Miracle-dz/UniFAR-FTUs huggingface dataset:
Population pharmacokinetics of nefopam in elderly, with or without renal impairment, and its link to treatment response.

AIMS Nefopam is a nonmorphinic central analgesic, for which no recommendation exists concerning adaptation of regimen in aged patients with or without renal impairment. The objective was to describe the pharmacology of nefopam in aged patients to obtain guidelines for practical use. METHODS Elderly patients (n = 48), 65-99 years old, with severe or moderate renal impairment or with normal renal function, were recruited. Nefopam (20 mg) was administered as a 30 min infusion postoperatively. Simultaneously, a 1 min intravenous infusion of iohexol was performed, in order to calculate the glomerular filtration rate. Blood samples were drawn to determine nefopam, desmethyl-nefopam and iohexol plasma concentrations. Nefopam and desmethyl-nefopam concentrations were analysed using a nonlinear mixed-effects modelling approach with Monolix version 4.1. 3. The association between pharmacokinetic parameters and treatment response was assessed using logistic regression. RESULTS A two-compartment open model was selected to describe the pharmacokinetics of nefopam. The typical population estimates (between-subject variability) for clearance, volume of distribution, intercompartmental clearance and peripheral volume were, respectively, 17.3 l h(-1) (53.2%), 114 l (121%), 80.7 l h(-1) (79%) and 208 l (63.6%). Morphine requirement was related to exposure of nefopam. Tachycardia and postoperative nausea and vomiting were best associated with maximal concentration and the rate of increase in nefopam plasma concentration. CONCLUSIONS We identified the nefopam pharmacokinetic predictors for morphine requirement and side-effects, such as tachycardia and postoperative nausea and vomiting. In order to maintain morphine sparing and decrease side-effects following a single dose of nefopam (20 mg), simulations suggest an infusion time of >45 min in elderly patients with or without renal impairment.
On a local theory of asymptotic integration for nonlinear ordinary differential equations

By revisiting an asymptotic integration theory of nonlinear ordinary differential equations due to J.K. Hale and N. Onuchic [Contributions Differential Equations 2 (1963), 61--75], we improve and generalize several recent results in the literature. As an application, we study the existence of bounded positive solutions to a large class of semi-linear elliptic partial differential equations via the subsolution-supersolution approach.
Efficient technique for screening drugs for activity against Trypanosoma cruzi using parasites expressing beta-galactosidase

A new drug screening method was devised utilizing Trypanosoma cruzi cells that express the Escherichia coli beta-galactosidase gene. Transfected parasites catalyze a colorimetric reaction with chlorophenol red beta-D-galactopyranoside as substrate. Parasite growth in the presence of drugs in microtiter plates was quantitated with an enzyme-linked immunosorbent assay reader. The assay was performed with the mammalian form of T. cruzi that requires intracellular growth on a monolayer of fibroblast cells. To determine if selective toxicity to the parasites was occurring, the viability of the host cells in the drug was assayed with AlamarBlue. The drugs benznidazole, fluconazole, and amphotericin B were shown to inhibit the parasites at concentrations similar to those previously reported. Several compounds were tested that are inhibitors of glyceraldehyde-3-phosphate dehydrogenase of the related organisms Leishmania mexicana and Trypanosoma brucei. One of these compounds, 2-guanidino-benzimidazole, had an 50% inhibitory concentration of 10 microM in our assay. Two derivatives of this compound were identified with in vitro activity at even lower concentrations. In addition, the assay was modified for testing compounds for lytic activity against the bloodstream form of the parasite under conditions used for storing blood products. Thus, an assay with beta-galactosidase-expressing T. cruzi greatly simplifies screening drugs for selective anti-T. cruzi activity, and three promising new compounds have been identified.
HIV infection is independently associated with frailty in middle-aged HIV type 1-infected individuals compared with similar but uninfected controls

Background:Frailty is an age-related syndrome of decreased physiological reserve and resistance to stressors, associated with increased morbidity and mortality in the general elderly population. An increased prevalence of frailty has been reported amongst HIV-infected individuals. Methods:Fried frailty phenotype was systematically assessed in predominantly virologically suppressed HIV type 1 (HIV-1)-infected and otherwise comparable HIV-uninfected participants aged at least 45 at enrollment into the AGEhIV Cohort Study. Multivariable ordinal logistic regression was used to investigate associations between HIV- and antiretroviral therapy-related covariates, markers of inflammation and body composition and prefrailty/frailty. Results: Data were available for 521 HIV-infected and 513 HIV-uninfected individuals. Prevalence of frailty (10.6 versus 2.7%) and prefrailty (50.7 versus 36.3%) were significantly higher in HIV-infected individuals (Ptrend < 0.001). HIV infection remained statistically significantly associated with prefrailty/frailty after adjustment for age, sex, race/ethnicity, smoking, hepatitis C infection, comorbidities and depression [adjusted odds ratio (ORadj) 2.16, P < 0.001]. A higher waist-to-hip ratio attenuated the coefficient of HIV-infected status (ORadj 1.93, P < 0.001), but not waist- or hip-circumference individually or markers of inflammation. Within the HIV-infected group, parameters related to body composition were most strongly and independently associated with prefrailty/frailty: current BMI less than 20 kg/m2 (OR 2.83, P < 0.001), nadir BMI less than 20 kg/m2 (OR 2.51, P < 0.001) and waist-to-hip ratio (OR 1.79 per 0.1 higher, P < 0.001). Conclusion:HIV infection was independently associated with prefrailty/frailty in middle-aged HIV-infected patients compared with HIV-uninfected controls. This partly may be mediated by the higher waist- and lower hip-circumference in the HIV-infected individuals, potentially partially caused by lipodystrophy, and in part be a consequence of historic weight loss associated with advanced HIV-disease.
A CMOS 6-mW 10-bit 100-MS/s Two-Step ADC

A 10-bit 100-MS/s two-step ADC was fabricated using a 90 nm CMOS technology. To reduce power consumption, the ADC uses latch-type comparators for signal digitalization and an open-loop amplifier for residue amplification. The accuracy of the comparators is improved by offset calibration. The gain accuracy and the linearity of the residue amplifier are enhanced by digital background calibration. The ADC consumes 6 mW from a 1 V supply. Measured SNR and SFDR are 58.2 dB and 75 dB respectively. Measured ENOB is 9.34 bits. The FOM is 100 fJ·V per conversion-step.
Wear Behaviour of Silicon Carbide/Electroless Nickel Composite Coatings at High Temperature

Abstract The present paper reports the results obtained from sliding wear tests performed at both room temperature and high temperature (100 and 300°C) on silicon carbide/nickel composite coatings annealed at 400°C in argon. The coatings were deposited industrially on AISI 1020 steel discs by using a proprietary self catalysing chemical reduction process (Hardex). The tests were conducted without lubrication in argon, employing a ball on disc tribometer. A load of 5 N was used at a constant sliding speed of 0·1 ms-1. The mating pair was an alumina ball of 6 mm diameter. For the tests performed at 25°C, the effect of heat treatment contributed to an improvement in the coating wear resistance of nearly 135%, when compared to the as deposited conditions. It was determined that the set of the experimental conditions for the wear test performed at high temperature, i.e. the load used, the nature of the mating surface, and the low velocity of the test, added to a small coating thickness to particle size ratio, created very severe conditions, which caused coating removal. Wear rates nearly 23 and 11·6 times larger were obtained for the heat treated coatings tested at 100 and 300°C, respectively when compared with the wear resistance of the heat treated coatings tested at 25°C.
Impaired cardiac function in chronic fatigue syndrome measured using magnetic resonance cardiac tagging

Abstract. Hollingsworth KG, Hodgson T, MacGowan GA, Blamire AM, Newton JL (Institute of Cellular Medicine, Campus for Ageing and Vitality; Institute of Genetic Medicine; and Institute for Ageing and Health, Campus for Ageing and Vitality; Newcastle University, Newcastle, UK). Impaired cardiac function in chronic fatigue syndrome measured using magnetic resonance cardiac tagging. J Intern Med 2012; 271: 264–270.
A Novel Millimeter-Wave Ultra-Wideband Bandpass Filter Using Microstrip Dual-Mode Ring Resonators Loaded with Open Tuning Stubs of Different Lengths

In this paper, a millimeter-wave ultra-wideband (UWB) bandpass filter is developed by cascading two microstrip dual-mode ring resonators loaded with lambda0/4 and 3lambda0/4 open tuning stubs, respectively. The ring resonators are analyzed by using the even-and odd-mode method, and closed-form formulas are derived to facilitate the design of transmission zeros of these resonators. The filter has a midband frequency of 25.5 GHz and a 3-dB bandwidth of 5 GHz (20%). Due to the multiple transmission zeros produced in both the lower and upper stopbands, the filter exhibits sharp attenuations near the passband and very wide stopbands. Over 13-35 GHz, the Federal Communications Commissions indoor limit is satisfied quite well.
Self-Medication Among School Students

Self-medication, usually with over-the-counter (OTC) medication, is reported as a community health problem that affects many people worldwide. Most self-medication practice usually begins with the onset of adolescence. A school-based cross-sectional study was conducted in Mafraq Governorate, Jordan, using a simple random sampling method to select 6 public schools from a total of 34 schools. The total sample consisted of 422 school students from Grades 7 through 12. Measures of central tendency and χ2 were used to compare the difference between the categorical variables. The prevalence of self-medication among the participants was 87.0%. Nearly 75% of self-medication was used for pain relief. The prevalence of self-medication among school students is very high and increases with age. School nurses and other local health-care workers must coordinate with school principals to disseminate health education campaigns about safe use of medication to provide awareness and education to school students, parents, and families.
Intermittent administration of parathyroid hormone improves the repairing process of rat calvaria defects: A histomorphometric and radiodensitometric study

Background The aim of this study was to evaluate the effects of intermittent treatment of parathyroid hormone (PTH (1-34)) on the bone regeneration of critically-sized rat calvarial bone defects. Material and Methods Thirty-two male rats were trephined (4mm fullthickness diameter), in the central part of the parietal bones and divided into 2 groups of 16. The PTH group received subcutaneous injections of PTH (1-34) at 40µg/kg, 3 times a week and the control (CTL) group received the vehicle in the same regimen. The rats were sacrificed at 4 weeks post-treatment regimen, the parietal bones were extracted and samples were evaluated through histomorphometry and radiodensitometry. Results The histological observations showed that the PTH group presented more “island-like” new bone between the defect margins with fibrous tissues than did the CTL group. The PTH group significantly exhibited greater histologic bone formation than did the CTL group (1.5mm ±0.7; 1.9 mm ± 0.6, p<0.05/ for residual bone defect). The radiodensitometry analysis revealed significant differences among the PTH and CTL groups (2.1 Al eq. ±0.04; 1.8Al eq. ±0.06, p<0.05), demonstrating an increase in bone mineral density. The PTH treatment contributed to the bone formation with a higher amount of mineral and/or fibrous tissue when compared with the CTL group. Conclusions The results suggest that it was possible to increase the process of bone regeneration by accelerating the healing process in rat calvarial defects through intermittent administration of the PTH treatment. Key words: Bone, skull, rats, bone regeneration, bone density.
The CgHaa1-Regulon Mediates Response and Tolerance to Acetic Acid Stress in the Human Pathogen Candida glabrata

To thrive in the acidic vaginal tract, Candida glabrata has to cope with high concentrations of acetic acid. The mechanisms underlying C. glabrata tolerance to acetic acid at low pH remain largely uncharacterized. In this work, the essential role of the CgHaa1 transcription factor (encoded by ORF CAGL0L09339g) in the response and tolerance of C. glabrata to acetic acid is demonstrated. Transcriptomic analysis showed that CgHaa1 regulates, directly or indirectly, the expression of about 75% of the genes activated under acetic acid stress. CgHaa1-activated targets are involved in multiple physiological functions including membrane transport, metabolism of carbohydrates and amino acids, regulation of the activity of the plasma membrane H+-ATPase, and adhesion. Under acetic acid stress, CgHaa1 increased the activity and the expression of the CgPma1 proton pump and contributed to increased colonization of vaginal epithelial cells by C. glabrata. CgHAA1, and two identified CgHaa1-activated targets, CgTPO3 and CgHSP30, are herein demonstrated to be determinants of C. glabrata tolerance to acetic acid. The protective effect of CgTpo3 and of CgHaa1 was linked to a role of these proteins in reducing the accumulation of acetic acid inside C. glabrata cells. In response to acetic acid stress, marked differences were found in the regulons controlled by CgHaa1 and by its S. cerevisiae ScHaa1 ortholog, demonstrating a clear divergent evolution of the two regulatory networks. The results gathered in this study significantly advance the understanding of the molecular mechanisms underlying the success of C. glabrata as a vaginal colonizer.
A Mathematical Model towards Understanding the Mechanism of Neuronal Regulation of Wake-NREMS-REMS States

In this study we have constructed a mathematical model of a recently proposed functional model known to be responsible for inducing waking, NREMS and REMS. Simulation studies using this model reproduced sleep-wake patterns as reported in normal animals. The model helps to explain neural mechanism(s) that underlie the transitions between wake, NREMS and REMS as well as how both the homeostatic sleep-drive and the circadian rhythm shape the duration of each of these episodes. In particular, this mathematical model demonstrates and confirms that an underlying mechanism for REMS generation is pre-synaptic inhibition from substantia nigra onto the REM-off terminals that project on REM-on neurons, as has been recently proposed. The importance of orexinergic neurons in stabilizing the wake-sleep cycle is demonstrated by showing how even small changes in inputs to or from those neurons can have a large impact on the ensuing dynamics. The results from this model allow us to make predictions of the neural mechanisms of regulation and patho-physiology of REMS.
Chronic hepatitis B in pregnancy: unique challenges and opportunities

Chronic hepatitis B (CHB) affects 350 million individuals worldwide. Perinatal transmission leads to high rates of chronic infection and complications, including cirrhosis and hepatocellular carcinoma. It is important to recognize and appropriately treat CHB in pregnancy, thereby reducing the risk of neonatal transmission and HBV-associated morbidity and mortality. Screening for CHB is recommended in all pregnant mothers as is universal vaccination of infants with hepatitis B virus (HBV) vaccine with or without hepatitis B immunoglobulin (HBIG). This has resulted in a lower incidence of HBsAg seropositivity and HCC in regions where universal infant vaccination has been endorsed. Mode of delivery and breastfeeding do not appear to affect HBV transmission rates based on available data. Overall, CHB does not increase perinatal maternal-fetal mortality. Administration of oral antiviral therapy during the third trimester to HBsAg-positive mothers with HBV DNA≥7 log IU/mL may be useful in preventing breakthrough infection. Treatment may be considered earlier in pregnancy for persistently active liver disease shown by high ALT, HBV DNA levels and/or significant hepatic fibrosis. Lamivudine, tenofovir and telbivudine are safe and effective and are the agents of choice in pregnancy. However, further clinical studies are necessary to elucidate the role of antiviral therapy in the pregnant HBV carrier.
Investigation of Angle-Ply Delamination Specimen For Interlaminar Strength Test

The use of fiber composite laminates in many structural applications requires that the designer be provided with accurate information about interlaminar strength. In particular, a knowledge of interlaminar tensile strength may be important in some cases. The delamination coupon, a specially designed angle-ply laminate developed by other investigators, is considered here in the role of an interlaminar tension test specimen. Exper imental results obtained with the delamination coupon suggest that the current procedure for design of such specimens must be changed to reduce the effect of interlaminar shear stress on the results, and that more accur ate analysis must be used before interlaminar tensile strength can be pre dicted with confidence.
Product Innovation and Growth: The Case of Integrated Circuits

A puzzling evidence stemming from the applied research on growth and innovation is that successful innovations do not appear to have a significant effect on sales growth rates, at odds with the expectation that successful innovators will prosper at the expenses of their less able competitors. The present paper tests a research hypothesis claiming that the level of observation at which applied research is typically conducted hampers the identification of a significant association between innovation and sales growth rates. Exploiting a unique and original database comprising detailed information on product innovations by leading semiconductor companies, we find components commercialized in the nearest past to positively affect the stream of corporate revenues.
An Integrated Drosophila Model System Reveals Unique Properties for F14512, a Novel Polyamine-Containing Anticancer Drug That Targets Topoisomerase II

F14512 is a novel anti-tumor molecule based on an epipodophyllotoxin core coupled to a cancer-cell vectoring spermine moiety. This polyamine linkage is assumed to ensure the preferential uptake of F14512 by cancer cells, strong interaction with DNA and potent inhibition of topoisomerase II (Topo II). The antitumor activity of F14512 in human tumor models is significantly higher than that of other epipodophyllotoxins in spite of a lower induction of DNA breakage. Hence, the demonstrated superiority of F14512 over other Topo II poisons might not result solely from its preferential uptake by cancer cells, but could also be due to unique effects on Topo II interactions with DNA. To further dissect the mechanism of action of F14512, we used Drosophila melanogaster mutants whose genetic background leads to an easily scored phenotype that is sensitive to changes in Topo II activity and/or localization. F14512 has antiproliferative properties in Drosophila cells and stabilizes ternary Topo II/DNA cleavable complexes at unique sites located in moderately repeated sequences, suggesting that the drug specifically targets a select and limited subset of genomic sequences. Feeding F14512 to developing mutant Drosophila larvae led to the recovery of flies expressing a striking phenotype, "Eye wide shut," where one eye is replaced by a first thoracic segment. Other recovered F14512-induced gain- and loss-of-function phenotypes similarly correspond to precise genetic dysfunctions. These complex in vivo results obtained in a whole developing organism can be reconciled with known genetic anomalies and constitute a remarkable instance of specific alterations of gene expression by ingestion of a drug. "Drosophila-based anticancer pharmacology" hence reveals unique properties for F14512, demonstrating the usefulness of an assay system that provides a low-cost, rapid and effective complement to mammalian models and permits the elucidation of fundamental mechanisms of action of candidate drugs of therapeutic interest in humans.
Associations Between Impaired Cerebral Blood Flow Autoregulation, Cerebral Oxygenation, and Biomarkers of Brain Injury and Postoperative Cognitive Dysfunction in Elderly Patients After Major Noncardiac Surgery

BACKGROUND: Increasing evidence links postoperative cognitive dysfunction (POCD) to surgery and anesthesia. POCD is recognized as an important neuropsychological adverse outcome in surgical patients, particularly the elderly. This prospective cohort study aimed to investigate whether POCD is associated with impaired intraoperative cerebral autoregulation and oxygenation, and increased levels of biomarkers of brain injury. METHODS: Study subjects were patients ≥65 years of age scheduled for major noncardiac surgery. Cognitive function was assessed before and 1 week after surgery. POCD was diagnosed if a decline of >1 standard deviation of z-scores was present in ≥2 variables of the test battery. The incidence of POCD 1 week after surgery was modeled as a multivariable function of the index of autoregulation (MxA) and tissue oxygenation index (TOI), adjusting for baseline neuropsychological assessment battery (Consortium to Establish a Registry for Alzheimer’s Disease-Neuropsychological Assessment Battery [CERAD-NAB]) total score and the maximum C-reactive protein (CRP) concentration. The biomarkers of brain injury neuron-specific enolase and S100&bgr; protein, age, and level of education were included in secondary multivariable logistic regression analyses. RESULTS: Of the 82 patients who completed the study, 38 (46%) presented with POCD 1 week after surgery. In the multivariable regression analysis, higher intraoperative MxA (odds ratio [OR; 95% confidence interval (CI)], 1.39 [1.01–1.90] for an increase of 0.1 units, P = . 08 after Bonferroni adjustment), signifying less effective autoregulation, was not associated with higher odds of POCD. The univariable logistic regression model for MxA yielded an association with POCD (OR [95% CI], 1.44 [1.06–1.95], P = .020). Tissue oxygenation index (1.12 [0.41–3.01] for an increase of 10%, P = 1.0 after Bonferroni adjustment) and baseline CERAD-NAB total score (0.80 [0.45–1.42] for an increase of 10 points, P = .45) did not affect the odds of POCD. POCD was associated with elevated CRP on postoperative day 2 (median [interquartile range]; 175 [81–294] vs 112 [62–142] mg/L, P = .033); however, the maximum CRP value (OR [95% CI], 1.35 [0.97–1.87] for a 2-fold increase, P = .07) had no distinct effect on POCD. CONCLUSIONS: Impairment of intraoperative cerebral blood flow autoregulation is not predictive of early POCD in elderly patients, although secondary analyses indicate that an association probably exists.
Does Cyclophosphamide Still Have a Role in the Treatment of Severe Inflammatory Eye Disease?

Abstract Cyclophosphamide is a highly effective immunosuppressive drug that has proven efficacy in the treatment of patients with severe inflammatory eye disease. It has the advantage of being able to be used either orally or intravenously, has a potent steroid-sparing effect, and is effective in inducing disease remission. The major limitations to the use of this alkylating agent are its frequent side effects. With the increasing availability of alternate forms of therapy it is time to review the therapeutic regimen for cyclophosphamide use in patients with inflammatory eye disease.