The regulation of hexokinase and phosphoglucomutase activity in Aspergillus nidulans.
The levels of glucose-6-phosphate and 6-phosphogluconate dehydrogenase in wildtype cells of Aspergillus nidulans varied with the carbon and nitrogen source. In general, hexokinase activity did not vary with carbon or nitrogen source. The ammonium derepressed mutant amrA1 had only 50% of the wildtype level of hexokinase. Phosphoglucomutase activity was low in wildtype cells grown with nitrate, but high in cells grown with ammonium when glucose was the carbon source. A non-inducible mutant, nirA-1, in the regulatory gene for nitrate reductase, had high phosphoglucomutase activity when grown with nitrate or ammonium. A constitutive mutant nirAc1, in the regulatory gene for nitrate reductase had low phosphoglucomutase activity when grown with nitrate or ammonium. The mutants nir-1 and nirAc1 are recessive and semi-dominant respectively for abnormal phosphoglucomutase activity.


Psychological predictors of retention in a low-threshold methadone maintenance treatment for opioid addicts: a 1-year follow-up study.
This study investigated the role of psychological variables and judicial problems in treatment retention for a low-threshold methadone program in Montreal, Canada. Logistic regression analyses were computed to examine associations between psychological variables (psychological distress, self-esteem, stages of change), criminal justice involvement, and treatment retention for 106 highly-disorganized opioid users. Higher methadone dosage was associated with increased odds of treatment retention, whereas criminal charges and lower self-esteem decreased these odds. Psychological variables could be identified early in treatment and targeted to increase potential treatment retention. Financial support for this study was provided by the Fonds de Recherche en Santé du Québec.


Dissociation of tubulin assembly-inhibiting and aggregation-promoting activities by a vinblastine derivative.
A fluorescent vinblastine analogue, vinblastine-4'-anthranilate (Antvin), that binds to the vinca site on tubulin, inhibits tubulin assembly but does not lead to spiral or other large aggregate formation at concentrations up to 1.6 mM. As judged by turbidity, 90 degrees light scattering and fluorescence anisotropy, little aggregation could be detected. This is in marked contrast to vinblastine and suggests that inhibition of assembly and aggregate formation can be dissociated from each other by suitable substitution in vinblastine.


Muscle damage responses of the elbow flexors to four maximal eccentric exercise bouts performed every 4 weeks.
Since little is known about the repeated bout effect of more than two eccentric exercise bouts, this study compared muscle damage responses among four exercise bouts. Fifteen young (21.8 +/- 1.9 years) men performed four bouts of 30 maximal isokinetic eccentric contractions of the elbow flexors every 4 weeks. Maximal voluntary elbow flexion isometric and concentric strength, range of motion at the elbow joint (ROM), upper arm circumference, blood markers of muscle damage, and muscle soreness were measured before and up to 120 h following each bout. Changes in all measures following the second to fourth bouts were significantly (P < 0.05) smaller than those after the first bout. The decreases in strength and ROM immediately after the fourth bout were significantly (P < 0.05) smaller than other bouts. It is concluded that the first bout confers the greatest adaptation, but further adaptation is induced when the exercise is repeated more than three times.


Vehicle effects on in vitro transdermal absorption of sevoflurane in the bullfrog, Rana catesbeiana.
The experimental objectives were to identify a vehicle which produces a homogenous formulation when combined with the anesthetic solution sevoflurane and understand the dermal absorption of sevoflurane in silastic membranes and amphibian skin in vitro utilizing a flow-through diffusion system. Seven vehicles were evaluated in varying ratios with 5 formulations resulting in the desired homogenous consistency for practical application. Sevoflurane diffusion across silastic membranes was influenced by pluronic/lecithin organogel (PLO), pluronic F 127 20% gel, and sterile lube. Flux and permeability across silastic membranes were significantly greater in sterile lube than in the other formulations. While no significant vehicle effects were observed in bullfrog skin, the flux-time profiles suggest that sevoflurane diffusion in bullfrog skin may be positively influenced by PLO. Future in vivo studies are required to assess sevoflurane retention after removal of these formulations to more accurately control the plane of anesthesia in amphibians.


Mineral metabolism and vitamin D in chronic kidney disease--more questions than answers.
Patients with chronic kidney disease (CKD) are at increased risk of total and cardiovascular morbidity and mortality. The underlying pathophysiology of this association remains largely unexplained and there is currently no clear interventional pathway. Emphasis has been placed on measuring serum levels of calcium, phosphate and parathyroid hormone (PTH) to monitor disease progression, driven by the assumption that achieving values within the 'normal' range will translate into improved outcomes. Retrospective studies have provided a body of evidence that abnormal levels of mineral biomarkers, and phosphate in particular, are associated with clinical events. Disturbances in vitamin D metabolism are also likely to contribute to the pathophysiology of CKD. Designing studies that yield useful information has proved to be difficult, partly owing to conceptual and financial limitations, but also because of the tight interdependency of calcium, phosphate and PTH, and the potential impact of vitamin D on these mineral metabolites. An intervention that perturbs any one of these factors is likely to exert effects on the others, making isolation of the individual variables almost impossible. However, some therapies in current use have the potential to act as probes to answer questions relating to the association between mineral biomarkers and outcomes in CKD.


Cytomegalovirus seropositivity is independently associated with cardiovascular disease in non-dialysis dependent chronic kidney disease.
Cardiovascular disease (CVD) is the leading cause of early death in patients with chronic kidney disease (CKD). Previous work has described an association between Cytomegalovirus (CMV) seropositivity and CVD amongst patients with dialysis dependent end stage renal disease. Whether CMV seropositivity is associated with CVD in non-dialysis dependent CKD has not been established. Investigate whether past CMV infection is associated with prevalent CVD in patients with non-dialysis dependent CKD. A retrospective observational study using the Renal Impairment in Secondary Care cohort, a study evaluating bio-clinical determinants of outcomes in patients with progressive CKD. We assayed cryopreserved serum samples collected at inception for anti-CMV IgG antibodies from 764 patients with stages 2 to 5 CKD (pre-dialysis) and investigated its relationship with prevalent CVD. Median estimated glomerular filtration was 24 ml/min/1.73 m2 (IQR 19-32). Sixty-eight percent of patients were CMV seropositive. CMV seropositivity was associated with older age, non-Caucasian ethnicity, diabetes and higher social deprivation index score. On univariable analysis, CMV seropositivity correlated with higher systolic blood pressure (P = 0.044), prevalent CVD (P < 0.001), ischaemic heart disease (P < 0.001) and cerebrovascular disease (P = 0.022). On multivariable analysis, CMV seropositive patients nearly twice as likely to have CVD compared to seronegative patients [Odds Ratio (OR) = 1.998, CI 1.231-3.242, P = 0.005]. In patients with non-dialysis CKD, CMV seropositivity is independently associated with a higher prevalence of CVD.


Hypoglycemia due to PI3K/AKT/mTOR signaling pathway defects: two novel cases and review of the literature.
The PI3K/AKT/mTOR signaling pathway is important for the regulation of multiple biological processes, including cellular growth and glucose metabolism. Defects of the PI3K/AKT/mTOR signaling pathway are not usually considered among the genetic causes of recurrent hypoglycemia in childhood. However, accumulating evidence links hypoglycemia with defects of this pathway. We describe here two cases of macrocephaly and hypoglycemia bearing genetic defects in genes involved in the PI3K/AKT/mTOR pathway. The first patient was diagnosed with a PTEN hamartoma tumour syndrome (PTHS) due to the de novo germline missense mutation c.[492 + 1G > A] of the PTEN gene. The second patient presented the autosomal dominant mental retardation-35 (MDR35) due to the heterozygous missense mutation c.592G > A in the PPP2R5D gene. A review of the literature on hypoglycemia and PI3K/AKT/mTOR signaling pathway defects, with a special focus on the metabolic characterization of hypoglycemia, is included. PI3K/AKT/mTOR pathway defects should be included in the differential diagnosis of patients with hypoglycemia and macrocephaly. Clinical suspicion and molecular confirmation are important, not just for an accurate genetic counselling but also for defining the follow-up management, including cancer surveillance. The biochemical profile of hypoglycemia varies among patients. While most patients are characterized by low plasmatic insulin levels, hyperinsulinemia has also been observed. Large patient cohorts are needed to gain a comprehensive profile of the biochemical patterns of hypoglycemia in such defects and eventually guide targeted therapeutic interventions.


Virtual High-Throughput Screening for Matrix Metalloproteinase Inhibitors.
Structure-based virtual screening (SBVS) is a common method for the fast identification of hit structures at the beginning of a medicinal chemistry program in drug discovery. The SBVS, described in this manuscript, is focused on finding small molecule hits that can be further utilized as a starting point for the development of inhibitors of matrix metalloproteinase 13 (MMP-13) via structure-based molecular design. We intended to identify a set of structurally diverse hits, which occupy all subsites (S1'-S3', S2, and S3) centering the zinc containing binding site of MMP-13, by the virtual screening of a chemical library comprising more than ten million commercially available compounds. In total, 23 compounds were found as potential MMP-13 inhibitors using Glide docking followed by the analysis of the structural interaction fingerprints (SIFt) of the docked structures.


Mechanisms of transport enhancement for self-propelled nanoswimmers in a porous matrix.
Micro/nanoswimmers convert diverse energy sources into directional movement, demonstrating significant promise for biomedical and environmental applications, many of which involve complex, tortuous, or crowded environments. Here, we investigated the transport behavior of self-propelled catalytic Janus particles in a complex interconnected porous void space, where the rate-determining step involves the escape from a cavity and translocation through holes to adjacent cavities. Surprisingly, self-propelled nanoswimmers escaped from cavities more than 20× faster than passive (Brownian) particles, despite the fact that the mobility of nanoswimmers was less than 2× greater than that of passive particles in unconfined bulk liquid. Combining experimental measurements, Monte Carlo simulations, and theoretical calculations, we found that the escape of nanoswimmers was enhanced by nuanced secondary effects of self-propulsion which were amplified in confined environments. In particular, active escape was facilitated by anomalously rapid confined short-time mobility, highly efficient surface-mediated searching for holes, and the effective abolition of entropic and/or electrostatic barriers at the exit hole regions by propulsion forces. The latter mechanism converted the escape process from barrier-limited to search-limited. These findings provide general and important insights into micro/nanoswimmer mobility in complex environments.


An effective psychological intervention in reducing internalized stigma and improving recovery outcomes in people with severe mental illness.
Internalized stigma reduces chances of clinical and subjective recovery in people with schizophrenia and other severe mental illness. To date, there is not enough evidence about an effective intervention to reduce internalized stigma that promotes clinical and subjective recovery in people with high internalized stigma and severe mental illness. The aim of this study was to evaluate the efficacy of a new psychological intervention named "Coping Internalized Stigma Program" (PAREI). An eight-session structured group-based integrative intervention was designed including psychoeducation, cognitive behavioural therapy, and mutual support. Fifty-four individuals with severe mental illness and a high level of internalized stigma were selected and randomly assigned to the PAREI intervention (n = 29) or to the control group (n = 25). The results of mixed ANOVAs revealed improvements in the PAREI group after treatment in the emotional dimension of internalized stigma, perceived legitimacy of discrimination, recovery expectations, and social functioning as compared to the control group. The results indicate that the PAREI represents a promising intervention tool to reduce internalized stigma, and to improve clinical and subjective recovery markers in people with severe mental illness and high internalized stigma.


Long-term cohort study of chronic hepatitis C according to interferon efficacy.
We investigated the prognosis of patients with C-viral chronic liver disease (C-CLD) according to the efficacy of interferon (IFN) therapy in a long-term retrospective cohort study. Of 721 patients with C-CLD who underwent liver biopsy between January 1986 and December 2005, 577 were treated with IFN, and 221 of these patients achieved sustained virological response (SVR) with a follow-up period of 9.9 ± 5.3 years. The annual rate of HCC development was 2.71%/year, 2.31%/year, and 0.24%/year in untreated, non-SVR, and SVR patients, respectively. Multivariate Cox proportional regression analysis showed that the risk of HCC development was significantly lower in SVR patients than in untreated or non-SVR patients; moreover, this risk was similar in non-SVR patients and untreated patients. The annual mortality rate in overall death was 3.19%/year, 1.98%/year, and 0.44%/year in untreated, non-SVR, and SVR patients, respectively. Multivariate Cox proportional hazards regression analysis showed that the SVR status reduced the risk ratio for overall death to 0.173, whereas the non-SVR status did not significantly reduce the risk ratio. The risk ratio of overall death and HCC development was significantly reduced in SVR patients, whereas no significant reduction was found in non-SVR patients in a long-term cohort study.


Early modifications of nucleic acid metabolism and nuclear lipid biosynthesis associated with antiproliferative activity of interferon-alpha on Daudi lymphoma cells.
The effect of human recombinant DNA interferon-alpha type A (rIFN alpha A) on nuclear lipid biosynthesis and on in vitro nucleic acid synthesis was investigated in Daudi lymphoma cells sensitive (Daudi Is) or resistant (Daudi Ir) to the antiproliferative activity of this glycoprotein. In the Daudi Is studied at 90 min and up to 8 h, relative proportions of 3H-labeled nuclear lipids were reproducibly altered as compared to controls: phosphatidylcholine increased while phosphatidylserine and total neutral lipids decreased. These changes were not detected in parallel studies of the whole cell extracts. No significant changes in the profiles of nuclear lipids were observed in Daudi Ir. Decreased rates of alpha DNA polymerase and of RNA transcription were evident within 90 min in the Daudi Is nuclei but not in untreated controls or nuclei from rIFN alpha A-treated Daudi Ir cells, thus suggesting a possible relationship of the rapid alterations of nuclear lipid biosynthesis in Daudi Is cells to the rIFN alpha A antiproliferative activity.


Serum lactate dehydrogenase isoenzyme pattern in neuroblastoma.
Total serum LDH activity and isoenzyme distribution were studied in children with neuroblastoma at the time of hospital admission. The total LDH was determined in 26 cases, and 20 (77%) of them showed elevation of its activity. On the other hand, in 9 of these 26 cases, the isoenzyme distribution was determined along with the total LDH. All 9 cases, 4 of them with normal total LDH activity, showed an abnormal isoenzyme pattern with a percentage increase in the intermediate fractions (malignant pattern). The results suggest the usefulness of the determination of serum LDH isoenzymes as a screening procedure in children with malignant tumors including neuroblastoma.


Corrigendum to "Cross-sectional analysis of students and school workers reveals a high number of asymptomatic SARS-CoV-2 infections during school reopening in Brazilian cities" [Heliyon 8 (11) (November 2022) Article e11368].
[This corrects the article DOI: 10.1016/j.heliyon.2022.e11368.].


Autopsy-confirmed multiple sclerosis in a white South African. A case report.
The clinical and autopsy findings of a 31-year-old white South African woman with multiple sclerosis are described. Diagnostic, epidemiological and therapeutic aspects are discussed.


Incidence and predictors of Melody® valve endocarditis: a prospective study.
Percutaneous pulmonary valve replacement (PPVR) has achieved standard of care for the management of dysfunctional right ventricular outflow tract. Because of increasing reports of Melody(®) valve (Medtronic, Inc., Minneapolis, MN, USA) infective endocarditis (IE), we aimed to evaluate its incidence and predictors of occurrence. We collected data on all patients who received a Melody valve in the pulmonary position from 2009 to 2012. A total of 86 consecutive patients underwent PPVR from 2009 to 2012; of these, five developed IE (5.8%). Freedom from IE was 91% at 50 months. Baseline demographics, type of conduit, PPVR procedural success, residual gradients and in situ duration of Melody valve were similar in IE and non-IE patients. A significant number of IE patients had additional unprotected invasive procedures during follow-up and abruptly discontinued antiplatelet therapy (P=0.0139 and P=0.002, respectively). The cumulative probability of survival without cardiovascular events for IE patients was 20% at 20 months, compared with 98.1% for non-IE patients (P<0.0001). Death was statistically associated with IE. Early- and late-onset IE of the Melody valve is emerging as a catastrophic complication of PPVR. Abrupt aspirin discontinuation and additional unprotected invasive procedures during follow-up are significant predictors of Melody valve IE. Owing to its rapidly progressive nature, aggressive invasive management should not be delayed.


TLSLeAF: automatic leaf angle estimates from single-scan terrestrial laser scanning.
Leaf angle distribution (LAD) in forest canopies affects estimates of leaf area, light interception, and global-scale photosynthesis, but is often simplified to a single theoretical value. Here, we present TLSLeAF (Terrestrial Laser Scanning Leaf Angle Function), an automated open-source method of deriving LADs from terrestrial laser scanning. TLSLeAF produces canopy-scale leaf angle and LADs by relying on gridded laser scanning data. The approach increases processing speed, improves angle estimates, and requires minimal user input. Key features are automation, leaf-wood classification, beta parameter output, and implementation in R to increase accessibility for the ecology community. TLSLeAF precisely estimates leaf angle with minimal distance effects on angular estimates while rapidly producing LADs on a consumer-grade machine. We challenge the popular spherical LAD assumption, showing sensitivity to ecosystem type in plant area index and foliage profile estimates that translate to c. 25% and c. 11% increases in canopy net photosynthesis (c. 25%) and solar-induced chlorophyll fluorescence (c. 11%). TLSLeAF can now be applied to the vast catalog of laser scanning data already available from ecosystems around the globe. The ease of use will enable widespread adoption of the method outside of remote-sensing experts, allowing greater accessibility for addressing ecological hypotheses and large-scale ecosystem modeling efforts.


Chloroquine in the Ugandan market fails quality test: a pharmacovigilance study.
Antimalaria treatment failure has been partly attributed to poor quality antimalarials in the drug market. A 1998 survey in Kampala showed that 55% of tablets and 62% of injection forms of chloroquine failed the quality test. This study was carried out as a follow-up to establish the quality of chloroquine tablet and injection dosage forms in the Ugandan drug market from June - November 2001. Chloroquine tablets and injection dosage forms, randomly purchased from pharmacies and drug shops in the four regions of Uganda, were assayed for content of the active ingredient according to the USP standard, using the HPLC method. Of the tablets samples surveyed, 39% failed the content test with 11% having sub-normal and 28% having supra-normal amounts, whilst 51% of the injection samples failed with 40% and 11% having sub-normal and supra-normal amounts respectively. There was overall improvement in the quality of chloroquine in Uganda compared with the 1998 figures, but the failure rates are still unacceptably high. The variations in the chloroquine amounts in both the tablet and injection forms may contribute to chloroquine toxicity or poor response during treatment. More vigorous pharmacovigilance on drugs entering the Ugandan drug market is needed.


hnRNPLL controls pluripotency exit of embryonic stem cells by modulating alternative splicing of Tbx3 and Bptf.
The regulatory circuitry underlying embryonic stem (ES) cell self-renewal is well defined, but how this circuitry is disintegrated to enable lineage specification is unclear. RNA-binding proteins (RBPs) have essential roles in RNA-mediated gene regulation, and preliminary data suggest that they might regulate ES cell fate. By combining bioinformatic analyses with functional screening, we identified seven RBPs played important roles for the exit from pluripotency of ES cells. We characterized hnRNPLL, which mainly functions as a global regulator of alternative splicing in ES cells. Specifically, hnRNPLL promotes multiple ES cell-preferred exon skipping events during the onset of ES cell differentiation. hnRNPLL depletion thus leads to sustained expression of ES cell-preferred isoforms, resulting in a differentiation deficiency that causes developmental defects and growth impairment in hnRNPLL-KO mice. In particular, hnRNPLL-mediated alternative splicing of two transcription factors, Bptf and Tbx3, is important for pluripotency exit. These data uncover the critical role of RBPs in pluripotency exit and suggest the application of targeting RBPs in controlling ES cell fate.


Etiopathogenesis of arrhythmogenic right ventricular cardiomyopathy.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterised by progressive fibro-fatty replacement of right ventricular myocardium. Earlier studies described ARVC as non-inflammatory, non-coronary disorder associated with arrhythmias, heart failure and sudden death due to functional exclusion of the right ventricle. Molecular genetic studies have identified nine different loci associated with ARVC; accordingly each locus is implicated for each type of ARVC (ARVC1-ARVC9). So far five genes have been identified as containing pathogenic mutations for ARVC. Though mutations in each of the gene/s indicate disruption of different pathways leading to the condition, the exact pathogenesis of the condition is still obscure. This review tries to understand the pathogenesis of the condition by examining the individual proteins implicated and relate them to the pathways that could play a role in the aetiology of the condition. Cardiac ryanodine receptor (RYR-2), which regulates intra-cellular Ca(2+) concentration by releasing Ca(2+) reserves from the sarcoplasmic reticulum (SR), was the first gene for ARVC. The mutation in this gene is believed to disrupt coupled gating of RYR-2, causing after-depolarisation, leading to arrhythmias followed by structural changes due to altered intra-cellular Ca(2+) levels. Three other genes implicated for ARVC, plakoglobin (Naxos disease), desmoplakin (ARVC8) and plakophilin (ARVC9) have prompted the speculation that ARVC is primarily a disease of desmosomes. But identification of TGFbeta-3 for ARVC1 and the role of all these three genes (plakoglobin, desmoplakin and plakophilin) in cardiac morphogenesis indicate some kind of signal-transducing pathway disruption in the condition. The finding that ARVC as a milder form of Uhl's anomaly indicates similar ontogeny for the condition. Further, discovery of apoptotic cells in the autopsy of the right ventricular myocardium of ARVC patients does indicate a common pathway for different types of ARVCs, which is more specific for the right ventricular myocardium involving desmosomal plaque proteins, growth factors and Ca(2+) receptors.


Daurisoline Inhibits ESCC by Inducing G1 Cell Cycle Arrest and Activating ER Stress to Trigger Noxa-Dependent Intrinsic and CHOP-DR5-Dependent Extrinsic Apoptosis via p-eIF2α-ATF4 Axis.
Esophageal squamous cell carcinoma (ESCC), one of the most malignant human cancers in clinic, requires novel treatment. Daurisoline (DAS) is a component of traditional Chinese herb, which exhibits anti-cancer effects by autophagy inhibition and metastasis suppression. However, the effect and mechanism of DAS on ESCC remain unclear. Here, we found that DAS inhibited cell proliferation and colony formation in both human ESCC cell lines EC1 and ECA109. Mechanistically, DAS induced p21-/p27-dependent G1 phase cell cycle arrest and apoptosis in a dose-dependent manner. The induction of apoptosis by DAS was largely dependent on the activation of the transcription factor ATF4 and its downstream NOXA-dependent intrinsic and CHOP-DR5-dependent extrinsic apoptotic pathway. ATF4 activation induced by DAS was due to the generation of excessive reactive oxygen species (ROS) and the subsequent activation of endoplasmic reticulum (ER) stress through the p-eIF2α-ATF4 signal pathway, which can be largely abrogated by N-acetylcysteine (NAC), a scavenger of ROS. Moreover, DAS treatment significantly inhibited tumor growth and reduced tumor weight in the tumor xenograft mouse model by up-regulating key proteins related to cell cycle arrest and apoptotic pathway. Taken together, these findings identified DAS as a novel candidate for the treatment of ESCC.


Cerebellar AMPA/KA receptor antagonism by CNQX inhibits vestibuloocular reflex adaptation.
Vestibuloocular reflex (VOR) performance and adaptation have been investigated during antagonism of cerebellar AMPA/quisqualate and kainate receptors (AMPA/KA) by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Injection of CNQX into the vestibulo-cerebellum of the goldfish before adaptation significantly inhibited and, at the highest dosage, completely prevented acquisition of adaptive reflex gain increases and decreases during a 3-h training period. Injection of CNQX before initiation of VOR adaptive training did not affect pre-adapted baseline performance of the reflex. Injection of CNQX, 1 to 2 h after the initiation of training did not alter the performance of adaptive gain increases that occurred before the injection. If injection of CNQX occurred at the end of adaptive training, there was an accelerated loss of the previously adapted gain changes during the retention period when the animal remained stationary in the dark. CNQX injection did not produce any permanent or long-term deficits, because goldfish could be retrained 48 h later to produce adaptive VOR gain changes similar to control animals. Thus, this work demonstrates that the AMPA/KA receptors located in the vestibulo-cerebellum of the goldfish are necessary for acquisition of short-term adaptive VOR gain increases and decreases. The deficit in adaptive capability was not the result of a deficit in performance, because CNQX did not inhibit an adaptive change that had already occurred as long as the adapting vestibular and visual stimulation continued. This adaptive performance could possibly be maintained by other glutamatergic (metabotropic) receptors located on the Purkinje cells. The retention of adapted gain increases and decreases after CNQX application was inhibited because AMPA/KA antagonism accelerated VOR gain loss after the completion of training when no vestibular or visual stimulation was present. Because the AMPA/KA receptors are located only in the molecular layer of the goldfish cerebellum, these results are, presumably, the result of AMPA/KA receptor antagonism at synapses located on the Purkinje cell dendrite tree.


Inhibitory effects of acetylcholine on neurones in the feline nucleus reticularis thalami.
1. Short iontophoretic pulses of acetylcholine (ACh) inhibited almost every spontaneously active cell encountered in the nucleus reticularis thalami of cats anaesthetized with a mixture of halothane, nitrous oxide and oxygen. On 200 cells the mean current needed to eject an effective inhibitory dose of ACh was 67 +/- 2 nA. When the ACh-evoked inhibition was mimicked by gamma-aminobutyric acid (GABA) or glycine on the same cell, the current required to release ACh was found to be approximately twice as great as that required to release an equally effective dose of GABA or glycine. 2. ACh inhibitions developed with a latency which was very much shorter than that for ACh excitation in cells of the ventrobasal complex. The latency of the ACh-evoked inhibition was as rapid as the onset and offset of the excitation of the same cells glutamate and their inhibition by GABA or glycine. 3. The firing pattern of ACh-inhibited neurones in the nucleus reticularis was characterized by periods of prolonged, high frequency bursts, and their mean firing frequency was 22 Hz. Raster dot displays and interspike interval histograms showed that whereas ACh suppressed the spikes that occurred between bursts much more readily than those that occurred during bursts, all spikes were equally sensitive to the depressant action of GABA and glycine. Large doses of ACh provoked or exaggerated burst activity. 4. ACh-evoked inhibition was extremely sensitive to blockade by short iontophoretic applications of atropine, which had no effect on the inhibitions evoked on the same cell equipotent doses of GABA or glycine. The ACh-evoked inhibitions were also antagonized by dihydro-beta-erythroidine released with slightly larger currents. When tested on the same cell, small iontophoretic applications of picrotoxin and bicuculline methoiodide blocked the inhibition evoked by GABA but had no effect on that evoked by ACh. Iontophoretic strychnine only rarely affected the inhibition evoked by ACh, while readily blocking the inhibition evoked on the same cell by an equipotent dose of glycine. In two cats, intravenous strychnine (1-2 mg/kg) had no effect on the ACh-evoked inhibition, while greatly reducing the sensitivity of the cell under study to glycine. 5. Only four out of forty-eight ACh-inhibted cells tested were inhibited by iontophoretic applications of either guanosine or adenosine 3':5'-phosphate. 6. Cells of the nucleus reticularis have been shown to have an inhibitory action on the thalamic relay cells, which are excited by ACh. It is suggested that the presence of both ACh excited and inhibited cells in different nuclei of the thalamus could be of considerable functional significance in gating sensory transmission through the thalamus.


Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus.
A major systemic lupus erythematosus (SLE) susceptibility locus lies within a common inversion polymorphism region (encompassing 3.8 - 4.5 Mb) located at 8p23. Initially implicated genes included FAM167A-BLK and XKR6, of which BLK received major attention due to its known role in B-cell biology. Recently, additional SLE risk carried in non-inverted background was also reported. In this case -control study, we further investigated the 'extended' 8p23 locus (~ 4 Mb) where we observed multiple SLE signals and assessed these signals for their relation to the inversion affecting this region. The study involved a North American discovery data set (~ 1200 subjects) and a replication data set (> 10 000 subjects) comprising European-descent individuals. Meta-analysis of 8p23 SNPs, with p < 0.05 in both data sets, identified 51 genome-wide significant SNPs (p < 5.0 × 10-8). While most of these SNPs were related to previously implicated signals (XKR6-FAM167A-BLK subregion), our results also revealed two 'new' SLE signals, including SGK223-CLDN23-MFHAS1 (6.06 × 10-9 ≤ meta p ≤ 4.88 × 10-8) and CTSB (meta p = 4.87 × 10-8) subregions that are located > 2 Mb upstream and ~ 0.3 Mb downstream from previously reported signals. Functional assessment of relevant SNPs indicated putative cis-effects on the expression of various genes at 8p23. Additional analyses in discovery sample, where the inversion genotypes were inferred, replicated the association of non-inverted status with SLE risk and suggested that a number of SLE risk alleles are predominantly carried in non-inverted background. Our results implicate multiple (known+novel) SLE signals/genes at the extended 8p23 locus, beyond previously reported signals/genes, and suggest that this broad locus contributes to SLE risk through the effects of multiple genes/pathways.


Enhancement of phytoextraction efficiency coupling Pteris vittata with low-dose biochar in arsenic-contaminated soil.
Phytoremediation of arsenic (As) by Pteris vittata (P. vittata) is a cost-effective and environmentally friendly method for restoring As-contaminated sites. However, the phytoextraction efficiency is low in some cases, such as clay soil, thus biochar was applied to enhance the efficiency of As extraction. The paper investigated the effect of biochar on soil characteristic, As mobility, and As uptake in P. vittata with a 90-day greenhouse experiment. Biochar derived from rice straw was added at rates of 0.5, 1.5, and 4% (w/w). The results showed that, under biochar amendment, soil pH raised from 5.24 to 6.03 and 4.91 to 5.85, soil dissolved organic carbon (DOC) increased 11.1-46.1% and 2.8-11.2%, respectively, in rhizosphere and bulk soils. Biochar also increased soil catalase (CAT) activity significantly, especially for the rhizosphere soil. Besides, biochar increased the labile As in the soils and transfer coefficient from roots to aboveground, thereby enhancing As accumulation by P. vittata tissues. The accumulation of As in fronds of P. vittata was up to 350 mg kg-1 in 1.5% biochar, which was more than twice the control and far beyond other biochar treatments. The results indicate that biochar addition is favorable to improve phytoremediation of P. vittata in As-contaminated soil and 1.5% (w/w) biochar may be a reasonable application ratio, thus providing an effective solution to enhance the efficiency of As phytoextraction.


Clinical characteristics and oncological outcomes of recurrent adult granulosa cell tumor of ovary: A retrospective study of seventy patients.
This study aimed to describe the clinicopathological characteristics of recurrent adult granulosa cell tumor and identify the risk factors for recurrence. Seventy recurrent adult granulosa cell tumor patients treated in Peking Union Medical College Hospital between 2000 and 2020 were retrospectively reviewed. The primary outcomes were progression-free survival after first recurrence (PFS-R), overall survival after first recurrence (OS-R) and recurrence frequency. The Kaplan-Meier analysis, univariate and multivariate Cox proportional hazard analysis, and the Prentice, Williams and Peterson counting process (PWP-CP) model were adopted. There were 70 patients included in the study, and recurrence occurred twice in more than 71% of patients, and 49.9% of patients relapsed ≥ three times. The recurrence pattern in over half of the patients at first recurrence was multifocal and distant disease, and abdominal or pelvic mass and liver metastasis were the most common. The 5-year PFS-R was 29.3%, and the 10-year PFS-R was 11.3%; the 5-year OS-R was 94.9%, and the 10-year OS-R was 87.9%. Kaplan-Meier analysis demonstrated that patients with distant recurrence and PFS1 (PFS when first recurrence occurred) ≤60 months had worse PFS-R (p = 0.017, 0.018), and patients with PFS-R ≤ 34 months had worse OS-R (p = 0.023). It demonstrated that PFS1 ≤ 60 months (hazard ratio, HR 1.9, 95% confidence interval [CI]: 1.1-3.4, p = 0.028) was an independent risk factor for PFS-R, and local lesion at recurrence (HR 0.488, 95% CI: 0.3-0.9, p = 0.027) was an independent protective factor for PFS-R. In addition, it demonstrated that PFS-R ≤ 33 months (HR 5.5, 95% CI: 1.2-25.3, p = 0.028) was an independent risk factor for OS-R. The PWP-CP analysis showed that laparoscopic operation (at each operation) could significantly increase recurrence times (p = 0.002, HR = 3.4), and no existence of gross residual lesion (R0) at each recurrence operation could significantly decrease recurrence frequency (p < 0.001, HR <0.001). The recurrence pattern in patients with recurrent adult granulosa cell tumor was characterized as late and repeated, multifocal, and distant relapse. It has been demonstrated that PFS1 ≤ 60 months and distant lesion at recurrence are independent risk factors for PFS-R, and PFS-R ≤ 33 months is an independent risk factor for OS-R. The PWP-CP model showed that the transabdominal approach and surgery reaching R0 could significantly decrease the recurrence frequency.


Efficient saccharification of wheat straw pretreated by solid particle-assisted ball milling with waste washing liquor recycling.
Wheat straw was pretreated using ball milling (BM) promoted by solid particles (NaOH, NaCl, citric acid). NaOH showed the best synergistic interaction effect, due to the breakage of β-1,4-glycosidic bonds among cellulose molecules by the alkali solid particles induced by BM. NaOH-BM pretreatment decreased the straw crystallinity from 46% to 21.4% and its average particle size from 398.3 to 50.6 μm in 1 h. After 4 h milling, the reducing-end concentration of cellulose increased by 3.8 times from 12.5 to 60.2 μM, with glucose yield increased by 2.1 times from 26.6% to 82.4% for 72 h enzymatic hydrolysis at cellulase loading of 15 FPU/g dry substrate. The pretreatment washing liquor was recycled for the re-treatment of partially pretreated biomass at 121 °C for 30 min, resulting in 99.4% glucose yield by enzymatic hydrolysis. BM assisted with alkali particles was an effective approach for improving biomass enzymatic saccharification.


Safety of transvaginal aspiration of cysts in pregnancies complicated with ovarian endometrioma.
Pregnancy complicated with ovarian endometrioma is a risk factor for preterm delivery and rupture or infection during pregnancy. This study aimed to clarify the effectiveness and safety of transvaginal aspiration during pregnancy for endometrioma diagnosed in the first trimester. This retrospective observational study included 8 pregnant women with endometrioma who underwent transvaginal cyst aspiration at 12-14 weeks (aspiration group) between March 2011-March 2018 and 23 pregnant women with endometrioma who refused aspiration during the same period (observation group). Characteristics of patients were compared in both groups. Safety, feasability and complications of transvaginal cyst aspiration were reported. Complications and obstetrical outcomes were reported and compared in both groups. The maximum cyst diameter was 8.9 ± 1.5 cm (mean ± standard deviation) in the aspiration group, which was significantly larger than that in the observation group (4.7 ± 0.2 cm). Four preterm deliveries (17.3%) occurred in the observation group and none in the aspiration group. The emergency cesarean section rate during delivery was 14.2% in the aspiration group and 43.7% in the observation group. The aspiration group tended to have lower rate of preterm deliveries and emergency cesarean sections, suggesting that cyst aspiration could be an effective, minimally invasive, and safe management option for endometrioma during pregnancy.


Structure of C8alpha-MACPF reveals mechanism of membrane attack in complement immune defense.
Membrane attack is important for mammalian immune defense against invading microorganisms and infected host cells. Proteins of the complement membrane attack complex (MAC) and the protein perforin share a common MACPF domain that is responsible for membrane insertion and pore formation. We determined the crystal structure of the MACPF domain of complement component C8alpha at 2.5 angstrom resolution and show that it is structurally homologous to the bacterial, pore-forming, cholesterol-dependent cytolysins. The structure displays two regions that (in the bacterial cytolysins) refold into transmembrane beta hairpins, forming the lining of a barrel pore. Local hydrophobicity explains why C8alpha is the first complement protein to insert into the membrane. The size of the MACPF domain is consistent with known C9 pore sizes. These data imply that these mammalian and bacterial cytolytic proteins share a common mechanism of membrane insertion.


A novel use of attenuation value (Hounsfield unit) in non-contrast CT: diagnosis of pyonephrosis in obstructed systems.
To evaluate the predictive value of attenuation value (HU) in renal pelvis urine for detecting renal pelvis urine culture (RPUC) positivity in obstructed urinary systems. The study group consisted of patients who had nephrostomy insertion performed because of obstructed system and suspicion of pyonephrosis and percutaneous nephrolithotomy (PCNL) patients who had obstructed calculi. Group 1 consisted of RPUC positive 28 patients during nephrostomy insertion or needle access in PCNL and group 2 consisted of 23 patients with negative RPUC. RPUC results and non-contrast computed tomography measurements [Hounsfield unit (HU)] were compared between group 1 and group 2. A cut-off value was determined for HU. All patients were grouped according to whether they were above or below this value. The median HU calculated from the renal pelvis was - 8.5 (range - 29/- 1) and 10 (range- 4/+ 17) (p < 0.001) in group 1 and group 2, respectively. The cut-off value of HU that predicted positive RPUC was 0. Sensitivity and specificity of HU when considering this cut-off value were 100% and 96%, respectively (p < 0.001). Whereas RPUC positivity was found in 96.6% (28/29) of patients with HU < 0, there were no patients with HU > 0 where RPUC positivity was detected (p < 0.001). In this cohort, we found that HU of the urine in the renal pelvis can be used to predict RPUC positivity.


MicroRNA-143 suppresses the proliferation and metastasis of human gastric cancer cells via modulation of STAT3 expression [Retraction].
[This retracts the article on p. 867 in vol. 12, PMID: 32269719.].


Fluctuating Storage of the Active Phase in a Mn-Na2 WO4 /SiO2 Catalyst for the Oxidative Coupling of Methane.
Structural dynamics of a Mn-Na2 WO4 /SiO2 catalyst were detected directly under reaction conditions during the oxidative coupling of methane via in situ XRD and operando Raman spectroscopy. A new concept of fluctuating storage and release of an active phase in heterogeneous catalysis is proposed that involves the transient generation of active sodium oxide species via a reversible reaction of Na2 WO4 with Mn7 SiO12 . The process is enabled by phase transitions and melting at the high reaction temperatures that are typically applied.


THE FITNESS CONSEQUENCES OF MULTIPLE-LOCUS HETEROZYGOSITY: THE RELATIONSHIP BETWEEN HETEROZYGOSITY AND GROWTH RATE IN PITCH PINE (PINUS RIGIDA MILL.).
Positive correlations between measures of "fitness" and the number of electrophoretic loci for which an individual is heterozygous have been observed in many species. Two major hypotheses have been proposed to explain this phenomenon: inbreeding depression and overdominance. Until recently, there has been no way to distinguish between these hypotheses. The overdominance model devised by Smouse (1986) is used here in a reanalysis of Ledig et al.'s (1983) study of heterozygosity and growth rate in eight populations of pitch pine and is contrasted with an inbreeding-depression analysis. Ledig et al. (1983) regressed mean growth rate per heterozygosity class on the number of heterozygous loci, a method of analysis which, although it points to general trends in the data, does not differentiate between hypotheses. The correlations they obtained in four populations were significant only because regressing on the means eliminates most of the sum of squares for error and does not weight the unequally sized heterozygosity classes. Reanalysis of Ledig et al.'s data using individuals, not means, showed no significant correlations between heterozygosity and fitness. A major assumption of Smouse's overdominance model is that genetic polymorphism is in part a reflection of selection for heterozygotes at genetic equlibrium. The homozygote for the most frequent allele at a locus should be more fit than a homozygote for a less frequent allele, with the heterozygote superior to both homozygotes. Smouse's model predicts a negative, linear relationship between fitness and "adaptive distance," a variable that for a heterozygote is zero and for homozygotes is equal to the inverse of the frequency of the corresponding allele. The adaptive-distance model accounted for between 15% and 50% of the variation in growth rate within eight P. rigida population samples by accounting for genotypic differences at eight polymorphic loci. This is over twice as much of the variation in growth rate accounted for by Ledig et al.'s (1983) analysis using individuals. Significant correlations were found between adaptive distance and growth rate in four of the eight populations, but in only two of the populations were more of the partial coefficients negative than positive, as would be predicted by the overdominance hypothesis. The remaining two populations in which correlations were significant did not lend themselves to such clear-cut interpretation, as the majority of the partial coefficients were positive. Positive partial coefficients indicate that the growth rate of the heterozygote is inferior to that of at least one of the homozygotes. The adaptive-distance analysis provides evidence that specific genotypes do play a role in determining growth rate in pitch pine. The correlation between growth rate and adaptive distance increased significantly with the age of the population, possibly reflecting competition subsequent to crown closure.


Fish endoparasite metacommunity in environments with different degrees of conservation in the western Brazilian Amazon.
Parasite communities correspond to the definition of metacommunity, as species interact and disperse within hosts. The present study evaluated parasite metacommunities in a tropical floodplain. The study was conducted in the Western Amazon around the municipalities of Cruzeiro do Sul, state of Acre, and Guajará, state of Amazonas, Brazil. Six sampling sites were selected and grouped into conserved and degraded environments. Fish were caught between periods of drought and flood, using passive and active sampling methods; in the laboratory, they were measured weighed, and necropsied. Parasites found were fixed, evaluated, and identified. Physical and chemical variables and environmental conservation characteristics were measured in all sites. Diversity index, ANOVA, Tukey, local contribution to beta diversity (LCBD), species contribution to beta diversity by individual species (SCBD), and variance partitioning were summarized. The α species diversity increased in conserved environments and varied between seasonal periods, mainly in detritivorous and omnivorous hosts. Local contributions to beta diversity showed significantly higher values in conserved environments for the endoparasite fauna of piscivorous and omnivorous hosts, indicating that these environments presented unique parasite infracommunities and revealing the conservation status of these environments. Variations in infracommunities were explained mainly by niche-based processes, including environmental conditions, degree of conservation, and host characteristics. Thus, these data will serve as a tool to understand the way parasite communities are structured, which is important information for the management and conservation of aquatic environments.


Esophageal adenocarcinoma after sleeve gastrectomy: actual or potential threat? Italian series and literature review.
Sleeve gastrectomy (SG) leads to esophageal mucosal damage in an elevated percentage of cases, configuring a clinical condition of Barrett's esophagus (BE) in a proportion as high as 15-18.8%. BE may rarely evolve into esophageal adenocarcinoma (EAC). To raise awareness of BE as a precancerous lesion which may progress toward malignancy after this popular bariatric procedure. Bariatric referral centers, Italy. All patients referred to our bariatric center who developed an EAC after SG between 2012 and 2019 were reviewed and consecutively included in this study. The available scientific literature regarding this complication is additionally reviewed. The 3 male patients comprised in this case series underwent laparoscopic SG between 2012 and 2015 in different bariatric referral centers. Age and body mass index at baseline ranged from 21-54 years and 43.1-75.6 kg/m2, respectively. All patients were lost to follow-up early after surgery (3.7 ± 1.4 months), and were diagnosed with EAC at a mean of 27.3 ± 7.6 months after SG. The 4 reported cases in the scientific literature developed an EAC at a mean of 32.5 ± 23 months from SG. Overall, a diagnosis of EAC was made approximately 30.3 ± 17.1 months postoperatively, which seems relatively and worryingly early after surgery. Although the rate and probability of progression from BE to EAC is still not well defined, assuming that the rising popularity and execution of SG leads to a growth in the BE incidence, then the preoperative identification and stratification of cancer risk factors in this subset of patients is strongly encouraged. Clinical and endoscopic follow-ups are essential to allow for prevention and early diagnosis and for epidemiologic data collection purposes.


Modulation of oligonucleotide-binding dynamics on WS2 nanosheet interfaces for detection of Alzheimer's disease biomarkers.
Non-covalent adsorption and desorption of oligonucleotides on two-dimensional nanosheets are widely employed to design nanobiosensors for the rapid optical detection of targets. A precise control over the weak interactions between nanosheet interfaces and oligonucleotides is crucial for a high-sensing performance. Herein, the interface of ultrathin WS2 nanosheets used as a fluorescence quencher was engineered by four different dextran polymers in an aqueous solution to control the adsorption kinetics and thermodynamics of the DNA probe. The WS2 nanosheets, functionalized by the carboxyl group-bearing dextran (CM-dex-WS2) or the trimethylammonium-modified dextran (TMA-dex-WS2), exhibited 3.6-fold faster adsorption rates of the fluorescein-labeled DNA probe (FAM-DNA), which led to the effective fluorescence quenching of FAM, compared to the nanosheets functionalized with pristine dextran (dex-WS2) or the hydrophobic phenoxy groups-bearing dextran (PhO-dex-WS2). Isothermal titration calorimetry measurements showed that the adsorption strength of FAM-DNA for CM-dex-WS2 was one order of magnitude greater than its hybridization energy for a target microRNA (miR-29a) that is well-known as an Alzheimer's disease (AD) biomarker, leading to the unfavorable desorption of the DNA probe from the surface. In contrast, TMA-dex-WS2 exhibited the proper adsorption strength of FAM-DNA, which was lower than its hybridization energy for miR-29a, leading to its favorable desorption from the nanosheet surface along with the noticeable restoration of the quenched fluorescence after its hybridization with miR-29a. Finally, the interface modulation of WS2 nanosheets allowed the selective and sensitive recognition of miR-29a against non-complementary RNA and single base-mismatched RNA in human serum via increases in target-specific fluorescence.


Improving effectiveness of clinical medicine: the need for better translation of science into practice.
Published research evidence does not automatically diffuse into clinical practice but requires active processes of translation that start with clinicians' awareness of the science and end with patient adherence to the recommended care. Many barriers thwart the uptake of valid and clinically important research into practice, with cognitive, motivational and sociological factors on the part of health professionals being among the most important. Encouraging clinicians to question the level of scientific certainty underpinning clinical practice and to actively seek evidence that may better inform clinical decisions is a priority for improving health care effectiveness. Although there are effective strategies for improving translation of research into practice, implementing them requires agreement between and buy-in from professional and managerial stakeholders.


Vascular complications of the intra-aortic balloon pump.
The lower extremity complications of 100 consecutive patients who required the placement of an intra-aortic balloon pump (IABP) during a 3-year period were studied. Indications for the IABP included hypotension during cardiac catheterization (33%) or coronary angioplasty (13%), hemodynamic instability after open heart surgery (35%), unstable angina (5%), and cardiac arrest (14%). The incidence of IABP morbidity was 29%. Complications included ischemia (25%), bleeding (2%), lymph fistula (1%), and femoral neuropathy (1%). Twenty patients required 1 or more surgical interventions for lower extremity vascular complications. The majority of patients who underwent operation (70%) had significant pre-existing arterial occlusive disease. Local femoral artery reconstruction or repair was performed in 18 patients. Two patients had adjunctive bypasses. Continued IABP support was required in four patients after treatment of complications. One patient (1%) had an above-knee amputation. Limb ischemia was treated nonoperatively by removal of the IABP in five patients. Color-flow duplex scans were useful in distinguishing hematomas from pseudoaneurysms as well as for assessing femoral artery flow. We conclude that: (1) limb ischemia remains the primary complication of the IABP; (2) pre-insertion documentation of the severity of existing peripheral arterial disease by noninvasive studies may aid in the management of subsequent acute limb ischemia; (3) femoral artery thrombectomy or endarterectomy is usually sufficient for revascularization; and (4) noninvasive color flow studies are an important diagnostic tool in the nonoperative management of limb complications.


Why do poor people behave poorly? Variation in adult health behaviours and psychosocial characteristics by stages of the socioeconomic lifecourse.
Attempts to explain socioeconomic inequalities in health have often made reference to the observation that poor health behaviours and psychosocial characteristics cluster in low socioeconomic status (SES) groups. Causal interpretation of the association between SES, health behaviour, psychosocial orientations, and health inequalities has been hampered because these factors and SES have usually been measured at the same point in time. Data from the Kuopio Ischaemic Heart Disease Risk Factor Study were used to examine the associations between measures of SES reflecting different stages of the lifecourse, health behaviours, and psychosocial characteristics in adulthood in a population-based study of 2674 middle-aged Finnish men. Results show that many adult behaviours and psychosocial dispositions detrimental to health are consistently related to poor childhood conditions, low levels of education, and blue-collar employment. Poor adult health behaviours and psychosocial characteristics were more prevalent among men whose parents were poor. Increases in income inequality which place children into low SES conditions may well produce a negative behavioural and psychosocial health dividend to be reaped in the future. Understanding that adult health behaviour and psychosocial orientations are associated with socioeconomic conditions throughout the lifecourse implies that efforts to reduce socioeconomic inequalities in health must recognize that economic policy is public health policy.


The mechanism of cell-mediated cytotoxicity. III. Protease-specific inhibitors preferentially block later events in cytotoxic T lymphocyte-mediated lysis than do inhibitors of methylation or thiol-reactive agents.
Highly active mouse cytotoxic T lymphocytes (CTL) generated in secondary mixed-lymphocyte responses were used to examine the manner in which adenosine derivatives, thiol-specific reagents, or protease-specific probes affected CTL-mediated lysis (CML). The adenosine deaminase inhibitor deoxycoformycin (dCF) enhanced inhibition by adenosine (AR) or by deoxyadenosine (AdR), but not by 7-deazaadenosine (tubercidin). L-Homocysteinethiolactone (L-Hcy) acted synergistically with AR, but not with AdR or tubercidin, to block CML. Thus, AR derivatives may act both by affecting cellular methylation reactions, as demonstrated by the synergism between AR and L-Hcy, and by inhibiting other events required for CML. Conditions were then established to determine whether these reagents preferentially affected either the Ca2+-independent initial stage of cytolysis or the subsequent Ca2+-dependent events. Methylation inhibitors blocked lysis most effectively if added before effector-target binding. Similarly, the nonpenetrating thiol-specific reagent quaternary ammonium monobromobimane (qBBr) was more inhibitory when added prior to the Ca2+-dependent stage. Protease inhibitors such as alpha-1-antichymotrypsin and protease substrates such as acetyltyrosine ethyl ester (ATEE) or tyrosine ethyl ester (TEE) also inhibited CML. But, in contrast to qBBr or methylation inhibitors, neither TEE nor ATEE was more effective when added prior to the initial effector-target interaction. Furthermore, TEE did not appreciably affect CTL binding to target cells at concentrations that nearly abrogated CML. Thus, the implicated protease step is unique in that it does not appear to participate in recognition or binding.


[Effect of thoracic bracing on lung function in children with neuromuscular disease].
Respiratory muscle weakness associated with scoliosis in neuromuscular disease leads to respiratory impairment. Children with scoliosis are usually treated with spinal bracing to delay the progress of disease. We studied the impact of spinal bracing on lung function in these children. Retrospective study of patient data from January 1997 to January 2003. Spirometry and measurement of lung volume involved 32 observations, corresponding to 17 children with neuromuscular disease, including 14 with spinal muscular atrophy. Data for children with and without a brace were studied. A total of 72% of the children had severe scoliosis (Cobb score>30 degrees ); 40% wore a Garchois brace. Children without a brace showed a mean vital capacity of 65% of predicted value, with a restrictive syndrome in 44% of observations. Children with a brace showed significantly reduced vital capacity (-4.6%; P<0.001) and forced expiratory volume in 1 s (-4.6%; P=0.002). The reduced vital capacity was lower in children with the Garchois brace: -1% (P=0.02). Severity of scoliosis and measured volumes were not related. Spinal bracing in children with neuromusclar disease leads to significant respiratory impairment. Assessment of pulmonary function is necessary when a brace is indicated. The Garchois brace might lead to less impairment of respiratory function.


Efficient gene delivery and silencing of mouse and human pancreatic islets.
In view of the importance of beta cells in glucose homeostasis and the profound repercussions of beta cell pathology on human health, the acquisition of tools to study pancreatic islet function is essential for the design of alternative novel therapies for diabetes. One promising approach toward this goal involves the modification of gene expression profile of beta cells. This study describes a new method of gene and siRNA delivery into human pancreatic islets by microporation technology. We demonstrated that mild islet distention with accutase greatly enhanced the transfection efficiency without compromising in vitro function (secretion, apoptosis and viability). As an example, the recently identified gene involved in type 2 diabetes, ZnT8, can be over-expressed or silenced by RNA interference using this technology. Microporation can also be used on rodent islets. Taken together, our results demonstrate that microporation technology can be used to modify gene expression in whole rodent and human islets without altering their in vitro function and will be key to the elucidation of the factors responsible for proper islet function.


The Bright Side of Grit in Burnout-Prevention: Exploring Grit in the Context of Demands-Resources Model among Chinese High School Students.
This study contributes to understanding students' emotional responses to academic stressors by integrating grit into the well-established Job Demands-Resources Model and by examining the relationship between academic demands, grit (consistency of interests, perseverance of effort), burnout, engagement, academic achievement, depression, and life satisfaction in Chinese students. We conducted a self-report study with N = 1527 Chinese high school students (Mage = 16.38 years, SD = 1.04). The results of structural equation modeling showed that after controlling for gender, socio-economic status, and school types, demands positively related to burnout and negatively related to engagement. Both facets of grit negatively related to exhaustion, whereas only perseverance of effort positively related to engagement. Burnout positively related to depression and negatively related to life satisfaction, whereas engagement positively related to life satisfaction. However, neither burnout nor engagement was related to academic achievement. Our findings indicate that grit may be protective against school burnout.


Relationship between periparturient diseases, metabolic markers and the dynamics of hair cortisol concentrations in dairy cows.
Hair cortisol concentration (HCC) might represent a promising marker for retrospective welfare assessment of dairy cows. The objective of the study was to explore the dynamics of HCC in diseased and healthy cows from eight-week ante partum (AP) to eight-week post partum (PP). Twenty-four pregnant cows were followed from drying off to week eight PP. Tail hair was used to measure cortisol at five different time points. The occurrence of peripartum diseases, lameness and the body condition score (BCS) were monitored on a weekly basis. Blood β-hydroxybutyric acid, non-esterified fatty acids, calcium and insulin-like growth factor-1 (IGF-1) concentrations were measured. The temperature-humidity index (THI) was continuously recorded. The median values of HCC in all cows were 0.4, 0.3, 0.6, 0.8 and 0.5 pg/mg at weeks eight, four AP, calving, weeks four, eight PP, respectively. There was no association between HCC and the occurrence of peripartum diseases (P ≥ 0.05). A positive correlation between HCC and BCS loss (P < 0.01) and THI (P < 0.05) was observed. The occurrence of peripartum diseases was associated with low IGF-1 during the study period but no relationship was found between cortisol and IGF-1 levels (P ≥ 0.05). Brown Swiss cows showed higher HCC (P < 0.01) at weeks eight, four AP, and week four PP and lower average milk yield (P < 0.05) than Holstein-Friesian cows. In conclusion, HCC was not a suitable marker for peripartum diseases but it could reflect a stress response, which is linked to BCS loss, heat stress and breed.


I-123 labeled hexadecenoic acid in comparison with Thallium-201 for myocardial imaging in coronary heart disease. A preliminary study.
The imaging properties of 123I-16-iodo-9-hexadecenoic acid (123I-HA), a terminally iodinated 17-carbon atom fatty acid analogue, were compared with Thallium-201 (201Tl). Because of its shorter half-life, favourable photon-energy and rapid myocardial turnover rate, 123I-HA possesses potential advantages in the study of regional myocardial perfusion and metabolism. Twelve patients with documented coronary artery disease (CAD) were studied; eight patients sustained an acute myocardial infarction, four patients suffered from unstable angina. Visually assessed, a similar distribution pattern and comparable imaging quality was demonstrated with both radionuclides. The scintigraphic results were also correlated with coronary arteriographic findings. A good relationship was found between the perfusion defects and the location of the coronary artery lesions in the patients with acute myocardial infarction. We conclude that 123I-HA is comparable to 201Tl in detecting areas of reduced myocardial perfusion in patients with CAD with the advantage of studying myocardial metabolism.


Development of a novel fully functional coagulation factor VIII with reduced immunogenicity utilizing an in silico prediction and deimmunization approach.
Up to 30% of hemophilia A patients develop inhibitory antibodies against the infused factor VIII (FVIII). The development of a deimmunized FVIII is an unmet high medical need. Although improved recombinant FVIII (rFVIII) products evolved within the last years, the immunogenicity has not been solved. A deimmunized FVIII could reduce the probability of inhibitor development, providing safer therapy. To develop a deimmunized FVIII molecule by modifying major histocompatibility complex (MHC) class II presentation, leading to a functional but less immunogenic molecule. We performed (1) in silico prediction of potentially immunogenic T cell epitopes and their modification by amino acid substitutions in the FVIII sequence, (2) evaluation of functional and structural similarity of the modified rFVIII to unmodified FVIII and registered products, and (3) confirmation of the reduced immunogenicity by in vitro testing. A partially deimmunized fully functional FVIII molecule incorporating 19 amino acid substitutions was generated. The substitutions led to a reduction of the immunogenicity score, indicating a reduced immunogenicity based on in silico calculations. This was confirmed in an in vitro dendritic cell (DC)--T cell assay. Using this assay, cells from healthy donors proved the significantly reduced immunogenicity of the modified FVIII variant by revealing less proliferation of T helper cells to this variant than to the unmodified FVIII. In silico predictions resulted in a partially deimmunized FVIII. This FVIII is fully functional and was demonstrated to be less immunogenic in in vitro testing. This approach may result in a reduction of the inhibitor risk for patients with hemophilia A.


Clinical and biochemical discriminants between functional hypothalamic amenorrhoea (FHA) and polycystic ovary syndrome (PCOS).
Secondary oligo/amenorrhoea occurs in 3%-5% of women of reproductive age. The two most common causes are polycystic ovary syndrome (PCOS) (2%-13%) and functional hypothalamic amenorrhoea (FHA) (1%-2%). Whilst both conditions have distinct pathophysiology and their diagnosis is supported by guidelines, in practice, differentiating these two common causes of menstrual disturbance is challenging. Moreover, both diagnoses are qualified by the need to first exclude other causes of menstrual disturbance. To review clinical, biochemical and radiological parameters that could aid the clinician in distinguishing PCOS and FHA as a cause of menstrual disturbance. FHA is uncommon in women with BMI > 24 kg/m2 , whereas both PCOS and FHA can occur in women with lower BMIs. AMH levels are markedly elevated in PCOS; however, milder increases may also be observed in FHA. Likewise, polycystic ovarian morphology (PCOM) is more frequently observed in FHA than in healthy women. Features that are differentially altered between PCOS and FHA include LH, androgen, insulin, AMH and SHBG levels, endometrial thickness and cortisol response to CRH. Other promising diagnostic tests with the potential to distinguish these two conditions pending further study include assessment of 5-alpha-reductase activity, leptin, INSL3, kisspeptin and inhibin B levels. Further data directly comparing the discriminatory potential of these markers to differentiate PCOS and FHA in women with secondary amenorrhoea would be of value in defining an objective probability for PCOS or FHA diagnosis.


Reducing risk, improving outcomes: bioengineering less immunogenic protein therapeutics.
One of the great surprises of the biologics revolution has been the discovery that recombinant human proteins, including monoclonals of human origin, can cause immune responses when administered to immune-competent subjects. Preclinical and clinical evaluations of the potential immunogenicity of biologics have been primarily focused on humoral immune responses and as a result, the critical contribution of T cells to the development of anti-monoclonal antibodies (also known as anti-drug antibodies or ADA) has been somewhat overlooked. Recent publications have confirmed the role of effector T cells and begun to explore the role of regulatory T cells in the development of anti-drug antibodies. This review will focus on the role of T-cell-dependent (Td) immunogenicity assessment in the preclinical and clinical phases of drug development and summarize new data on regulatory T-cell epitopes contained in the Fc and CH1 domains of IgG. Recommendations for Td immunogenicity screening and assessment provided in this article may contribute to the development of safer protein-based drugs for human use.


Single-cell atlas of the first intra-mammalian developmental stage of the human parasite Schistosoma mansoni.
Over 250 million people suffer from schistosomiasis, a tropical disease caused by parasitic flatworms known as schistosomes. Humans become infected by free-swimming, water-borne larvae, which penetrate the skin. The earliest intra-mammalian stage, called the schistosomulum, undergoes a series of developmental transitions. These changes are critical for the parasite to adapt to its new environment as it navigates through host tissues to reach its niche, where it will grow to reproductive maturity. Unravelling the mechanisms that drive intra-mammalian development requires knowledge of the spatial organisation and transcriptional dynamics of different cell types that comprise the schistomulum body. To fill these important knowledge gaps, we perform single-cell RNA sequencing on two-day old schistosomula of Schistosoma mansoni. We identify likely gene expression profiles for muscle, nervous system, tegument, oesophageal gland, parenchymal/primordial gut cells, and stem cells. In addition, we validate cell markers for all these clusters by in situ hybridisation in schistosomula and adult parasites. Taken together, this study provides a comprehensive cell-type atlas for the early intra-mammalian stage of this devastating metazoan parasite.


A Principles Framework for Digital Provision of Medical Information for Healthcare Professionals.
European pharmaceutical companies have a legal requirement to provide non-promotional medical information (MI) services to support healthcare professionals (HCPs) using their medicinal products. While we are seeing an increased HCP preference and expectation towards digital channels, the lack of a compliance framework relating to the provision of non-promotional MI services is a key factor complicating and compromising the ability for companies to meet this need. Meanwhile, the internet is dominated by a large volume of unregulated, easy access, and potentially low-quality information from diverse sources. The Medical Information Leaders in Europe (MILE) association is therefore proposing a framework of principles to support pharmaceutical companies with the digital provision of MI services; these relate to digital access to non-promotional, medicinal product information to support clinical decision making and patient care. The three established European national MI associations have already considered the framework and expressed their endorsement. MILE continues to invite stakeholders, including pharmaceutical companies, regulators, national industry associations and healthcare professional bodies to engage and help refine and implement this framework. This publication does not constitute legal advice; decision making and accountability remains with each pharmaceutical company.


[Advances in uro-oncology «Oncoforum»: the best of 2011].
To put forth new findings in urologic oncology with impact in the clinical practice, presented in the principal annual meetings (EAU, ESTRO, AUA, ASCO and ASTRO). The reporters of the OncoUrology Forum select and classify the summaries on genitourinary cancer based on the impact on present or future practice. This document includes the summaries having the highest scores. The OncoUrology Forum committee considered the following messages important. The PIVOT study shows that radical prostatectomy reduces the specific mortality of prostate cancer (PCa) compared to follow-up in observation, in localized high risk PCa or PSA >10 ng/mL. Dissection of the pelvic lymph nodes should be done in all the patients with bladder cancer treated by radical cystectomy, regardless of the tumor stage, in accordance with baseline analysis of the Surveillance, Epidemiology and End Results (SEER) data. An analysis of the SEER of patients with renal cancer concluded that the radical nephrectomy is associated to worse cardiovascular and overall survival compared to those treated with partial nephrectomy in localized renal cell carcinoma of ≤2 cm. In patients with nonseminomatous germ cells cancer, retroperitoneal lymph node dissection should not be omitted when the residual tumor size is ≤1 cm because of the considerably high risk of teratoma and viable cancer. Although these studies do not offer a final response for all the oncourological subjects, these results will have an impact on the daily clinical practice.


[Double prepapillary arterial loop and arterial occlusion].
The prepapillary vascular loops are rare congenital vascular anomalies. Often unilateral and asymptomatic, they may be complicated by ischemic events by twisting or thrombosis of the loop. We report a rare case of double prepapillary arterial loop complicated by left retinal ischemia due to thrombosis of the loop.


Towards radiologist-level cancer risk assessment in CT lung screening using deep learning.
Lung cancer is the leading cause of cancer mortality in the US, responsible for more deaths than breast, prostate, colon and pancreas cancer combined and large population studies have indicated that low-dose computed tomography (CT) screening of the chest can significantly reduce this death rate. Recently, the usefulness of Deep Learning (DL) models for lung cancer risk assessment has been demonstrated. However, in many cases model performances are evaluated on small/medium size test sets, thus not providing strong model generalization and stability guarantees which are necessary for clinical adoption. In this work, our goal is to contribute towards clinical adoption by investigating a deep learning framework on larger and heterogeneous datasets while also comparing to state-of-the-art models. Three low-dose CT lung cancer screening datasets were used: National Lung Screening Trial (NLST, n = 3410), Lahey Hospital and Medical Center (LHMC, n = 3154) data, Kaggle competition data (from both stages, n = 1397 + 505) and the University of Chicago data (UCM, a subset of NLST, annotated by radiologists, n = 132). At the first stage, our framework employs a nodule detector; while in the second stage, we use both the image context around the nodules and nodule features as inputs to a neural network that estimates the malignancy risk for the entire CT scan. We trained our algorithm on a part of the NLST dataset, and validated it on the other datasets. Special care was taken to ensure there was no patient overlap between the train and validation sets. The proposed deep learning model is shown to: (a) generalize well across all three data sets, achieving AUC between 86% to 94%, with our external test-set (LHMC) being at least twice as large compared to other works; (b) have better performance than the widely accepted PanCan Risk Model, achieving 6 and 9% better AUC score in our two test sets; (c) have improved performance compared to the state-of-the-art represented by the winners of the Kaggle Data Science Bowl 2017 competition on lung cancer screening; (d) have comparable performance to radiologists in estimating cancer risk at a patient level.


Time-dependent variation in the biodistribution of C₆₀ in rats determined by liquid chromatography-tandem mass spectrometry.
We examined the biodistribution of C(60) in rats after tail vein administration using LC-MS/MS. C(60) was detected in various tissues, such as brain, kidneys, liver, lungs, and spleen of rats. On the other hand, no C(60) was found in blood. The highest C(60) concentration was observed in the lungs, followed by spleen, liver, kidneys, and brain. These results suggested that C(60) injected in the tail vein could be filtered by lung capillary vessels and accumulate in the lungs prior to being distributed to other tissues. Moreover, C(60) not being detected in the blood indicates that clearance of C(60) from the blood by filtration might effectively occur in the lungs. The time-dependent variation in the biodistribution of C(60) was evaluated. A time-dependent decrease in C(60) concentrations was observed in all tissues, except spleen. Moreover, a decreasing trend of C(60) levels differed among tissues, which could be due to differences in accumulation. These results suggest that unmodified C(60) and/or C(60) metabolites by metabolic enzymes could be excreted into feces and/or urine. In further studies, the metabolic and excretion pathways of C(60) should be evaluated to understand the toxicokinetics of C(60).


Revascularization and tissue regeneration of an empty root canal space is enhanced by a direct blood supply and stem cells.
Regenerative endodontics is an innovative treatment concept aiming to regenerate pulp, dentin and root structures. In the diseased or necrotic tooth, the limitation in vascular supply renders successful tissue regeneration/generation in a whole tooth challenging. The aim of this study is to evaluate the ability of vascularized tissue to develop within a pulpless tooth using tissue engineering techniques. A pulpless tooth chamber, filled with collagen I gel containing isolated rat dental pulp cells (DPC) and angiogenic growth factors, was placed into a hole created in the femoral cortex or into its own tooth socket, respectively. The gross, histological and biochemical characteristics of the de novo tissue were evaluated at 4 and 8 weeks post-transplantation. Tooth revascularization and tissue generation was observed only in the femur group, confirming the important role of vascular supply in tissue regeneration. The addition of cells and growth factors significantly promoted connective tissue production in the tooth chamber. Successful revascularization and tissue regeneration in this model demonstrate the importance of a direct vascular supply and the advantages of a stem cell approach.


Development and External Validation of a Clinical Nomogram for Individually Predicting Survival of Metaplastic Breast Cancer.
Few studies have concerned the prognosis of metaplastic breast cancer (MpBC), a rare and diverse malignancy. A prognostic index estimating the MpBC survival would be attractive in clinical practice. We retrospectively analyzed MpBC patients from the Surveillance, Epidemiology, and End Results (SEER) database. Prognostic factors were identified and the final nomogram was developed to predict the 1-, 3-, or 5-year overall survival (OS). Calibration curves were provided to internally validate the performance of the nomogram and discriminative ability was appraised by concordance index (C-index). A total of 1017 MpBC patients diagnosed between 2010 and 2015 were assigned into 3:1 as training set (n = 763) and SEER validation set (n = 254). An external validation was performed by an individual set of 94 MpBC patients from National Cancer Center in China from 2010 to 2018. The nomogram finally consisted of 7 independent prognostic factors and presented a good accuracy for predicting the OS with the C-index of 0.77 (95% CI: 0.751-0.786). Interestingly, the nomogram based on the western (including 92.5% non-Asian) SEER validation population (C-index of nomogram: 0.76, 95% CI: 0.737-0.796) also has an optimal discrimination in Asian population (C-index of nomogram: 0.70). The calibration plots of the nomogram predictions were also accurate and corresponded closely with the actual survival rates. This novel nomogram was accurate enough to predict the OS by using readily available clinicopathologic factors in MpBC general population, which could provide individualized recommendations for patients and clinical decisions for physicians.


Effects of nutritional status on plasma leptin levels and in vitro regulation of adipocyte leptin expression and secretion in rainbow trout.
As leptin has a key role on appetite, knowledge about leptin regulation is important in order to understand the control of energy balance. We aimed to explore the modulatory effects of adiposity on plasma leptin levels in vivo and the role of potential regulators on leptin expression and secretion in rainbow trout adipocytes in vitro. Fish were fed a regular diet twice daily ad libitum or a high-energy diet once daily at two ration levels; satiation (SA group) or restricted (RE group) to 25% of satiation, for 8weeks. RE fish had significantly reduced growth (p<0.001) and adipose tissue weight (p<0.001), and higher plasma leptin levels (p=0.022) compared with SA fish. Moreover, plasma leptin levels negatively correlated with mesenteric fat index (p=0.009). Adipocytes isolated from the different fish were treated with insulin, ghrelin, leucine, eicosapentaenoic acid or left untreated (control). In adipocytes from fish fed regular diet, insulin and ghrelin increased leptin secretion dose-dependently (p=0.002; p=0.033, respectively). Leptin secretion in control adipocytes was significantly higher in RE than in SA fish (p=0.022) in agreement with the in vivo findings, indicating that adipose tissue may contribute to the circulating leptin levels. No treatment effects were observed in adipocytes from the high-energy diet groups, neither in leptin expression nor secretion, except that leptin secretion was significantly reduced by leucine in RE fish adipocytes (p=0.025). Overall, these data show that the regulation of leptin in rainbow trout adipocytes by hormones and nutrients seems to be on secretion, rather than at the transcriptional level.


Efficient alkene hydrosilation with bis(8-quinolyl)phosphine (NPN) nickel catalysts. The dominant role of silyl-over hydrido-nickel catalytic intermediates.
A cationic nickel complex of the bis(8-quinolyl)(3,5-di-tert-butylphenoxy)phosphine (NPN) ligand, [(NPN)NiCl]+, is a precursor to efficient catalysts for the hydrosilation of alkenes with a variety of hydrosilanes under mild conditions and low catalyst loadings. DFT studies reveal the presence of two coupled catalytic cycles based on [(NPN)NiH]+ and [(NPN)NiSiR3]+ active species, with the latter being more efficient for producing the product. The preferred silyl-based catalysis is not due to a more facile insertion of alkene into the Ni-Si (vs. Ni-H) bond, but by consistent and efficient conversions of the hydride to the silyl complex.


Frequent KIT mutations in skin lesions of patients with BRAF wild-type Langerhans cell histiocytosis.
Langerhans cell histiocytosis (LCH) is characterized by mutations of the RAS-RAF-MAPK signaling pathway. We analyzed MAP2K1, NRAS and KIT mutation incidence in skin lesions of BRAF wild-type (wt) LCH patients. We evaluated the occurrence of MAP2K1, NRAS and KIT mutations in seven LCH and one indeterminate cell histiocytosis (ICH) patients. MAP2K1 mutation frequency was found to be 3/7 (42.9%) in LCH and also found in ICH. Similarly, the KIT mutation frequency was found to be equally prevalent (4/7, 57.1%) in LCH and also occurred in ICH. Involvement of KIT exons in LCH-ICH indicated that exon 9/11/18 were equally prevalent followed by exon 13. This exploratory analysis on BRAF-wt LCH revealed a KIT mutation rate comparable to MAP2K1. Although the detected KIT mutations are different from activating mutations found in other KIT-dependent neoplasms, our data suggest that KIT-inhibitors might have a role in treating BRAF-wt LCH patients.


Predictors of noncompliance with warfarin therapy in an outpatient anticoagulation clinic.
To test variables associated with the Health Belief Model, the Patient Satisfaction Model, and patient demographics in predicting compliance with warfarin therapy. Descriptive study using chart and pharmacy database review as well as patient questionnaires. Outpatient anticoagulation clinic in an academic medical center. Seventy-five patients who had received warfarin therapy over the previous 6 months. Clinicians interviewed patients using a subscale of the Beliefs About Anticoagulation Survey and a Patient Satisfaction Model. Perceived barriers to compliance with warfarin therapy and marital status explained 21.7% of the variance in calculations of refill adherence (p<0.001). Compliance with warfarin therapy was assessed using a validated compliance self-report survey and outpatient pharmacy dispensing data. Perceived barriers and current living conditions explained 33.2% of the variance in self-reported noncompliance (p<0.001). Logistic regression analysis, conducted to attempt to predict patients with an 80% refill adherence threshold, correctly classified compliance 85.3% of the time. This investigation provided some insight into the factors predictive of noncompliance in a low-income, outpatient population. Perceived barriers, marital status, living arrangements, and drug regimen played significant roles in warfarin noncompliance. Our results provide more evidence supporting the use of refill adherence and patient self-report as measures of noncompliance. This linkage helps validate compliance as a useful surrogate of patient health outcomes. This study also offers a model that can help clinicians identify patients at significant risk of noncompliant behavior.


Plasma levels of fetuin-A and risk of coronary heart disease in US women: the Nurses' Health Study.
Fetuin-A may be involved in the etiology of coronary heart disease (CHD) through opposing pathways (ie, promoting insulin resistance and inhibiting ectopic calcification). We aimed to explicitly examine whether systemic inflammation, a factor leading to elevated vascular calcification, may modify the association between fetuin-A and CHD risk. During 16 years of follow-up (1990-2006), we prospectively identified and confirmed 466 incident fatal or nonfatal CHD case in the Nurses' Health Study. For each case, 1 healthy control was selected using risk-set sampling from 26 245 eligible participants. Cases and controls were matched for age, smoking status, fasting status, and date of blood draw. After multivariate adjustment for lifestyle factors, body mass index, diet, and blood lipids, fetuin-A levels were not associated with CHD risk in the whole population: odds ratio (OR) (95% CI) comparing extreme quintiles of fetuin-A was 0.79 (0.44 to 1.40). However, a significant inverse association was observed among participants with higher C-reactive protein levels (Pinteraction=0.04). The OR (95% CI) comparing highest versus lowest quintiles of fetuin-A was 0.50 (0.26 to 0.97; Ptrend=0.004) when C-reactive protein levels were above population median (0.20 mg/dL), whereas among the remainder of the participants, the corresponding OR (95% CI) was 1.09 (0.58 to 2.05; Ptrend=0.75). In this population of US women, fetuin-A levels were associated with lower CHD risk when C-reactive protein levels were high, but null association was observed among participants with lower C-reactive protein levels. This divergent pattern of association needs replication in future studies.


Diversion colitis in inflammatory bowel disease (IBD) is distinct from that in non-IBD: Reappraisal of diversion colitis.
The significant histologic overlap between diversion colitis and inflammatory bowel disease (IBD) poses a diagnostic challenge. We aimed to identify histologic features that are characteristic of diverted colon segments among patients with IBD and compare them with histologic features identified in IBD colectomies. Archived slides from resected diverted colon segments from patients with (n = 79) and without (n = 80) IBD and the corresponding prior colectomies (n = 52) of the IBD patients were reviewed. Clinical and endoscopic data were collected, and a series of histologic features were evaluated and graded. Compared to the non-IBD group, IBD patients were more likely to be symptomatic and present with abnormal endoscopic findings (P < .05). The severity of inflammatory activity, crypt architectural distortion, mucosal atrophy, transmural inflammation, intramucosal lymphoid aggregates (IMLAs), and transmural lymphoid aggregates (TMLAs) were significantly greater in diverted segments in IBD cases than controls (P < .001). The severity of inflammatory activity, IMLAs, TMLAs, and transmural inflammation and the presence of ulcer(s) in the diverted colon segments of IBD patients were associated with the histologic features reflective of IBD activity such as inflammatory activity, transmural inflammation and ulcer(s) in the preceding colectomies (P < .05). Diversion colitis developing in the setting of IBD is endoscopically and histologically distinct from that observed among individuals without IBD. Inflammatory activity, presence of ulcer(s), IMLAs, TMLAs, and transmural inflammation in diverted colon segments of IBD patients may, in part, reflect the severity of underlying IBD rather than pure diversion colitis.


Evaluation on the recurrent cases of early gastric carcinoma.
In the First Department of Surgery, Faculty of Medicine, Chiba University, 213 cases with early gastric carcinoma have undergone an excision from 1955 to 1975. The observed 5-year, relative 5-year, observed 10-year, and relative 10-year survival rates of these cases amount to 89.3%, 99.8% and 98.0% respectively. The present investigation concerns 13 of these patients with diagnosed postoperative recurrent cases. The post-operative gastric carcinima recurrence might be classified to metastasis to liver and lymphnodes, peritoneal dissemination, residual gastric recurrence and recurrence in miscellaneous organs. The 13 cases involved 2 cases of liver metastasis, 9 cases of residual gastric recurrence and 2 cases of recurrence in miscellaneous organs. Nine of these cases underwent re-operations which were grouped to 6 cases of residual gastrectomy, 2 cases of excision of miscellaneous organs (cecum and rectum), and 1 case exploratory laparotomy. The development in the cases is characterized by 3 cases of stump persistent carcinoma at the residual stomach due to stump carcinoma positive in excision, 2 cases of residual gastric carcinoma due to lymphatic vessel invasion and 6 cases of multiple carcinoma.


A naturally occurring HA-stabilizing amino acid (HA1-Y17) in an A(H9N2) low-pathogenic influenza virus contributes to airborne transmission.
Despite the accumulation of evidence showing that airborne transmissible influenza A virus (IAV) typically has a lower pH threshold for hemagglutinin (HA) fusion activation, the underlying mechanism for such a link remains unclear. In our study, by using a pair of isogenic recombinant A(H9N2) viruses with a phenotypical difference in virus airborne transmission in a ferret model due to an acid-destabilizing mutation (HA1-Y17H) in the HA, we demonstrate that an acid-stable A(H9N2) virus possesses a multitude of advantages over its less stable counterpart, including better fitness in the ferret respiratory tract, more effective aerosol emission from infected animals, and improved host susceptibility. Our study provides supporting evidence for the requirement of acid stability in efficient airborne transmission of IAV and sheds light on fundamental mechanisms for virus airborne transmission.


Quantification of gastric mucosal microcirculation as a surrogate marker of portal hypertension by spatially resolved subdiffuse reflectance spectroscopy in diagnosis of cirrhosis: a proof-of-concept study.
Portal pressure can be used to identify patients with chronic liver disease who have progressed to cirrhosis. Portal pressure can also provide accurate prognostication for patients with cirrhosis. However, there are no practical means for assessment of portal pressure. Although it is well established that the gastric mucosal blood supply increases in patients with cirrhosis, this has been difficult to quantify reproducibly. Our group has developed a novel spectroscopic technology called spatially resolved subdiffuse reflectance spectroscopy (SRSRS), which enables quantification of mucosal microcirculation. We aim to ascertain if quantification of the gastric mucosal microcirculation with SRSRS correlates with clinical evidence of portal hypertension. Patients undergoing EGD for clinical indications had 10 measurements taken in the endoscopically normal gastric fundus via SRSRS probe to assess the microcirculation. Cases were defined as patients with cirrhosis (n = 18), and controls were those without evidence of liver disease (n = 18); this was corroborated with transient elastography. The blood volume fraction (P = .06) and subdiffuse reflectance (P = .02) from a shallow depth in the gastric fundus were higher in patients with cirrhosis than those without. These markers were combined to yield an overall optical marker that can differentiate patients with cirrhosis from controls with a sensitivity of 72% and specificity of 94% (area under receiver operating curve, 0.82). Spectroscopic quantification of gastric fundal mucosal microcirculation is a promising surrogate of clinical correlates of portal hypertension. This approach may represent a less-intrusive surrogate biomarker for liver disease prognostication and potentially response to therapy.


The prognostic effect of metastasis patterns on overall survival in patients with distant metastatic bladder cancer: a SEER population-based analysis.
The prognostic impact of different distant metastases pattern in bladder cancer is unexplored still now. The aim of this study is to investigate the impact of different distant metastases pattern on the survival of patients with stage IV bladder cancers. A SEER analysis was performed and the overall survival was calculated by the Kaplan-Meier method. Multivariable Cox regression models were used to further analyze survival outcome and other prognostic factors. A total of 90,382 eligible cases were retrieved in the Surveillance, Epidemiology, and End Results database. Among these patients, stage of IV bladder cancer accounted for 7.03% (6354/90382) at initial diagnosis. Patients who suffered metastasis occupied 35.51% (2256/6354). Comparing with other three single metastases, the patients with liver metastasis exhibited worst OS whose mean of survival was 7.118 months. Multivariate analysis with Cox hazard regression model showed that metastatic site was an independent prognostic factor of OS in patients with single metastasis (P < 0.05). The results of univariate survival analysis showed that metastatic pattern, sex, age, race, tumor stage, N-classification, differentiated grade, histological type, chemotherapy, radiotherapy and insurance status were not significantly correlated with overall survival of patients with two or three metastatic sites (all, P > 0.05). Bone was the most common site of single metastasis for bladder cancers. Patients with liver metastasis had worse survival outcome comparing with other three distant metastases. Knowledge of these differences in metastatic patterns might help to better guide pre-treatment evaluation of bladder cancer and make determination regarding curative-intent interventions.