Individual exposure of ambient particulate matters and eosinophilic chronic rhinosinusitis with nasal Polyps: Dose-Response, mediation effects and recurrence prediction.
We evaluated the association between ambient particulate matter (PM) exposure and eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP), and predicted the CRSwNP recurrence risk using machine learning algorithms. In total, 1,086 patients with CRSwNP were recruited from nine hospitals in China during 2014-2019. The average annual concentrations of ambient PMs before surgery were assessed using satellite-based daily concentrations of PM2.5 and PM10 for a 1 × 1-km2 area. Linear regression and logistic regression models were used to evaluate the associations of PM exposure with eosinophilia and risks of eosinophilic CRSwNPs. In addition, mediation effect analysis was used to validate the interrelationships of the aforementioned factors. Finally, machine learning algorithms were used to predict the recurrence risks of CRSwNPs. There was a significantly increased risk of eosinophilic CRSwNPs with each 10 μg/m3 increase in PMs, with odds ratios (ORs) of 1.039 (95% confidence interval [CI] = 1.007-1.073) for PM10 and 1.058 (95% CI = 1.007- 1.112) for PM2.5. Eosinophils had a significant mediation effect, which accounted for 52% and 35% of the relationships of CRSwNP recurrence with PM10 and PM2.5, respectively. Finally, we developed a naïve Bayesian model to predict the risk of CRSwNP recurrence based on PM exposure, inflammatory data, and patients' demographic factors. Increased PM exposure is associated with an increased risk of eosinophilic CRSwNP in China. Therefore, patients with eosinophilic CRSwNP should reduce PM exposure to mitigate its harmful impacts.


[The surgical treatment of high myopia with dura mater. The results obtained long term (a clinical study)].
The paper presents the postoperative results obtained by performing scleroplasty with dura-mater in 127 progressive myopic eyes. The authors consider that the homologue dura-mater represents a high quality material to make scleral plasties. The evolution of myopia has ceased in over 60% of the cases.


The prognostic value of inducible nitric oxide synthase in local prostate cancer.
To compare the clinical and histological data from patients with prostate cancer with the results of the immunohistochemical analysis of inducible nitric oxide synthase (iNOS), and thus determine the prognostic value of iNOS. The study included 82 patients (mean age 64.6 years, SD 6.1) with local prostate cancer treated by radical prostatectomy in two Finnish hospitals. Their mean (SD) follow-up was 3.3 (2.2) years. An immunohistochemical method was used to detect the expression of iNOS in these specimens, and the expression graded according to staining intensity as none, weak or strong. There was weak or strong expression of iNOS in 25 (31%) and 56 (68%) of the patients, respectively, and one specimen was negative for iNOS. Strong expression of iNOS was related to high a preoperative prostate specific antigen (PSA) level (P = 0.006) and high pT classification (P < 0.001), but not to nodal status, grade, seminal vesicle or capsular invasion, surgical margin status, perineural infiltration, tumour infiltrating lymphocytes or proliferation rate of cancer cells. A PSA failure was detected in 29 patients but was not predicted by iNOS expression. A Cox multivariate analysis showed that surgical margin positivity, seminal vesicle involvement and number of tumour infiltrating lymphocytes predicted the PSA failure. A high expression of iNOS was related to a high pT classification and the preoperative PSA level but not to other established prognostic factors; iNOS expression was not a predictor of PSA failure in patients with local prostate cancer.


RACTS: a prospective randomized antiplatelet trial of cilostazol versus ticlopidine in patients undergoing coronary stenting: long-term clinical and angiographic outcome.
We compared the efficacy of cilostazol for the prevention of late restenosis and acute or subacute stent thrombosis with that of ticlopidine. Cilostazol has been used for antiplatelet therapy after coronary stent implantation, but the results are controversial. Patients scheduled for stent implantation were randomly assigned to receive either cilostazol (100 mg twice daily for 6 months, n=201) or ticlopidine (250 mg twice daily for 1 month, n=196). All patients also received oral aspirin (100 mg once daily for 6 months). Coronary angiography was performed at baseline and immediately and 6 months after coronary stenting. Clinical follow-up was continued up to 9 months postprocedure. There was no significant difference in the composite incidence of death, myocardial infarction, stroke, and stent thrombosis between the 2 groups [cilostazol (1.5%) versus ticlopidine (3.6%), P=0.216], but the target lesion revascularization rate per patient was significantly lower in the cilostazol group than in the ticlopidine group (22.9% vs 32.7%, P=0.030) 9 months post-coronary stenting. Medication withdrawn because of drug-related side effects tended to be higher in the ticlopidine group than that in the cilostazol group (3.5% vs 8.2%, P=0.054). At follow-up angiography, the minimal luminal diameters (2.31+/-1.06 vs 2.10+/-1.16, P=0.057) tended to be larger and the restenosis rates lower (23.3% vs 30.9%, P=0.086) in the cilostazol group than in the ticlopidine group. Aspirin plus cilostazol is a comparable antithrombotic regimen to aspirin plus ticlopidine after elective coronary stenting, but the rate of target lesion revascularization was significantly lower in the cilostazol group than in the ticlopidine group.


Effectiveness of non-pharmacological traditional Chinese medicine combined with conventional therapy in treating fibromyalgia: a systematic review and meta-analysis.
Fibromyalgia is a chronic musculoskeletal disorder characterized by generalized pain, which is also known as "muscular rheumatism" in Chinese medicine. We undertook this systematic review to evaluate the effectiveness of non-pharmacological traditional Chinese medicine (TCM) combined with conventional therapy on pain, health status, depression, and the quality of life of fibromyalgia patients. Studies were retrieved from five electronic databases (PubMed, the Cumulative Index to Nursing and Allied Health, Cochrane Library, Embase, and Web of Science) with publication date up to August 2022. We included randomized controlled trials examining the effects of a combination of non-pharmacological TCM and conventional therapy on pain intensity, health status, depression, and quality of life. Four randomized controlled trials with 384 fibromyalgia patients met the inclusion criteria. Results of the meta-analysis showed that non-pharmacological TCM combined with conventional therapy exerted significant positive effects on alleviating pain at the post-intervention time point than conventional therapy only (visual analog scale WMD1 = -1.410, P < 0.01; pressure pain threshold WMD2 = 0.830, P < 0.001, respectively). Significant differences in pain assessment were also observed between the two groups after a long-term follow-up (12 months) (WMD1 = -1.040 and WMD2= 0.380, all P < 0.05). The combination therapy group also showed a greater reduction in fibromyalgia impact questionnaire than the control group after a long-term follow-up (WMD = -6.690, P < 0.05). Depression and pain-related quality of life showed no difference between groups (all P > 0.05). Non-pharmacological TCM combined with conventional therapy may be more effective in alleviating pain and improving health status than conventional therapy only. However, it remains some concerns over the safety and clinic application. Identifier: CRD42022352991.


Hypoalbuminemia is a risk factor for invasive fungal infections and poor outcomes in infected kidney transplant recipients.
Invasive fungal infections (IFI), are estimated to occur in 2%-14% of kidney transplant recipients (KTRs) in the current era of immune suppression and are associated with high mortality rates. We hypothesized that hypoalbuminemia in KTRs is a risk factor for IFI and would be associated with poor outcomes. In this study, using data from a prospective cohort registry, we describe the frequency of IFI due to Blastomycosis, Coccidioidomycosis, Histoplasmosis, Aspergillosis, and Cryptococcus in KTRs with serum albumin levels measured 3-6 months before diagnosis. Controls were selected based on incidence density sampling. KTRs were divided into three groups based on the pre-IFI serum albumin level: normal (≥4 g/dL), mild (3-4 g/dL), or severe (<3 g/dL) hypoalbuminemia. Outcomes of interest were uncensored graft failure after IFI and overall mortality. A total of 113 KTRs with IFI were compared with 348 controls. The incidence rate of IFI among individuals with normal, mild, and severe hypoalbuminemia was 3.6, 8.7, and 29.3 per 100 person-years, respectively. After adjustment for multiple variables, the trend for risk of uncensored graft failure following IFI was greater in KTRS with mild (HR = 2.1; 95% CI, .75-6.1) and severe (HR = 4.47; 95% CI, 1.56-12.8) hypoalbuminemia (P-trend < .001) compared to those with normal serum albumin. Similarly, mortality was higher in severe hypoalbuminemia (HR = 1.9; 95% CI, .67-5.6) compared to normal serum albumin (P-trend < .001). Hypoalbuminemia precedes the diagnosis of IFI in KTRs, and is associated with poor outcomes following IFI. Hypoalbuminemia may be a useful predictor of IFI in KTRs and could be incorporated into screening algorithms.


Population-based study of breast cancer survival in Cote d'Or (France): prognostic factors and relative survival.
Few population-based studies have reported jointly analyses of relative survival according to the following prognostic factors: tumour-node-metastasis (TNM) stage, age, number of examined and positive nodes, hormonal status, histological Scarff, Bloom and Richardson (SBR) grade, tumour extension, hormone receptor status and tumour multifocal status. Data on female invasive breast cancer were provided by the Cote d'Or breast cancer registry. The Kaplan-Meier method and log-rank test were used to estimate and compare the survival probability at 1, 5, 10 and 15 years. The effect of prognostic factors on survival was assessed with crude and relative multivariate survival analyses. Crude survival seemed to be worse in patients aged >60 years compared with those aged 45-60 (P > 0.0001), whereas relative survival did not differ. TNM stage, histological SBR grade, progesterone receptor status, tumour multifocal status, locoregional extension and the period of diagnosis were independent prognostic factors of crude and relative survival. Breast cancer is influenced by many factors. Despite the absence of any association between the number of examined nodes and overall survival in this study, the number of nodes removed, in conjunction with other prognostic factors, may be useful in selecting node-negative patients for systemic therapy.


Changes in the balance between membrane-bound and soluble forms of CD95 (Fas) during selection of tumor cells in vivo.
Studies concerning the expression of the receptor CD95 (Fas) by tumor cells and the role of this protein in apoptosis induced by the effector host cells that bear Fas-ligand are mainly focused on the membrane-bound form of Fas. There are only a few data about the production of the soluble form of Fas by the tumor cells, its role in the interaction with the effector host cells, and the possible changes in the synthesis of this protein during tumor progression. In the present work, three in vitro transformed parental cell lines of different origin and 24 of their variants isolated after a short cycle of natural selection in vivo were studied. It was demonstrated for the first time that: 1) production of the soluble Fas by all selected in vivo variant tumor cell lines increased significantly (2-10-fold) in comparison to the initial (parental) cell lines and did not depend on the origin of the parental lines. At the same time, the expression of the membrane-bound form of Fas decreased considerably; 2) variations of the balance between membrane-bound and soluble forms of Fas in selected in vivo variant cells and the expression of the [H(2)O(2)(CA) + PGE(S)]-phenotype by these cells (this phenotype determines one of the essential mechanisms of the protection of a tumor cell in vivo) possibly represent independent secondary changes acquired during tumor progression in vivo.


Quantitative techniques in 18FDG PET scanning in oncology.
The clinical applications of (18)F-fluoro-2-deoxyglucose ((18)FDG) positron emission tomography (PET) in oncology are becoming established. While simple static scanning techniques are used for the majority of routine clinical examinations, increasing use of PET in clinical trials to monitor treatment response with (18)FDG and novel tracers reflecting different pharmacodynamic end points, often necessitates a more complex and quantitative analysis of radiopharmaceutical kinetics. A wide range of PET analysis techniques exist, ranging from simple visual analysis and semiquantitative methods to full dynamic studies with kinetic analysis. These methods are discussed, focusing particularly on the available methodologies that can be utilised in clinical trials.


Regulation of Nur77 expression by β-catenin and its mitogenic effect in colon cancer cells.
The orphan nuclear receptor Nur77 is an immediate-early response gene whose expression is rapidly induced by various extracellular stimuli. The aims of this study were to study the role of Nur77 expression in the growth and survival of colon cancer cells and the mechanism by which Nur77 expression was regulated. We showed that levels of Nur77 were elevated in a majority of human colon tumors (9/12) compared to their nontumorous tissues and that Nur77 expression could be strongly induced by different colonic carcinogens including deoxycholic acid (DCA). DCA-induced Nur77 expression resulted in up-regulation of antiapoptotic BRE and angiogenic VEGF, and it enhanced the growth, colony formation, and migration of colon cancer cells. In studying the mechanism by which Nur77 was regulated in colon cancer cells, we found that β-catenin was involved in induction of Nur77 expression through its activation of the transcriptional activity of AP-1 (c-Fos/c-Jun) that bound to and transactivated the Nur77 promoter. Together, our results demonstrate that Nur77 acts to promote the growth and survival of colon cancer cells and serves as an important mediator of the Wnt/β-catenin and AP-1 signaling pathways.


The role of cytokines in the failing human heart.
Despite repeated attempts to develop a unifying hypothesis that explains the clinical syndrome of heart failure, no single conceptual paradigm has withstood the test of time. In this regard, recent studies have shown that a class of biologically active molecules, generically referred to as cytokines, are overexposed in heart failure. This article will review recent clinical and experimental material that suggest proinflammatory (stress activated) cytokines such as tumor necrosis factor-alpha (TFN-alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6) may play a role in the pathogenesis of congestive heart failure. The scope of this article includes an overview of the biology of cytokines in the heart, as well as review of the clinical studies that have documented elevated levels of cytokines and cytokine receptors in patients with heart failure.


Competition between two high- and low-affinity protein-binding sites in myosin VI controls its cellular function.
Myosin VI is involved in many cellular processes ranging from endocytosis to transcription. This multifunctional potential is achieved through alternative isoform splicing and through interactions of myosin VI with a diverse network of binding partners. However, the interplay between these two modes of regulation remains unexplored. To this end, we compared two different binding partners and their interactions with myosin VI by exploring the kinetic properties of recombinant proteins and their distribution in mammalian cells using fluorescence imaging. We found that selectivity for these binding partners is achieved through a high-affinity motif and a low-affinity motif within myosin VI. These two motifs allow competition among partners for myosin VI. Exploring how this competition affects the activity of nuclear myosin VI, we demonstrate the impact of a concentration-driven interaction with the low-affinity binding partner DAB2, finding that this interaction blocks the ability of nuclear myosin VI to bind DNA and its transcriptional activity in vitro We conclude that loss of DAB2, a tumor suppressor, may enhance myosin VI-mediated transcription. We propose that the frequent loss of specific myosin VI partner proteins during the onset of cancer leads to a higher level of nuclear myosin VI activity.


Role of thrombophilic gene polymorphisms in branch retinal vein occlusion.
Branch retinal vein occlusion (BRVO) is a common cause of severe visual loss. Numerous risk factors, including arterial hypertension, diabetes mellitus, and arteriosclerosis, have been identified. Gene polymorphisms affecting hemostasis may also play a role in the pathogenesis of BRVO. The present study was therefore done to determine the prevalence of genetic polymorphisms in factors implicated in hypercoagulability among patients with BRVO. Retrospective case-control study. The study cohort consisted of 294 patients with BRVO and 294 control subjects, matched for age and gender. Determination of genotypes was done by allele-specific digestion of polymerase chain reaction products, or by 5' exonuclease assay (TaqMan). Genotypes of factor V R506Q (factor V Leiden), prothrombin 20210G>A, fibrinogen beta -455G> A, factor XII (FXII) 46C>T, and ITGA2 807C>T (platelet glycoprotein Ia [GPIa] 807C>T) and ITGB3 L59P (platelet GPIIIa PlA1/PlA2) polymorphisms. Genotype distributions of the investigated gene polymorphisms did not differ significantly between patients and control subjects. In contrast, significantly increased prevalences of arterial hypertension and hypercholesterolemia were found among patients with BRVO. In a logistic regression analysis, the presence of arterial hypertension was associated with an odds ratio (OR) of 2.32 (95% confidence interval [CI], 1.62-3.32), whereas hypercholesterolemia yielded an OR of 2.54 (95% CI, 1.74-3.70) for BRVO. Our data indicate that the prevalences of the investigated gene polymorphisms do not differ significantly in patients with BRVO and control subjects. This suggests that these polymorphisms are not major risk factors for BRVO.


Mobility dynamics of migrant workers and their socio-behavioral parameters related to malaria in Tier II, Artemisinin Resistance Containment Zone, Myanmar.
Areas with dynamic population movements are likely to be associated with higher levels of drug-resistant malaria. Myanmar Artemisinin Resistance Containment (MARC) Project has been launching since 2012. One of its components includes enhancing strategic approaches for mobile/migrant populations. We aimed to ascertain the estimated population of mobile migrant workers and their families in terms of stability in work setting in townships classified as tier II (areas with significant inflows of people from areas with credible evidence of artemisinin resistance) for Artemisinin resistance; to identify knowledge, attitudes and practices related to prevention and control of malaria and to recommend cost-effective strategies in planning for prevention and control of malaria. A prospective cross-sectional study conducted between June to December 2013 that covered 1,899 migrant groups from 16 tier II townships of Bago Region, and Kayin and Kayah States. Trained data collectors used a pre-tested and subsequently modified questionnaire and interviewed 2,381 respondents. Data of migrant groups were analyzed and compared by category depending upon the stability of their work setting. The estimated population of the 1,899 migrant groups categorized into three on the nature of their work setting was 56,030. Bago region was the commonest reported source of origin of migrant groups as well as their transit. Malaria volunteers were mostly within the reach of category 1 migrant groups (43/66, 65.2 %). Less stable migrant groups in category 3 had limited access to malaria information (14.7 %) and malaria care providers (22.1 %), low level of awareness and use of long-lasting insecticide-treated nets (46.6 and 38.8 %). Also, they had poor knowledge on malaria prevention on confirming suspected malaria and on using artemisinin combined therapy (ACT). Within two weeks prior to the survey, only 16.5 % of respondents in all categories combined reported acute undifferentiated fever. Mobility dynamics of migrant groups was complex and increased their vulnerability to malaria. This phenomenon was accentuated in less stable areas. Even though migrant workers were familiar with rapid diagnostic tests for malaria, ACT still needed wide recognition to improve practices supportive of MARC including the use of appropriate personal protection. High mobility calls for re-designation of tier II townships to optimize ACT resistance containment.


Mechanisms for activation and inhibition of carboxypeptidase A catalyzed hydrolyses of peptides and esters.
3,3-Diphenylpropanoate (DPP) activates the carboxypeptidase A catalyzed hydrolysis of benzoylglycyl-L-phenylalanine (BzGly-L-Phe) (Ka = 2.1 x 10 (-3) M) and inhibits ester hydrolysis uncompetitively (K1 =2.1 X 10 (-3) M). A common modifier binding site located adjacent to the peptide and ester substrate binding sites is proposed. The forms of the pathways proposed for activation and inhibition are remarkably similar.


Anaphylactic relase of a basophil kallikrein-like activity. II. A mediator of immediate hypersensitivity reactions.
This report describes the immune release of a new mediator from human peripheral leukocytes, a basophil kallikrein-like activity (BK-A). The release process is initiated by the interaction of antigen on anti-IgE with cell-bound IgE, and appears to be similar in mechanism to the relase of histamine and other mediators of the immediate hypersensitivity reaction. The dose-response relationships and kinetics of histamine and BK-A release from antigen-challenged peripheral leukocytes are similar. The relase of the BK-A is calcium and temperature dependent, requires metabolic energy, and is controlled by hormone-receptor interactions that influence the cellular level of cyclic AMP, as has been described for other mediators of immediate hypersensitivity reactions. The data indicate that the interaction of BK-A with human plasma kininogen, generates immunoreactive kinin. We conclude that the antigen-IgE interation leads to the release from human basophils of a new mediator, a basophil kallikrein-like activity which may well be a link between reactions of immediate hypersenstivitity and the plasma and/or tissue kinin-generating systems.


Association of Aspirin Resistance with Increased Mortality in Ischemic Stroke.
To investigate the association of aspirin resistance (AR) with mortality in a cohort of Chinese patients with acute ischemic stroke (AIS). One hundred and ninety-six ischemic stroke patients who received at least 7 days of aspirin therapy prior to stroke onset were enrolled. The outcome measure was all-cause and cardiovascular disease (CVD) mortality at 1-year follow-up. The relation of AR with the two end points was investigated with the use of logistic regression models. The median age of included patients was 65(IQR, 56-76) years and 82(41.8%) were female. Thirty-five patients were defined as AR; thus, the rate was 17.9% (95%CI, 12.5% to 23.2%). The median NIHSS score was significantly higher in patients with AR than those with AS [12 (IQR, 10-17) vs. 7 (IQR, 4-10); Z=5.188; P<0.001]. Similarly, the median infarct volume was also significantly higher in AR than in AS [18.8 (IQR, 4.3-25.2) ml vs. 13.2 (IQR, 3.3-18.7) ml; Z=3.322; P=0.008]. During follow-up there were 43 patients (21.9%) died, including 24 CVD mortality (12.2%). In univariate logistic regression analysis, we found that the rate of all-cause mortality and CVD mortality increased by 390% (OR=4.90; 95%CI:2.24-10.75) and 422% (OR=5.22; 95%CI, 2.10-12.98) in AR group. After adjusting for all other significant predictors, AR still associated with high mortality and the rate of all-cause mortality and CVD mortality increased by 215% (OR=3.15; 95%CI:1.88-4.93) and 231% (OR=3.31; 95%CI, 1.96-522), respectively. The present study shows that AR was a useful prognostic marker of all-cause or CVD mortality in Chinese patients with AIS.


Utility of the estimated glucose disposal rate as a marker of microvascular complications in young adults with type 1 diabetes.
In 61 young adults with type 1 diabetes mellitus, the estimated glucose disposal rate (eGDR), a validated marker for insulin resistance, correlated positively with the prevalence of microvascular complications. In the absence of an established vascular risk calculator specific to diabetes, the eGDR may present a useful clinical tool in the assessment of complication risk in type 1 diabetes.


Urinary phthalate metabolites and their mixtures are associated with advanced sperm epigenetic aging in a general population.
We have recently shown that sperm epigenetic age (SEA), a surrogate measure of biological aging in sperm, is associated with couples' time-to-pregnancy (TTP). Advanced SEA was also observed among smokers, suggesting its susceptibility to environmental exposures. Therefore, we assessed the association between urinary phthalate metabolites and SEA in male partners of couples planning to conceive among the general population. The Longitudinal Investigation of Fertility and the Environment (LIFE) Study was a prospective multi-site and general population cohort study of couples who were interested in becoming pregnant. Among male partners (n = 333), eleven urinary phthalate metabolites were measured and SEA was previously developed using Super Learner ensemble algorithm. Multivariable linear regression was used to evaluate associations of SEA with individual metabolites. Bayesian kernel machine regression (BKMR), quantile g-computation (qgcomp) and weighted quantile sum (WQS) models were used for mixture analyses. Covariates included were BMI, cotinine, race and urinary creatinine. In the single metabolite multivariate analyses, nine (82%) phthalate metabolites displayed positive trends with SEA (range: 0.05-0.47 years). Of these metabolites, advanced SEA was significantly associated with interquartile range increases in exposure of three phthalates [MEHHP (β = 0.23, 95% CI: 0.03, 0.43, p = 0.03), MMP (β = 0.24, 95% CI: 0.01, 0.47, p = 0.04), and MiBP (β = 0.47, 95% CI: 0.14, 0.81, p = 0.01)]. Additionally, in BKMR and qgcomp (p = 0.06), but not WQS models, phthalate mixtures showed an overall positive trend with SEA, with MiBP, MMP and MBzP as major drivers of the mixture effects. This is the first study that combined single exposure and mixture models to associate male phthalate exposures with advanced epigenetic aging of sperm in men planning to conceive among the general population. Our findings suggest that phthalate exposure may contribute to the acceleration of biological aging of sperm.


Combined treatment with erlotinib and a transforming growth factor-β type I receptor inhibitor effectively suppresses the enhanced motility of erlotinib-resistant non-small-cell lung cancer cells.
: Despite an initial dramatic response to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, the majority of non-small cell lung cancer (NSCLC) patients with EGFR-activating mutations develop acquired resistance. Therefore, there is an urgent need to elucidate the unknown mechanisms and biological behaviors of EGFR TKI-resistant lung tumors. We investigated the motility of EGFR TKI-resistant cells, as these characteristics are relevant to cancer metastasis. : Erlotinib-resistant PC-9ER cells were generated from PC-9 NSCLC cells, which harbor an EGFR-activating mutation, and used in this study. We investigated the involvement of the transforming growth factor beta (TGF-β) pathway in cell motility, and tested the effects of erlotinib and TGF-β type I receptor (RI) inhibition on cell motility. : PC-9ER cells displayed enhanced motility resulting from autocrine activation of the TGF-β pathway. Increased TGF-β2 secretion resulting from TGF-β2 up-regulation at the transcriptional level was suggested to be responsible for the phosphorylation of Smad2 and the subsequently elevated transcriptional regulatory activity in PC-9ER cells. The motility of PC-9ER cells was suppressed by treatment with either the TGF-βRI inhibitor LY364947 or erlotinib, and greater suppression was observed when used in combination. LY364947 or erlotinib exerted no growth-inhibitory effects, suggesting that motility and growth are driven by different signaling pathways in PC-9ER cells. : Our results imply that blockade of the TGF-β signaling pathway combined with continuous EGFR TKI treatment will be beneficial in preventing metastasis in patients with EGFR TKI-resistant NSCLC without the EGFR T790M resistance mutation.


Magnetic resonance imaging of the cerebral aqueduct.
1.5 Tesla MRI examinations were evaluated for aqueductal configuration, hydrocephalus and flow-related signal void in 70 patients with juxtaaqueductal pathology and in 20 normal controls. In the 70 cases with pathology, the aqueduct was obliterated or distorted in 34, dilated in 3, normal in 29 and not evaluable in 4. A definite flow-related signal void indicated CSF movement within the aqueduct in all normal examinations. Flow-related signal void was absent in some, but not all, patients with aqueductal obliteration and distortion. CSF turbulence can create an intra-aqueductal signal void in the dilated proximal aqueduct, despite more distal obstruction. Thus hydrocephalus related to aqueductal obstruction is frequently, but not always, associated with absence of signal void.


Multiple sclerosis-associated agent. Failure of MS brain and serum to depress the polymorph count in normal mice and mice inoculated with cells containing C/type particles.
The groups that originally reported and confirmed the demonstration of a multiple sclerosis associated agent (MSAA) are now, along with others, unable to reproduce this effect. In view of this confusion and the potential importance of this work for multiple sclerosis (MS) we have done a strict double-blind trial using larger groups of mice (10) and counting more cells (900) than in previous reports to offset the high variability of mouse polymorphonuclear neutrophil (PMN) counts. Sera from 5 active MS patients and 4 normal subjects were tested in mice, half of which had previously been injected with PAM line cells (containing C-type particles and subject to reduced cell yield when cultured with MS brain extract). No significant PMN depression was found in either MS or normals on any basis of comparison. However, a significant depression was seen following PAM cell injection irrespective of serum origin. Higher counting accuracy did not reduce PMN variability. A single MS brain specimen was also without effect. consequently we have been unable to confirm the existence of an MSAA as defined by PMN depression in mice.


Clinical trials in veterinary oncology: a clinician's viewpoint.
Review of the veterinary oncology literature is important for keeping up-to-date, but it can be time-consuming and sometimes frustrating. Results of clinical trials are published in a variety of formats, including case descriptions, review articles, retrospective studies, and prospective trials. They may be found as abstracts, which usually present preliminary data and interpretation, as interesting items or commentary in a newsletter, or as articles in referred journals. In this "clinician's viewpoint," a practical approach to sifting through the mountains of literature is offered.


[Condition of the teeth and oral hygiene in medical students, stomatological branch, Palacky University Olomouc].
The paper deals with assessment of the cariosity of teeth, hygiene of the oral cavity, needs and quality of treatment in 126 dental medical students, Palacký University, Olomouc in the school year 1987/88. From the assembled results it may be concluded that the health consciousness of care of oral health even in groups of interested persons, as we may anticipate in dental the students is not reflected in their attitude to their own health. This is the more problematical as it may make us think that health education is not a sufficient impulse for medical students.


[Azoospermia and 45,X/46,XY chromosomal mosaicism: a case report].
Chromosomal abnormalities are common in patients with oligozoospermia or azoospermia. We report the case of a 32-year patient, with male phenotype, and without hormonal or morphological abnormalities, with a severely reduced spermatogenesis. It was revealed a 45,X/46,XY gonadal dysgenesis. We have reviewed the various problems inherent in the discovery of this rare gonadal dysgenesis, including genetic, cancer and fertility risks.


Reliability of antinuclear matrix protein 2 antibody assays in idiopathic inflammatory myopathies is dependent on target protein properties.
A line blotting assay (LB) is currently used to detect myositis-specific autoantibodies (MSAs) in patients with idiopathic inflammatory myopathies (IIMs), because of its simplicity; however, the sensitivity and specificity of this assay is low. The aim of this study is to evaluate the accuracy of the commercial LB in detection of antinuclear matrix protein 2 (NXP2) antibody. Seventy-seven serum samples from patients with IIMs, in which anti-NXP2 antibodies were detected through immunoprecipitation and western blotting (IP-WB) using K562 cell lysate, were enrolled. All samples were assessed by LB and IP-WB using recombinant human NXP2 whole protein (rNXP2) produced by insect cells, and the positive rates of each assay were compared. Thirty-two samples (41.6%) showed false-negativity by LB, which includes 11 samples with negative results by IP-WB using rNXP2. Relative intensities of IP-WB using cell lysate were significantly higher in the samples with positive results by both LB and IP-WB using rNXP2, compared to samples with positive by IP-WB using rNXP2 but negative by LB. Three of 11 samples with negative results by both LB and IP-WB using rNXP2 revealed high antibody titers. Further, differences in post-transcriptional SUMOylation were observed between recombinant and natural NXP2 proteins. In conclusion, the LB showed low sensitivity for detection of anti-NXP2 antibody, an effect exacerbated at low titers of anti-NXP2 antibodies. Moreover, there appears to be differences in the reactivities of antibodies to recombinant and natural NXP2 proteins with different post-transcriptional modifications.


Smartphone App-Based and Paper-Based Patient-Reported Outcomes Using a Disease-Specific Questionnaire for Dry Eye Disease: Randomized Crossover Equivalence Study.
Using traditional patient-reported outcomes (PROs), such as paper-based questionnaires, is cumbersome in the era of web-based medical consultation and telemedicine. Electronic PROs may reduce the burden on patients if implemented widely. Considering promising reports of DryEyeRhythm, our in-house mHealth smartphone app for investigating dry eye disease (DED) and the electronic and paper-based Ocular Surface Disease Index (OSDI) should be evaluated and compared to determine their equivalency. The purpose of this study is to assess the equivalence between smartphone app-based and paper-based questionnaires for DED. This prospective, nonblinded, randomized crossover study enrolled 34 participants between April 2022 and June 2022 at a university hospital in Japan. The participants were allocated randomly into 2 groups in a 1:1 ratio. The paper-app group initially responded to the paper-based Japanese version of the OSDI (J-OSDI), followed by the app-based J-OSDI. The app-paper group responded to similar questionnaires but in reverse order. We performed an equivalence test based on minimal clinically important differences to assess the equivalence of the J-OSDI total scores between the 2 platforms (paper-based vs app-based). A 95% CI of the mean difference between the J-OSDI total scores within the ±7.0 range between the 2 platforms indicated equivalence. The internal consistency and agreement of the app-based J-OSDI were assessed with Cronbach α coefficients and intraclass correlation coefficient values. A total of 33 participants were included in this study. The total scores for the app- and paper-based J-OSDI indicated satisfactory equivalence per our study definition (mean difference 1.8, 95% CI -1.4 to 5.0). Moreover, the app-based J-OSDI total score demonstrated good internal consistency and agreement (Cronbach α=.958; intraclass correlation=0.919; 95% CI 0.842 to 0.959) and was significantly correlated with its paper-based counterpart (Pearson correlation=0.932, P<.001). This study demonstrated the equivalence of PROs between the app- and paper-based J-OSDI. Implementing the app-based J-OSDI in various scenarios, including telehealth, may have implications for the early diagnosis of DED and longitudinal monitoring of PROs.


Young investigator challenge: The utility of GATA3 immunohistochemistry in the evaluation of metastatic breast carcinomas in malignant effusions.
It is not uncommon to encounter challenges in the immunohistochemical confirmation of metastatic breast cancer given the limited sensitivities of mammaglobin and gross cystic disease fluid protein 15 (GCDFP-15/BRST-2) and the significant proportion of triple-negative breast carcinomas (ie, tumors that are negative for estrogen receptor [ER], and progesterone receptor [PgR], and human epidermal growth factor 2 [HER2]). GATA binding protein 3 (GATA3) has emerged as a potentially useful immunohistochemical adjunct during the evaluation of metastatic breast carcinomas in cytology specimens. The objective of the current study was to examine GATA3 expression in the context of malignant effusions secondary to both mammary and extramammary malignancies. In total, 306 malignant effusions (from 62 metastatic breast carcinomas and 244 extramammary malignancies) were examined using GATA3 immunohistochemistry. Effusions with metastatic breast carcinoma were also examined using immunohistochemistry for additional breast markers (ER, PgR, HER2, mammaglobin, and GCDFP-15/BRST-2). GATA3 immunohistochemistry highlighted the tumor cells in 58 of the 62 samples (93.5%) from patients with metastatic breast carcinoma, which was higher than the observed sensitivity of immunohistochemistry for ER (63.8%), PgR (41.4%), HER2 (15.5%), mammaglobin (22.4%), and GCDFP-15/BRST-2 (5.2%). GATA3 expression also was observed in a subset of malignant effusions secondary to extramammary primaries, specifically, in 28 of 244 specimens (11.5%). GATA3 is a highly sensitive marker for the detection of metastatic breast carcinomas in effusion specimens. However, this marker is not entirely specific for malignancies of breast origin. Thus, GATA3 should be used in conjunction with additional immunohistochemical markers during the cytologic evaluation of malignant effusions.


Picosecond time-resolved fluorescence spectroscopy of K-590 in the bacteriorhodopsin photocycle.
The fluorescence spectrum of a distinct isometric and conformational intermediate formed on the 10(-11) s time scale during the bacteriorhodopsin (BR) photocycle is observed at room temperature using a two laser, pump-probe technique with picosecond time resolution. The BR photocycle is initiated by pulsed (8 ps) excitation at 565 nm, whereas the fluorescence is generated by 4-ps laser pulses at 590 nm. The unstructured fluorescence extends from 650 to 880 nm and appears in the same general spectral region as the fluorescence spectrum assigned to BR-570. The transient fluorescence spectrum can be distinguished from that assigned to BR-570 by a larger emission quantum yield (approximately twice that of BR-570) and by a maximum intensity near 731 nm (shifted 17 nm to higher energy from the maximum of the BR-570 fluorescence spectrum). The fluorescence spectrum of BR-570 only is measured with low energy, picosecond pulsed excitation at 590 nm and is in good agreement with recent data in the literature. The assignment of the transient fluorescence spectrum to the K-590 intermediate is based on its appearance at time delays longer than 40 ps. The K-590 fluorescence spectrum remains unchanged over the entire 40-100-ps interval. The relevance of these fluorescence data with respect to the molecular mechanism used to model the primary processes in the BR photocycle also is discussed.


The interactions between MnO2+/Mn3+ complexes and ascorbates. A pulse radiolysis study.
The reactivity between various MnO2+/Mn3+ complexes and ascorbic acid/ascorbate were studied using pulse radiolysis. Experimental results indicate that Mn3+-sulfate reacts with both AH2/AH- via metal-ascorbate complexes. MnO2+-formate and Mn3+-pyrophosphate both appear to react by electron transfer with no evidence of complex formation. All of these metal complexes, with the exception of Mn3+-pyrophosphate, react as fast or faster with ascorbate than free O2-. The significance of this observation in light of metal-induced oxygen toxicity will be discussed.


Long-term Outcomes of Cemented Total Hip Arthroplasty in Patients with Ankylosing Spondylitis at a Minimum Follow-up of 10 Years.
This study was performed to evaluate long-term clinical and radiologic outcomes of cemented total hip arthroplasty in patients with ankylosing spondylitis. A retrospective study of 12 patients (16 cases) diagnosed with ankylosing spondylitis undergoing total hip arthroplasty with cemented femoral stem from November 2002 to January 2006 with a minimum follow up of 10 years. Clinical outcomes were assessed using Harris Hip Scores and measures of pain and range of motion. Radiologic outcomes were assessed with serial plain X-ray. Fixation and stability of implant, enthesopathy of ischium and development of heterotopic ossification were also evaluated. Mean Harris Hip Scores significantly improved from pre-operative levels (58 points; range, 39-81 points) to post-operative (92 points; range, 68-100 points). Mean flexion contracture levels decreased from preoperative (13°) to post-operative (5°), and mean post-operative range of motion improved 106° compared to preoperative levels. No newly developed osteolysis lesions or implant loosening were observed in last follow up X-rays. One heterotopic ossification and one greater trochanter fracture were observed. Greater trochanter fracture was treated conservatively, and was resulted in bony union. No patients underwent revisions. This study revealed positive long-term clinical and radiologic outcomes following total hip arthroplasty with cemented femoral stems in patients with ankylosing spondylitis patients.


The impact of drying on structure of sedimentary organic matter in wetlands: Probing with native and amended polycyclic aromatic hydrocarbons.
Wetland sediments undergo dry-wet cycles that may change their structural properties and affect geochemical behavior of associated organic compounds. In this study, we examined the effect of drying on particle size distributions and the rapid (24h) sorption reactions of polycyclic aromatic hydrocarbons (PAHs) with salt marsh sediments in Nueces Delta, South Texas. Drying reduced the fraction of fine particles in organically richer sediments, indicating structural rearrangement of organic matter and mineral aggregates. Among the 16 EPA priority PAHs examined, dried sediment preferentially released 1.0-7.5% of phenanthrene, fluoranthene and pyrene to added seawater (solid: water mass ratio of 1/100) - significantly greater than release from sediments maintained in the wet state. On the other hand, drying also increased the affinity of sedimentary organic matter (SOM) for experimentally amended (deuterated) phenanthrene relative to continually wet sediments. Further, deuterated phenanthrene was even more effectively retained when it was added to wet sediment that was subsequently dried and rewetted. These apparently contradictory results can be reconciled and explained by SOM having a heterogeneous distribution of hydrophobic and hydrophilic zones - e.g., a zonal model. We propose that drying changed the orientation of amphiphilic SOM, exposing hydrophobic zones and promoting the release of some of their native PAHs to water. Freshly amended PAHs were only able to penetrate into the surface hydrophobic zone and/or deeper but rapidly accessible ("kinetic") zone in wet sediments due to the brief adsorption contact time. Subsequent drying presumably then induced structural changes in SOM that isolated these amended PAHs in sites inaccessible to water exchange in the next rewetting. These results provide insights into structural changes of SOM upon drying, and help predict the fate of compounds such as organic contaminants during drought/flood oscillations.


Can intravenous oxytocin infusion counteract hyperinflammation in COVID-19 infected patients?
Based on its well-documented anti-inflammatory and restorative properties we propose trials with the natural hormone oxytocin for treatment of hospitalised Covid-19 patients. We searched for, retrieved, and commented on specific literature regarding multiple functions of oxytocin with a special focus on its modulation of inflammatory, immune, and restorative functions. Available data gathered in animals and humans support the anti-inflammatory properties of oxytocin. The multiple anti-inflammatory effects of oxytocin have been demonstrated in vitro and in vivo in various animal models and also in humans in response to intravenous infusion of oxytocin. Furthermore, oxytocin has been documented to activate several types of protective and restorative mechanisms and to exert positive effects on the immune system. In addition, to being anti-inflammatory, it may be hypothesised, that oxytocin may be less suppressive on adaptive immune systems, as compared with glucocorticoids. Finally, by its restorative effects coupled with its anti-stress and healing properties, oxytocin may shorten the recovery period of the Covid-19 patients.


The crystal structure of Rv0793, a hypothetical monooxygenase from M. tuberculosis.
Mycobacterium tuberculosis infects millions worldwide. The Structural Genomics Consortium for M. tuberculosis has targeted all genes from this bacterium in hopes of discovering and developing new therapeutic agents. Open reading frame Rv0793 from M. tuberculosis was annotated with an unknown function. The 3-dimensional structure of Rv0793 has been solved to 1.6 A resolution. Its structure is very similar to that of Streptomyces coelicolor ActVA-Orf6, a monooxygenase that participates in tailoring of polyketide antibiotics in the absence of a cofactor. It is also similar to the recently solved structure of YgiN, a quinol monooxygenase from Escherichia coli. In addition, the structure of Rv0793 is similar to several structures of other proteins with unknown function. These latter structures have been determined recently as a result of structural genomic projects for various bacterial species. In M. tuberculosis, Rv0793 and its homologs may represent a class of monooygenases acting as reactive oxygen species scavengers that are essential for evading host defenses. Since the most prevalent mode of attack by the host defense on M. tuberculosis is by reactive oxygen species and reactive nitrogen species, Rv0793 may provide a novel target to combat infection by M. tuberculosis.


Value of including loupes in prosthodontic and endodontic components of dental degrees: a systematic review.
Background It is crucial dental students graduate with sound knowledge of endodontics and prosthodontics. The use of loupes is important for these due to their intricate nature, but there is currently no standardisation of curricula.Objective This systematic review investigates the value of including loupes in completing dental degrees and their benefits to dental students.Methods Literature was searched from inception to February 2022 in PubMed, Embase and Scopus. Articles included were primary studies of dental students studying endodontics or prosthodontics, which had outcomes related to the value of utilising loupes in learning, clinical application and ergonomics.Results A total of 1,489 articles were retrieved, of which 14 relevant articles were identified. These articles discussed student perceptions and the impact on visual acuity, ergonomic practices and dental procedures. Overall, students perceived that loupes increased self-confidence and allowed a greater operative view but were initially difficult to use. Using loupes resulted in greater visual acuity than no magnification and improved ergonomic practices by reducing neck angulation and improving posture. Students also received better grades when using loupes during cavity access preparation or root canal therapy.Conclusion The use of loupes by dental students can be beneficial if there is initial teaching on their use.


Comparative relaxant effects of the NO donors sodium nitroprusside, DEA/NO and SPER/NO in rabbit carotid arteries.
1. Sodium nitroprusside (SNP, 10(-9)-3x10(-4) M), diethylamine/NO complex (DEA/NO, 10(-9)-10(-4) M) and spermine/NO complex (SPER/NO, 10(-8)-3x10(-4) M) induced concentration-dependent relaxation of isolated rabbit carotid arteries precontracted with KCl (50 mM) or with histamine (3x10(-6) M). 2. In KCl-precontracted arteries the order of potency was SNP=DEA/NO>SPER/NO, and in histamine-precontracted arteries the order of potency was SNP>DEA/NO>SPER/NO. Relaxations to the three NO donors were significantly higher in histamine-precontracted arteries than in KCl-precontracted arteries. 3. The guanylyl cyclase inhibitor methylene blue (10(-5) M) significantly inhibited relaxations to the three NO donors in histamine-precontracted arteries and, to a lesser extent, in KCl-precontracted arteries. 4. In conclusion, the NO donors SNP, DEA/NO and SPER/NO induce quantitatively different relaxation of rabbit carotid artery. Both, lower relaxant effects in depolarized arteries and inhibition of relaxation by methylene blue indicate the mediation of cGMP formation in the relaxant effects of the three NO donors.


[Evolution of microbial flora and organic matter in bottled mineral water].
A 15-week survey was carried out by the authors in order to detect the total microbial count and the quantity of organic matter in mineral waters bottled in dark glass containers and stored at room temperature. Two different and significant increases were registered at the 2nd and 11th week respectively. A relation between microbial count and organic matter was observed during the period examined.


The use of serum segesterone acetate levels to assess adherence of trial participants with a contraceptive vaginal ring.
To determine the incidence of out-of-range segesterone acetate (NES) concentrations in participants of a pharmacokinetic/pharmacodynamic trial of a continuous use contraceptive vaginal ring (CVR) releasing NES and estradiol (E2). We hypothesized that out-of-range concentrations reflect nonadherent ring use and predict ovulation risk. We conducted a secondary analysis of data from a prospective, multi-centered, randomized, Phase IIa dose-finding trial for a CVR releasing NES and E2. Our primary outcome was the risk of ovulation associated with out-of-range NES events. We calculated the 5th and 95th percentile NES concentrations of subjects at steady state to determine high and low cutoffs. We used a Fisher's exact test to determine group differences, and calculated the relative risk of ovulation for each group. We analyzed available serum NES data from cycles 2 (n = 172), 3 (n = 156) and 7 (n = 115) to determine the 5th and 95th percentile of all NES concentrations (64, 296 pg/mL). In the 443 cycles of observation, no ovulations occurred in participants with NES concentrations within the expected range. In contrast, we found ovulatory elevations of progesterone in 21 cycles with out-of-range values. Of these, 15 (71%) cycles had evidence of one or more nonadherent low and 6 (29%) one or more unexpected peak. The relative risk of ovulation increased with evidence of multiple non-adherent levels. We found out-of-range NES concentrations, suggestive of improper use of a CVR associated with an increased risk of ovulation, with a direct relationship between the number of out-of-range events and the relative risk. The results of this study support the use of out-of-range serum NES values as a marker of adherence in contraceptive clinical trials of continuous vaginal rings, and suggest that nonadherence occurs even in early phase clinical trials with close monitoring.


Controversial issues in vitiligo patients: a review of old and recent treatments.
Vitiligo is quite a common hypopigmentary disorder, which may affect both children and adults with important psychological effects due to the well-known leopard skin-like appearance. The authors summarize in the present study the published evidence on vitiligo with particular interest on the controversial aspects of the disease, such as its definition and the available treatments.


Updating the risk profile of fatal head trauma: an autopsy study with focus on age- and sex-dependent differences.
Fatal head trauma (FHT) represents one of the most frequent causes of death diagnosed in forensic pathology. However, profound statistic autopsy data on FHT is still sparse. Therefore, the purpose of this study was to investigate the circumstances and injury patterns of FHT with particular focus on age and sex, and additionally, to describe a recent risk profile of FHT. To this end, the forensic autopsy records of each FHT case at a large German university hospital during a 10-year period (2006-2015) were analyzed retrospectively (n = 372). The male-female ratio was 2.6:1. Regarding median age, females were 12.5 years older than males. Traffic-associated FHT represents the major mechanism of death, followed by fall-associated FHT. While accident was the major manner of death and presented a similar distribution of age and sex, homicides were the only subgroup with a significantly lower ratio between males and females. Skull fractures occurred in 78.2% and intracranial hemorrhages in 80.6% of all cases. In summary and partly in contrast to clinical data on head trauma, FHT still occurs predominantly in male individuals under the age of 45 years, in the context of traffic accidents and affected by alcohol intake. Improvements in traffic security as well as continuing surveillance of the incidence of FHT by forensic autopsies are necessary to further reduce the incidence of FHT.


Spontaneous degenerative maculopathy in the monkey.
Maculopathy has many varied facets. The subhuman diurnal primate demonstrates some of the changes occasionally seen in clinical practice. Examination of 574 diurnal subhuman primates, mostly older rhesus monkeys, revealed the following: drusen-like bodies in the macula and frequently elsewhere in the eye grounds of 5.9%; crescent shaped lesions suggestive of choroidal rupture; and macular and perimacular lesions associated with myopia and complicated by choroidal neovascular ingrowth.


Visualization of tumor heterogeneity by in situ padlock probe technology in colorectal cancer.
Tumor heterogeneity is considered a major cause for therapy resistance in colorectal cancer. Sub-populations of cells with different genetic alterations may exist in spatially distinct areas. Upon therapy, resistant sub-clones may enrich and ultimately lead to disease progression. Although ample data are available on tumors which are heterogeneous on a morphological level, only little is known about morphologically homogeneous tumors. We aimed to investigate if morphologically homogeneous colorectal cancer can harbor a heterogeneous genetic landscape. We chose to microdissect six morphologically homogeneous colorectal carcinomas into several areas and performed next-generation sequencing (NGS) to identify tumors with genetic heterogeneity. We then applied an mRNA-based in situ mutation detection technology based on padlock probes to localize and visualize mutations directly in the tumor tissue. In three out of six tumors, NGS revealed a high rate of variability of mutations between different tumor areas. We selected two cases for in situ mutation detection to visualize genetic heterogeneity. In situ mutation detection confirmed differences in mutant allele frequencies between different tumor areas of morphological homogeneous tumors. We conclude that genetic heterogeneity in morphologically homogeneous colorectal cancer is an observable, but underreported event. Our results illustrate the power of in situ mutation analysis to visualize genetic heterogeneity directly in tumor tissue.


Cathepsin cleavage of sirtuin 1 in endothelial progenitor cells mediates stress-induced premature senescence.
Stress-induced premature senescence (SIPS) of endothelial cells (ECs) has emerged as a contributor to global EC dysfunction. One of the cellular abnormalities mechanistically linked to SIPS is lysosomal dysfunction. In this study, we examined the impact of a range of cardiovascular risk factors on the expression of sirtuin 1 (SIRT1), SIPS, and apoptosis, and we documented the role of SIRT1 in reduced EC and endothelial progenitor cell (EPC) viability. These findings were confirmed in mice with selective endothelial SIRT1 knockout. The effects of stressors could be partially mimicked by inducing lysosomal membrane permeabilization or inhibiting autophagy, and were reversed by a cathepsin inhibitor. We provide evidence that SIRT1 is an important substrate of cysteine cathepsins B, S, and L. An antioxidant/peroxynitrite scavenger, ebselen, prevented stress-induced SIRT1 depletion and subversion of autophagy by mitigating lysosomal dysfunction. In conclusion, our data advance the concept of "stem cell aging" by establishing the critical role of lysosomal dysfunction in the development of SIPS through the cathepsin-induced proteolytic cleavage of SIRT1, a mechanism linking cell stress to apoptosis and SIPS. Ebselen potently protects lysosomal membrane integrity, preventing cathepsin-induced cleavage of SIRT 1 in EPCs and blunting SIPS and apoptotic cell death induced by relevant cardiovascular stressors. The proposed mechanism of SIRT1 depletion in stress has all of the attributes of being a paradigm of SIPS of EPCs.


Natural core-shell structure activated carbon beads derived from Litsea glutinosa seeds for removal of methylene blue: Facile preparation, characterization, and adsorption properties.
In this study, natural core-shell structure activated carbon beads (ACBs) from Litsea glutinosa seeds were successfully produced, characterized, and applied for adsorption of methylene blue (MB). The ACBs were prepared using single-step carbonization-activation with NaHCO3 at the optimized activation temperature, time, and activating agent concentration of 450 °C, 60 min, and 5%, respectively. Batch experiments were performed to determine the optimum adsorption conditions, suitable kinetic and isotherm models, and thermodynamic parameters for the adsorption of MB onto ACBs. The results showed that the ACBs were displayed as highly porous natural core-shell spheres with a diameter of about 5 mm. The adsorption of MB dye on ACBs was a spontaneous endothermic process, followed the Langmuir isotherm and the pseudo-second-order kinetic models with the rate-controlling step of both external diffusion and intra-particle diffusion. At the optimum conditions (pH of 9, the contact time of 10 h, the temperature of 40 °C, and an adsorbent dosage of 6 g/L), the maximum adsorption capacity reached 29.03 mg/g. The thermal method turned out to be more suitable for regenerating ACBs compared to the chemical method. The ACBs exhibited high reusability and stability, its adsorption efficiency could maintain more than 90% after five consecutive cycles of use. The electrostatic attraction, π-π interaction, hydrogen bonding, and pore-filling were identified as primary contributions to the adsorption mechanism. The overall results revealed that the ACBs could be used as a potential adsorbent for removing MB from water media.


The landscape of hervRNAs transcribed from human endogenous retroviruses across human body sites.
Human endogenous retroviruses (HERVs), the remnants of ancient retroviruses, account for 8% of the human genome, but most have lost their transcriptional abilities under physiological conditions. However, mounting evidence shows that several expressed HERVs do exert biological functions. Here, we systematically characterize physiologically expressed HERVs and examine whether they may give insight into the molecular fundamentals of human development and disease. We systematically identify 13,889 expressed HERVs across normal body sites and demonstrate that they are expressed in body site-specific patterns and also by sex, ethnicity, and age. Analyzing cis-ERV-related quantitative trait loci, we find that 5435 hervRNAs are regulated by genetic variants. Combining this with a genome-wide association study, we elucidate that the dysregulation of expressed HERVs might be associated with various complex diseases, particularly neurodegenerative and psychiatric diseases. We further find that physiologically activated hervRNAs are associated with histone modifications rather than DNA demethylation. Our results present a locus-specific landscape of physiologically expressed hervRNAs, which represent a hidden layer of genetic architecture in development and disease.


Common bile duct exploration in a Libyan hospital. Utilization of choledochoscopy in an effort to improve results.
Over a three-year period, 849 patients had a cholecystectomy for gallstones, at the Central Hospital, Tripoli, Libya. In 133 patients the common bile duct was explored. Under the particular circumstances in which the operation is performed, choledochoscopy was shown to have important advantages to the patient in both locating common duct stones and in ensuring that none is left behind.


Reducing inappropriate behaviors of developmentally disabled adults using antecedent aerobic dance exercises.
The effects of aerobic dance exercise on inappropriate behaviors of two developmentally disabled adults were observed in a day activities center. The experimental phase, in which the subjects engaged in exercise with seven other individuals on Monday, Wednesday, and Friday of each week, was preceded and followed by baseline phases in which subjects did not exercise and in which there were no contingencies in effect for the dependent variables. Exercises consisted of those commonly used in exercise dance classes. Observations occurred during 15 minute periods immediately before and following exercise while subjects engaged in regular classroom activities. Observations also occurred in the same time periods on no-exercise days during all phases. Behaviors observed included inappropriate vocalizations, repetitive movements, and off-task. Results indicate for both subjects a decrease in each of the inappropriate behaviors as a result of exercise.


Involving Parents/Family in Treatment during the Transition from Late Adolescence to Young Adulthood: Rationale, Strategies, Ethics, and Legal Issues.
The progression from adolescence to adulthood is a time of tremendous change, characterized by issues of identity formation, autonomy, and shifting relationship dynamics. The family is embedded in all aspects of this transition and serves as both a protective support and a limiting factor, a complicated duality that raises psychological, ethical, and legal issues. This article discusses the influence of familial factors and provides assessment strategies for evaluating the family in relation to treatment of transitional age youth. It is increasingly evident that family engagement is a significant contributor to outcomes for transitional age youth seeking mental health treatment.


Prognostic parameters in myelodysplastic syndromes: a multiple regression analysis.
The influence on survival of 21 basic clinical and hematologic parameters was evaluated in 72 patients with previously untreated myelodysplastic syndromes (MDS). Only five parameters were significant by both survival curves and multiple regression analyses: hemoglobin level, bone marrow (BM) cellularity (estimated from trephine BM biopsies), BM blast percentage, age and BM erythro/myeloid (E/M) ratio. Using these parameters, multiple regression analysis enabled us to predict 34% of the survival of all MDS patients (p less than 0.002), 38% of that of patients who had stable disease (p less than 0.04) and over 80% of that of patients who developed acute leukemia (p less than 0.02). High BM cellularity was the most predictive factor for the development of leukemia. No factor was predictive for patients who died of cytopenic or other complications.


Impact of Switching From Prasugrel to Clopidogrel Shortly After a Percutaneous Coronary Intervention Without a Loading Dose of Clopidogrel.
To determine the safety and efficacy of administering prasugrel at the time of percutaneous coronary intervention (PCI), and switching to clopidogrel, without reloading. Prasugrel has faster onset of action and appears to be of greater benefit than clopidogrel, particularly early after PCI. However, long-term prasugrel increases bleeding. Many physicians at Geisinger Medical Center (GMC) administer prasugrel before PCI and switch to clopidogrel afterward. The safety and efficacy of this strategy has not been studied. We performed a retrospective study using electronic medical records and identified patients at GMC who underwent PCI between February 1, 2009 and January 31, 2012 and received a loading dose of prasugrel with a subsequent switch to clopidogrel, without reloading. The primary endpoint was major adverse cardiovascular event (MACE), defined as death, myocardial infarction (MI), stroke, or stent thrombosis, 7 days after the first dose of clopidogrel. Secondary endpoints included MACE at 30 days, individual MACE components at 7 and 30 days post procedure, and bleeding as defined by the Bleeding Academic Research Consortium (BARC) at 1 day and 30 days. A total of 151 patients met inclusion criteria. One patient suffered a MACE on day 7 (0.7%; 95% confidence interval, 0.03%-3.33%). One patient had an MI between 8-30 days. Two patients had BARC bleeding (type 2 and type 3b) 30 days post PCI. In this small, retrospective analysis, the results of loading patients with prasugrel for PCI and switching them to clopidogrel without a loading dose appear to be encouraging.


Trends and patterns in cancer nanotechnology research: A survey of NCI's caNanoLab and nanotechnology characterization laboratory.
Cancer nanotechnologies possess immense potential as therapeutic and diagnostic treatment modalities and have undergone significant and rapid advancement in recent years. With this emergence, the complexities of data standards in the field are on the rise. Data sharing and reanalysis is essential to more fully utilize this complex, interdisciplinary information to answer research questions, promote the technologies, optimize use of funding, and maximize the return on scientific investments. In order to support this, various data-sharing portals and repositories have been developed which not only provide searchable nanomaterial characterization data, but also provide access to standardized protocols for synthesis and characterization of nanomaterials as well as cutting-edge publications. The National Cancer Institute's (NCI) caNanoLab is a dedicated repository for all aspects pertaining to cancer-related nanotechnology data. The searchable database provides a unique opportunity for data mining and the use of artificial intelligence and machine learning, which aims to be an essential arm of future research studies, potentially speeding the design and optimization of next-generation therapies. It also provides an opportunity to track the latest trends and patterns in nanomedicine research. This manuscript provides the first look at such trends extracted from caNanoLab and compares these to similar metrics from the NCI's Nanotechnology Characterization Laboratory, a laboratory providing preclinical characterization of cancer nanotechnologies to researchers around the globe. Together, these analyses provide insight into the emerging interests of the research community and rise of promising nanoparticle technologies.


[Influence of the expression of heat shock protein 70 in maxillofacial squamous cell carcinoma by thermochemotherapy].
To study the influence of thermochemotheraphy on the expression of HSP70 in maxillofacial squamous cell carcinoma. 12 patients were treated with thermochemotheraphy twice a week, altogether 10 times. After 8 mg of Pingyangmycin infused, the patients were treated with microwave hyperthermia at 43 degrees C for 40 min. The part of carcinoma tissue was removed with surgical operations at before treatment and aftre five times of treatment. The expression of HSP70 in tumor cells was determined by SP immunohistochemcial method. The expression of HSP70 in tumor cells was enhanced obviously by thermochemotherapy. Special high expression of HSP70 in the tumor cells was induced by thermochemotherapy. With the antigen presenting action and other action, HSP70 have special antitumor effect.


Porphyria cutanea tarda and HLA-linked hemochromatosis. Evidence against a systematic association.
This study was designed to test the hypothesis that a hemochromatosis allele is implicated in the expression of porphyria cutanea tarda. HLA phenotypes were determined in 69 porphyria cutanea tarda patients, 42 of which had the sporadic type (normal erythrocyte uroporphyrinogen decarboxylase activity) and 27 unrelated patients who had the familial type (diminished erythrocyte uroporphyrinogen decarboxylase activity). The incidence of HLA antigen A3, a marker of the hemochromatosis allele, was identical in the sporadic patients (23.8%), in the familial patients (22.2%), and in the controls (24.5%). Furthermore, no clinical difference could be found between A3 and non-A3 patients. These results demonstrate no systematic association between hemochromatosis and porphyria cutanea tarda in the population studied. Another HLA-linked gene, however, could be implicated in the expression of the disease as HLA antigen DR7 presented an incidence statistically different (p less than 0.05) between sporadic (16.6%) and familial patients (43%).


The effectiveness of immediate feedback during the objective structured clinical examination.
Using eight different physical examination or technical stations, 400 examinations were conducted to evaluate the effectiveness of immediate feedback during the Objective Structured Clinical Examination (OSCE). The test group comprised 50 medical students who underwent a standard 4-minute examination followed by 2 minutes of feedback. Immediately following feedback the students repeated an identical 4-minute examination scored by the same examiners. The control group consisted of 50 students from the same class who underwent an identical testing sequence, but instead of receiving feedback, they were instructed to continue their examinations for an additional 2 minutes before repeating the stations. Simple repetition of the task did not significantly improve score (mean increase 2.0%, NS). Extending the testing period from 4 to 6 minutes resulted in a small but significant increase in score (mean 6.7%, P less than 0.001). However, there was a much larger increase in the scores obtained following 2 minutes of immediate feedback compared to pre-feedback performance (mean 26.3%, P less than 0.0001). The majority of students and examiners felt that feedback, as administered in this study, was valuable both as a learning and teaching experience. Short periods of immediate feedback during an OSCE are practical and can improve competency in the performance of criterion-based tasks, at least over the short term. In addition, such feedback provides students with valuable self-assessment that may stimulate further learning.


Surface-fill H2S-releasing silk fibroin hydrogel for brain repair through the repression of neuronal pyroptosis.
Traumatic brain injury (TBI) remains the major cause of disability and mortality worldwide due to the persistent neuroinflammation and neuronal death induced by TBI. Among them, pyroptosis, a specific type of programmed cell death (PCD) triggered by inflammatory signals, plays a significant part in the pathological process after TBI. Inhibition of neuroinflammation and pyroptosis is considered a possible strategy for the treatment of TBI. In our previous study, exogenous hydrogen sulfide(H2S) exerted a neuroprotective effect after TBI. Here, we developed a surface-fill H2S-releasing silk fibroin (SF) hydrogel (H2S@SF hydrogel) to achieve small-dose local administration and avoid volatile and toxic side effects. We used a controlled cortical impact (CCI) to establish a mild TBI model in mice to examine the effect of H2S@SF hydrogel on TBI-induced pyroptosis. We found that H2S@SF hydrogel inhibited the expression of H2S synthase in neurons after TBI and significantly inhibited TBI-induced neuronal pyroptosis. In addition, immunofluorescence staining results showed that the necroptosis protein receptor-interacting serine/threonine-protein kinase 1 (RIPK1) partially colocalized with the pyroptosis protein Gasdermin D (GSDMD) in the same cells. H2S@SF hydrogel can also inhibit the expression of the necroptosis protein. Moreover, H2S@SF hydrogel also alleviates brain edema and the degree of neurodegeneration in the acute phase of TBI. The neuroprotective effect of H2S@SF hydrogel was further confirmed by wire-grip test, open field test, Morris water maze, beam balance test, radial arm maze, tail suspension, and forced swimming test. Lastly, we also measured spared tissue volume, reactive astrocytes and activated microglia to demonstrate H2S@SF hydrogel impacts on long-term prognosis in TBI. Our study provides a new theoretical basis for the treatment of H2S after TBI and the clinical application of H2S@SF hydrogel. STATEMENT OF SIGNIFICANCE: Silk fibroin (SF) hydrogel controls the release of hydrogen sulfide (H2S) to inhibit neuronal pyroptosis and neuroinflammation in injured brain tissue. In this study, we synthesized a surface-fill H2S-releasing silk fibroin hydrogel, which could slowly release H2S to reshape the homeostasis of endogenous H2S in injured neurons and inhibit neuronal pyroptosis in a mouse model of traumatic brain injury. Meanwhile, H2S@SF hydrogel could alleviate brain edema and the degree of neurodegeneration, improve motor dysfunction, anxious behavior and memory impairment caused by TBI, reduce tissue loss and ameliorate neuroinflammation. Our study provides a new theoretical basis for the treatment of H2S after TBI and the clinical application of H2S@SF hydrogel.


Structural basis of high-affinity nuclear localization signal interactions with importin-α.
Classical nuclear localization signals (cNLSs), comprising one (monopartite cNLSs) or two clusters of basic residues connected by a 10-12 residue linker (bipartite cNLSs), are recognized by the nuclear import factor importin-α. The cNLSs bind along a concave groove on importin-α; however, specificity determinants of cNLSs remain poorly understood. We present a structural and interaction analysis study of importin-α binding to both designed and naturally occurring high-affinity cNLS-like sequences; the peptide inhibitors Bimax1 and Bimax2, and cNLS peptides of cap-binding protein 80. Our data suggest that cNLSs and cNLS-like sequences can achieve high affinity through maximizing interactions at the importin-α minor site, and by taking advantage of multiple linker region interactions. Our study defines an extended set of binding cavities on the importin-α surface, and also expands on recent observations that longer linker sequences are allowed, and that long-range electrostatic complementarity can contribute to cNLS-binding affinity. Altogether, our study explains the molecular and structural basis of the results of a number of recent studies, including systematic mutagenesis and peptide library approaches, and provides an improved level of understanding on the specificity determinants of a cNLS. Our results have implications for identifying cNLSs in novel proteins.


Characterization of basal and methylxanthine-stimulated Ca2+ transport in abalone spermatozoa.
Methylxanthines, such as 1-methyl-3-isobutylxanthine (MIX) and theophylline, stimulate abalone sperm 45Ca2+ uptake in a time- and concentration-dependent manner. MIX is the most potent compound tested, and the ability of these compounds to alter 45Ca2+ uptake resides with methyl or isobutyl substitution of the xanthine nucleus at multiple sites. Methylxanthine-stimulated 45Ca2+ uptake does not occur as a secondary consequence of cyclic nucleotide phosphodiesterase inhibition, and added cyclic nucleotides are also without effect. The dramatic elevation of intracellular cAMP concentrations and induction of the acrosome reaction of sperm incubated with methylxanthines in the presence of Ca2+ is mediated by a primary effect of methylxanthines on Ca2+ transport. Basal 45Ca2+ uptake occurs through a verapamil-insensitive site that obeys the properties of a simple diffusion-mediated process. MIX-stimulated 45Ca2+ uptake occurs through a carrier-mediated transport site that has low affinity for Ca2+ (Km = 19.9 mM) and is verapamil sensitive. 45Ca2+ uptake through both basal and MIX-stimulated sites is enhanced by low extracellular Na+ concentrations (less than or equal to 15 mM) and is not affected by either extracellular Mg2+ or K+ X 45Ca2+ uptake through both sites is pH sensitive, but this sensitivity is different for each site. These data suggest that methylxanthines can affect sperm function via primary effects on Ca2+ transport, which occur through a specific carrier-mediated site(s). It is possible that many of the previously described effects of methylxanthines on sperm function are mediated via such changes in Ca2+ conductance.


Regenerating Corticospinal Axons Innervate Phenotypically Appropriate Neurons within Neural Stem Cell Grafts.
Neural progenitor cell grafts form new relays across sites of spinal cord injury (SCI). Using a panel of neuronal markers, we demonstrate that spinal neural progenitor grafts to sites of rodent SCI adopt diverse spinal motor and sensory interneuronal fates, representing most neuronal subtypes of the intact spinal cord, and spontaneously segregate into domains of distinct cell clusters. Host corticospinal motor axons regenerating into neural progenitor grafts innervate appropriate pre-motor interneurons, based on trans-synaptic tracing with herpes simplex virus. A human spinal neural progenitor cell graft to a non-human primate also received topographically appropriate corticospinal axon regeneration. Thus, grafted spinal neural progenitor cells give rise to a variety of neuronal progeny that are typical of the normal spinal cord; remarkably, regenerating injured adult corticospinal motor axons spontaneously locate appropriate motor domains in the heterogeneous, developing graft environment, without a need for additional exogenous guidance.


Chemical root to shoot signaling under drought.
Chemical signals are important for plant adaptation to water stress. As soils become dry, root-sourced signals are transported via the xylem to leaves and result in reduced water loss and decreased leaf growth. The presence of chemical signals in xylem sap is accepted, but the identity of these signals is controversial. Abscisic acid (ABA), pH, cytokinins, a precursor of ethylene, malate and other unidentified factors have all been implicated in root to shoot signaling under drought. This review describes current knowledge of, and advances in, research on chemical signals that are sent from roots under drought. The contribution of these different potential signals is discussed within the context of their role in stress signaling.


The Born-Infeld vortices induced from a generalized Higgs mechanism.
We construct self-dual Born-Infeld vortices induced from a generalized Higgs mechanism. Two specific models of the theory are of focused interest where the Higgs potential is either of a |ϕ|4- or |ϕ|6-type. For the |ϕ|4-model, we obtain a sharp existence and uniqueness theorem for doubly periodic and planar vortices. For doubly periodic solutions, a necessary and sufficient condition for the existence is explicitly derived in terms of the vortex number, the Born-Infeld parameter, and the size of the periodic lattice domain. For the |ϕ|6-model, we show that both topological and non-topological vortices are present. This new phenomenon distinguishes the model from the classical Born-Infeld-Higgs theory studied earlier in the literature. A series of results regarding doubly periodic, topological, and non-topological vortices in the |ϕ|6-model are also established.


Fluoxetine improves bone microarchitecture and mechanical properties in rodents undergoing chronic mild stress - an animal model of depression.
Depression is one of the most prevalent mental disorders associated with reductions in bone mineral density and increased fracture risk. Fluoxetine is a highly prescribed selective serotonin reuptake inhibitor (SSRI) in the treatment of depression and is reported to be a risk factor for fractures. The present study examined the effect of fluoxetine on bone microarchitecture and the mechanical properties under chronic mild stress (CMS), a rodent model of depression. Thirty-one 6-9 week-old rats were allocated to 4 groups: 1) CMS + fluoxetine group (n = 10), 2) fluoxetine-only group (n = 5), 3) CMS + placebo group (n = 10) and 4) control group (no CMS and treatment) (n = 6). After 16 weeks, bone microarchitecture of the distal femur was analyzed by µCT. Mechanical properties were assessed by the three-point bending test, and antidepressant efficacy was determined by sucrose preference and forced swimming tests. Significant correlations were found between volume of sucrose intake and bone volume/tissue volume (BV/TV) (p = 0.019) and elastic absorption energy (p = 0.001) in the fluoxetine only group. The fluoxetine-only group showed significantly higher in the second moment of area in y-direction (p = 0.0298), horizontal outer diameter (mm) (p = 0.0488) and average midshaft thickness (mm) (p = 0.00047) than control group. Comparing with the control group, there was a significant reduction in trabecular number (Tb.N) in the CMS + fluoxetine group (p = 0.026) but not the fluoxetine-only group (p > 0.05). Significant increases in trabecular separation were observed in the metaphysis of CMS + placebo (p = 0.003) and CMS + fluoxetine (p = 0.004) groups when compared to the control group but not in the fluoxetine-only group (p > 0.05). During the three-point bending test, the fluoxetine-only group demonstrated significantly higher structural strength than controls (p = 0.04). Micro computed tomography (µCT) slices showed loss of trabecular bone in the metaphysis region of the CMS + fluoxetine and CMS + placebo groups but not the fluoxetine-only and control groups. In an animal model of depression, the adverse effect on the bone microarchitecture was caused by CMS but not by fluoxetine. Without exposure to CMS, fluoxetine significantly increased the cross-sectional area, trabecular bone area, structural strength and osteoblasts / bone area as compared to control condition.


The Mechanism of the Anti-Cardiac Hypertrophy Effect of Glycyrrhizic Acid Is Related to Reducing STIM1-Dependent Store-Operated Calcium Entry.
We explored the anti-cardiac hypertrophy mechanism of glycyrrhizic acid from the perspective of calcium regulation under pathological conditions. For this purpose, we used a rat model of myocardial hypertrophy induced by pressure overload. The effect of glycyrrhizic acid on BP was measured non-invasively with a sphygmomanometer and recorded in PC. In rats with modeled cardiac hypertrophy, the effect of GA on expression of type 1 matrix interaction molecules was determined in horizontal tissues and cultured cardiomyocytes of the left ventricle. The laser confocal microscopy and calcium ion probe Fluo-4 AM were used to assess the effect of glycyrrhizic acid on stromal interaction molecule 1 (STIM1)-dependent store-operated calcium entry in cultured cardiomyocytes derived from the hypertrophic myocardium. Glycyrrhizic acid exerted the anti-hypertrophic effect in rats with hypertrophic myocardium by down-regulating STIM1 protein expression and reducing the intensity of STIM1-dependent store-operated calcium entry.


Comparing Rates of Change in Moderate to Advanced Glaucoma: Retinal Nerve Fiber Layer Versus Bruch Membrane Opening-Minimum Rim Width.
To compare rates of change (RoC) of peripapillary retinal nerve fiber layer (RNFL) and Bruch membrane opening-based minimum rim width (BMO-MRW) thickness in moderate-to-advanced glaucoma. Prospective cohort study. Longitudinal optical coherence tomography (OCT) optic nerve head volume scans of 113 eyes of 113 glaucoma patients with moderate-to-advanced or central damage were exported. This study estimated and compared global and sectoral RoC with linear mixed effects models and simple linear regression (SLR) of RNFL and BMO-MRW thickness. Permutation analyses were used to test significance of RoC in the SLR model. It also compared longitudinal signal-to-noise ratios (LSNR) defined as RoC divided by residual standard deviation (SD) between the two groups. Mean (SD) follow-up and median (IQR) OCT scan sessions were 5.2 (1.3) years and 10 (8-11), respectively. Baseline average (SD) visual field mean deviation was -9.2 (5.8) dB. Based on SLR, a higher proportion of significant negative RNFL RoC was observed compared to BMO-MRW in the inferotemporal (35% vs 20%; P = .015) and inferonasal (42% vs 17%; P < .001) sectors. Permutation analyses also demonstrated a higher proportion of worsening RNFL RoC than BMO-MRW in the inferotemporal (P = .026) and inferonasal (P < .001) sectors along with overall lower positive RoC. Longitudinal signal-to-noise ratios for RNFL were significantly more negative than for BMO-MRW globally, and in the inferotemporal, inferonasal, and superonasal sectors (P ≤ .01). Longitudinal RNFL OCT measurements are more likely to detect structural change and demonstrate better LSNR compared with BMO-MRW in eyes with central or moderate-to-advanced glaucoma damage at baseline.


Isoflurane for the management of status epilepticus.
When conventional therapy fails in status epilepticus, general anesthesia is recommended. We present our experience with isoflurane, an inhalational anesthetic, in the management of a patient with refractory status epilepticus. The seizures were controlled with relatively small concentrations of isoflurane. Hypotension, the only adverse effect of isoflurane, was managed with fluid and dopamine infusions.


State and Local Government Pension Funding on the Eve of the COVID-19 Recession.
This article examines the funding of public pension plans through 2019. Particular attention is paid to the impact of the Governmental Accounting Standards Board's Standard No. 68. It addressed (1) discount rates, (2) amortization periods, (3) asset valuation and smoothing, and (4) the actuarial cost method used. The combined effect of these measures has been to increase the amount of public pension underfunding significantly. The actuarial funded ratio of the 126 plans in the Public Plans Database went from 101.9 in 2001 to 71.9 in 2019, on the eve of the COVID-19 recession. It will no doubt continue to worsen in the years ahead. The extent of that likely worsening is also explored.


Skeletal abnormalities of tricho-rhino-phalangeal syndrome type I.
The tricho-rhino-phalangeal syndrome (TRPS) type I is a rare genetic disorder related to the TRPS1 gene mutation in chromosome 8, characterized by craniofacial abnormalities and disturbances in formation and maturation of bone matrix. The hallmarks are sparse and brittle hair, tendency to premature baldness, bulbous nose called pear-shaped, long and flat filter and low ear implantation. The most noticeable skeletal changes are clinodactyly, phalangeal epiphyses of the hands appearing as cone-shaped, short stature and hip joint malformations. We report a case of a teenager boy diagnosed with TRPS and referred for rheumatologic evaluation due to joint complaints.


Worldwide distribution of type II diabetes-associated TCF7L2 SNPs: evidence for stratification in Europe.
Type II diabetes is a multifactorial disease with a complex etiology. Numerous genes have been implicated in disease pathogenesis. In particular, SNPs at the TCF7L2 locus have consistently shown strong associations with type II diabetes. This study characterizes the global distribution of type II diabetes-associated TCF7L2 SNPs utilizing HapMap, HGDP-CEPH, and Alfred databases and the literature. High frequencies of rs7903146(T), rs12255372(T), and rs7901695(C) SNPs are observed in Africa, Europe, and the Middle East, but they are reduced and almost absent in Southeast Asian and Native American populations. In contrast, rs11196218(A) has the highest frequency in Eurasia but is reduced in sub-Saharan African and Native American populations. Regional variations in rs7903146(T) follow a gradient of decreasing frequency from southern into northeastern Europe. These findings demonstrate extensive global and regional variations in the frequencies of TCF7L2 SNPs, which may contribute to differences in the incidence of type II diabetes worldwide.


Intraperitoneal P-32 after negative second-look laparotomy in ovarian carcinoma.
Thirty-one patients underwent a negative second-look laparotomy between 1976 and 1986. Fourteen patients received intraperitoneal chromic phosphate (P-32) after a negative second-look laparotomy. There has been no local recurrence (zero of 14) and no deaths attributable to recurrent disease. Local control and disease-free survival are 100%, with a minimum follow-up of 2 years and a mean follow-up of 4 years. Seventeen patients received no further therapy because of patient refusal, poor diffusion, or other contraindications to P-32 installation. Four of 17 patients undergoing negative second-look procedures without the addition of P-32 have subsequently recurred. This difference is highly suggestive (P = .076). There have been no major complications with the addition of P-32. The use of intraperitoneal P-32 after negative second-look laparotomies on ovarian carcinoma is well tolerated and effective in preventing recurrence.


A method for extracting tumor events from clinical CT examination reports.
Accurate and efficient extraction of key information related to diseases from medical examination reports, such as X-ray and ultrasound images, CT scans, and others, is crucial for accurate diagnosis and treatment. These reports provide a detailed record of a patient's health condition and are an important part of the clinical examination process. By organizing this information in a structured way, doctors can more easily review and analyze the data, leading to better patient care. In this paper, we introduce a new technique for extracting useful information from unstructured clinical text examination reports, which we refer to as a medical event extraction (EE) task. Our approach is based on Machine Reading Comprehension (MRC) and involves two sub-tasks: Question Answerability Judgment (QAJ) and Span Selection (SS). We use BERT to build a question answerability discriminator (Judger) that determines whether a reading comprehension question can be answered or not, thereby avoiding the extraction of arguments from unanswerable questions. The SS sub-task first obtains the encoding of each word in the medical text from the final layer of BERT's Transformer, then utilizes the attention mechanism to identify important information related to the answer from these word encodings. This information is then input into a bidirectional LSTM (BiLSTM) module to obtain a global representation of the text, which is used, along with the softmax function, to predict the span of the answer (i.e., the start and end positions of the answer in the text report). We use interpretable methods to calculate the Jensen-Shannon Divergence (JSD) score between various layers of the network and confirm that our model has strong word representation capabilities, enabling it to effectively extract contextual information from medical reports. Our experiments demonstrate that our method outperforms existing medical event extraction methods, achieving state-of-the-art results with a notable F1 score.


Surgical management of tumors involving the orbit.
Surgical treatment of orbital tumors is a complex task that requires thorough preparation and precise planning. Since a large variety of tumors of different origins, anatomical extents, and histologic subtypes affect the globe, no "1-size-fits-all" approach can be offered. To describe an integrative approach for the optimal surgical management of patients with orbital tumors based on a review of the literature and on our own experience at a high-volume cancer center. Peer-reviewed English-language literature and a single-center cohort of patients undergoing orbital exenteration with eye sparing, reconstruction, and preservation of orbital function. Surgical treatment of orbital tumors is a complex task that requires thorough preparation and precise planning that would be aided by an algorithm. We offer an algorithm that summarizes our approach toward the 2 main decision points of orbital surgery: extent of resection and method of reconstruction.


Synthesis and pharmacological activities of some condensed 4-chloro-2,2-dialkyl chromene-3-carbaldehyde derivatives.
Some new hydrazono 5a,b, thiosemicarbazono 6a-c, and oximo chromenes 7a-c were prepared via the reaction of the corresponding beta-chlorocarbaldehyde 3 with hydrazine, aromatic hydrazine, thiosemicarbazide and hydroxylamine hydrochloride, respectively. In addition, ether derivatives 8a-h were prepared from the corresponding aldoximes 7a-c. The new products were tested for anti-inflammatory and ulcerogenic score activities compared to indomethacin.


The effect of ultrasonic on reducing anti-browning minimum effective concentration of purslane extract on fresh-cut potato slices during storage.
Enzymatic browning is one of the major difficulties for the preservation and commercial value of fresh-cut products. To research more healthy and inexpensive anti-browning methods, we investigated the effect of ultrasonic coupling purslane extract on the browning resistance of fresh-cut potato during 8d storage at 4 °C. Firstly, the optimal ultrasonic time (10 min) was obtained. Then, the results showed that the combined application with lower purslane extract concentration (0.02%, w/w) could achieve a better anti-browning effect than the optimal concentration of alone purslane extract (0.05%, w/w). The combined application not only significantly inhibited the key enzyme activities of polyphenol oxidase (PPO) and peroxidase (POD), but also effectively reduced the damage to cell membrane, maintained its integrity and permeability. Meanwhile, it also improved antioxidant capacity during storage. Overall, the ultrasonic cavitation combined with purslane extract would be a promising method for fresh-cut industry.


Nucleotide-dependent conformational changes in the DnaA-like core of the origin recognition complex.
Structural details of initiator proteins for DNA replication have provided clues to the molecular events in this process. EM reconstructions of the Drosophila melanogaster origin recognition complex (ORC) reveal nucleotide-dependent conformational changes in the core of the complex. All five AAA+ domains in ORC contain a conserved structural element that, in DnaA, promotes formation of a right-handed helix, indicating that helical AAA+ substructures may be a feature of all initiators. A DnaA helical pentamer can be docked into ORC, and the location of Orc5 uniquely positions this core. The results suggest that ATP-dependent conformational changes observed in ORC derive from reorientation of the AAA+ domains. By analogy to the DNA-wrapping activity of DnaA, we posit that ORC together with Cdc6 prepares origin DNA for helicase loading through mechanisms related to the established pathway of prokaryotes.


Simultaneous determination of six active components in traditional herbal medicine 'Oyaksungisan' by HPLC-DAD.
In this study, an effective high performance liquid chromatography-diode array detector (HPLC-DAD) method was established for simultaneous determination of six marker compounds, ephedrine hydrochloride, 6-gingerol, glycyrrhizin, hesperidin, imperatorin and ferulic acid, in a Korean traditional prescription, Oyaksungisan, which is used for hemiplegia, arthralgia and paralysis. The six marker compounds of Oyaksungisan were separated on a LUNA C18 column (S-5 μm, 4.6 mm I.D. × 250 mm) at a column temperature of 35°C. The gradient elution was composed of water with 0.1% trifluoroacetic acid and methanol. The detection UV wavelengths were set at 207, 250, 280 and 320 nm. Calibration curves for the six compounds showed good linear regressions (R (2) > 0.9999). The limits of detection and limits of quantification were within the ranges 0.003-0.01 and 0.01-0.04 μg/ml, respectively. The relative standard deviation (RSD) values of intra- and inter-day testing were within the ranges 0.10-1.82 and 0.04-1.59%, respectively. The results of the recovery test were 95.05-104.27% with a RSD value of 0.11-1.85%. In conclusion, the simultaneous determination method developed was useful in the quality evaluation of Oyaksungisan.