Miracle-dz/UniFAR-FTUs huggingface dataset:
Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.

PURPOSE The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT), which removes chloroethylation or methylation damage from the O(6) position of guanine. O(6)-benzylguanine (O(6)-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial of carmustine (BCNU) plus O(6)-BG to define the toxicity and maximum-tolerated dose (MTD) of BCNU in conjunction with the preadministration of O(6)-BG with recurrent or progressive malignant glioma. PATIENTS AND METHODS Patients were treated with O(6)-BG at a dose of 100 mg/m(2) followed 1 hour later by BCNU. Cohorts of three to six patients were treated with escalating doses of BCNU, and patients were observed for at least 6 weeks before being considered assessable for toxicity. Plasma samples were collected and analyzed for O(6)-BG, 8-oxo-O(6)-BG, and 8-oxoguanine concentration. RESULTS Twenty-three patients were treated (22 with glioblastoma multiforme and one with anaplastic astrocytoma). Four dose levels of BCNU (13.5, 27, 40, and 55 mg/m(2)) were evaluated, with the highest dose level being complicated by grade 3 or 4 thrombocytopenia and neutropenia. O(6)-BG rapidly disappeared from plasma (elimination half-life = 0. 54 +/- 0.14 hours) and was converted to a longer-lived metabolite, 8-oxo-O(6)-BG (elimination half-life = 5.6 +/- 2.7 hours) and further to 8-oxoguanine. There was no detectable O(6)-BG 5 hours after the start of the O(6)-BG infusion; however, 8-oxo-O(6)-BG and 8-oxoguanine concentrations were detected 25 hours after O(6)-BG infusion. The mean area under the concentration-time curve (AUC) of 8-oxo-O(6)-BG was 17.5 times greater than the mean AUC for O(6)-BG. CONCLUSION These results indicate that the MTD of BCNU when given in combination with O(6)-BG at a dose of 100 mg/m(2) is 40 mg/m(2) administered at 6-week intervals. This study provides the foundation for a phase II trial of O(6)-BG plus BCNU in nitrosourea-resistant malignant glioma.
Infant Mortality in American Indians and Alaska Natives 1995–1999 and 2000–2004

Objectives. (1) To determine the infant mortality rate (IMR) in American Indians/Alaska Natives (AI/AN) and Whites between 1995–1999 and 2000–2004. (2) To compare the leading causes of infant mortality in AI/AN and Whites. (3) To examine differences in neonatal vs. postneonatal causes of death in Whites and AI/AN. Methods. Using the 1995–99 and 2000–04 Centers for Disease Control and Prevention’s National Center for Health Statistics national linked birth/infant death data, we examined neonatal and post-neonatal IMR among AI/AN and Whites. Results. AI/AN experienced significantly greater overall IMR in 1995–1999 and 2000–2004 than Whites. While the reduction in the IMR between these time periods was statistically significant for Whites, the reduction among AI/AN was not. We found that AI/AN had an IMR 1.5 times as high as that of Whites. Conclusions. While the overall IMR has decreased in AI/AN, disparities in postneonatal IMR persist between AI/AN and Whites.
Enzymatic mechanisms of ethanol oxidation in the brain.

BACKGROUND The exact enzymatic mechanisms of ethanol oxidation in the brain are still unclear. The catalase-mediated oxidation of ethanol was demonstrated in rat brain using incubation of brain homogenates with catalase inhibitors. The role of the alcohol dehydrogenase (ADH) or cytochrome P450-dependent system in this process is possible, but has not been confirmed. The objective of the study was to determine the contribution of the different enzymatic pathways to ethanol oxidation in brain homogenates from mice and rats. METHODS Three approaches were used to investigate the enzymatic mechanisms of ethanol oxidation in the brain of rats and mice: (1) preincubation of brain homogenates with inhibitors of the ethanol-metabolizing enzymes (catalase, CYP2E1, ADH, and ALDH); (2) utilization of mice with genetic deficiency in ethanol-metabolizing enzymes (catalase, CYP2E1, or both enzymes); and (3) determination of ethanol oxidation in brain subcellular fractions known to have differential activity of ethanol-metabolizing enzymes. The ethanol-derived acetaldehyde (AC) and acetate were determined in brain samples by gas chromatography. RESULTS The catalase inhibitors sodium azide (5 mM) and aminotriazole (5 mM) as well as CYP2E1 inhibitors diallyl sulfide (2 mM) and beta-phenethyl isothiocyanate (0.1 mM) lowered significantly the accumulation of the ethanol-derived AC and acetate in brain homogenates. The ADH inhibitor 4-methyl pyrazole (5 mM) significantly decreased the acetate but not the AC accumulation. Ethanol-derived AC accumulation in brain homogenates of acatalasemic mice was 47% of the control value, 91% in CYP2E1-null mice, and 24% in double mutants (with deficiency of both catalase and CYP2E1). The highest levels of ethanol oxidation were found in microsomal and peroxisomal subcellular brain fractions, where CYP2E1 and catalase are located, respectively. CONCLUSIONS Catalase is the key enzyme of ethanol oxidation in the brain of rodents: it may be responsible for about 60% of the process. CYP2E1 plays an important role in ethanol oxidation in the rodent brains. Alcohol dehydrogenase plays a minor role, if any, in this process. Aldehyde dehydrogenase plays the crucial role in the further oxidation of ethanol-derived AC in the brain homogenates.
HIV subtype may explain sexual transmission

A subtype of HIV that spreads more easily in heterosexual than homosexual men or injecting drug misusers may explain different patterns of transmission of the disease worldwide. In Thailand, India, and sub-Saharan Africa about 90% of HIV-1 infections are acquired through heterosexual contact compared with 10% in the US and western Europe. So far scientists have identified nine subtypes of HIV-1 from A through to I. Subtypes A, C, and D predominate in Africa, E and B are common in Thailand, and C is the main type in India. In the US and western …
Antioxidant enzymes suppress nitric oxide production through the inhibition of NF-kappa B activation: role of H(2)O(2) and nitric oxide in inducible nitric oxide synthase expression in macrophages.

Reactive molecules O(-)(2), H(2)O(2), and nitrogen monoxide (NO) are produced from macrophages following exposure to lipopolysaccharide (LPS) and involved in cellular signaling for gene expression. Experiments were carried out to determine whether these molecules regulate inducible nitric oxide synthase (iNOS) gene expression in RAW264.7 macrophages exposed to LPS. NO production was inhibited by the antioxidative enzymes catalase, horseradish peroxidase, and myeloperoxidase but not by superoxide dismutase (SOD). In contrast, the NO-producing activity of LPS-stimulated RAW264.7 cells was enhanced by the NO scavengers hemoglobin (Hb) and myoglobin. The antioxidant enzymes decreased levels of iNOS mRNA and protein in LPS-stimulated RAW264.7 cells, whereas the NOS inhibitor N(G)-monomethyl-L-arginine as well as Hb increased the level of iNOS protein but not mRNA, indicating that NO inhibits iNOS protein expression. NF-kappa B was activated in LPS-stimulated RAW264.7 cells and the activation was significantly inhibited by antioxidant enzymes, but not by Hb. Similar results were obtained using LPS-stimulated rodent peritoneal macrophages. Extracellular O(-)(2) generation by LPS-stimulated macrophages was suppressed by SOD, but not by antioxidative enzymes, while accumulation of intracellular reactive oxygen species was inhibited by antioxidative enzymes, but not by SOD. Exogenous H(2)O(2) induced NF-kappa B activation in macrophages, which was inhibited by catalase and pyrroline dithiocarbamate (PDTC). H(2)O(2) enhanced iNOS expression and NO production in peritoneal macrophages when added with interferon-gamma, and the effect of H(2)O(2) was inhibited by catalase and PDTC. These findings suggest that H(2)O(2) production from LPS-stimulated macrophages participates in the upregulation of iNOS expression via NF-kappa B activation and that NO is a negative feedback inhibitor of iNOS protein expression.
Herbal remedies affecting coagulation: A review

Context: Herbal remedies are used to treat a large variety of diseases, including blood-related disorders. However, a number of herbal preparations have been reported to cause variations in clotting time, this is mainly by disruption of the coagulation cascade. Objective: The compiling of plants investigated for effects on the coagulation cascade. Methods: Information was withdrawn from Google Scholar and the journal databases Scopus and PubMed. Results: Sixty-five herbal remedies were identified with antiplatelet, anticoagulant, or coagulating ability. Bioactive compounds included polyphenols, taxanes, coumarins, saponins, fucoidans, and polysaccharides. Conclusion: Although research has been conducted on the effect of herbal remedies on coagulation, most information relies on in vitro assays. Contradictory evidence is present on bleeding risks with herbal uses, though herb–drug interactions pose a threat. As the safety of many herbals has not been proven, nor their effect on blood parameters determined, the use of herbal preparations before undergoing any surgical procedure should discontinued.
Long-term effects of the "Heidelberg Model of Music Therapy" in patients with chronic tinnitus.

OBJECTIVE The "Heidelberg Model of Music Therapy for Chronic Tinnitus" is a manualized short term treatment (nine 50-minutes sessions of individualized therapy on five consecutive days). It has proven to be efficient in reducing tinnitus symptoms in the short run. Now the long-term impact of the treatment after up to 5.4 years should be explored. MATERIALS AND METHODS 206 patients who had attended the neuro-music therapy were addressed in a structured follow-up questionnaire survey. 107 complete questionnaires entered analysis. Follow-up time was 2.65 (SD 1.1) years. RESULTS 76% of the patients achieved a reliable reduction in their tinnitus scores, the overall tinnitus distress as measured by the Mini-TQ diminished from 11.9 (SD = 4.9) to 7.4 (SD = 5.2) points, 87% of the patients were satisfied by the way they were treated during therapy, and 71% of the patients did not undergo any further treatment after. Evaluation of therapeutic elements displays, that only music therapy specific interventions were rated helpful by the patients. Tinnitus related factors (such as tinnitus pitch or loudness, time since onset) did not influence therapy outcome but female gender, positive therapeutic relationship, and higher initial Mini-TQ scores became apparent as factors predicting better chances for greater therapy success. DISCUSSION The "Heidelberg Model of Music Therapy for Chronic Tinnitus" seems to be effective in the long run. The outcome effect size of d' = 0.89, can be accounted for as "large" effect and falls into the upper range value compared to established treatments.
Nonmotility and phagocytic resistance of Pseudomonas aeruginosa isolates from chronically colonized patients with cystic fibrosis

Although Pseudomonas aeruginosa chronically colonizes most older patients with cystic fibrosis (CF), bacterial features responsible for its persistence are understood poorly. We observed that many P. aeruginosa isolates from chronically colonized patients were nonmotile and resistant to phagocytosis by macrophages. P. aeruginosa isolates were collected from 20 CF patients for up to 10 years. Isolates from early colonization were highly motile and expressed both flagellin and pilin. However, many isolates from chronically colonized patients lacked flagellin expression and were nonmotile; a total of 1,030 P. aeruginosa CF isolates were examined, of which 39% were nonmotile. Moreover, sequential isolates recovered from several of the CF patients were consistently nonmotile for up to 10 years. Lack of motility was rare among environmental isolates (1.4%) and other clinical isolates (3.7%) of P. aeruginosa examined. Partial complementation of motility in nonmotile P. aeruginosa isolates was achieved by introduction of extra copies of the rpoN locus carried on plasmid pPT212, indicating that the alternate sigma factor, RpoN, may be involved in the coordinate regulation of virulence factors during CF infection. We hypothesize that the nonmotile phenotype may provide P. aeruginosa a survival advantage in chronic CF infection by enabling it to resist phagocytosis and conserve energy.
Disqualified for disability pension – a case/referent study

Objectives: To analyse medical and other determinants for decisions about rejection or acceptance of applications for disability pension. Methods: A register-based retrospective case-control study was carried out in the area of a county in mid-Sweden. Cases were all individuals rejected a full disability pension 1999 – 2000, in all 99 cases. Controls were every tenth person granted a full disability pension during the same period, 198 individuals. Determinants were recorded from the protocols at the Social Insurance Office. Results: Unemployment (OR = 7.1, CI = 3.1 – 16.4), living in the main municipality, (OR = 2.8, CI = 1.4 – 5.8) and age below 50 years (OR = 0.4, CI = 0.2 – 0.8) were determinants for rejection of disability pension. Medical status, as described in the Social Insurance act, had no association with the outcome. Conclusions: There appear to be variations in praxis of rejection of applicants between Social Insurance boards in different geographical areas due to reasons other than medical. Socio-economic situation of the applicant may have an influence. Established criteria for determining work ability are needed.
Integrated use of ultra scale‐down and financial modeling to identify optimal conditions for the precipitation and centrifugal recovery of milk proteins

This article investigates the integrated application of ultra scale‐down (USD) techniques and economic modeling as a means for identifying optimal bioprocess operating conditions. The benefits of the approach are illustrated for the recovery of lactoperoxidase (LPO) from bovine milk. In the process, milk is skimmed to deplete its lipid content, before being subjected to low pH incubation with acetic acid in order to precipitate the primary impurity (casein). Following removal of the solids by disk stack centrifugation, pH adjustment and filtration, cation exchange chromatography is used as a positive mode column step to bind the LPO before it is polished and freeze dried. An economic model of this process was used to identify where greatest product loss occurs and hence where the largest opportunity cost was being incurred. Scale‐down analysis was used to characterize the influence of the critical steps, identified as precipitation and centrifugation, upon LPO recovery. A mathematical model was used to relate the centrifuge feed flowrate and discharge interval to the supernatant yield, and it was shown that increasing the centrifugal solids residence time achieved superior solids de‐watering and so higher product yield, although this also increased the overall processing time. To resolve this conflict, scale‐down data were used again in conjunction with an economic model to determine the most suitable conditions that maximized annual profit and minimized operating costs. The results demonstrate the power of combining USD data with models of economic and process performance in order to establish the best overall operating strategies for biopharmaceutical manufacture. © 2011 American Institute of Chemical Engineers Biotechnol. Prog. , 2011
Cultivating Creativity: Faculty Conceptions of Creativity in Agricultural Communications Students

Creativity has been deemed as an essential skill in agricultural communications graduates by both industry and academia, and it has a pivotal role in student success within the classroom and the workforce. In order to foster students’ creative thinking skills, faculty must turn away from traditional norms of lecture-based delivery and foster an environment where students are actively creating and engaging in the learning process. The purpose of this study was to provide insight on the nature of creativity as it relates to agricultural communications curriculum—focused on pedagogical strategies and creative assessments. This qualitative case study examined how agricultural communications faculty understood and facilitated creativity within their respective classrooms using in-depth, face-to-face interviews and documents. The findings revealed a lack of a cohesive language as it relates to creativity. Additionally, the results explored different pedagogical practices that facilitate creative thinking, and the various ways faculty perceive creative assessments. Based on participants’ responses, a social constructivist alignment in the classroom could prove beneficial in fostering a creative classroom environment. Additionally, the use of scaffolding (changing the level of instructor support) has proven useful in nurturing creative thought and constructing knowledge.
Binding STAT2 by the Acidic Domain of Human Cytomegalovirus IE1 Promotes Viral Growth and Is Negatively Regulated by SUMO

ABSTRACT The human cytomegalovirus (HCMV) 72-kDa immediate-early 1 (IE1) protein is thought to modulate cellular antiviral functions impacting on promyelocytic leukemia (PML) nuclear bodies and signal transducer and activator of transcription (STAT) signaling. IE1 consists of four distinct regions: an amino-terminal region required for nuclear localization, a large central hydrophobic region responsible for PML targeting and transactivation activity, an acidic domain, and a carboxyl-terminal chromatin tethering domain. We found that the acidic domain of IE1 is required for binding to STAT2. A mutant HCMV encoding IE1(Δ421-475) with the acidic domain deleted was generated. In mutant virus-infected cells, IE1(Δ421-475) failed to bind to STAT2. The growth of mutant virus was only slightly delayed at a high multiplicity of infection (MOI) but was severely impaired at a low MOI with low-level accumulation of viral proteins. When cells were pretreated with beta interferon, the mutant virus showed an additional 1,000-fold reduction in viral growth, even at a high MOI, compared to the wild type. The inhibition of STAT2 loading on the target promoter upon infection was markedly reduced with mutant virus. Furthermore, sumoylation of IE1 at this acidic domain was found to abolish the activity of IE1 to bind to STAT2 and repress the interferon-stimulated genes. Our results provide genetic evidence that IE1 binding to STAT2 requires the 55-amino-acid acidic domain and promotes viral growth by interfering with interferon signaling and demonstrate that this viral activity is negatively regulated by a cellular sumoylation pathway.
Phase I study of a novel capecitabine schedule based on the Norton-Simon mathematical model in patients with metastatic breast cancer.

PURPOSE This study was conducted to determine, in patients with advanced-stage breast cancer, the maximum tolerated dose (MTD) of capecitabine administered orally for 7 days followed by a 7-day rest (7/7), a schedule based on a mathematical method for the optimization of anticancer drug scheduling. PATIENTS AND METHODS Eligible patients had measurable, metastatic breast cancer. There was no limit to number of prior treatments. A standard, three-patients-per-cohort dose-escalation scheme used flat-dose capecitabine beginning at 1,500 mg orally twice daily (bid) on a 7/7 schedule. Each cohort was monitored for 28 days before escalation to the next cohort to assess for delayed toxicity. Response was evaluated radiographically every 12 weeks; toxicity was assessed every 2 weeks. RESULTS Twenty-one patients were treated on study. The most frequently reported treatment-related grade 2/3 adverse events were hand-foot syndrome (29%), leukopenia/neutropenia (24%), and fatigue (19%). Grade 3 toxicity was transient and easily managed. Three patients experienced grade 3 hand-foot syndrome; one of these patients had grade 3 diarrhea. There were no grade 4 events. The MTD of capecitabine 7/7 is 2,000 mg twice daily. CONCLUSION As predicted by mathematical modeling, capecitabine dosing for 7 days followed by a 7-day rest is well tolerated. Efficacy of this schedule is being determined in a phase II clinical trial in patients with advanced breast cancer.
An efficient topology for multilevel inverters: Design specifications and modulation technique

This manuscript introduces an efficient and generalized basic topology adopted for multilevel inverters. It is shown that the proposed structure is in line with significant savings in part counts and control devices. According to the basic topology, a new structure for sub-multilevel inverter is suggested. In continue, cascaded multilevel inverter is realized based on the series connection of n sub-multilevel inverters. By calculating the blocking voltage across the switches, the modulation technique is described for the proposed structure. A comprehensive analysis is founded to compare the proposed cascaded structure with the conventional CHB topology and the recently archived structures. The working conditions and performance of the proposed structure is verified through the simulation studies conducted in MATLAB/Simulink platform. Results are discussed in depth.
Effect of Valproate on Cerebral Metabolism and Blood Flow: An 18F‐2‐Deoxyglusose and 15O Water Positron Emission Tomography Study

Summary: We compared the effect of valproate (VPA) on cerebral metabolic rate for glucose (CMRGlc) and cerebral blood flow (CBF), measured with 18F‐2–deoxyglucose (I8FDG) and 15O water positron emission tomography (PET), in 10 normal volunteers. Mean VPA dose was 17.7 mg/kg, and mean VPA level was 82.1 mg/L (±16.5) for 4 weeks. VPA reduced global CMRGlc by 9.4% (9.60 2 0.76 vs. 8.59 ± 1.02 mg Glc/min/100 g, p < 0.05) and regionally in all anatomic areas (p < 0.05 for 11 of 26 areas). VPA diminished global CBF by 14.9% (56.55 ± 6.70 vs. 47.48 ± 4.42 ml/min/100 g, p < 0.002) and regionally in all anatomic areas (p < 0.05 for 12 of 26 areas). No significant correlation was noted between VPA level and either global CMRGlc or CBF. The effect of VPA on global CMRGlc is similar to that of carbamazepine (CBZ) and phenytoin but less than that of phenobarbital, Valium, or combination therapy with VPA and CBZ. VPA reduced regional CBF (rCBF) but not CMRGlc in the thalamus, an effect that may be associated with VPA's mechanism of action against generalized seizures.
Subtype‐specific regulation of the expression and function of muscarinic acetylcholine receptors in embryonic chicken retinal cells

We examined the effect of long‐term agonist exposure on muscarinic acetylcholine receptor expression and function in embryonic chicken retinal cells. Long‐term carbachol exposure induced a time‐ and concentration‐dependent decrease in M2, M3 and M4 muscarinic receptor numbers. Kinetic analyses revealed a first‐order process with similar rate constants for all three subtypes. Both the maximal decrease and the agonist potency for regulation of M3 were significantly higher than those for M2 and M4. Upon agonist removal, M2 and M4 numbers returned to control values, but M3 recovery after 24 h was no higher than 40%. Agonist treatment did not alter the levels of receptor mRNAs. Receptor inactivation with a covalent alkylating antagonist demonstrated that the partial M3 protein recovery was not due to a decreased intrinsic basal rate of synthesis, suggesting that it is induced by agonist treatment. Prolonged carbachol exposure induced concomitant decreases in muscarinic‐mediated inhibition of cyclic AMP accumulation which were completely reversed after agonist removal. Sustained receptor activation also promoted significant decreases in muscarinic receptor‐stimulated phosphoinositide turnover, which were only partially reversed after agonist removal. These data demonstrate subtype‐specific regulation of the expression and function of muscarinic receptors in the retina.