Miracle-dz/UniFAR-FTUs huggingface dataset:
A study on the metabolism of etoposide and possible interactions with antitumor or supporting agents by human liver microsomes.

The metabolism of etoposide was investigated by using human liver microsomes and nine recombinant human cytochrome P450 (CYP) isoforms to identify the CYP isoform(s) involved in the major metabolic pathway (3'-demethylation) of etoposide as well as to evaluate the possible metabolic interactions with several antitumor or supporting agents. The 3'-demethylation of etoposide followed a Michaelis-Menten one-enzyme kinetic behavior in six human liver microsomal samples. The relationships were assessed with six different human liver microsomes between the 3'-demethylation of etoposide and metabolic activities for substrate probes of the respective CYP isoforms, showing a significant correlation (r = 0. 932, P < .01) only with 6beta-hydroxylation of testosterone, a marker substrate for CYP3A4. Inhibitor/substrate probes for CYP3A4, ketoconazole, troleandomycin, verapamil and cyclosporin, or supporting agents, vincristine and prednisolone, inhibited etoposide 3'-demethylation by human liver microsomes. p-Nitrophenol, a substrate for CYP2E1, also inhibited etoposide 3'-demethylation. Among the nine recombinant human CYP isoforms, CYP3A4 exhibited the highest catalytic activity with respect to etoposide 3'-demethylation, compared with the minor activities of CYP1A2 and 2E1. Collectively, these data suggest that etoposide 3'-demethylation is mediated mainly by CYP3A4 and to a minor extent by CYP1A2 and 2E1. Furthermore, some supporting agents (vincristine and prednisolone) and the substrates of CYP3A4, which may be coadministered with etoposide during the cancer chemotherapies, inhibit the etoposide 3'-demethylation activity in vitro. The results may provide clinical implications with respect to the possible metabolic interactions between etoposide and other drugs studied herein in patients with cancer undergoing etoposide concurrently with either of them.
Nonincrease Everywhere of the Brownian Motion Process

The (linear, separable) Brownian motion process has been studied more than any other stochastic process. It has many applications and, at least since Bachelier, probabilists have been at(tract,ed by its delicate and curious properties. It furnished, in the hands of N. Jyiener, the first instance of a satisfactorily defined nondiscrete stochastic process n-ith continuous time parameter, and it is this work on Browninn motion (also known as Wiener space) that suggested t,he, now universally adopted, method of A. N. Kolmogorov for defining stochastic processes. Moat advanced books on probability devote some space to t,his process but the more delicate results are beyond their scope. A notable exception is P. L&y [2] which contains a x.ery profound study of t,he process. However, though the proof of our principal result could be expedited by appealing to some advanced work on Brownian motion xe preferred a presentation using only the simpler and better known properties of the process. The Brownian motion process can be described as a probability space whose elements are all continuous functions defined on the whole real line and vanishing at the origin. The principal aim of this paper is to pro\-e the, to US rather unexpected, result that the probabilify of the set of fw&ions uAich increase at least at one point is zero. [A function is said to increase at a point if its values slightly to t#he right (left) of this point are not smaller (larger) t,han its value at the point,. ] A formal statement of this result, will be given in the nest section and its significance will be discussed in the following one. Section 4 will give an interesting, though wrong and leading to a wrong result, heuristic argument. The
Biomarkers of Environmental Enteropathy, Inflammation, Stunting, and Impaired Growth in Children in Northeast Brazil

Critical to the design and assessment of interventions for enteropathy and its developmental consequences in children living in impoverished conditions are non-invasive biomarkers that can detect intestinal damage and predict its effects on growth and development. We therefore assessed fecal, urinary and systemic biomarkers of enteropathy and growth predictors in 375 6–26 month-old children with varying degrees of malnutrition (stunting or wasting) in Northeast Brazil. 301 of these children returned for followup anthropometry after 2-6m. Biomarkers that correlated with stunting included plasma IgA anti-LPS and anti-FliC, zonulin (if >12m old), and intestinal FABP (I-FABP, suggesting prior barrier disruption); and with citrulline, tryptophan and with lower serum amyloid A (SAA) (suggesting impaired defenses). In contrast, subsequent growth was predicted in those with higher fecal MPO or A1AT and also by higher L/M, plasma LPS, I-FABP and SAA (showing intestinal barrier disruption and inflammation). Better growth was predicted in girls with higher plasma citrulline and in boys with higher plasma tryptophan. Interactions were also seen with fecal MPO and neopterin in predicting subsequent growth impairment. Biomarkers clustered into markers of 1) functional intestinal barrier disruption and translocation, 2) structural intestinal barrier disruption and inflammation and 3) systemic inflammation. Principle components pathway analyses also showed that L/M with %L, I-FABP and MPO associate with impaired growth, while also (like MPO) associating with a systemic inflammation cluster of kynurenine, LBP, sCD14, SAA and K/T. Systemic evidence of LPS translocation associated with stunting, while markers of barrier disruption or repair (A1AT and Reg1 with low zonulin) associated with fecal MPO and neopterin. We conclude that key noninvasive biomarkers of intestinal barrier disruption, LPS translocation and of intestinal and systemic inflammation can help elucidate how we recognize, understand, and assess effective interventions for enteropathy and its growth and developmental consequences in children in impoverished settings.
The shared and unique genetic relationship between mental well-being, depression and anxiety symptoms and cognitive function in healthy twins

ABSTRACT Alterations to cognitive function are often reported with depression and anxiety symptoms, yet few studies have examined the same associations with mental well-being. This study examined the association between mental well-being, depression and anxiety symptoms and cognitive function in 1502 healthy adult monozygotic (MZ) and dizygotic (DZ) twins, and the shared/unique contribution of genetic (G) and environmental (E) variance. Using linear mixed models, mental well-being was positively associated (p < .01) with sustained attention (β = 0.127), inhibition (β = 0.096), cognitive flexibility (β = 0.149), motor coordination (β = 0.114) and working memory (β = 0.156), whereas depression and anxiety symptoms were associated (p < .01) with poorer sustained attention (β = −0.134), inhibition (β = −0.139), cognitive flexibility (β = −0.116) and executive function (β = −0.139). Bivariate twin modelling showed well-being shared a small environmental correlation with motor coordination and a small genetic correlation with working memory. Trivariate twin modelling showed well-being shared a small genetic correlation with inhibition, whereas depression and anxiety symptoms shared a small environmental correlation with inhibition. The remaining variance was mostly driven by unique G and/or E variance. Overall, well-being and depression and anxiety symptoms show both independent and shared relationships with cognitive functions but this is largely attributable to unique G or E variance and small shared G/E variance between pairs of variables.
Natalizumab treatment leads to an increase in circulating CXCR3-expressing B cells

Objective: To study the effects of natalizumab treatment on subgroups of circulating peripheral blood B cell populations. Methods: We studied the proportions and absolute numbers of CD19+CD20+, CD10+, and CD5+ B cell populations, and determined very late activation antigen-4 and chemokine receptor CXCR3, CCR5, and CCR6 expression on B cells in the peripheral blood of 14 natalizumab-treated patients with relapsing-remitting multiple sclerosis. Five blood samples per patient were obtained longitudinally before and during the first year of treatment. Blood samples were analyzed by 6-color flow cytometry. Results: Proportions of B cells and CD10+ pre–B cells were significantly increased, and very late activation antigen-4 expression on the B cell surface was significantly decreased already after 1 week of natalizumab treatment. Natalizumab-induced sustained increase in the proportion and absolute number of CXCR3-expressing B cells was statistically significant after 1 month of treatment. There were no changes in the proportions of CCR5- or CCR6-expressing B cells. Conclusions: The rapid and persistent increase in circulating CXCR3-expressing B cells in response to natalizumab treatment possibly reflects the relevance of this chemokine receptor in controlling migration of B cells into the CNS in humans in vivo.
Predictors of seizures during pregnancy in women with epilepsy

We aimed to characterize the seizure pattern during pregnancy in a large cohort of women with epilepsy (WWE) and identify possible predictors of seizure relapse during pregnancy. We recorded the antiepileptic drug (AED) use and seizure frequency for WWE during the prepregnancy month and pregnancy. The seizure profile was correlated with the clinical details and seizure type as abstracted from the clinical records maintained in the registry. Of the 1,297 pregnancies in WWE with complete seizure data, 47.8% were seizure‐free during pregnancy. Seizure relapse was highest during the three peripartum days. Women with partial seizures‐had higher risk of relapse (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.2–2.0) than those with generalized seizures. They had two peaks of seizure relapse (second to third month and sixth month). Those with generalized seizures had one peak at first trimester. Those who were on polytherapy had increased risk of seizures (OR 2.98, 95% CI 2.3–3.9) when compared to those on monotherapy. Those who had seizures in the prepregnancy month had higher risk (OR 15, 95% CI 9–25.1) of seizures during pregnancy when compared to those who were seizure‐free during that period. On multiple logistic regression, prepregnancy seizure was the most important predictor of seizures during pregnancy.
Occurrence of Myocardial Ischemia in Patients Undergoing Pharmacologic Stress Echocardiography: The Impact of Type-D Personality

Background: Type-D personality has been identified as a risk factor for general and cardiac mortality in patients with coronary artery disease (CAD). Dobutamine-atropine stress echocardiography (DASE) is an established method for non-invasive evaluation of myocardial ischemia in patients with CAD. The objective of this study was to evaluate the prevalence of type-D personality and its association with the occurrence of myocardial ischemia as assessed by DASE. Methods: This case-control study enrolled 306 patients (61 ± 9.6 years, 57.8% female) who were referred by physicians to assessment of myocardial ischemia. Before undergoing DASE, the patients answered the type-D scale, which identifies type-D personality. Results: Type-D personality was identified in 106 patients (34.6%). DASE was positive for myocardial ischemia in 32.4% (99) of 306 participants there was no significant association between type-D personality and ischemic changes on DASE (P = 0.941; odds ratio: 0.98; confidence interval 95%: 0.57-1.69). Chest pain was the only clinical variable with statistically significant prevalence in type-D personality patients (77.4% vs. 57.0%; P < 0.001). Conclusions: Type-D personality was not a significant risk factor for the presence of ischemic changes on DASE. Patients with type-D personality tended to complain more frequently of chest pain than non-type-D patients.
Chlorhexidine-Impregnated Dressing for Prevention of Catheter-Related Bloodstream Infection: A Meta-Analysis*

Objective:To assess the efficacy of a chlorhexidine-impregnated dressing for prevention of central venous catheter–related colonization and catheter-related bloodstream infection using meta-analysis. Data Sources:Multiple computerized database searches supplemented by manual searches including relevant conference proceedings. Study Selection:Randomized controlled trials evaluating the efficacy of a chlorhexidine-impregnated dressing compared with conventional dressings for prevention of catheter colonization and catheter-related bloodstream infection. Data Extraction:Data were extracted on patient and catheter characteristics and outcomes. Data Synthesis:Nine randomized controlled trials met the inclusion criteria. Use of a chlorhexidine-impregnated dressing resulted in a reduced prevalence of catheter-related bloodstream infection (random effects relative risk, 0.60; 95% CI, 0.41–0.88, p = 0.009). The prevalence of catheter colonization was also markedly reduced in the chlorhexidine-impregnated dressing group (random effects relative risk, 0.52; 95% CI, 0.43–0.64; p < 0.001). There was significant benefit for prevention of catheter colonization and catheter-related bloodstream infection, including arterial catheters used for hemodynamic monitoring. Other than in low birth weight infants, adverse effects were rare and minor. Conclusions:Our analysis shows that a chlorhexidine-impregnated dressing is beneficial in preventing catheter colonization and, more importantly, catheter-related bloodstream infection and warrants routine use in patients at high risk of catheter-related bloodstream infection and central venous catheter or arterial catheter colonization.
Simulation of Action Potential Propagation in an Inhomogeneous Sheet of Coupled Excitable Cells

Cable theory and active equivalent circuits have been used to simulate the propagation of action potentials along a single nerve or muscle fiber by representing the cell as a unidimensional cable composed of isopotential segments. We extended this method to a two-dimensional sheet of cells which in many ways represents the atrium. Our method consisted of solving for the potential profile of a sheet composed of a large number of isopotential membrane patches, each of which was represented by an active equivalent circuit in which the ionic conductances were functions of voltage and time. The patches were arranged in a rectangular array with resistive interconnections that could be varied over the sheet. We used this model to study the effect of various inhomogeneities on conduction velocity and the resulting wave fronts in a sheet of excitable tissue. Some of these inhomogeneities included different effective internal resistances in the x and y directions, preferential pathways, and discrete regions of changing resistive connections. The results showed that very localized changes in membrane properties or cellular interconnections produce changes in the wave front over broad areas. This model provides a method for computing the wave fronts of action potential propagation in any two-dimensional inhomogeneous sheet of coupled excitable cells.
The GRK2 Overexpression Is a Primary Hallmark of Mitochondrial Lesions during Early Alzheimer Disease

Increasing evidence points to vascular damage as an early contributor to the development of two leading causes of age-associated dementia, namely Alzheimer disease (AD) and AD-like pathology such as stroke. This review focuses on the role of G protein-coupled receptor kinases (GRKs) as they relate to dementia and how the cardio and cerebrovasculature is involved in AD pathogenesis. The exploration of GRKs in AD pathogenesis may help bridge gaps in our understanding of the heart-brain connection in relation to neurovisceral damage and vascular complications of AD. The a priori basis for this inquiry stems from the fact that kinases of this family regulate numerous receptor functions in the brain, myocardium and elsewhere. The aim of this review is to discuss the finding of GRK2 overexpression in the context of early AD pathogenesis. Also, we consider the consequences for this overexpression as a loss of G-protein coupled receptor (GPCR) regulation, as well as suggest a potential role for GPCRs and GRKs in a unifying theory of AD pathogenesis through the cerebrovasculature. Finally, we synthesize this newer information in an attempt to put it into context with GRKs as regulators of cellular function, which makes these proteins potential diagnostic and therapeutic targets for future pharmacological intervention.
Identification of the proximate and ultimate forms of the carcinogen 15,16-dihydro-11-methylcyclopenta[a]phenanthren-17-one.

Abstract Enzymatic hydrolysis of calf thymus DNA treated in vitro with the carcinogen 15,16-dihydro-11-methylcyclopenta[ a ]phenanthren-17-one and a microsomal enzyme system followed by column chromatography disclosed two adduct fractions, A and B, eluting after the natural nucleosides. Isolation and hydrolysis of the DNA from the skin of mice treated topically with 15,16-dihydro-11-methylcyclopenta[ a ]phenanthren-17-one or from mouse embryo cells exposed to 15,16-dihydro-11-methylcyclopenta[ a ]phenathren-17-one in culture gave mainly Adduct B identical with that obtained in vitro . The seven main metabolites formed from 15,16-dihydro-11-methylcyclopenta[ a ]phenanthren-17-one with the microsomal system were isolated by high-pressure liquid chromatography and were individually incubated with DNA and the activating system; the DNA was subsequently recovered and analyzed. Adduct B arose from a single metabolite identified on the basis of its ultraviolet and mass spectra together with its general chemical behavior as a 3,4-dihydro- trans -3,4-dihydroxy derivative of 15,16-dihydro-11-methylcyclopenta[ a ]phenanthren-17-one. In addition, this metabolite was the most mutagenic in the Ames test, being more active than the carcinogen itself. This metabolite is therefore the proximate form of the carcinogen. The ultraviolet spectrum of Adduct B resembled that of a 1,2,3,4-tetrahydro derivative of 15,16-dihydro-11-methylcyclopenta[ a ]phenanthren-17-one, while the chromatographic mobility of the adduct on Sephadex LH-20 was markedly increased by inclusion of borate in the eluant, indicating a cis -diol system. Since the 3,4-diol is trans , this suggests further metabolism of the benzo ring. It is therefore proposed that the ultimate carcinogen is a 1,2-dihydro-1,2-epoxy-3,4-dihydro- trans -3,4-diol of 15,16-dihydro-11-methylcyclopenta[ a ]phenanthren-17-one.
Localization of cannabinoid receptor mRNA in rat brain

Cannabinoid receptor mRNA was localized in adult rat brain by 35S‐tailed oligonucleotide probes and in situ hybridization histochemistry. Labelling is described as uniform or non‐uniform depending on the relative intensities of individual cells expressing cannabinoid receptor mRNA within a given region or nucleus. Uniform labelling was found in the hypothalamus, thalamus, basal ganglia, cerebellum and brainstem. Non‐uniform labelling that resulted from the presence of cells displaying two easily distinguishable intensities of hybridization signals was observed in several regions and nuclei in the forebrain (cerebral cortex, hippocampus, amygdala, certain olfactory structures). Olfactory‐associated structures, basal ganglia, hippocampus, and cerebellar cortex displayed the heaviest amounts of labelling. Many regions that displayed cannabinoid receptor mRNA could reasonably be identified as sources for cannabinoid receptors on the basis of well documented hodologic data. Other sites that were also clearly labelled could not be assigned as logical sources of cannabinoid receptors. The localization of cannabinoid receptor mRNA indicates that sensory, motor, cognitive, limbic, and autonomic systems should all be influenced by the activation of this receptor by either exogenous cannabimimetics, including marijuana, or the yet unknown endogenous “cannabinoid” ligand. © 1993 Wiley‐Liss, Inc.
The inverse relationship between food price and energy density: is it spurious?

Abstract Objective An important debate in the literature is whether or not higher energy-dense foods are cheaper than less energy-dense foods. The present communication develops and applies an easy statistical test to determine if the relationship between food price and energy density is an artifact of how the data units are constructed (i.e. is it ‘spurious’ or ‘real’? ). Design After matching data on 4430 different foods from the National Health and Nutrition Examination Survey with corresponding prices from the Center for Nutrition Policy and Promotion’s Food Prices Database, we use a simple regression model to test if the relationship between food price and energy density is ‘real’ or ‘spurious’. Setting USA. Subjects Total sample size is 4430 observations of consumed foods from 4578 participants from the non-institutionalized US adult population (aged 19 years and over). Results Over all 4430 foods, the null hypothesis of a spurious inverse relationship between food price per energy density and energy density is not rejected. When the analysis is broken down by twenty-five food groups, there are only two cases where the inverse relationship is not spurious. In fact, the majority of non-spurious relationships between food price and energy density are positive, not negative. Conclusions One of the main arguments put forth regarding the poor diet quality of low-income households is that high energy-dense food is cheaper than lower energy-dense food. We find almost no statistical support for higher energy-dense food being cheaper than low energy-dense food. While economics certainly plays a role in explaining low nutritional quality, more sophisticated economic arguments are required and discussed.
Long-term efficacy and safety outcomes with OROS-MPH in adults with ADHD

Methylphenidate (MPH) is widely prescribed for adults with attention deficit hyperactivity disorder (ADHD), but data on long-term treatment and maintenance of effect are lacking. Osmotic release oral system-methylphenidate (OROS–MPH) was evaluated in a 52-wk open-label study in subjects who had previously completed a short-term placebo-controlled trial and short-term open-label extension. Efficacy was assessed using the investigator- and subject-rated Conners’ Adult ADHD Rating Scales (CAARS:O-SV and CAARS:S-S), and the Clinical Global Impression – Severity (CGI-S), Sheehan Disability Scale (SDS) and Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Subjects completing ≥52 wk of treatment were eligible for a 4-wk randomized, placebo-controlled withdrawal phase in which loss of treatment effect was assessed using CAARS:O-SV and CGI-S. In the open-label phase (n=156), mean CAARS:O-SV score decreased from baseline by 1.9±7.8 (p<0.01), and small, statistically significant improvements from baseline were observed for CAARS:S-S, CGI-S and SDS. In the double-blind phase (OROS-MPH, n=23; placebo, n=22), CAARS:O-SV increased from double-blind baseline in the OROS-MPH and placebo arms (4.0±7.6 vs. 6.5±7.8, not statistically significant). Long-term OROS-MPH treatment was well tolerated, and there was no evidence of withdrawal or rebound after discontinuation. In conclusion, the short-term benefits of OROS-MPH continue during long-term open-label treatment. Maintenance of efficacy in a placebo-controlled withdrawal design remains to be confirmed in larger patient populations.