Miracle-dz/UniFAR-FTUs huggingface dataset:
Continuous versus Short-Term Infusion of Cefuroxime: Assessment of Concept Based on Plasma, Subcutaneous Tissue, and Bone Pharmacokinetics in an Animal Model

ABSTRACT The relatively short half-lives of most β-lactams suggest that continuous infusion of these time-dependent antimicrobials may be favorable compared to short-term infusion. Nevertheless, only limited solid-tissue pharmacokinetic data are available to support this theory. In this study, we randomly assigned 12 pigs to receive cefuroxime as either a short-term or continuous infusion. Measurements of cefuroxime were obtained every 30 min in plasma, subcutaneous tissue, and bone. For the measurements in solid tissues, microdialysis was applied. A two-compartment population model was fitted separately to the drug concentration data for the different tissues using a nonlinear mixed-effects regression model. Estimates of the pharmacokinetic parameters and time with concentrations above the MIC were derived using Monte Carlo simulations. Except for subcutaneous tissue in the short-term infusion group, the tissue penetration was incomplete for all tissues. For short-term infusion, the tissue penetration ratios were 0.97 (95% confidence interval [CI], 0.67 to 1.39), 0.61 (95% CI, 0.51 to 0.73), and 0.45 (95% CI, 0.36 to 0.56) for subcutaneous tissue, cancellous bone, and cortical bone, respectively. For continuous infusion, they were 0.53 (95% CI, 0.33 to 0.84), 0.38 (95% CI, 0.23 to 0.57), and 0.27 (95% CI, 0.13 to 0.48) for the same tissues, respectively. The absolute areas under the concentration-time curve were also lower in the continuous infusion group. Nevertheless, a significantly longer time with concentrations above the MIC was found for continuous infusion up until MICs of 4, 2, 2, and 0.5 μg/ml for plasma and the same three tissues mentioned above, respectively. For drugs with a short half-life, like cefuroxime, continuous infusion seems to be favorable compared to short-term infusion; however, incomplete tissue penetration and high MIC strains may jeopardize the continuous infusion approach.
Diffusion-perfusion MRI characterization of post-recanalization hyperperfusion in humans

Background: Animal and human studies have demonstrated that postischemic hyperperfusion may occur both early and late timepoints following acute cerebral ischemia. Objective: To use diffusion-perfusion MRI to characterize hyperperfusion in humans following intra-arterial thrombolysis. Methods: MRI were performed before treatment, several hours following vessel recanalization, and at day 7 in patients successfully recanalized with intra-arterial thrombolytics. Results: Hyperperfusion was visualized in 5 of 12 patients within several hours after recanalization (mean volume, 18 mL; range, 7 to 40 mL), and in 6 of 11 patients at day 7 (mean volume, 28 mL; range, 4 to 45 mL). Within the core region of hyperperfusion, mean cerebral blood flow was 2.1 times greater than in the contralateral homologous region at the early time point, and 3.1 times greater at day 7. Seventy-nine percent of voxels with hyperperfusion at day 7 demonstrated infarction at day 7, whereas only 36% of voxels (within the initial hypoperfusion region) not showing hyperperfusion at day 7 demonstrated infarction at day 7. Mean pretreatment apparent diffusion coefficient (ADC) and perfusion values were more impaired in voxels that subsequently developed hyperperfusion compared with other at-risk voxels (all p values < 0.0001). There were no significant differences in the degree of clinical improvement in patients with regions of hyperperfusion versus those without, although sample size limited power to detect group differences. Conclusions: Postischemic hyperperfusion, visualized with perfusion MRI in humans following recanalization by intra-arterial thrombolytic therapy, occurred in about 40% of patients within hours and in about 50% of patients at day 7. Hyperperfusion developed mainly in regions that went on to infarction. Compared with other abnormal regions, tissues that developed postischemic hyperperfusion had greater bioenergetic compromise in pretreatment apparent diffusion coefficient values and greater impairment in pretreatment blood flow measures.
Durability of First Line Antiretroviral Therapy: Reasons and Predictive Factors for Modifications in a Swaziland Cohort

Background: Optimizing initial antiretroviral therapy (ART) regimens is critical in improving the durability of treatment efficacy and patient prognosis. Reasons for and risk factors relating to the need for ART modifications were evaluated in an outpatient cohort in Mbabane, Swaziland. Methods: We examined routine clinical data for 782 patients initiating first-line ART between 1 March 2006 and 31 March 2008. Treatment modification was defined as either a first time single drug substitution or first time regimen switch. Multivariate piecewise Cox regression models were used to identify risk factors for ART modification. Results: Over a median follow-up period of 21 months, 17.5% of patients modified their regimen. Drug toxicity (incidence rate of 6.3 per 100 person years (95% CI 5.2-7.7)) accounted for 76.6% of the reasons for modification. Drug contra-indications (incidence rate 9.5 per 100 person years (95% CI 6.5-13.9)), namely tuberculosis (13.1%) and pregnancy (6.6%), accounted for 19.7% of modifications. In the adjusted multivariate Cox piecewise regression model, beyond 11 months on ART, a baseline CD4 cell count 60kg (HR 2.40; 95% CI: 1.43 – 4.04) and increase in age (HR 1.03; 95% CI: 1.00 – 1.05) increased the risk of modification. Conclusions: Initiating ART earlier, at higher CD4 counts, avoiding drugs with poor safety profiles, such as d4T, and identifying individuals who may require tuberculosis treatment or may become pregnant could reduce modification rates. This would improve regimen tolerability, while preserving future treatment options.
Drivers under the influence of drugs of abuse: quantification of cocaine and impaired driving

In recent years, the interest in oral fluid as a biological matrix has significantly increased, particularly for detecting driving under the influence of drugs. In this study, the concentration of cocaine and its relationship with clinical symptoms in drivers suspected of driving under the influence of drugs was evaluated. A total of 154 samples of oral fluid, which tested positive for cocaine in previous immunoassay screening, Cozart Drug Detector System, were confirmed using gas chromatography/mass spectrometry method. In Catalonia, during 2007–2010, there were 1791 samples positive for cocaine among a total of 3468 samples taken from drivers who tested positive for any drug of abuse. The evaluation of clinical symptoms was through a questionnaire that was filled in by the police officers who collected the samples. The mean concentration of cocaine was 4.11 mg/l and median concentration was 0.38 mg/l (range 0.01–345.64 mg/l). Clinical impairment symptoms such as motor coordination, walking, speech, mood and state of pupils were not significant. The testing of oral fluids presents fewer ethical problems than blood or urine.
Specific and efficient gene transfer strategy offers new potentialities for the treatment of motor neurone diseases

Several growth factors are candidates for the therapy of motor neurone diseases. However, there is no efficient, safe, and practicable administration route which hampers the clinical use of these potentially therapeutic agents. We show that specific and high yield gene transfer into motor neurones can be obtained by peripheral intramuscular injections of recombinant adenoviruses. These vectors are retrogradely transported from muscular motor units to motor neurone cell bodies. Gene transfer can thus be specifically targeted to particular regions of the spinal cord by appropriate choice of the injected muscle. The efficiency of gene transfer is high, with 58–100% of the motor neurones afferent to the injected muscle expressing the transgene. This new therapeutic protocol allows specific targeting of motor neurones without lesioning the spinal cord, and should avoid undesirable side effects associated with systemic administration of therapeutic factors.
The fibrinolytic receptor for urokinase activates the G protein-coupled chemotactic receptor FPRL1/LXA4R

The function of urokinase and its receptor is essential for cell migration in pathological conditions, as shown by the analysis of knockout mice phenotypes. How a protease of a fibrinolytic pathway can induce migration is not understood and no link between this protease and migration-promoting G protein-coupled receptors has been described. We now show that FPRL1/LXA4R, a G protein-coupled receptor for a number of polypeptides and for the endogenous lipoxin A4 (LXA4), is the link between urokinase-type plasminogen activator (uPA) and migration as it directly interacts with an activated, soluble, cleaved form of uPA receptor (uPAR) (D2D388–274) to induce chemotaxis. In this article we show that (i) both uPAR and FPRL1/LXA4R are necessary for the chemotactic activity of uPA whereas FPRL1/LXA4R is sufficient to mediate D2D388–274-induced cell migration. (ii) Inhibition or desensitization of FPRL1/LXA4R by antibodies or specific ligands specifically prevents chemotaxis induced by D2D388–274 in THP-1 cells and human peripheral blood monocytes. (iii) Desensitization of FPRL1/LXA4R prevents the activation of tyrosine kinase Hck induced by D2D388–274. (iv) D2D388–274 directly binds to FPRL1/LXA4R and is competed by two specific FPRL1/LXA4R agonists, the synthetic MMK-1 peptide and a stable analog of LXA4. Thus, a naturally produced cleaved form of uPAR is a unique endogenous chemotactic agonist for FPRL1/LXA4R receptor and its activity can be antagonized by specific ligands. These results provide the first direct link, to our knowledge, between the fibrinolytic machinery and the inflammatory response, demonstrating that uPA-derived peptide fragments can activate a specific chemotactic receptor.
Use of bupropion with SRIs and venlafaxine

Because of reported efficacy of combining classes of antidepressants, 25 patients were treated with bupropion in combination with SRI's and venlafaxine. Fifteen patients inadequately responsive to monotherapy received combination treatment; ten patients without residual symptoms received adjunctive bupropion to treat SRI‐ or venlafaxine‐induced side effects. Fourteen subjects (56%) responded, 11 (44%) did not. Twelve of 15 subjects receiving combination treatment to boost the effects of monotherapy responded, while only 2 of 10 subjects receiving combination treatment for side effects responded. Combination therapy was well tolerated even by geriatric and “medically frail” patients. Depression and Anxiety 7:73–75, 1998. © 1998 Wiley‐Liss, Inc.
DISTRIBUTION OF CYTOCHROME C AND MYOGLOBIN IN RATS WITH DIETARY IRON DEFICIENCY.

A decrease in cytochrome c and myoglobin concentrations was observed in young rats made anemic on a low-iron diet. The degree of depletion of hemeprotein varied according to tissue. In the iron-deficient rat, myoglobin and cytochrome c were most depleted in skeletal muscle which contains the major portion of these proteins. Cytochrome c expressed as percentage of corresponding control mean concentrations was 44% in skeletal muscle, 61% in intestinal mucosa, 69% in kidney, 79% in diaphragm, 89% in heart, and 97% in brain. Myoglobin in the iron-deficient rats was 44% of the corresponding control concentration in skeletal muscle, 63% in diaphragmatic muscle, and 80% in heart muscle. The variations in degree of hemeprotein depletion in response to iron deprivation appeared to be related to organ function, growth rate, and cell turnover. Cardiac and diaphragmatic muscle, whose function is essential to survival, resisted the loss of myoglobin and cytochrome c to a greater extent than did skeletal muscle. Severe depletion of hemeprotein was observed in tissues with a rapid rate of growth such as skeletal muscle or a rapid cell turnover as in the case of intestinal mucosa. Brain, which grows minimally during the period of iron deprivation, was unchanged in its cytochrome c content. A significant impairment of oxidative metabolism in the iron deficient rat was suggested by a reduction in the rate of respiration of muscle homogenates.
In Vivo gp41 Antibodies Targeting the 2F5 Monoclonal Antibody Epitope Mediate Human Immunodeficiency Virus Type 1 Neutralization Breadth

ABSTRACT The broadly neutralizing human monoclonal antibodies (MAbs) 2F5 and 4E10, both targeting the highly conserved human immunodeficiency virus type 1 (HIV-1) envelope membrane proximal external region (MPER), are among the MAbs with the broadest heterologous neutralizing activity and are of considerable interest for HIV-1 vaccine development. We have identified serum antibodies from an HIV-infected subject that both were broadly neutralizing and specifically targeted MPER epitopes that overlap the 2F5 epitope. These MPER-specific antibodies were made 15 to 20 months following transmission and concomitantly with the development of autoantibodies. Our findings suggest that multiple events (i.e., genetic predisposition and HIV-1 immune dysregulation) may be required for induction of broadly reactive gp41 MPER antibodies in natural infection.
The efficacy of manual toothbrushes following a brushing exercise: a systematic review.

AIM To determine the efficacy of manual tooth brushing with respect to toothbrush design and brushing duration. MATERIAL AND METHODS The PubMed-MEDLINE and Cochrane CENTRAL were searched through October 2010 to identify appropriate studies. The outcome measurement was dental plaque removal following subject brushing. RESULTS The search yielded 2119 titles and abstracts. Ultimately, 59 papers with 212 brushing exercises as separate legs of the experiments and meeting the eligibility criteria were selected. Overall, a brushing exercise provides a 42% (21) plaque score reduction (95% CI: 41.23; 42.03). Of the brushing studies providing data as assessed according to the Quigley and Hein plaque index, the weighted mean reduction from baseline in plaque scores was 30% (95% CI: 26.79; 33.21). A weighted mean plaque score reduction of 53% (95% CI: 49.51; 56.49) was observed in the experiments using the Navy plaque index. Subanalysis between the different bristle tuft configurations illustrated variation in plaque removal ability (24-61%). The angled bristle design numerically showed the highest mean plaque reduction with either index. A subanalysis of brushing duration revealed after 1 min, a mean reduction of 27% and after 2 min, 41%. CONCLUSION The efficacy in plaque removal following a brushing exercise is a reduction from baseline plaque scores of 42% on average, with a variation of 30-53% dependent on the plaque index used. The available evidence indicates that bristle tuft arrangement (flat trim, multilevel, angled) and brushing duration are factors that contribute to the variation in observed efficacy.
A Formula for the Fréchet Derivative of a Generalized Matrix Function

We state and prove an analogue of the Daleckii--Krein theorem, thus obtaining an explicit formula for the Frechet derivative of generalized matrix functions. Moreover, we prove the differentiability of generalized matrix functions of real matrices under very mild assumptions. For complex matrices, we argue that, under the same assumptions, generalized matrix functions are real-differentiable but generally not complex-differentiable. Finally, we discuss the application of our results to the study of the condition number of generalized matrix functions. Along our way, we also derive generalized matrix functional analogues of a few classical theorems on polynomial interpolation of classical matrix functions and their derivatives.
Pop3p is essential for the activity of the RNase MRP and RNase P ribonucleoproteins in vivo

RNase MRP is a ribonucleoprotein (RNP) particle which is involved in the processing of pre‐rRNA at site A3 in internal transcribed spacer 1. Although RNase MRP has been analysed functionally, the structure and composition of the particle are not well characterized. A genetic screen for mutants which are synthetically lethal (sl) with a temperature‐sensitive (ts) mutation in the RNA component of RNase MRP (rrp2‐1) identified an essential gene, POP3, which encodes a basic protein of 22.6 kDa predicted molecular weight. Overexpression of Pop3p fully suppresses the ts growth phenotype of the rrp2‐1 allele at 34°C and gives partial suppression at 37°C. Depletion of Pop3p in vivo results in a phenotype characteristic of the loss of RNase MRP activity; A3 cleavage is inhibited, leading to under‐accumulation of the short form of the 5.8S rRNA (5.8SS) and formation of an aberrant 5.8S rRNA precursor which is 5′‐extended to site A2. Pop3p depletion also inhibits pre‐tRNA processing; tRNA primary transcripts accumulate, as well as spliced but 5′‐ and 3′‐unprocessed pre‐tRNAs. The Pop3p depletion phenotype resembles those previously described for mutations in components of RNase MRP and RNase P (rrp2‐1, rpr1‐1 and pop1‐1). Immunoprecipitation of epitope‐tagged Pop3p co‐precipitates the RNA components of both RNase MRP and RNase P. Pop3p is, therefore, a common component of both RNPs and is required for their enzymatic functions in vivo. The ubiquitous RNase P RNP, which has a single protein component in Bacteria and Archaea, requires at least two protein subunits for its function in eukaryotic cells.
Inhibition of epidermal growth factor signaling by the cardiac glycoside ouabain in medulloblastoma

Epidermal growth factor (EGF) signaling regulates cell growth, proliferation, and differentiation. Upon receptor binding, EGF triggers cascades of downstream signaling, including the MAPK and phosphoinositide‐3‐kinase (PI3K)/Akt signaling pathways. Aberrant expression/activation of EGFR is found in multiple human cancers, including medulloblastoma, the most prevalent pediatric brain cancer, and often has been associated with metastasis, poor prognosis, and resistance to chemotherapy. Na,K‐ATPase is an ion pump well known for its role in intracellular ion homeostasis. Recent studies showed that Na,K‐ATPase also functions as a signaling platform and revealed a role in EGFR, MAPK, and PI3K signaling. While both EGFR and Na,K‐ATPase seem to modulate similar signaling pathways, cardiac glycosides that are steroid‐like inhibitors of Na,K‐ATPase, exhibit antiproliferative and proapoptotic properties in cancer cells. Thus, we sought to better understand the relationship between EGF and cardiac glycoside signaling. Here, we show that in medulloblastoma cells, both EGF and ouabain activate Erk1/2 and PI3K/Akt signaling. Nevertheless, in medulloblastoma cells ouabain did not transactivate EGFR as has been reported in various other cell lines. Indeed, ouabain inhibited EGF‐induced Erk1/2 and Akt activation and, moreover, prevented EGF‐induced formation of actin stress fibers and cell motility, probably by activating a stress signaling response. Na,K‐ATPase has been proposed to act as a signaling scaffold and our studies suggest that in medulloblastoma cells Na,K‐ATPase might act as a check point to integrate EGF‐associated signaling pathways. Thus, Na,K‐ATPase might serve as a valid target to develop novel therapeutic approaches in tumors with aberrant activation of the EGFR signaling cascades.
Pathophysiological role of enhanced bone marrow adipogenesis in diabetic complications

Diabetes leads to complications in select organ systems primarily by disrupting the vasculature of the target organs. These complications include both micro- (cardiomyopathy, retinopathy, nephropathy, and neuropathy) and macro-(atherosclerosis) angiopathies. Bone marrow angiopathy is also evident in both experimental models of the disease as well as in human diabetes. In addition to vascular disruption, bone loss and increased marrow adiposity have become hallmarks of the diabetic bone phenotype. Emerging evidence now implicates enhanced marrow adipogenesis and changes to cellular makeup of the marrow in a novel mechanistic link between various secondary complications of diabetes. In this review, we explore the mechanisms of enhanced marrow adipogenesis in diabetes and the link between changes to marrow cellular composition, and disruption and depletion of reparative stem cells.
Exploration of high-performance ports in Zynq-7000 devices with different traffic conditions

This paper presents experimental results that allow high-performance ports in Zynq microchips to be evaluated taking into account parallel computations and their influence on throughput of FIR filters. All projects are based on Xilinx components. We found that although parallel traffic leads to performance degradation, actual throughput is reduced not very significantly. The results of experiments are discussed.
Investigation of time-dependency of intracranial brain shift and its relation to the extent of tumor removal using intra-operative MRI

Abstract The object of the paper is to investigate intra-operative brainshift and its relation to the extent of tumor removal. Repeated T1w 3D datasets were acquired at different time points intra-operatively (T0; T1; T2. Tx) using a vertical open 0.5T MR scanner in six patients with intracranial tumor. An offline analysis with initial linear registration, intensity adjustment and finally nonlinear registration of the first versus subsequent time points (T0/T1; T0/T2. T0/Tx) was performed, yielding a 3D displacement vector field that describes the brainshift. Brainshift was analysed qualitatively and quantitatively. A semi-automatic segmentation technique was used for calculation of the tumor size and the size of tumor remnants. Semi-automatic segmentation was reliable in all but two cases. Segmentation was difficult and unreliable in astrocytomas grade II. The shift basically followed gravity. The major shift reached levels up to 25 mm. Significant shift was observed at the first time point (T0). Intra-operative brainshift can be analysed qualitatively and also captured quantitatively. Neuronavigation that is based on pre-operatively acquired datasets is associated with a significant risk of surgical morbidity at a very early time point. Parallelisation on a workstation cluster may reduce computation time so that information about the displacement can facilitate updated navigation.
The Use of Cognitive-Behavioral Therapy to Promote Authenticity

Glassgoldâ€™s (2009) case study offers an excellent example of combining LGB-specific empirical findings with established treatments that have been shown to work for the general treatment-seeking population. In doing so, she helps her client, Felix, take a stand about who he is as a gay man and thus move towards a more authentic self. Â I focus this commentary on 1) the potential hazards of masculine ideology on gay male development, 2) the use of cognitive-behavior therapy (CBT) to promote our gay clientsâ€™ authenticity in the face of challenges to healthy sexual orientation development, and 3) the need for empirical tests of the integration of LGB-specific research findings into established treatment approaches. Although the field still awaits controlled trials of affirmative approaches to LGB-specific clinical issues, this should not stop clinicians from drawing on the relevant empirical work to facilitate successful treatments of our LGB clientsâ€™ presenting issues. Glassgoldâ€™s approach serves as an excellent example of the integration of this research into a cognitive-behavioral conceptualization of anxiety and panic. Â Â