Impact of ecosystem metabolism on CO2 emissions: Insights from high-resolution time series of pH measured in situ.
Lakes and reservoirs are important sources/sinks of atmospheric CO2. Primary production and respiration transforming inorganic to organic carbon and vice versa alter CO2 concentrations in the surface waters and thus affect CO2 emissions. Here we investigate the link between net-production (NEP) and CO2 concentrations and emissions at high temporal resolution over more than two months in a German pump storage reservoir. Continuous in-situ pH measurements in combination with few alkalinity measurements provided concentrations of CO2 and dissolved inorganic carbon (DIC) at high temporal resolution over more than 75 days. Time series of metabolic rates of carbon were determined with an open-water diel pH technique, which utilizes the diel changes in DIC obtained from the observed diel changes in pH and data on alkalinity. During the measuring period, average NEP was positive and CO2 concentrations were typically substantially under-saturated. On average, the reservoir acted as a sink for CO2, whereby CO2 uptake was 39% larger in the evening than in the morning. Only few consecutive days with negative NEP were sufficient to turn the reservoir temporally into a source of CO2. Therefore, the average CO2 uptake determined from continuous data can be 80% larger to 30% smaller than estimates of average uptake based on bi-weekly data. Daily mean NEP explained only 9% and 4% of the variance of daily mean DIC and CO2. Note that NEP is proportional to the time derivative of DIC and therefore not expected to correlate well with DIC in general. Because CO2 changes nonlinearly with DIC, NEP explains less variance of CO2 than of DIC. Numerical experiments confirmed the arguments above and revealed that at positive average NEP the total CO2 uptake over several weeks is not well predicted by average NEP but depends on the detailed temporal pattern of NEP. However, if average NEP is negative, average NEP may be a good predictor of total CO2 emissions. Similar conclusions apply for high and low alkalinity waters, but uptake rates and temporal variability of CO2 emissions are smaller in high than in low alkalinity waters. Assessment of the link between NEP and CO2 emissions requires differentiation between lakes with different alkalinity and, because of the non-linear relationship between NEP and CO2, strongly benefits from data with high temporal resolution especially during time-periods with positive net-production.


The mechanism of the changes in splanchnic blood flow after feeding.
Introduction of hydrolysed protein solution into the duodenum increased in the dog hepatic artery and portal venous blood flow. The reaction is, however, smaller than after the introduction of 0.1 N HCl. The introduction of 30% glucose solution has no effect an splanchnic circulation. Splanchnicotomy combined with coeliac ganglion denervation as well as the blockade of the sympathetic alpha receptors abolished the circulatory reaction. Both interventions leads, however, to a decrease is splanchnic vascular resistance similar to that observed after intraduodenal introduction of acid in normal dogs. It is concluded that the circulatory reaction occuring in consequence of the acidifying of duodenal contents after feeding is due to the reduction of abolition of the sympathetic vasomotor tone in the splanchnic vascular bed.


Identification of polydisperse RNA in the cytoplasm of neurons isolated from the immature brain cortex.
The cytoplasmic RNA of 10-day-old rats was studied in bulk-isolated, cortical neurons, obtained under conditions which minimize nuclear contamination. Two RNA fractions, one enriched rRNA and the other in "polydisperse" RNA, were obtained by differential extraction with phenol. Gel electrophoresis and pulse labelling with 5-[3H]uridine were used to confirm the delayed appearance of newly synthesized rRNA in the cytoplasm and to demonstrate its stability. "Polydisperse" RNA appeared in the cytoplasm earlier and had a shorter half-life than rRNA. A wide range of molecular weights for this RNA was found with no predominant individual species. A set of cytoplasmic RNA components of molecular size between 28S and 18S was also present probably reflecting the in vivo degradation of rRNA. The significance of the unexpectedly high amounts of neuronal polydisperse RNA is discussed.


Bloom development of toxic dinoflagellate Alexandrium catenella (Group I) in Jinhae-Masan Bay, Korea: Germination strategy of resting cysts in relation to temperature and salinity.
To better understand the role of resting cysts in the outbreak of paralytic shellfish poisoning and bloom dynamics in Jinhae-Masan Bay, Korea, this study investigated the germination features of ellipsoidal Alexandrium cysts isolated from sediments collected in winter and summer under different combinations of temperature and salinity. Morphology and phylogeny of germling cells revealed that the ellipsoidal Alexandrium cysts belong to Alexandrium catenella (Group I). The cysts could germinate across a wide range of temperature (5-25 °C) with germination success within 5 days, indicating that continuous seeding for the maintenance of vegetative cells in the water column may occur through the year without an endogenous clock to regulate germination timing. In addition, the cyst germination of A. catenella (Group I) was not controlled by seasonal salinity changes. Based on the results, this study provides a schematic scenario of the bloom development of A. catenella (Group I) in Jinhae-Masan Bay, Korea.


Delayed repair of stanford type-A dissection following fulminant cerebral infarction.
We report an impressive case in which a complete infarction of the right hemisphere due to an acute occlusion of the right carotid artery had developed. After cerebral decompression and neurological rehabilitation, the persisting dissection of the ascending aorta and both carotid arteries was successfully repaired in one session.


Osteoarthritis year in review: rehabilitation and outcomes.
This review highlights seminal publications of rehabilitation interventions and outcomes in osteoarthritis (OA) of the hip or knee. Medline, CINAHL, and Embase databases from September 2010 through August 2011 were searched using the key words 'osteoarthritis', rehabilitation, physical therapy, exercise, and outcome(s), limited to human and English. Rehabilitation intervention studies were included if they were randomized trials (RCT), systematic reviews or meta-analyses. Studies of surgical interventions were excluded unless they included evaluation of a rehabilitation intervention. Outcome studies were included if they contributed methodologically to advancing outcome measurement. Reviews of measurement properties of outcomes were excluded. Eight publications were selected and reviewed that relate to interventions evaluating manual therapy in hip or knee OA, tele-rehabilitation and performance and participation measures as outcomes. One systematic review of hip and knee OA, one meta-analysis of knee OA provide limited support for the benefit of manual therapy with exercise for improving pain and function to a lesser extent in the short-term (3 months). Study quality overall was low. One high quality RCT in knee replacement of usual outpatient physiotherapy vs internet-based tele-rehabilitation based on a non-inferiority analysis demonstrated comparable outcomes on Western Ontario McMaster Universities' Osteoarthritis questionnaire (WOMAC) pain and function and performance measures. Three studies demonstrated that observed performance measures such as timed walk tests and stair-climbing and timed-up-and-go measure concepts differ from self-report of difficulty with physical function. Additionally, two studies showed differential times of recovery following total knee replacement (TKR). Two studies evaluated participation. One demonstrated the conceptual distinction of activity limitations and participation and a second re-analyzed trial data from knee OA studies. In one study, there were larger effects in combined activity/participation than for activity alone for arthroscopic lavage compared to intraarticular steroid and, in a second study, the effect was larger for activity with an advanced pharmacy intervention whereas the physiotherapy intervention demonstrated a larger effect for activity/participation. Interventions of manual therapy for hip and knee OA provided limited evidence of effectiveness. These studies are of limited quality due to lack of blinding and disclosure of co-intervention. Tele-rehabilitation may be a viable option to improve access to rehabilitation post joint replacement for those in rural and remote areas. Data continue to support the need to include performance measures as well as patient-reported outcomes in evaluating outcomes in OA. Additionally, measures of participation should be considered as core outcomes.


Association between plasma uric acid and insulin resistance in type 2 diabetes: A Mendelian randomization analysis.
Circulating uric acid levels were associated with insulin resistance, but the causality is unclear. We aimed to investigate the association between plasma uric acid and insulin resistance in newly diagnosed type 2 diabetes (T2D). We enrolled 1,938 patients who underwent a 75-g oral glucose tolerance test. Insulin resistance was estimated based on the homeostatic model assessment index (HOMA2-IR) and the Matsuda index. Uric acid was measured in fasting plasma by uricase-peroxidase method. We genotyped single nucleotide polymorphisms (SNPs) that were recently identified as top hits in genome-wide association studies of uric acid levels. A weighted genetic risk score (wGRS) was calculated based on the associations between selected SNPs and uric acid levels. The adjusted β coefficients for Ln-transformed Matsuda index and HOMA2-IR per 1 mg/dL uric acid increment were -0.070 (95%CI: -0.089, -0.052) and 0.057 (95%CI: 0.039, 0.075). These associations were more pronounced among women than men. In Mendelian randomization analysis, the wGRS raised uric acid by 0.225 mg/dL (95%CI: 0.138, 0.312) per SD increase of the score. However, no association was observed between the wGRS and insulin resistance indices whether in men or women. Elevated plasma uric acid was associated with higher risk of insulin resistance, along with observation of gender difference in such association. However, our study does not support a causal role of plasma uric acid on insulin resistance among newly diagnosed T2D patients.


High-Throughput Screening of Substrate Specificity for Protein Tyrosine Phosphatases (PTPs) on Phosphopeptide Microarrays.
Phosphatases are a family of enzymes responsible for the dephosphorylation of biomolecules. Phosphatases play essential roles in cell cycle regulation, signal transduction, and cellular communication. In recent years, one type of phosphatases, protein tyrosine phosphatases (PTPs), emerges as important therapeutic targets for complex and devastating diseases. Nevertheless, the physiological roles, substrate specificity, and downstream targets for PTPs remain largely unknown. To demonstrate how microarrays can be applied to characterizing PTPs, we describe here a phosphopeptide microarray strategy for activity-based high-throughput screening of PTPs substrate specificity. This is followed by a kinetic microarray assay and microplate assay to determine the rate constants of dephosphorylation by PTPs. This microarray strategy has been successfully applied to identifying several potent and selective substrates against different PTPs. These substrates could be used to design potent and selective PTPs inhibitors in the future.


Laparoscopic lymph node biopsy for lymphoma with a novel use of indocyanine green fluorescence in a 66-year-old male patient.
Indocyanine green (ICG) near-infrared fluorescence is primarily employed in detecting Intraoperative sentinel lymph node (SLN) mapping or to evaluate the extent of radical lymphadenectomy mainly in colo-rectal and gastric cancer. To date there are no reports indicating the use of this dye to detect pathologic lymphatic tissue when a lymph node biopsy for suspected lymphoproliferative disease is performed. A 66-year-old male patient was admitted to the hospital for severe pain of left renal colic type. A computed tomography (CT) scan and a positron emission tomography (PET) showed a left hydroureteronephrosis due to ureter compression by paraortic solid tissue of lymphomatous aspect with a standardized uptake value (SUV) of 15. Multiple lymphadenopathies on paracaval, para-aortic and common iliac sites were present as well. A laparoscopic lymph node biopsy (LLB) was planned for diagnostic purposes. After induction of anesthesia a ICG solution was injected Intradermally at both inguinal regions. At laparoscopy a complete visualization of the pathologic lymphnodes was achieved, enabling incisional biopsies of the lymphomatous mass. Histopathological examination showed an extranodal localization of an aggressive B-cell non-Hodgkin lymphoma. ICG-fluorescence seems to offer a simple and safe method for pathologic lymph node detection. LLB in the suspicion of intra abdominal lymphoma can largely take advantage by this novel opportunity not yet tested to date. More studies with large case series are needed to confirm the efficacy of ICG-fluorescence for detecting pathologic lymph nodes.


Trogocytosis and cross-dressing in antigen presentation.
Antigen (Ag)-presenting cells capture or synthesize Ags that are processed into peptides bound and displayed on the plasma membrane by major histocompatibility complex (MHC) molecules. Here, we review a mechanism that enables cells to present Ag-loaded MHC molecules that they have not produced themselves, namely trogocytosis. During trogocytosis, a cell acquires fragments from another living cell without, in most cases, affecting the viability of the donor cell. The trogocytic cell can incorporate into its own plasma membrane (becoming cross-dressed) proteins acquired from the donor cell, including intact Ag and MHC molecules. Trogocytosis and cross-dressing expand the immunological functions that immune and nonimmune cells are able to carry out, with both beneficial and deleterious consequences.


Bone Marrow Endothelial Cells Take Up Blood-Borne Immune Complexes via Fcγ Receptor IIb2 in an Erythropoietin-Dependent Manner.
Immune complexes (ICs) in blood are efficiently removed mainly by liver reticuloendothelial systems consisting of sinusoidal endothelial cells and Kupffer cells expressing FcγR. The bone marrow (BM) also has sinusoidal vasculatures, and sinusoidal BM endothelial cells (BMECs) bear unique function, including hematopoietic niches and traffic regulation of hematopoietic cells. In this study, we found that sinusoidal BMECs express FcγRIIb2, which is markedly increased in anemic conditions or by the administration of erythropoietin (Epo) in healthy mice. BMECs expressed Epo receptor (EpoR), and the Epo-induced increase in FcγRIIb2 expression was abolished in Epor-/- ::HG1-Epor transgenic mice, which lack EpoR in BMECs except for BM erythroblasts, suggesting the effect was directly mediated via EpoR on BMECs. Further, although BMECs hardly captured i.v.-injected soluble ICs in healthy mice, Epo administration induced a remarkable increase in the uptake of ICs in a FcγRIIb-dependent manner. Enhancement of the IC incorporation capacity by Epo was also observed in cultured BMECs in vitro, suggesting the direct effect of Epo on BMECs. Moreover, we found that i.v.-injected ICs in Epo-treated mice were more rapidly removed from the circulation than in PBS-treated mice. These results reveal a novel function of BMECs to efficiently remove circulating blood-borne ICs in an FcγRIIb2-mediated manner.


Interaction of glycylglycine and Na+ at the mucosal border of guinea-pig small intestine. A non-mutual stimulation of transport.
Sodium-dependence of glycylglycine (Gly-Gly) influx and stimulation of Na+ transport by Gly-Gly were studied in everted sacs, sheet preparations and brush-border membrane vesicles isolated from guinea-pig ileum. Gly-Gly influx was found to be independent of the presence of Na+, while Na+ transport was stimulated by Gly-Gly as evidenced by increases in transmural potential difference (PDt), short-circuit current (Isc) and Na+ influx. The change in PDt (delta PDt) induced by Gly-Gly was a saturable function of Gly-Gly concentration, showing a Michaelis-Menten type relationship. The half-saturation concentration for Gly-Gly estimated from the electrical data was nearly identical with that estimated from influx data. At a constant Gly-Gly concentration the relationship between Isc and Na+ concentration was sigmoid, and the Hill coefficient was 1.5. Kinetic analysis according to Garay and Garrahan indicates that each Gly-Gly carrier has two equivalent non-interacting binding sites for Na+, and that translocation of Na+ occurs when the two Na+ sites on the carrier loaded with Gly-Gly are occupied by Na+. However, our results indicate that the resultant Na+ flow is not capable of stimulating Gly-Gly translocation.


Kinetics and molecular docking studies of kaempferol and its prenylated derivatives as aldose reductase inhibitors.
Aldose reductase inhibitors (ARIs) suppressing the hyperglycemia-induced polyol pathway have been provided as potential therapeutic candidates in the treatment and prevention of diabetic complications. Based upon structure-activity relationships of desmethylanhydroicaritin (1) and sophoflavescenol (2) as promising ARIs, 3,4'-dihydroxy flavonols with a prenyl or lavandulyl group at the C-8 position and a hydroxyl or methoxy group at the C-5 position are important for aldose reductase (AR) inhibition. In order to prove the above results, a combination of computational prediction and enzyme kinetics has begun to emerge as an effective screening technique for the potential. In the present study, we predicted the 3D structure of AR in rat and human using a docking algorithm to simulate binding between AR and prenylated flavonoids (1 and 2) and kaempferol (3) and scrutinized the reversible inhibition of AR by these ARIs. Docking simulation results of 1-3 demonstrated negative binding energies (Autodock 4.0=-9.11 to -7.64 kcal/mol; Fred 2.0=-79.54 to -51.84 kcal/mol) and an additional hydrogen bond through Phe122 and Trp219, in addition to the previously proposed interaction of AR and phenolics through Trp20, Tyr48, His110, and Trp111 residues, indicating that the presence of 8-prenyl and 5-methyl groups might potentiate tighter binding to the active site of the enzyme and more effective AR inhibitors. Moreover, types of AR inhibition were different depending on the presence or absence of the 8-prenyl group, in that 1 and 2 are mixed inhibitors with respective Ki values of 0.69 μM and 0.94 μM, while 3 showed noncompetitive inhibition with a Ki value of 4.65 μM. The present study suggests that an effective strategy for screening potential ARIs could be established by predicting 3D structural conformation of prenylated flavonoids and the orientation within the enzyme as well as by simultaneously determining the mode of enzyme inhibition.


Analysis of Zfhx1a mutant mice reveals palatal shelf contact-independent medial edge epithelial differentiation during palate fusion.
Cleft palate is a common birth defect that involves disruptions in multiple developmental steps such as growth, differentiation, elevation, and fusion. Medial edge epithelial (MEE) differentiation is essential for palate fusion. An important question is whether the MEE differentiation that occurs during fusion is induced by palate shelf contact or is programmed intrinsically by the palate shelf itself. Here, we report that the loss of Zfhx1a function in mice leads to a cleft palate phenotype that is mainly attributable to a delay in palate elevation. Zfhx1a encodes a transcription regulatory protein that modulates several signaling pathways including those activated by members of the transforming growth factor-beta (TGF-beta) superfamily. Loss of Zfhx1a function in mice leads to a complete cleft palate with 100% penetrance. Zfhx1a mutant palatal shelves display normal cell differentiation and proliferation and are able to fuse in an in vitro culture system. The only defect detected was a delay of 24-48 h in palatal shelf elevation. Using the Zfhx1a mutant as a model, we studied the relationship between MEE differentiation and palate contact/adhesion. We found that down-regulation of Jag2 expression in the MEE cells, a key differentiation event establishing palate fusion competence, was independent of palate contact/adhesion. Moreover, the expression of several key factors essential for fusion, such as TGF-beta3 and MMP13, was also down-regulated at embryonic stage 16.5 in a contact-independent manner, suggesting that differentiation of the medial edge epithelium was largely programmed through an intrinsic mechanism within the palate shelf.


Purification of HIV-1 gag virus-like particles and separation of other extracellular particles.
Enveloped virus-like particles (VLPs) are increasingly used as vaccines and immunotherapeutics. Frequently, very time consuming density gradient centrifugation techniques are used for purification of VLPs. However, the progress towards optimized large-scale VLP production increased the demand for fast, cost efficient and scale able purification processes. We developed a chromatographic procedure for purification of HIV-1 gag VLPs produced in CHO cells. The clarified and filtered cell culture supernatant was directly processed on an anion-exchange monolith. The majority of host cell impurities passed through the column, whereas the VLPs were eluted by a linear or step salt gradient; the major fraction of DNA was eluted prior to VLPs and particles in the range of 100-200nm in diameter could be separated into two fractions. The earlier eluted fraction was enriched with extracellular particles associated to exosomes or microvesicles, whereas the late eluting fractions contained the majority of most pure HIV-1 gag VLPs. DNA content in the exosome-containing fraction could not be reduced by Benzonase treatment which indicated that the DNA was encapsulated. Many exosome markers were identified by proteomic analysis in this fraction. We present a laboratory method that could serve as a basis for rapid downstream processing of enveloped VLPs. Up to 2000 doses, each containing 1×10(9) particles, could be processed with a 1mL monolith within 47min. The method compared to density gradient centrifugation has a 220-fold improvement in productivity.


Tutorial: methods for three-dimensional visualization of archival tissue material.
Analysis of three-dimensional patient specimens is gaining increasing relevance for understanding the principles of tissue structure as well as the biology and mechanisms underlying disease. New technologies are improving our ability to visualize large volume of tissues with subcellular resolution. One resource often overlooked is archival tissue maintained for decades in hospitals and research archives around the world. Accessing the wealth of information stored within these samples requires the use of appropriate methods. This tutorial introduces the range of sample preparation and microscopy approaches available for three-dimensional visualization of archival tissue. We summarize key aspects of the relevant techniques and common issues encountered when using archival tissue, including registration and antibody penetration. We also discuss analysis pipelines required to process, visualize and analyze the data and criteria to guide decision-making. The methods outlined in this tutorial provide an important and sustainable avenue for validating three-dimensional tissue organization and mechanisms of disease.


Value: Changes in the Detection and Recognition Thresholds of Three Basic Tastes in Lung Cancer Patients Receiving Cisplatin and Paclitaxel and Its Association with Nutritional and Quality of Life Parameters.
We evaluated the effects of cisplatin and paclitaxel on taste acuity and their associations with nutritional and health-related quality of life (HRQL) in patients with advanced non-small-cell lung cancer (NSCLC). Forty chemotherapy (CT)-naïve patients were assessed at baseline and after two cycles of paclitaxel and cisplatin. The taste evaluation was performed using a rinsing technique to identify detection and recognition thresholds (DT and RT) of bitter, sweet, and umami tastes. At baseline, 37.5% of the patients reported dysgeusia. After CT, the patients showed lower medians DT (p = 0.017) and RT (p = 0.028) for umami taste. These decreases were associated with clinical neuropathy, worse HRQL, and a tendency toward increased appetite loss. Additionally, CT did not significantly reduce the median DT for sweet (p = 0.09), which is associated with lower intake of protein (p = 0.015), animal protein (p = 0.010), fat (p = 0.004), and iron (p = 0.047). CT decreased the median DT for bitter (p = 0.035); however, this decrease was not associated with nutritional parameters or with HRQL. Sensitivity to taste increased with paclitaxel and cisplatin CT, making foods more unpleasant, and it was associated with neuropathy, worse HRQL, and reduced nutrient intake in advanced NSCLC patients. The protocol was registered at clinicaltrials.gov (NCT01540045).


Metronidazole bioassay with increased sensitivity.
The bioassay of metronidazole using Clostridium butyricum incorporated in agar plates detected concentrations higher than 1.0 microgram/ml. Gentamicin in the sample did not affect the growth of the target organism or the inhibition by metronidazole. Penicillin in the sample could be eliminated by the incorporation of penicillinase in the agar or by using as the target organism a surface inoculum of the penicillin-resistant Bacteroides fragilis. Increasing duration and temperature of aerobic prediffusion before allowing the growth of the strictly anaerobic Cl. butyricum increased the diameters of inhibition by metronidazole, but did not affect the threshold of detectability. The incorporation of metronidazole in the agar increased the sensitivity of the assay ten- to 100-fold.


Non-vitamin K Antagonist Oral Anticoagulant, Warfarin, and ABC Pathway Adherence on Hierarchical Outcomes: Win Ratio Analysis of the COOL-AF Registry.
Atrial fibrillation (AF) Better Care (ABC) pathway adherence is associated with improved outcomes. Clinical trials have shown that non-vitamin K antagonist oral anticoagulants (NOACs) are as least as effective as warfarin for stroke prevention in AF patients. The Win Ratio method, analyzing hierarchical composite outcomes considering event timing and severity, has limited data on its use in Asians. We aim to apply Win Ratio in a registry to access the comparative effectiveness of NOACs versus warfarin and ABC adherence versus nonadherence in Asian patients with AF. Our study included nonvalvular AF patients from the nationwide prospective COOL-AF registry in Thailand. The NOAC-treated group was compared with the warfarin-treated group using the Win Ratio, with the following order: all-cause death, intracranial hemorrhage (ICH), ischemic stroke/transient ischemic attack/systemic embolism, non-ICH major bleeding, and myocardial infarction or heart failure. ABC pathway adherence versus nonadherence was also compared. A Win Ratio greater than 1.00 indicating a better outcome. The analysis included 2,568 patients, with 228 in the NOAC group and 2,340 in the warfarin group. The NOAC group had more wins than the warfarin group, with an unmatched Win Ratio of 1.64 (95% confidence interval [CI]: 1.22-2.20; p < 0.001). When compared with nonadherence, ABC pathway adherence was associated with a Win Ratio of 1.57 (95% CI: 1.33-1.85; p < 0.001). This Win Ratio analysis demonstrates the significant benefits of NOACs over warfarin and ABC pathway adherence over nonadherence in reducing the composite outcome in patients with AF.


Circ-RPL15/miR-146b-3p/VEGFA feedback loop is responsible for triggering proliferation and migration in glioma.
This study aims to elucidate the role of circ-RPL15 in the progression of glioma. Circ-RPL15 levels in glioma tissues and normal brain tissues were detected. Subcellular distribution of circ-RPL15 was examined. The binding between miR-146b-3p and circ-RPL15 was verified by Luciferase assay. Potential targets of miR-146b-3p were further determined. The influences of the circ-RPL15/miR-146b-3p/VEGFA feedback loop on proliferative and migratory abilities in T98G and U251 cells were detected by cell counting kit-8 (CCK-8) and transwell assay, respectively. Circ-RPL15 and VEGFA were upregulated in glioma tissues than normal ones, whereas miR-146b-3p was downregulated. Circ-RPL15 was mainly distributed in the cytoplasm. The interaction in the circ-RPL15/miR-146b-3p/VEGFA feedback loop was indicated by Luciferase assay, and it markedly promoted proliferative and migratory abilities in glioma. Circ-RPL15 triggers proliferative and migratory potentials in glioma by competitively binding miR-146b-3p and thus upregulates VEGFA.


[Multifactor Organizational Stress Risk Questionnaire--MOSRQ: a preliminary study of dimensions and structure].
INTRODUCTION. The aim of the present study is to demonstrate the validity of the MOSRQ, a questionnaire for the assessment of work related stress risk. This questionnaire has 38 items: 19 related to organizational stressors and 19 to strains. Firstly, it was performed a critical analysis of instruments reported in scientific literature; then relevant items about sources and consequences of work related stress were selected in order to obtain the questionnaire. Finally MOSRQ was administered to a sample of 2314 subjects mainly employed in private firms belonging to industry and service sectors. MOSRQ obtains a good index of reliability (alpha = .89 for organizational stressor/antecedents and alpha = .92 for strain/outcome). Factor analysis presents a structure with 3 factors both for the antecedents and for the outcomes of work related stress. In conclusion, it is claimed that MOSRQ has the necessary psychometric characteristics for use in research as well as in organizational contexts.


The clinical value of active T-rosette-forming cells in urine after renal transplantation.
We examined 960 urine specimens from 12 renal transplant patients for the presence of thymus-derived rosette-forming cells as a post-transplant study. Active T-rosette-forming cells appeared in the urine before or simultaneously with an increase in serum creatinine during all 14 acute rejection crises. Moreover, the active urinary T-rosette-forming cells disappeared promptly after pulse treatment with large doses of methylprednisolone in 11 rejection crises, which resolved completely, while in patients with continued detection of active T-rosette-forming cells in the urine rejection crises recurred within a few weeks. It is suggested that the test for active urinary T-rosette-forming cells is a simple and reliable method to diagnose acute renal allograft rejection.


Myxomavirus as a vector for the immunisation of sheep: protection study against challenge with bluetongue virus.
Recombinant poxviruses are well suited for the development of new vaccine vectors. Our previous data supported the idea that Myxomavirus (MYXV) is efficient at priming antibody responses in sheep. To provide definitive evidence on the potential of MYXV for vaccination against infectious diseases in ruminants, we investigated the immune protection provided by recombinant MYXV against bluetongue, a devastating disease in sheep. To test this concept, sheep were injected twice with an MYXV expressing the immunodominant VP2 protein (SG33-VP2). The SG33-VP2 vector promoted the production of neutralising antibodies and partially protected sheep against disease after challenge with a highly virulent strain of serotype-8 bluetongue virus (BTV-8). In contrast, an MYXV expressing both VP2 and VP5 proteins (SG33-VP2/5) elicited very little protection. The expression levels of the VP2 and VP5 proteins suggested that, greater than the co-expression of the VP5 protein which was previously thought to favour anti-VP2 antibody response, the high expression of VP2 may be critical in the MYXV context to stimulate a protective response in sheep. This highlights the requirement for a careful examination of antigen expression before any conclusion can be drawn on the respective role of the protective antigens. As a proof of principle, our study shows that an MYXV vaccine vector is possible in ruminants.


Individual and school level correlates of moderate to vigorous physical activity among school-children in Germany--a multi-level analysis.
Young people spend half of their days in school, but evidence concerning the influence of school environment on the physical activity (PA) of pupils is still inconsistent. A better understanding of potential correlates of PA on the school-level and their possible interaction with individual aspects is needed to improve the development of more effective interventions. We used data from the 2009/10 German Health Behaviour in School-aged Children study (HBSC)-sample (n=5,005 students aged 11-15 years) including self-reported moderate to vigorous intensity PA as well as a variety of biological, demographic and behavioral correlates and matched them with school-level data from the national school principals' HBSC questionnaire. We analyzed the associations of individual- and school-level correlates with MVPA by gender-specific multi-level regression. Only a small share of the overall variation in student's PA was attributable to the school-level. Consequently, the associations of individual-level correlates with PA were stronger than those of the school-level. Our analysis revealed significant associations of individual-level (i.e. age, consumption of softdrinks, overweight) as well as school-level correlates (i.e. the availability of a football ground and a swimming pool) with MVPA. We also observed some gender-specific findings especially for the school level correlates. Cross-level interactions between individual- and school-level were not apparent. Our findings indicate the usefulness of applying an ecological framework to understand and explain complex health behaviors like PA. As we found gender-specific association it might be important to acknowledge that boys and girls have specific needs to be more physically active. Further research should also take other features/elements of the school environment and neighborhood as well as socio-cognitive correlates into account to advance the field.


Therapy-induced modulation of extracellular vesicles in hepatocellular carcinoma.
Despite rapid development of anti-tumorigenic treatments, the clinical outcome for hepatocellular carcinoma (HCC) is still far from satisfactory. With a deeper understanding about tumor microenvironment (TME), the critical role of extracellular vesicles (EVs) as intercellular liaison has come into spotlight. The dynamic functionality of these nanoparticles revealed cancer cells can employ both tumor and non-tumorous components for their own benefit, so as to mediate cell-to-cell communication and interchange of oncogenic biomolecules. Increasing studies on HCC-derived EVs have identified various irregulated biomolecules, that may serve as biomarkers or therapeutic targets. In this review, we first introduce the current knowledge about EVs and how they operate to maintain a healthy liver microenvironment. We then summarize some of the aberrant observations reported on HCC-derived EVs and how they contribute to HCC pathogenesis. Finally, we describe how current treatments for HCC alter behavior of EVs, which may shed light for potential prognostic markers and therapeutic strategies.


Correction to: Heparin resistance in COVID‑19 patients in the intensive care unit.
In the original publication of this article, one of the co-author name "D. de Monteverde-Robb" was inadvertently mentioned as "R. de Monteverde-Robb". The correct author name is "D. de Monteverde-Robb". This error has been corrected with this erratum.


Direct targeting of Arabidopsis cysteine synthase complexes with synthetic polypeptides to selectively deregulate cysteine synthesis.
Biosynthesis of cysteine is one of the fundamental processes in plants providing the reduced sulfur for cell metabolism. It is accomplished by the sequential action of two enzymes, serine acetyltransferase (SAT) and O-acetylserine (thiol) lyase (OAS-TL). Together they constitute the hetero-oligomeric cysteine synthase (CS) complex through specific protein-protein interactions influencing the rate of cysteine production. The aim of our studies was to deregulate the CS complex formation in order to investigate its function in the control of sulfur homeostasis and optimize cysteine synthesis. Computational modeling was used to build a model of the Arabidopsis thaliana mitochondrial CS complex. Several polypeptides based on OAS-TL C amino-acid sequence found at SAT-OASTL interaction sites were designed as probable competitors for SAT3 binding. After verification of the binding in a yeast two-hybrid assay, the most strongly interacting polypeptide was introduced to different cellular compartments of Arabidopsis cell via genetic transformation. Moderate increase in total SAT and OAS-TL activities, but not thiols content, was observed dependent on the transgenic line and sulfur availability in the hydroponic medium. Though our studies demonstrate the proof of principle, they also suggest more complex interaction of both enzymes underlying the mechanism of their reciprocal regulation.


2D 1H-31P solid-state NMR studies of the dependence of inter-bilayer water dynamics on lipid headgroup structure and membrane peptides.
The dynamics of hydration-water in several phospholipid membranes of different compositions is studied by 2D (1)H-(31)P heteronuclear correlation NMR under magic-angle spinning. By using a (1)H T(2) filter before and a (1)H mixing-time after the evolution period and (31)P detection, inter-bilayer water is selectively detected without resonance overlap from bulk water outside the multilamellar vesicles. Moreover the (1)H T(2) relaxation time of the inter-bilayer water is measured. Lipid membranes with labile protons either in the lipid headgroup or in sterols exhibit water-(31)P correlation peaks while membranes free of exchangeable protons do not, indicating that the mechanism for water-lipid correlation is chemical exchange followed by relayed magnetization transfer to (31)P. In the absence of membrane proteins, the inter-bilayer water (1)H T(2)'s are several tens of milliseconds. Incorporation of charged membrane peptides shortened this inter-bilayer water T(2) significantly. This T(2) reduction is attributed to the peptides' exchangeable protons, molecular motion and intermolecular hydrogen bonding, which affect the water dynamics and the chemically relayed magnetization transfer process.


Sugar Chips immobilized with synthetic sulfated disaccharides of heparin/heparan sulfate partial structure.
Carbohydrate chip technology has a great potential for the high-throughput evaluation of carbohydrate-protein interactions. Herein, we report syntheses of novel sulfated oligosaccharides possessing heparin and heparan sulfate partial disaccharide structures, their immobilization on gold-coated chips to prepare array-type Sugar Chips, and evaluation of binding potencies of proteins by surface plasmon resonance (SPR) imaging technology. Sulfated oligosaccharides were efficiently synthesized from glucosamine and uronic acid moieties. Synthesized sulfated oligosaccharides were then easily immobilized on gold-coated chips using previously reported methods. The effectiveness of this analytical method was confirmed in binding experiments between the chips and heparin binding proteins, fibronectin and recombinant human von Willebrand factor A1 domain (rh-vWf-A1), where specific partial structures of heparin or heparan sulfate responsible for binding were identified.


Protein quality of several multi-component, commercially prepared foods.
Eleven commercial food products that may be considered by consumers to be major sources of protein were evaluated. Most of these items contained significant amounts of carbohydrate in the form of cereal products or purified sugars. Seven of the products were at least equal to casein in protein efficiency ratio (PER). Canned spaghetti and meat balls, the TV dinner, canned chicken-and-vegetable baby food, and food bars had PER values between 91 and 73 per cent of that of casein, while PER values for ground beef and high-protein cereal were significantly higher than casein.


A human cell system for detecting asbestos cytogenotoxicity in vitro.
Crocidolite, a carcinogenic asbestos in humans, specifically induces mesothelioma. We investigated the cytogenotoxic effects of crocidolite in a human mesothelioma cell line, MSTO211H, and a human promyelocytic leukemia cell line, HL60. Using confocal laser scanning microscopy, we found that the MSTO211H cells had phagocytotic activity, whereas the HL60 cells did not. In the MSTO211H cells, crocidolite decreased the cell population and increased the numbers of polynucleated cells (PN) and tetraploid cells, and increased the coefficients of variation (CV) of DNA contents in G0/G1 cells and the formation of 8-hydroxydeoxyguanosine. In contrast, crocidolite showed none of these cytogenotoxic effects in HL60 cells. To investigate the importance of phagocytosis in the cytogenotoxicity of crocidolite, we sorted the crocidolite-phagocytosed cells from less-phagocytosed cells by fluorescence-activated cell sorting, and studied the differences in cytogenotoxicity between these two cell groups. We found significant increases in the numbers of PN and tetraploid cells and the CV in the crocidolite-phagocytosed cells compared to the less-phagocytosed cells. These findings indicate that MSTO211H cells are susceptible to the cytogenotoxic effects of asbestos due to their phagocytotic activity, and that the MSTO211H cell line is suitable for the detection of such effects on human cells by asbestos and other materials which need to be phagocytosed to exert their toxicity.


Modern approach to an old technique: Narrative revision of techniques used to locate the epidural space.
Since the first description of the epidural technique during the 1920s, the continuous progress of knowledge of the anatomy and physiology of the epidural space has allowed the development of different techniques to locate this space while increasing both the safety and efficacy of the procedure. The most common techniques used today are based on the two main characteristics of the epidural space: the difference in distensibility between the ligamentum flavum and the epidural space, and the existence of negative pressure within the epidural space. However, over recent years, technological advances have allowed the development of new techniques to locate the epidural space based on other physical properties of tissues. Some are still in the experimental phase, but others, like ultrasound-location have reached a clinical phase and are being used increasingly in daily practice.


A novel -66T/C polymorphism in Fc epsilon RI alpha-chain promoter affecting the transcription activity: possible relationship to allergic diseases.
We found a novel polymorphism, -66T/C, in the promoter region of human FcepsilonRIalpha, the specific component of the high affinity receptor for IgE (FcepsilonRI), which is essential for the cell surface expression of FcepsilonRI and the binding of IgE Ab. When the effect of the single nucleotide replacement on the promoter function was analyzed, the transcription activity of the T allele promoter was found to be higher than that of the C allele promoter, and was markedly up-regulated by the overexpression of GATA-1 when compared with the C allele promoter. This is probably because the promoter with T at -66 has an additional GATA-1-binding motif in the region, which may assure higher affinity of the transcription factor to the promoter. In accordance with this, EMSA actually indicated that GATA-1 bound to the T allele probe (-80/-59) with the affinity higher than that to the C allele probe. Statistical analysis suggested that a significant portion of nonallergic individuals has heterozygous -66T/C genotype, while most of allergic individuals have homozygous -66T/T genotype in Japanese population. Our findings for the first time demonstrate the presence of FcepsilonRIalpha polymorphism related to the allergic diseases.


Climate variability, human wildlife conflict and population dynamics of lions Panthera leo.
Large carnivores are threatened by habitat loss, declining prey populations and direct persecution. Pride dynamics of eight lion prides in the centre of the Etosha National Park, Namibia are described during a 16-year study. Since the beginning of the 1980s, the number of adult and subadult lions declined continuously to two third of its initial population size, and reached a new equilibrium in the 1990s. Pride sizes decreased from 6.3 adult females in 1989 to 2.8 lionesses in 1997. While the number of adult females declined continuously, the number of adult males, subadult females and subadult males remained constant over the years. A severe drought period, lasting for more than 20 years, led to declining prey populations inside the lions' territory. Besides declining prey populations, conflict with humans at the border of Etosha puts substantial pressure onto the lion population: 82% of all known lion mortalities were caused by humans, and most of these consisted of adult females (28%) and subadult males (29%). I postulate that the considerable decline in the lion population is a response to declining prey populations, and although the human predator conflict is severe, it does not seem to limit the size of Etosha's lion population.


A decade of pelvic vascular injuries during the Global War on Terror.
Pelvic vascular injuries (PVIs) rarely occur in isolation and are often associated with significant morbidity. The purpose of this study was to examine the incidence, trends, and early outcomes of PVIs sustained in combat. The Department of Defense Trauma Registry was queried to identify all patients treated with PVIs during the first 10 years of Operation Enduring Freedom. Patient demographics, mechanism of injury, type of vascular injury, in-theater complications, and early clinical outcomes were examined. From 2003 to 2012, 143 patients (99% male) sustained a PVI in Afghanistan. During this period, there was a persistent increase in the percentage of patient visits (0.4% in 2003 to 2.0% in 2012). The mean Injury Severity Score (ISS) was 24. Sixty-six percent of patient injuries were secondary to explosions. Improvised explosive devices (IEDs) encountered by dismounted personnel accounted for 47% of all injuries and were associated with a significantly higher ISS (28) compared with all other mechanisms of injury (P < .01). There were 85 (43%) arterial and 112 (57%) venous PVIs. The most frequent arterial injury was the common iliac artery. Injury to the femoral vein was associated with a higher median transfusion requirement. One patient died in combat theater. Injuries from IEDs had higher rates of coagulopathy, acidosis, and hypothermia compared with other mechanisms of injury (P = .03). Forty-two patients (29%) sustained early infectious complications. Injuries from explosions were also associated with a significantly higher rate of infectious complications compared with other mechanisms of injury (P < .01). PVIs have occurred with increasing frequency during Operation Enduring Freedom. Despite a persistently low mortality, complication and infection rates remain high, particularly when injuries are secondary to explosions. IEDs are associated with higher ISS and complication rates. Future studies must continue to focus on the prevention and treatment of PVIs sustained in combat, particularly those caused by explosions.


Expression of nitric oxide synthases in leukocytes in nasal polyps.
Nitric oxide (NO) has various roles in airway physiology and pathophysiology. Monitoring exhaled NO levels is increasingly common to measure airways inflammation and inhaled NO studied for its therapeutic value in premature infants and adult respiratory distress syndrome. NO is produced by 3 isoforms of NO synthase (NOS1, 2, 3), and each can play distinct and perhaps overlapping roles in the airways. However, the distribution, regulation, and functions of NOS in various cells in the upper airways, particularly in leukocytes, are incompletely understood. To characterize the expression of NOS isoforms in leukocytes in normal middle turbinate tissues (MT) and in inflammatory nasal tissue (nasal polyps, NP). Normal MT tissue was collected from surgical specimens that were to be discarded. The NP samples were from surgical tissue archives of 15 patients with chronic rhinosinusitis. Isoforms of NOS in cells were identified by double immunostaining using NOS isoform-specific and leukocyte-specific (mast cell, eosinophil, macrophage, neutrophil, or T cell) antibodies. The proportion of total cells below the epithelium that were positive for each isoform of NOS was higher in NP than in MT. Each isoform of NOS was found in all leukocyte populations studied, and there were significant differences in the percentage of leukocytes expressing NOS isoforms between MT and NP. All isoforms of NOS are expressed in leukocytes in MT and NP, and their expression varies among leukocyte types. Our data provide a basis to investigate the regulation, cell distribution, and distinct functions of NOS isoforms in normal and inflamed nasal tissues.


Feasibility of Dual Living Donor Liver Transplantation From Donors With Complex Portal Vein Variations.
Living donor liver transplantation (LDLT) from donors with complex portal vein anomalies has been considered a challenging procedure because vasculobiliary variations of the donor's liver may lead to significant increases in donor and recipient complications. The use of donors with anatomic variations may be considered under the accurate preoperative planning if a more suitable donor is not available. We report a successful dual LDLT for 2 donors with portal vein anomaly to overcome the small-for-size graft syndrome and secure donor safety. A 62-year-old man was referred to our institution for liver transplant because of hepatitis B-related liver cirrhosis with hepatocellular carcinoma. The only available donors were his son and his daughter-in-law, one with type IV portal venous anatomic variation and the other with type III variation. Neither of the 2 available donors were suitable as a single donor because of the complexity of the portal vein reconstruction and the donor's safety. Therefore, the decision was made to perform LDLT using dual graft, and we planned to harvest the right posterior sector graph from the first donor together with the left lobe graft of the second donor. Donor hepatectomy and recipient total hepatectomy were performed in the usual manner. He has recovered well with normal graft function, and there has been no tumor recurrence after dual LDLT. Dual graft LDLT using right posterior sector and left lobe graft could be undertaken successfully to overcome the small-for-size graft syndrome and secure the safety of donors in cases with the complex portal vein anomalies.


Adrenal cavernous Hemangioma;A rare diagnosis of adrenal incidentaloma:A case report, and literature review.
Adrenal cavernous hemangioma is an extremely rare benign tumor. To date, less than 70 cases have been reported in the literature. In most of the cases, the tumor is hormonally silent, discovered incidentally and the diagnosis is made postoperatively. Pre-operative differentiation between this benign tumor and other malignant adrenal tumors is challenging. In this article we present a case of a non-functioning adrenal incidentaloma that was managed by laparoscopic adrenalectomy. The post-operative histological diagnosis was adrenal cavernous hemangioma.


Anaerobic phenanthrene biodegradation by a new salt-tolerant/halophilic and nitrate-reducing Virgibacillus halodenitrificans strain PheN4 and metabolic processes exploration.
The biodegradation of polycyclic aromatic hydrocarbons (PAHs) under hypersaline environments has received increasing attention, whereas the study of anaerobic PAH biodegradation under hypersaline environments is still lacking. Here, we found a pure culture designated PheN4, which was affiliated with Virgibacillus halodenitrificans and could degrade phenanthrene with nitrate as the terminal electron acceptor and a wide range of salinities (from 0.3% to 20%) under anaerobic environments. The optimal salinity for biodegradation of phenanthrene by PheN4 was 5%, which could degrade 93.5% of 0.62 ± 0.04 mM phenanthrene within 10 days with the initial inoculum of 0.01 gVSS/L. Meanwhile, an increased microbial amount could efficiently promote the phenanthrene biodegradation rate. The metabolic processes of anaerobic phenanthrene biodegradation under hypersaline conditions by PheN4 were proposed based on intermediates and genome analyses. Phenanthrene was initially activated via methylation to form 2-methylphenanthrene. Next, fumarate addition and β-oxidation or direct oxidation of the methyl group, ring reduction and ring cleavage were identified as the midstream and downstream steps. In addition, PheN4 could utilize benzene, naphthalene, and anthracene as carbon sources, but Benz[a]anthracene, pyrene, and Benzo[a]pyrene could not be biodegraded by PheN4. This study could provide some guidance for the bioremediation of PAH pollutants in anaerobic and hypersaline zones.


Experimental evidence for interactive habitat segregation between roach (Rutilus rutilus) and rudd (Scardinius erythrophthalmus) in a shallow eutrophic lake.
The competitive interactions between roach (Rutilus rutilus) and rudd (Scardinius erythrophthalmus) were investigated in two habitats, the open water and the waterlily zone. The growth rates of both species in enclosures were lower when confined together than when alone, demonstrating interspecific competition. Allopatric roach had the highest growth rate in both habitats although the open water was preferred. The diets of both species were dominated by zooplankton in both the open water and waterlily zones. In laboratory experiments, roach had significantly higher feeding rates than rudd when fed D. magna and Cyclops sp. The impact of roach on the mean sizes and densities of zooplankton in the enclosures, together with the results from the laboratory study, indicate that roach were competitively superior in the open water. Because of high mortality in the sympatric waterlily enclosure, no conclusions about interspecific competition in this habitat could be drawn. The observed habitat segregation between roach and rudd was at least partly interactive.


Expression of glutamate transporters in human and rat retina and rat optic nerve.
l-Glutamate is the major excitatory transmitter in the vertebrate retina and plays a central role in the transmission of the various retinal neurons. Glutamate is removed from the extracellular space by at least five different glutamate transporters. The cellular distribution of these has been studied so far mainly using immunocytochemistry. In the present study non-radioactive in situ hybridisation using complementary RNA probes was applied in order to identify the cell types of rat retina and optic nerve expressing generic GLT1, GLT1 variant (GLT1v or GLT1B), GLAST and EAAC1. The results were compared with immunocytochemical data achieved using affinity-purified antibodies against transporter peptides. In the immunohistochemical studies the human retina was included. The study showed that in the rat retina GLT1v and EAAC1 were coexpressed in various cell types, i.e. photoreceptor, bipolar, horizontal, amacrine, ganglion and Müller cells, whereas GLAST was only detected in Müller cells and astrocytes. In the rat optic nerve GLT1v and EAAC1 were preferentially expressed in oligodendrocytes, whereas GLAST was revealed to be present mainly in astrocytes. Generic GLT1 could not be detected in the retina or optic nerve. The cellular distribution of glutamate transporters (only immunocytochemistry) in the human retina was very similar to that of the rat retina. Remarkable results of our studies were that generic GLT1 was not detectable in the rat (and human) retina and that GLT1v and EAAC1 were demonstrable in most cell types of the retina (including photoreceptor cells and their terminals).


Outcomes of Venoarterial Extracorporeal Membrane Oxygenation Plus Intra-Aortic Balloon Pumping for Treatment of Acute Myocardial Infarction Complicated by Cardiogenic Shock.
Background Clinical outcomes of acute myocardial infarction complicated by cardiogenic shock remain poor with high in-hospital mortality. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has been widely used for patients with acute myocardial infarction complicated by cardiogenic shock refractory to conservative therapy, which is likely fatal without mechanical circulatory support. However, whether additional intra-aortic balloon pumping (IABP) use during VA-ECMO support improves clinical outcomes remains controversial. This study sought to investigate prognostic impact of the combined VA-ECMO plus IABP treatment compared with VA-ECMO alone. Methods and Results From the nationwide Japanese administrative case-mix Diagnostic Procedure Combination (DPC), the JROAD (Japanese Registry of All Cardiac and Vascular Diseases)-DPC, we identified 3815 patients with acute myocardial infarction complicated by cardiogenic shock who underwent primary percutaneous coronary intervention and managed with VA-ECMO. Of these, 2964 patients (77.7%) were managed with IABP (VA-ECMO plus IABP), whereas 851 (22.3%) were managed without IABP (VA-ECMO alone). We compared in-hospital, 7-day, and 30-day mortality between the VA-ECMO plus IABP versus the VA-ECMO alone support. Patients managed with VA-ECMO plus IABP demonstrated significantly lower in-hospital, 7-day, and 30-day mortality than those managed with VA-ECMO alone (adjusted odds ratios [95% CI] of 0.47 [95% CI, 0.38-0.59], 0.41 [95% CI, 0.33-0.51], and 0.30 [95% CI, 0.25-0.37], respectively). The findings were consistent in the propensity matching and inverse probability of treatment-weighting models. Conclusions This large-scale, nationwide study demonstrated that the combination of VA-ECMO plus IABP support was associated with significantly lower mortality compared with VA-ECMO support alone in patients presenting with acute myocardial infarction complicated by cardiogenic shock who underwent primary percutaneous coronary intervention.


Heat Shock Protein HSP60 in Left Ventricular Cardiomyocytes of Hypertensive Rats with and without Insulin-Dependent Diabetes Mellitus.
In cardiomyocytes, high molecular ATP-dependent HSP70 and HSP90 play an important role in protecting the myocardium from abnormal proteins that appear, in particular, due to activation of oxidative stress. Molecular chaperone HSP60 is of particular importance for cardiomyocytes as it is responsible for assembly of mitochondrial matrix proteins. We studied the peculiarities of expression of HSP60 in left ventricular cardiomyocytes in hypertension, insulin-dependent diabetes mellitus, and their combination. The experiment was performed on 38-week-old male Wistar-Kyoto and SHR (spontaneously hypertensive) rats aged 38-57 weeks. Insulin-dependent diabetes mellitus was modeled by a single parenteral administration of 65 mg/kg streptozotocin. Expression of HSP60 in left ventricular cardiomyocytes was evaluated by immunohistochemical methods. It was found that hypertension, diabetes mellitus, and their combination are associated with a significant decrease in the content of HSP60 in left ventricular cardiomyocytes in comparison with the control. This finding can be considered as a pathogenetic mechanism of myocardial damage induced by hypertension and diabetes mellitus.


Citrus flavonoid naringenin inhibits TLR2 expression in adipocytes.
Toll-like receptors (TLRs) were recently shown to be involved in obesity-induced inflammation in adipose tissue, which contributes to the development of insulin resistance and type 2 diabetes. Thus, the appropriate regulation of TLR expression or activation is an important strategy for improving obesity-related diseases. In this report, we show that naringenin, a citrus flavonoid, inhibits TLR2 expression during adipocyte differentiation. This effect is mediated in part through peroxisome proliferator-activated receptor γ activation. In addition, naringenin suppresses TLR2 expression induced by the co-culture of differentiated adipocytes and macrophages and also inhibits tumor necrosis factor-α (TNF-α)-induced TLR2 expression by inhibiting the activation of nuclear factor-κB and c-Jun NH2-terminal kinase pathways in differentiated adipocytes. Furthermore, naringenin decreases TLR2 expression in adipose tissue of high-fat diet-fed mice. These results are correlated with the improvement of hyperglycemia and the suppression of inflammatory mediators, including TNF-α and monocyte chemotactic protein-1. Taken together, these data suggest that naringenin exhibits anti-inflammatory properties, presumably by inhibiting TLR2 expression in adipocytes. Our findings suggest a molecular mechanism by which naringenin exerts beneficial effects against obesity-related diseases.


Mechanisms of isoquercitrin attenuates ovalbumin glycation: Investigation by spectroscopy, spectrometry and molecular docking.
This research firstly investigated the inhibitory effect of isoquercitrin (ISQ) on Ovalbumin (OVA) glycation. The mechanism was elucidated through the interaction between OVA and ISQ, and changes in glycation sites and degree of each site as deduced by spectroscopy, spectrometry and molecular docking. ISQ significantly inhibited OVA glycation by attenuating the conformational change induced by glycation. It quenched the fluorescence of Trp via static mechanism, and exposed Trp residues to a more hydrophobic surroundings. Formation of OVA-ISQ complex was a endothermic processing driven by hydrophobic interactions, van der Waals forces and hydrogen bonds. LC-Orbitrap-MS/MS revealed that ISQ altered the location of glycation and alleviated the glycation degree of most sites. Molecular docking results indicated that ISQ inserted into the hydrophobic pocket of OVA with six hydrogen bonds and one π-π stacking formed between ISQ and the amino acid residues of OVA, leading to the altered glycation activity of some sites.


Behavioral, Cognitive, and Motor Preparation Deficits in a Visual Cued Spatial Attention Task in Autism Spectrum Disorder.
Abnormalities in motor skills have been regarded as part of the symptomatology characterizing autism spectrum disorder (ASD). It has been estimated that 80 % of subjects with autism display "motor dyspraxia" or clumsiness that are not readily identified in a routine neurological examination. In this study we used behavioral measures, event-related potentials (ERP), and lateralized readiness potential (LRP) to study cognitive and motor preparation deficits contributing to the dyspraxia of autism. A modified Posner cueing task was used to analyze motor preparation abnormalities in children with autism and in typically developing children (N = 30/per group). In this task, subjects engage in preparing motor response based on a visual cue, and then execute a motor movement based on the subsequent imperative stimulus. The experimental conditions, such as the validity of the cue and the spatial location of the target stimuli were manipulated to influence motor response selection, preparation, and execution. Reaction time and accuracy benefited from validly cued targets in both groups, while main effects of target spatial position were more obvious in the autism group. The main ERP findings were prolonged and more negative early frontal potentials in the ASD in incongruent trials in both types of spatial location. The LRP amplitude was larger in incongruent trials and had stronger effect in the children with ASD. These effects were better expressed at the earlier stages of LRP, specifically those related to response selection, and showed difficulties at the cognitive phase of stimulus processing rather that at the motor execution stage. The LRP measures at different stages reflect the chronology of cognitive aspects of movement preparation and are sensitive to manipulations of cue correctness, thus representing very useful biomarker in autism dyspraxia research. Future studies may use more advance and diverse manipulations of movement preparation demands in testing more refined specifics of dyspraxia symptoms to investigate functional connectivity abnormalities underlying motor skills deficits in autism.


Is the relationship between early-onset cannabis use and educational attainment causal or due to common liability?
Several studies have shown that early cannabis use is correlated with poor educational performance including high school drop-out. The predominant explanation for this relationship is that cannabis use causes disengagement from education. Another explanation is that the association between early cannabis use and educational attainment is not causal, but the result of overlapping risk factors that increase the likelihood of both early cannabis use and disengagement from education. These confounding factors could be of genetic and/or environmental origin. Here we use data from a large community-based sample of adult twins (N=3337) who completed a comprehensive semi-structured telephone interview. We first apply the classical twin-design to determine whether genetic and/or environmental influences underlie the relationship between early-onset cannabis use (prior to age 18) and early school leaving. Next, with a co-twin control design we investigate whether the relationship between the two variables is more likely due to direct causality or overlapping risk factors. We find a significant phenotypic correlation between early-onset cannabis use and early school leaving (r=0.26), which could be explained by familial influences (of genetic and/or shared environmental origin). The pattern of odds ratios found in the co-twin control design is not consistent with direct causation, but rather suggests that the association is due to shared environmental factors influencing both variables. Our findings suggest that the relationship between early-onset cannabis use and school leaving is due to shared environmental risk factors influencing both the risk of early-onset cannabis use and early school leaving.


A Negative Feedback Loop and Transcription Factor Cooperation Regulate Zonal Gene Induction by 2, 3, 7, 8-Tetrachlorodibenzo-p-Dioxin in the Mouse Liver.
The cytochrome P450 (Cyp) proteins Cyp1A1 and Cyp1A2 are strongly induced in the mouse liver by the potent environmental toxicant 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), acting through the aryl hydrocarbon receptor (AHR). The induction of Cyp1A1 is localized within the centrilobular regions of the mouse liver at low doses of TCDD, progressing to pan-lobular induction at higher doses. Even without chemical perturbation, metabolic functions and associated genes are basally zonated in the liver lobule along the central-to-portal axis. To investigate the mechanistic basis of spatially restricted gene induction by TCDD, we have developed a multiscale computational model of the mouse liver lobule with single-cell resolution. The spatial location of individual hepatocytes in the model was calibrated from previously published high-resolution images. A systems biology model of the network of biochemical signaling pathways underlying Cyp1A1 and Cyp1A2 induction was then incorporated into each hepatocyte in the model. Model simulations showed that a negative feedback loop formed by binding of the induced Cyp1A2 protein to TCDD, together with cooperative gene induction by the β-catenin/AHR/TCDD transcription factor complex and β-catenin, help produce the spatially localized induction pattern of Cyp1A1. Although endogenous WNT regulates the metabolic zonation of many genes, it was not a driver of zonal Cyp1A1 induction in our model. Conclusion: In this work, we used data-driven computational modeling to identify the mechanistic basis of zonally restricted gene expression induced by the potent and persistent environmental pollutant TCDD. The multiscale model and derived results clarify the mechanisms of dose-dependent hepatic gene induction responses to TCDD. Additionally, this work contributes to our broader understanding of spatial gene regulation along the liver lobule.


Treatment of Pain in Rabbits.
Rabbits occupy facets of veterinary medicine spanning from companion mammals, wildlife medicine, zoologic species, and research models. Therefore, analgesia is required for a variety of conditions in rabbits and is a critical component of patient care. Considerations when selecting an analgesic protocol in rabbits include timing of administration, route of administration, degree or anticipated pain, ability to access or use controlled drugs, systemic health, and any potential side effects. This review focuses on pharmacologic and locoregional management of pain in rabbits and emphasizes the need for further studies on pain management in this species.


Cost-effectiveness of a workplace-based incentivized weight loss program.
To evaluate the cost-effectiveness ratios of a nursing home-based incentivized Behavioral Weight Management Program (BWMP) from the employer's perspective. Seventy-two overweight and obese health care workers completed the BWMP (n = 35 incentivized; n = 37 nonincentivized). Weight change outcomes were compared for the pre- (0) and postintervention (28 weeks) follow-up periods within and between sites. Comprehensive estimates of BWMP direct program costs and avoided costs of absenteeism and productivity improvements were estimated to evaluate a business case. There was a significant difference (P = 0.01) between the average per-participant weight change between incentivized sites (-7.4 lb) and nonincentivized sites (-2.2 lb). The cost-effectiveness ratios per pound of weight loss were $25.5 and $58.1, respectively. In general, incentivized BWMPs were more cost effective. To generate a business case, enhancement in productivity becomes a critical factor and future research needs to investigate it further.


Attenuation of hypertension development by scavenging methylglyoxal in fructose-treated rats.
Methylglyoxal is a reactive dicarbonyl intermediate of metabolism produced in the body. It reacts with certain proteins and forms damaging advanced glycation endproducts (AGEs) such as N epsilon-carboxyethyl-lysine (CEL) and N epsilon-carboxymethyl-lysine (CML). Increased methylglyoxal levels are found in diabetes mellitus and associated with hypertension development in the spontaneously hypertensive rats (SHR). The purpose of this study was to investigate whether increased endogenous formation of methylglyoxal and methylglyoxal-induced AGEs caused hypertension development in normotensive Sprague Dawley rats. The rats were fed chronically for 16 weeks with fructose, a known precursor of methylglyoxal formation. One group of rats was cotreated with fructose and metformin, an AGEs formation inhibitor. Methylglyoxal and reduced glutathione (GSH) were measured by high performance liquid chromatography, whereas hydrogen peroxide was measured by a dicholorofluorescin assay. Immunohistochemistry was performed for endothelial nitric oxide synthase (eNOS), CEL and CML. Fructose-fed rats had elevated blood pressure, serum methylglyoxal and triglycerides and reduced serum levels of GSH. Methylglyoxal, hydrogen peroxide and CEL were increased in the aorta, whereas eNOS was reduced. CEL and CML were also increased in the mesenteric artery endothelium along with media/lumen ratio, signifying structural remodelling. All the harmful changes in fructose-fed rats were attenuated in metformin and fructose cotreated rats. Increased methylglyoxal, AGEs, oxidative stress and reduced eNOS along with structural remodeling of the vessel wall in the aorta and mesenteric artery likely play a role in the pathogenesis of hypertension.


Sense and nonsense of yT-staging on MRI after chemoradiotherapy in rectal cancer.
The aim of this work was to investigate the value of rectal cancer T-staging on MRI after chemoradiotherapy (ymrT-staging) in relation to the degree of fibrotic transformation of the tumour bed as assessed using the pathological tumour regression grade (pTRG) of Mandard as a standard of reference. Twenty two radiologists, including five rectal MRI experts and 17 'nonexperts' (general/abdominal radiologists), evaluated the ymrT stage on the restaging MRIs of 90 rectal cancer patients after chemoradiotherapy. The ymrT stage was compared with the final ypT stage at histopathology; the percentages of correct staging (ymrT = ypT), understaging (ymrT < ypT) and overstaging (ymrT > ypT) were calculated and compared between patients with predominant tumour at histopathology (pTRG4-5) and patients with predominant fibrosis (pTRG1-3). Interobserver agreement (IOA) was computed using Krippendorff's alpha. Average ymrT/ypT stage concordance was 48% for the experts and 43% for the nonexperts; ymrT/ypT stage concordance was significantly higher in the pTRG4-5 subgroup (58% vs. 41% for the pTRG1-3 group; p = 0.01), with the best results for the MRI experts. Overstaging was the main source of error, especially in the pTRG1-3 subgroup (average overstaging rate 38%-44% vs. 13%-55% in the pTRG4-5 subgroup). IOA was higher for the expert versus nonexpert readers (α = 0.67 vs. α = 0.39). ymrT-staging is moderately accurate; accuracy is higher in poorly responding patients with predominant tumour but low in good responders with predominant fibrosis, resulting in significant overstaging. Radiologists should shift their focus from ymrT-staging to detecting gross residual (and progressive) disease, and identifying potential candidates for organ preservation who would benefit from further clinical and endoscopic evaluation to guide final treatment planning.


Polycomb group-mediated histone H2A monoubiquitination in epigenome regulation and nuclear processes.
Histone posttranslational modifications are key regulators of chromatin-associated processes including gene expression, DNA replication and DNA repair. Monoubiquitinated histone H2A, H2Aub (K118 in Drosophila or K119 in vertebrates) is catalyzed by the Polycomb group (PcG) repressive complex 1 (PRC1) and reversed by the PcG-repressive deubiquitinase (PR-DUB)/BAP1 complex. Here we critically assess the current knowledge regarding H2Aub deposition and removal, its crosstalk with PcG repressive complex 2 (PRC2)-mediated histone H3K27 methylation, and the recent attempts toward discovering its readers and solving its enigmatic functions. We also discuss mounting evidence of the involvement of H2A ubiquitination in human pathologies including cancer, while highlighting some knowledge gaps that remain to be addressed.


Acute effects of BZP, TFMPP and the combination of BZP and TFMPP in comparison to dexamphetamine on an auditory oddball task using electroencephalography: a single-dose study.
Piperazine-based designer drugs such as benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) have been marketed and sold as legal alternatives to dexamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) until 2008 in New Zealand. When administered in combination, BZP + TFMPP have been reported to produce drug-drug synergism in rodents by stimulating the release of dopamine and serotonin. This study was to evaluate the acute event-related potential effects of BZP, TFMPP or the combination of BZP + TFMPP compared with dexamphetamine in young healthy male adults. A double-blind, randomised, placebo-controlled study investigated the effects of BZP, TFMPP, the combination of BZP + TFMPP, and dexamphetamine on the event-related potentials during an auditory oddball task. Healthy, right-handed males were given a single oral dose of either BZP (200 mg), TFMPP (60 mg), a combination of BZP + TFMPP (100/30 mg), dexamphetamine (20 mg) or placebo (lactose) and tested both before and 120 min after drug administration. A single dose of either TMFPP (t = -2.29, p = 0.03) or dexamphetamine (t = -2.33, p = 0.02) significantly reduced the P300 amplitude. A similar trend was also found in BZP. In contrast, BZP and TFMPP in combination has no effect. Neither P300 latency nor the mean reaction time was affected by any of the drug treatments. In addition, neither the P100 nor the P200 component was significantly affected following any of the drug treatments. A single oral dose of BZP or TFMPP, but not the combination of BZP/TFMPP, affected auditory sensory-evoked P300 potential in a manner similar to dexamphetamine.


The EORTC ophthalmic oncology quality of life questionnaire module (EORTC QLQ-OPT30). Development and pre-testing (Phase I-III).
The research objective was to develop a questionnaire module to be used, in addition to the European Organisation into Research and Treatment of Cancer (EORTC) QLQ-C30, for measurement of quality of life (QL) among patients with uveal melanoma treated with methods such as transpupillary thermotherapy, plaque radiotherapy, proton beam radiotherapy, local resection, and enucleation. The present paper describes the development through Phases I-III. Relevant QL issues were generated from literature search and from interviews with ophthalmologists, nurses, and patients with uveal melanoma representing three major treatment options: enucleation, plaque brachytherapy, and proton beam therapy. The provisional module was pretested in 61 patients from Finland, Sweden, and UK. The EORTC QLQ-OPT30 module consists of 26 items for all patients, and four additional items for patients receiving treatments other than enucleation. It measures ocular irritation, vision impairment, headache, worry about recurrent disease, problems with driving, problems with appearance functional problems due to vision impairment, and problems reading. Several treatment modalities are available for uveal melanoma. There is limited knowledge of the impact of these treatments on QL in the long and short term. We hope that the OPT30 module together with the EORTC QLQ-C30 core questionnaire can be a useful tool in research.


Vascularized atrial tissue patch cardiomyoplasty with omentopexy improves cardiac performance after myocardial infarction.
The tissue-engineered cardiac patch can alleviate ventricular remodeling and improve functional recovery in experimental myocardial infarction. However, the size of the engineered patch is limited due to insufficient vascularization. This study evaluated the effects of autologous atrial tissue patch cardiomyoplasty and omentopexy in rats with myocardial infarction. Myocardial infarction was induced by left coronary artery ligation in Sprague-Dawley rats. Three weeks later, either a patch of left atrium (A group) or omentum (O group) or both (OA group) were placed over the infarct zone. The atrial tissue patch was harvested from the autologous left atrial appendage along its long axis. The rats in the Control group received rethoracotomy only. After 4 weeks, the survival of the transplanted atrial tissue patch, ventricular remodeling, and cardiac performance were examined. After 4 weeks, surviving myocardium was only detected in the OA group, as indicated by immunolabeling of cardiac troponin-I. Compared with the Control group, only animals in the OA group showed improved heart function assessed by left ventricular ejection fraction (57.9% ± 5.8% vs 47.5% ± 4.5%, p < 0.05) and left ventricular fractional shortening (25.2% ± 3.6% vs 20.7% ± 2.0%, p < 0.05). The histologic analysis demonstrated increased scar thickness in the OA group. This was accompanied by increased angiogenesis of the border zone but decreased expression and activity of matrix metalloproteinase and endothelin-1 levels. The omentopexy supported the survival of the autologous atrial tissue patch, which resulted in attenuated ventricular remodeling and restoration of heart function in rats with myocardial infarction. Our findings might represent a novel therapeutic strategy for heart failure.


An improved facility for the inspection, treatment and control of footrot.
An improved facility for the treatment of footrot is described. It consists of a continuous flow system designed for the inspection and treatment of large numbers of stock. It is considered that such a system is an essential prerequisite before embarking on a treatment programme.


Hypertension clinic proves effective.
Hypertension can best be combatted through patient education and early detection. A screening clinic can be an excellent way of reaching the public if follow-up is diligent.


Psychiatric consultation and referral.
Over half of patients with psychiatric problems are seen by primary care physicians. Many of these patients will benefit from psychiatric consultation when the diagnosis is unclear or when the patient is not responding to treatment. Good communication between referring physician, consulting physician, and patient are essential to ensure a good result. Specific problems that should lead to consultation include: patient's request, unclear diagnosis, poor results from treatment, and crisis situations such as suicide attempts. Consultation-liaison psychiatry services in the primary care setting are becoming more popular and are an excellent way of improving communication between primary care physicians and psychiatrists. Further development of this role of the psychiatrist in the primary care setting has great potential of improving the quality of care delivered patients with psychiatric problems who seek care from their primary care physician. It appears that the majority of patients continue to seek care for their psychiatric symptoms from their primary care physician. Open communication and ease of consultation with psychiatrists can make the care of these patients even more rewarding to the primary care physician.


Malignant hemangioendothelioma of the spleen. A case report with ultrastructural observations.
A case of malignant hemangioendothelioma of the spleen is reported. Light and electron microscopic evidence suggests that the tumor is a neoplastic proliferation of the two cell types, one resembling the "sinus endothelial" cell of the normal spleen, and the other resembling the "fixed reticular cell" of splenic red pulp.


Preventing eviction during pregnancy: a cost-effectiveness analysis of a theoretical safety-net program.
Eviction during pregnancy has been shown to be associated with adverse birth outcomes. A safety net program focused on covering the costs of rent during pregnancy may aid in preventing adverse complications. This study aimed to evaluate the cost-effectiveness of a program covering the cost of rent to prevent eviction during pregnancy. A cost-effectiveness model using TreeAge software was designed to evaluate the cost, effectiveness, and incremental cost-effectiveness ratio associated with eviction compared to no eviction during pregnancy. The cost of eviction from a societal perspective was compared to the annual cost of housing in the no eviction group, which was estimated by the median contract rent in the United States from 2021 national census data. Birth outcomes included preterm birth, neonatal death, and major neurodevelopmental delay. Probabilities and costs were derived from the literature. The cost-effectiveness threshold was set at $100,000/QALY. We performed univariable and multivariable sensitivity analyses to assess the robustness of the results. In our theoretical cohort of 30,000 pregnant individuals aged 15 to 44 years facing eviction annually, the no eviction during pregnancy strategy was associated with 1427 fewer preterm births, 47 fewer neonatal deaths, and 44 fewer cases of neurodevelopmental delay compared to eviction. At the median cost of rent in the United States, the no eviction strategy was associated with increased quality-adjusted life-years and decreased costs. Therefore, the no eviction strategy was the dominant strategy. In univariate sensitivity analysis varying the cost of housing, no eviction remained the cost-effective strategy and was cost-saving when rent was below $1016 per month. The no eviction strategy is cost-effective and reduces cases of preterm birth, neonatal death, and neurodevelopmental delay. When rent is below the median of $1016 per month, no eviction is the cost-saving strategy. These findings suggest that policies supporting social programmatic implementation for rent coverage for pregnant people at risk of eviction have the potential to be highly beneficial in reducing costs and disparities in perinatal outcomes.


Relationship between electrophoretic mobility of erythrocytes and blood erythrocyte count in rats.
A significant curvilinear relationship was found between erythrocyte count in rat blood and electrokinetic characteristics of these cells. Electrophoretic mobility of erythrocytes remained unchanged, slightly increased, or decreased with increasing cell count in the vascular bed depending on animal state. Excessive increase in the number of erythrocytes was accompanied by accumulation of cells with low electrophoretic mobility in the electric field.


Evaluation of antioxidant capacity and aroma quality of breast milk.
It is important to understand the difference and similarity in antioxidant capacity and aroma quality between formula and breast milk for purposes of modifying infant formulas. We evaluated the antioxidant properties and aroma quality of infant formula and breast milk. Six breast milk samples and four infant formulas were used. Antioxidant properties were measured using the following methods: 2,2-diphenyl-1-picryhydrazyl free radical scavenging capacity, oxygen radical absorbance capacity, total phenolic content, and phenolic composition. Aroma quality was determined using the electronic nose. The 2,2-diphenyl-1-picryhydrazyl free radical scavenging activity for formula and breast milk ranged from 45.3% to 61.8% and from 52.8% to 61.2%, respectively. Oxygen radical absorbance capacity ranged from 28.8 to 31.9 g/kg for formula and from 25.5 to 39.2 g/kg for breast milk. Total phenolic content ranged from 422 to 751 mg/kg and from 329to 797 mg/kg for formula and milk, respectively. p-Hydroxybenzoic acid, p-coumaric acid, and ferulic acid were detected with values ranging from 614 to 635, 1391 to 1444, and 1425 to 1490 microg/kg in breast milk and from 783 to 3594, 1449 to 1510, and 1447 to 1561 microg/kg in formulas. Electronic nose results indicated that the aroma quality of formula controls 2, 3, and 4 was similar to that of breast milk. Differences and similarities in antioxidant properties and aroma quality were found among some of the formulas and breast milk. The contribution of phenolic acids to total antioxidant capacity was limited.


Author Correction: Amine hemilability enables boron to mechanistically resemble either hydride or proton.
During the revision of this Article prior to publication, a computational study was reported (Vallejos, M. M. & Pellegrinet, S. C. Theoretical study of the BF3-promoted rearrangement of oxiranyl N-methyliminodiacetic acid boronates. J. Org. Chem. 82, 5917-5925; 2017) that evaluates the nucleophilic boryl transfer mechanism predicted in this Article; this reference has now been added as number 19, and the subsequent references renumbered.


Inflammation and hearing status in mid-childhood and mid-life: a population-based cross-sectional study.
Lifelong inflammation - known to be associated with many non-communicable diseases - has not been thoroughly investigated in hearing. We aimed to determine if glycoprotein A (GlycA), a novel biomarker of chronic inflammation, is associated with hearing acuity in mid-childhood and mid-life. Population-based cross-sectional study within the Longitudinal Study of Australian Children with plasma GlycA and audiometry data (1169 children and 1316 parents). We calculated high Fletcher Index (mean threshold across 1, 2 and 4 kHz), defining hearing loss as threshold >15 decibel hearing level (dB HL) (better ear). Linear/logistic regression quantified associations of GlycA with hearing threshold/loss. Mean [standard deviation (SD)] high Fletcher Indices (dB HL) were 8.0 (5.7) for children and 13.1 (6.9) for adults, with 8.7% and 26.1% respectively showing hearing loss. 1-SD rise in GlycA (children 0.13 mmol/L, adults 0.17 mmol/L) predicted higher hearing thresholds for the lower individual frequencies [1 kHz: children β 0.8, 95% confidence interval (CI) 0.3-1.3; adults β 0.8, 95% CI 0.2-1.4]. This same pattern was evident for the high Fletcher Index (children β 0.7, 95% CI 0.3-1.1; adults β 0.8, 95% CI 0.3-1.4). This translated into 1-SD rise in GlycA predicting adult hearing loss [odds ratio (OR) 1.2, 95% CI 1.0-1.5] with similar but attenuated patterns in children. GlycA is associated with poorer hearing by mid-childhood. This potentially reframes hearing loss as a life-course condition with inflammatory antecedents common to other non-communicable diseases. Replication and mechanistic studies could inform causal inference and early prevention efforts.


Current situation and challenges concerning nursing education in Pakistan.
Despite the advancements in the nursing education and nursing education-based research worldwide, nursing remains an undervalued profession in Pakistan and the nursing education system is steadily evolving. The purpose of this discussion is two-fold: (i) to describe the nursing education system in Pakistan and (ii) to analyze the status, trends, and challenges in nursing education and nursing education-based research in comparison with the international nursing education standards.


A randomized controlled trial of two simple mind-body programs, Kirtan Kriya meditation and music listening, for adults with subjective cognitive decline: Feasibility and acceptability.
In this randomized controlled trial (RCT), we assessed the feasibility and acceptability of two simple home-based relaxation programs in adults experiencing subjective cognitive decline, a strong predictor of Alzheimer's disease. Sixty participants were randomized to a beginner Kirtan Kriya meditation (KK) program or a music listening (ML) program. Participants were asked to practice 12min daily for the first 12 weeks, then as often as they liked for the following 3 months. Participants underwent assessments at baseline, 12 weeks, and 6 months to evaluate changes in key outcomes. Feasibility and acceptability were evaluated by measuring recruitment and retention rates, assessment visit attendance, practice adherence, and treatment expectancy; exit questionnaires completed at 12 weeks and 6 months provided additional data regarding participant experience with the study, perceived barriers to and facilitators of practice, reasons for drop-out, and views regarding the assigned intervention. Fifty-three participants (88%) completed the 6 month study. Adherence in both groups was excellent, with participants completing 93% (91% KK, 94% ML) of sessions on average in the first 12 weeks, and 71% (68% KK, 74% ML) during the 3 month, practice-optional, follow-up period. At week 12, over 80% of participants indicated they were likely to continue practicing following study completion. Responses to both structured and open-ended exit questionnaire items also suggested high satisfaction with both programs. Findings of this RCT of a beginner meditation practice and a simple ML program suggest that both programs were well accepted and the practices are feasible in adults with early memory loss.


Investigation of thermodynamic properties of poly(methyl methacrylate-co-n-butylacrylate-co-cyclopentyl styryl-polyhedral oligomeric silsesquioxane) by inverse gas chromatography.
The thermodynamic properties of poly(methyl methacrylate-co-butyl acrylate-co-cyclo -pentylstyryl polyhedral oligomeric silsesquioxane) (poly(MMA-co-BA-co-styryl-POSS)) were investigated by means of inverse gas chromatography (IGC) using 20 different kinds of solvents as the probes. Some thermodynamic parameters, such as molar heats of sorption, weight fraction activity coefficient, Flory-Huggins interaction parameter, partial molar heats of mixing and solubility parameter were obtained to judge the interactions between POSS-contained polymers and solvents and the solubility of the polymers in these solvents. It was found that acetates, aromatic hydrocarbons and hydrocarbon halides were good solvents, n-hexane, ethanol, n-propanol, n-butanol and n-pentanol were moderate solvents, while n-heptane, n-octane, n-nonane, n-decane and methanol were poor solvents for all POSS-contained polymers within the experimental temperature range. Incorporation of POSS in polymer increased the solubility of polymers in solvents, and the more the POSS in polymer was, the better the solubility was and stronger the hydrogen bonding interaction was, but the POSS content in polymers seemed to have no obvious influence on the solubility parameter of polymers.


Evolution of novel O-methyltransferases from the Vanilla planifolia caffeic acid O-methyltransferase.
The biosynthesis of many plant secondary compounds involves the methylation of one or more hydroxyl groups, catalyzed by O-methyltransferases (OMTs). Here, we report the characterization of two OMTs, Van OMT-2 and Van OMT-3, from the orchid Vanilla planifolia Andrews. These enzymes catalyze the methylation of a single outer hydroxyl group in substrates possessing a 1,2,3-trihydroxybenzene moiety, such as methyl gallate and myricetin. This is a substrate requirement not previously reported for any OMTs. Based on sequence analysis these enzymes are most similar to caffeic acid O-methyltransferases (COMTs), but they have negligible activity with typical COMT substrates. Seven of 12 conserved substrate-binding residues in COMTs are altered in Van OMT-2 and Van OMT-3. Phylogenetic analysis of the sequences suggests that Van OMT-2 and Van OMT-3 evolved from the V. planifolia COMT. These V. planifolia OMTs are new instances of COMT-like enzymes with novel substrate preferences.


Podophyllum hexandrum prevents radiation-induced neuronal damage in postnatal rats exposed in utero.
Podophyllum hexandrum has been shown to mitigate radiation injuries and especially the haemopoietic syndrome in adult mice. To monitor the radiation-induced changes in the nervous system, the neurons of postnatal young mice and their modification by P. hexandrum, were studied histologically for differences in the apical and basal dendritic branching and intersections in the CA1 neurons of the hippocampal region of rats which were delivered a 2 Gy gamma dose while in utero (day 17 of gestation). Irradiation significantly reduced the dendritic branching and intersections but pre-irradiation administration of the extract of P. hexandrum (i.p. 200 mg/kg/b.w., 2 h) reduced the damage in postnatal young mice. These studies indicate that P. hexandrum provides protection to neurons against radiation-induced damage and the mechanism of neuronal damage and its repair need to be investigated further.


Platelet-derived growth factor-C and -D in the cardiovascular system and diseases.
The cardiovascular system is among the first organs formed during development and is pivotal for the formation and function of the rest of the organs and tissues. Therefore, the function and homeostasis of the cardiovascular system are finely regulated by many important molecules. Extensive studies have shown that platelet-derived growth factors (PDGFs) and their receptors are critical regulators of the cardiovascular system. Even though PDGF-C and PDGF-D are relatively new members of the PDGF family, their critical roles in the cardiovascular system as angiogenic and survival factors have been amply demonstrated. Understanding the functions of PDGF-C and PDGF-D and the signaling pathways involved may provide novel insights into both basic biomedical research and new therapeutic possibilities for the treatment of cardiovascular diseases.


Increased serum interleukin-6 level as a predictive biomarker for atrial fibrillation: A systematic review and meta-analysis.
Atrial fibrillation (AF) is related to a higher risk of thromboembolic events and mortality. Some studies have demonstrated that the inflammatory biomarker interleukin-6 (IL-6) is associated with a higher risk of higher thrombosis in AF patients, but the real effect of IL-6 remains a controversy. We conducted a systematic review and meta-analysis to investigate the association between IL-6 and thromboembolic events, as well as bleeding events, acute coronary syndrome (ACS) events and all-cause mortality in AF. A total of five studies involving 22 928 patients met our inclusion criteria for the systematic review. The higher level of IL-6 in AF patients is related to long-term thromboembolic events including stroke (RR 1.44, CI 95% 1.09-1.90, p=0.01). IL-6 meant a higher risk of long-term bleeding risk (RR 1.36, CI 95% 1.06-1.74, p=0.02), ACS risk (RR 1.81, CI 95% 1.43-2.30, p<0.001) and all-cause mortality (RR 2.35, CI 95% 2.09-2.65, p<0.001). A higher level of IL-6 may predict a greater number of long-term thromboembolic events and bleeding events, ACS events and mortality in AF patients. Further studies such as the cut-off point of IL-6 need to be conducted in the future.