Feedback modeling of non-esterified fatty acids in rats after nicotinic acid infusions

A feedback model was developed to describe the tolerance and oscillatory rebound seen in non-esterified fatty acid (NEFA) plasma concentrations following intravenous infusions of nicotinic acid (NiAc) to male Sprague-Dawley rats. NiAc was administered as an intravenous infusion over 30 min (0, 1, 5 or 20 μmol kg−1 of body weight) or over 300 min (0, 5, 10 or 51 μmol kg−1 of body weight), to healthy rats (n = 63), and serial arterial blood samples were taken for measurement of NiAc and NEFA plasma concentrations. Data were analyzed using nonlinear mixed effects modeling (NONMEM). The disposition of NiAc was described by a two-compartment model with endogenous turnover rate and two parallel capacity-limited elimination processes. The plasma concentration of NiAc was driving NEFA (R) turnover via an inhibitory drug-mechanism function acting on the formation of NEFA. The NEFA turnover was described by a feedback model with a moderator distributed over a series of transit compartments, where the first compartment (M1) inhibited the formation of R and the last compartment (MN) stimulated the loss of R. All processes regulating plasma NEFA concentrations were assumed to be captured by the moderator function. The potency, IC50, of NiAc was 45 nmol L−1, the fractional turnover rate kout was 0.41 L mmol−1 min−1 and the turnover rate of moderator ktol was 0.027 min−1. A lower physiological limit of NEFA was modeled as a NiAc-independent release (kcap) of NEFA into plasma and was estimated to 0.032 mmol L−1 min−1. This model can be used to provide information about factors that determine the time-course of NEFA response following different modes, rates and routes of administration of NiAc. The proposed model may also serve as a preclinical tool for analyzing and simulating drug-induced changes in plasma NEFA concentrations after treatment with NiAc or NiAc analogues

The efficacy of iron chelator regimes in reducing cardiac and hepatic iron in patients with thalassaemia major: a clinical observational study

<p>Abstract</p> <p>Background</p> <p>Available iron chelation regimes in thalassaemia may achieve different changes in cardiac and hepatic iron as assessed by MR. The aim of this study was to assess the efficacy of four available iron chelator regimes in 232 thalassaemia major patients by assessing the rate of change in repeated measurements of cardiac and hepatic MR.</p> <p>Results</p> <p>For the heart, deferiprone and the combination of deferiprone and deferoxamine significantly reduced cardiac iron at all levels of iron loading. As patients were on deferasirox for a shorter time, a second analysis ("Initial interval analysis") assessing the change between the first two recorded MR results for both cardiac and hepatic iron (minimum interval 12 months) was made. Combination therapy achieved the most rapid fall in cardiac iron load at all levels and deferiprone alone was significantly effective with moderate and mild iron load. In the liver, deferasirox effected significant falls in iron load and combination therapy resulted in the most rapid decline.</p> <p>Conclusion</p> <p>With the knowledge of the efficacy of the different available regimes and the specific iron load in the heart and the liver, appropriate tailoring of chelation therapy should allow clearance of iron. Combination therapy is best in reducing both cardiac and hepatic iron, while monotherapy with deferiprone or deferasirox are effective in the heart and liver respectively. The outcomes of this study may be useful to physicians as to the chelation they should prescribe according to the levels of iron load found in the heart and liver by MR.</p

The effects of intranasal esketamine on on-road driving performance in patients with major depressive disorder or persistent depressive disorder

Background: Intranasal esketamine demonstrates rapid improvement of depressive symptoms. However, transient adverse effects (dissociation, sedation and dizziness) may occur, which could impact driving performance. Aims: To evaluate the effects of 84 mg intranasal esketamine on driving performance in unipolar major depressive disorder (MDD) or persistent depressive disorder (PDD) patients. Methods: The study consisted of two parts. Part A was a single-blind, double-dummy, randomized three-period, cross-over study to compare effects of esketamine versus placebo on next morning driving, 18 ± 2 h post-treatment. Alcohol was administered to demonstrate assay sensitivity. In Part B, same-day driving, 6 ± 0.5 hours post-treatment, was assessed during twice weekly esketamine administration for 3 weeks. Twenty-seven patients with mild-to-moderate MDD or PDD without psychotic features completed a 100 km on-the-road driving test on a public highway in normal traffic. The primary outcome was standard deviation of lateral position (SDLP; cm; weaving of car). Results: In Part A, alcohol impaired driving performance compared to placebo: Least-square means (95% CI), p-value for delta SDLP (cm) compared with placebo: (ΔSDLP = + 1.83 (1.03; 2.62), p < 0.001), whereas esketamine did not: (ΔSDLP = −0.23 (−1.04; 0.58), p = 0.572). In Part B, weekly driving tests showed no differences between placebo baseline SDLP and after esketamine administration over 3 weeks: Day 11: (ΔSDLP = −0.96 (−3.72; 1.81), p = 0.493), Day 18: (ΔSDLP = −0.56 (−3.33; 2.20), p = 0.686) and Day 25: (ΔSDLP = −1.05 (−3.82; 1.71), p = 0.451). Conclusions: In this study, esketamine did not impair on-road driving performance the next morning following a single dose, or on same day after repeated administration

Optimal Design of a Trickle Bed Reactor for Light Fuel Oxidative Desulfurization based on Experiments and Modelling

YesIn this work, the performance of oxidative desulfurization (ODS) of dibenzothiophene (DBT) in light gas oil (LGO) is evaluated with a homemade manganese oxide (MnO2/γ-Al2O3) catalyst. The catalyst is prepared by Incipient Wetness Impregnation (IWI) method with air under moderate operating conditions. The effect of different reaction parameters such as reaction temperature, liquid hour space velocity and initial concentration of DBT are also investigated experimentally. Developing a detailed and a validated trickle bed reactor (TBR) process model that can be employed for design and optimization of the ODS process, it is important to develop kinetic models for the relevant reactions with high accuracy. Best kinetic model for the ODS process taking into account hydrodynamic factors (mainly, catalyst effectiveness factor, catalyst wetting efficiency and internal diffusion) and the physical properties affecting the oxidation process is developed utilizing data from pilot plant experiments. An optimization technique based upon the minimization of the sum of the squared error between the experimental and predicted composition of oxidation process is used to determine the best parameters of the kinetic models. The predicted product conversion showed very good agreement with the experimental data for a wide range of the operating condition with absolute average errors less than 5%

Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome

Opioids may inhibit the 5-HT transporter (SERT) and the noradrenaline transporter (NET). NET inhibition may contribute to analgesia, and SERT inhibition or interactions with 5-HT receptors may cause serotonergic toxicity. However, the effects of different opioids on the human SERT, NET and 5-HT receptors have not been sufficiently studied.; We determined the potencies of different opioids to inhibit the SERT and NET in vitro using human transporter-transfected HEK293 cells. We also tested binding affinities at 5-HT; 1A; , 5-HT; 2A; and 5-HT; 2C; receptors. Additionally, we assessed clinical cases of the serotonin syndrome associated with each opioid reported by PubMed and a World Health Organization database.; Dextromethorphan, l(R)-methadone, racemic methadone, pethidine, tramadol and tapentadol inhibited the SERT at or close to observed drug plasma or estimated brain concentrations in patients. Tapentadol was the most potent NET inhibitor. Pethidine, tramadol, l(R)-methadone, racemic methadone, dextromethorphan and O-desmethyltramadol also inhibited the NET. 6-Monoacetylmorphine, buprenorphine, codeine, dihydrocodeine, heroin, hydrocodone, hydromorphone, morphine, oxycodone and oxymorphone did not inhibit the SERT or NET. Fentanyl interacted with 5-HT; 1A; receptors and methadone, pethidine and fentanyl with 5-HT; 2A; receptors, in the low micromolar range. Opioids most frequently associated with the serotonin syndrome are tramadol, fentanyl, tapentadol, oxycodone, methadone and dextromethorphan.; Some synthetic opioids interact with the SERT and NET at potentially clinically relevant concentrations. SERT inhibition by tramadol, tapentadol, methadone, dextromethorphan and pethidine may contribute to the serotonin syndrome. Direct effects on 5-HT; 1A; and/or 5-HT; 2A; receptors could be involved with methadone and pethidine

A Comparison of Two Self-Managed Spelling Interventions: Cover, Copy, and Compare and Taped Spelling Intervention

Cover, copy, and compare (CCC) is an effective academic intervention for many academic subjects, but most often implemented as a spelling intervention. Taped interventions (TI) have also been found to be effective in increasing academic performance (Freeman & McLaughlin, 1984), but are most often implemented as math interventions. Recently, a Taped Spelling Intervention (TSI) was developed and found to be effective in improving the spelling of middle school students with learning disabilities (McCallum, Schmitt, Evans, Schaffner, & Long, 2014). CCC and TSI are self-managed interventions that include error self-correction components and high rates of opportunities to respond. Both interventions are viewed favorably by students and teachers. Direct comparisons of CCC and other taped interventions have previously been examined (Poncy, Skinner, & Jaspers, 2007; Poncy, Skinner, & McCallum, 2012), but this is the first study to directly compare CCC and the recently developed TSI. The current study compared the effects of CCC and TSI on the spelling accuracy of four fifth-grade students with identified learning disabilities in reading and writing. The effectiveness of the two interventions was compared by way of an adapted alternating treatments design (Barlow & Hayes, 1979), taking into account instructional time required by each intervention and the resultant learning rates. The TSI condition included the use of a media device in the form of an iPhone while experimenter-created intervention worksheets were used during the CCC condition. Lists of grade level spelling words were compiled from AIMSweb, a tightly controlled for difficulty, curriculum-based measurement system. Three spelling word lists were used in the study (one word list per condition including a control condition) with each list consisting of 10 words made up of 75 correct letter sequences. The effectiveness of the interventions was evaluated using visual analyses. Specifically, mean total words correct (TWC) and mean correct letter sequences (CLS) for each word list were graphed and visual analysis was used to compare the trends of the data. Both interventions (CCC and TSI) resulted in increased mean TWC and CLS for each of the students when compared to his initial baseline assessments. In terms of TWC, CCC was most effective for two of the students and TSI was most effective for another student. Regarding CLS, three students performed better by way of TSI when compared to CCC. Learning rate was higher in the CCC condition and students generally preferred CCC over TSI. Spelling gains were maintained on an assessment administered approximately two-weeks following the final intervention session. Discussion focuses on the importance of easily implemented, socially acceptable, time- and cost-efficient interventions for increasing the academic performance of students, and the value of comparative analyses for choosing appropriate interventions. Practical implications, recommendations for use, limitations, and direction for future research will be discussed

Mechanical overload induces muscle hypertrophy in mice with lowered serum IGF-1

Decreased serum levels of IGF-1 result in lower muscle and body weights. Muscular autocrine/paracrine IGF-I may be stimulated in response to mechanical overload. Purpose: to determine whether normal levels of serum IGF-I are required for the increased muscle mass tha occurs in habitual mechanical overload. Design: The Liver IGF-I Deficient (LID) mouse has selective disruption of the liver IGF-I alleles, resulting in 20-25% of normal serum IGF-1 levels. Wildtype, LL, mice have normal circulating levels of IGF-1. LID and LL mice, 15-16 mos of age, were divided into resistance trained (LID-TR n=11, LL-TR n = 10) and sedentary groups (LID-NT n = 9, LL-NT n = 8). The resistance training protocol consisted of ladder climbing (85°, 1.5cm spacing), utilizing progressive overload. Initially weights, 50% of body weight (BW) were attached to the base of their tail, and the resistance was progressively increased. The training protocol was performed twice a day, every third day for 16-18 weeks, with the mice pulling over 3X their body weight during their last bouts. The in situ physiological parameters of the Plantaris muscle were determined. Results: SP[subscript o],SP[subscript t], as well as TPT & 1/2 RT were the same among groups. The Plantaris muscle was the most responsive to the weight training, exhibiting a 12 % (p < 0.05) increase in absolute weight in both training groups vs. their sedentary counterparts. Other hindlimb muscles increased by 7-9% (p <0.05). Hematoxylin-Eosin staining revealed cellular damage in both training groups. The LID-TR group sustained damage in 1.4% of myofibers, while the LL-TR only showed damage in 0.5% of myofibers (p <0.05). No cellular damage was evident in either sedentary group. Central nuclei were visualized utilizing laminin antibody staining. In the LID-TR group 1.8% of myofibers showed central nuclei vs. 0.5% in the LL-TR (p <0.05). The central nuclei were mostly localized around the areas of cellular damage. Conclusion: The degree of hypertrophy was the greatest in the plantaris and FHL muscle, as expected from this type of training. In this experiment, decreased serum IGF-1Ea levels did not attenuate the muscular hypertrophy induced by habitual mechanical overload. The LID-TR group was able to hypertrophy to the same degree as the LL-TR animals. Even though they weighed significantly less than their sedentary counterparts, their muscle weights in the FHL and Plantaris were greater. Satellite activation was not hindered either as evidenced by the significantly higher levels of central nuclei in the LID-TR group. The increased number of central nuclei found in the LID-TR group is likely due in part to the increased levels of damage, as the majority was localized around the areas of damage. Neverthless, the data shows that satellite activation is not hindered in the presence of reduced IGF-1Ea. The compensatory mechanisms for the adaptation evidenced in this study need to be elucidated. Release of IGF-1Eb can be a likely reason, as IGF-1Eb has been shown to be more potent in inducing muscle hypertrophy, and thus may be able to compensate for the reduced serum levels of IGF-1Ea (Goldspink 2002). Individual steps among the cascade of intracellular signals activated by IGF-1Ea may also be amplified to allow normal hypertrophy during muscle overloadKinesiology and Health Educatio