Miracle-dz/UniFAR-FTUs huggingface dataset:
Fenretinide induces sustained‐activation of JNK/p38 MAPK and apoptosis in a reactive oxygen species‐dependent manner in neuroblastoma cells

Fenretinide, which mediates apoptosis in neuroblastoma cells, is being considered as a novel therapeutic for neuroblastoma. The cytotoxic mechanisms of fenretinide, however, have not been fully elucidated. Sustained‐activation of JNK and p38 MAPK signaling has been shown recently to have a pivotal role in stress‐induced apoptosis. Whether fenretinide activates the signaling in neuroblastoma cells is not known. In the present study, fenretinide induced sustained‐activation of both JNK and p38 MAPK in neuroblastoma cells. Pretreatment with the antioxidant L‐ascorbic acid almost completely inhibited the accumulation of fenretinide‐induced intracellular reactive oxygen species (ROS), activation of JNK and p38 MAPK and apoptosis. Intracellular ROS production and activation of stress signaling was not altered by fenretinide in resistant neuroblastoma cells. Our study demonstrates that in neuroblastoma cells, fenretinide induces sustained‐activation of JNK and p38 MAPK in an ROS‐dependent manner and indicates that JNK and p38 MAPK signaling might mediate fenretinide‐induced apoptosis. Our results also indicate that suppression of the fenretinide‐induced ROS productive system and the downstream JNK and p38 MAPK signaling pathways causes neuroblastoma cells to become resistant to fenretinide. © 2004 Wiley‐Liss, Inc.
Cleaved but not endogenous secretory RAGE is associated with outcome in acute ischemic stroke

Objective: To investigate the expression patterns of 2 soluble isoforms of receptor for advanced glycation end-product (RAGE), including endogenous secretory RAGE (esRAGE) and cleaved RAGE (cRAGE), and their associations with outcome in acute ischemic stroke (IS). Methods: Acute IS patients (n = 106) and age- and sex-matched controls (n = 150) were recruited. Plasma levels of total soluble RAGE (sRAGE) and esRAGE in patients at <48 hours and 48–72 hours after IS and in controls were measured by ELISA. The level of cRAGE was calculated by subtracting the level of sRAGE from that of esRAGE. Poor outcome was defined as modified Rankin Scale score >2 at 3 months after stroke. Results: The plasma levels of cRAGE were significantly higher and correlated to those of esRAGE (p < 0.001). The plasma levels of esRAGE and cRAGE were both significantly higher in IS patients <48 hours and 48–72 hours after onset than in controls, but only level of cRAGE at <48 hours was independently associated with poor outcome after adjusting for clinical variables (odds ratio 2.44; 95% confidence interval 1.16–5.16; p = 0.019). Conclusion: The plasma level of cRAGE at <48 hours after IS, rather than esRAGE, is a significant predictor of acute IS outcome.
Localization of BiP to translating ribosomes increases soluble accumulation of secreted eukaryotic proteins in an Escherichia coli cell‐free system

The endoplasmic reticulum (ER) resident Hsp70 chaperone, BiP, docks to the Sec translocon and interacts co‐translationally with polypeptides entering the ER to encourage proper folding. In order to recreate this interaction in Escherichia coli cell‐free protein synthesis (CFPS) reactions, a fusion protein was formed between the ribosome‐binding portion of the E. coli protein trigger factor (TF) and BiP. The biophysical affinity to ribosomes as well as the characteristic Hsp70 ATPase activity were both verified for the fusion protein. When added to E. coli‐based CFPS reactions, the TF–BiP fusion chaperone increased soluble yields of several protein fragments that are normally secreted through the ER and have poor solubility in typical CFPS reactions. For comparison, a fusion between TF and the native E. coli Hsp70, DnaK, was also constructed. This fusion was also biologically active and increased soluble yields of certain protein targets in CFPS. The TF–BiP fusion described in this study can be seen as a first step in reconstituting and better understanding ER folding pathways in the prokaryotic environment of E. coli CFPS. Biotechnol. Bioeng. 2011; 108:1739–1748. © 2011 Wiley Periodicals, Inc.
Hierarchical patterns of global human Y-chromosome diversity.

We examined 43 biallelic polymorphisms on the nonrecombining portion of the Y chromosome (NRY) in 50 human populations encompassing a total of 2,858 males to study the geographic structure of Y-chromosome variation. Patterns of NRY diversity varied according to geographic region and method/level of comparison. For example, populations from Central Asia had the highest levels of heterozygosity, while African populations exhibited a higher level of mean pairwise differences among haplotypes. At the global level, 36% of the total variance of NRY haplotypes was attributable to differences among populations (i.e., Phi(ST) = 0.36). When a series of AMOVA analyses was performed on different groupings of the 50 populations, high levels of among-groups variance (Phi(CT)) were found between Africans, Native Americans, and a single group containing all 36 remaining populations. The same three population groupings formed distinct clusters in multidimensional scaling plots. A nested cladistic analysis (NCA) demonstrated that both population structure processes (recurrent gene flow restricted by isolation by distance and long-distance dispersals) and population history events (contiguous range expansions and long-distance colonizations) were instrumental in explaining this tripartite division of global NRY diversity. As in our previous analyses of smaller NRY data sets, the NCA detected a global contiguous range expansion out of Africa at the level of the total cladogram. Our new results support a general scenario in which, after an early out-of-Africa range expansion, global-scale patterns of NRY variation were mainly influenced by migrations out of Asia. Two other notable findings of the NCA were (1) Europe as a "receiver" of intercontinental signals primarily from Asia, and (2) the large number of intracontinental signals within Africa. Our AMOVA analyses also supported the hypothesis that patrilocality effects are evident at local and regional scales, rather than at intercontinental and global levels. Finally, our results underscore the importance of subdivision of the human paternal gene pool and imply that caution should be exercised when using models and experimental strategies based on the assumption of panmixia.
Sociodemographic Correlates of HIV Discordant and Concordant Couples in Anambra State, Nigeria

Background The contribution of discordant partnerships to the burden of HIV/AIDS is significant. An understanding of the characteristics of HIV-affected couples will help modify preventive strategies. The aim of this study was to compare the HIV discordant and concordant partnerships for sociodemographic determinants in comprehensive health centers in Anambra State, Nigeria. Methods This was an institution based case-control study of 289 (148 HIV-concordant and 141 HIV-discordant) couples, selected using multistage sampling technique. Data collection was done through nterview using semi-structured questionnaire, while analysis was performed with Statistical Package for Social Sciences version 22.0. Chi-square and t tests were used to identify statistically significant associations between variables. Significance level was set at p value of ≤ 0.05. Results There were more HIV-discordant positive males 83(28.6%) than females 58(20.1%) (p = 0.043). The mean age (SD) of respondents was 37.8(9.8) years. Concordant couples tended to be younger than discordant couples, with differences in mean ages of 2.41 years (p = 0.028) for males and 2.87 years (p = 0.007) for females. There were no significant differences in proportion of remarriages (p = 0.625) and type of marriage (p = 0.900). The majority of remarriages among discordant couples 15(65.2%), were due to divorce of previous spouses (p = 0.054). Conclusions This study found that there were more HIV positive males than females among discordant couples; females in discordant relationships were generally younger than their concordant counterparts. Concordant couples tended to be younger than discordant couples. Such knowledge should be factored in designing novel couple-targeted preventive strategies.
Cardiac and metabolic responses to "space invaders": an instance of metabolically-exaggerated cardiac adjustment?

Heart rate, plus various ventilatory and metabolic indices, were monitored while 24 male subjects played a computer game of the “space invaders” type and during a control condition, in which analogous but ineffective actions were requested and the game proceeded automatically. Relative to baseline, subjects showed much larger increases in heart rate during “space invaders” than during the control condition. However, oxygen consumption, carbon dioxide production, respiratory rate and volume also increased more. While the absolute magnitude of metabolic differences between conditions could be regarded as modest relative to heart rate differences, given the effective range of variations possible for each parameter, the existence of highly significant differences in oxygen consumption and carbon dioxide production militates against assertions of overall cardiac-metabolic independence during “space invaders. ” Nevertheless, analysis of individual differences in heart rate reactivity would seem to provide some evidence of metabolically-unjustified heart rate changes during “space invaders. ” High heart rate reactors during “space invaders” did not differ from low reactors in either oxygen consumption or carbon dioxide production. In addition, this relatively high heart rate reactivity was specific to the “space invaders” condition; high and low heart rate reactors displayed no differences in heart rate, or in any other physiological measure, during the control condition or during baseline.
Isolation and immunizations with hepatitis A viral structural proteins: induction of antiprotein, antiviral, and neutralizing responses

An immune affinity purification procedure for hepatitis A virus (HAV) was designed which yielded milligram quantities of the virus with greater than 95% purity. The major structural proteins VP-1, VP-2, and VP-3 were isolated from the purified virus by electroelution from sodium dodecyl sulfate-polyacrylamide gels and used to immunize Lewis rats (three to four doses, 10 to 15 micrograms per dose). The two Lewis rats immunized with VP-1 developed a strong antibody response to VP-1, as determined by Western blot analysis and immune precipitation of the denatured protein. These animals also developed a good antibody response to the whole virus, as demonstrated by a positive response in a competitive radioimmunoassay (HAV antibody test) and by precipitation of the whole virus. In addition, both animals developed a low titer neutralizing antibody to HAV, as demonstrated by an in vitro cell culture assay. While the two rats receiving VP-2 developed only minimal responses to the protein and to the virus by the same assays described above, one of the two developed a significant neutralizing antibody to HAV. The immunization of one Lewis rat with VP-3 induced a good antibody response to both denatured protein and the whole virus. This serum sample was also demonstrated to neutralize the viral infectivity. Finally, two rabbits that had received inoculations of sodium dodecyl sulfate and heat-disrupted HAV (containing 20 to 30 micrograms of each protein per dose) developed good antiprotein responses to all of the proteins and good antiviral responses, including a consistently significant neutralizing activity. The neutralizing antibody responses suggest that the structural proteins of HAV, or a portion of them, could provide the basis for a subunit vaccine for HAV.
Review: Aspirin and Diabetes Mellitus: revisiting an old player

Type 2 Diabetes Mellitus confers an excess risk of cardiovascular disease. The mechanisms involved in the development of the disease are an active field of research, and prompt the development of newer and safer therapeutics with implications for cardiovascular disease. Currently there is increasing awareness of the role of platelet dysfunction, low-grade chronic inflammation and thrombogenesis in the pathophysiology of insulin resistance, T2DM, as well as type 1 diabetes mellitus and cardiovascular disease. This new evolving knowledge has allowed a better understanding of the role of aspirin, an old medication with proven beneficial effects on patients with established cardiovascular disease. The influence of salicylates on insulin resistance, glucose homeostasis, platelet function and inflammatory pathways, in particular related to the activation of the NFκB pathway, is a promising field of active research, and will help in the management of both diabetes mellitus and atherosclerotic-related cardiovascular disease.
Finger Cold-Induced Vasodilatation, Sympathetic Skin Response, and R—R Interval Variation in Patients With Progressive Spinal Muscular Atrophy

To elucidate autonomic function in spinal muscular atrophy, we evaluated finger cold-induced vasodilatation, sympathetic skin response, and R—R interval variation in 10 patients with spinal muscular atrophy: 7 of type 1, 2 of type 2, and 1 of type 3. Results of finger cold-induced vasodilatation, sympathetic skin response, and R—R interval variation were compared with those of healthy children. Finger cold-induced vasodilatation was abnormal in 6 of 10patients with spinal muscular atrophy; it was normal in the healthy children. The mean sympathetic skin response latency and amplitude did not differ significantly from those of the healthy children. Amplitudes of sympathetic skin response to sound stimulation were absent or low in all six patients with spinal muscular atrophy. No significant difference was found in the mean R—R interval variation of patients with spinal muscular atrophy and healthy children. Results show that some patients with spinal muscular atrophy have autonomic dysfunction, especially sympathetic nerve hyperactivity, that resembles dysfunction observed in amyotrophic lateral sclerosis. (J Child Neurol 2005;20:871—875).
HPC-Based Intelligent Volt/VAr Control of Unbalanced Distribution Smart Grid in the Presence of Noise

The performance of Volt/VAr optimization has been significantly improved due to the integration of measurement data obtained from the advanced metering infrastructure of a smart grid. However, most of the existing works lack: 1) realistic unbalanced multi-phase distribution system modeling; 2) scalability of the Volt/VAr algorithm for larger test system; and 3) ability to handle gross errors and noise in data processing. In this paper, we consider realistic distribution system models that include unbalanced loadings and multi-phased feeders and the presence of gross errors such as communication errors and device malfunction, as well as random noise. At the core of the optimization process is an intelligent particle swarm optimization-based technique that is parallelized using high performance computing technique to solve Volt/VAr-based power loss minimization problem. Extensive experiments covering the different aspects of the proposed framework show significant improvement over existing Volt/VAr approaches in terms of both the accuracy and scalability on IEEE 123 node and a larger IEEE 8500 node benchmark test systems.
X‐Linked Nonsyndromic Sinus Node Dysfunction and Atrial Fibrillation Caused by Emerin Mutation

Introduction: Atrial fibrillation (AF) is a heritable disorder with male predilection, suggesting a sex chromosome defect in certain patients. Loss‐of‐function truncation mutations in EMD, encoding the nuclear membrane protein emerin, cause X‐linked Emery‐Dreifuss muscular dystrophy (EDMD) characterized by localized contractures and skeletal myopathy in adolescence, sinus node dysfunction (SND) in early adulthood, and atrial fibrillation as a variably associated trait. This study sought to identify the genetic basis for male‐restricted, nonsyndromic sinus node dysfunction and AF in a multigenerational family.
Cost-effectiveness of asthma therapy: a comprehensive review

Abstract Background: Asthma has an important impact in terms of both direct and indirect costs. In Europe, the disease costs € 19 000 million a year. Moreover, the cost is greater among patients with severe uncontrolled asthma and is even higher when the work productivity is also taken into account. Improved control of the disease results in cost savings. In this context, cost-effectiveness and cost-utility studies offer important information for clinicians in deciding the best treatment options for asthmatic patients and contribute to ensure an efficient use of the available healthcare resources. Methods: An English and Spanish literature search using electronic search engines (PubMed and EMBASE) was conducted in peer-review journals, from 2009 to June 2014. In order to perform the search for the most suitable and representative articles, key words were selected (“asthma”, “cost-effectiveness”, “cost-utility”, “QALY”, “cost-benefit”, “economic impact of asthma” “healthcare cost”, “asthma treatment” and “work productivity with asthma”). Results: Two-hundred forty-three titles and abstracts were identified by the primary literature search. The full text of the potentially 76 eligible papers was reviewed, and 22 articles were qualified to be finally included. Conclusions: This article provides a comprehensive review on the evidence of cost-effectiveness of asthma treatments derived from the published literature and offers an overall summary of the socioeconomic burden of asthma and its relationship with the degree of disease control. Management alternatives, such as the use of combination therapy with ICS/LABA or omalizumab, when administered according to their current therapeutic indications, have been shown to be cost-effective.
Isolation and preliminary biochemical characterization of the gonococcal H.8 antigen

We have presented a method for the extraction and isolation of the gonococcal H.8 antigen. There was no evidence of contamination by other gonococcal proteins, phospholipids, or LPS. The purified H.8 antigen was subjected to preliminary analysis and appeared to be a proteolipid consisting of both protein and lipid components. The amino acid composition was unusual; the peptide portion of the antigen was an alanine and proline-rich molecule that lacked aromatic and sulfur- containing amino acids. The overall amino acid composition is hydrophobic. A lipid constituent was also identified; it was made up of at least two lipid components, which were unique to the H.8 molecule. The chemical nature of the association of the protein and lipid is presently unknown, but it is clearly a tenacious one.
A probiotic treatment containing Lactobacillus, Bifidobacterium and Enterococcus improves IBS symptoms in an open label trial

Objective: To evaluate the efficacy and safety of live combined Bifidobacterium, Lactobacillus and Enterococcus capsules in treatment of irritable bowel syndrome. Methods: Eighty-five patients [male 32, female 53; age (45.31±11.72) years] were given live combined Bifidobacterium, Lactobacillus and Enterococcus capsules 1260 mg/d t.i. d. ×4 weeks. Syndrome scales were used to evaluate the efficacy in gastrointestinal syndrome. Fecal flora was also measured before and after the treatment. Six bacteria were cultured and the colony forming units were counted in stool. SPSS was used for data analysis. Results: Seventy-four patients finished the follow-up. No side-effect was found. For treatment of irritable bowel syndrome, the effective rate of live combined Bifidobacterium, Lactobacillus and Enterococcus capsules was 56.8% in the second week, 74.3% in the fourth week and 73.0% in the sixth week. Single symptom was improved, especially in abdominal pain and stool character. The probiotica containing live combined Bifidobacterium, Lactobacillus and Enterococcus could increase bifidobacterium count (P<0.01) and lactobacillus count (P<0.05); decrease bacteroides count (P<0.05) and enterococci count (P<0.01); No obvious changes were observed in clostridium difficile colonitis and enterobacteriaceae (P>0.05). Conclusion: The result of the study indicated that the administration of live combined Bifidobacterium, Lactobacillus and Enterococcus improved the symptom of irritable bowel syndrome and that there was a gradual increase of this effect. Thereafter conditions remained stable for 2 weeks. That improvement may be associated with alterations in gastrointestinal flora.
Herpes Simplex Virus Antigens Directly Activate NK Cells via TLR2, Thus Facilitating Their Presentation to CD4 T Lymphocytes

NK cells infiltrate human herpetic lesions, but their role has been underexplored. HSV can stimulate innate immune responses via surface TLR2, which is expressed on monocyte-derived dendritic cells (DCs) and NK cells. In this study, UV-inactivated HSV1/2 and immunodominant HSV2 glycoprotein D peptides conjugated to the TLR2 agonist dipalmitoyl-S-glyceryl cysteine stimulated CD4 T lymphocyte IFN-γ responses within PBMCs or in coculture with monocyte-derived DCs. NK cells contributed markedly to the PBMC responses. Furthermore, NK cells alone were activated directly by both Ags, also upregulating HLA-DR and HLA-DQ and then they activated autologous CD4 T lymphocytes. Using Transwells, Ag-stimulated NK cells and CD4 T lymphocytes were shown to interact through both cell-to-cell contact and cytokines, differing in relative importance in different donors. A distinct immunological synapse between Ag-stimulated NK cells and CD4 T lymphocytes was observed, indicating the significance of their cell-to-cell contact. A large proportion (57%) of NK cells was also in contact with CD4 T lymphocytes in the dermal infiltrate of human recurrent herpetic lesions. Thus, NK cells stimulated by TLR2-activating HSV Ags can present Ag alone or augment the role of DCs in vitro and perhaps in herpetic lesions or draining lymph nodes. In addition to DCs, NK cells should be considered as targets for adjuvants during HSV vaccine development.
Legal and Regulatory Education and Training Needs in the Healthcare Industry

ABSTRACT As in any other industry, laws and regulations significantly impact the functioning of the healthcare industry. Some laws, such as those relating to malpractice and social insurance systems, affect the manner in which the industry operates. Other laws, such as those regulating antitrust and employment practices, affect the organization and the environment in which the industry operates. It is increasingly important that practitioners and managers be cognizant of this complex and dynamic legal minefield. This study examined healthcare managers and executives' knowledge of 9 key issues in the legal and regulatory environment of the healthcare industry. Specifically, the study focused on knowledge concerning tort and contract liability, insurance law, labor and employment regulation, criminal and ethical responsibility, antitrust regulation, the law governing business associations and recent developments. Findings suggest that the levels of knowledge required to manage legal and regulatory issues are much greater than the existing levels of knowledge.