One hertz repetitive transcranial magnetic stimulation over dorsal premotor cortex enhances offline motor memory consolidation for sequence‐specific implicit learning

Consolidation of motor memories associated with skilled practice can occur both online, concurrent with practice, and offline, after practice has ended. The current study investigated the role of dorsal premotor cortex (PMd) in early offline motor memory consolidation of implicit sequence‐specific learning. Thirty‐three participants were assigned to one of three groups of repetitive transcranial magnetic stimulation (rTMS) over left PMd (5 Hz, 1 Hz or control) immediately following practice of a novel continuous tracking task. There was no additional practice following rTMS. This procedure was repeated for 4 days. The continuous tracking task contained a repeated sequence that could be learned implicitly and random sequences that could not. On a separate fifth day, a retention test was performed to assess implicit sequence‐specific motor learning of the task. Tracking error was decreased for the group who received 1 Hz rTMS over the PMd during the early consolidation period immediately following practice compared with control or 5 Hz rTMS. Enhanced sequence‐specific learning with 1 Hz rTMS following practice was due to greater offline consolidation, not differences in online learning between the groups within practice days. A follow‐up experiment revealed that stimulation of PMd following practice did not differentially change motor cortical excitability, suggesting that changes in offline consolidation can be largely attributed to stimulation‐induced changes in PMd. These findings support a differential role for the PMd in support of online and offline sequence‐specific learning of a visuomotor task and offer converging evidence for competing memory systems.     

Clinical and histological evaluation of immediate-loaded posterior implants in nonhuman primates

PURPOSE: To evaluate a square-thread design implant and compare the bone-implant contact percentage between immediate-loaded and nonloaded implants (controls) in nonhuman primates. MATERIALS: Five nonhuman primates each received 3 implants, with a total of 5 control implants and 10 immediate-loaded implants in posterior regions of the mouth. Ninety days after surgery (and function was appropriate), block sections of the implants were removed and sectioned in 200-mum thick pieces. The block sections were stained with modified Masson for evaluation of the bone-implant contact percentage. RESULTS: One of the immediate-loaded implants failed. The bone-implant contact percentage of control implants ranged from 50.34% to 64.13% and averaged 56.3%. The bone-implant contact percentage of immediate-loaded implants ranged from 43.23% to 75.72%, with an average of 62.4%. Two implants had lower bone-implant contact percentage than the others, and when these are not included in the evaluation, the bone-implant contact percentage average increased to 67.6%. CONCLUSIONS: Immediate-loaded implants in the nonhuman primates often have a higher bone-implant contact percentage at 90 days than unloaded implants. The bone remodeling is different for loaded implant-bone interfaces than for unloaded conditions. However, 1 immediate-loaded implant failed, and 2 implants had lower bone-implant contact percentage than controls. Therefore, although there are benefits of immediate loading, there appear to also be some risks.     

An investigation of antidiabetic activities of bioactive compounds in Euphorbia hirta Linn using molecular docking and pharmacophore

Herbal remedies have been considered as potential medication for diabetes type 2 treatment. Bitter melons, onions, or Goryeong Ginsengs are popular herbals and their functions in diabetes patients have been well documented. Recently, the Euphorbia hirta has been shown to have strong effects on diabetes in mice, however, there has been no research clearly indicating what the active compound is. The main purpose of the current study was therefore to evaluate whether a relationship exists between various bioactive compounds in E. hirta Linn and targeted protein relating diabetes type 2 in human. In view of this, extraction from E. hirta Linn was tested if they contained the bioactive compounds. This process involved the docking of 3D structures of those substances (ligand) into targeted proteins: 11-β hydroxysteroid dehydrogenase type 1, glutamine: fructose-6-phosphate amidotransferase, protein phosphatase, and mono-ADP-ribosyltransferase sirtuin-6. Then, LigandScout was applied to evaluate the bond formed between ligand and the binding pocket in the protein. These test identified in eight substances with high binding affinity (<?8.0 kcal/mol) to all four interested proteins of this article. The substances are quercetrin, rutin, myricitrin, cyanidin 3,5-O-diglucoside, pelargonium 3,5-diglucose in “flavonoid family” and α-amyrine, β-amyrine, taraxerol in “terpenes group.” The result can be explained by the 2D picture which showed hydrophobic interaction, hydrogen bond acceptor, and hydrogen bond donor forming between carbonyl oxygen molecules of ligand with free residues in the protein. These pictures of the bonding provide evidence that E. hirta Linn may prove to be an effective treatment for diabetes type 2.     

Impact of Transjugular Intrahepatic Portosystemic Shunt Creation on Intermediate-Term Model for End-Stage Liver Disease Score Progression

Purpose

To assess the impact of transjugular intrahepatic portosystemic shunt (TIPS) creation on Model for End-stage Liver Disease (MELD) score temporal progression in patients with liver cirrhosis.

Materials and methods

In this single-institution retrospective study, 256 consecutive patients who underwent TIPS creation between 1999 and 2013 were identified for potential investigation. Inclusion criteria for analysis consisted of at least 6 months of post-TIPS clinical follow-up with available lab values at 1, 3, 6, and, if available, 12 months post-TIPS for MELD score calculation. Patients who were lost to follow-up or expired within 6 months, lacked sufficient lab follow-up, or underwent liver transplantation within 6 months of TIPS were excluded from the study cohort. Within-patient variance in MELD score was assessed using repeated-measures analysis of variance.

Results

Sixty-six patients met criteria for study inclusion. TIPS were created for variceal hemorrhage (n = 26) or ascites, hydrothorax, or portal vein thrombosis (n = 40). Hemodynamic success rate was 97% (64/66) and median portosystemic pressure gradient reduction was 13 mm Hg. Median baseline MELD score was 14 (range 7–26). Low MELD scores (≤10, n = 16) increased in sequential scores over 1-year follow-up (median increase +3.5), intermediate MELD scores (11–18, n = 34) showed general stability in successive scores over 1-year follow-up (median increase +1), and high MELD scores (≥19, n = 16) decreased in serial scores over 1-year follow-up (median decrease −4); these trends are compatible with published MELD progression tendencies in cirrhotic patients without TIPS. However, the MELD score changes were not statistically significant (P = .172) on within-subject comparison.

Conclusions

Among patients with liver cirrhosis who recover from the procedure, TIPS creation does not alter the natural MELD score evolution during intermediate term follow-up, and as such does not significantly alter liver transplant candidacy.     

Development of physiologically based pharmacokinetic model to evaluate the relative systemic exposure to quetiapine after administration of IR and XR formulations to adults,children and adolescents

Quetiapine is an atypical antipsychotic drug with a high permeability, moderate solubility and defined as a Biopharmaceutics Classification System class ll compound. The pharmacokinetics (PK) of the quetiapine immediate‐release (IR) formulation has been studied in both adults and children, but the quetiapine extended‐release (XR) formulation has only been conducted in adults. The purpose of the current study was to use physiologically based pharmacokinetic modeling (PBPK) quantitatively to predict the PK of the XR formulation in children and adolescents. Using a ‘learn and confirm’ approach, PBPK models were developed employing in vitro ADME and physicochemical data, clinical PK data of quetiapine IR/XR in adults and clinical PK data of quetiapine IR in children. These models can predict well the effects of CYP3A4 inhibition and induction on the PK of quetiapine, the PK profile of quetiapine IR in children and adults, and the PK profile of quetiapine XR in adults. The AUC and C_max ratios (children vs adults) for the different age groups were in reasonable agreement with the observed ratios. In addition, the PBPK model predicted that children and adolescents are likely to achieve a similar exposure following administration of either the XR formulation once daily or the IR formulation twice daily at similar total daily doses. The results from the study can help inform dosing regimens in pediatrics using the quetiapine XR formulation. Copyright © 2014 John Wiley & Sons, Ltd.     

Synthesis of benzo[4,5]imidazo[1,2-a]pyrimidines and 2,3-dihydroquinazolin-4(1H)-ones under metal-free and solvent-free conditions for minimizing waste generation

Brønsted acidic ionic liquid was found to be an efficient and recyclable catalyst for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidines and 2,3-dihydroquinazolin-4(1H)-ones. The reactions proceeded smoothly with a broad scope of substrates providing the expected products in good to excellent yields under an atom-economical pathway. The low-cost recyclable catalyst, metal- and solvent-free conditions, and the ease of product isolation are the highlighted advantages in solving the issue of trace metal contamination in synthesized pharmaceuticals.

A facile, efficient, and atom-economic method for preparing benzo[4,5]imidazo[1,2-a]pyrimidines and 2,3-dihydroquinazolin-4(1H)-ones under metal- and solvent-free condition has been developed.     

Association between lung function decline and obstructive sleep apnoea: the ALEC study

Sleep and Breathing - To study changes in lung function among individuals with a risk of obstructive sleep apnoea (OSA), and if asthma affected this relationship. We used data from the European...