Molecular imaging to enlighten cancer immunotherapies and underlying involved processes.
Cancer immunotherapy has led to impressive antitumor effects. However, not all patients respond to immunotherapy, serious toxicity can occur and combination therapy may be warranted. Strategies for rational early treatment choices are urgently required. In the absence of ideal accompanying biomarkers it remains challenging to capture the dynamic, heterogeneous and complex tumor behavior. Tumor immune response involves next to tumor cells, numerous other cells and molecules in the tumor microenvironment. We review research to identify potential novel imaging biomarkers by non-invasive whole body molecular imaging with positron emission tomography and single-photon emission computed tomography for cancer immunotherapy. Firstly, imaging with radiolabeled immune checkpoint targeting molecules. Secondly, imaging of immune cells with ex vivo or in vivo radiolabeled tracers and thirdly, imaging extracellular matrix components, including adhesion molecules, growth factors and cytokines. These molecular imaging strategies - used alone, in combination or serially - could potentially contribute to patient selection upfront or early during immunotherapy.


Computed tomographic evaluation of therapeutically induced changes in primary and secondary brain tumors.
A prospective study was initiated to evaluate computed tomography as a method for monitoring therapeutically induced changes in brain tumors. Early postoperative scans may be misleading in the evaluation of residual tumor because of trauma to the blood-brain barrier during operation. The size of the dominant mass (17/25), enhancement (11/25), edema (11/25), and ventricular distortion (14/25) were decreased in many patients after radiation therapy. Occasional tumors increased in size during radiation therapy (3/25). Enlargement of the lateral ventricles developed in 9 of 25 patients. Computed tomography offers definite advantages over nuclide brain scans, angiography and other diagnostic studies for evaluating therapeutically induced changes in brain tumors.


Long-term follow-up after laparoscopic treatment for endometriosis: multivariate analysis of predictive factors for recurrence of endometriotic lesions and pain.
To investigate factors that might influence the recurrence of both painful symptoms and endometriotic lesions following laparoscopic treatment of endometriosis. Retrospective cohort study in a University teaching hospital. We reviewed data from patients referred for laparoscopy between March 1993 and November 2007. We selected women who were followed up throughout Transvaginal-ultrasound (TV-US) after a first conservative laparoscopy for endometriosis. After laparoscopy, all patients were followed up according to an internal protocol: a standard gynaecologic examination, the assessment of painful symptoms and a TV-US scan that were repeated at 3, 6, and 12 months, and subsequently on a yearly basis. Sixteen factors were assessed by univariable and multivariable Cox proportional hazards models to evaluate their associations with recurrence of endometriotic lesions and pain related-endometriosis. 401 women were enrolled. A total of 154 (38.4%) experienced moderate or severe pain after laparoscopy; endometriotic lesions were observed by TV-US in 74 (18.4%) patients. In the multivariable model, age at menarche, severity of chronic pelvic pain (CPP) and dysmenorrhoea prior to surgery were significant risk factors for recurrence/occurrence of pain. Age at the first laparoscopy, stage of disease, pre-operative severity of CPP, and pregnancy were predictive factors of the recurrence for such lesions. The severity of CPP prior to the first laparoscopy showed the only significant factor in the overall prediction of recurrence of pain and endometriotic lesions. Patients with severe CPP at the time of their first surgery might represent a sub-group of women with a more aggressive form of endometriosis.


Knowledge mapping of programmed cell death in osteonecrosis of femoral head: a bibliometric analysis (2000-2022).
Osteonecrosis of the femoral head (ONFH) is a common, refractory and disabling disease of orthopedic department, which is one of the common causes of hip pain and dysfunction. Recent studies have shown that much progress has been made in the research of programmed cell death (PCD) in ONFH. However, there is no bibliometric analysis in this research field. This study aims to provide a comprehensive overview of the knowledge structure and research hot spots of PCD in ONFH through bibliometrics. The literature search related to ONFH and PCD was conducted on the Web of Science Core Collection (WoSCC) database from 2002 to 2021. The VOSviewers, "bibliometrix" R package and CiteSpace were used to conduct this bibliometric analysis. In total, 346 articles from 27 countries led by China and USA and Japan were included. The number of publications related to PCD in ONFH is increasing year by year. Shanghai Jiao Tong University, Xi An Jiao Tong University, Wuhan University and Huazhong University of Science and Technology are the main research institutions. Molecular Medicine Reports is the most popular journal in the field of PCD in ONFH, and Clinical Orthopaedics and Related Research is the most cocited journal. These publications come from 1882 authors among which Peng Hao, Sun Wei, Zhang Chang-Qing, Zhang Jian and Wang Kun-zheng had published the most papers and Ronald S Weinstein was cocited most often. Apoptosis, osteonecrosis, osteonecrosis of the femoral head, glucocorticoid and femoral head appeared are the main topics the field of PCD in ONFH. Autophagy was most likely to be the current research hot spot for PCD in ONFH. This is the first bibliometric study that comprehensively summarizes the research trends and developments of PCD in ONFH. This information identified recent research frontiers and hot directions, which will provide a reference for scholars studying PCD in ONFH.


Pulmonary vein isolation with complex fractionated atrial electrogram ablation for paroxysmal and nonparoxysmal atrial fibrillation: A meta-analysis.
Pulmonary vein isolation (PVI) is recognized as a potentially curative treatment for atrial fibrillation (AF). Ablation of complex fractionated atrial electrograms (CFAEs) in addition to PVI has been advocated as a means to improve procedural outcomes, but the benefit remains unclear. This study sought t synthesize the available data testing the incremental benefit of adding CFAE ablation to PVI. We performed a meta-analysis of controlled studies comparing the effect of PVI with CFAE ablation vs. PVI alone in patients with paroxysmal and nonparoxysmal AF. Of the 481 reports identified, 8 studies met our inclusion criteria. There was a statistically significant increase in freedom from atrial tachyarrhythmia (AT) with the addition of CFAE ablation (relative risk [RR] 1.15, P = .03). In the 5 reports of nonparoxysmal AF (3 randomized controlled trials, 1 controlled clinical trial, and 1 trial using matched historical controls), addition of CFAE ablation resulted in a statistically significant increase in freedom from AT (n = 112 of 181 [62%] for PVI+CFAE vs. n = 84 of 179 [47%] for PVI alone; RR 1.32, P = .02). In trials of paroxysmal AF (3 randomized controlled trials and 1 trial using matched historical controls), addition of CFAE ablation did not result in a statistically significant increase in freedom from AT (n = 131 of 166 [79%] for PVI+CFAE vs. n = 122 of 164 [74%] for PVI alone; RR 1.04, P = .52). In these studies of patients with nonparoxysmal AF, addition of CFAE ablation to PVI results in greater improvement in freedom from AF. No additional benefit of this combined approach was observed in patients with paroxysmal AF.


A case of carcinoma ex pleomorphic adenoma arising from multinodular pleomorphic adenoma of the buccal region.
In multinodular lesions or tumors with mixed benign and malignant components, malignant elements may be undetectable using fine-needle aspiration biopsy/cytology in preoperative pathological diagnosis of some cases, because of sampling error.


Stabilizing defects in metal-organic frameworks: pendant Lewis basic sites as capping agents in UiO-66-type MOFs toward highly stable and defective porous materials.
An isostructural series of zirconium-based metal-organic frameworks (ZrMOFs) with UiO-66-type structure (including three previously unreported materials) have been successfully synthesized from combination of mono- and di-substituted terephthalic acids (H2BDC-R, -R = -2OH: 2,5-dihydroxyterephthalic acid; -2SH: 2,5-dimercaptoterephthalic acid; -SMe: 2-methylsulfanyl-terephthalic acid; -2SEtSMe: 2,5-bis[[2-(methylthio)ethyl]thio]-terephthalic acid; -2OEtOMe: 2,5-bis[[2-(methyloxy)ethyl]oxy]terephthalic acid) and ZrCl4 to produce the MOFs termed UiO-66-R. UiO-66-2SEtSMe is found to be highly defective, with approximately half the expected number of ligands missing (as compared to nondefective structure), and exhibiting mesoporosity. Thioether functionalities are shown to stabilize UiO-66-type MOFs in acidic (pH = 2) and basic (pH = 12) aqueous environments. In preparation of UiO-66-type MOFs with sterically demanding pendant groups (such as in -2SEtSMe and -2OEtOMe), pendant Lewis basic sites serve to stabilize the formation of highly defective MOFs, whereas removal of such pendant Lewis basic sites results in formation of amorphous material. UiO-66-2SH and -2SEtSMe both effectively adsorb Ag+ and Hg2+ from acidic aqueous solutions (up to >99% removal, Kd > 104), whereas UiO-66-SMe shows potential to separate Ag+ from Hg2+ in acidic aqueous solutions.


Induction of dedifferentiated clones of LLC-PK1 cells upon long-term exposure to dichlorovinylcysteine.
Dichlorovinylcysteine (DCVC), the key metabolite of the nephrotoxic and nephrocarcinogenic chemicals, trichloroethylene and dichloroacetylene, exerts potent acute cellular toxicity in LLC-PK1 cells (Vamvakas S., Bittner, D., Dekant, W. and Anders, M.W. (1992). Events that precede and that follow S-(1,2-dichlorovinyl)-L-cysteine-induced release of mitochondrial Ca2+ and their association with cytotoxicity to renal cells. Biochem. Pharmacol. 44, 1131-1138). In the present study we investigated whether long-term exposure of LLC-PK1 cells to low, non-cytotoxic concentrations of DCVC results in stable morphological and biochemical dedifferentiation. After 7 weeks exposure to 1 and 5 microM DCVC, morphologically changed single cells were picked under the microscope and cultured in absence of DCVC for 4-8 weeks. In contrast to the physiological cuboidal shape of untreated LLC-PK1 cells, the clones derived from long-term exposure to DCVC consisted of elongated, spindle-shaped cells tending to form irregular borders. Moreover, glucose uptake, pH-dependent ammonia production and dome formation, important indicators of the renal tubule origin of the LLC-PK1 cells, were severely impaired in the clones. In addition to the loss of membrane polarity, the clones exhibited altered composition of the nuclear matrix and intermediate filament proteins by two-dimensional gel electrophoresis, increased poly(ADP-ribosyl)ation of nuclear proteins and enhanced expression of c-fos. The induction of dedifferentiated LLC-PK1 clones with stable characteristics upon long-term exposure to the nephrocarcinogen DCVC may represent a useful in vitro model to study biochemical alterations involved in chronic renal toxicity and carcinogenicity.


Alterations in complex lipids in tumor tissue of patients with colorectal cancer.
Accumulating evidence indicates alterations in lipid metabolism and lipid composition in neoplastic tissue. Earlier nuclear magnetic resonance studies showed that the contents of major lipid groups, such as triacylglycerols, phospholipids and cholesterol, are changed in colon cancer tissue. In this study, a more detailed analysis of lipids in cancer and tumor adjacent tissues from colorectal cancer patients, using liquid chromatography-mass spectrometry, allowed for comparison of 199 different lipids between cancer tissue and tumor adjacent tissue using principal component analysis. Significant differences were found in 67 lipid compounds between the two types of tissue; many of these lipid compounds are bioactive lipids such as ceramides, lysophospholipids or sterols and can influence the development of cancer. Additionally, increased levels of phospholipids and sphingolipids were present, which are major components of the cell membrane, and increases in these lipids can lead to changes in cell membrane properties. This study showed that many complex lipids are significantly increased or decreased in colon cancer tissue, reflecting significant alterations in lipid metabolism. This knowledge can be used for the selection of potential molecular targets of novel anticancer strategies based on the modulation of lipid metabolism and the composition of the cell membrane in colorectal cancer cells.


Radical-intent hypofractionated radiotherapy for locally advanced non-small-cell lung cancer: a systematic review of the literature.
To identify survival and toxicity characteristics associated with radical-intent hypofractionated radiotherapy for the treatment of stage III non-small-cell lung cancer (NSCLC). Relevant studies were identified from a systematic PubMed search of articles published between January 1990 and January 2014. All studies were peer reviewed and included both retrospective and prospective studies of NSCLC patients being treated with radical hypofractionated radiotherapy. Data on overall survival (OS) and toxicity were extracted from each of the studies where available. Of 685 studies initially identified by the search, a total of 33 studies were found to be relevant and were included in this systematic review. The number of fractions ranged from 15 to 35, the dose per fraction ranged from 2.3 to 3.5 Gy, and the delivered dose ranged from 45.0 to 85.5 Gy. Fifteen of the studies included concurrent chemotherapy, while 18 did not. OS was found to be associated with tumor biological effective dose, with the Pearson correlation coefficient ranging from 0.34 to 0.48. For both concurrent and nonconcurrent chemoradiotherapy acute pulmonary, late esophageal and late pulmonary incidences of toxicity ranged from 1.2% to 12.2%, but had 95% confidence intervals that included zero. The greatest incidence of toxicity was acute esophageal toxicity at 14.9% (95% confidence interval, 0.7%, 29.1%). There is a moderate linear relationship between biological effective dose and OS, and greater acute esophageal toxicity with concurrent chemotherapy. Improving outcomes in stage III NSCLC may involve some form of hypofractionation in the context of systemic concurrent therapy.


Anxiety and its relationship with sleep disturbance and problematic smartphone use among Chinese medical students during COVID-19 home confinement - A structural equation model analysis.
The majority of medical students in China have experienced home confinement and a reliance on online resources to study medicine since the outbreak of COVID-19. More time spent studying online during the COVID-19 pandemic may be a potential risk factor for problematic smartphone use, since smartphones have become the most commonly used device for accessing the internet. The objective of the present study was to explore the association between anxiety, smartphone problematic use and sleep disturbance among medical students during the enforced COVID-19 home confinement. Altogether, 666 medical students validly answered a self-administered questionnaire, which included the Chinese version of the Generalized Anxiety Disorder scale, Smartphone addiction scale - short version, and the PROMIS Sleep Disturbance scale (short form). Hierarchical multiple regression analyses were employed to explore the associated factors of anxiety. Structural equation modeling was conducted to test hypothesized associations. Anxiety was significantly associated with problematic smartphone use and sleep disturbance among medical students during the COVID-19 pandemic. Problematic smartphone use not only directly affected anxiety, but also exerted a significant indirect effect on anxiety via sleep disturbance. A significant decrease of the path coefficient of problematic smartphone use on anxiety (from β=0.53 to β=0.22, P<0.01) was observed with sleep disturbance being modeled as a mediator. Limitations include its cross-sectional design and samples recruited from only one medical school. The detrimental impact of problematic smartphone use and the importance of sleep health on mitigating anxiety should be highlighted and incorporated into medical education.


Morpho-histological, histochemical, and molecular evidences related to cellular reprogramming during somatic embryogenesis of the model grass Brachypodium distachyon.
The wild grass species Brachypodium distachyon (L.) has been proposed as a new model for temperate grasses. Among the biotechnological tools already developed for the species, an efficient induction protocol of somatic embryogenesis (SE) using immature zygotic embryos has provided the basis for genetic transformation studies. However, a systematic work to better understanding the basic cellular and molecular mechanisms that underlie the SE process of this grass species is still missing. Here, we present new insights at the morpho-histological, histochemical, and molecular aspects of B. distachyon SE pathway. Somatic embryos arose from embryogenic callus formed by cells derived from the protodermal-dividing cells of the scutellum. These protodermal cells showed typical meristematic features and high protein accumulation which were interpreted as the first observable steps towards the acquisition of a competent state. Starch content decreased along embryogenic callus differentiation supporting the idea that carbohydrate reserves are essential to morphogenetic processes. Interestingly, starch accumulation was also observed at late stages of SE process. Searches in databanks revealed three sequences available annotated as BdSERK, being two copies corresponding to SERK1 and one showing greater identity to SERK2. In silico analysis confirmed the presence of characteristic domains in a B. distachyon Somatic Embryogenesis Receptor Kinase genes candidates (BdSERKs), which suggests SERK functions are conserved in B. distachyon. In situ hybridization demonstrated the presence of transcripts of BdSERK1 in all development since globular until scutellar stages. The results reported in this study convey important information about the morphogenetic events in the embryogenic pathway which has been lacking in B. distachyon. This study also demonstrates that B. distachyon provides a useful model system for investigating the genetic regulation of SE in grass species.


Social anxiety and the interpretation of morphed facial expressions following exclusion and inclusion.
Negative interpretation biases are postulated to play etiological and maintaining roles in social anxiety (SA). However, empirical support for interpretation biases of facial expression in SA is inconsistent. Given the importance of signals of (dis)approval in SA, our objective was to examine whether SA is associated with enhanced sensitivity to such signals especially following exclusion. In Study 1, participants (N = 139) underwent an exclusion/inclusion manipulation and were then presented with video clips of smiles gradually changing into disgust expressions (smile-to-disgust). In Study 2 (N = 203), participants saw smile-to-disgust as well as disgust-to-smile clips following an exclusion/inclusion manipulation. Participants' task in both studies was to detect the offset of the initial expression. Results of Study 1 show that detection latency of smiles' disappearance is negatively associated with SA severity. The results of Study 2 suggest that this association is stronger following exclusion, and specific to the smile-to-disgust as opposed to the disgust-to-smile, transitions. Our studies did not examine whether the observed interpretation bias was specific to SA. Our findings support and refine cognitive theories of SA, suggesting that interpretation biases for facial information in SA may be especially pronounced following exclusion.


Mild and selective Ru-catalyzed formylation and Fe-catalyzed acylation of free (N-H) indoles using anilines as the carbonyl source.
C3-selective formylation and acylation of free (N-H) indoles under mild conditions can be achieved by using Ru- and Fe-catalyzed oxidative coupling of free (N-H) indoles with anilines, respectively. Both processes are operationally simple, compatible with a variety of functional groups and generally provide the desired products in good yields. (13)C-labeling experiments unambiguously established that the carbonylic carbon in the formylation products originated from methyl group of N-methyl aniline.


Short-term therapy with celecoxib and lansoprazole modulates Th1/ Th2 immune response in human gastric mucosa.
Selective cyclooxygenase-2 (COX-2) inhibitors and proton pump inhibitors may exert immune-mediated effects in human gastric mucosa. T-cell immune response plays a role in Helicobacter pylori-induced pathogenesis. This study evaluated effects of celecoxib and lansoprazole on T-helper (Th) 1 and Th2 immune response in human gastric mucosa. Dyspeptic patients with or without osteoarticular pain were given one of the following 4-week therapies: celecoxib 200 mg, celecoxib 200 mg plus lansoprazole 30 mg, and lansoprazole 30 mg daily. Expression of COX-2, T-bet, and pSTAT6 and production of prostaglandin E₂ (PGE₂), interferon (IFN)-γ, and interleukin (IL)-4 were determined in gastric biopsies before and after therapy. Histology was evaluated. Cyclooxygenase-2 expression and PGE₂ production was higher, and Th1 signaling pathway was predominant in H. pylori-infected vs. uninfected patients. T-bet expression and IFN-γ production increased, while STAT6 activation and IL-4 production decreased following therapy with celecoxib and celecoxib plus lansoprazole, respectively. Th1 and Th2 signaling pathways down-regulated after therapy with lansoprazole, and this was associated with an improvement of gastritis. Effect of therapy was not affected by H. pylori status. Celecoxib and lansoprazole modulate Th1/Th2 immune response in human gastric mucosa. The use of these drugs may interfere with long-term course of gastritis.


[Coupling of microbial processes of methane and ammonium oxidation in soils].
The effect of ammonium ions on the activity of methane oxidation in soils was studied. The degree of inhibition of the methanotrophic activity in the presence of ammonium in the soil solution was quantitatively assessed as dependent on ammonium concentration and the properties of different types of soils of the European part of Russia.


Amyloid in a patient with Reiter's syndrome - secondary or coincidental? Differentiation with potassium permanganate.
A patient with Reiter's syndrome developed a pulmonary nodule composed of amyloid. Reiter's syndrome has been reported as 1 of the diseases associated with secondary systemic amyloidosis. Isolated nodular pulmonary amyloid has not been reported to become systemic. Potassium permanganate treatment of amyloid abolishes congo red stain affinity for amyloid of unknown origin found in secondary amyloidosis. However, the amyloid of immunoglobulin origin, characteristic of primary amyloid, is resistant to KMnO4. The amyloid deposit from our patient was resistant to KMnO4 which suggested that the pulmonary amyloid was a coincidental nodular amyloid deposit in the lung rather than secondary amyloidosis.


Mildly elevated diastolic blood pressure increases subsequent risk of breast cancer in postmenopausal women in the Health Examinees-Gem study.
Epidemiological evidence suggests that hypertension is associated with breast cancer risk. However, previous studies disregard blood pressure components in the healthy population. We aimed to examine the relationship between systolic and diastolic blood pressure and breast cancer risk in a Korean population-based prospective cohort. A total of 73,031 women from the Health Examinees Gem Study were followed from baseline (2004 to 2013) through 2018. Systolic and diastolic blood pressure were measured by trainee physicians at baseline recruitment and then categorized based on the international guidelines for clinical hypertension. Associations between systolic and diastolic blood pressure with overall breast cancer and stratified by premenopausal and postmenopausal status were evaluated using adjusted multivariable Cox proportional hazard regression. A total of 858 breast cancer cases were recorded for a median follow-up period of 9 years. Compared with the normal DBP category (< 85 mmHg), the normal-high category was positively associated with breast cancer risk in postmenopausal women (85-89 mmHg, HR 1.73 95% CI 1.28-2.33), but not in premenopausal women (85-89 mmHg, HR 0.87 95% CI 0.56-1.35). Similar results were found when all cases of self-reported hypertension were excluded. Results for SBP did not show a significant association with breast cancer risk. The association between DBP and breast cancer suggests DBP could be an important factor in cancer prevention, especially for women after menopause. Our study provides a first detailed approach to understanding the importance of diastolic blood pressure for breast cancer prevention and warrants further investigation.


Poly(hydroxybutyrate-co-hydroxyvalerate) nanocapsules as enzyme carriers for cancer therapy: an in vitro study.
In the present paper, poly(3-hydroxybutyrate-co-3-hydroxyvalerate) nanocapsules were prepared by a double emulsion-solvent evaporation procedure (w/o/ w) for the encapsulation of model enzymes (L-asparaginase, catalase, glucose oxidase) and bovine serum albumin. To increase the encapsulation efficiency and activity of the encapsulated enzyme, numerous modifications were made in the compositions of the phases of double emulsion. For the preparation of low molecular weight PHBV, the polymer was treated with sodium borohydride. A 14-fold decrease in molecular weight (from 297000 to 21000) was observed upon 4 h of incubation. Although the amount of encapsulated protein was not increased, the enzyme activity increased upon use of low molecular weight PHBV, indicating that these nanocapsules have a higher permeability to solutes (reactants and products). The adjustment of the second water phase to the isoelectric point of the proteins significantly increased the encapsulation yields of catalase, L-asparaginase and BSA. Likewise, polyethylene glycol coupling significantly increased the entrapment efficiency as well as the activity of catalase and L-asparaginase. A combination of the various optimum preparation conditions further increased the encapsulated catalase activity (about six-fold) in comparison to the initial basic conditions (with no modification and no isoelectric point adjustment).


Prediction of post-stroke urinary tract infection risk in immobile patients using machine learning: an observational cohort study.
Urinary tract infection (UTI) is one of major nosocomial infections significantly affecting the outcomes of immobile stroke patients. Previous studies have identified several risk factors, but it is still challenging to accurately estimate personal UTI risk. To develop predictive models for UTI risk identification for immobile stroke patients. Research data were collected from our previous multicentre study. Derivation cohort included 3982 immobile stroke patients collected from November 1st, 2015 to June 30th, 2016; external validation cohort included 3837 patients collected from November 1st, 2016 to July 30th, 2017. Six machine learning models and an ensemble learning model were derived, based on 80% of derivation cohort, and effectiveness was evaluated with the remaining 20%. Shapley additive explanation values were used to determine feature importance and examine the clinical significance of prediction models. In all, 2.59% (103/3982) patients were diagnosed with UTI in derivation cohort, 1.38% (53/3837) in external cohort. The ensemble learning model performed the best in area under the receiver operating characteristic (ROC) curve in internal validation (82.2%); second best in external validation (80.8%). In addition, the ensemble learning model performed the best sensitivity in both internal and external validation sets (80.9% and 81.1%, respectively). Seven UTI risk factors (pneumonia, glucocorticoid use, female sex, mixed cerebrovascular disease, increased age, prolonged length of stay, and duration of catheterization) were also identified. This ensemble learning model demonstrated promising performance. Future work should continue to develop a more concise scoring tool based on machine learning models and prospectively examining the model in practical use, thus improving clinical outcomes.


Urban Neighborhood Characteristics and the Spatial Distribution of Home and Community-Based Service Organizations in Michigan Metropolitan Statistical Areas.
Living in a neighborhood with dense HCBS organizations can promote older adults' health and well-being and may mitigate health disparities generated by living in materially deprived urban neighborhoods. Using 2016 US County Business Patterns and the American Community Survey (2013-2017), focused on 516 ZIP Codes in Michigan Metropolitan Statistical Areas, this study examines the association between neighborhood characteristics and the relative density of businesses offering services for older adults and persons with disabilities (e.g., senior centers, adult day service centers, personal care) and businesses offering home health care. Results from a series of spatial econometric models show that social care organization density tends to be high in neighborhoods with a greater number of residents who have a bachelor's degree, who are older, and who are in poverty. Home health care density was not explained by neighborhood factors. Multiple neighborhood socio-demographic indicators explain the spatial distribution of social care organizations.


Use of a sequential multiple assignment randomized trial to test contingency management and an integrated behavioral economic and mindfulness intervention for buprenorphine-naloxone medication adherence for opioid use disorder.
Buprenorphine-naloxone is a medication shown to improve outcomes for individuals seeking treatment for opioid use disorder (OUD); however, outcomes are limited by low medication adherence rates. This is especially true during the early stages of treatment. The present study proposes to utilize a sequential multiple assignment randomized trial design to compare two psychological interventions targeting buprenorphine-naloxone adherence: (1) contingency management (CM) and (2) brief motivational interviewing plus substance-free activities session plus mindfulness (BSM). Participants will be N = 280 adults who present to a university-based addictions clinic seeking treatment for OUD. Participants will be randomized to condition to receive 4 sessions of their assigned intervention (CM or BSM). Participants who are adherent, defined as attending physician appointments and having buprenorphine present in urine toxicology, will enter maintenance intervention for an additional 6 months. Those who are not adherent will be re-randomized to receive either the other intervention or both interventions. Follow-up will occur at 8 months post-randomization. This novel design will examine the benefit of sequential treatment decisions following non-adherence. The primary outcome of this study is buprenorphine-naloxone medication adherence, as assessed by physician visit attendance and presence of buprenorphine in urine. Results will elicit the relative efficacy of CM and BSM compared to one another and whether keeping the initial treatment approach when adding the alternative approach for initially non-adherent individuals is beneficial. ClinicalTrials.gov NCT04080180.


[Complex coronary reconstructions using the internal mammary artery. Technique of surgical angioplasty, preliminary results].
A technique of coronary surgical angioplasty is described. The long arteriotomy of the coronary artery over the stenosis is closed with the Internal Thoracic Artery (ITA) giving an enlargement patch effect. The majority of the atheromatous plaque is excluded from the lumen of the anastomosis and placed outside the suture line. The origin of the collateral arteries is preserved in the vascular lumen. The remodeled coronary artery is composed of a small gutter of native coronary artery and the whole surface of the ITA wall. In some cases, it is useful to associate a limited endarterectomy with the angioplasty. 66 surgical angioplasties have been performed in extensive coronary disease. Operative mortality was 5.4% with a myocardial infarction rate of 5.4%.


The natural history of schizophrenia: a 5-year prospective follow-up of a representative sample of schizophrenics by means of a standardized clinical and social assessment.
A comprehensive, representative cohort of 121 schizophrenics from a delimited catchment area, hospitalized in the course of 20 months (1973--4) and who met PSE criteria, was collected for a therapeutic trial (1976--6) in which, during the year after discharge, standardized clinical and social assessments has been made by personal interview at home. Standardized observations were repeated 4 years later. Follow-up was 99% complete. 48% of the cohort and 58% of the first admissions had a good outcome. Females fared significantly better than males.


A mesenteric traction syndrome affects near-infrared spectroscopy evaluated cerebral oxygenation because skin blood flow increases.
During abdominal surgery manipulation of internal organs may induce a "mesenteric traction syndrome" (MTS) including a triad of flushing, hypotension, and tachycardia that lasts for about 30 min. We evaluated whether MTS affects near-infrared spectroscopy (NIRS) assessed frontal lobe oxygenation (ScO2) by an increase in forehead skin blood flow (SkBF). The study intended to include 10 patients who developed MTS during pancreaticoduodenectomy and 22 patients were enrolled (age 61 ± 8 years; mean ± SD). NIRS determined ScO2, laser Doppler flowmetry determined SkBF, cardiac output (CO) was evaluated by pulse-contour analysis (Modelflow), and transcranial Doppler assessed middle cerebral artery mean flow velocity (MCA Vmean). MTS was identified by flushing within 60 min after start of surgery. MTS developed 20 min (12-24; median with range) after the start of surgery and heart rate (78 ± 16 vs. 68 ± 17 bpm; P = 0.0032), CO (6.2 ± 1.4 vs. 5.3 ± 1.1 L min-1; P = 0.0086), SkBF (98 ± 35 vs. 80 ± 23 PU; P = 0.0271), and ScO2 (71 ± 6 vs. 67 ± 8%; P < 0.0001), but not MCA Vmean (32 ± 8 vs. 32 ± 7; P = 0.1881) were largest in the patients who developed MTS. In some patients undergoing abdominal surgery NIRS-determined ScO2 is at least temporarily affected by an increase in extra-cranial perfusion independent of cerebral blood flow as indicated by MCA Vmean. Thus, NIRS evaluation of ScO2 may overestimate cerebral oxygenation if patients flush during surgery.


2-Step PLT16-AST44 method: Simplified liver fibrosis detection system in patients with non-alcoholic fatty liver disease.
Accurate detection of the hepatic fibrosis stage is essential to estimate the outcome of patients with non-alcoholic fatty liver disease (NAFLD). Many formulas, biomarkers, and imaging tests are being developed to predict advanced liver fibrosis without performing a liver biopsy. However, these tests do not have high efficiency in detecting early-stage hepatic fibrosis. Therefore, we aimed to detect the presence of hepatic fibrosis (≥F1) merely by using only standard clinical markers. A total of 436 patients with NAFLD who underwent liver biopsy were retrospectively enrolled as the discovery cohort (316 patients) and the validation cohort (120 patients). Liver biopsy and laboratory data were matched to extract simple parameters for identifying ≥F1. We developed a novel simplified ≥F1 detecting system, designated as 2-Step PLT16-AST44 method, where (1) PLT of 16 × 104 /μl or less, or (2) PLT greater than 16 × 104 /μl and AST greater than 44 U/L is determined as having ≥F1 fibrosis. The 2-Step PLT16-AST44 method had a sensitivity of 68%, a specificity of 90%, a positive predictive value (PPV) of 97%, a negative predictive value (NPV) of 40%, and an accuracy of 72% to detect ≥F1 fibrosis in the discovery cohort. Validation studies further supported these results. Despite its simplicity, the 2-Step PLT16-AST44 method's power to detect ≥F1 fibrosis in total NAFLD patients was comparable to hyaluronic acid, type 4 collagen 7S, FIB-4, and APRI. We propose the 2-Step PLT16-AST44 method as a simple and beneficial early-stage hepatic fibrosis detection system.


Testicular rupture after blunt scrotal trauma in children: A case report and literature review.
Blunt testicular trauma with rupture of albuginea is one of the rarest emergencies in children. Medical history and Testicular Doppler Ultrasound lead to diagnosis. Appropriate management is necessary to preserve the testis. Follow-up to adulthood is recommended to assess the impact on fertility.


Neurotological diagnosis of vestibular disorders in children.
The most marked findings in a group of 66 children were a spontaneous nystagmus presenting in 29% of the cases, and an abnormal caloric reaction in 40%. For qualitative and quantitative assessments of the positional test and caloric stimulation, at our University ENT department at Erlangen we use the positiogram and frequency calorigram described here, which are particularly suitable for follow-up observations and for the purpose of providing an expert medical opinion.


Enhancer Dependent Repositioning of TCRb Locus with Respect to the Chromosome Territory.
Intranuclear position of several genes is dynamically altered during development concordant with their activation. To understand this dynamic, but non-random, nuclear organization, it is important to identify the relevant regulatory elements and trans acting factors. Murine TCRb locus gets activated during thymic development. Enhancer Eb is important for VDJ recombination at TCRb locus as it is critically required for establishment of recombination center. Our analysis revealed that TCRb locus gets located out of the chromosome territory specifically in developing thymocytes. Further, CRISPR/Cas9 based deletion mutagenesis established an unambiguous role of enhancer Eb in defining TCRb location relative to chromosome territory. The ability to reposition the target locus relative to chromosome territory highlights a novel aspect pertaining to activity of enhancers which may contribute to their ability to regulate gene expression. Additionally, our observations have implications for understanding the role of enhancers in three-dimensional genome organization and function.


Scalable 18,650 aqueous-based supercapacitors using hydrophobicity concept of anti-corrosion graphite passivation layer.
Scalable aqueous-based supercapacitors are ideal as future energy storage technologies due to their great safety, low cost, and environmental friendliness. However, the corrosion of metal current collectors e.g., aluminium (Al) foil in aqueous solutions limits their practical applications. In this work, we demonstrate a low-cost, scalable, and simple method to prepare an anti-corrosion current collector using a concept of hydrophobicity by coating the hydrophobic graphite passivation layer on the Al foil via a roll-to-roll coating technology at the semi-automation scale of production pilot plant of 18,650 cylindrical supercapacitor cells. All qualities of materials, electrodes, and production process are therefore in the quality control as the same level of commercial supercapacitors. In addition, the effects of the graphite coating layer have been fundamentally evaluated. We have found that the graphite-coated layer can improve the interfacial contact without air void space between the activated carbon active material layer and the Al foil current collector. Importantly, it can suppress the corrosion and the formation of resistive oxide film resulting in better rate capability and excellent cycling stability without capacitance loss after long cycling. The scalable supercapacitor prototypes here in this work may pave the way to practical 18,650 supercapacitors for sustainable energy storage systems in the future.


Actinomyces in Pregnancy: A Review of the Literature.
Actinomyces is commonly found in many areas of the body where it derives a benefit without harming the host. When it does infect the host during pregnancy, is that infection a threat to the obstetric patient and does that infection cause adverse pregnancy outcomes? The aim of this study was to review what is known about Actinomyces infections and the impact of an Actinomyces infection on pregnancy outcomes. A PubMed search was undertaken with the search years unlimited to April 1, 2016, and restricted to articles in English. The search terms included "actinomyces," "pregnancy," "prenatal," "maternal," "actinomyces infection," "pregnancy," "chorioamnionitis," "preterm labor," "premature birth," or "postpartum actinomyces." Eighteen of the 154 identified articles are the basis of this review. Actinomyces is a rod-like positive bacterium. The diagnosis of an Actinomyces infection can be by culture or Gram stain. Actinomyces is commensal and typically only infects after a mucosal break or lesion. Seventeen cases were identified in pregnancy. Ten cases were complicated by chorioamnionitis and a preterm delivery. A nidus leading to infection was identified in 12 of the cases including women with a cervical cerclage, dental abscesses, appendicitis, renal actinomycosis, and ovarian abscesses. Adverse pregnancy outcomes have been linked with periodontal disease, but treatment did not prevent preterm delivery in a randomized, blinded, controlled trial. Actinomyces infections in pregnancy are rare but, if they occur, have been linked primarily with preterm deliveries. Obstetricians and gynecologists, family physicians. After completing this activity, the learner should be better able to identify the areas of the body where Actinomyces infections occur and how the infections typically occur, identify the pathophysiologic changes that occur during pregnancy that might lead to an Actinomyces infection and how that infection may affect pregnancy outcomes, and describe the treatment for mild and severe Actinomyces infections.


Impact of Angiotensin Receptor Blocker Use on Overall Survival Among Patients Undergoing Resection for Pancreatic Cancer.
Pancreatic cancer has higher concentrations of angiotensin II compared with other cancers. This study sought to assess the effect of angiotensin II receptor blockers (ARBs) on survival of patients undergoing resection using a large, nationally representative dataset. Patients undergoing pancreatic cancer resection were identified in the Truven Health MarketScan database. Multivariable Cox proportional hazards regression was used to assess the effect of ARB use on overall survival. A total of 4299 patients were identified, among whom 479 (11.1%) filled a prescription for an ARB. Mean patient age was 54.5 years (SD = 8.6 years); 2187 (51.1%) were female. Exactly 49.4% (n = 2125) of patients had a Charlson comorbidity index >2 at the time of surgery (n = 2125, 49.4%) and 59.6% (n = 2563) underwent a pancreaticoduodenectomy. Kaplan-Meier estimates of survival at 1, 2, and 4 years were 62.8% (95% CI: 61.3-64.2%), 38.2% (95% CI: 36.6-39.8%), and 19.0% (95% CI: 17.1-21.0%), respectively. On multivariable analysis, ARB use was associated with a 24% decreased risk of death over the 5-year period in which patients were under observation (HR = 0.76, 95% CI: 0.67-0.87, p < 0.001). ARB use was associated with improved survival in patients undergoing resection of pancreatic cancer. Further research is required into the differential effect of ARBs in the treatment of pancreatic cancer.


Assessment and classification of never operated and recurrent cryptoglandular fistulas-in-ano using hydrogen peroxide enhanced transanal ultrasound.
Classification and visualization of fistula-in ano is used to determine surgical treatment according to the type of fistula, predict the recurrence rate and incontinence risk and compare the results of treatment published in literature. Hydrogen peroxide enhanced transanal ultrasound (HPUS) with the peroxide introduced through the external opening of the fistula gives a clear and accurate visualization of the track in relation to the sphincters. The aim of this study was to review never operated and recurrent cryptoglandular fistulas-in-ano visualized with the aid of HPUS in order to establish the anatomical differences. Eighty-one patients with never operated (48) or recurrent (33) cryptoglandular fistulas-in-ano were assessed by clinical examination and HPUS. Never operated fistulas were single track, trans- or inter-sphincteric fistulas in 80%. In 15%, the tracks were sinus with no connection to the pectinate line. Two patients (5%) had a transsphincteric fistula with a ramification. No supra- or extra-sphincteric fistulas were found in the never operated fistula group. In the recurrent fistula patients, 57% had a single trans or intersphincteric track, 15% of the patients had a single track supra or extrasphincteric fistula and 27% had a ramified fistula. All never operated cryptoglandulair fistulas-in-ano were inter- or trans-sphincteric. An extra track was found in 5%. Recurrent fistulas-in-ano were supra or extrasphincteric in 15% and ramified in 27%. Therefore, never operated fistula-in-ano does not require any special investigation before surgical treatment. However, before treating recurrent fistulas, visualization by HPUS is recommended to detect supra or extrasphincteric fistulas or ramification.


Machine learning models predict delayed hyponatremia post-transsphenoidal surgery using clinically available features.
Delayed hyponatremia (DHN), a unique complication, is the leading cause of unexpected readmission after pituitary surgery. Therefore, this study aimed to develop tools for predicting postoperative DHN in patients undergoing endoscopic transsphenoidal surgery (eTSS) for pituitary neuroendocrine tumors (PitNETs). This was a single-center, retrospective study involving 193 patients with PitNETs who underwent eTSS. The objective variable was DHN, defined as serum sodium levels < 135 mmol/L at ≥ 1 time between post operative days 3 and 9. We trained four machine learning models to predict this objective variable using the clinical variables available preoperatively and on the first postoperative day. The clinical variables included patient characteristics, pituitary-related hormone levels, blood test results, radiological findings, and postoperative complications. The random forest (RF) model demonstrated the highest (0.759 ± 0.039) area under the curve of the receiver operating characteristic curve (ROC-AUC), followed by the support vector machine (0.747 ± 0.034), the light gradient boosting machine (LGBM: 0.738 ± 0.026), and the logistic regression (0.710 ± 0.028). The highest accuracy (0.746 ± 0.029) was observed in the LGBM model. The best-performing RF model was based on 24 features, nine of which were clinically available preoperatively. The proposed machine learning models with pre- and post-resection features predicted DHN after the resection of PitNETs.


LIMK1 promotes peritoneal metastasis of gastric cancer and is a therapeutic target.
Peritoneal metastasis is a common form of metastasis among advanced gastric cancer patients. In this study, we reported the identification of LIM domain kinase 1 (LIMK1) as a promoter of gastric cancer peritoneal metastasis, and its potential to be a therapeutic target of dabrafenib (DAB). Using transcriptomic sequencing of paired gastric cancer peritoneal metastasis, primary tumors, and normal gastric tissues, we first unveiled that LIMK1 is selectively up-regulated in metastatic tumors. Increased LIMK1 in gastric cancer peritoneal metastasis was validated by immunohistochemistry analysis of an independent patient cohort. In vitro functional studies demonstrated that LIMK1 knockout or knockdown significantly inhibited cell migration and invasion of gastric cancer cells. LIMK1 knockout also abrogated peritoneal and liver metastases of gastric cancer cells in nude mice in vivo. Dabrafenib, a small molecule targeting LIMK1, was found to decrease cell migration and invasion of gastric cancer cells in vitro and abolish peritoneal and liver metastasis formation in vivo. Mechanistically, either LIMK1 knockout or Dabrafenib inhibited LIMK1 expression and phosphorylation of its downstream target cofilin. Taken together, our results demonstrated that LIMK1 functions as a metastasis promoter in gastric cancer by inhibiting LIMK1-p-cofilin and that Dabrafenib has the potential to serve as a novel treatment for gastric cancer peritoneal metastasis.


Serotype-specific and cross-reactive neutralizing antibody responses in cynomolgus monkeys after infection with multiple dengue virus serotypes.
Neutralizing antibody responses were examined in monkeys after dengue virus infections. In monkeys that had been infected once or twice with DENV-2, neutralizing antibody was cross-reactive with all four serotypes after secondary or tertiary infection with DENV-3. In monkeys that had been inoculated with DENV-1 and DENV-2 in the primary and secondary infections, neutralizing antibody titers did not increase after tertiary infection with DENV-3. These results indicate that antibody responses after secondary and tertiary infections with different serotypes are cross-reactive with all four serotypes, consistent with what has been observed in humans, and suggest that monkeys are useful for determining neutralizing antibody responses.


Diskectomy in temporomandibular joints with internal derangement: a follow-up study.
To follow up a series of patients treated consecutively who had undergone a diskectomy 2 years previously because of persistent pain and disk displacement in the temporomandibular joint. Sixteen subjects rated their current symptoms during 1 week and were systematically examined for signs of temporomandibular disorders clinically and radiographically by independent observers. Subjectively, all subjects were satisfied with the operation. Five rated their current pain as significant during masticatory function. Some signs of temporomandibular disorders, usually related to function, were registered in all subjects. Postoperative mandibular movements were improved but still below normal range. Signs and symptoms correlated significantly. Surgical complications were nonexistent, but radiographic changes were extensive. Erosion and flattening of the condyle were common. It was verified that subjects with persistent pain and disk displacement benefit subjectively and clinically from diskectomy. The radiographic outcomes appear less encouraging. Only prospective, randomized, and controlled studies can eventually clarify the effectiveness of diskectomy in relieving pain caused by displacements in the temporomandibular joint.


Mechanistic insight into the capacity of natural polar phenolic compounds to abolish Alzheimer's disease-associated pathogenic effects of apoE4 forms.
Polar phenols found in plant foods have been suggested to act protectively against pathogenic processes underlying Alzheimer's disease (AD), such as oxidative stress. The major risk factor for AD is apolipoprotein E4 (apoE4) and apoE4 forms can affect AD-related processes. It was shown previously that the hereditary apoE4 mutant apoE4[L28P], as well as the apoE4 fragment apoE4-165, induce neuronal oxidative stress. The effect of polar phenols on AD-related pathogenic functions of apoE4 forms is largely unexplored. The aim was to examine the effect of Corinthian currant polar phenolic extract and specific polar phenols resveratrol, quercetin, kaempferol and epigallocatechin gallate on AD-related functions of apoE4 forms. The polar phenolic extract and the individual compounds restored the viability of human neuroblastoma SK-N-SH cells in the presence of lipoprotein-associated apoE4[L28P] and prevented changes in cellular redox status. Furthermore, resveratrol, quercetin, kaempferol and epigallocatechin gallate prevented redox status changes induced by Aβ42 uptake in SK-N-SH cells treated with lipid-free apoE4[L28P] or apoE4-165. Investigation of the molecular mechanism of action of these polar phenols showed that resveratrol prevented cellular Aβ42 uptake via changes in cell membrane fluidity. Interestingly, kaempferol prevented cellular Aβ42 uptake by apoE4[L28P], but not by apoE4-165, due to a modulating effect on apoE4[L28P] secondary structure and stability. The action of quercetin and epigallocatechin gallate could be attributed to free radical-scavenging or other protective activity. Overall, it is shown for the first time that natural compounds could modify the structure of apoE4 forms and ameliorate AD-related pathogenic effects of apoE4 forms.


NAST: Nonadiabatic Statistical Theory Package for Predicting Kinetics of Spin-Dependent Processes.
We present a nonadiabatic statistical theory (NAST) package for predicting kinetics of spin-dependent processes, such as intersystem crossings, spin-forbidden unimolecular reactions, and spin crossovers. The NAST package can calculate the probabilities and rates of transitions between the electronic states of different spin multiplicities. Both the microcanonical (energy-dependent) and canonical (temperature-dependent) rate constants can be obtained. Quantum effects, including tunneling, zero-point vibrational energy, and reaction path interference, can be accounted for. In the limit of an adiabatic unimolecular reaction proceeding on a single electronic state, NAST reduces to the traditional transition state theory. Because NAST requires molecular properties at only a few points on potential energy surfaces, it can be applied to large molecular systems, used with accurate high-level electronic structure methods, and employed to study slow nonadiabatic processes. The essential NAST input data include the nuclear Hessian at the reactant minimum, as well as the nuclear Hessians, energy gradients, and spin-orbit coupling at the minimum energy crossing point (MECP) between two states. The additional computational tools included in the NAST package can be used to extract the required input data from the output files of electronic structure packages, calculate the effective Hessian at the MECP, and fit the reaction coordinate for more advanced NAST calculations. We describe the theory, its implementation, and three examples of application to different molecular systems.


[Electronic data processing-assisted epicrisis in clinico-psychiatric documentation of findings].
The medical profession is using computers to an increasing extent, and the graphic epicrises described here, which is intended mainly to augment the conventional epicrisis, is another useful application. It is based on a standardised psychopathological examination and documentation procedure and permits the course of psychopathological syndromes to be demonstrated in an illustrative way.


Xylanase production in solid state fermentation by Aspergillus niger mutant using statistical experimental designs.
The initial moisture content, cultivation time, inoculum size and concentration of basal medium were optimized in solid state fermentation (SSF) for the production of xylanase by an Aspergillus niger mutant using statistical experimental designs. The cultivation time and concentration of basal medium were the most important factors affecting xylanase activity. An inoculum size of 5 x 10(5) spores/g, initial moisture content of 65%, cultivation time of 5 days and 10 times concentration of basal medium containing 50 times concentration of corn steep liquor were optimum for xylanase production in SSF. Under the optimized conditions, the activity and productivity of xylanase obtained after 5 days of fermentation were 5,071 IU/g of rice straw and 14,790 IU l(-1) h(-1), respectively. The xylanase activity predicted by a polynomial model was 5,484 IU/g of rice straw.


Quail-chick chimeras and eye development.
The quail-chick chimera is a stable and precise labeling technique that allows tracing of definite cells and their progeny without interfering with normal development of two related avian species. This technique utilizes the transplantation of quail tissues into chick embryo or vice versa. The region of interest (graft) is removed from the donor and replaced in the stage-matched host embryo. The quail-chick chimeras can be analyzed by immunolabeling donor-derived cells with species-specific antibodies, or by differential staining of the nucleus. The use of the quail-chick chimera technique is valuable to eye development studies since its formation involves coalition of tissues from different embryonic origins: the ectoderm, neuroectoderm, and neural crest cells derived from the interaction between the ectoderm and neural ectoderm. This chapter describes the protocols for using quail-chick chimeras to identify neural crest- and ectoderm-derived components of the eye. This technique can be used in combination with molecular biology techniques in functional studies to determine the cellular and tissue interactions involved in eye development.


The role of calcium in the regulation of glucose uptake in isolated working rat heart.
Catecholamines or ischemia may increase myocardial glucose uptake by an increase in intracellular calcium. We tested the hypothesis that increasing or decreasing extracellular calcium supply would change glucose uptake. Hearts were perfused for 60 min at a physiological workload with Krebs-Henseleit buffer containing glucose (5 mM) and oleate (0.4 mM; bound to 1% BSA). Calcium concentration was 2.5 mM. In group A (control; n = 12), insulin (1 mU/ml) was added at 30 min. In Group B (n = 7), the calcium concentration was increased to 5.0 and 7.5 mM at 20 min and 40 min, respectively. In Group C (n = 7), verapamil was added at 20 min (0.25 microM) and 40 min (1.0 microM) to decrease calcium influx. In group D (n = 7), EDTA was added at 20 min (0.5 mM) and at 40 min (1.5 mM) to decrease the free extracellular calcium. Glucose uptake was measured by 3H2O production from [2-3H]glucose and cardiac work was measured simultaneously. Cardiac power in group B was 8.24 +/- 0.60 mW at 2.5 mM calcium, 9.45 +/- 0.50 mW at 5 mM calcium and 7.99 +/- 0.99 mW at 7.5 mM calcium (n.s.). The addition of verapamil decreased contractile function in a dose-dependent manner (8.50 +/- 0.74 vs. 3.11 +/- 0.84 vs. 1.48 +/- 0.39 mW, p < 0.01) suggesting that verapamil decreased cytosolic calcium concentration. A similar dose-dependent reduction in contractile performance was observed in the EDTA group (8.44 +/- 0.81 vs. 7.42 +/- 0.96 vs. 4.03 +/- 1.32 mW, p < 0.01). Glucose uptake was 1.35 +/- 0.11 micromol/min/g dry weight under control conditions. Glucose uptake increased threefold with the addition of insulin. Increasing extracellular [Ca2+] did not affect glucose uptake. Decreasing Ca2+ availability showed a trend towards a decrease in glucose uptake (n.s.), which was minor compared to the decrease in contractile function. We conclude that extracellular calcium does not regulate glucose uptake in the isolated working rat heart in the presence of glucose and fatty acids as substrates. The trend of decreased glucose uptake when calcium supply was limited may be due to dramatically reduced energy demand and not directly due to changes in calcium.


Production of nitrite by dengue virus-induced cytotoxic factor.
Dengue type 2 virus (DV) infection induces production of a cytokine, the cytotoxic factor (CF) in the spleen of mice. The present study was undertaken to investigate the production of nitrite (NO2-) by the spleen cells of mice in vitro and in vivo following inoculation of DV or CF. Maximum NO2- production occurred at 45 min after inoculation of 5 microg CF, both in vitro and in vivo. The NO2- was produced by macrophages and T cells and not by B cells. Pretreatment of CF with anti-CF antisera inhibited production of NO2-. DV-stimulated spleen cell culture supernatants showed peak production of CF and NO2- at 72h. In DV-infected mouse spleen, maximum NO2- production occurred at 8-11 days post-infection, which correlated with peak cytotoxic activity in the spleen. Pretreatment of spleen cells with N(G)-monomethyl L-arginine (NMMA) inhibited NO2- production. NO2- production was abrogated in a dose-dependent manner by treatment of spleen cells with Ca2+ channel blocking drug, Nifedipine. The findings demonstrate that DV-induced CF induces production of NO2- in spleen cells, probably in a Ca2+-dependent manner, and may be a mechanism of target cell killing.


Parabacteroides distasonis ameliorates hepatic fibrosis potentially via modulating intestinal bile acid metabolism and hepatocyte pyroptosis in male mice.
Parabacteroides distasonis (P. distasonis) plays an important role in human health, including diabetes, colorectal cancer and inflammatory bowel disease. Here, we show that P. distasonis is decreased in patients with hepatic fibrosis, and that administration of P. distasonis to male mice improves thioacetamide (TAA)- and methionine and choline-deficient (MCD) diet-induced hepatic fibrosis. Administration of P. distasonis also leads to increased bile salt hydrolase (BSH) activity, inhibition of intestinal farnesoid X receptor (FXR) signaling and decreased taurochenodeoxycholic acid (TCDCA) levels in liver. TCDCA produces toxicity in mouse primary hepatic cells (HSCs) and induces mitochondrial permeability transition (MPT) and Caspase-11 pyroptosis in mice. The decrease of TCDCA by P. distasonis improves activation of HSCs through decreasing MPT-Caspase-11 pyroptosis in hepatocytes. Celastrol, a compound reported to increase P. distasonis abundance in mice, promotes the growth of P. distasonis with concomitant enhancement of bile acid excretion and improvement of hepatic fibrosis in male mice. These data suggest that supplementation of P. distasonis may be a promising means to ameliorate hepatic fibrosis.


Catalytic hairpin assembly induced dual signal enhancement for rapid detection of miRNA using fluorescence light-up silver nanocluster.
A novel method of catalytic hairpin assembly (CHA) induced dual signal enhancement is developed for rapid detection of miRNA based on fluorescence light-up silver nanocluster (Ag NC). By the hybridization of a hairpin DNA and a single-stranded DNA, a unique probe is firstly designed. In the terminals of this probe, DNA-Ag NCs can be formed and display very weak fluorescence. In the presence of the target miRNA, the reaction of CHA can be triggered, forming two kinds of double-stranded complexes, in which the terminal DNA-Ag NCs are in close proximity to G-rich overhangs and the fluorescent signal can be dramatically enhanced. Compared with many other enzyme-based amplification strategies, this one exhibits distinct advantages of simplicity in experimental operation and a rapid detection process (within 1 h). Moreover, this assay exhibits an excellent selectivity and is successfully applied in the detection of miRNAs in complex biological media, which confirms the reliability and practicality of this protocol.


Two-dimensional simulations of Rayleigh-Taylor instability in elastic-plastic media.
Two-dimensional numerical simulations for the Rayleigh-Taylor instability in an elastic-plastic medium are presented. Recent predictions of the theory regarding the asymmetric growth of peaks and valleys during the linear phase of the instability evolution are confirmed. Extension to the nonlinear regime reveals singular features, such as the long delay in achieving the nonlinear saturation and an intermediate phase with growth rate larger than the classical one.


Association between antennal phenotype, wing polymorphism and sex in the genus Mepraia (Reduviidae: Triatominae).
Mepraia spinolai and Mepraia gajardoi (Hemiptera, Reduviidae) are only found in the arid regions of northern Chile. Mepraia is the only genus of Triatominae with marked wing polymorphism. Females of both species are micropterous, males of M. spinolai may be micropterous, brachypterous or macropterous, while males of M. gajardoi are always brachypterous. Because of this wing polymorphism, Mepraia can be used as a model to analyze morphological adaptations related to the flying activity and evolutionary relationships in the Triatominae. The study presented here analyses the antennal phenotype of the Mepraia species and carries out a comparison with the two species of Triatoma included in the spinolai complex (Triatoma eratyrusiformis and Triatoma breyeri). The analysis of the antennal phenotype of Mepraia showed a marked intraspecific phenotypic variability related with sex and wing condition. The number and length of multiporous trichoid sensilla (TH) on the pedicel are significantly higher and longer in winged males and are strongly reduced in females. The great length of the TH sensillum is an infrequent characteristic within Triatominae. The results show that phenetic distances between sexes are greater than between the two species. Similarity between the Mepraia species and T. eratyrusiformis was found as they all show long bristles (BR) and TH and two sized basiconic receptors (BA), a pattern that have not been observed in other species of Triatominae. These characters are not present in T. breyeri.


Automatic detection of ground glass opacities on lung HRCT using multiple neural networks.
The purpose of this study was to implement neural networks and expert rules for the automatic detection of ground glass opacities (GG) on high-resolution computed tomography (HRCT). Different approaches using self-organizing neural nets as well as classifications of lung HRCT with and without the use of explicit textural parameters have been applied in preliminary studies. In the present study a hybrid network of three single nets and an expert rule was applied for the detection of GG on 120 HRCT scans from 20 patients suffering from different lung diseases. Single nets alone were not capable to reliably detect or exclude GG since the false-positive rate was greater than 100 % with regard to the area truly involved, more than 50 pixels throughout, and the true-positive rate was greater than 95 %. The hybrid network correctly classified 91 of 120 scans. Mild GG was false positive in 15 cases with less than 50 pixels, which was judged not clinically relevant. The pitfalls were: partial volume effects of bronchovascular bundles and the chest wall. Motion artefacts and diaphragm were responsible for 11 misclassifications. Hybrid networks represent a promising tool for an automatic pathology-detecting system. They are ready to use as a diagnostic assistant for detection, quantification and follow-up of ground glass opacities, and further applications are underway.


Effect of maternal use of flaxseed oil during pregnancy and lactation on glucose metabolism and pancreas histomorphometry of male offspring from diabetic rats.
Investigate if the maternal use of flaxseed oil prevents pancreatic alterations in the offspring of diabetic mothers. Diabetes was induced in female wistar rats (n=12) by a high-fat diet and low-dose of streptozotocin. After the confirmation of the diabetes (glucose >300 mg/dL), rats were mated and once pregnancy was confirmed, they were allocated into three groups (n=6): high-fat group (HFG); flaxseed oil group (FOG); and control group (CG) (nondiabetic rats). At weaning, male offspring (n=12/group) received a standard chow diet. The animals were euthanized in two phases: at 100 and at 180 days, (n=6/group). The pancreas was collected for histomorphometric and immunohistochemistry analysis. HFG showed hypertrophy of pancreatic islets at 100 and at 180 days (p<0.0001), while the FOG offspring had islets with smaller diameters compared to HFG at both phases of sacrifice (p<0.0001). HFG had a lower percentage of small islets when compared to CG and FOG, which had a higher percentage when compared to HFG (p=0.0053) at 100 days. At 180 days HFG showed higher percentage of larger islets (p=0.00137) and lower percentage of smaller islets (p=0.00112), when compared to FOG. HFG showed lower islet insulin immunodensity at 100 days (p<0.0001) and 180 days (p<0.0001), whereas FOG was similar to CG (p<0.0001) at 100 days and higher at 180 days (p<0.0001). Flaxseed oil reduced the damage caused by maternal hyperglycemia, promoting normal pancreas histomorphometry and β cell mass.


Isolation and characterization of the Drosophila translational elongation factor 2 gene.
We have isolated a cDNA clone that encodes the Drosophila melanogaster elongation factor 2 (EF2), a protein involved in the elongation step of protein synthesis. This identification was based on the high degree of its amino acid sequence identity (greater than 80%) to that of hamster EF2. The gene encoding Drosophila EF2 is found at position 39E-F of the 2L chromosomal arm and maybe identical to the M(2)H locus, which produces a Minute phenotype when mutated. The genomic organization of the locus includes four exons. Conserved sequence segments shared with a variety of GTP binding proteins are found in the amino terminal third of the protein, and segments unique to EF2 and its prokaryotic functional homolog, EF-G, are in the carboxy terminal half; these two regions are segregated in two respective exons.


[Radiation TherapisTs Radiographer (RTTs) and risk management in radiotherapy: An international survey].
In order to study the role perception and the effective involvement of Radiation TherapisTs (RTTs) in risk management in radiotherapy, a survey was developed and distributed in five countries (France, Switzerland, Belgium, Ireland, the Netherlands). The article presents the results of this survey and the comparison between the different countries. Overall, the results of the survey show a good involvement and perception of the RTTs around the risk management approach, although training in this area has yet to be systematized. Although with differences in the results between the participating countries, the survey seems to highlight the deployment of preventive actions that are evaluated as not very effective by the respondents and by the international scientific literature.


A comprehensive approach to complementary and alternative medicine usage among patients from a vascular department.
Use of complementary and alternative medicine (CAM) therapies had been described in patients with disabling, chronic and painful conditions; these characteristics define the majority of vascular surgery (VS) entities. A lack of disclosure about CAM use from patients has been universally cited and may impact effective patient-doctor communication. Our primary objective was to describe CAM use, modalities, perceived benefits, safety, and associated factors among adult patients attending a VS outpatient clinic; we additionally explored patient's attitudes about CAM disclosure with their primary vascular surgeon. This cross-sectional study invited 223 consecutive outpatients to an interview where the ICAM-Q (International Complementary and Alternative Medicine Questionnaire) and the PDRQ-9 (Patient-Doctor Relationship Questionnaire-9 items) were applied. In addition, sociodemographics, vascular disease and treatment-related information, comorbidity, and disease severity characteristics were obtained. Appropriated statistics was used; multiple logistic regression analysis identified factors associated to CAM use. All statistical tests were two-sided, and a p value ≤ 0.05 was considered significant. IRB approval was obtained. Patients recruited were primary females (69%) and had a median age of 65 years (54-75). Most frequent vascular diagnoses were chronic venous insufficiency (36.2%) and peripheral artery disease (26%). There were 104 (46.6%) patients who referred CAM use, primarily self-helped practices (96%), and use of herbal, vitamins, or homeopathic medicines (23.7%). Overall, the majority of the patients perceived CAM modalities helpful and 94.6% denied any adverse event. Female sex (OR: 1.768, 95% CI: 0.997-3.135, p = 0.051) and hospitalization during the previous year (OR: 3.173, 95% CI: 1.492-6.748, p = 0.003) were associated to CAM use. The majority of the patients (77%) agreed about CAM disclosure with their primary vascular surgeon; meanwhile, among CAM users, up to 54.9% did not disclose it, and their main reasons were "Doctor didn't ask" (32%) and "I consider it unnecessary" (16%). The patient-doctor relationship was rated by the patients with high scores. CAM use is frequent and perceived as safe and beneficial among VS outpatients; nonetheless, patients do not disclose CAM use with their primary vascular surgeons, and a wide range of reasons are given by the patients that prevent effective and open communication.


[Studies on the problem of DNA constancy during embryogenesis (Urodela, Triturus vulgaris)].
1. During early embryogenesis (from morula to late tail-bud) of Triturus vulgaris the DNA content of isolated nuclei from various regions was measured cytophotometrically. The measurement data (50 to 70 for each region and developmental stage) were collated to so-called karyograms, which show the DNA doubling during interphase and serve for determining the "normal" DNA content (DNA value of G1-nuclei). 2. Thereby it became evident that the DNA content of G1-nuclei is not constant in the course of development, but varies with stage and region specifically. Beginning with high values, DNA decreases from morula to early gastrula. In the neuroectoderm (region 2), chordamesoderm (region 1), and endoderm (region 4) remarkable DNA increases of short duration occur at one time in the mid to late gastrula and at another time in the late neurula. By contrast in the presumptive epidermis an increase of DNA has only been detected during gastrulation. 3. With regard to the extent and rate of changes in DNA content there are good agreements on the one hand and considerable differences between various regions on the other. 4. In explantation experiments these results (with the exception of endoderm) could be confirmed for isolated material too. Thus non-induced ectoderm of the gastrula shows just the first DNA increase, but induced ectoderm shows also the second one. In isolated presumptive chordamesoderm both phases of DNA increase are visible, whereas isolated endoderm is characterized by absolute constancy of DNA. 5. In isolated ectoderm Actinomycin D (1 and 2 Μg/ml) prevents the additional DNA synthesis during gastrulation, whereas the second DNA increase is not impaired. (Actinomycin D does not interfere with the normal DNA reduplication.) 6. Puromycin (20 Μ/ml) has no influence on the DNA increase in the course of gastrulation and neurulation. 7. The temporal correlation of both phases of additional DNA synthesis with well-known embryological, cytological, and biochemical changes in the embryo leads to the assumption that the phase-specific increase of DNA is an expression of enhanced gene activity in definite regions of the embryo. The possibility of partial amplification of genes for the purpose of increase of transcription capacity is discussed, and a parallel is drawn with the multiplication of the nucleolus organizer during the maturation of oocytes.


The Relationship Timeline: A Method for the Study of Shared Lived Experiences in Relational Contexts.
Lifeline methods-graphic illustrations of the pathways of lived experience traveled by individuals from birth to anticipated death-have been useful in the study of lived experience. Existing lifeline methods and research focus on the individual experience; absent from this literature are the collective experiences of those in intimate relationships. In this paper, based on our research with 120 same-sex couples, we present a method to allow for the joint creation of relationship timelines, which serve as the basis for eliciting dyadic data in multiple forms: graphic representations of relationship development through couples' creation of a timeline of key events and periods; qualitative narratives of couples' shared experiences; and quantitative ratings of significant events and periods in their lives together. Lessons learned from the application of this Relationship Timeline Method are discussed, as are implications for future study of the shared lived experience.


A review of paediatric admissions to a general intensive therapy unit over a 13-year period.
Paediatric admissions to a general ITU are briefly reviewed. Although it may not be an ideal arrangement it is suggested that children can be safely cared for in such a unit. The problems created by the child with acute upper airway obstruction are discussed to demonstrate the way in which the unit is organized to receive acutely ill children.


Theoretical simulation and experimental design of selenium and gold incorporated polymer-based microcarriers for ROS-mediated combined photothermal therapy.
Recently, multi-modal combined photothermal therapy (PTT) with the use of photo-active materials has attracted significant attention for cancer treatment. However, drug carriers enabling efficient heating at the tumor site are yet to be designed: this is a fundamental requirement for broad implementation of PTT in clinics. In this work, we design and develop hybrid carriers based on multilayer capsules integrated with selenium nanoparticles (Se NPs) and gold nanorods (Au NRs) to realize reactive oxygen species (ROS)-mediated combined PTT. We show theoretically and experimentally that cooperative interaction of Se NPs with Au NRs improves the heat release efficiency of the developed capsules. In addition, after uptake by tumor cells, intracellular ROS level amplified by Se NPs inhibits the tumor growth. As a consequence, the synergy between Se NPs and Au NRs exhibits the advantages of hybrid carriers such as (i) improved photothermal conversion efficiency and (ii) dual-therapeutic effect. The results of in vitro and in vivo experiments demonstrate that the combination of ROS-mediated therapy and PTT has a higher tumor inhibition efficiency compared to the single-agent treatment (using only Se-loaded or Au-loaded capsules). Furthermore, the developed hybrid carriers show negligible in vivo toxicity towards major organs such as the heart, lungs, liver, kidneys and spleen. This study not only provides a potential strategy for the design of multifunctional "all-in-one" carriers, but also contributes to the development of combined PTT in clinical practice.


Trial of combined warfarin plus dipyridamole or aspirin therapy in prosthetic heart valve replacement: danger of aspirin compared with dipyridamole.
Despite the use of oral anticoagulation in patients with prosthetic heart valves, persistent thromboembolism over time warrants a search for improved methods of prevention. Thus, patients receiving 1 or more mechanical prosthetic heart valves were randomized to therapy with warfarin plus dipyridamole (400 mg/day) or warfarin plus aspirin (500 mg/day) on the basis of location and type of valve and surgeon, and followed up with a concurrent, nonrandomized control group taking warfarin alone. In 534 patients followed up 1,319 patient-years, excessive bleeding (necessitating blood transfusion or hospitalization) was noted in the warfarin plus aspirin group (23 of 170 [14%], or 6.0/100 patient-years) compared with warfarin plus dipyridamole (7 of 181 [4%], or 1.6/100 patient-years, p less than 0.001), or warfarin alone (9 of 183 [5%], or 1.8/100 patient-years, p less than 0.001). A trend was evident toward a reduction in thromboembolism in the warfarin plus dipyridamole group (2 of 181 [1%], or 0.5/100 patient-years) as compared with warfarin plus aspirin (7 of 170 [4%], or 1.8/100 patient-years), or warfarin alone (6 of 183 [4%], or 1.2/100 patient-years). Adequacy of anticoagulation (based on 12,720 prothrombin time determinations) was similar in all 3 groups with 65% of prothrombin times in the therapeutic range (1.5 less than or equal to prothrombin time/control less than or equal to 2.5), 30% too low, and 5% too high. Warfarin plus aspirin therapy resulted in excessive bleeding and is contraindicated. Longer follow-up study is needed to determine whether further separation of the incidence of thromboembolism can be detected.


AE0047-mediated calcium channel blocking in vascular smooth muscles.
1. This experiment was designed to pharmacologically characterize a novel calcium channel blocker, AE0047. 2. After 1-hr treatment with each drug (10(-6) M), K(+)-induced contraction in rat aortic strip was clearly depressed by nifedipine and manidipine and slightly depressed by AE0047. After a wash out of the preparation in drug-free medium, the inhibition of K(+)-induced contraction by nifedipine or manidipine was abolished or unchanged, respectively. In contrast, AE0047-produced inhibition was reinforced with time after removal of the drug. 3. A cell membrane depolarization-induced 45Ca uptake into tissue was depressed completely by nifedipine, but, if it was washed out, merely 20% inhibition of control remained. AE0047-produced inhibition became prominent after drug removal. Manidipine did not have the same inhibitory effect after wash out. 4. A receptor-binding study indicated that affinity of AE0047 and manidipine for the dihydropyridine-sensitive Ca channel receptor was lower than that of nifedipine. AE0047, unlike nifedipine and manidipine, inhibited [3H]PN200-110 binding more strongly when a 4-hr preincubation was used than without extended incubation. 5. The drug molecule of AE0047 was highly partitioned into the lipid bilayer of the synaptosome in canine cerebral cortices. In the synaptic membrane and liposomes, both prepared from canine cerebral cortices, the respective partition coefficients of the drug were 6997 +/- 2309 and 422 +/- 28 against 1395 +/- 161 and 24 +/- 2 of nitrendipine. 6. AE0047 showed slower onset of inhibition against K(+)-induced contraction and enhanced Ca influx compared with manidipine and nifedipine. These results may suggest that AE0047 requires a long period of time to occupy the dihydropyridine-sensitive sites within the Ca channel, which was detected by decreased specific [3H]PN200-110 binding, and to inhibit K(+)-induced Ca influx into rat aorta.


Correlation Between Gait and Near-Infrared Brain Functional Connectivity Under Cognitive Tasks in Elderly Subjects With Mild Cognitive Impairment.
Older adults with mild cognitive impairment (MCI) have a high risk of developing Alzheimer's disease. Gait performance is a potential clinical marker for the progression of MCI into dementia. However, the relationship between gait and brain functional connectivity (FC) in older adults with MCI remains unclear. Forty-five subjects [MCI group, n = 23; healthy control (HC) group, n = 22] were recruited. Each subject performed a walking task (Task 01), counting backward-walking task (Task 02), naming animals-walking task (Task 03), and calculating-walking task (Task 04). The gait parameters and cerebral oxygenation signals from the left prefrontal cortex (LPFC), right prefrontal cortex (RPFC), left motor cortex (LMC), right motor cortex (RMC), left occipital leaf cortex (LOL), and right occipital leaf cortex (ROL) were obtained simultaneously. Wavelet phase coherence was calculated in two frequency intervals: low frequency (interval I, 0.052-0.145 Hz) and very low frequency (interval II, 0.021-0.052 Hz). Results showed that the FC of RPFC-RMC is significantly lower in interval I in Task 03 compared with that in Task 02 in the MCI group (p = 0.001). Also, the right relative symmetry index (IDpsR) is significantly lower in Task 03 compared with that in Task 02 (p = 0.000). The IDpsR is positively correlated with the FC of RPFC-RMC in interval I in the MCI group (R = 0.205, p = 0.041). The gait symmetry such as left relative symmetry index (IDpsL) and IDpsR is significantly lower in the dual-task (DT) situation compared with the single task in the two groups (p < 0.05). The results suggested that the IDpsR might reflect abnormal change in FC of RPFC-RMC in interval I in the MCI population during Task 03. The gait symmetry is affected by DTs in both groups. The findings of this study may have a pivotal role in the early monitoring and intervention of brain dysfunction among older adults with MCI.


Orosomucoid in human pregnancy serum diminishes bioavailability of the progesterone antagonist RU 486 in rats.
Bioavailability of the progesterone antagonist RU 486 was examined in vivo by measurement of first-pass uptake by hepatic and uterine tissues in rats. Presence of human pregnancy serum or alpha 1-acid glycoprotein (orosomucoid) in injection vehicles diminished uptake of this steroid, which suggests limited bioavailability. These data indicate that elevated human serum orosomucoid levels may account for some failures of RU 486 in early pregnancy termination.


Reverse total shoulder arthroplasty for the management of failed shoulder arthroplasty with proximal humeral bone loss: is allograft augmentation necessary?
Patients undergoing revision shoulder arthroplasty frequently have deficient proximal humeral bone stock. Proximal humeral allograft has been recommended to augment reverse total shoulder arthroplasty (RTSA) to improve stability and function. This study reports the results of RTSA without proximal humeral allograft in patients with proximal humeral bone loss secondary to failed shoulder arthroplasty. From 2005 to 2008, 251 patients were enrolled in a prospective RTSA cohort study. Significant humeral bone loss was demonstrated in 15 of 56 undergoing revision for failed arthroplasty. Average age was 67 years. Average bone loss measured 38.4 mm (range, 26-72 mm). Patients were followed up for a minimum of 2 years with American Shoulder and Elbow Surgeons (ASES), Subjective Shoulder Value (SSV), Constant Score (CS), and visual analog scale (VAS) pain scores, as well as self-reported satisfaction and radiographs. Patients demonstrated significant improvement in mean CS (23.0 to 44.2), ASES (38.2 to 68.3), ASES activities of daily living (7.0 to 15.9), SSV (19.2 to 75.8), and VAS pain (4.6 to 1.6) scores. Thirteen of 15 patients reported satisfaction (87%). Range of motion improved in forward flexion (38.3° to 103.2°) and external rotation (-0.5° to 11.9°). Radiographs demonstrated notching in 3 patients (20%), no humeral subsidence or loosening, and prosthetic fracture of 1 modular humeral stem. Use of RTSA for failed shoulder arthroplasty and deficient humeral bone stock provides a significant clinical benefit without the need for allograft augmentation. Monoblock humeral component use may diminish risk for prosthetic fracture.


Critical period for dopaminergic neuroprotection by hormonal replacement in menopausal rats.
The neuroprotective effects of menopausal hormonal therapy in Parkinson's disease have not yet been clarified, and it is not known whether there is a critical period. Estrogen induced significant protection against 6-hydroxydopamine-induced dopaminergic degeneration when administered immediately or 6 weeks, but not 20 weeks after ovariectomy. In the substantia nigra, ovariectomy induced a decrease in levels of estrogen receptor-α and increased angiotensin activity, NADPH-oxidase activity, and expression of neuroinflammatory markers, which were regulated by estrogen administered immediately or 6 weeks but not 20 weeks after ovariectomy. Interestingly, treatment with angiotensin receptor antagonists after the critical period induced a significant level of neuroprotection. In cultures, treatment with 1-methyl-4-phenylpyridinium induced an increase in astrocyte-derived angiotensinogen and dopaminergic neuron death, which were inhibited by estrogen receptor α agonists. In microglial cells, estrogen receptor β agonists inhibited the angiotensin-induced increase in inflammatory markers. The results suggest that there is a critical period for the neuroprotective effect of estrogen against dopaminergic cell death, and local estrogen receptor α and renin-angiotensin system play a major role.


The in vivo inactivation of GABA and other inhibitory amino acids in the cat nervous system.
In cats anaesthetised with pentobarbitone, the effect of inhibitors of the in vitro cellular uptake of GABA were tested on the responses of single central neurones to GABA and other depressant amino acids. (4)- AND (-)-nepecotic acid, (4)-2,4-diaminobutyric acid (DABA) and 2,2-dimethyl-beta-alanine, enhanced the action of GABA on spinal, cerebellar and cerebral cortical neurones. In the spinal cord DABA, and to a less estent (-)-nipecotic acid, enhanced the action of beta-alanine, whereas the actions of glycine and taurine were unaffected by DABA and reduced by (-)-nipecotic acid. In the cerebellum and cerebral cortex, these two substances enhanced the action of GABA, usually to a greater extent than that of beta-alanine and taurine, although this specificity was not marked. The GABA-mediated basket cell inhibition of Purkinje cells in the cerebellum was unaffected by DABA and (-)-nipecotic acid, and neither substance appears suitable for determining the role of uptake processes in the inactivation of synapitcally released GABA. Quantitatively these in vivo results agree more closely with recent vitro uptake studies in cat tissue than the previously published data on rat cerebral cortex and dorsal root ganglia, and the observations provide further evidence for the importance of cellular uptake in maintaining low extraneuronal concentrations of inhibitory amino acid transmitters.


Radiographic demonstration of oronasal fistulas in patients with cleft palate with the use of barium sulfate contrast.
The purpose of this investigation was to determine the overlapping and unique contributions that radiographic techniques might provide for accurate characterization of hard palate fistulas associated with cleft palate. Five subjects with oronasal fistulas were selected for radiographic imaging, and their informed consent was obtained. Results indicated that radiographs with contrast can provide important supplemental and unique information. Qualitative descriptions of the inferior-superior course and location, and the size of the narrowest aperture could be obtained from the combination of maxillary occlusal, posteroanterior tomographic, and lateral tomographic projections. This information could not be obtained from the common clinical methods in use to describe fistulas. This technique can provide valuable information to all members of a multidisciplinary cleft palate team to document palatal fistulas for both clinical and research purposes.


A comparison of the initial retinal ganglion cell projection to the contralateral superior colliculus in albino and pigmented rats.
Newborn albino and pigmented rats received localised Fast blue (FB) injections into the most caudal part of the contralateral superior colliculus (SC). A proportion of retinal ganglion cells (RGC's) from the temporal retina which in the adult projects exclusively to the rostral half of the colliculus are labelled by injections to the caudal colliculus in neonatal animals. The majority of these cells die during the period of naturally occurring cell death in the retina, which occurs during the first 10 postnatal days. The object of this experiment was to see whether albino rats, which have well documented abnormalities in axon pathfinding in their visual system, had a larger number of cells in temporal retina which initially project to caudal colliculus than pigmented animals. On postnatal day 2 (P2), the ratio of temporal to nasal RGCs projecting to the caudal SC is greater in albino than pigmented rats (6.2% vs 2.65%). After the wave of naturally occurring cell death, at P14, when many of the neonatal errors have been eliminated, the ratio of temporal to nasal RGC's is reduced to 1.71% for albinos versus 1.53% for pigmented rats.


Lymphoplasmacyte-rich meningioma: a case report with histological and immunohistochemical studies.
This report concerns a 64-year-old woman with a lymphoplasmacyte-rich meningioma. Radiographically and macroscopically, the tumor had the appearance of an ordinary meningioma. Components of the meningothelial cells were positively immunostained for epithelial membrane antigen. The results of immunohistochemical assays with the antibodies to surface markers of lymphocytes L26 and UCHL-1 indicated that the lymphoplasmacellular proliferation was not neoplastic but probably represented an immune reaction of the host.


Heregulin-beta1 promotes metastasis of breast cancer cell line SKBR3 through upregulation of Snail and induction of epithelial-mesenchymal transition.
HRG-beta1 stimulation of breast cancer cell line SKBR3 resulted in not only increased cell migration and invasion, upregulation of some mesenchymal markers, and downregulation of epithelial marker, but also upregulation of transcription factor Snail and its nuclear translocation. Similar results were acquired for cells transfected with Snail cDNA. Furthermore, downregulation of Snail by siRNA attenuated HRG-beta1 induced EMT-like phenotype. Inhibition of Akt kinase activation by a PI3K inhibitor LY294002, or exogenous expression of a kinase-dead mutant of Akt abrogated the increase of Snail expression induced by HRG-beta1. Conversely, expression of a constitutively active Akt resulted in increase of Snail expression. These results indicated that Snail upregulation by HRG-beta1 is mediated via the PI3K/Akt signaling pathway and that Snail plays a key role in HRG-beta1 induced breast cancer cell metastasis through induction of EMT.


Structure of a novel thrombin inhibitor with an uncharged D-amino acid as P1 residue.
Thrombin, the ultimate proteinase of the coagulation cascade, is an attractive target for the treatment of a variety of cardiovascular diseases. Previously, a series of novel thrombin inhibitors, discovered by employing a powerful and new computer-assisted multiparameter optimization process (CADDIS), have been synthesized. We have now crystallized the complex of human alpha-thrombin with the most potent of these inhibitors, 8-5 (K(i)=3 nM), and have determined its 2.3A X-ray crystal structure. The Fourier map displayed clear electron density for the inhibitor. The central part of the inhibitor binds in an improved melagatran-like mode, while the structure identifies a d-tyrosine as P1 residue which forms a charged hydrogen bond with Asp 189 of thrombin. This is the first crystal structure of a thrombin-inhibitor complex, where an uncharged inhibitor residue makes hydrogen bonds within the thrombin S1 pocket. Additionally, novel favourable intermolecular hydrogen bonds of the inhibitor with the thrombin backbone become possible due to the d-configuration of the P1 residue. Two flanking voluminous side chains increase the strength of the subjacent hydrogen bonding system by shielding it from the bulk solvent.


Antibiofilm activity of cell-free supernatants of vaginal isolates of Corynebacterium amycolatum against Pseudomonas aeruginosa and Klebsiella pneumoniae.
Biofilm formation is an important factor in the development of antibiotic resistance and chronic infection. In this study, we demonstrated that the cell-free supernatant of vaginal isolates of C. amycolatum caused a reduction in biofilm formation, destroyed the preformed biofilms, altered the cell surface properties and reduced the production of exopolysaccharides in clinical isolates of P. aeruginosa и Kl. pneumoniae. Microscopic observations showed that P. aeruginosa and Kl. pneumoniae biofilm formed small clusters scattered over the surface after treatment with cell-free supernatant of C. amycolatum ICIS 99, in contrast to the dense aggregates observed in controls, as well as the flat, scattered, and unstructured biofilm architecture after treatment of preformed biofilms cell-free supernatant. The cells were flat and relatively unstructured. Based on these results, we hypothesize that C. amycolatum likely produces secondary metabolites with antimicrobial activity and utilizes a similar mechanism of action to bacteriocins and/or biosurfactants. The data obtained open the prospect of studying the metabolic profile of the cell-free supernatant of C. amycolatum to understand the nature and mechanism of the detected antibacterial action and provide further support for the probiotic potential of C. amycolatum vaginal isolates.


Financial effects for families after the death of a disabled or chronically ill child: a neglected dimension of bereavement.
To investigate the financial circumstances of families whose child had died after a long-term illness and the factors contributing to financial difficulties. Qualitative exploration involved semi-structured interviews with a purposive sample of 16 families whose child had died in the last 2 years and who were in touch with a children's hospice. All parents were affected by loss of or reduction in social security benefits. This could result in an immediate drop in income of as much as 72%. Paying for funerals and headstones could be hard. Financial problems after the child's death often had origins in the period of care, when parents had reduced incomes but faced extra costs of care. Some families had got into debt. Re-engaging with employment could be a slow process, and it was not clear where professional responsibility lay in providing financial advice and support. Insensitive treatment by administrative agencies increased problems for parents. Findings provide further evidence of the financial impact for families of caring for severely disabled children. This study shows how this impact can extend far into the period after death. Findings indicate the need for financial advice and support to families both during the period of care and after bereavement.