Miracle-dz/UniFAR-FTUs huggingface dataset:
Demethylation metabolism of roxithromycin in humans and rats.

AIM To investigate the demethylated metabolites of roxithromycin (RXM) in humans and rats, and to study the antibiotic activity of these metabolites in vitro. METHODS The demethylated metabolites of RXM in humans and in rats were identified by liquid chromatography-mass spectrometry (LC-MS), and the in vitro antibiotic activities of them against three standard strains were also studied compared with those of the parent drug and some other metabolites of RXM. RESULTS O-Demethylation of RXM was one of the main metabolic routes of RXM in humans, whereas N-demethylation metabolism was more predominant in rats. O-Demethyl-RXM appeared to be equally effective with RXM. CONCLUSION The O-demethyl-RXM was an active metabolite in humans, and there were some species differences in RXM demethylation metabolism between humans and rats.
Ironic midwives

In this article, I argue that despite their philosophical differences, Nietzsche and Kierkegaard share a philosophical method or style rooted in the irony of Socrates. Such irony, when used to distance the author of a written work from its reader, effects the same sort of relationship between the author and the truth as was characteristic of Socrates. Thus, by way of writing in a certain, artful way, both Kierkegaard and Nietzsche are able to pull away from their readers, depriving themselves of all authority and leaving the question of what is true in what they write ultimately up to the consideration, discernment and interpretation of the reader. As such, I conclude, Nietzsche and Kierkegaard are akin as two different instances of the Socratic midwife or maieutician.
The Forward Rates for Multifactor Model of Term Structure “With Square Root”

The multi-factor model “with square root” is discussed in details. For such model, the representation of state variable process in the integral form is derived and its covariance matrix is found. The special attention to the problem connected with the tendency for the term structure of long-term forward rates to slope downwards is given. For multi-factor models with square root the following results are derived: representations of the forward rate curve through the volatility of the state variable process and through the volatility of zero coupon yield process are obtained; the expectations, variances and co-variances for the forward rates and the yield process volatility are calculated; the expectation and the variance for the derivative of forward rate are found; the Brown − Schaefer approximation for the spread of forward rate is examined. As examples two three-factor models (BDFS and Chen models) are examined. On the basis of the estimates of parameters of these models received by empirical way the numerical analysis including calculation of covariance matrices of process of state variables, calculation of an expectation of the local variance of yield process and calculation of the variance of zero coupon yield have been fulfilled.
Evaluation of the Aptima® HIV‐1 Quant Dx assay for HIV‐1 RNA viral load detection and quantitation in plasma of HIV‐1‐infected individuals: A comparison with Abbott RealTime HIV‐1 assay

The Hologic Aptima® HIV‐1 Quant Dx assay (Aptima HIV) is a real‐time transcription‐mediated amplification method CE‐approved for use in diagnosis and monitoring of HIV‐1 infection. The analytical performance of this new assay was compared to the FDA‐approved Abbott RealTime HIV‐1 (RealTime). The evaluation was performed using 220 clinical plasma samples, the WHO 3rd HIV‐1 International Standard, and the QCMD HIV‐1 RNA EQA. Concordance on qualitative results, correlation between quantitative results, accuracy, and reproducibility of viral load data were analyzed. The ability to measure HIV‐1 subtypes was assessed on the second WHO International Reference Preparation Panel for HIV‐1 Subtypes. With clinical samples, inter‐assay agreement for qualitative results was high (91.8%) with Cohen's kappa statistic equal to 0.836. For samples with quantitative results in both assays (n = 93), Lin's concordance correlation coefficient was 0.980 (P < 0.0001) and mean differences of measurement, conducted according to Bland–Altman method, was low (0.115 log10 copies/ml). The Aptima HIV quantified the WHO 3rd HIV‐1 International Standard diluted from 2000 to 31 cp/ml (5,700–88 IU/ml) at expected values with excellent linearity (R2 > 0.970) and showed higher sensitivity compared to RealTime being able to detect HIV‐1 RNA in 10 out of 10 replicates containing down to 7 cp/ml (20 IU/ml). Reproducibility was very high, even at low HIV‐1 RNA values. The Aptima HIV was able to detect and accurately quantify all the main HIV‐1 subtypes in both reference panels and clinical samples. Besides excellent performance, Aptima HIV shows full automation, ease of use, and improved workflow compared to RealTime. J. Med. Virol. 88:1535–1544, 2016. © 2016 Wiley Periodicals, Inc.
Rapid response systems: A systematic review*

Context:Rapid response systems have been advocated as a potential model to identify and intervene in patients who are experiencing deterioration on general hospital wards. Objective:To conduct a meta-analysis to evaluate the impact of rapid response systems on hospital mortality and cardiac arrest rates. Data Source:We searched MEDLINE, EMBASE, and the Cochrane Library from January 1, 1990, to June 30, 2005, for all studies relevant to rapid response systems. We restricted the search to the English language and by age category (all adults: ≥19 years). Study Selection:We selected observational and randomized trials of rapid response systems that provided empirical data on hospital mortality and cardiac arrest in control and intervention groups. We reviewed 10,228 abstracts and identified eight relevant studies meeting these criteria. Data Synthesis:Of the included studies, five used historical controls, one used concurrent controls, and two used a cluster-randomized design. The pooled relative risk for hospital mortality comparing rapid response teams to control was 0.76 (95% confidence interval, 0.39–1.48) between the two randomized studies and 0.87 (95% confidence interval, 0.73–1.04) among the five observational studies. The pooled relative risk for cardiac arrest comparing rapid response systems to control was 0.94 (95% confidence interval, 0.79–1.13) in the single randomized study and 0.70 (95% confidence interval, 0.56–0.92) in four observational studies. Conclusions:We found weak evidence that rapid response systems are associated with a reduction in hospital mortality and cardiac arrest rates, but limitations in the quality of the original studies, the wide confidence intervals, and the presence of heterogeneity limited our ability to conclude that rapid response systems are effective interventions. Large randomized controlled trials are needed to clarify the efficacy of rapid response systems before they should become standard of care.
The missing evidence in favour of restricting emigration

Debating Brain Drain is an excellent book and I have learned much from both Gillian Brock's and Michael Blake's contributions.1 In this commentary, I will focus on Brock's contribution in part because I largely agree with Blake's position. But I also think that Blake neglects to emphasise some important epistemic considerations that weigh against Brock's argument. Brock argues for the view that legitimate states can permissibly require skilled citizens to complete compulsory service before they can emigrate. One component of Brock's argument for compulsory service requirements is that these programmes would reduce deprivation. For example, many poor countries have few doctors, nurses and other health workers. If health workers emigrate from these countries, then the citizens of these countries may lack access to adequate medical care. Suppose though that states required health workers to complete compulsory service before they can emigrate. This policy might help alleviate the shortage of health workers in poor countries. Brock's argument for compulsory service has other facets as well. She argues that skilled citizens have moral responsibilities to remain in their countries for a period of time and states can therefore compel these citizens to stay. But Brock indicates that compulsory service programmes for skilled citizens …
Issues and challenges in pediatric asthma

Much recent attention has been focused on pediatric asthma, with regard to both epidemiological trends and appropriate treatment (1). With regard to the former, statistics on the rising asthma-associated morbidity and prevalence indicate a disproportionate effect on children. With regard to the latter, recent studies have clearly documented a state of chronic airway inflammation in asthma in its mildest forms and in children. As such, attention to the reduction of inflammation therapeutically is increasing substantially via the introduction of new and improved drugs/delivery methods. However, it is of interest that alarming epidemiological trends are occurring at a time of unprecedented increase in the level of understanding of asthma pathogenesis and the spectrum and number of very effective therapies in the asthma marketplace. This suggests that currently available therapies are not being used effectively. For these therapies to be effective, both education and behavioral modification for both prescribing physicians andpatients will be essential (2). With regard to behavioral modification, physicians must modify their prescribing habits, which are often driven by convenience and time constraints, and patients must modify behaviors that lessen their adherence to prescribed therapies. For certain drug classes a difference exits between ‘‘efficacy’’ and ‘‘effectiveness’’. For example, a drug that had demonstrated ‘‘efficacy’’ in published controlled clinical trials may have poor ‘‘effectiveness’’ in patients treated in a practice because it tastes unpleasant. Efficacy is established under optimal, controlled conditions. The enrolled patients are healthy (other than the disease under study) and must adhere to therapy during a typical 12-week period. Moreover, they receive extensive teaching about medication use to achieve optimal inhaled drug delivery. In a clinical ‘‘real-world’’ practice where a drug is used for many months or years without close monitoring, many or all of these parameters are often not controlled and patients therefore do not experience the potential benefit of a drug prescription. They often do not understand the risks and benefits of a given drug and how to achieve optimal benefit. It thus behoves clinicians to consider patient-driven factors that gain effectiveness from a drug with established efficacy when they choose daily controller therapy for asthmatics, especially in children (3). These adherence-promoting factors include ease of use and provision of the minimal required level of education about the benefit/risk of the drug.
Apoptosis Signal-regulating Kinase 1 Controls the Proapoptotic Function of Death-associated Protein (Daxx) in the Cytoplasm*

Although Daxx (death-associated protein) was first reported to mediate the apoptotic signal from Fas to JNK in the cytoplasm, other data suggested that Daxx is mainly located in the nucleus as a transcriptional regulator. Here, we demonstrated that cellular localization of Daxx could be determined by the relative concentration of a proapoptotic kinase, apoptosis signal-regulating kinase 1 (ASK1) by using immunofluorescence and transcriptional reporter assay. ASK1 sequestered Daxx in the cytoplasm and inhibited the repressive activity of Daxx in transcription. In addition, Daxx was bound to the activated Fas only in the presence of ASK1, accelerating the Fas-mediated apoptosis. These results suggest that Daxx requires ASK1 for its cytoplasmic localization and Fas-mediated signaling. Taken together, we could conclude that ASK1 controls the dual function of Daxx as a transcriptional repressor in the nucleus and as a proapoptotic signal mediator in the cytoplasm.
Analogy, Frequency, and Sound Change. The Case of Dutch Devoicing

This study investigates the roles of phonetic analogy and lexical frequency in an ongoing sound change, the devoicing of fricatives in Dutch, which occurs mainly in the Netherlands and to a lesser degree in Flanders. In the experiment, Dutch and Flemish students read two variants of 98 words: the standard and a nonstandard form with the incorrect voice value of the fricative. Dutch students chose the non-standard forms with devoiced fricatives more often than Flemish students. Moreover, devoicing, though a gradual process, appeared lexically diffused, affecting first the words that are low in frequency and phonetically similar to words with voiceless fricatives. *
MicroRNA‐15b represents an independent prognostic parameter and is correlated with tumor cell proliferation and apoptosis in malignant melanoma

MicroRNAs (miRNAs) are small noncoding RNAs (∼22 bp) that posttranscriptionally regulate gene expression. MiRNAs possess oncogenic or tumor suppressor activity in various tumors but little is known about miRNA expression pattern in malignant melanoma. We determined the expression level of 16 potentially relevant miRNAs (miR‐15a, miR‐15b, miR‐16, miR‐34a, miR‐210, let‐7I, miR‐23a, miR‐23b, miR‐24, miR‐27a, miR‐27b, miR‐100, miR‐137, miR‐222, miR‐373‐1, miR‐373*) by real‐time PCR in 6 preparations of normal melanocytes vs. 10 melanoma cell lines and in formalin fixed paraffin embedded tissue of 11 melanocytic nevi versus 16 melanomas. MiR‐15b and miR‐210 were significantly upregulated, miR‐34a was significantly downregulated in melanomas compared with melanocytic nevi. These 3 miRNAs were analyzed in a total of 128 primary melanomas from patients with detailed clinical follow‐up information. High expression of miR‐15b (but not miR‐210 upregulation and miR‐34a downregulation) was significantly associated with poor recurrence free survival and overall survival by univariate Kaplan‐Meier and multivariate Cox analyses. Downregulation of miR‐15b in two melanoma cell lines with high miR‐15b expression by transfection with anti‐miR‐15b siRNA was associated with reduced tumor cell proliferation, whereas apoptosis was increased. In summary, miRNA expression levels show distinct differences comparing benign and malignant melanocytic cell proliferations and can provide independent prognostic informations. MiR‐15b appears to represent a particular important miRNA in melanoma that is associated with poor prognosis and tumorigenesis.
Involvement of high plasma corticosterone status and activation of brain regional serotonin metabolism in long-term erythrosine-induced rearing motor hyper activity in young adult male rats

Long-term consumption of artificial food color(s) can induce behavioral hyperactivity in human and experimental aminals, but no neurobiochemical mechanism is defined. This study investigates the role of brain regional serotonin metabolism including its turnover, MAO-A activity, and plasma corticosterone status in relation to behavioral disturbances due to an artificial food color, erythrosine. Long-term (15 or 30 consecutive days) erythrosine administration with higher dosage (10 or 100 mg/kg/day, p.o.) produced optimal hyperactive state in exploratory behavior (rearing motor activity) after 2 h of last erythrosine administration, in young adult male albino rats. Erythrosine-induced stimulation in brain regional (medulla-pons, hypothalamus, hippocampus, and corpus striatum) serotonin metabolism (measuring steady state levels of 5-HT and 5-HIAA, MAO-A activity), including its turnover (pargyline-induced 5-HT accumulation and 5-HIAA declination rate), as well as plasma corticosterone were also observed depending on dosage(s) and duration(s) of erythrosine administration under similar experimental conditions. The lower dosage of erythrosine (1 mg/kg/day, p.o.) under similar conditions did not affect either of the above. These findings suggests (a) the induction as well as optimal effect of long-term erythrosine (artificial food color) on behavioral hyperactivity in parallel with increase in 5-HT level in brain regions, (b) the activation of brain regional serotonin biosynthesis in accordance with plasma corticosterone status under such behavioral hyperactivity, and (c) a possible inhibitory influence of the enhanced glucocorticoids–serotonin interaction on erythrosine-induced rearing motor hyperactivity in young adult mammals.
The Early Effect of Olanzapine and Risperidone on Insulin Secretion in Atypical-naïve Schizophrenic Patients

Abstract: Recently, increasing attention has been drawn to the potential diabetogenic effect of atypical antipsychotics. The goal of this prospective study is to evaluate the early effect of olanzapine and risperidone treatment on pancreatic β-cell function in atypical-naive schizophrenic patients. Twenty-six subjects were assigned randomly to therapy with olanzapine or risperidone for 14 days. The metabolic parameters were quantitatively assessed by using the intravenous glucose tolerance test. The levels of fasting glucose, fasting insulin, lipid profiles, and leptin were also assessed. There were no significant within-group changes in weight or body mass index for both groups after 2 weeks of treatment. The levels of fasting glucose, fasting insulin, cholesterol, or leptin did not change in both groups. The triglyceride level significantly increased in olanzapine group. Glucose disappearance rate and insulin sensitivity did not change in both groups. Insulin secretion significantly decreased in olanzapine group. After 2 weeks of olanzapine treatment, schizophrenic patients decreased insulin secretory response to a hyperglycemic challenge. The results of this study support the hypothesis that olanzapine might directly impair pancreatic β-cell function.
A role for histone deacetylases in the cellular and behavioral mechanisms underlying learning and memory

Histone deacetylases (HDACs) are a family of chromatin remodeling enzymes that restrict access of transcription factors to the DNA, thereby repressing gene expression. In contrast, histone acetyltransferases (HATs) relax the chromatin structure allowing for an active chromatin state and promoting gene transcription. Accumulating data have demonstrated a crucial function for histone acetylation and histone deacetylation in regulating the cellular and behavioral mechanisms underlying synaptic plasticity and learning and memory. In trying to delineate the roles of individual HDACs, genetic tools have been used to manipulate HDAC expression in rodents, uncovering distinct contributions of individual HDACs in regulating the processes of memory formation. Moreover, recent findings have suggested an important role for HDAC inhibitors in enhancing learning and memory processes as well as ameliorating symptoms related to neurodegenerative diseases. In this review, we focus on the role of HDACs in learning and memory, as well as significant data emerging from the field in support of HDAC inhibitors as potential therapeutic targets for the treatment of cognitive disorders.
Changes in DNA polymerase activity associated with cell fusion in cultures of embryonic muscle

In cultures of differentiating chicken embryo muscle cells there is a steep decline in DNA polymerase activity which closely parallels the time of rapid cell fusion and the formation of multinucleated myotubes. The DNA polymerase activity remaining in the cultures is almost completely associated with single unfused cells. Cell fusion does not require a confluent culture and fusion capability appears to be severely reduced in the remaining single cells following an approximately ten hour time period during which the majority of fusion takes place. A model is presented to explain the observed kinetics of cell growth and cell fusion in vitro.
Sequence-Based Analysis of the Intestinal Microbiota of Sows and Their Offspring Fed Genetically Modified Maize Expressing a Truncated Form of Bacillus thuringiensis Cry1Ab Protein (Bt Maize)

ABSTRACT The aim was to investigate transgenerational effects of feeding genetically modified (GM) maize expressing a truncated form of Bacillus thuringiensis Cry1Ab protein (Bt maize) to sows and their offspring on maternal and offspring intestinal microbiota. Sows were assigned to either non-GM or GM maize dietary treatments during gestation and lactation. At weaning, offspring were assigned within sow treatment to non-GM or GM maize diets for 115 days, as follows: (i) non-GM maize-fed sow/non-GM maize-fed offspring (non-GM/non-GM), (ii) non-GM maize-fed sow/GM maize-fed offspring (non-GM/GM), (iii) GM maize-fed sow/non-GM maize-fed offspring (GM/non-GM), and (iv) GM maize-fed sow/GM maize-fed offspring (GM/GM). Offspring of GM maize-fed sows had higher counts of fecal total anaerobes and Enterobacteriaceae at days 70 and 100 postweaning, respectively. At day 115 postweaning, GM/non-GM offspring had lower ileal Enterobacteriaceae counts than non-GM/non-GM or GM/GM offspring and lower ileal total anaerobes than pigs on the other treatments. GM maize-fed offspring also had higher ileal total anaerobe counts than non-GM maize-fed offspring, and cecal total anaerobes were lower in non-GM/GM and GM/non-GM offspring than in those from the non-GM/non-GM treatment. The only differences observed for major bacterial phyla using 16S rRNA gene sequencing were that fecal Proteobacteria were less abundant in GM maize-fed sows prior to farrowing and in offspring at weaning, with fecal Firmicutes more abundant in offspring. While other differences occurred, they were not observed consistently in offspring, were mostly encountered for low-abundance, low-frequency bacterial taxa, and were not associated with pathology. Therefore, their biological relevance is questionable. This confirms the lack of adverse effects of GM maize on the intestinal microbiota of pigs, even following transgenerational consumption.
HER‐2/neu expression in extramammary Paget disease: a clinicopathologic and immunohistochemistry study of 47 cases with and without underlying malignancy

Extramammary Paget disease (EMPD) is an infrequent skin cancer sometimes representing a secondary event caused by extension of an underlying carcinoma. Her‐2/neu overexpression in breast cancer is correlated with a more aggressive behavior, but anti‐Her‐2/neu therapy improves survival in these patients. We investigated Her‐2/neu expression by immunohistochemistry in cases of EMPD with and without underlying malignancy to try to correlate with tumor recurrence, progression and possible targeted therapy. Forty‐seven cases were analyzed (6 from the scrotum, 7 perianal region, 1 axilla and 33 vulva). Two cases had invasive EMPD (one from vulva and one from scrotum). The overall Her‐2/neu expression was 31.9%. Of the noninvasive EMPD of the vulva (32 cases), Her‐2/neu was shown in 38%. The case of invasive vulvar EMPD was negative. All six scrotal EMPD lacked Her2/neu expression. Her‐2/neu was expressed in two of seven perianal cases (33.3%). The EMPD on the axilla (one case) was negative. Eighteen cases had recurrence, and of these, 44.4% expressed Her‐2/neu in the initial lesion. A high proportion of EMPD showed Her‐2/neu expression (31.9%), indicating that these patients may benefit from targeted therapy. The proportion of positive cases was higher in lesions that had recurred at last follow up (44.4%), suggesting a more aggressive behavior.