Miracle-dz/UniFAR-FTUs huggingface dataset:
Tanshinone I enhances learning and memory, and ameliorates memory impairment in mice via the extracellular signal‐regulated kinase signalling pathway

Background and purpose: The intracellular signalling kinase, extracellular signal‐regulated kinase 1/2 (ERK1/2) is required for new memory formation, suggesting that control of ERK signalling might be a target for the treatment of cognitive dysfunction. Previously, we reported that tanshinone congeners have ameliorating effects on drug‐induced memory impairment in mice. Here, we have investigated possible modes of action of tanshinone I on learning and memory, associated with ERK phosphorylation.
[Evaluation of enzyme-linked immunosorbent assay for the diagnosis of Helicobacter pylori infection in children and adolescents].

BACKGROUND Helicobacter pylori infection is recognized as the most frequent cause of chronic gastritis in adults and children. The diagnosis is accomplished with invasive methods in fragments of endoscopic gastric biopsies and non-invasive methods. The enzyme-linked immunosorbent assay constitutes a simple, fast exam and of low cost with high sensibility in adult patients. AIM The purpose of this study was to evaluate the ELISA method for the infection diagnosis for Helicobacter pylori in children and adolescents using the Cobas Core II kit (Roche). Helicobacter pylori was positive when the rapid urease test and the histology were both positive or when the culture was positive and Helicobacter pylori negative when all the tests were negative. PATIENTS/METHODS Eleven hundred patients were studied, their age ranged from 3 months and 16 years, (mean = 8y 7m +/-; 4.0; median = 9y 5m). Helicobacter pylori infection was diagnosed in 47.7% (53/111). RESULT Sensitivity was 83.0% and 86.0%; specificity was 70.6% and 71.0%, using the cutoff of 7 U/mL and 5 U/mL, respectively. When only the positive culture was used as gold standard and the cutoff of 5 U/mL, the sensitivity was 93.3%. In patients older than 10 years, the sensibility was 90.6% and 96.8%; specificity was 71.0% and 61.9%, with the cutoff of 7 U/mL and 5 U/mL, respectively. CONCLUSION ELISA method had good sensitivity in children older than 10 years, using the cutoff 5 U/mL, but the specificity was low.
A synopsis of the WPA Educational Program on Personality Disorders

This article describes the headlines of the Educational Program on Personality Disorders produced by the WPA Section on Personality Disorders and the International Society on the Study of Personality Disorders. Lifelong personality traits serve as a substrate and a context for understanding more florid and distinct forms of psychopathology. Personality disorders affect at least 10% of the population, and the direct and indirect social costs associated with crime, substance abuse, increased need for medical care, family disruption, delayed recovery from clinical syndromes and medical diseases is substantial. Numerous theories, models and methods have been proposed to describe and to understand personality and its disorders: descriptive, statistical, psychoanalytic, evolutionary, neurobiologic. Classification has either taken a prototypical or a polythetic approach, but in recent years dimensional formats for classifying personalities have gained more interest. Personality pathology has a complex and variable character of interwoven developmental bio-psycho-social influences. A number of reliable instruments for assessment of personality and its disorders have emerged during the last three decades and a wide range of tailored psychotherapeutic techniques are now available. Personality disorders are treatable and remission is more likely than treatment resistance. Education is needed for all health professionals in psychiatric services. The full WPA program is available to be downloaded for free from WPA's website www.wpanet. org.
Definitions of biochemical failure that best predict clinical failure in patients with prostate cancer treated with external beam radiation alone: a multi-institutional pooled analysis.

PURPOSE Pooled data on 4,839 patients with T1-2 prostate cancer treated with external beam radiation therapy (RT) alone at 9 institutions have previously provided long-term biochemical failure (BF) and clinical outcomes using the American Society for Therapeutic Radiology and Oncology (ASTRO) definition. In this report we determined the sensitivity and specificity of several BF definitions using distant failure (DF) alone or clinical failure (CF), defined as local failure (LF) and/or DF. MATERIALS AND METHODS The pooled cohort was treated between 1986 and 1995 with external beam RT (60 Gy or greater) without pre-RT androgen suppression or planned post-RT adjuvant androgen suppression. Median followup was 6.3 years. The sensitivity and specificity of 102 definitions of BF relative to DF and LF were assessed. RESULTS The BF definitions with higher sensitivity and specificity than the ASTRO definition for DF only and CF are reported. The sensitivity and specificity of the ASTRO definition to predict DF alone was 55% and 68%, respectively. Three definitions had higher sensitivity and specificity, namely prostate specific antigen (PSA) greater than current nadir (lowest PSA prior to current measurement) plus 3 ng/ml (sensitivity 76% and specificity 72%), dated at the call (failure date as the date when the criterion was met), PSA greater than absolute nadir plus 2 ng/ml (sensitivity 72% and specificity 70%), dated at the call, or 2 consecutive increases of at least 0.5 ng/ml, back dated (sensitivity 69% and specificity 73%). The sensitivity and specificity of the ASTRO definition to predict CF was 60% and 72%, respectively. Three definitions had higher sensitivity and specificity, namely PSA greater than current nadir plus 3 ng/ml (sensitivity 66% and specificity 77%), dated at the call, PSA greater than absolute nadir plus 2 ng/ml (sensitivity 64% and specificity 74%), dated at the call, or 2 consecutive increases of at least 0.5 ng/ml, back dated (sensitivity 67% and specificity 78%). CONCLUSIONS Using what is to our knowledge the largest data set of patients with prostate cancer treated with RT alone we correlated multiple definitions of BF with the strict clinical end points of DF alone and CF (DF or local failure). Defining BF as PSA greater than absolute nadir plus 2 ng/ml, dated at the call, PSA greater than current nadir plus 3 ng/ml, dated at the call, or 2 consecutive increases of at least 0.5 ng/ml, back dated, had higher sensitivity and specificity for DF alone or CF compared with the ASTRO definition. This information should contribute to the discussion regarding suggested modifications to the ASTRO definition of biochemical failure.
Evaluation of clindamycin in combination with quinine against multidrug-resistant strains of Plasmodium falciparum.

Abstract The efficacy of clindamycin, a slow acting antimalarial, in combination with a rapid acting schizonticidal drug, quinine, was determined against three multidrug-resistant strains of Plasmodium falciparum (Cambodian I, Burma [Thau] and Panama II). No recrudescences occurred after treatment with quinine 650 mg orally every 8 hours for 3 days and clindamycin 450 mg orally every 6 hours for 3 days, when administered either simultaneously or sequentially. Quinine alone for 3 days was not curative against infections with these strains. During a 3-day course of therapy, blood levels of quinine or clindamycin were not influenced by administration of the other drug.
Rural–Nonrural Differences in College Attendance Patterns

Using data from the National Education Longitudinal Study of 1988, this study documented college attendance patterns of rural youth in terms of the selectivity of first postsecondary institution of attendance, the timing of transition to postsecondary education, and the continuity of enrollment. The study also examined how these college attendance patterns among rural students differed from those among their nonrural counterparts and which factors explained these rural–nonrural differences. Results showed that rural youth were less likely than their nonrural counterparts to attend a selective institution. In addition, rural youth were more likely to delay entry to postsecondary education compared to their urban counterparts. Finally, rural students were less likely than their urban counterparts to be continuously enrolled in college. Much of these rural–nonrural disparities in college attendance patterns were explained by rural–nonrural differences in socioeconomic status and high school preparation. Policy implications, limitations of the study, and future research directions are also discussed.
BCL-2 Hypermethylation Is a Potential Biomarker of Sensitivity to Antimitotic Chemotherapy in Endocrine-Resistant Breast Cancer

Overexpression of the antiapoptotic factor BCL-2 is a frequent feature of malignant disease and is commonly associated with poor prognosis and resistance to conventional chemotherapy. In breast cancer, however, high BCL-2 expression is associated with favorable prognosis, estrogen receptor (ER) positivity, and low tumor grade, whereas low expression is included in several molecular signatures associated with resistance to endocrine therapy. In the present study, we correlate BCL-2 expression and DNA methylation profiles in human breast cancer and in multiple cell models of acquired endocrine resistance to determine whether BCL-2 hypermethylation could provide a useful biomarker of response to cytotoxic therapy. In human disease, diminished expression of BCL-2 was associated with hypermethylation of the second exon, in a region that overlapped a CpG island and an ER-binding site. Hypermethylation of this region, which occurred in 10% of primary tumors, provided a stronger predictor of patient survival (P = 0.019) when compared with gene expression (n = 522). In multiple cell models of acquired endocrine resistance, BCL-2 expression was significantly reduced in parallel with increased DNA methylation of the exon 2 region. The reduction of BCL-2 expression in endocrine-resistant cells lowered their apoptotic threshold to antimitotic agents: nocodazole, paclitaxel, and the PLK1 inhibitor BI2536. This phenomenon could be reversed with ectopic expression of BCL-2, and rescued with the BCL-2 inhibitor ABT-737. Collectively, these data imply that BCL-2 hypermethylation provides a robust biomarker of response to current and next-generation cytotoxic agents in endocrine-resistant breast cancer, which may prove beneficial in directing therapeutic strategy for patients with nonresectable, metastatic disease. Mol Cancer Ther; 12(9); 1874–85. ©2013 AACR.
HIV-1 in blood monocytes: frequency of detection of proviral DNA using PCR and comparison with the total CD4 count.

In vivo infection of monocytes/macrophages by the human immunodeficiency virus (HIV) has been investigated in many studies since these cells were suggested to provide a reservoir for the virus. In this study, we wanted to find out whether HIV provirus could be detected in circulating monocytes and whether it could be compared with the provirus found in T lymphocytes (T-Ly). Twenty-one seropositive subjects were studied. The amplification method (PCR) was used with three different primer pairs (in gag, env, and long terminal repeat regions of the viral genome) to detect the HIV-1 genome in monocytes and T-Ly separated by an immunomagnetic isolation technique. Of 21 monocyte samples, 13 (61.9%) were positive with at least one primer pair. Furthermore, the provirus harboured in 9 of those 13 monocyte-positive samples differed, with respect to pattern of primer response, from the provirus found in T-Ly. When comparing primer responses of monocytes and T-Ly, most of the differences were found to have occurred with the env primers (8 of 9 cases). Dilution experiments with the 8 E5 cell line revealed that 9 of 12 T-Ly contained 15-150 HIV DNA copies per 150,000 cells while 8 of 11 positive monocytes contained less than 15 copies. However, monocyte samples from two asymptomatic individuals and an AIDS patient showed high levels of HIV DNA, comparable to those obtained in T-Ly. Finally, it was also found that the monocyte-positive subjects were more immunosuppressed than the negative ones, as shown by the total CD4 count of both groups (means of 269 T4/mm3 and 573 T4/mm3, respectively). (ABSTRACT TRUNCATED AT 250 WORDS)
Genetic and Molecular Regulation of Extrasynaptic GABA-A Receptors in the Brain: Therapeutic Insights for Epilepsy

GABA-A receptors play a pivotal role in many brain diseases. Epilepsy is caused by acquired conditions and genetic defects in GABA receptor channels regulating neuronal excitability in the brain. The latter is referred to as GABA channelopathies. In the last two decades, major advances have been made in the genetics of epilepsy. The presence of specific GABAergic genetic abnormalities leading to some of the classic epileptic syndromes has been identified. Advances in molecular cloning and recombinant systems have helped characterize mutations in GABA-A receptor subunit genes in clinical neurology. GABA-A receptors are the prime targets for neurosteroids (NSs). However, GABA-A receptors are not static but undergo rapid changes in their number or composition in response to the neuroendocrine milieu. This review describes the recent advances in the genetic and neuroendocrine control of extrasynaptic and synaptic GABA-A receptors in epilepsy and its impact on neurologic conditions. It highlights the current knowledge of GABA genetics in epilepsy, with an emphasis on the neuroendocrine regulation of extrasynaptic GABA-A receptors in network excitability and seizure susceptibility. Recent advances in molecular regulation of extrasynaptic GABA-A receptor–mediated tonic inhibition are providing unique new therapeutic approaches for epilepsy, status epilepticus, and certain brain disorders. The discovery of an extrasynaptic molecular mechanism represents a milestone for developing novel therapies such as NS replacement therapy for catamenial epilepsy.
Crystallographic evidence for a new ensemble of ligand-induced allosteric transitions in hemoglobin: the T-to-T(high) quaternary transitions.

A detailed description of hemoglobin cooperativity requires knowledge of the dimer-dimer interactions responsible for the low ligand affinity of the quaternary-T tetramer, the "quaternary-T constraints", along with stereochemical pathways that specify how ligand binding disrupts these quaternary constraints. The recent mutagenic screen of Noble et al. [Noble, R. W. , et al. (2001) Biochemistry 40, 12357-12368] has identified the major region of quaternary constraint to be a cluster of residues at the alpha1beta2 interface that is centered at Trp37beta. In this paper, crystallographic studies are presented for most of the mutant hemoglobins studied by Noble et al. These crystallographic experiments identify structural transitions-referred to as T-to-T(High) transitions-between the quaternary-T structure of wild-type deoxyhemoglobin and an ensemble of related T-like quaternary structures that are induced by some mutations in the Trp37beta cluster and/or by exposing crystals of wild-type or mutant deoxyhemoglobins to oxygen. The T-to-T(High) quaternary transitions consist of a rotation of the alpha1beta1 dimer relative to the alpha2beta2 dimer as well as a coupled alphabeta dimer bending component that consists of a small rotation of the alpha1 subunit relative to the beta1 subunit (and a symmetry related rotation of the alpha2 subunit relative to the beta2 subunit). In addition, differences in subunit tertiary structure associated with the T-to-T(High) transitions suggest two stereochemical pathways (one associated with the alpha subunits and one associated with the betasubunits) by which ligand binding specifically disrupts quaternary constraints in the Trp37beta cluster. In the alpha subunits, ligand binding induces a shift of the heme iron producing tension in a chain of covalent bonds that extends from the Fe-N(epsilon)(2)His(F8)alpha1 bond to the peptide backbone bonds of residues His87(F8)alpha1 and Ala88(F9)alpha1. This tension induces an alpha-to-pi transition in the COOH-terminal end of the F-helix that shifts the beta-carbon of Ala88alpha1 by approximately 1.5 A directly into the side chain of Tyr140alpha1 (a key residue in the Trp37beta2 cluster). Collectively these structural changes constitute a relatively short pathway by which ligand binding forces Tyr140alpha1 into the alpha1beta2 interface disrupting quaternary constraints associated with the Trp37beta2 cluster. In the beta subunits, our analysis suggests a more extended energy transduction pathway in which ligand-induced beta1-heme movement triggers tertiary changes in the beta1 subunit that promote alpha1beta1 dimer bending that disrupts quaternary constraints in the Trp37beta2 cluster at the alpha1beta2 interface.
Antigen‐specific immunotherapy for murine lung metastatic tumors expressing human papillomavirus type 16 E7 oncoprotein

An important goal of cancer immunotherapy is to prevent and treat tumor metastasis. We have previously reported a recombinant vaccinia‐based vaccine (Sig/E7/LAMP‐1) that demonstrated significant anti‐tumor effect in a subcutaneous tumor challenge model. In this study, we investigated the potency of the Sig/E7/LAMP‐1 vaccine in preventing and treating metastatic tumors. A tumor metastasis model was generated by injecting human papillomavirus type 16 (HPV‐16) E6/E7 expressing tumor cells, designated TC‐1, into the tail vein of syngeneic C57BL/6 mice. All the naive mice injected with 1 × 106 TC‐1 cells developed tumors confined exclusively to the lungs within 1 month. For in vivo tumor prevention experiments, mice were vaccinated with Sig/E7/LAMP‐1 followed by tumor challenge. While tumor growth was observed in all of the mice (10/10) in the control groups, 8 of 10 vaccinated mice (80%) remained tumor‐free 2 months post‐tumor challenge. For in vivo treatment experiments, mice were first inoculated with TC‐1 cells and then vaccinated with Sig/E7/LAMP‐1. Treatment with Sig/E7/LAMP‐1 was effective in eliminating preexisting tumor cells in 4 of 5 vaccinated mice. Most importantly, treatment with Sig/E7/LAMP‐1 resulted in regression of fully established lung tumors in 50% (5/10) of vaccinated mice. Our data suggest that the Sig/E7/LAMP‐1 vaccine is effective in controlling the hematogenous spread of TC‐1 tumor cells. In addition, the TC‐1 lung metastasis model can be used to test the efficacy of various E6/E7‐specific vaccines and immunotherapeutic strategies. Int. J. Cancer 78:41–45, 1998. © 1998 Wiley‐Liss, Inc.
Neural tube defects in mice exposed to tap water

In May of 2006 we suddenly began to observe neural tube defects (NTDs) in embryos of untreated control mice. We hypothesized the mice were being exposed unknowingly to a teratogenic agent and investigated the cause. Our results suggested that NTDs were not resulting from bedding material, feed, strain, or source of the mice. Additionally, mice were negative for routine and comprehensive screens of pathogens. To further test whether the NTDs resulted from infectious or genetic cause localized to our facility, we obtained three strains of timed pregnant mice from commercial suppliers located in four different states. All strains and sources of mice arrived in our laboratory with NTDs, implying that commercially available mice were possibly exposed to a teratogen prior to purchase. Our investigation eventually concluded that exposure to tap water was causing the NTDs. The incidence of NTDs was greatest in purchased mice provided tap water and lowest in purchased mice provided distilled deionized water (DDI). Providing mice DDI water for two generations (F2‐DDI) eliminated the NTDs. When F2‐DDI mice were provided tap water from three different urban areas prior to breeding, their offspring again developed NTDs. Increased length of exposure to tap water significantly increased the incidence of NTDs. These results indicate that a contaminant in municipal tap water is likely causing NTDs in mice. The unknown teratogen appears to have a wide geographic distribution but has not yet been identified. Water analysis is currently underway to identify candidate contaminants that might be responsible for the malformations. © 2010 Wiley Periodicals, Inc. Environ Toxicol, 2011.
Responses of the sheep blowflies Lucilia sericata and Lcuprina to odour and the development of semiochemical baits

Abstract. The literature relating to the attraction of the sheep blowflies Lucilia sericata and Lucilia cuprina to their ovine hosts is reviewed. The responses of the two species are similar and different components of the behaviour leading to host location and oviposition appear to involve at least two distinct sets of semiochemical cues. Activation, upwind orientation and landing appear to occur in response to putrefactive sulphur‐rich volatiles, originating from bacterial decomposition products. Oviposition is elicited primarily by the presence of ammonia‐rich compounds; moisture, pheromones and tactile stimuli may also act as oviposition stimuli. There is a pronounced sex difference in the response of Lucilia to semiochemicals with a higher proportion of females attracted than males and a higher proportion of gravid than non‐gravid females. While the mechanisms of host location by Lucilia are of intrinsic interest, understanding the responses to semiochemicals is important in the attempt to develop powerful synthetic baits for deployment with the traps or targets used for population sampling or suppression. The literature is discussed with respect to the development of synthetic semiochemical baits.
Synthesis, Biological Evaluation of 1,1‐Diarylethylenes as a Novel Class of Antimitotic Agents

The cytotoxic activities of 23 new isocombretastatin A derivatives with modifications on the B‐ring were investigated. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. Compounds isoFCA‐4 (2 e), isoCA‐4 (2 k) and isoNH2CA‐4 (2 s) were the most cytotoxic, and strongly inhibited tubulin polymerization with IC50 values of 4, 2 and 1.5 μM, respectively. These derivatives were found to be 10‐fold more active than phenstatin and colchicine with respect to growth inhibition but displayed similar activities as tubulin polymerization inhibitors. In addition, cell cycle arrest in the G2/M phase and subsequent apoptosis was observed in three cancer cell lines when treated with these compounds. The disruptive effect of 2 e, 2 k and 2 s on the vessel‐like structures formed by human umbilical vein endothelial cells (HUVEC) suggest that these compounds may act as vascular disrupting agents. Both compounds 2 k and 2 s have the potential for further prodrug modification and development as vascular disrupting agents for treatment of solid tumors.