Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacokinetics of Solithromycin (CEM-101) after Single or Multiple Oral Doses and Effects of Food on Single-Dose Bioavailability in Healthy Adult Subjects

ABSTRACT The pharmacokinetics of orally administered solithromycin (CEM-101), a novel fluoroketolide, were evaluated in healthy subjects in three phase 1 studies. In two randomized, double-blinded, placebo-controlled studies, escalating single oral doses of solithromycin (50 to 1,600 mg) or seven oral daily doses (200 to 600 mg) of solithromycin were administered. A third study evaluated the effects of food on the bioavailability of single oral doses (400 mg) of solithromycin. Following single doses, the median time to peak concentration (Tmax) ranged from 1.5 h to 6 h. The mean maximum measured plasma concentration (Cmax) ranged from 0.0223 μg/ml to 19.647 μg/ml, and the area under the concentration-versus-time curve from time zero to time t (AUC0–t) ranged from 0.0402 μg · h/ml to 28.599 μg · h/ml. There was no effect of high-fat food on the oral bioavailability of solithromycin. In the multiple-dose study, after 7 days, the mean maximum measured plasma solithromycin concentration at steady-state (Cmax,ss) ranged from 0.248 to 1.50 μg/ml, and the area under the concentration-versus-time curve over the final dosing interval (AUCτ) ranged from 2.310 to 18.41 μg · h/ml. These values indicate a greater than proportional increase in exposure at 200 and 400 mg but a proportional exposure at 600 mg. Median Tmax values remained constant between day 1 and day 7. Moderate accumulation ratios of solithromycin were observed after 7 days of dosing. All dose regimens of solithromycin were well tolerated, and no discontinuations due to an adverse event occurred. The human pharmacokinetic profile and tolerability of solithromycin, combined with its in vitro potency and efficacy in animal models against a broad spectrum of pathogens, support further development of solithromycin.
Characterization and Regulation of β1‐Adrenergic Receptors in a Human Neuroepithelioma Cell Line

Abstract: Intact human neuroepithelioma SK‐N‐MC cells bound the β‐adrenergic antagonist (–)‐[3H]‐CGP 12177 with a KD of 0.13 nM and a Bmax of 17,500 sites/cell. When the cells were exposed to β‐adrenergic agonists, they accumulated cyclic AMP in the following order of potency: isoproterenol norepinephrine > epinephrine, which is indicative of a β1‐subtype receptor. Membranes prepared from the cells bound (–)‐3‐[125I]iodocyanopindolol with a KD of 11.5 pM. Inhibition of agonist‐stimulated cyclic AMP production and competition binding experiments indicated that the β1‐selective antagonists CGP 20712A and ICI 89,406 were much more potent than the β2‐selective antagonist ICI 118,551. Analysis of the displacement curves indicated that the cells contained only β1‐adrenergic receptors. Northern blot analysis of SK‐N‐MC mRNA using cDNA probes for the β1‐ and β2‐adrenergic receptors revealed the presence of a very strong β1‐adrenergic receptor mRNA signal, while under the same conditions no β2‐adrenergic receptor mRNA was observed. Thus, SK‐N‐MC cells appear to express a pure population of β1‐adrenergic receptors. When the cells were exposed to isoproterenol, there was no observable desensitization during the first hour. After longer exposure, desensitization slowly occurred and the receptors slowly down‐regulated to 50% of control levels by 24 h. Other agents that elevate cyclic AMP levels, such as forskolin, cholera toxin, and cyclic AMP analogues, caused no or little substantial receptor loss.
Testing the effects of sensory stimulation as a collateral-based therapeutic for ischemic stroke in C57BL/6J and CD1 mouse strains

Utilizing a rat model of ischemic stroke, we have previously shown that sensory stimulation can completely protect rats from impending ischemic damage of cortex if this treatment is delivered within the first two hours post-permanent middle cerebral artery occlusion (pMCAo). The current study sought to extend our findings in rats to mice, which would allow new avenues of research not available in rats. Thus, young adult C57BL/6J and CD1 mice were tested for protection from ischemic stroke with the same protective sensory stimulation-based treatment. Cortical activity and blood flow were assessed with intrinsic signal optical imaging (ISOI) and laser speckle imaging (LSI), respectively, and histological analysis (TTC) was performed at the completion of the experiments. Standing in stark contrast to the positive results observed in rats, in both strains we found that there were no differences between treated and untreated mice at 24 hours post-pMCAo in terms of infarct volume, negative functional imaging results, and major reduction in retrograde collateral blood flow as compared to pre-pMCAo baseline and surgical controls. Also, no differences were found between the strains in terms of theses variables. Potential reasons for the differences between rats and mice are discussed.
A group cognitive behaviour therapy programme with metastatic breast cancer patients

One‐hundred and twenty‐four patients with metastatic breast cancer were randomised to either a group Cognitive Behaviour Therapy (CBT) intervention, or to a no‐therapy control group condition. Both groups received standard oncological care; however, therapy recipients also attended eight weekly sessions of group CBT, followed by a family night, and three further monthly sessions. Patients completed the ‘Profile of Mood States’ (POMS) and the Coopersmith Self‐esteem Inventory (CSI) before and after therapy, and at 3 and 6 month follow‐up periods. Outcome data in the period following therapy showed reduced depression and total mood disturbance, as well as improved self‐esteem amongst therapy participants, relative to a no‐therapy control group. These improvements were no longer evident at the 3 or 6 month follow‐up assessments. We also report on the difficulties associated with conducting a group intervention with this patient cohort. Copyright © 1999 John Wiley & Sons, Ltd.
Efficient Algorithm Design for GPR Imaging of Landmines

Ground-penetrating radar (GPR) is used to image and detect subterranean objects, for example, in landmine detection. Although full 3-D inversion of GPR measurements is possible for simple algorithms such as backprojection, it is impractical when using more advanced algorithms that involve ℓ1 - minimization. Many of the algorithms used for GPR imaging involve the storage, or online generation, of a huge dictionary matrix created from discretizing a high-dimensional nonlinear model. This parametric model includes all the target features that need to be extracted, including 3-D location, object orientation, and target type. As more parameters are added to the model, the dimensionality increases. If uniform sampling is done over high-dimensional parameter space, the size of the dictionary and the complexity of the inversion algorithms rapidly grow, exceeding the capability of real-time processors. This paper shows that strategic structuring of the dictionary, which takes advantage of translational invariance in the model, can reduce the dictionary storage by several orders of magnitude and exploit the fast Fourier transform for fast computation of previously highly impractical, bordering on impossible, 3-D GPR imaging problems.
On the policy space of smart specialization strategies

ABSTRACT This paper is about ‘smart specialization strategies’ as an innovation (or industrial) policy approach. Being a sector non-neutral policy, while promoting a bottom-up principle of entrepreneurial initiative and dynamics, ‘smart specialization strategies’ occupy a particular place in the innovation policy space. This place is naturally not only filled with ‘smart specialization strategies’, but also several other approaches in development policy and industrial policy share similar goals and logics. In the paper we will build the innovation policy space, emphasize two important bifurcations within it and explain why various policy approaches are located in the same subspace and what makes them rather similar in terms of governance principles.
DNA fragmentation: manifestation of target cell destruction mediated by cytotoxic T-cell lines, lymphotoxin-secreting helper T-cell clones, and cell-free lymphotoxin-containing supernatant.

A Lyt-2+, trinitrophenyl-specific, lymphotoxin-secreting, cytotoxic T-cell line, PCl 55, mediates the digestion of target cell DNA into discretely sized fragments. This phenomenon manifests itself within 30 min after effector cell encounter as measured by the release of 3H counts from target cells prelabeled with [3H]deoxythymidine and occurs even at very low effector to target cell ratios (0.25:1). A Lyt-1+, ovalbumin-specific, lymphotoxin-secreting T-helper cell clone, 5.9. 24, is also able to mediate fragmentation of target cell DNA over a time course essentially indistinguishable from the cytotoxic T lymphocyte-mediated hit. Cell-free lymphotoxin-containing supernatants also cause release of DNA from targets, although they require a longer time course, on the order of 24 hr. In contrast, lysis of cells by antibody plus complement or Triton X-100 does not result in DNA release even after extended periods of incubation (24 hr). All three treatments that result in the release of DNA from cells cause fragmentation of that DNA into discretely sized pieces that are multiples of 200 base pairs. The results thus suggest that cytotoxic T cells, lymphotoxin-secreting helper clones with cytolytic activity, and lymphotoxin all effect target cell destruction by means of a similar mechanism and that observed differences in time course and the absence of target cell specificity in killing mediated by lymphotoxin may simply reflect differences in the mode of toxin delivery.
Molecular identification of prey in predator diets

In many situations prey choice by predators in the field cannot be established or quantified using direct observation. The remains of some prey may be visually identified in the guts and faeces of predators but not all predators ingest such hard remains and even those that do consume them may also ingest soft‐bodies prey that leave no recognizable remnants. The result is, at best, a biased picture of prey choice. A range of molecular techniques and applications are reviewed that allow prey remains to be identified, often to the species and even stage level. These techniques, all of which are still in use, include enzyme electrophoresis, a range of immunological approaches using polyclonal and monoclonal antibodies to detect protein epitopes, and recently developed polymerase chain reaction (PCR)‐based methods for detecting prey DNA. Analyses may be postmortem, on invertebrate and vertebrate predators collected from the field, or noninvasive assays of the remains in regurgitated bird pellets or vertebrate faeces. It was concluded that although monoclonal antibodies are currently the most effective method in use today, PCR‐based techniques have proved to be highly effective and versatile in recent laboratory trials and are likely to rapidly displace all other approaches.
In vivo gene expression directed by synthetic promoter constructions restricted to the -10 and -35 consensus hexamers of E. coli.

Two synthetic DNA sequences, carrying no other known E. coli promoter element than the consensus hexamers (CH) TTGACA (CH-35) and TATAAT CH(-10), spaced by 17 bp, were inserted in pBR329, in a position enabling transcription of the complete Cmr gene. The region upstream of the Cmr transcription start was carefully cleared of w.t. promoter elements (full deletion of the wild type (w.t.) Cmr promoter upstream +2 and large portion of an upstream coding sequence). Both synthetic promoters, which differ only by the sequences of the spacers (non consensus, constrained in AT or GC) support in vivo high level Cmr gene expression. The GC rich spacer is associated with transcription start at the usual +1 position, but with the AT rich spacer, transcription starts at several places, mainly in CH(-10). Rearranged promoter sequences derived from the synthetic ones upon transformation with partly ligated plasmids, yield new insights on the role of the standard CH pair, the size of the spacer and the sequence downstream of CH(-10).
Four-Leg-Based Fault-Tolerant Matrix Converter Schemes Based on Switching Function and Space Vector Methods

A four-leg-based fault-tolerant matrix converter topology is proposed, along with switching function and space vector approaches for modulation schemes, to improve the reliability of matrix converter drives. The four-leg-based fault-tolerant structure utilizes an additional redundant phase module. Based on the reconfigured hardware topology, fault-tolerant modulation strategies with both switching function and space vector approaches are developed to provide the matrix converter drives with continuous and disturbance-free operation. Pulsewidth-modulated algorithms with closed-form expressions, based on a switching function matrix, are presented to synthesize redefined output waveforms with reconfigured converter structures. Furthermore, a space-vector-based scheme using the indirect equivalent circuit with the fictitious dc link is also developed for the fault-tolerant topology after failures. Experimental results show the feasibility of the proposed four-leg-based fault-remedial approach, along with the developed modulation techniques.
Validation of a Novel Air Toxic Risk Model with Air Monitoring

Three modeling systems were used to estimate human health risks from air pollution: two versions of MNRiskS (for Minnesota Risk Screening), and the USEPA National Air Toxics Assessment (NATA). MNRiskS is a unique cumulative risk modeling system used to assess risks from multiple air toxics, sources, and pathways on a local to a state‐wide scale. In addition, ambient outdoor air monitoring data were available for estimation of risks and comparison with the modeled estimates of air concentrations. Highest air concentrations and estimated risks were generally found in the Minneapolis‐St. Paul metropolitan area and lowest risks in undeveloped rural areas. Emissions from mobile and area (nonpoint) sources created greater estimated risks than emissions from point sources. Highest cancer risks were via ingestion pathway exposures to dioxins and related compounds. Diesel particles, acrolein, and formaldehyde created the highest estimated inhalation health impacts. Model‐estimated air concentrations were generally highest for NATA and lowest for the AERMOD version of MNRiskS. This validation study showed reasonable agreement between available measurements and model predictions, although results varied among pollutants, and predictions were often lower than measurements. The results increased confidence in identifying pollutants, pathways, geographic areas, sources, and receptors of potential concern, and thus provide a basis for informing pollution reduction strategies and focusing efforts on specific pollutants (diesel particles, acrolein, and formaldehyde), geographic areas (urban centers), and source categories (nonpoint sources). The results heighten concerns about risks from food chain exposures to dioxins and PAHs. Risk estimates were sensitive to variations in methodologies for treating emissions, dispersion, deposition, exposure, and toxicity.
Impact of comorbidities on the measurement of health in patients with ankle osteoarthritis.

BACKGROUND Investigators seeking to understand the impact of musculoskeletal disorders commonly use validated outcome instruments to assess the effect of diseases on physical function and quality of life. However, the influence of concomitant systemic or musculoskeletal comorbidities on these scores has not been widely considered in orthopaedic research. The purpose of this study was to determine how morbidity unrelated to the ankle influences the perception of physical function and pain by patients with ankle osteoarthritis. METHODS Short Form-36 (SF-36) Physical Component Summary (PCS) and Mental Component Summary (MCS) scores, Ankle Osteoarthritis Scale (AOS) pain scale scores, demographic data, and systemic and musculoskeletal comorbidities were determined prospectively for 195 patients with ankle osteoarthritis and ninety-five age and gender-matched controls. The effect of systemic and musculoskeletal comorbidities on each of the scores was determined. RESULTS On the average, patients with ankle osteoarthritis had a relatively normal MCS score (47 +/- 13 points) and a markedly diminished PCS score (32 +/- 8 points). Both of these scores averaged 50 +/- 9 points in the control group. The AOS pain score averaged 61 +/- 23 points in the group with ankle osteoarthritis, whereas it averaged 10 +/- 15 points in the control group. We found the perception of ankle pain by patients with ankle osteoarthritis to be significantly and linearly associated with the number of other musculoskeletal problems (not related to the foot or ankle). CONCLUSIONS The degree of physical impairment associated with ankle osteoarthritis, as measured with the SF-36, is equivalent to that reported to be associated with severely disabling medical problems including end-stage kidney disease and congestive heart failure. The perception of ankle health status as measured with a validated, patient-oriented, anatomically specific instrument is influenced by the patients' perception of their overall musculoskeletal comorbidity status. The authors of clinical studies using these instruments should adjust for concomitant musculoskeletal disease.
Career paths of hotel general managers in Turkey

ABSTRACT This article investigates the career paths of hotel general managers (HGMs) in a developing country, namely Turkey. Based on an in-depth literature review, a questionnaire was developed and data were collected from 168 HGMs in Turkey. Compared to previous studies, this study found a higher percentage of female HGMs working in hotels. According to the research findings, almost half of the respondents received formal education in hospitality and tourism. The participating respondents most frequently reached the HGM position through working in the front office department and the food and beverage department. Honesty, interpersonal skills, and loyalty were found to be the top three characteristics that helped the participants become HGMs. In terms of required skills, communication, human relations, taking initiatives, and the ability to formulate plans were the top four skills for the participants in their career development. Finally, learning a foreign language, having a college degree, and developing long-term career goals were the top three personal development strategies. This is one of the first studies investigating HGMs career paths in a developing country and it offers specific theoretical and practical implications on this important topic.
MUTUAL FUND OUTPERFORMANCE AND GROWTH

Does better performance lead to more assets? We examine nearly 30,000 mutual funds to determine the effect that a fund’s outperformance relative to its peers has on the fund’s later asset size. We find that a fund that earns ten percent more than the size-weighted average of its peers in its style group in one year will on average experience an extra 5% excess asset growth in the subsequent year. The findings are robust to all types of fund styles and all fund sizes, with two exceptions: small funds of any style and very large fixed income funds.
Comparison of early feeding pattern dynamics in female and male rats after reversible ventromedial nucleus of hypothalamus block.

BACKGROUND In the hypothalamus, a number of interconnected foci, including the ventromedial nucleus of hypothalamus (VMN), interact to control food intake (FI). FI is a function of meal number (MN) and meal size (MZ). Because gender differences exist in feeding patterns, we aimed at investigating the role of the VMN in determining the relationship of MZ and MN in female and male rats. METHODS FI and feeding patterns of 10 female and 12 male Fischer-344 rats were studied after VMN block, achieved via stereotaxically located intra-VMN microinjection of the neuronal blocker, colchicine (0.32 microgram dissolved in 50 nL of isotonic injectate and instilled on each side into the VMN). RESULTS After colchicine injection in normal female rats, an immediate and significant increase in FI occurs as a result of the following: 1) increased MZ in dark and light phases and 2) increased light phase MN with consequent loss of the normal diurnal cycle in FI. Recovery of feeding cycle and normal vaginal smear pattern occurred by study's end. In normal male rats, VMN block resulted in the following: 1) an increase in FI resulting from increased MN occurring predominantly during the light phase, thereby 2) disrupting the usual light/dark feeding cycle. CONCLUSIONS Sexual differences in regulation of FI occur after temporary reversible VMN block: in female rats, MZ is more sensitive to experimental modulation, whereas in male rats it is MN.
Coronary Heart Disease Mortality Is Actually Low in Diabetic Japanese by Direct Comparison With the Joslin Cohort

OBJECTIVE To identify the mortality rate from coronary heart disease (CHD) in diabetic Japanese by directly comparing the Tokyo University Hospital cohort and the Joslin cohort using identical protocols. RESEARCH DESIGN AND METHODS Five hundred thirty-eight diabetic patients who were treated at Tokyo University Hospital with a 35- to 62-year age range at entry and with a diabetes duration of <5 years were followed retrospectively for more than 24 years. RESULTS The percentage of patients who survived at the end of the 24-year period was higher in the Tokyo University cohort (42%) than in the Joslin cohort (12%). The percentage of patients who died from CHD was remarkably lower in the Tokyo University cohort (11%) than in the Joslin cohort (39%). The CHD mortality rate was lower in the Tokyo University cohort than in the Joslin cohort, regardless of the duration of diabetes. CONCLUSIONS Our study confirmed the previous finding that the CHD mortality is lower in diabetic Japanese than in diabetic Caucasians.
Family Experiences During the Dying Process After Withdrawal of Life-Sustaining Therapy

Background:Life-sustaining therapy is commonly withdrawn in intensive care units, yet little is known about the perceptions of families when a critically ill patient dies after life-sustaining therapy is withdrawn. Aim:The purpose of this investigation was to understand the experience of families when a family member had an unexpected life-threatening illness or injury and who died after life-sustaining therapy was withdrawn. Methods:This investigation used a hermeneutic phenomenological approach. Interviews were conducted with family members after the patient’s death. All interviews were transcribed with units of meaning and clusters, and then categories inductively determined. Methodological rigor was established. Setting/Participants:A purposive sample of family members was recruited into the study from 3 intensive care units. Twenty-two family members participated in the study. Results:Six categories evolved from the analysis: preparing for the dying process, the dying environment, perceptions of patient comfort, the death vigil, essential aspects of care, and together as a family. Families described the death vigil as extremely difficult. Family members described several aspects of care as very meaningful to them during the dying process. Families described how important it was for the family to be together as a family during the dying process.