identification of Escherichia coli and Helicobacter pylori in biological samples by capillary zone electrophoresis.
The differences in surface charge of different bacteria can be exploited for their separation by capillary electrophoresis. However, this method of separation of microorganisms is beset with various drawbacks such as adhesion of bacteria to the fused silica surface or cluster formation. To overcome these phenomena we investigated the addition of poly(ethylene oxide) as a focusing agent to the running buffer and used calcium and myoinositol hexakisphosphate as specific ions that interact with the bacterial surface, changing its electrical properties and electrophoretic mobilities. In the present work, we applied CZE to identification of E. coli in infected urine (direct injection) from patients with urinary tract infections and to identification of Helicobacter pylori, which is a gram-negative bacillus responsible for one of the most common infections found in humans worldwide. Helicobacter pylori colonize the stomach and are responsible for severe diseases of the gastric tract, ranging from chronic gastric ulcer to gastric cancer.


TIM-3 Genetic Variations Affect Susceptibility to Osteoarthritis by Interfering with Interferon Gamma in CD4+ T Cells.
Osteoarthritis (OA) is the most common type of arthritis, in which T cell responses and cytokines may play critical roles in the development of the disease. TIM-3 may affect immune responses and is correlated with decreased expression of interferon gamma (INF-γ) in CD4+ T cells. In the current study, we investigated the association between polymorphisms in the TIM-3 gene and susceptibility to OA. Two polymorphisms in TIM-3, -574G/T and +4259T/G polymorphisms, were identified in OA cases and healthy donors by polymerase chain reaction-restriction fragment length polymorphism method. Data revealed that the prevalence of TIM-3 +4259T/G genotype was significantly elevated in OA patients than in the healthy donors after adjustment (Odds ratio [OR] = 2.67, 95% confidence interval [CI] 1.32-5.11, P < 0.001). Similarly, the TIM-3 +4259G allele presented a positive association with the risk of OA after adjustment (OR = 2.58, 95% CI 1.29-4.82, P = 0.003). The TIM-3 -574G/T polymorphism did not show any correlation with the disease. We further examined whether the two TIM-3 polymorphisms could affect INF-γ expression in CD4+ T cells. Data revealed that subjects carrying polymorphic +4259TG genotype had significantly higher mRNA and protein levels of INF-γ in CD4+ T cells compared to wild-type GG genotype (P < 0.001 and P < 0.01). These results indicated that TIM-3 polymorphism is associated with increased susceptibility to OA possibly by upregulating INF-γ expression in CD4+ T cells.


[Team conflicts in connection with Katharina P].
The complex care of a terminal nursing home patient with a bowel obstruction tests general practitioner and nursing staff to their limits. It becomes apparent that challenging palliative patients can only be dealt with in a team setting.


Dysregulated systemic lymphocytes affect the balance of osteogenic/adipogenic differentiation of bone mesenchymal stem cells after local irradiation.
While it is known that irradiation can induce local and systemic bone loss over time, how focal irradiation induces systemic bone complications remains unclear. Immune cells are thought to be crucial to bone homeostasis, and abnormal immune cells lead to serious disruption of bone homeostasis, such as in acute lymphoblastic leukaemia. This disruption primarily occurs due to inhibition of the osteogenic differentiation of bone mesenchymal stem cells (BMSCs). In this study, we detected local and systemic bone loss in trabecular bone by micro-computed tomography (micro-CT) and measurement of peroxisome proliferator-activated receptor gamma (PPARγ) and runt-related transcription factor 2 (RUNX2) expression in BMSCs using real-time polymerase chain reaction and western blotting. Additionally, changes in lymphocytes (B cells and CD4+ and CD8+ T cells) in the peripheral blood and bone marrow were analysed by flow cytometry. BMSC-derived osteoblasts and adipocytes, cultured in osteogenic or adipogenic media or co-cultured with lymphocytes, were detected by BCIP/NBT, Alizarin Red S and Oil Red O staining. Focal irradiation induced local and systemic bone loss in trabecular bone. Increased PPARγ expression and decreased RUNX2 expression were observed, accompanied by upregulated adipogenesis and downregulated osteogenesis of BMSCs. B cells and CD8+ T lymphocytes were increased in the blood and bone marrow after irradiation, while CD4+ T lymphocytes were decreased in the blood. Inhibition of RUNX2 expression and reduction of alkaline phosphatase activity and mineralization deposits were observed in lymphocyte-co-cultured BMSCs, accompanied by an increase in PPARγ expression and in the number of lipid droplets. Focal irradiation induced local and systemic bone loss in trabecular bone. Increased B cells and CD8+ T lymphocytes led to systemic bone loss by decreasing BMSC osteogenesis.


Interhospital Transfer for the Management of Acute Pulmonary Embolism.
There are increasing treatment options for the management of acute pulmonary embolism (PE), though many are only available at tertiary care centers. Patients with acute pulmonary embolism with high-risk features are often transferred for consideration of such therapies. There are limited data describing outcomes in patients transferred with acute pulmonary embolism. We evaluated patients with acute pulmonary embolism at our tertiary care center from August 2012 through August 2018 and compared clinical characteristics, pulmonary embolism features, management, and outcomes in those transferred for acute pulmonary embolism to those that were not transferred. Of 2050 patients with pulmonary embolism included in the study, 432 (21.1%) were transferred from an outside hospital with a known diagnosis of pulmonary embolism. Patients transferred had a lower rate of malignancy (22.2% vs 33.3%; P < .001) and median Charlson comorbidity index (3 vs 4; P < .001). A higher percentage of patients transferred were classified as intermediate- or high-risk pulmonary embolism (62.5% vs 43.0%; P <.001) and more frequently received advanced therapy beyond anticoagulation alone (12.5% vs 3.2%, P < .001). Overall survival to discharge was similar between groups, though definite pulmonary embolism-related mortality was higher in the transferred group (38.5% vs 9.4%, P = .004). More than 1 in 5 patients treated for acute pulmonary embolism at a tertiary care center were transferred from an outside facility. Transferred patients had higher risk pulmonary embolism features, more often received advanced therapy, and had higher definite pulmonary embolism-related mortality. There are opportunities to further optimize outcomes of patients transferred for management of acute pulmonary embolism.


Low dose cyclophosphamide: Mechanisms of T cell modulation.
Cyclophosphamide is considered one of the most successful chemotherapy drugs and is listed on the World Health Organisations List of Essential Medicines. Since its initial synthesis in 1958, it has been widely used to treat a range of cancers but its use has been declining due to the advent of platinum based and other chemotherapy agents. However, cyclophosphamide is still used either as a single agent or as adjuvant therapy to treat lymphomas, and breast and ovarian cancers at much lower doses. The efficacy of low dose cyclophosphamide is primarily due to its ability to promote anti-tumour immunity, by selectively depleting regulatory T cells and enhancing effector T cell function. Compared to effecter T cells, regulatory T cells have metabolic adaptations that make them more susceptible to cyclophosphamide-mediated cytotoxicity. In this review, we highlight the potential for improving the efficacy of low dose cyclophosphamide by combining insights on the mechanisms of cyclophosphamide-mediated cytotoxicity, and how these cytotoxic effects of cyclophosphamide influence T cell function, thereby contributing to anti-tumour immunity.


Psychotropic effects of sidnocarb and ladasten in inbred mice with different reaction to emotional stress.
Dose-dependent relationship of the effects of sidnocarb and Ladasten on open field behavior and free motor activity was studied in inbred C57Bl/6 and BALB/c mice differing by emotional stress reaction phenotype. Ladasten in a dose of 10 mg/kg produced activating and anxiolytic effects on BALB/c mice in the open field test. Combined injection of Ladasten (10 mg/kg) and sidnocarb (6 or 12 mg/kg) activated animal behavior in both tests.


Identification and characterization of innate lymphoid cells generated from pluripotent stem cells.
Innate lymphoid cells (ILCs) play important roles in regulating tissue homeostasis and innate immune responses. Generation of ILCs after engraftment of pluripotent stem cell (PSC)-derived hematopoietic progenitors (iHPCs) has not yet been reported. Here, we document that ILCs exist in Rag2-/-Il2rg-/- recipients engrafted with PSC-derived iHPCs guided by Runx1 and Hoxa9 expression. Upon transplantation, iHPCs immediately give rise to ILC-related progenitors containing common helper ILC progenitors in the bone marrow, followed by a more restricted population named ILC progenitors, which are able to further differentiate into mature ILCs in the primary and secondary immunodeficient recipients. The PSC-derived ILCs exhibit multiple tissue distributions and normal immunological functions. Single-cell transcriptomics illustrates the developmental trajectory of PSC-derived ILCs in vivo, which is consistent with that of natural ILCs. Our study provides insights into the generation of ILCs in animals transplanted with PSC-derived iHPCs as a cell source.