Miracle-dz/UniFAR-FTUs huggingface dataset:
Safety, Tolerability, and Pharmacokinetics of Escalating High Doses of Ivermectin in Healthy Adult Subjects

Safety and pharmacokinetics (PK) of the antiparasitic drug ivermectin, administered in higher and/or more frequent doses than currently approved for human use, were evaluated in a double‐blind, placebo‐controlled, dose escalation study. Subjects (n = 68) were assigned to one of four panels (3:1, ivermectin/placebo): 30 or 60 mg (three times a week) or 90 or 120 mg (single dose). The 30 mg panel (range: 347–594 μg/kg) also received a single dose with food after a 1‐week washout. Safety assessments addressed both known ivermectin CNS effects and general toxicity. The primary safety endpoint was mydriasis, accurately quantitated by pupillometry. Ivermectin was generally well tolerated, with no indication of associated CNS toxicity for doses up to 10 times the highest FDA‐approved dose of 200 μg/kg. All dose regimens had a mydriatic effect similar to placebo. Adverse experiences were similar between ivermectin and placebo and did not increase with dose. Following single doses of 30 to 120 mg, AUC and Cmax were generally dose proportional, with tmax ∼4 hours and t1/2 ∼18 hours. The geometric mean AUC of 30 mg ivermectin was 2.6 times higher when administered with food. Geometric mean AUC ratios (day 7/day 1) were 1.24 and 1.40 for the 30 and 60 mg doses, respectively, indicating that the accumulation of ivermectin given every fourth day is minimal. This study demonstrated that ivermectin is generally well tolerated at these higher doses and more frequent regimens.
Integrated Diagnostic and Treatment Approach for the Medical Patient Who Has Had Psychologic Trauma

Background. Physicians often treat patients with physical illnesses that have a functional component. Investigators have discovered that many of these patients have unresolved emotional problems associated with histories of trauma and abuse. Methods. Abused and traumatized patients with medical complaints often seek medical help. Empathic nonpsychiatrist physicians play an important role in the care of these patients. The physician's efforts can be augmented by a trained RN to provide supportive stress training and nutrition education and by a mental health professional to provide psychotherapy when needed. Results. In the case presented, the patient had symptomatic improvement when her physician empathically provided medical treatment, involved the staff and a trained RN in the healing effort, and made an appropriate referral to a mental health professional. Conclusion. This unified diagnostic and treatment approach for traumatized patients with medical problems can be rewarding, efficacious, and cost effective.
Association of pre-pregnancy body mass index with future offspring metabolic profile: findings from three independent European birth cohorts

Background A high proportion of women start pregnancy overweight/obese. According to the developmental overnutrition hypothesis, this could lead offspring to have metabolic disruption throughout their lives, and, thus perpetuate the obesity epidemic across generations. Concerns about this hypothesis are influencing antenatal care. However, it is unknown whether maternal pregnancy adiposity is associated with long-term risk of adverse metabolic profiles in offspring, and if so, whether this association is causal, via intrauterine mechanisms, or explained by shared familial (genetic, lifestyle, socioeconomic) characteristics. We aimed to determine if associations between maternal body mass index (BMI) with offspring systemic metabolite profile are causal via intrauterine mechanisms or familial factors. Methods and Findings We used one and two-stage individual participant data (IPD) metaanalysis, and a negative-control (paternal BMI) to examine the association between maternal prepregnancy BMI and offspring serum metabolome from three European birth cohorts (offspring age at metabolite assessment 16, 17 and 31 years). Circulating metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics. Results from one-stage IPD meta-analysis (N=5327 to 5377 mother-father-offspring trios) showed that increasing maternal and paternal BMI was associated with an adverse cardio-metabolic profile in offspring. We observed strong positive associations with VLDL-lipoproteins, VLDL-C, VLDL-triglycerides, VLDL-diameter, branched/aromatic amino acids, glycoprotein acetyls, and triglycerides, and strong negative associations with HDL-lipoprotein, HDL-diameter, HDL-C, HDL2-C and HDL3-C (all P<0.003). Stronger magnitudes of associations were present for maternal compared with paternal BMI across these associations, however there was no strong statistical evidence for heterogeneity between them (all bootstrap P >0.003, equivalent to 0.05 after accounting for multiple testing). Results were similar in each individual cohort, and in the two-stage analysis. Offspring BMI showed similar patterns of crosssectional association with metabolic profiles as for parental pre-pregnancy BMI associations, but with greater magnitudes. Adjustment of the parent BMI-offspring metabolite associations for offspring BMI suggested the parental associations were largely due to the association of parental BMI measures with offspring BMI. Conclusion Our findings suggest that maternal BMI-offspring metabolome associations are likely to be largely due to shared genetic or familial lifestyle confounding, rather than intrauterine programming mechanisms. They do not support the introduction of measures to reduce maternal BMI in order to prevent adverse offspring cardio-metabolic health.
Comparative and phylogenetic analysis of developmental sequences

Summary Event pairing has been proposed for the optimization of developmental sequences (event sequences) on a given phylogenetic hypothesis (cladogram) to determine instances of sequence heterochrony. Here, we show that event pairing is faulty, leading to the optimization of impossible hypothetical ancestors, the underestimation of the lengths of the developmental sequences on the tree, and the proposition of synapomorphies that are not supported by the data. When used for phylogenetic analysis, event pairing can even produce cladograms that are inconsistent with the data. These errors are caused by the fact that event pairing treats dependent features as if they were independent. We present a new method for comparative and phylogenetic analysis of developmental sequences that does not exhibit these errors. Our method applies Search‐based character optimization and treats the entire developmental sequence as a single character that is then analyzed by using an edit cost function, which specifies the transformation cost between pairs of observed and unobserved character states, and dynamic programming. In other words, the developmental sequence is directly optimized on the tree. We used event pairing as an edit cost function, but others are possible.
Bioaccumulation of polycyclic aromatic compounds: 1. Bioconcentration in two marine species and in semipermeable membrane devices during chronic exposure to dispersed crude oil

Assessing the fate in marine biota of hydrocarbons derived from oil particles that are discharged during exploration and production is of relevant environmental concern. However, a rather complex experimental setup is required to carry out such investigations. In this study, a sophisticated tool, the continuous‐flow system (CFS), was used to mimic dispersed oil exposure to marine biota. Polycyclic aromatic hydrocarbon (PAH) uptake was studied in two species, the blue mussel Mytilus edulis and juvenile of the turbot Scophthalmus maximus, and in semipermeable membrane devices (SPMD) exposed to crude oil dispersed in a flow‐through system. After an exposure period of 8 to 21 d, elimination in organisms and devices was analyzed for 9 to 10 d following transfer to PAH‐free seawater. Principal component analysis (PCA) revealed different PAH patterns. In mussel and SPMD, the PAH profiles were very close to that analyzed in seawater. Slight differences were, however, indicated for large molecules with log Kow above six. Nonachievement of steady‐state concentration and bioavailability of PAH in oil droplets may account for these differences. The PAH composition in fish revealed only congeners with two to three aromatic rings. A combination of bioavailability and efficient metabolism of the larger PAH molecules may explain this pattern. The CFS made possible a better understanding of some critical factors governing bioconcentration in marine biota from dispersed oil. Yet the results illustrate that uptake of PAH from exposure to oil particles is complex and that different species may bioconcentrate different molecules depending on factors like life style and metabolic capability to degrade the potential harmful substances. Hence, risk assessment of the actual impact of discharges to marine biota should consider these essential biological and ecological factors.
What hope for African primate diversity

Available empirical evidence suggests that many primate populations are increasingly threatened by anthropogenic actions and we present evidence to indicate that Africa is a continent of particular concern in terms of global primate conservation. We review the causes and consequences of decline in primate diversity in Africa and argue that the major causes of decline fall into four interrelated categories: deforestation, bushmeat harvest, disease and climate change. We go on to evaluate the rarity and distribution of species to identify those species that may be particularly vulnerable to threats and examine whether these species share any characteristic traits. Two factors are identified that suggest that our current evaluation of extinction risk may be overly optimistic; evidence suggests that the value of existing forest fragments may have been credited with greater conservation value in supporting primate populations than they actually have and it is clear that the extinction debt from historical deforestation has not being adequately considered. We use this evaluation to suggest what future actions will be advantageous to advance primate conservation in Africa and evaluate some very positive conservation gains that are currently occurring.
Frequency response subtraction for simple measurement of intrinsic laser dynamic properties

The authors describe a new technique for extracting the intrinsic laser-diode dynamic properties accurately. This simple technique eliminates the need for accurate microwave calibration of the test equipment and problems of microwave reflections, nonideal frequency response of laser mount, and detector. The effect of the parasitic components of the laser diode are also eliminated from the results so that measurements of important dynamic properties of the laser can be found up to high frequencies (10-20 GHz) on standard laser diodes. The techinque being used to measure variations of resonance peak and damping factor at different bias levels for a standard bulk active region 1.3 mu m laser diode is shown. <<ETX>>
Immunological and metabolic effects of cis-9, trans-11-conjugated linoleic acid in subjects with birch pollen allergy

Animal studies suggest that conjugated linoleic acid (CLA) may modulate the immune response, while studies in healthy human subjects have shown little effect and results are controversial. However, the effects of CLA may be more prominent in situations of immune imbalance, such as allergy. We studied the effects of the natural CLA isomer, cis-9, trans-11-CLA, on allergy symptoms and immunological parameters in subjects with birch pollen allergy. In a randomised, placebo-controlled study, forty subjects (20–46 years) with diagnosed birch pollen allergy received 2 g CLA/d in capsules, which contained 65·3 % cis-9, trans-11-CLA and 8·5 % trans-10, cis-12-CLA (n 20), or placebo (high-oleic acid sunflower-seed oil) (n 20) for 12 weeks. The supplementation began 8 weeks before the birch pollen season and continued throughout the season. Allergy symptoms and use of medication were recorded daily. Lymphocyte subsets, cytokine production, immunoglobulins, C-reactive protein, lipid and glucose metabolism and lipid peroxidation were assessed before and after supplementation. The CLA group reported a better overall feeling of wellbeing (P < 0·05) and less sneezing (P < 0·05) during the pollen season. CLA supplementation decreased the in vitro production of TNF-α (P < 0·01), interferon-γ (P < 0·05) and IL-5 (P < 0·05). Total plasma IgE and birch-specific IgE concentrations did not differ between groups, whereas plasma IgA (P < 0·05), granulocyte macrophage colony-stimulating factor (P < 0·05) and eosinophil-derived neurotoxin (P < 0·05) concentrations were lower after CLA supplementation. Urinary excretion of 8-iso-PGF2α, a major F2-isoprostane (P < 0·01), and 15-keto-dihydro-PGF2α, a primary PGF2α metabolite (P < 0·05), increased in the CLA group. The results suggest that cis-9, trans-11-CLA has modest anti-inflammatory effects in allergic subjects.
Neuropsychological Performance in Patients With Depression is Associated With Clinical, Etiological and Genetic Risk Factors

The present study explores neuropsychological functioning in patients with depression with reference to key clinical, etiological and genetic features. In comparison to healthy volunteers, patients with severe depression demonstrated poorer performance on all neuropsychological tests except for WAIS-R Vocabulary and a 64-item computerized version of the Wisconsin Card Sorting Test. On average, patients exhibited significant impairments (greater than –2 standard deviation units) on tests of simple reaction time, Part B of the Trail Making Test and Raven’s Colored Progressive Matrices. When performance decrements were analyzed with reference to key clinical features, patients with melancholia performed more poorly on WAIS-R Vocabulary, semantic fluency and choice reaction time than those with nonmelancholic depression. After controlling for age, those patients with late-onset depression (i.e., age of onset =50 years) exhibited poorer performance on a computerized version of the Tower of London test in comparison to those with an early onset. While there was no relationship between neuropsychological test scores and summed vascular risk factors or apolipoprotein E genotypes, presence of the methylenetetrahydrofolate reductase gene mutation was associated with slowed reaction time. The differential relationships between clinical, etiological and genetic risks and neuropsychological performance supports the presence of unique pathophysiological mechanisms in distinct subgroups of patients. These findings underscore the need to consider subtypes when investigating neuropsychological deficits in patients with depression.
Magnetic Stimulation of the Quadriceps Femoris Muscle: Comparison of Pain with Electrical Stimulation

Han T-R, Shin H-I, Kim I-S: Magnetic stimulation of the quadriceps femoris muscle: Comparison of pain with electrical stimulation. Am J Phys Med Rehabil 2006;85:593–599. Objective:The objective of this study was to compare pain induced by magnetic stimulation of the quadriceps femoris (QF) muscle with that induced by transcutaneous neuromuscular electrical stimulation (NMES). Design:Magnetic stimulation and transcutaneous NMES were applied to QF muscles of 17 normal volunteers. The intensity of each mode of stimulation was increased in a stepwise manner. Peak torque values of isometric contractions of QF muscles and visual analog scale (VAS) scores were recorded at each intensity level. The VAS scores of the two stimulating modalities were compared at the intensity-generating same peak torque values. Results:The median VAS scores for electrical and magnetic stimulation were 5.7 and 0.3, respectively. The median difference between the VAS scores for electrical and magnetic stimulation was 3.7 (range, 1.7–8.5). The mean of the maximum peak torque obtained from each subject was higher in magnetic stimulation than in electrical stimulation (9.5 ± 4.8 vs. 4.4 ± 2.9 Nm). Conclusions:Magnetic stimulation of the QF muscle produced less pain at the same level of isometric peak torque than did transcutaneous NMES. Magnetic stimulation is a potential alternative to transcutaneous NMES, especially for persons with intact or residual sensory function.
A Nonplatinum Combination in Metastatic Transitional Cell Carcinoma

Objective:Cisplatin-based chemotherapy is the most effective standard treatment available for patients with metastatic bladder cancer. For those patients who are unable to receive cisplatin, other effective combination treatments are needed. The objective of this research was to determine if a combination of paclitaxel and gemcitabine would be effective in patients who were unable to receive cisplatin or have failed cisplatin treatment. Methods:Patients with histologic-proven metastatic bladder cancer who had measurable disease were eligible. Patients received chemotherapy (in an outpatient clinic) with paclitaxel at 110 mg/m2 plus 1000 mg/m2 gemcitabine on days 1 and 15 of a 28-day cycle. Patients were evaluated after 2 cycles of therapy using computed tomography and bone scan imaging. Results:An objective response rate was achieved in 61% of the patients (13 of 18 subjects). Fifty-five percent of the patients who were previously treated with chemotherapy had an objective response (11 of 18 subjects). The median duration of response was 5 months and the toxicity was mild. All patients with low-risk disease had a response (8 of 18 subjects), compared with a 30% response rate in the intermediate-/high-risk group (P = 0.001, 10 of 18 subjects). Conclusions:The combination of paclitaxel and gemcitabine given in an every 2-week regimen is very well tolerated and has significant activity in previously treated patients with metastatic transitional cell carcinoma. The combination of paclitaxel and gemcitabine appears to be effective for patients with good-risk disease who are unable to take cisplatin-based chemotherapy.
Characteristics of period-one oscillations in semiconductor lasers subject to optical injection

The characteristics of period-one oscillations in semiconductor lasers subject to optical injection are experimentally and theoretically investigated. Attention is mainly paid to the relative dependence of the frequency and the magnitude between the principal oscillation and the first sideband in period-one oscillations as a function of the detuning frequency and the injection strength of the injection signal. The frequency separation between the two signals is found to decrease as the injection strength and the detuning frequency reduce. The magnitude of the principal oscillation decreases with the decreasing injection strength and the increasing detuning frequency, while that of the first sideband grows at the same time. At some operating conditions, the magnitude of the first sideband dominates that of the original principal oscillation, resulting in a frequency shift of the principal oscillation from the injection frequency to the first sideband. Similar studies are also done for the stable injection locking to explore the transition of the frequency and the magnitude characteristics across the Hopf bifurcation line. The effects of different bias current levels of the injected laser on the frequency and the magnitude characteristics of period-one oscillations are also investigated.
Cooking frequency may enhance survival in Taiwanese elderly

Abstract Objective To investigate the association between cooking behaviour and long-term survival among elderly Taiwanese. Design Cohort study. The duration of follow-up was the interval between the date of interview and the date of death or 31 December 2008, when censored for survivors. Information used included demographics, socio-economic status, health behaviours, cooking frequencies, physical function, cognitive function, nutrition knowledge awareness, eating out habits and food and nutrient intakes. These data were linked to death records. Cox proportional-hazards models were used to evaluate cooking frequency on death from 1999 to 2008 with related covariate adjustments. Setting Elderly Nutrition and Health Survey in Taiwan, 1999–2000. Subjects Nationally representative free-living elderly people aged ≥65 years (n 1888). Results During a 10-year follow-up, 695 participants died. Those who cooked most frequently were younger, women, unmarried, less educated, non-drinkers of alcohol, non-smokers, without chewing difficulty, had spouse as dinner companion, normal cognition, who walked or shopped more than twice weekly, who ate less meat and more vegetables. Highly frequent cooking (>5 times/week, compared with never) predicted survival (hazard ratio (HR) = 0·47; 95 % CI, 0·36, 0·61); with adjustment for physical function, cognitive function, nutrition knowledge awareness and other covariates, HR was 0·59 (95 % CI, 0·41, 0·86). Women benefited more from cooking more frequently than did men, with decreased HR, 51 % v. 24 %, when most was compared with least. A 2-year delay in the assessment of survivorship led to similar findings. Conclusions Cooking behaviour favourably predicts survivorship. Highly frequent cooking may favour women more than men.
Genome-wide identification of peroxisome proliferator response elements using integrated computational genomics s⃞ Published, JLR Papers in Press, April 3, 2006.

Peroxisome proliferator-activated receptor (PPAR) agonists are currently used therapeutically in humans, even though many of their direct gene targets are unknown. Because PPARs can directly regulate gene expression through peroxisome proliferator response elements (PPREs), we pursued the computational prediction of PPREs on a genome-wide scale. Contrary to current hypotheses, PPREs are not isotype-specific, nor do flanking nucleotides confer additional information. However, a position weight matrix-based search for PPREs within upstream conserved elements yielded sufficient selectivity for a genome-wide search. Additionally, a novel motif occurring with greater prevalence than PPREs was revealed. Microarray and gene ontology analyses further validated our search technique and provided new functional clusters of genes that were not previously known to be directly regulated by PPARs (e.g., chromatin remodeling, DNA damage response, Wnt, and mitogen-activated protein kinase signaling). This first genome-wide library of high-confidence predicted PPAR target genes will be a valuable resource to PPAR biologists.