Theory-based analysis of clinical efficacy of triptans using receptor occupancy

Background

Triptans, serotonin 5-HT_1B/1D receptor agonists, exert their action by targeting serotonin 5-HT_1B/1D receptors, are used for treatment of migraine attack. Presently, 5 different triptans, namely sumatriptan, zolmitriptan, eletriptan, rizatriptan, and naratriptan, are marketed in Japan. In the present study, we retrospectively analyzed the relationships of clinical efficacy (headache relief) in Japanese and 5-HT_1B/1D receptor occupancy (Φ_1B and Φ_1D). Receptor occupancies were calculated from both the pharmacokinetic and pharmacodynamic data of triptans.

Methods

To evaluate the total amount of exposure to drug, we calculated the area under the plasma concentration-time curve (AUC_cp) and the areas under the time curves for Ф_1B and Ф_1D (AUC_Ф^1B and AUC_Ф^1D). Moreover, parameters expressing drug transfer and binding rates (A _cp , A _Ф ^1B , A _Ф ^1D ) were calculated.

Results

Our calculations showed that Ф_max^1B and Ф_max^1D were relatively high at 32.0-89.4% and 68.4-96.2%, respectively, suggesting that it is likely that a high occupancy is necessary to attain the clinical effect. In addition, the relationships between therapeutic effect and AUC_cp, AUC_Φ^1B, AUC_Φ^1D, and A _cp  · AUC_cp differed with each drug and administered form, whereas a significant relationship was found between the therapeutic effect and A _Φ ^1B  · AUC_Φ^1B or A _Φ ^1D  · AUC_Φ^1D that was not affected by the drug and the form of administration.

Conclusions

These results suggest that receptor occupancy can be used as a parameter for a common index to evaluate the therapeutic effect. We considered that the present findings provide useful information to support the proper use of triptans.     

Impact of motion correction on reproducibility and spatial variability of quantitative myocardial T2 mapping

Background

To evaluate and quantify the impact of a novel image-based motion correction technique in myocardial T₂ mapping in terms of measurement reproducibility and spatial variability.

Methods

Twelve healthy adult subjects were imaged using breath-hold (BH), free breathing (FB), and free breathing with respiratory navigator gating (FB + NAV) myocardial T₂ mapping sequences. Fifty patients referred for clinical CMR were imaged using the FB + NAV sequence. All sequences used a T₂ prepared (T₂prep) steady-state free precession acquisition. In-plane myocardial motion was corrected using an adaptive registration of varying contrast-weighted images for improved tissue characterization (ARCTIC). DICE similarity coefficient (DSC) and myocardial boundary errors (MBE) were measured to quantify the motion estimation accuracy in healthy subjects. T₂ mapping reproducibility and spatial variability were evaluated in healthy subjects using 5 repetitions of the FB + NAV sequence with either 4 or 20 T₂prep echo times (TE). Subjective T₂ map quality was assessed in patients by an experienced reader using a 4-point scale (1-non diagnostic, 4-excellent).

Results

ARCTIC led to increased DSC in BH data (0.85 ± 0.08 vs. 0.90 ± 0.02, p = 0.007), FB data (0.78 ± 0.13 vs. 0.90 ± 0.21, p < 0.001), and FB + NAV data (0.86 ± 0.05 vs. 0.90 ± 0.02, p = 0.002), and reduced MBE in BH data (0.90 ± 0.40 vs. 0.64 ± 0.19 mm, p = 0.005), FB data (1.21 ± 0.65 vs. 0.63 ± 0.10 mm, p < 0.001), and FB + NAV data (0.81 ± 0.21 vs. 0.63 ± 0.08 mm, p < 0.001). Improved reproducibility (4TE: 5.3 ± 2.5 ms vs. 4.0 ± 1.5 ms, p = 0.016; 20TE: 3.9 ± 2.3 ms vs. 2.2 ± 0.5 ms, p = 0.002), reduced spatial variability (4TE: 12.8 ± 3.5 ms vs. 10.3 ± 2.5 ms, p < 0.001; 20TE: 9.7 ± 3.5 ms vs. 7.5 ± 1.4 ms) and improved subjective score of T₂ map quality (3.43 ± 0.79 vs. 3.69 ± 0.55, p < 0.001) were obtained using ARCTIC.

Conclusions

The ARCTIC technique substantially reduces spatial mis-alignment among T₂-weighted images and improves the reproducibility and spatial variability of in-vivo T₂ mapping.     

Myocardial T1 and T2 mapping at 3?T: reference values,influencing factors and implications

Background

Myocardial T₁ and T₂ mapping using cardiovascular magnetic resonance (CMR) are promising to improve tissue characterization and early disease detection. This study aimed at analyzing the feasibility of T₁ and T₂ mapping at 3 T and providing reference values.

Methods

Sixty healthy volunteers (30 males/females, each 20 from 20–39 years, 40–59 years, 60–80 years) underwent left-ventricular T₁ and T₂ mapping in 3 short-axis slices at 3 T. For T₂ mapping, 3 single-shot steady-state free precession (SSFP) images with different T₂ preparation times were acquired. For T₁ mapping, modified Look-Locker inversion recovery technique with 11 single shot SSFP images was used before and after injection of gadolinium contrast. T₁ and T₂ relaxation times were quantified for each slice and each myocardial segment.

Results

Mean T₂ and T₁ (pre-/post-contrast) times were: 44.1 ms/1157.1 ms/427.3 ms (base), 45.1 ms/1158.7 ms/411.2 ms (middle), 46.9 ms/1180.6 ms/399.7 ms (apex). T₂ and pre-contrast T₁ increased from base to apex, post-contrast T₁ decreased. Relevant inter-subject variability was apparent (scatter factor 1.08/1.05/1.11 for T₂/pre-contrast T₁/post-contrast T₁). T₂ and post-contrast T₁ were influenced by heart rate (p < 0.0001, p = 0.0020), pre-contrast T₁ by age (p < 0.0001). Inter- and intra-observer agreement of T₂ (r = 0.95; r = 0.95) and T₁ (r = 0.91; r = 0.93) were high. T₂ maps: 97.7% of all segments were diagnostic and 2.3% were excluded (susceptibility artifact). T₁ maps (pre-/post-contrast): 91.6%/93.9% were diagnostic, 8.4%/6.1% were excluded (predominantly susceptibility artifact 7.7%/3.2%).

Conclusions

Myocardial T₂ and T₁ reference values for the specific CMR setting are provided. The diagnostic impact of the high inter-subject variability of T₂ and T₁ relaxation times requires further investigation.     

Extended characterisation of the serotonin 2A (5-HT2A) receptor-selective PET radiotracer 11C-MDL100907 in humans: quantitative analysis, test-retest reproducibility, and vulnerability to endogenous 5-HT tone

Introduction

Scanning properties and analytic methodology of the 5-HT_2A receptor-selective positron emission tomography (PET) tracer ¹¹C-MDL100907 have been partially characterised in previous reports. We present an extended characterisation in healthy human subjects.

Methods

64 ¹¹C-MDL100907 PET scans with metabolite-corrected arterial input function were performed in 39 healthy adults (18-55 years). 12 subjects were scanned twice (duration 150 min) to provide data on plasma analysis, model order estimation, and stability and test-retest characteristics of outcome measures. All other scans were 90 min duration. 3 subjects completed scanning at baseline and following 5-HT_2A receptor antagonist medication (risperidone or ciproheptadine) to provide definitive data on the suitability of the cerebellum as reference region. 10 subjects were scanned under reduced 5-HT and control conditions using rapid tryptophan depletion to investigate vulnerability to competition with endogenous 5-HT. 13 subjects were scanned as controls in clinical protocols. Pooled data were used to analyse the relationship between tracer injected mass and receptor occupancy, and age-related decline in 5-HT_2A receptors.

Results

Optimum analytic method was a 2-tissue compartment model with arterial input function. However, basis function implementation of SRTM may be suitable for measuring between-group differences non-invasively and warrants further investigation. Scan duration of 90 min achieved stable outcome measures in all cortical regions except orbitofrontal which required 120 min. Binding potential (BP_P and BP_ND) test-retest variability was very good (7-11%) in neocortical regions other than orbitofrontal, and moderately good (14-20%) in orbitofrontal cortex and medial temporal lobe. Saturation occupancy of 5-HT_2A receptors by risperidone validates the use of the cerebellum as a region devoid of specific binding for the purposes of PET. We advocate a mass limit of 4.6 μg to remain below 5% receptor occupancy. ¹¹C-MDL100907 specific binding is not vulnerable to competition with endogenous 5-HT in humans. Paradoxical decreases in BP_ND were found in right prefrontal cortex following reduced 5-HT, possibly representing receptor internalisation. Mean age-related decline in brain 5-HT_2A receptors was 14.0 ± 5.0% per decade, and higher in prefrontal regions.

Conclusions

Our data confirm and extend support for ¹¹C-MDL100907 as a PET tracer with very favourable properties for quantifying 5-HT_2A receptors in the human brain.     

Serotonin,glutamate and glycerol are released after the injection of hypertonic saline into human masseter muscles – a microdialysis study

Background

Chronic myalgia is associated with higher muscle levels of certain algesic biomarkers. The aim of this study was to investigate if hypertonic saline-induced jaw myalgia also leads to release of such biomarkers and if there were any sex differences in this respect.

Methods

Healthy participants, 15 men and 15 aged-matched women (25.7 ± 4.3 years) participated. Intramuscular microdialysis into masseter muscles was performed to sample serotonin (5-HT), glutamate, lactate, pyruvate, glucose and glycerol. After 2 hours 0.2 mL hypertonic saline (58.5 mg/mL) was injected into the masseter on one side and 0.2 mL isotonic saline (9 mg/mL) into the contralateral masseter close to the microdialysis catheter. Microdialysis continued for 1 hour after the injections. Pressure pain thresholds (PPT) and pain were assessed before and after injections.

Results

The median (IQR) peak pain intensity (0–100 visual analogue scale) after hypertonic saline was 52.5 (38.0) and after isotonic saline 7.5 (24.0) (p < 0.05). 5-HT, glutamate and glycerol increased after hypertonic saline injection (p < 0.05). Lactate, pyruvate and glucose showed no change. PPT after microdialysis was reduced on both sides (p < 0.05) but without side differences. Pain after hypertonic saline injection correlated positively to 5-HT (p < 0.05) and negatively to glycerol (p < 0.05).

Conclusions

5-HT, glutamate and glycerol increased after a painful hypertonic saline injection into the masseter muscle, but without sex differences. Since increased levels of 5-HT and glutamate have been reported in chronic myalgia, this strengthens the validity of the pain model. Glycerol warrants further investigations.     

Blocking the A2B adenosine receptor alleviates myocardial damage by inhibiting spleen-derived MDSC mobilisation after acute myocardial infarction

BackgroundMyeloid-derived suppressor cell (MDSC) mobilisation is an important immune event in acute myocardial infarction (AMI). The A_2B adenosine receptor (A_2BAR) plays key role in regulating MDSC function, but its specific involvement in MDSC mobilisation in AMI remains unclear.MethodsIn AMI patients, the circulating MDSC ratio and A_2BAR mRNA expression were measured. A mouse AMI model was established by left anterior descending coronary artery (LADCA) ligation. MDSCs were analysed by FACS and immunofluorescence staining (of heart tissue). A_2BAR mRNA expression was assessed by qRT-PCR. Myocardial injury was detected by HE staining. Myocardial cell apoptosis was analysed by immunohistochemistry. Cardiac systolic function was evaluated by transthoracic echocardiography.ResultsIn AMI patients, the circulating MDSC ratio was increased and positively correlated with A_2BAR mRNA expression (r = 0.86, p < 0.01). In AMI model mice, the percentage of MDSCs was increased in the circulation and infarcted heart and decreased in the spleen. MRS-1754-mediated A_2BAR inhibition decreased the MDSC ratio in the circulation and infarcted heart and prevented the decrease in MDSC number in the spleens of mice with AMI. A_2BAR blockade inhibited myocardial cell apoptosis, alleviated myocardial inflammatory injury, and improved myocardial systolic function in the AMI mouse model. Similar results were found in mice after splenectomy. Additionally, spleen-derived MDSC injection increased the MDSC ratio in the infarcted heart, increased myocardial cell apoptosis, aggravated myocardial injury, and decreased cardiac systolic function in mice with AMI.ConclusionBlocking A_2BAR alleviates myocardial damage and improves myocardial systolic function through inhibition of spleen-derived MDSC mobilisation after AMI.

Key Messages

• Spleen-derived MDSC mobilisation aggravates myocardial inflammatory injury within 24 h of AMI.
• A_2BAR promotes spleen-derived MDSC mobilisation within 24 h of AMI.
• Blocking A_2BAR improves myocardial systolic function through inhibition of spleen-derived MDSC mobilisation.

     

Na–Ga–Si type-I clathrate single crystals grown via Na evaporation using Na–Ga and Na–Ga–Sn fluxes

Single crystals of a Na–Ga–Si clathrate, Na₈Ga_5.70Si_40.30, of size 2.9 mm were grown via the evaporation of Na from a Na–Ga–Si melt with the molar ratio of Na : Ga : Si = 4 : 1 : 2 at 773 K for 21 h under an Ar atmosphere. The crystal structure was analyzed using X-ray diffraction with the model of the type-I clathrate (cubic, a = 10.3266(2) Å, space group Pm$\bar{3}$n, no. 223). By adding Sn to a Na–Ga–Si melt (Na : Ga : Si : Sn = 6 : 1 : 2 : 1), single crystals of Na₈Ga_xSi_46−x (x = 4.94–5.52, a = 10.3020(2)–10.3210(3) Å), with the maximum size of 3.7 mm, were obtained via Na evaporation at 723–873 K. The electrical resistivities of Na₈Ga_5.70Si_40.30 and Na₈Ga_4.94Si_41.06 were 1.40 and 0.72 mΩ cm, respectively, at 300 K, and metallic temperature dependences of the resistivities were observed. In the Si L_2,3 soft X-ray emission spectrum of Na₈Ga_5.70Si_40.30, a weak peak originating from the lowest conduction band in the undoped Si₄₆ was observed at an emission energy of 98 eV.

Single crystals of a Na–Ga–Si clathrate, Na₈Ga_4.94Si_41.06, of size 3.7 mm were grown via the evaporation of Na from a Na–Ga–Si–Sn melt with the molar ratio of Na : Ga : Si : Sn = 6 : 1 : 2 : 1 at 873 K for 3 h under an Ar atmosphere.     

Soluble platelet-endothelial cell adhesion molecule-1, a biomarker of ventilator-induced lung injury

Introduction

Endothelial cell injury is an important component of acute lung injury. Platelet-endothelial cell adhesion molecule-1 (PECAM1) is a transmembrane protein that connects endothelial cells to one another and can be detected as a soluble, truncated protein (sPECAM1) in serum. We hypothesized that injurious mechanical ventilation (MV) leads to shedding of PECAM1 from lung endothelial cells resulting in increasing sPECAM1 levels in the systemic circulation.

Methods

We studied 36 Sprague–Dawley rats in two prospective, randomized, controlled studies (healthy and septic) using established animal models of ventilator-induced lung injury. Animals (n = 6 in each group) were randomized to spontaneous breathing or two MV strategies: low tidal volume (V_T) (6 ml/kg) and high-V_T (20 ml/kg) on 2 cmH₂O of positive end-expiratory pressure (PEEP). In low-V_T septic animals, 10 cmH₂O of PEEP was applied. We performed pulmonary histological and physiological evaluation and measured lung PECAM1 protein content and serum sPECAM1 levels after four hours ventilation period.

Results

High-V_T MV caused severe lung injury in healthy and septic animals, and decreased lung PECAM1 protein content (P < 0.001). Animals on high-V_T had a four- to six-fold increase of mean sPECAM1 serum levels than the unventilated counterpart (35.4 ± 10.4 versus 5.6 ± 1.7 ng/ml in healthy rats; 156.8 ± 47.6 versus 35.6 ± 12.6 ng/ml in septic rats) (P < 0.0001). Low-V_T MV prevented these changes. Levels of sPECAM1 in healthy animals on high-V_T MV paralleled the sPECAM1 levels of non-ventilated septic animals.

Conclusions

Our findings suggest that circulating sPECAM1 may represent a promising biomarker for the detection and monitoring of ventilator-induced lung injury.     

Evaluation of diastolic function by three-dimensional volume tracking of the mitral annulus with cardiovascular magnetic resonance: comparison with tissue Doppler imaging

Background

Measurement of mitral annulus (MA) dynamics is an important component of the evaluation of left ventricular (LV) diastolic function; MA velocities are commonly measured using tissue Doppler imaging (TDI). This study aimed to examine the clinical potential of a semi-automated cardiovascular magnetic resonance (CMR) technique for quantifying global LV diastolic function, using 3D volume tracking of the MA with conventional cine-CMR images.

Methods

124 consecutive patients with normal ejection fraction underwent both clinically indicated transthoracic echocardiography (TTE) and CMR within 2 months. Interpolated 3D reconstruction of the MA over time was performed with semi-automated atrioventricular junction (AVJ) tracking in long-axis cine-CMR images, producing an MA sweep volume over the cardiac cycle. CMR-based diastolic function was evaluated, using the following parameters: peak volume sweep rates in early diastole (PSR_E) and atrial systole (PSR_A), PSR_E/PSR_A ratio, deceleration time of sweep volume (DT_SV), and 50% diastolic sweep volume recovery time (DSVRT₅₀); these were compared with TTE diastolic measurements.

Results

Patients with TTE-based diastolic dysfunction (n = 62) showed significantly different normalized MA sweep volume profiles compared to those with TTE-based normal diastolic function (n = 62), including a lower PSR_E (5.25 ± 1.38 s⁻¹ vs. 7.72 ± 1.7 s⁻¹), a higher PSR_A (6.56 ± 1.99 s⁻¹ vs. 4.67 ± 1.38 s⁻¹), a lower PSR_E/PSR_A ratio (0.9 ± 0.44 vs. 1.82 ± 0.69), a longer DT_SV (144 ± 55 ms vs. 96 ± 37 ms), and a longer DSVRT₅₀ (25.0 ± 11.0% vs. 15.6 ± 4.0%) (all p < 0.05). CMR diastolic parameters were independent predictors of TTE-based diastolic dysfunction after adjusting for left ventricular hypertrophy, hypertension, and coronary artery disease. Good correlations were observed between CMR PSR_E/PSR_A and early-to-late diastolic annular velocity ratios (e′/a′) measured by TDI (r = 0.756 to 0.828, p < 0.001).

Conclusions

3D MA sweep volumes generated by semi-automated AVJ tracking in routinely acquired CMR images yielded diastolic parameters that were effective in identifying patients with diastolic dysfunction when correlated with TTE-based variables.     

Copper–cobalt catalysts supported on mechanically mixed HZSM-5 and γ-Al2O3 for higher alcohols synthesis via carbon monoxide hydrogenation

Mechanically mixed γ-Al₂O₃ and HZSM-5 (Si/Al = 50) with different mass ratio were utilized as support for Cu–Co higher alcohol synthesis catalysts prepared through incipient wetness impregnation. The textural and structural properties were studied using Ar low temperature adsorption and desorption, H₂-temperature programmed reduction (H₂-TPR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), transmission electron microscope (TEM) and catalytic performance measurements. The results indicated that the mechanically mixed HZSM-5 and γ-Al₂O₃ supported copper–cobalt catalysts were superior to either γ-Al₂O₃ or HZSM-5 supported ones with the same metal loading. The results revealed that using HZSM-5 and γ-Al₂O₃ mechanically mixed benefited the dispersion of metallic phases and stronger synergetic functions between smaller nanoparticles containing copper and/or cobalt, which is essential for HAS from CO hydrogenation. Under working conditions of P = 5.0 MPa, T = 300 °C, V(H₂) : V(CO) : V(N₂) = 4 : 2 : 1 and GHSV = 7200 mL g⁻¹ h⁻¹, mechanically mixed HZSM-5 and γ-Al₂O₃ supported catalysts showed higher catalytic activity than those over single support. For CuCo catalysts upon support containing 50.0 wt% HZSM-5 and 50.0 wt% γ-Al₂O₃, the CO conversion was 21.3% and the C₂₊ alcohol selectivity was 41.8%.

CuCo bimetallic catalysts over the mixed supports showed smaller average particle size, better dispersion of cobalt and copper species, and good activity for higher alcohols synthesis.     

Hypercapnia attenuates ventilator-induced diaphragm atrophy and modulates dysfunction

Introduction

Diaphragm weakness induced by prolonged mechanical ventilation may contribute to difficult weaning from the ventilator. Hypercapnia is an accepted side effect of low tidal volume mechanical ventilation, but the effects of hypercapnia on respiratory muscle function are largely unknown. The present study investigated the effect of hypercapnia on ventilator-induced diaphragm inflammation, atrophy and function.

Methods

Male Wistar rats (n = 10 per group) were unventilated (CON), mechanically ventilated for 18 hours without (MV) or with hypercapnia (MV + H, Fico₂ = 0.05). Diaphragm muscle was excised for structural, biochemical and functional analyses.

Results

Myosin concentration in the diaphragm was decreased in MV versus CON, but not in MV + H versus CON. MV reduced diaphragm force by approximately 22% compared with CON. The force-generating capacity of diaphragm fibers from MV + H rats was approximately 14% lower compared with CON. Inflammatory cytokines were elevated in the diaphragm of MV rats, but not in the MV + H group. Diaphragm proteasome activity did not significantly differ between MV and CON. However, proteasome activity in the diaphragm of MV + H was significantly lower compared with CON. LC3B-II a marker of lysosomal autophagy was increased in both MV and MV + H. Incubation of MV + H diaphragm muscle fibers with the antioxidant dithiothreitol restored force generation of diaphragm fibers.

Conclusions

Hypercapnia partly protects the diaphragm against adverse effects of mechanical ventilation.     

Endogenous assessment of chronic myocardial infarction with T1ρ-mapping in patients

Background

Detection of cardiac fibrosis based on endogenous magnetic resonance (MR) characteristics of the myocardium would yield a measurement that can provide quantitative information, is independent of contrast agent concentration, renal function and timing. In ex vivo myocardial infarction (MI) tissue, it has been shown that a significantly higher T_1ρ is found in the MI region, and studies in animal models of chronic MI showed the first in vivo evidence for the ability to detect myocardial fibrosis with native T_1ρ-mapping. In this study we aimed to translate and validate T_1ρ-mapping for endogenous detection of chronic MI in patients.

Methods

We first performed a study in a porcine animal model of chronic MI to validate the implementation of T_1ρ-mapping on a clinical cardiovascular MR scanner and studied the correlation with histology. Subsequently a clinical protocol was developed, to assess the feasibility of scar tissue detection with native T_1ρ-mapping in patients (n = 21) with chronic MI, and correlated with gold standard late gadolinium enhancement (LGE) CMR. Four T_1ρ-weighted images were acquired using a spin-lock preparation pulse with varying duration (0, 13, 27, 45 ms) and an amplitude of 750 Hz, and a T_1ρ-map was calculated. The resulting T_1ρ-maps and LGE images were scored qualitatively for the presence and extent of myocardial scarring using the 17-segment AHA model.

Results

In the animal model (n = 9) a significantly higher T_1ρ relaxation time was found in the infarct region (61 ± 11 ms), compared to healthy remote myocardium (36 ± 4 ms) . In patients a higher T_1ρ relaxation time (79 ± 11 ms) was found in the infarct region than in remote myocardium (54 ± 6 ms). Overlap in the scoring of scar tissue on LGE images and T_1ρ-maps was 74%.

Conclusion

We have shown the feasibility of native T_1ρ-mapping for detection of infarct area in patients with a chronic myocardial infarction. In the near future, improvements on the T_1ρ -mapping sequence could provide a higher sensitivity and specificity. This endogenous method could be an alternative for LGE imaging, and provide additional quantitative information on myocardial tissue characteristics.     

Chemical reaction characteristics,structural transformation and electrochemical performances of new cathode LiVPO4F/C synthesized by a novel one-step method for lithium ion batteries

A new cathode LiVPO₄F/C with a high working voltage of around 4.2 V was synthesized by a novel one-step method. The color of the solution turns green, which implies that V₂O₅ is successfully reduced to V³⁺. The reaction thermodynamics indicates that LiVPO₄F/C is formed when the sintering temperature is higher than 650 °C, while the accompanying impurity phase Li₃V₂(PO₄)₃/C is also generated. The reaction kinetics proves that the reaction is third order and the activated energy is 208.9 kJ mol⁻¹. X-ray photoelectron spectra imply that the components of LiVPO₄F/C prepared at 800 °C (LVPF800) are in their appropriate valence. LVPF800 is composed of micron secondary particles aggregating from nano subglobose. The structural transformation shows that the V : P : F ratio in LVPF800 is close to 1 : 1 : 1. The reason behind generation of impurity Li₃V₂(PO₄)₃ at a high temperature of 850 °C is demonstrated directly, which is mainly due to the volatilization of VF₃. The electrochemical performances of the cathode are related to the crystallite content of LiVPO₄F/C and Li₃V₂(PO₄)₃/C. The specific capacities at 0.2 and 5C of LVPF800 are as high as 139.3 and 116.5 mA h g⁻¹. Electrochemical analysis reveals that LVPF800 possesses an excellent reversibility in the extraction and insertion process and minimum charge transfer resistance.

Uniform LiVPO₄F/C primary particles and lattice coated with carbon layer forms at 800 °C. Larger impurity Li₃V₂(PO₄)₃/C particles are generated at 850 °C.     

Urapidil permeates the intact blood-brain barrier

Objective To determine the plasma and cerebrospinal fluid (CSF) levels of urapidil after i.v. administration and the effect on CSF serotonin and 5-hydroxyindoleacetic acid (5-HIAA) concentrations.Design Open, single-dose study.Setting Post-surgery following neurosurgical removal of the hypophysis (n=5) or aneurysm clipping (n=1).Patients 6 patients, aged 32–71 years, with intact bloodbrain barrier (BBB); 1 patient was studied twice.Interventions Single dose of 25 mg urapidil i.v. as prophylaxis of BP increase during extubation or as treatment of hypertensive episodes.Measurements and results Urapidil, serotonin and 5-HIAA were measured by HPLC in CSF during 8 h after urapidil administration. Urapidil was detected in CSF as soon as 5 min after injection in 3 patients. The concentration ratio of plasma/CSF after the distribution phase was about 51. No significant effect on serotonin and 5-HIAA in CSF was seen.Conclusion After administration of a therapeutic dose, urapidil permeates the BBB and may interact with central 5-HT_1A-receptors.The study was performed at the Department of Anaesthesia, University of the Saarland, Homburg, Germany     

Improving the performance of quantum-dot light-emitting diodes via an organic–inorganic hybrid hole injection layer

Poly(3,4-ethylenedioxythiophene):poly(styrene-sulfonate) (PEDOT:PSS) is a commonly used material for the hole injection layer (HIL) in quantum-dot light-emitting diodes (QLEDs). In this work, we improved the performance of the QLED by using an organic–inorganic hybrid HIL. The hybrid HIL was prepared by mixing PEDOT:PSS with vanadium oxide (V₂O₅), which is a transition-metal oxide (TMO). The hole injection properties of PEDOT:PSS were improved according to the amount of V₂O₅ mixed into the PEDOT:PSS. The maximum luminance and current efficiency were 36 198 cd m⁻² and 13.9 cd A⁻¹, respectively, when the ratio of PEDOT:PSS and V₂O₅ was 10 : 1. Moreover, the operating lifetime exceeded 300 h, which is 10 times longer than the lifetime of the device with only PEDOT:PSS HIL. The improvement was analyzed using ultraviolet and X-ray photoelectron spectroscopy. We found that the density of state (DOS) of PEDOT:PSS near the Fermi energy level was increased by mixing V₂O₅. Therefore, the increase of DOS improved the hole injection and the performance of QLEDs. The result shows that the hybrid HIL can improve the performance and the stability of QLEDs.

The performance of the quantum-dot light-emitting diodes was improved by using an organic–inorganic hybrid hole injection layer.     

Chemical and thermal properties of VO2 mechanochemically derived from V2O5 by co-milling with paraffin wax

A novel mechanochemical reduction process of V₂O₅ to VO₂ was established by milling with paraffin wax (PW, average molecular weight 254–646), serving as a reductant. The reduction progressed with increasing milling time and mass ratio V₂O₅ : PW (MRVP). The mechanochemically derived VO₂ became phase pure after milling for 3 h with an MRVP of 30 : 1 and exhibited a reversible polymorphic transformation between tetragonal and monoclinic phases at around 53–60 °C and 67–79 °C during heating and cooling, respectively. The latent heat was above 20 J g⁻¹ in both processes, being superior to those of commercial VO₂. Doping of starting V₂O₅ with Cr, Mo or W at 1 at% in the form of oxide did not increase the latent heat. This is another difference from the conventionally prepared doped VO₂. These anomalous heat storage properties of mechanochemically derived VO₂ were discussed mainly on the basis of X-ray photoelectron spectroscopy V_2p3/2 peaks combined with ion etching. The observed relatively high heat storage capacity of undoped VO₂ is primarily ascribed to the abundance of V⁴⁺ ionic states introduced during milling with PW, which were stabilized with simultaneously introduced structural degradation throughout the entire particles. The possible role of a remaining small amount of PW was also discussed.

Reduction of V₂O₅via a mechano-chemical route brings about unique electronic states of vanadium. The resulting VO₂ exhibits high latent heat storage during heating (a) and cooling (b).     

5-HT7 receptor activation inhibits mechanical hypersensitivity secondary to capsaicin sensitization in mice

This work aimed to evaluate the potential role of the 5-HT₇ receptor in nociception secondary to a sensitizing stimulus in mice. For this purpose, the effects of relevant ligands (5-HT₇ receptor agonists: AS-19, MSD-5a, E-55888; 5-HT₇ receptor antagonists: SB-258719, SB-269970; 5-HT_1A receptor agonist: F-13640; 5-HT_1A receptor antagonist: WAY-100635) were assessed on capsaicin-induced mechanical hypersensitivity, a pain behavior involving hypersensitivity of dorsal horn neurons (central sensitization). For the 5-HT₇ receptor agonists used, binding profile and intrinsic efficacy to stimulate cAMP formation in HEK-293F cells expressing the human 5-HT₇ receptor were also evaluated. AS-19 and E-55888 were selective for 5-HT₇ receptors. E-55888 was a full agonist whereas AS-19 and MSD-5a behaved as partial agonists, with maximal effects corresponding to 77% and 61%, respectively, of the cAMP response evoked by the full agonist 5-HT. Our in vivo results revealed that systemic administration of 5-HT₇ receptor agonists exerted a clear-cut dose-dependent antinociceptive effect that was prevented by 5-HT₇ receptor antagonists, but not by the 5-HT_1A receptor antagonist. The order of efficacy (E-55888 > AS-19 > MSD-5a) matched their in vitro efficacy as 5-HT₇ receptor agonists. Contrary to agonists, a dose-dependent promotion of mechanical hypersensitivity was observed after administration of 5-HT₇ receptor antagonists, substantiating the involvement of the 5-HT₇ receptor in the control of capsaicin-induced mechanical hypersensitivity. These findings suggest that serotonin exerts an inhibitory role in the control of nociception through activation of 5-HT₇ receptors, and point to a new potential therapeutic use of 5-HT₇ receptor agonists in the field of analgesia.     

SUSTAINED ISOMETRIC SHOULDER CONTRACTION ON MUSCULAR STRENGTH AND ENDURANCE: A RANDOMIZED CLINICAL TRIAL

Background

The Advanced Throwers Ten Exercise Program incorporates sustained isometric contractions in conjunction with dynamic shoulder movements. It has been suggested that incorporating isometric holds may facilitate greater increases in muscular strength and endurance. However, no objective evidence currently exists to support this claim.

Hypothesis/Purpose

The purpose of this research was to compare the effects of a sustained muscle contraction resistive training program (Advanced Throwers Ten Program) to a more traditional exercise training protocol to determine if increases in shoulder muscular strength and endurance occur in an otherwise healthy population. It was hypothesized that utilizing a sustained isometric hold during a shoulder scaption exercise from the Advanced Throwers Ten would produce greater increases in shoulder strength and endurance as compared to a traditional training program incorporating a isotonic scapular plane abduction (scaption) exercise.

Study Design

Randomized Clinical Trial.

Method

Fifty healthy participants were enrolled in this study, of which 25 were randomized into the traditional training group (age: 26 ± 8, height:172 ± 10 cm, weight: 73 ± 13 kg, Marx Activity Scale: 11 ± 4) and 25 were randomized to the Advanced Throwers Ten group (age: 28 ± 9, height: 169 ± 23 cm, weight: 74 ± 16 kg, Marx Activity Scale: 11 ± 5). No pre‐intervention differences existed between the groups (P>0.05). Arm endurance and strength data were collected pre and post intervention using a portable load cell (BTE Evaluator, Hanover, MD). Both within and between group analyses were done in order to investigate average torque (strength) and angular impulse (endurance) changes.

Results

The traditional and Advanced Throwers Ten groups both significantly improved torque and angular impulse on both the dominant and non‐dominant arms by 10–14%. There were no differences in strength or endurance following the interventions between the two training groups (p>0.75).

Conclusions;

Both training approaches increased strength and endurance as the muscle loads were consistent between protocols indicating that either approach will have positive effects.

Level of Evidence

Level 2     

A disproportionate contribution of papillary muscles and trabeculations to total left ventricular mass makes choice of cardiovascular magnetic resonance analysis technique critical in Fabry disease

Background

Sphingolipid deposition in Fabry disease causes left ventricular (LV) hypertrophy, of which the accurate assessment is essential. Cardiovascular magnetic resonance (CMR) has been proposed as the gold standard. However, there is debate in the literature as to whether papillary muscles and trabeculations (P&T) should be included in LV mass (LVM).

Methods/results

We examined the accuracy of 2 CMR methods of assessing LVM and LV volumes, including (M_incP&T) or excluding (M_exP&T) P&T, in a cohort of Fabry disease subjects (n = 20) compared to a matched control group (n = 20). Significant differences between the two measurement methods were observed for LV end-diastolic volume, LV end-systolic volume, LVM, and LV ejection fraction (LVEF) in both groups. These differences were significantly greater in the Fabry group compared to controls, except for LVEF. P&T contributed to a greater percentage of LVM in Fabry subjects than controls (20 ± 1% vs 13 ± 2%, p = 0.01). In the control group, both volume-derived methods (M_incP&T or M_exP&T) provided accurate SV measurements compared with the internal reference of velocity-encoded aortic flow. In the Fabry group, inclusion of P&T (M_incP&T) resulted in good concordance with phase contrast flow imaging (difference between flow and volume techniques: 1 ± 3 ml, p = 0.7).

Conclusion

The volumetric contribution of P&T in Fabry disease is markedly increased relative to healthy controls. Failure to account for this results in significant underestimation of LVM and results in misclassification of a proportion of subjects.