Treatment of obesity with thermogenic beta-adrenoceptor agonists: studies on BRL 26830A in rodents.
Studies on BRL 26830A in rodents have shown that thermogenic beta-adrenoceptor agonists have potential for the therapy of obesity. BRL 26830A reduced body weight gain in ob/ob mice and fa/fa rats by reducing lipid accumulation. It had no effect on lean body mass. BRL 26830A did not reduce food intake, its anti-obesity effect being due to stimulation of energy expenditure. This thermic effect was enhanced in the obese animals by repeat dosing. BRL 26830A did not affect body weight gain in the lean counterparts of the obese animals because its thermic effect in lean animals was reduced by repeat dosing. Brown adipose tissue is an important site of BRL 26830A-induced thermogenesis. A single dose of BRL 26830A raised brown adipose tissue temperature, depleted brown adipose tissue lipid and unmasked GDP-binding sites in brown adipose tissue mitochondria. Repeat dosing caused hypertrophy of brown adipose tissue and improved cold tolerance in mice. In-vitro studies showed that the rat brown adipocyte beta-adrenoceptor does not fall into the beta 1/beta 2 classification and BRL 28410, which mediates the biological effects of BRL 26830A in vivo, selectively stimulated the brown adipocyte receptor. It is concluded that BRL 26830A achieves its anti-obesity effect by mimicking natural mechanisms involved in thermogenesis and the control of body weight.


Endotoxemia-enhanced renal vascular reactivity to endothelin-1 in cirrhotic rats.
Hepatorenal syndrome (HRS), a severe complication of advanced cirrhosis, is defined as hypoperfusion of kidneys resulting from intense renal vasoconstriction in response to generalized systemic arterial vasodilatation. Nevertheless, the mechanisms have been barely investigated. Cumulative studies demonstrated renal vasodilatation in portal hypertensive and compensated cirrhotic rats. Previously, we identified that blunted renal vascular reactivity of portal hypertensive rats was reversed after lipopolysaccharide (LPS). This study was therefore conducted to delineate the sequence of renal vascular alternation and underlying mechanisms in LPS-treated cirrhotic rats. Sprague-Dawley rats were randomly allocated to receive sham surgery (Sham) or common bile duct ligation (CBDL). LPS was induced on the 28th day after surgery. Kidney perfusion was performed at 0.5 or 3 h after LPS to evaluate renal vascular response to endothelin-1 (ET-1). Endotoxemia increased serum ET-1 levels ( P < 0.0001) and renal arterial blood flow ( P < 0.05) in both Sham and CBDL rats. CBDL rats showed enhanced renal vascular reactivity to ET-1 at 3 h after LPS ( P = 0.026). Pretreatment with endothelin receptor type A (ETA) antagonist abrogated the LPS-enhanced renal vascular response in CBDL rats ( P < 0.001). There were significantly lower inducible nitric oxide synthase (iNOS) expression but higher ETA and phosphorylated extracellular signal-regulated kinase (p-ERK) expressions in renal medulla of endotoxemic CBDL rats ( P < 0.05). We concluded that LPS-induced renal iNOS inhibition, ETA upregulation, and subsequent ERK signaling activation may participate in renal vascular hyperreactivity in cirrhosis. ET-1-targeted therapy may be feasible in the control of HRS. NEW & NOTEWORTHY Hepatorenal syndrome (HRS) occurred in advanced cirrhosis after large-volume paracentesis or bacterial peritonitis. We demonstrated that intraperitoneal lipopolysaccharide (LPS) enhanced renal vascular reactivity to endothelin-1 (ET-1) in cirrhotic rats, accompanied by inducible nitric oxide synthase inhibition, endothelin receptor type A (ETA) upregulation, and subsequent extracellular signal-regulated kinase activation in renal medulla. Pretreatment with ETA antagonist abrogated the LPS-enhanced renal vascular response in common bile duct ligation rats. These findings suggest that further clinical investigation of ET-1-targeted therapy may be feasible in the control of HRS.


[Epstein-Barr virus cerebellitis in an 11-year-old girl].
The authors report an eleven year old girl who manifested predominantly an acute cerebellar syndrome secondary to infection by Epstein Barr Virus. This complication is unusual and males are predominantly affected. The diagnostic and common physiopathological hypothesis are discussed.


Induction of ASAP (MAP9) contributes to p53 stabilization in response to DNA damage.
p53 is a key tumor suppressor that controls DNA damage response and genomic integrity. In response to genotoxic stress, p53 is stabilized and activated, resulting in controlled activation of genes involved in cell cycle arrest, DNA repair and/or apoptosis. ASAP is a centrosome- and spindle-associated protein, the deregulation of which induces severe mitotic defects. We show here that following double-strand break DNA formation, ASAP directly interacts with and stabilizes p53 by enhancing its p300-mediated acetylation and blocking its MDM2-mediated ubiquitination and degradation, leading to an increase of p53 transcriptional activity. Upon DNA damage, ASAP is transiently accumulated before being degraded upon persistent damage. This work links the p53 response with the cytoskeleton and confirms that the DNA-damaging signaling pathway is coordinated by centrosomal proteins. We reveal the existence of a new pathway through which ASAP signals the DNA damage response by regulating the p300-MDM2-p53 loop. These results point out ASAP as a possible target for the design of drugs to sensitize radio-resistant tumors.


The ethics of medical tourism: from the United Kingdom to India seeking medical care.
Is the practice of UK patients traveling to India as medical tourists morally justified? This article addresses that question by examining three ethically relevant issues. First, the key factor motivating citizens of the United Kingdom to seek medical treatment in India is identified and analyzed. Second, the life prospects of the majority of the citizens of the two nations are compared to determine whether the United Kingdom is morally warranted in relying on India to meet the medical needs of its citizens. Third, as neoliberal reforms are justified on the grounds that they will help the indigent populations affected by them, the impact of medical tourism--a neoliberal initiative--on India's socially and economically marginalized groups is scrutinized.


Hodgkin's lymphoma in an adolescent with systemic lupus erythematosus.
An adolescent female with systemic lupus erythematosus (SLE) with diffuse proliferative lupus nephritis subsequently contracted Hodgkin's lymphoma, mixed cellularity type. Prior to the diagnosis of Hodgkin's lymphoma, hypogammaglobulinemia developed with IgG deficiency. The nephritis, which improved on steroid therapy, remitted entirely after nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP) therapy. The hypogammaglobulinemia also remitted after chemotherapy for Hodgkin's lymphoma. The literature concerning the association of SLE and Hodgkin's lymphoma is reviewed. The significance of this concurrence is discussed in regard to the possible pathophysiology and the clinical management.


Reproducibility and reliability of computed tomography volumetry in estimation of the right-lobe graft weight in adult-to-adult living donor liver transplantation: Cantlie's line vs portal vein territorialization.
In living-donor liver transplantation (LDLT), liver volume assessment is a mandatory step in determining donor appropriateness. This study aimed to compare reliability and reproducibility between two major methods to define virtual hepatectomy plane, based on Cantlie's line (CTV-Cantlie) and portal vein territorialization (CTV-PVT) for right-lobe graft weight estimation in LDLT. A total of 188 donors who underwent preoperative CT scans were included. The liver was divided into right and left lobes using CTV-Cantlie and CTV-PTV measurements by two readers. Intraclass correlation coefficient (ICC) was used to determine interreader variability of hepatic weight measured using each CTV method. Intraoperative graft weight (IOW) was used as reference standard of right-lobe graft weight. Pearson correlation test was performed to determine correlation coefficients between presumed graft weight by each CTV method and IOW. Intraclass correlation coefficients for total liver weight were roughly equivalent between the two CTV methods (CTV-Cantlie: 0.965 [95% CI, 0.954-0.974], CTV-PVT: 0.977 [0.970-0.983]). However, ICCs of right-and left-lobe weights between two readers were higher with CTV-PVT (0.997 and 0.850) than with CTV-Cantlie (0.829 and 0.668). The IOW was 716.0 ± 162.0 g. Correlation coefficients between presumed graft weight by CTV-Cantlie or CTV-PVT and IOW were 0.722 and 0.807, respectively (both P < .001). For estimation of the right-lobe graft weight in LDLT, CTV-PVT may provide higher reliability and reproducibility than CTV-Cantlie.


Novel Hump Measurement System With a 3D Camera for Early Diagnosis of Patients With Adolescent Idiopathic Scoliosis: A Study of Accuracy and Reliability.
Background Adolescent idiopathic scoliosis (AIS) is a potentially progressive deformity, and early detection is crucial for timely intervention. However, the methods and criteria justifying screening for pediatric scoliosis remain controversial. We have, therefore, independently developed a Digital Moiré (DM) as a tool for scoliosis screening. The purpose of this study was to assess the usefulness of DM for scoliosis screening. Methods From March 2016 to March 2017, 126 patients (18 boys, 108 girls, mean age: 13.2 ± 2.2 years) with AIS underwent radiographic imaging of their whole spine. We tested the accuracy and reliability of DM by categorizing the examination results as Class 0 (no abnormality), Class 1 (return visit in one year), and Class 2 (further examination needed) and determined the distribution of the population by Cobb angle. The intra/inter-rater reliability and receiver operating characteristic (ROC) analyses were used to categorize the patients with positive findings into Class 1 or 2. Results Regarding the population distribution per Cobb angle in each of the distributions, 11 patients (8.7%) were Class 0, of which nine and two patients had Cobb angle ≤ 10 ° and > 10 °, respectively. There were 20 (15.9% ) Class 1 cases, of which 17 and three had Cobb angle ≤ 10 ° and > 10 °, respectively. Of the 95 (75.4%) Class 2 cases, five and 90 had a Cobb angle of ≤ 10 ° and > 10 °, respectively. The receiver operating characteristic (ROC) analysis of patients with positive findings showed that the area under the curve (AUC), sensitivity, specificity, and false-positive rate were 0.76, 0.98, 0.53, and 0.47, respectively, when predicting Cobb angle > 10°. Intra-rater and inter-rater reliability were 0.73 and 0.70, respectively. Conclusions This study demonstrated the usefulness of DM for determining whether a child with AIS requires a follow-up observation such as radiograph. Our findings suggest that the novel DM shows high accuracy and reliability for scoliosis screening.


Conversion of a metastable superhydrophobic surface to an ultraphobic surface.
Superhydrophobic surfaces in Wenzel and metastable wetting state were prepared and the conversion of such surfaces to ultraphobic surfaces was reported by the application of a fine-scale roughness. Silicon nitride substrates with hexagonally arranged pillars were prepared by micromachining. The two-scale roughness was achieved by coating these substrates with 60 nm silica nanoparticles. The surface was made hydrophobic by silanization with octadecytrichlorosilane (OTS). Wettability studies of the silicon nitride flat surface, silicon nitride pillars, and the surfaces with two-scale roughness showed that a two-scale roughness can effectively improve the hydrophobicity of surfaces with a higher apparent contact angle and reduced contact angle hysteresis when the original rough surface was in a metastable or Wenzel state. This study shows the pathway of converting a metastable hydrophobic surface to an ultraphobic surface by the introduction of a fine-scale roughness, which adds to the literature a new aspect of fine-scale roughness effect.


A clinical study on familial heart diseases.
Clinical pictures of 107 cases of familial heart diseases belonging to 30 families were studied. 1. Initial manifestations frequently observed were palpitation, chest pain, becoming aware of irregular heart beats, dyspnea and a syncopal attack. The initial manifestation was most frequently observed in the second or the third decade. In familial idiopathic cardiomyopathy a systolic murmur was the most common auscultatory findingd followed by the third and fourth heart sounds. 2. The cardiothoracic ratio was not necessarily increased. 3. In the ECG of familial idiopathic cardiomyopathy, arrythmia was frequently observed. A-V block was rare but a premature ventricular contraction was frequent. During a syncopal attack, the ECG showed ventricular trachycardia. An abnormal Q-wave, ST segment depression and a negative T-wave were also observed but their incidence did not differ from one lead to the other. Some cases of familial heart diseases showed QTc-prolongation but QTc was not over 0.47 seconds and was not as markedly prolonged as in familial QT-prolongation syndrome. 4. A similarity of clinical findings was observed among cases belonging to the same family. There was a striking similarity among the patients belonging to the same family in initial symptoms, characters of a systolic murmur, morphology of the cardiac silhouette, morphology of an abnormal Q-wave or ST segment depression and in the leads which showed these abnormalities. 5. The most frequent mode of death was sudden death. A cardiothoracic ratio of 0.6 or more, an abnormal R-wave in V1 suggesting high dorsal wall damage, left axis deviation, and the low voltage of Sv1 + Rv5 of 1.5 mV or less suggested a poor prognosis.


Histone Methyltransferase G9a Drives Chemotherapy Resistance by Regulating the Glutamate-Cysteine Ligase Catalytic Subunit in Head and Neck Squamous Cell Carcinoma.
Transient chemotherapeutic response is a major obstacle to treating head and neck squamous cell carcinomas (HNSCC). Histone methyltransferase G9a has recently been shown to be abundantly expressed in HNSCC, and is required to maintain the malignant phenotype. In this study, we found that high G9a expression is significantly associated with poor chemotherapeutic response and disease-free survival in HNSCC patients. Similarly, G9a expression and enzymatic activity were elevated in cisplatin-resistant HNSCC cells. Genetic or pharmacologic inhibition of G9a sensitized the resistant cells to cisplatin, increasing cellular apoptosis. Mechanistic investigations indicated that G9a contributes to transcriptional activation of the glutamate-cysteine ligase catalytic subunit (GCLC), which results in upregulation of cellular glutathione (GSH) and drug resistance. In addition, we observed a significant positive correlation between G9a and GCLC expression in tumors of HNSCC patients. Taken together, our findings provide evidence that G9a protects HNSCC cells against chemotherapy by increasing the synthesis of GSH, and imply G9a as a promising target for overcoming cisplatin resistance in HNSCC. Mol Cancer Ther; 16(7); 1421-34. ©2017 AACR.


Operational performance of the NIJI-III superconducting storage ring.
The operational performance of the NIJI-III superconducting storage ring has been studied with particular attention focused on the vacuum performance of the cold-bore chamber. Photon-stimulated gas desorption in the cold-bore chamber was examined after commissioning the storage ring. It was confirmed that the photon-stimulated gas desorption due to diffuse reflection of synchrotron radiation at the absorber was not dominant in the gas desorption when the electron beam was accumulated in the storage ring.


[Histiocytic sarcoma:a clinicopathologic study of 4 cases].
To investigate the clinicopathologic features, immunophenotyping, differential diagnoses and prognosis of histiocytic sarcoma (HS). The clinical and pathologic findings of 4 cases of HS were reviewed. The samples were used for paraffin section, HE stain, immunohistochemistry stain by EnVision method, electron microscope observation. Follow-up information was available in all patients. The age of patients, 2 males and 2 females, ranged from 22 to 65 years old (median, 43.25 years). The sites of involvement included lymph node (2 cases), skin or soft tissue (1 case) and colon (1 case). The tumor cells were widespread infiltration, diffused distribution, no adhesion to each other. Tumor cells were middling and large, round, orbicular-ovate, polygon, epithelium appearance, plentiful cytoplasm and acidophilia, cystose. Nucelus was round, orbicular-ovate, dissymmetry. Nuclear chromatin was vacuole appearance, basophilia nucleolus, caryocinesia and pathological mitotic figure. Three of the cases showed conjugate nuclei, increased pleomorphism with multinucleated tumor giant cell formation. Focal cytoplasmic with foamy appearance was identified in 2 cases. One case demonstrated foci of spindly sarcomatoid appearance. Hemophagocytosis was identified in 2 cases. The tumor cells of 4 cases were often accompanied by various numbers of inflammatory cells. Immunohistochemical study showed that all cases were diffusely positive for α-1-ACT, CD68, CDl63 and lysozyme. Three of 4 cases also expressed CD45, CD45RO. The electron microscope results of 4 cases showed that the tumor cells were plentiful cytoplasm and a few cytolysosome in the cytoplasm, and no birbeck cytorrhyctes, cell-cell junction and digitation. Amongst the 4 patients with follow-up information available, three died of the disease 6-13 months after diagnosis. One patient, whose lesion was localized at the skin and soft tissue, survived at the present time. HS was a scarce malignant tumor with mature histiocyte morphology and immunophenotype character. The diagnosis should be based on tissue morphology, immunohistochemistry and electron microscope observation to exclude other disorders.


The composition of dietary fat directly influences glucose-stimulated insulin secretion in rats.
Acute elevations of plasma free fatty acid (FFA) levels augment glucose-stimulated insulin secretion (GSIS). Prolonged elevations of FFA levels reportedly impair GSIS, but no one has previously compared GSIS after prolonged exposure to saturated or unsaturated fat. Rats received a low-fat diet (Low-Fat) or one enriched with either saturated (Lard) or unsaturated fat (Soy) for 4 weeks. Insulin responses during hyperglycemic clamps were augmented by saturated but not unsaturated fat (580 +/- 25, 325 +/- 30, and 380 +/- 50 pmol x l(-1) x min(-1) in Lard, Soy, and Low-Fat groups, respectively). Despite hyperinsulinemia, the amount of glucose infused was lower in the Lard compared with the Low-Fat group. Separate studies measured GSIS from the perfused pancreas. Without fatty acids in the perfusate, insulin output in the Lard group (135 +/- 22 ng/30 min) matched that of Low-Fat rats (115 +/- 13 ng/30 min), but exceeded that of Soy rats (80 +/- 7 ng/30 min). When FFAs in the perfusate mimicked the quantity and composition of plasma FFAs in intact animals, in vivo insulin secretory patterns were restored. Because the GSIS of rats consuming Lard diets consistently exceeded that of the Soy group, we also assessed responses after 48-h infusions of lard or soy oil. Again, lard oil exhibited greater insulinotropic potency. These data indicate that prolonged exposure to saturated fat enhances GSIS (but this does not entirely compensate for insulin resistance), whereas unsaturated fat, given in the diet or by infusion, impairs GSIS. Inferences regarding the impact of fatty acids on GSIS that are based on models using unsaturated fat may not reflect the effects of saturated fat.


Cancer risk perception and physician communication behaviors on cervical cancer and colorectal cancer screening.
Women 50-65 years of age have the lowest cervical and colorectal cancer (CRC) screening rates among ages recommended for screening. The primary aim of this work is to determine how cancer risk perceptions and provider communication behaviors, in addition to known demographic factors, influence the uptake of both cervical and CRC screening or a single screen among women in southeast Michigan. Fourteen health services and communication behavior questions were adapted from the Health Information National Trends Survey (HINTS) and administered to a multiethnic sample of adults in southeast Michigan. The outcome variable was self-reported up-to-date cervical cancer and/or CRC screening as defined by the United States Preventive Services Task Force (USPSTF). Demographic and cancer risk/communication behavior responses of the four screening populations (both tests, one test, no tests) were analyzed with multinomial regression for all comparisons. Of the 394 respondents, 54% were up to date for both cervical and CRC screening, 21% were up to date with only cervical cancer screening and 12% were up to date for only CRC screening. Of the 14 risk perception and communication behavior questions, only 'Did your primary care physician (PCP) involve you in the decisions about your health care as much as you wanted?' was significantly associated with women having both screens compared to only cervical cancer screening (aOR 1.67; 95% CI: 1.08, 2.57). The multivariate model showed age, and Middle East and North African (MENA) ethnicity and Black race, in addition to PCP-patient dyad decision-making to be associated with the cancer screenings women completed. Optimizing PCP-patient decision-making in health care may increase opportunities for both cervical cancer and CRC screening either in the office or by self-sampling. Understanding the effects of age and the different interventional strategies needed for MENA women compared to Black women will inform future intervention trials aimed to increase both cancer screenings. This work was supported by NIH through the Michigan Institute for Clinical and Health Research UL1TR002240 and by NCI through The University of Michigan Rogel Cancer Center P30CA046592-29-S4 grants.


Influence of socioprofessional conditions on blood pressure levels and hypertension control. Epidemiologic study of 6,665 subjects in the Paris district.
A total of 6,665 subjects (3,896 men and 2,769 women) employed by small and medium-sized companies in the Paris region were examined. Mean systolic blood pressure (SBP) was significantly higher in the lowest than in the highest occupational categories (p less than 0.001), even when results were adjusted for age (p less than 0.001) and body mass index (p less than 0.001). Diastolic blood pressure (DBP) differed among the occupational categories (p less than 0.001); the differences were still significant after adjustment for age but not for body mass index, suggesting that the latter might be partly responsible for the differences in DBP. Prevalence of hypertension was 14.7% and was negatively associated with a high occupational category (p less than 0.001). Multivariate analysis confirmed the influence of occupational category on SBP (p less than 0.001). Exposure to noise at work and assembly line work were associated with high SBP (p less than 0.01 for both). Of the subjects with detected hypertension, 65.6% were aware of their illness, and 35.3% were undergoing treatment. Both the percentage of treated patients and compliance with treatment were positively associated with occupational category (p less than 0.01 in both cases). Among women, SBP of treated hypertensives was higher in the lowest than in the highest occupational categories (p less than 0.05). It is suggested that the differences in blood pressure levels observed among occupational categories are partly due to working conditions, and that poor compliance with treatment among the low occupational categories enhances these differences.


MicroRNA-326 suppresses the proliferation, migration and invasion of cervical cancer cells by targeting ELK1.
Although microRNAs (miRNAs or miRs) are able to function as oncogenes or tumor suppressors, the role of miR-326 in regulating human cervical cancer cells remains unclear. In the present study, the expression of miR-326 was identified to be downregulated in cervical cancer cell lines and primary tumor samples, and the overexpression of miR-326 decreased cell proliferation, migration and invasion in cervical cell lines. Bioinformatics prediction and experimental validation results revealed that the function of miR-326 was achieved by targeting and repressing ETS domain-containing protein Elk-1 (ELK1) expression. ELK1 was targeted directly by miR-326, which was downregulated in human cervical cancer tissues compared with that in adjacent normal tissues. The results of the present study suggest that miR-326, a potential tumor suppressor, may be used in the treatment of cervical cancer.


Hsa-miR-155-5p drives aneuploidy at early stages of cellular transformation.
Hsa-miR-155-5p (miR-155) is overexpressed in most solid and hematological malignancies. It promotes loss of genomic integrity in cancer cells by targeting genes involved in microsatellite instability and DNA repair; however, the link between miR-155 and aneuploidy has been scarcely investigated. Here we describe a novel mechanism by which miR-155 causes chromosomal instability. Using osteosarcoma cells (U2OS) and normal human dermal fibroblast (HDF), two well-established models for the study of chromosome congression, we demonstrate that miR-155 targets the spindle checkpoint proteins BUB1, CENP-F, and ZW10, thus compromising chromosome alignment at the metaphase plate. In U2OS cells, exogenous miR-155 expression reduced the recruitment of BUB1, CENP-F, and ZW10 to the kinetochores which resulted in defective chromosome congression. In contrast, during in vitro transformation of HDF by enforced expression of SV40 Large T antigen and human telomerase (HDFLT/hTERT), inhibition of miR-155 reduced chromosome congression errors and aneuploidy at early passages. Using live-cell imaging we observed that miR-155 delays progression through mitosis, indicating an activated mitotic spindle checkpoint, which likely fails to reduce aneuploidy. Overall, this study provides insight into a mechanism that generates aneuploidy at early stages of cellular transformation, pointing to a role for miR-155 in chromosomal instability at tumor onset.


The relationship between the plasma concentration of bepridil and its efficacy in the treatment of atrial fibrillation in Japanese patients.
Bepridil hydrochloride is used for treatment of atrial fibrillation (AF) in Japan. We investigated the relationship between plasma concentrations of bepridil just before dosing (Cbep) and its clinical efficacy in Japanese patients (n=36) with AF. Patients were treated orally with 100, 150 or 200 mg/d bepridil. Cbep were measured with UV-HPLC. In the first 14 d, when 150, 200, 250 or 300 ng/mL was set as a boundary value, the efficacy of bepridil was significantly higher in all patients with Cbep above than below the boundary value (p<0.05). In the maintenance stage (3 months longer after starting therapy), the efficacy of bepridil was significantly higher in patients with Cbep above than below 300 ng/mL (p=0.04). The clinical efficacy of bepridil was closely related to Cbep. The target value of Cbep to obtain a clinical benefit was approximately 300 ng/mL. Monitoring Cbep should be useful in the treatment of patients with AF.


Synthesis and characterisation of poly(lactide-co-glycolide) nanospheres using vitamin E emulsifier prepared through one-step oil-in-water emulsion and solvent evaporation techniques.
Nanoparticulate drug delivery systems are of considerable therapeutic interest for delivery of drugs across from the blood-brain barrier. In this study, the ability of sodium chloride (NaCl) and different percentages of a water-soluble form of natural vitamin E, on the formation of poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs), as a potential carrier for drug delivery, was investigated. According to the obtained results, by increasing the percentage of natural vitamin E, the average particle size decreased and the range of diameters came closer. After using 0.26 w/v % vitamin E, the average size of the PLGA particles became <100 nm. Moreover, the particles containing NaCl led to the formation of even smaller particles. In addition, no obvious cytotoxicity was observed at various natural vitamin E amounts in one and three days, and the modified PLGA NPs could be considered biocompatible since they showed a little decrease in cellular viability.


Should all embryos be cultured to blastocyst for advanced maternal age women with low ovarian reserve: a single center retrospective study.
The purpose of this study is to determine whether all-blastocyst-culture can benefit advanced maternal age (AMA) patients with low ovarian reserve. We retrospectively analyze AMA patients with low ovarian reserve undergoing IVF/ICSI in Reproductive Medicine Research Center of the Sixth Affiliated Hospital of Sun Yat-sen University from May 2016 to August 2017. We divide them into group A (all-blastocyst-culture) and group B (none-blastocystculture) based on different culture approach of D3 transferrable embryo. We compared the cumulative biochemical pregnancy rate and cumulative clinical pregnancy rate between them. A total of 261 eligible patients are included, with 151 in group A and 110 in group B. The basic conditions of the two groups show no difference. Cumulative biochemical pregnancy rate/clinical pregnancy rate in group A is higher than that of group B, though not statistically significant (p > .05). After removing patients canceling embryo transfer due to failure in blastocyst culture, the cumulative biochemical pregnancy rate/clinical pregnancy rate in group A is significantly higher than group B (p < .05). Multivariate analysis showed that female age and the number of D3 transferrable embryo are risk factors for the failure of blastocyst culture (OR = 0.672 and 2.270, 95%CI 0.511-0.883 and 1.203-4.284, p = .004 and p = .011, respectively). Hence, we drew to conclusion that all-blastocyst-culture will not adversely affect the pregnancy outcome of AMA patients with low ovarian reserve.


A time correlation function theory describing static field enhanced third order optical effects at interfaces.
Sum vibrational frequency spectroscopy, a second order optical process, is interface specific in the dipole approximation. At charged interfaces, there exists a static field, and as a direct consequence, the experimentally detected signal is a combination of enhanced second and static field induced third order contributions. There is significant evidence in the literature of the importance/relative magnitude of this third order contribution, but no previous molecularly detailed approach existed to separately calculate the second and third order contributions. Thus, for the first time, a molecularly detailed time correlation function theory is derived here that allows for the second and third order contributions to sum frequency vibrational spectra to be individually determined. Further, a practical, molecular dynamics based, implementation procedure for the derived correlation functions that describe the third order phenomenon is also presented. This approach includes a novel generalization of point atomic polarizability models to calculate the hyperpolarizability of a molecular system. The full system hyperpolarizability appears in the time correlation functions responsible for third order contributions in the presence of a static field.


Identification of C3b-Binding Small-Molecule Complement Inhibitors Using Cheminformatics.
The complement system is an elegantly regulated biochemical cascade formed by the collective molecular recognition properties and proteolytic activities of more than two dozen membrane-bound or serum proteins. Complement plays diverse roles in human physiology, such as acting as a sentry against invading microorganisms, priming of the adaptive immune response, and removal of immune complexes. However, dysregulation of complement can serve as a trigger for a wide range of human diseases, which include autoimmune, inflammatory, and degenerative conditions. Despite several potential advantages of modulating complement with small-molecule inhibitors, small-molecule drugs are highly underrepresented in the current complement-directed therapeutics pipeline. In this study, we have employed a cheminformatics drug discovery approach based on the extensive structural and functional knowledge available for the central proteolytic fragment of the cascade, C3b. Using parallel in silico screening methodologies, we identified 45 small molecules that putatively bind C3b near ligand-guided functional hot spots. Surface plasmon resonance experiments resulted in the validation of seven dose-dependent C3b-binding compounds. Competition-based biochemical assays demonstrated the ability of several C3b-binding compounds to interfere with binding of the original C3b ligand that guided their discovery. In vitro assays of complement function identified a single complement inhibitory compound, termed cmp-5, and mechanistic studies of the cmp-5 inhibitory mode revealed it acts at the level of C5 activation. This study has led to the identification of a promising new class of C3b-binding small-molecule complement inhibitors and, to our knowledge, provides the first demonstration of cheminformatics-based, complement-directed drug discovery.


Effectiveness of the Use of Near-Infrared Spectroscopy to Treat Acute Type A Aortic Dissection Complicated with Limb Ischemia: Report of a Case.
We report an effectiveness of the use of near-infrared spectroscopy to evaluate the limb perfusion, which helps to continuously measure the tissue oxygen index of bilateral legs in treating acute type A aortic dissection complicated with limb ischemia. A 62-year-old man underwent total arch replacement for acute type A aortic dissection with limb ischemia. Intraoperative retrograde true lumen perfusion via bilateral femoral arteries during cardiopulmonary bypass improved ischemic condition of bilateral legs before the resection of primary intimal tear, and the use of near-infrared spectroscopy made it possible to assess additional revascularizations to the lower limbs were required or not.


Subcapsular sinus macrophage fragmentation and CD169+ bleb acquisition by closely associated IL-17-committed innate-like lymphocytes.
Subcapsular sinus macrophages (SSMs) in lymph nodes are rapidly exposed to antigens arriving in afferent lymph and have a role in their capture and display to B cells. In tissue sections SSMs exhibit long cellular processes and express high amounts of CD169. Here, we show that many of the cells present in lymph node cell suspensions that stain for CD169 are not macrophages but lymphocytes that have acquired SSM-derived membrane blebs. The CD169 bleb(+) lymphocytes are enriched for IL-17 committed IL-7Rα(hi)CCR6(+) T cells and NK cells. In addition, the CD169 staining detected on small numbers of CD11c(hi) dendritic cells is frequently associated with membrane blebs. Counter intuitively the CD169 bleb(+) lymphocytes are mostly CD4 and CD8 negative whereas many SSMs express CD4. In situ, many IL-7Rα(hi) cells are present at the subcapsular sinus and interfollicular regions and migrate in close association with CD169(+) macrophages. These findings suggest SSMs undergo fragmentation during tissue preparation and release blebs that are acquired by closely associated cells. They also suggest an intimate crosstalk between SSMs and IL-17 committed innate-like lymphocytes that may help provide early protection of the lymph node against lymph-borne invaders.


A trojan horse approach for silencing thymidylate synthase.
In this paper we present a new and possibly more effective way of inhibiting thymidylate synthase (TS) in cells than through the use of substrate analogue inhibitors. An inactive double mutant of TS (DM), Arg(126)Glu/Cys(146)Trp, is shown to progressively impair the reactivation of native Escherichia coli TS when the two are denatured together in vitro. The individual single mutant proteins Arg(126)Glu and Cys(146)Trp showed little or no inhibition. When the DM is introduced into E. coli and induced from an expression plasmid, the mutant subunits act as a decoy in deceiving newly formed native TS subunits to fold with them to yield inactive heterodimers. As a consequence of the depletion of TS, the cells die a "thymineless" death when grown in medium devoid of thymine. Addition of thymine to the medium enables the cells to grow normally, although only very low levels of TS activity could be detected in those cells containing induced DM. The individual single-site mutations of the DM, Arg(126)Glu and Cys(146)Trp, did not inhibit growth, as might be expected from the in vitro studies. However, when a nontoxic level of 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) is added to growing DM-transformed cells, the combination is lethal to the cells. These experiments suggest that a similar dominant-negative response to the DM of TS could be affected in tumor cells, for which preliminary evidence is presented. This technique, either alone or combined with other modalities, suggest a new approach to targeting cells for chemotherapy.


Bifurcation analysis of a discrete-time compartmental model for hypertensive or diabetic patients exposed to COVID-19.
In this article, a mathematical model for hypertensive or diabetic patients open to COVID-19 is considered along with a set of first-order nonlinear differential equations. Moreover, the method of piecewise arguments is used to discretize the continuous system. The mathematical system is said to reveal six equilibria, namely, extinction equilibrium, boundary equilibrium, quarantined-free equilibrium, exposure-free equilibrium, endemic equilibrium, and the equilibrium free from susceptible population. Local stability conditions are developed for our discrete-time mathematical system about each of its equilibrium point. The existence of period-doubling bifurcation and chaos is studied in the absence of isolated population. It is shown that our system will become unstable and experiences the chaos when the quarantined compartment is empty, which is true in biological meanings. The existence of Neimark-Sacker bifurcation is studied for the endemic equilibrium point. Moreover, it is shown numerically that our discrete-time mathematical system experiences the period-doubling bifurcation about its endemic equilibrium. To control the period-doubling bifurcation, Neimark-Sacker bifurcation, a generalized hybrid control methodology is used. Moreover, this model is analyzed along with generalized hybrid control in order to eliminate chaos and oscillation epidemiologically presenting the significance of quarantine in the COVID-19 environment.


Anticancer activity and phytochemical composition of wild Gundelia tournefortii.
Artichoke-like wild thistles are often used in Palestinian cuisine. One of the most commercially recognized species of these wild edible thistles is Gundelia tournefortii, a common plant in the Mediterranean region. G. tournefortii, or 'Akoob' in Arabic, remains uncultivated, harvested wild by local populations and considered highly valuable due to its reputed health benefits. The present study aimed to investigate the anticancer effects of G. tournefortii on the human colon carcinoma HCT-116 cell line. Methanol and hexane extracts were identified to exert considerable antitumor activity against the HCT-116 cancer cell line, while the aqueous extract was inactive. The phytochemical profiles of the methanol and hexane extracts were investigated using gas chromatography-mass spectrometry. A total of 6 of the 27 natural compounds identified, including sitosterol, stigmasterol, lupeol, gitoxigenin, α-amyrin and artemisinin, have been previously validated as being active against cancerous cells. Therefore, the presence of these phytochemicals in G. tournefortii is of importance in its role in preventing and treating cancer.


Development of galvanostatic Fourier transform electrochemical impedance spectroscopy.
Here, we report development of the galvanostatic Fourier transform electrochemical impedance spectroscopy (FTEIS), which monitors impedance of electrochemical reactions activated by current steps. We first derive relevant relations for potential change upon application of a step current, obtain impedances theoretically from the relations by simulation, and verify them with experimental results. The validity of the galvanostatic FTEIS technique is demonstrated by measuring impedances of a semiconductive silicon wafer using the conventional frequency response analysis (FRA), the potentiostatic FTEIS, and the galvanostatic FTEIS methods, and the results are in excellent agreement with each other. This work is significant in that the galvanostatic FTEIS would allow one to record impedance changes during charge/discharge cycles of secondary batteries and fuel cells as well as electrochemically irreversible systems which may produce noise level chronoamperometric currents by potentiostatic techniques.


[Anesthesia for a patient with polyarteritis nodosa who has a history of multiple drug allergies].
There has been little information about anesthesia for a patient with a history of multiple drug allergies. We gave anesthesia for a 32-year-old woman with polyarteritis nodosa and history of multiple drug allergies. She was scheduled to undergo bilateral tonsilectomy. We could not perform the preoperative screening of the drugs using a dermal test because of a high risk of anaphylactic shock. Anesthesia was induced with sevoflurane and nitrous oxide and maintained with sevoflurane, nitrous oxide, and fentanyl. The intra- and postoperative course was uneventful. It is important to inquire history of allergies adequately for preoperative recognition of allergens. General anesthesia with sevoflurane would be useful for a patient with history of multiple drug allergies.


Development and evaluation of a full-scale spray scrubber for ammonia recovery and production of nitrogen fertilizer at poultry facilities.
Significant ammonia emissions from animal facilities need to be controlled due to its negative impacts on human health and the environment. The use of acid spray scrubber is promising, as it simultaneously mitigates and recovers ammonia emission for fertilizer. Its low pressure drop contribution on axial fans makes it applicable on US farms. This study develops a full-scale acid spray scrubber to recover ammonia emissions from commercial poultry facilities and produce nitrogen fertilizer. The scrubber performance and economic feasibility were evaluated at a commercial poultry manure composting facility that released ammonia from exhaust fans with concentrations of 66-278 ppmv and total emission rate of 96,143 kg yr(-1). The scrubber consisted of 15 spray scrubber modules, each equipped with three full-cone nozzles that used dilute sulphuric acid as the medium. Each nozzle was operated at 0.59 MPa with a droplet size of 113 μm and liquid flow rate of 1.8 L min(-1). The scrubber was installed with a 1.3-m exhaust fan and field tested in four seasons. Results showed that the scrubber achieved high NH3 removal efficiencies (71-81%) and low pressure drop (<25 Pa). Estimated water and acid losses are 0.9 and 0.04 ml m(-3) air treated, respectively. Power consumption rate was between 89.48 and 107.48 kWh d(-1). The scrubber effluents containing 22-36% (m/v) ammonium sulphate are comparable to the commercial-grade nitrogen fertilizer. Preliminary economic analysis indicated that the break-even time is one year. This study demonstrates that acid spray scrubbers can economically and effectively recover NH3 from animal facilities for fertilizer.


Liver-derived CTL in hepatitis C virus infection: breadth and specificity of responses in a cohort of persons with chronic infection.
Hepatitis C virus (HCV)-specific CTL have been found within the inflammatory infiltrate of the liver of chronically infected individuals, but the breadth and specificity of the CTL response in relation to viral load are less well characterized. In this study, we analyzed the intrahepatic CTL response in liver biopsy specimens from 44 chronically infected subjects. Liver-infiltrating lymphocytes were expanded polyclonally in bulk cultures, and multiple clones were derived by limiting dilution. HCV-specific CTL responses directed at genotype 1a structural proteins were assessed in all subjects, and 22 subjects were tested more comprehensively using vectors expressing all structural and nonstructural HCV Ags. CTL responses were further characterized to determine the HLA restriction and optimal epitopes recognized. In those persons screened for recognition of all HCV Ags, HLA class I-restricted CTL were detected in 45%. Nineteen different CTL epitopes were identified, which were distributed throughout the genome; only one epitope was targeted by more than one person. In those persons with CTL responses, the breadth of response ranged from one to five epitopes. There was no correlation between the presence of a detectable CTL response and viral load. These results indicate considerable heterogeneity in detectable HCV-specific CTL responses in chronically infected persons. The mechanisms by which HCV persists during chronic infection remain to be clarified.


[Small-intestine tumor with ectopic pancreas tissue and acute pancreatitis].
Ectopic pancreas tissue is usually a rare and incidental finding during surgery. Reports of discovery during surgery vary between 0.17% and 0.83%. We report on an 86-year-old woman admitted to the surgical ward with abdominal pain. Due to suspicion of a perforated gastric ulcer, an exploratory laparatomy was performed. An 8 x 5 cm tumor was found in the ileum 10 cm from the ligament of Treitz. Microscopic examination revealed, surprisingly, pancreatic tissue in the submucosa of the ileum with inflammation and transmural perforation. There was no indication of malignancy.


The oxadiazolyldiazenido(1-) ligand: a remarkably versatile platform for the synthesis of heteropolynuclear transition metal complexes.
Cyclo-condensation of aroyl hydrazides with the cationic tungsten-dichlorodiazomethane complex [BrW(dppe)2(N2CCl2)]+ affords neutral oxadiazolyldiazenido(1-) complexes which react readily with a wide range of transition and non-transition metal species to afford a novel series of crystallographically-characterised heteropolynuclear complexes containing bridging oxadiazolyldiazenido(1-) ligands.


Regulation of IGF-I receptor signaling in diabetic cardiac muscle: dysregulation of cytosolic and mitochondria HSP60.
Insulin deficiency downregulates HSP60 and IGF-I receptor signaling and disrupts intracellular signaling homeostasis in diabetic cardiac muscle. Our previous studies had shown that IGF-I receptor signaling can be modulated by the abundance of HSP60. Since HSP60 localizes to the cytoplasmic compartment and mitochondria, this study was carried out to determine the distribution of cytosolic and mitochondria HSP60 in diabetic myocardium and to explore whether cytosolic HSP60 can modulate IGF-I receptor signaling in cardiac muscle cells. In streptozotocin-induced diabetes, both the cytosolic and mitochondrial fractions of HSP60 were decreased in the myocardium. Incubating primary cardiomyocytes with insulin leads to increased abundance of HSP60 in the cytosolic and mitochondria compartments. To determine whether cytosolic HSP60 can modulate IGF-I receptor signaling, we used rhodamine 6G to deplete functional mitochondria in cardiomyocytes. In the mitochondria-depleted cells, overexpression of HSP60 with adenoviral vector increased the abundance of IGF-I receptor, enhanced IGF-I-activated receptor phosphorylation, and augmented IGF-I activation of Akt and ERK. Thus overexpressing HSP60 in the cytosolic compartment enhanced IGF-I receptor signaling through upregulation of IGF-I receptor protein. However, IGF-I receptor signaling was significantly reduced in the mitochondria-depleted cells, which suggested that maintaining normal IGF-I receptor signaling in cardiomyocytes required functioning mitochondria. The effect of cytosolic HSP60 involved suppression of ubiquitin conjugation to IGF-I receptor in cardiomyocytes. These data suggest two different mechanisms that can regulate IGF-I signaling, one via cytosolic HSP60 suppression of IGF-I receptor ubiquitination and the other via mitochondria modulation. These findings provide new insight into the regulation of IGF-I signaling in diabetic cardiomyopathy.


C-cell adenoma containing variously sized thyroid follicles in a horse.
A thyroid gland tumor, showing unusual histology, was identified in a 13-year-old male Andalusian horse. Microscopically, the tumor consisted of neoplastic proliferation of C-cell (parafollicular cell) with cytoplasmic fine granules, containing diffusely distributed, variously sized colloid-containing follicles. Immunohistochemically, the neoplastic C-cell were positive for calcitonin and follicleforming epithelial cells showed a positive reaction for thyroglobulin. Ultrastructurally, membrane-bound secretory granules up to 250 nm in diameter were found in the cytoplasm of the parafollicular cells, whereas the follicular epithelial cells had microvilli, junctional complex, and well-developed endoplasmic reticulum.


[Safety evaluation of niuhuang jiedu tablet].
Realgar-containing Niuhuang Jiedu tablet (NHJD) has been applied in clinic for more than 800 years. However, because realgar contains arsenic (As), it has aroused wide concerns and controversies both at home and abroad. Currently, there are two misunderstandings about realgar-containing Chinese patent medicines. First, some people exaggerated realgar's toxicity as that of arsenic. Second, they recommended to remove realgar from traditional Chinese medicine compounds. In this paper, the authors summarized the advance in studies on NHJD, and proposed different opinions: (1) It is inappropriate to take total As as the index in safety evaluation of NHJD. (2) The toxicity of NHJD is dependent on the dose and duration of administration. (3) Realgar is an active ingredient of NHJD, and shall be deeply studied. Classic realgar-containing traditional Chinese medicine prescriptions, such as Niuhuang Jiedu tablet, shall be evaluated with rigorous modern scientific basis, with the aim to guide rational and safe application.


Fabrication and characterization of gold nanoflowers formed via chitosan-tripolyphosphate template films for biomedical applications.
Flowerlike gold nanostructure was facilely prepared by the seed-mediated growth of gold nanoparticles in chitosan-TPP template films. Firstly, chitosan nanoparticles, spontaneously formed by inter and/or intra cross-linking with TPP, were transformed into gel-type of chitosan-TPP films under strong sonication process. After then, gold seeds (1-3 nm) were entrapped in chitosan-TPP films via electrostatic interactions, and the resulting films were subsequently used as a template for growing gold nanoparticles and subsequent formation of anisotropic gold nanoflowers. The size and optical properties of gold nanoflowers were controlled simply by changing the ratio of gold salts to chitosan-TPP template films. Gold nanoflowers consisted of many aggregated nanodots exhibited broad Plasmon-derived absorption bands with strong red-shift into NIR wavelength, which might be a good prospect for SERS and biomedical applications.


Expression of adhesion proteins E-cadherin, alpha-catenin, beta-catenin and gamma-catenin is different in T1 and T2 breast tumours.
Breast cancer is the most common malignancy in women. Although an increasing number of patients with breast cancer are being cured by surgery, a considerable number of patients suffer relapse in the form of metastases after surgery. E-cadherin and catenins have documented roles in breast cancer progression. Mammography is supposed to decrease breast cancer mortality by detecting tumours while they are small and before they have reached a clinically detectable stage. In the present study, we wanted to evaluate whether there are differences in expression patterns of adhesion proteins, shown to be crucial in the metastatic process, between small tumours detected by mammography and clinically detected large tumours. Expression of E-cadherin, alpha-catenin, beta-catenin and gamma-catenin was analysed using immunohistochemistry methods in 86 invasive breast carcinomas detected by mammography and compared with 90 clinically palpable invasive breast carcinomas. In the group of tumours detected by mammography (86 samples), reduced expression of E-cadherin was observed in 12 (14%) samples. Reduced expression of alpha-catenin was observed in four (4.6%) samples, and three (3.5%) samples showed reduced expression of beta-catenin. All samples showed strong expression of gamma-catenin. When expression patterns of these proteins were evaluated in 90 clinically detected tumours, we observed reduced expression of E-cadherin in 58 (64.4%) samples, 12 (13.3%) samples showed reduced expression of alpha-catenin, while nine (10%) samples showed reduced expression of beta-catenin. Strong expression of gamma-catenin was detected in all tumours also in this group.Statistical analyses revealed a highly significant difference in expression of E-cadherin (p<0.001). However, no statistically significant differences were observed in expression of alpha-catenin (p = 0.081) and beta-catenin (p = 0.092) between the two groups of tumours. Results indicate that T1 breast tumours harbour less alterations in E-cadherin-catenin complexes and therefore are probably less likely to disseminate, and patients probably have a better prognosis than if tumours are diagnosed as T2.


Insulin-like growth factor (IGF)-I and IGF binding protein-3 concentrations in fluid from human stimulated follicles.
Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) play an important role in regulating follicle growth and maturation. We have evaluated whether responsiveness to gonadotrophins during an in-vitro fertilization (IVF) treatment is related to follicular fluid IGF-I and IGFBP-3 concentrations. We also investigated if a difference is present in IGF-I and IGFBP-3 concentrations between patients treated with human menopausal gonadotrophin (HMG) and patients treated with highly purified follicle stimulating hormone (FSH). We have measured IGF-I and IGFBP-3 in follicular fluid from pre-ovulatory follicles in an IVF programme. All 70 patients were stimulated after being down-regulated with a gonadotrophin-releasing hormone (GnRH) analogue. IGF-I concentrations in follicular fluid were significantly inversely correlated with the number of ampoules FSH administered and number of days of FSH administration, and significantly correlated with the number of follicles aspirated. IGFBP-3 concentrations were not correlated with any other parameter measured nor were IGF-I and IGFBP-3 concentrations correlated. IGFBP-3 concentrations were significantly higher in patients receiving highly purified FSH compared with patients receiving HMG (P < 0.005). These results are new evidence that IGF-I concentration in follicular fluid is higher in women who respond better to follicular stimulation, i.e. women who grow many follicles, women who need a shorter duration of stimulation and women who need fewer ampoules FSH before oocyte retrieval.


Candida glabrata Biofilms: How Far Have We Come?
Infections caused by Candida species have been increasing in the last decades and can result in local or systemic infections, with high morbidity and mortality. After Candida albicans, Candida glabrata is one of the most prevalent pathogenic fungi in humans. In addition to the high antifungal drugs resistance and inability to form hyphae or secret hydrolases, C. glabrata retain many virulence factors that contribute to its extreme aggressiveness and result in a low therapeutic response and serious recurrent candidiasis, particularly biofilm formation ability. For their extraordinary organization, especially regarding the complex structure of the matrix, biofilms are very resistant to antifungal treatments. Thus, new approaches to the treatment of C. glabrata's biofilms are emerging. In this article, the knowledge available on C. glabrata's resistance will be highlighted, with a special focus on biofilms, as well as new therapeutic alternatives to control them.


Orangutan behavior in Kutai National Park after drought and fire damage: Adjustments to short- and long-term natural forest regeneration.
This study aimed to develop a long-term picture of orangutan (Pongo pygmaeus morio) behavioral adjustments to damaged masting forest around Mentoko, Kutai National Park, Indonesia. Mentoko is regenerating from two severe burnings and is one of few areas where orangutans were well-studied before and early after damage. We studied orangutans' feeding ecology, diet, and activity budgets 12-15 years after the second burning then compared our findings with earlier pre- and post-damage ones to assess the changes and factors involved. By our study, we predicted (1) improved feeding ecology compared to early in regeneration, (2) behavior diverging from the normal foraging strategy and (3) behavior shifting toward pre-damage patterns with improving feeding ecology. Data were behavioral observations on 42 orangutans (422 full day follows, 3,522 hr) and tree plot measures of feeding ecology. Findings were consistent with the first and third predictions but not the second: (1) feeding ecology had improved (plant food abundance was near per-damage levels, but species composition had changed); (2) foraging strategies showed no divergence from normal (fallback-preferred food switches in diet and activity budget adjustments were both normal, notably travel did not reduce), (3) diet and activity budgets had reverted to near pre-damage values by our study. Differently than post-damage studies on other orangutans but consistent with those on other primates, our comparisons showed behavioral adjustments were flexible, multiple vs. single, and influenced by multiple factors. Factors likely involved at Mentoko include type and spatial configuration of damage, duration of regeneration, and P. p. morio's recognized resilience. Findings have value for orangutan and nature conservation in showing that recovery to near-normal levels from severe habitat damage is possible within ca 15 years and in adding to understanding of the factors and processes that contribute to recovery.


Antidepressant administration modulates stress-induced DNA methylation and DNA methyltransferase expression in rat prefrontal cortex and hippocampus.
Stress and antidepressant treatment can modulate DNA methylation in promoter region of genes related to neuroplasticity and mood regulation, thus implicating this epigenetic mechanism in depression neurobiology and treatment. Accordingly, systemic administration of DNA methyltransferase (DNMT) inhibitors induces antidepressant-like effects in rodents. DNA methylation is conveyed by DNMT 1, 3a and 3b isoforms, which are differentially expressed in the brain. In order to investigate if the behavioral effects of antidepressants could be associated with changes in DNA methylation and DNMT expression, we investigated the effects induced by acute and repeated antidepressant treatment on DNA methylation and DNMT expression (1, 3a and 3b isoforms) in different brain regions of rats exposed to a stress model of depression, the learned helplessness (LH). Therefore, rats were exposed to pretest and treated with one or seven injections of vehicle or imipramine (15 mg kg-1), with test session performed one hour after the last injection. Chronic, but not acute, imipramine administration attenuated escape failures during the test, a well described antidepressant-like effect in this model. DNA methylation and DNMT (1, 3a and 3b) levels were measured in the dorsal and ventral hippocampus (dHPC, vHPC) and in the prefrontal cortex (PFC) of rats exposed to stress and treatment. Stress increased DNA methylation, DNMT3a and DNMT3b expression in the dHPC and PFC. Chronic, but not acute, imipramine administration attenuated stress effects only in the PFC. These results suggest the regulation of DNA methylation in the PFC may be an important mechanism for antidepressant-like effects in the LH model.


Dipole driven bonding schemes of quinonoid zwitterions on surfaces.
The permanent dipole of quinonoid zwitterions changes significantly when the molecules adsorb on Ag(111) and Cu(111) surfaces. STM reveals that sub-monolayers of adsorbed molecules can exhibit parallel dipole alignment on Ag(111), in strong contrast with the antiparallel ordering prevailing in the crystalline state and retrieved on Cu(111) surfaces, which minimizes the dipoles electrostatic interaction energy. DFT shows that the rearrangement of electron density upon adsorption is a result of donation from the molecular HOMO to the surface, and back donation to the LUMO with a concomitant charge transfer that effectively reduces the overall charge dipole.


New Therapeutic Approach to Treat Allergic Rhinitis & Bronchial Asthma, Considering These Two as One United Airway Disease.
The relationship between allergic rhinitis and asthma is now established, and most of the clinical, epidemiological and biological data recommend integrated management. This review discusses rhinosinusitis as a co-morbid condition, a precipitating or triggering condition, and an epiphenomenon as an integrated part of the disease. A better understanding and a more pragmatic method of diagnosis and management is needed using cost-effective long-term strategies. Allergic Rhinitis, though a non-life threatening disease, its pathogenesis reveals that Bronchial Asthma also develops by the same aetiopathogenesis. The United airway disease hypothesis proposes that the upper & lower airway diseases are both manifestations of a single inflammatory process and studies have already proved it. Allergic Rhinitis when once develops if not treated vigorously, can later turn up to Asthma. As chronic inflammation is the central process which is actually continuously changing pathologically the lower respiratory tract & helping to develop Bronchial Asthma. The conventional therapies for Allergic Rhinitis such as antihistamines & decongestants are only symptom relievers, to stop the ongoing pathogenesis of Bronchial Asthma to develop it, the chronic inflammatory process should have to be stopped. This can be done by corticosteroid nasal sprays. Also Asthma with Rhinitis is better controlled by them. Even Bronchial Asthma treatment should be started with inhaler corticosteroid therapy rather than getting it after intermittent use of only bronchodilators (salbutamol) only.


[Brugada syndrome].
Brugada syndrome (BrS) is, along with the long QT syndrome, one of the most frequently diagnosed inherited arrhythmogenic syndromes. It is a primary electric heart disease manifested by ST segment elevations in the right precordial leads. BrS is responsible for more than 4% of all sudden deaths and at least 20% of sudden deaths in patients with structurally normal hearts. In 1998, the first mutations in the gene coding the structure of the cardiac sodium channel were identified in patients with BrS. Nowadays, several hundreds of mutations in at least 8 genes have been already associated with BrS. Functional consequences of many of these mutations on the molecular level have been revealed and, in some of them, even the consequences for the overall cardiac electrophysiology were suggested thank to the mathematical modelling. However, despite intense study of many scientific teams and formulation of several hypotheses, arrhythmogenic mechanisms in BrS have not been fully elucidated yet. This review provides a contemporary view of clinical symptoms, pathophysiology, diagnostics and therapy in BrS.


[Use of arginine in intruterine growth retardation (IUGR). Authors' experience].
Asymmetrical intrauterine growth retardation (IUGR) represents a foetal mechanism, consequent to placental insufficiency, due to many factors: genetic, vascular, malformative. At present, no therapy is really efficient. The aim of this study was to evaluate the efficacy, in these pathological conditions, of the use of L-arginine. This amino-acid improves GH-RH incretion, with consequent increase of plasmatic GH influencing somatic growth. L-arginine moreover, is the obligatory precursor for nitric oxide (NO) enzymatic synthesis (Endothelial-derived relaxing factor). NO helps the prolapse of smooth musculature and, consequently, the improvement of placental blood circulation. On the basis of the double activity of NO, vasodilatation and GH-RH induction, 43 pregnant women have been treated suffering from IUGR, diagnosed by ultrasonic examination an by evaluation of Doppler velocimetry values, from 30th week of gestation, administering L-arginine (Bioarginina, 6 g per os/day). Periodically, USG and Doppler velocimetry examinations were performed to evalue foetal growth and possible increase of peripheral vessels resistance. 32 patients improved the clinical course of pregnancy: 19 recovered the whole retardation; 9 only one week; 4 had premature delivery after 36 weeks with foetal weight coincident with gestational age. The positive results suggest the prosecution of clinical studies in order to attempt the achievement of an effective pharmacological treatment of IUGR.


USE OF X-RAYS IN THE DETECTION OF CALCIUM IN BIOLOGICAL TISSUES AT MICROLEVEL.
By using x-rays at a microlevel (that is, at magnifications of 35 x and more) the smallest quantities of calcium in tissues can be visualized. The method of stain historadiography recommended permits the combined study of histological specimens and their radiographs. The study of specimens in series not only serves to exclude artefacts but also helps to identify the calcium-containing microstructures.


Toward a theoretically based measurement model of the good life.
A theoretically based conceptualization of the good life should differentiate 4 dimensions-the hedonist good life, the dialectical good life, the humanist good life, and the formalist good life. These 4 dimensions incorporate previous fragmentary measures, such as life satisfaction, depression, work alienation, and marital satisfaction, to produce an integrative view. In the present study, 276 Hong Kong Chinese husbands and wives responded to a survey of 13 indicators for these 4 good life dimensions. Confirmatory hierarchical factor analysis showed that these indicators identified the 4 dimensions of the good life, which in turn converged to identify a second-order factor of the overall good life. The model demonstrates discriminant validity in that the first-order factors had high loadings on the overall good life factor despite being linked by a social desirability factor. Analysis further showed that the second-order factor model applied equally well to husbands and wives. Thus, the conceptualization appears to be theoretically and empirically adequate in incorporating previous conceptualizations of the good life.


Population screening for colorectal cancer.
Each year in the UK, around 16,000 people die from colorectal cancer. At disease presentation, around 55% of people have advanced cancer that has spread to lymph nodes, metastasised to other organs or is so locally advanced that surgery is unlikely to be curative (Dukes' stage C or D). Overall 5-year survival for colorectal cancer in the UK is around 47-51% (compared to 64% in the USA), but only 7% at most in those presenting with metastatic disease. These facts underlie the current introduction of national bowel screening programmes in the UK. Here we assess the role of screening of the general population in reducing mortality from colorectal cancer. We do not consider the screening arrangements needed for high-risk populations, including those with inflammatory bowel disease or a strong family history of colorectal cancer.


Epidemiology of Coronavirus Disease Outbreak among Crewmembers on Cruise Ship, Nagasaki City, Japan, April 2020.
In April 2020, a coronavirus disease (COVID-19) outbreak occurred on the cruise ship Costa Atlantica in Nagasaki, Japan. Our outbreak investigation included 623 multinational crewmembers onboard on April 20. Median age was 31 years; 84% were men. Each crewmember was isolated or quarantined in a single room inside the ship, and monitoring of health status was supported by a remote health monitoring system. Crewmembers with more severe illness were hospitalized. The investigation found that the outbreak started in late March and peaked in late April, resulting in 149 laboratory-confirmed and 107 probable cases of infection with severe acute respiratory syndrome coronavirus 2. Six case-patients were hospitalized for COVID-19 pneumonia, including 1 in severe condition and 2 who required oxygen administration, but no deaths occurred. Although the virus can spread rapidly on a cruise ship, we describe how prompt isolation and quarantine combined with a sensitive syndromic surveillance system can control a COVID-19 outbreak.


Quantitative chemical exchange saturation transfer with hyperpolarized nuclei (qHyper-CEST): sensing xenon-host exchange dynamics and binding affinities by NMR.
The reversible binding of xenon to host molecules has found numerous applications in nuclear magnetic resonance studies. Quantitative characterization of the Xe exchange dynamics is important to understand and optimize the physico-chemical behavior of such Xe hosts, but is often challenging to achieve at low host concentrations. We have investigated a sensitive quantification technique based on chemical exchange saturation transfer with hyperpolarized nuclei, qHyper-CEST. Using simulated signals we demonstrated that qHyper-CEST yielded accurate and precise results and was robust in the presence of large amounts of noise (10%). This is of particular importance for samples with completely unknown exchange rates. Using these findings we experimentally determined the following exchange parameters for the Xe host cryptophane-A monoacid in dimethyl sulfoxide in one type of experiment: the ratio of bound and free Xe, the Xe exchange rate, the resonance frequencies of free and bound Xe, the Xe host occupancy, and the Xe binding constant. Taken together, qHyper-CEST facilitates sensitive quantification of the Xe exchange dynamics and binding to hydrophobic cavities and has the potential to analyze many different host systems or binding sites. This makes qHyper-CEST an indispensable tool for the efficient design of highly specific biosensors.


Toxin ζ Triggers a Survival Response to Cope with Stress and Persistence.
Bacteria have evolved complex regulatory controls in response to various environmental stresses. Protein toxins of the ζ superfamily, found in prominent human pathogens, are broadly distributed in nature. We show that ζ is a uridine diphosphate-N-acetylglucosamine (UNAG)-dependent ATPase whose activity is inhibited in vitro by stoichiometric concentrations of ε2 antitoxin. In vivo, transient ζ expression promotes a reversible multi-level response by altering the pool of signaling purine nucleotides, which leads to growth arrest (dormancy), although a small cell subpopulation persists rather than tolerating toxin action. High c-di-AMP levels (absence of phosphodiesterase GdpP) decrease, and low c-di-AMP levels (absence of diadenylate cyclase DisA) increase the rate of ζ persistence. The absence of CodY, a transition regulator from exponential to stationary phase, sensitizes cells to toxin action, and suppresses persisters formed in the ΔdisA context. These changes, which do not affect the levels of stochastic ampicillin (Amp) persistence, sensitize cells to toxin and Amp action. Our findings provide an explanation for the connection between ζ-mediated growth arrest (with alterations in the GTP and c-di-AMP pools) and persistence formation.


Ocfentanil overdose fatality in the recreational drug scene.
This paper describes the first reported death involving ocfentanil, a potent synthetic opioid and structure analogue of fentanyl abused as a new psychoactive substance in the recreational drug scene. A 17-year-old man with a history of illegal substance abuse was found dead in his home after snorting a brown powder purchased over the internet with bitcoins. Acetaminophen, caffeine and ocfentanil were identified in the powder by gas chromatography mass spectrometry and reversed-phase liquid chromatography with diode array detector. Quantitation of ocfentanil in biological samples was performed using a target analysis based on liquid-liquid extraction and ultra performance liquid chromatography tandem mass spectrometry. In the femoral blood taken at the external body examination, the following concentrations were measured: ocfentanil 15.3μg/L, acetaminophen 45mg/L and caffeine 0.23mg/L. Tissues sampled at autopsy were analyzed to study the distribution of ocfentanil. The comprehensive systematic toxicological analysis on the post-mortem blood and tissue samples was negative for other compounds. Based on circumstantial evidence, autopsy findings and the results of the toxicological analysis, the medical examiner concluded that the cause of death was an acute intoxication with ocfentanil. The manner of death was assumed to be accidental after snorting the powder.


Case Report of High-Grade Atrioventricular Block and Takotsubo Cardiomyopathy.
Takotsubo cardiomyopathy (TTC) is a condition with a good long-term prognosis. However, when the TTC is due to a life-threatening arrhythmia, such as atrioventricular block (AVB), several considerations must be made regarding treatment. A 71-year-old woman with a history of ischemic stroke presented after a syncopal episode. Before passing out, the patient was walking, nauseous, lightheaded, dizzy, and short of breath. In the emergency department, the blood pressure was 230/120 mmHg, and the heart rate was 38 beats per minute, but the patient was asymptomatic. An electrocardiogram showed a new-onset 2:1 AVB, bifascicular block, and prolonged PR and corrected QT intervals. An echocardiogram revealed a new-onset ejection fraction of 30% to 35%; hypokinesis of the apex, mid-inferoseptum, mid-anterolateral, apical to mid-inferior, and apical to mid-anterior walls; and hyperkinesis of the basal segments. The cardiac catheterization illustrated normal coronary arteries without significant stenosis. Therefore, the patient was diagnosed with TTC and 2:1 AVB. She was treated with lisinopril and metoprolol succinate and received a dual-chamber pacemaker. At the follow-up visit, the patient's ejection fraction and hypokinetic segments improved. She denied any recurrence of syncope, and her pacemaker was functioning appropriately. When AVB or other arrhythmias initiate a TTC, the patient can experience sudden cardiac death and decompensate quickly. Therefore, clinicians should understand this rare but fatal complication because these patients require pacemakers and beta blockers.


Study on human subjects - influence of stress and alcohol in simulated traffic situations.
This report presents a research study plan on human subjects - the influence of stress and alcohol in simulated traffic situations under an H2020 project named SIMUSAFE. This research study focuses on road-users', i.e., car drivers, motorcyclists, bicyclists and pedestrians, behaviour in relation to retrospective studies, where interaction between the users are considered. Here, the study includes sample size, inclusion/exclusion criteria, detailed study plan, protocols, potential test scenarios and all related ethical issues. The study plan has been included in a national ethics application and received approval for implementation.


Diagnostic Value of Epigastric Ultrasound and Suprasternal Notch Ultrasound in Comparison with Standard Capnography in Confirmation of Endotracheal Tube Placement after Intubation.
Endotracheal intubation is the basic method of providing a safe cross-sectional airway area and the incorrect placement can be dangerous and causes complications. So this study aimed to access the diagnostic value of color Doppler epigastric ultrasound and linear probe suprasternal notch ultrasound in comparison with standard capnography in confirmation of endotracheal tube (ETT) placement after intubation. This diagnostic value study was conducted on 104 patients requiring intubation who were referred to the Emergency Department. After the intubation, color Doppler epigastric ultrasound and suprasternal notch ultrasound as well as the standard capnography were used to confirm the placement ETT. The sensitivity and specificity of color Doppler epigastric ultrasound were 97.96% and 100%, for suprasternal notch ultrasound were 98.98% and 66.67%, and for combination of the both methods were 96.94% and 100% respectively that showed the significant diagnostic value in the confirmation of ETT placement (P < 0.001). The mean of elapsed time to confirm the ETT placement by the standard capnography method (17.95 ± 2.45 s) was significantly more than the two methods of epigastric ultrasound (10.38 ± 4.65 s) and suprasternal notch ultrasound (5.08 ± 4.45 s) as well as the combined method with the mean of 15.46 ± 8.31 s (P < 0.001). The results of this study showed that although ultrasound is a potentially accurate, fast, and reliable method to confirm the endotracheal tube placement, but suprasternal notch ultrasound is considered to be a more appropriate diagnostic technique due to its higher sensitivity and less detection time compared to epigastric ultrasound and combined method.


Organelle luminal dependence of (+)strand RNA virus replication reveals a hidden druggable target.
Positive-strand RNA viruses replicate their genomes in membrane-bounded cytoplasmic complexes. We show that endoplasmic reticulum (ER)-linked genomic RNA replication by brome mosaic virus (BMV), a well-studied member of the alphavirus superfamily, depends on the ER luminal thiol oxidase ERO1. We further show that BMV RNA replication protein 1a, a key protein for the formation and function of vesicular BMV RNA replication compartments on ER membranes, permeabilizes these membranes to release oxidizing potential from the ER lumen. Conserved amphipathic sequences in 1a are sufficient to permeabilize liposomes, and mutations in these sequences simultaneously block membrane permeabilization, formation of a disulfide-linked, oxidized 1a multimer, 1a's RNA capping function, and productive genome replication. These results reveal new transmembrane complexities in positive-strand RNA virus replication, show that-as previously reported for certain picornaviruses and flaviviruses-some alphavirus superfamily members encode viroporins, identify roles for such viroporins in genome replication, and provide a potential new foundation for broad-spectrum antivirals.


"Cubs Click It For Safety": a school-based intervention for Tween passenger safety.
Children ages 8-12 years, also called "Tweens," demonstrate a number of risk factors for motor vehicle injury, including lack of restraint use and front seating position, yet few interventions have targeted this group. We implemented a school-based educational intervention designed to increase awareness and encourage safer transportation of these children. A local school collaborated with the study team to develop educational materials based on the school mascot and allowed use of school-based media (bulletin boards, closed circuit TV, and newsletters) to deliver key messages about restraint use and back seating position. Selected students participated in delivering the message and in evaluation activities, increasing peer support for the program. Evaluation consisted of surveys of reported and observed restraint use and rear seating for children and restraint use for parents before and after the educational intervention. School support for the program was excellent and student enthusiasm was high. Parent awareness of safe positioning for children improved, with parents endorsing seat belts alone versus seat belts with a booster seat for children ages 5-8 falling from 37% to 25% (p < 0.004). Child report of restraint use increased from 78% to 89% (p < 0.001). Reported exposure to the campaign messages was high with 77% of parents and 89% of students recalling the campaign at the end of the year. Observed restraint use for both adults and children was somewhat lower than reported use. Restraint use by parents was about 80% both before and after the intervention. Restraint use by children increased from 71% to 91% (0.001). No changes were noted in front seating position for children. Short term positive changes in observed restraint use and knowledge about safer transportation of children were encouraging. Further study of the program, including a controlled study of the intervention, are needed to demonstrate longer term effectiveness.


[Effects of high-yielding rice cultivar and cultivation pattern on methane emission from paddy field].
A field experiment was conducted to observe the effects of high-yielding rice cultivars (early rice Luliangyou No. 996 and Chuanfeng No. 1, and late rice T you No. 259) and cultivation patterns (direct sowing and transplanting) on the methane emission from paddy field. The methane emission from early rice field before drying was 52%-73% of the total, while drainage and drying decreased the methane emission significantly. For late rice field, the methane emission during vegetative growth stage was 70% of the total. Under direct sowing of early rice, the average methane flux was lower, but the total methane emission was higher, compared with those under transplanting. As for late rice, both the average methane flux and the total methane emission were higher under direct sowing than under transplanting. There existed significant differences in the methane emission per unit grain production of early rice and late rice between direct sowing and transplanting. The methane emission per unit grain production under direct sowing of early rice super hybrid was increased by 4.84 g CH4 x kg(-1), compared with that under transplanting, and the emission under direct sowing of conventional early rice was increased by 3.48 g CH4 x kg(-1), compared with that under transplanting. The emission under direct sowing of hybrid rice was 6.67 g CH4 x kg(-1) higher than that under transplanting. In the same cultivation area and the same time period of direct sowing and transplanting, the methane emission was in the order of direct sowing of conventional early rice > transplanting of conventional early rice > direct sowing of early rice super hybrid > transplanting of early rice super hybrid, and direct sowing of late rice > transplanting of late rice.


High Throughput Approaches to Unravel the Mechanism of Action of a New Vanadium-Based Compound against Trypanosoma cruzi.
Treatment for Chagas disease, a parasitosis caused by Trypanosoma cruzi, has always been based on two drugs, nifurtimox and benznidazole, despite the toxic side effects described after prolonged prescription. In this work, we study a new prospective antitrypanosomal drug based on vanadium, here named VIVO(5Brsal)(aminophen). We found a good IC50 value, (3.76 ± 0.08) μM, on CL Brener epimastigotes. The analysis of cell death mechanism allowed us to rule out the implication of a mechanism based on early apoptosis or necrosis. Recovery assays revealed a trypanostatic effect, accompanied by cell shape and motility alterations. An uptake mostly associated with the insoluble fraction of the parasites was deduced through vanadium determinations. Concordantly, no drastic changes of the parasite transcriptome were detected after 6 h of treatment. Instead, proteomic analysis uncovered the modulation of proteins involved in different processes such as energy and redox metabolism, transport systems, detoxifying pathways, ribosomal protein synthesis, and proteasome protein degradation. Overall, the results here presented lead us to propose that VIVO(5Brsal)(aminophen) exerts a trypanostatic effect on T. cruzi affecting parasite insoluble proteins.


Physical fitness and body composition in relation to physical activity in prepubescent Senegalese children.
Relationships among estimated body composition, habitual physical activity, and physical fitness were considered in Senegalese children 8.5-13.5 years of age. Anthropometric dimensions (arm and calf circumferences, trunk, and extremity skinfolds, body mass index), four motor performances (dash, standing long jump, throw, grip strength), a step-test (cardiorespiratory fitness), and heart rate (HR) monitoring (physical activity) were collected in 140 children (66 boys and 74 girls). Age and sex had a major effect on indicators of body composition and physical fitness. Height stunting used as an indicator of chronic undernutrition had a remarkable effect on body composition but only a limited influence on physical fitness. Physical activity, represented by percentage of time above the flex-HR (%fHR), did not vary with sex, age, and nutritional status. However, there was a low-to-moderate correlation between %fHR and several body composition indices, grip strength, and cardiorespiratory fitness. Comparisons of children in the upper and lower quartiles of %fHR indicated that better indices of body composition in boys, and better strength and cardiorespiratory fitness in girls were positively associated with a higher level of physical activity. Am. J. Hum. Biol. 10:385-396, 1998. © 1998 Wiley-Liss, Inc.


Evaluation of multiple vascular reconstructive procedures with synthetic graft occlusions.
The objective of this study was to evaluate the efficiency of multiple vascular reconstructive procedures in the presence of an occluded synthetic graft. Over a four year period seventy-seven occluded synthetic grafts were treated with urokinase and reconstruction. Follow-up ranged from 1 to 1627 days (4 years, 5 1/2 months). Kaplan-Meier and generalized Wilcoxon test were used to determine patency and limb salvage rates. The cases were divided into three groups according to the number of previous reconstructive events. Group I consisted of patients that had undergone one previous vascular reconstructive procedure. Group II consisted of patients that had undergone two previous vascular reconstructive procedures. Group III consisted of patients who had undergone three or more previous reconstructive procedures. In Group I, the one, two, and three year patency rates were 48.6%, 34.7%, and 26.0% and the limb salvage rates were 76.2%, 67.9%, and 67.9% for one, two, and three years respectively. The Group II patency rates were 41.9%, 24.4%, and 16.3% and the limb salvage rates were 73.7%, 66.3%, and 66.3%. The Group III patency rates were 31.8%, 5.5%, and 5.5% and the limb salvage rates were 76.6%, 54.8%, and 54.8%. The patency rate was significantly reduced when Group III was compared to Group I (p < 0.01). There was no statistically significant difference in limb salvage rates between any of the groups. These results indicate that the number of secondary vascular reconstructive procedures combined with thrombolysis had no correlation with the prognosis of limb salvage.(ABSTRACT TRUNCATED AT 250 WORDS)


The Involvement of Sortilin/NTSR3 in Depression as the Progenitor of Spadin and Its Role in the Membrane Expression of TREK-1.
The molecular identification of sortilin, also called neurotensin receptor-3, from three different biochemical approaches already predicted the involvement of the protein in numerous biological and cellular functions. The first important observation was that sortilin is synthesized as a precursor that is converted to a mature protein after cleavage by the protein convertase furin in late Golgi compartments. This maturation leads to the formation of a 44 amino acid peptide, the propeptide (PE). The release of this peptide when matured sortilin reached the plasma membrane remained to be demonstrated. Sortilin has been also shown to be shedded by matrix metalloproteases releasing a large extracellular fragment identified as soluble sortilin. Therefore, sortilin has been shown to interact with several proteins and receptors confirming its role in the sorting of cellular components to the plasma membrane and/or to the lysosomal pathway. Interestingly, sortilin physically interacts with the two pore domain potassium channel TREK-1 and the PE as well as its synthetic analog spadin is able to block the activation of TREK-1 highlighting their role in the depression pathology. The present review describes the advance of research that led to these results and how both the soluble form of sortilin and the sortilin-derived PE have been detected in human serum and whose levels are affected in patients with major depressive disorder (MDD). The use of spadin as an antidepressant and the further role of soluble sortilin and of sortilin-derived PE as potential biomarkers during depression statement and/or remission of the pathology are considered and discussed in this review.


Study of Selected Outcomes of Medical Students Who Fail USMLE Step 1.
Passage of the United States Medical Licensing Exam (USMLE) is required to obtain a medical license in the United States. Currently the majority of US medical schools require passage of USMLE Step 1 for either promotion to the third year or graduation from medical school. Virginia Commonwealth University School of Medicine (VCUSOM) requires that students take the USMLE but does not require passing of USMLE Step 1 for promotion or graduation. This policy enabled the authors to analyze performance outcomes during clinical rotations and monitor the residency match for a group of students who failed USMLE Step 1 on the first attempt. Third year clerkship grades and residency match results were reviewed for 64 students of the graduating classes of 1999-2005 who failed Step 1 on the first attempt. An equal number of students who passed Step 1 were randomly selected from each class as a comparison group. Average clinical performance ratings, NBME subject exam scores and final third year clerkship grades for the two groups were compared. Residency match rates and specialty certification were also compared. The USMLE Fail Group had more Pass and fewer Honors clerkship grades than the comparison group. Subject exam scores were significantly lower in the USMLE Fail Group in all clerkships. Clinical performance ratings were significantly lower in the Fail group in three out of six clerkships: Internal Medicine, Pediatrics, and Psychiatry. However, 82% of the USMLE Fail Group later passed USMLE Step 1 and 2. Fifty-nine of the 64 students in the USMLE Fail Group matched for a residency, whereas all of the students in the Pass Group matched for a residency. Students who fail USMLE Step 1 have lower final clerkship grades due in part to lower NBME subject exam scores. The majority of these students, however, successfully pass USMLE Step 1 prior to graduation, go on to graduate medical training, and become board certified in their specialty.


Low-level transcutaneous electrical stimulation of the auricular branch of vagus nerve ameliorates left ventricular remodeling and dysfunction by downregulation of matrix metalloproteinase 9 and transforming growth factor β1.
Vagus nerve stimulation improves left ventricular (LV) remodeling by downregulation of matrix metalloproteinase 9 (MMP-9) and transforming growth factor β1 (TGF-β1). Our previous study found that low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve (LL-TS) could be substituted for vagus nerve stimulation to reverse cardiac remodeling. So, we hypothesize that LL-TS could ameliorate LV remodeling by regulation of MMP-9 and TGF-β1 after myocardial infarction (MI). Twenty-two beagle dogs were randomly divided into a control group (MI was induced by permanent ligation of the left coronary artery, n = 8), an LL-TS group (MI with long-term intermittent LL-TS, n = 8), and a normal group (sham ligation without stimulation, n = 6). At the end of 6 weeks follow-up, LL-TS significantly reduced LV end-systolic and end-diastolic dimensions, improved ejection fraction and ratio of early (E) to late (A) peak mitral inflow velocity. LL-TS attenuated interstitial fibrosis and collagen degradation in the noninfarcted myocardium compared with the control group. Elevated level of MMP-9 and TGF-β1 in LV tissue and peripheral plasma were diminished in the LL-TS treated dogs. LL-TS improves cardiac function and prevents cardiac remodeling in the late stages after MI by downregulation of MMP-9 and TGF-β1 expression.


[Population-related peculiarities of molecular stress-responsive systems of bivalve mollusk under the effect of tetrazine pesticide].
Tetrazine pesticides are widely used for the treatment of crops in most EU countries and USA. However, data about the effect of environmentally realistic concentrations of biocides on the molecular stress response system in non-target organisms are absent. The aim of our study was the comparison of adaptive capability of bivalve mollusk Anodonta cygnea from two populations under the effects of commercial pesticide Apollo in terms of biochemical parameters of the digestive gland. The differences between parameters of oxidative stress and glutathione transferase activity in specimens of control groups from clean (I group) and polluted (B group) areas have been shown. Under the effect of Apollo, the level of protein carbonyls and microsomal oxidation processes increased, and the level of metallothioneins and oxyradical formation decreased in the specimens from both populations. However, the treatment provoked the activation of antioxidant processes in the I group and their inhibition in B group. Potentially the injury of cellular thiols, glutathione and metallothioneins, seems to be key point of tetrazine pesticides toxicity.


Classification algorithm using halftone features of counterfeit bills and CNN.
With recent advancements in image processing and printing technology, home printers have improved in performance and grown more widespread. As such, they have been increasingly used in counterfeiting and forgery. Most counterfeit bills in Korea have been created using home scanners and printers. The identification of printer model is thus necessary to rapidly track down criminals and solve crimes. Household printers can be largely divided into inkjet and laser printers. These two types of printers print halftone textures instead of continuous images. This study proposed a technique of printer classification based on halftone textures that can be observed in printed documents. Since halftone textures are expressed as periodic lattices, the images were transformed via FFT, which is highly effective at expressing periodicity. ResNet, known for its superior gradient flow, was used for training. The experiment was conducted on 12 color laser jets and 2 inkjets. Scans of bills printed by each printer were used, and halftone texture analysis was performed on these images for printer model classification. Each image was cropped into several parts; one of the cropped parts was analyzed. The analysis showed that laser printers could be 100% distinguished from inkjet printers. An accuracy of 98.44% was achieved in make classification. When 50 cropped images were used instead of a single image, the technique achieved 100% accuracy in model classification. The proposed technique is non-destructive; it offers high accessibility and efficiency as it can be performed using a scanner alone, without requiring additional optical equipment.


The treatment of rejection. A trial of acetylsalicylic acid, dipyridamole, and heparin.
Serial studies of platelet and fibrinogen survival were performed in 26 nonimmunosuppressed dogs after allogenic renal transplant operations. Treatment with acetylsalicylic acid, dipyridamole, and heparin failed to improve the selective platelet destruction which occurred in untreated animals, and it did not improve postoperative longevity. There was a high incidence of postoperative wound and intrarenal hemorrhage after heparin treatment. These results are consistent with the hypothesis that platelet destruction is a consequence rather than the cause of acute graft rejection, and it is concluded that antithrombotic therapy is not of practical benefit in preventing acute rejection.


N,N'-Bis(2-cyclohexylethyl)naphtho[2,3-b:6,7-b']dithiophene Diimides: Effects of Substituents.
Naphtho[2,3-b:6,7-b']dithiophene-4,5,9,10-tetracarboxylic diimide (NDTI) is a promising electron-deficient building block for n-type organic conductors, and the performance of NDTI-based field-effect transistors (FETs) is largely dependent on the substituents that alter the supramolecular organization in the solid state and, in turn, the intermolecular orbital overlap. For this reason, the rational selection of substituent on imide nitrogen atoms and/or thiophene α-positions is the key to developing superior n-type organic semiconductors. We here report new NDTI derivatives having N-(2-cyclohexylethyl) groups. Despite their one-dimensional packing structures in the solid state regardless of the presence or absence of chlorine groups at the thiophene α-positions, their FETs show promising performance with electron mobilities higher than 0.1 cm²·V(-1)·s(-1) under ambient conditions. We also discuss how the cyclohexylethyl groups affect the packing structure in comparison with analogous n-octyl derivatives having the same number of carbon atoms.