A Single-centre, Before-After Study of the Short- and Long-term Efficacy of Narivent® in the Treatment of Nasal Congestion

Objective:Nasal congestion is a common symptom in allergic and nonallergic rhinitis, rhinosinusitis and nasal polyposis. The present study evaluated the clinical effectiveness of Narivent®, an osmo..

Human adipose-derived stromal cells transplantation prolongs reproductive lifespan on mouse models of mild and severe premature ovarian insufficiency

Background Although recent studies have investigated the ability of Mesenchymal Stromal Cells (MSCs) to alleviate short-term ovarian damage in animal models of chemotherapy-induced Premature Ovarian Insufficiency (POI), no data are available on reproductive lifespan recovery, especially in a severe POI condition. For this reason, we investigated the potential of MSCs isolated from human adipose tissue (hASCs), since they are easy to harvest and abundant, in ameliorating the length and performance of reproductive life in both mild and severe chemotherapy-induced murine POI models. Methods Mild and severe POI models were established by intraperitoneally administering a light (12 mg/kg busulfan + 120 mg/kg cyclophosphamide) or heavy (30 mg/kg busulfan + 120 mg/kg cyclophosphamide) dose of chemotherapy, respectively, in CD1 mice. In both cases, a week later, 1 × 106 hASCs were transplanted systemically through the tail vein. After four additional weeks, some females were sacrificed to collect ovaries for morphological evaluation. H&E staining was performed to assess stroma alteration and to count follicle numbers; immunofluorescence staining for αSMA was used to analyse vascularization. Of the remaining females, some were mated after superovulation to collect 2-cell embryos in order to evaluate their pre-implantation developmental capacity in vitro, while others were naturally mated to monitor litters and reproductive lifespan length. F1 litters’ weight, ovaries and reproductive lifespan were also analysed. Results hASC transplantation alleviated ovarian weight loss and size decrease and reduced alterations on ovarian stroma and vasculature, concurrently preventing the progressive follicle stockpile depletion caused by chemotherapy. These effects were associated with the preservation of the oocyte competence to develop into blastocyst in vitro and, more interestingly, with a significant decrease of chemotherapy-induced POI features, like shortness of reproductive lifespan, reduced number of litters and longer time to plug (the latter only presented in the severe POI model). Conclusion Human ASC transplantation was able to significantly reduce all the alterations induced by the chemotherapeutic treatment, while improving oocyte quality and prolonging reproductive functions, thus counteracting infertility. These results, strengthened by the use of an outbred model, support the potential applications of hASCs in women with POI, nowadays mainly induced by anticancer therapies

"Solid state charge trapping": Examples of polymer systems showing memory effect

The paper reports on a characteristic property of electroactive materials bearing an electron-rich and an electron-poor moiety, known as charge trapping. As examples of materials that exhibit this phenomenon, films of poly(4,4"-dipentoxy-4\u27-(2,2\u27-dicyano)ethenyl-2,2\u27:5\u27,2"-terthiophene), poly(2,3-dihexylthieno[3,4-b]pyrazine) and a blend between a fulleropyrrolidine derivative and poly(3-hexylthiophene) were investigated by cyclic voltammetry, spectroelectrochemistry and electrochemical quartz crystal microbalance. In the cyclic voltammetry, the reduction processes show the reverse oxidation potential about 1 V higher than the expected value, indicating a strong stabilization of the corresponding anion species. The mechanism leading to the stabilisation of the anions is discussed and the results indicate that the investigated materials exhibit a remarkable and quite stable memory effect

Myocardial Perfusion Defects in Hypertrophic Cardiomyopathy Mutation Carriers

Background Impaired myocardial blood flow (MBF) in the absence of epicardial coronary disease is a feature of hypertrophic cardiomyopathy (HCM). Although most evident in hypertrophied or scarred segments, reduced MBF can occur in apparently normal segments. We hypothesized that impaired MBF and myocardial perfusion reserve, quantified using perfusion mapping cardiac magnetic resonance, might occur in the absence of overt left ventricular hypertrophy (LVH) and late gadolinium enhancement, in mutation carriers without LVH criteria for HCM (genotype-positive, left ventricular hypertrophy-negative). Methods and Results A single center, case-control study investigated MBF and myocardial perfusion reserve (the ratio of MBF at stress:rest), along with other pre-phenotypic features of HCM. Individuals with genotype-positive, left ventricular hypertrophy-negative (n=50) with likely pathogenic/pathogenic variants and no evidence of LVH, and matched controls (n=28) underwent cardiac magnetic resonance. Cardiac magnetic resonance identified LVH-fulfilling criteria for HCM in 5 patients who were excluded. Individuals with genotype-positive, left ventricular hypertrophy-negative had longer indexed anterior mitral valve leaflet length (12.52±2.1 versus 11.55±1.6 mm/m2, P=0.03), lower left ventricular end-systolic volume (21.0±6.9 versus 26.7±6.2 mm/m2, P≤0.005) and higher left ventricular ejection fraction (71.9±5.5 versus 65.8±4.4%, P≤0.005). Maximum wall thickness was not significantly different (9.03±1.95 versus 8.37±1.2 mm, P=0.075), and no subject had significant late gadolinium enhancement (minor right ventricle‒insertion point late gadolinium enhancement only). Perfusion mapping demonstrated visual perfusion defects in 9 (20%) carriers versus 0 controls (P=0.011). These were almost all septal or near right ventricle insertion points. Globally, myocardial perfusion reserve was lower in carriers (2.77±0.83 versus 3.24±0.63, P=0.009), with a subendocardial:subepicardial myocardial perfusion reserve gradient (2.55±0.75 versus 3.2±0.65, P=<0.005; 3.01±0.96 versus 3.47±0.75, P=0.026) but equivalent MBF (2.75±0.82 versus 2.65±0.69 mL/g per min, P=0.826). Conclusions Regional and global impaired myocardial perfusion can occur in HCM mutation carriers, in the absence of significant hypertrophy or scarring

Two-Minute k-Space and Time–accelerated Aortic Four-dimensional Flow MRI: Dual-Center Study of Feasibility and Impact on Velocity and Wall Shear Stress Quantification

PURPOSE: To investigate the two-center feasibility of highly k-space and time (k-t)–accelerated 2-minute aortic four-dimensional (4D) flow MRI and to evaluate its performance for the quantification of velocities and wall shear stress (WSS). MATERIALS AND METHODS: This cross-sectional study prospectively included 68 participants (center 1, 11 healthy volunteers [mean age ± standard deviation, 61 years ± 15] and 16 patients with aortic disease [mean age, 60 years ± 10]; center 2, 14 healthy volunteers [mean age, 38 years ± 13] and 27 patients with aortic or cardiac disease [mean age, 78 years ± 18]). Each participant underwent highly accelerated 4D flow MRI (k-t acceleration, acceleration factor of 5) of the thoracic aorta. For comparison, conventional 4D flow MRI (acceleration factor of 2) was acquired in the participants at center 1 (n = 27). Regional aortic peak systolic velocities and three-dimensional WSS were quantified. RESULTS: k-t–accelerated scan times (center 1, 2:03 minutes ± 0:29; center 2, 2:06 minutes ± 0:20) were significantly reduced compared with conventional 4D flow MRI (center 1, 12:38 minutes ± 2:25; P < .0001). Overall good agreement was found between the two techniques (absolute differences ≤15%), but proximal aortic WSS was significantly underestimated in patients by using k-t–accelerated 4D flow when compared with conventional 4D flow (P ≤ .03). k-t–accelerated 4D flow MRI was reproducible (intra- and interobserver intraclass correlation coefficient ≥0.98) and identified significantly increased peak velocities and WSS in patients with stenotic (P ≤ .003) or bicuspid (P ≤ .04) aortic valves compared with healthy volunteers. In addition, k-t–accelerated 4D flow MRI–derived velocities and WSS were inversely related to age (r ≥−0.53; P ≤ .03) over all healthy volunteers. CONCLUSION: k-t–accelerated aortic 4D flow MRI providing 2-minute scan times was feasible and reproducible at two centers. Although consistent healthy aging- and disease-related changes in aortic hemodynamics were observed, care should be taken when considering WSS, which can be underestimated in patients

Mechanisms of iron-based catalysis investigated using model compounds

The catalytic mechanism of highly active, nanophase, iron-based coal liquefaction catalysts was investigated using a series of model compounds. The iron-oxide phases ferric oxyhydroxysulfate (OHS), 6-line ferrihydrite, hematite, and goethite, were evaluated as catalyst precursors with systematically substituted diphenylmethanes in the presence of a hydrogen donating solvent. The activity of the catalysts was observed to be dependent upon the functionality on the model compounds. The results of these model compound studies and their relationship to possible reaction mechanisms are presented

Quantitative myocardial perfusion in coronary artery disease: A perfusion mapping study

BACKGROUND: Cardiac MR stress perfusion remains a qualitative technique in clinical practice due to technical and postprocessing challenges. However, automated inline perfusion mapping now permits myocardial blood flow (MBF, ml/g/min) quantification on-the-fly without user input. PURPOSE: To investigate the diagnostic performance of this novel technique in detecting occlusive coronary artery disease (CAD) in patients scheduled to undergo coronary angiography. STUDY TYPE: Prospective, observational. SUBJECTS: Fifty patients with suspected CAD and 24 healthy volunteers. FIELD STRENGTH: 1.5T. SEQUENCE: "Dual" sequence multislice 2D saturation recovery. ASSESSMENT: All patients underwent cardiac MR with perfusion mapping and invasive coronary angiography; the healthy volunteers had MR with perfusion mapping alone. STATISTICAL TESTS: Comparison between numerical variables was performed using an independent t-test. Receiver operator characteristic (ROC) curves were generated for transmyocardial, endocardial stress MBF, and myocardial perfusion reserve (MPR, the stress:rest MBF ratio) to diagnose severe (>70%) stenoses as measured by 3D quantitative coronary angiography (QCA). ROC curves were compared by the method of DeLong et al. RESULTS: Compared with volunteers, patients had lower stress MBF and MPR even in vessels with 70%), MBF and MPR decreased. To diagnose occlusive (>70%) CAD, endocardial and transmyocardial stress MBF were superior to MPR (area under the curve 0.92 [95% CI 0.86-0.97] vs. 0.90 [95% CI 0.84-0.95] and 0.80 [95% CI 0.72-0.87], respectively). An endocardial threshold of 1.31 ml/g/min provided a per-coronary artery sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 90%, 82%, 50%, and 98%, with a per-patient diagnostic performance of 100%, 66%, 57%, and 100%, respectively. DATA CONCLUSION: Perfusion mapping can diagnose occlusive CAD with high accuracy and, in particular, high sensitivity and NPV make it a potential "rule-out" test. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 2

Progress in the discovery of selective, high affinity A2B adenosine receptor antagonists as clinical candidates

The selective, high affinity A2B adenosine receptor (AdoR) antagonists that were synthesized by several research groups should aid in determining the role of the A2B AdoR in inflammatory diseases like asthma or rheumatoid arthritis (RA) and angiogenic diseases like diabetic retinopathy or cancer. CV Therapeutics scientists discovered the selective, high affinity A2B AdoR antagonist 10, a 8-(4-pyrazolyl)-xanthine derivative [CVT-6883, Ki(hA2B) = 22 nM; Ki(hA1) = 1,940 nM; Ki(hA2A) = 3,280; and Ki(hA3) = 1,070 nM] that has favorable pharmacokinetic (PK) properties (t1/2 = 4 h and F > 35% rat). Compound 10 demonstrated functional antagonism at the A2B AdoR (KB = 6 nM) and efficacy in a mouse model of asthma. In two phase 1 clinical trials, CVT-6883 was found to be safe, well tolerated, and suitable for once daily dosing. A second compound 20, 8-(5-pyrazolyl)-xanthine, has been nominated for development from Baraldi’s group in conjunction with King Pharmaceuticals that has favorable A2B AdoR affinity and selectivity [Ki(hA2B) = 5.5 nM; Ki(hA1) > 1,000 nM; Ki(hA2A) > 1,000; and Ki(hA3) > 1,000 nM], and it has been demonstrated to be a functional antagonist. A third compound 32, a 2-aminopyrimidine, from the Almirall group has high A2B AdoR affinity and selectivity [Ki(hA2B) = 17 nM; Ki(hA1) > 1,000 nM; Ki(hA2A) > 2,500; and Ki(hA3) > 1,000 nM], and 32 has been moved into preclinical safety testing. Since three highly selective, high affinity A2B AdoR antagonists have been nominated for development with 10 (CVT-6883) being the furthest along in the development process, the role of the A2B AdoR in various disease states will soon be established

Signaling of the human P2Y(1) receptor measured by a yeast growth assay with comparisons to assays of phospholipase C and calcium mobilization in 1321N1 human astrocytoma cells

The human P2Y(1) receptor was expressed in the yeast Saccharomyces cerevisiae strain MPY578q5, which is engineered to couple to mammalian G protein-coupled receptors (GPCRs) and requires agonist-induced activation for growth. A range of known P2Y(1) receptor agonists were examined with the yeast growth assay system, and the results were validated by comparing with potencies in the transfected 1321N1 astrocytoma cell line, in which calcium mobilization was measured with a FLIPR (fluorometric-imaging plate reader). The data were also compared with those from phospholipase C activation and radioligand binding with the use of a newly available radioligand [(3)H]MRS2279 (2-chloro-N(6)-methyl-(N)-methanocarba-2’-deoxyadenosine-3’,5’bisphosphate). In the yeast growth assay, the rank order of potency of 2-MeSADP (2-methylthioadenosine 5’-diphosphate), ADP (adenosine 5’-diphosphate), and ATP (adenosine 5’-triphosphate) is the same as those in other assay systems, i.e., 2-MeSADP>ADP>ATP. The P2Y(1)-selective antagonist MRS2179 (N(6)-methyl-2-deoxyadenosine-3’,5’-bisphosphate) was shown to act as an antagonist with similar potency in all systems. The results suggest that the yeast expression system is suitable for screening P2Y(1) receptor ligands, both agonists and antagonists. The yeast system should be useful for random mutagenesis of GPCRs to identify mutants with certain properties, such as selective potency enhancement for small synthetic molecules and constitutive activity

Maximal Wall Thickness Measurement in Hypertrophic Cardiomyopathy: Biomarker Variability and its Impact on Clinical Care

OBJECTIVES: The aim of this study was to define the variability of maximal wall thickness (MWT) measurements across modalities and predict its impact on care in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND: Left ventricular MWT measured by echocardiography or cardiovascular magnetic resonance (CMR) contributes to the diagnosis of HCM, stratifies risk, and guides key decisions, including whether to place an implantable cardioverter-defibrillator (ICD). METHODS: A 20-center global network provided paired echocardiographic and CMR data sets from patients with HCM, from which 17 paired data sets of the highest quality were selected. These were presented as 7 randomly ordered pairs (at 6 cardiac conferences) to experienced readers who report HCM imaging in their daily practice, and their MWT caliper measurements were captured. The impact of measurement variability on ICD insertion decisions was estimated in 769 separately recruited multicenter patients with HCM using the European Society of Cardiology algorithm for 5-year risk for sudden cardiac death. RESULTS: MWT analysis was completed by 70 readers (from 6 continents; 91% with >5 years' experience). Seventy-nine percent and 68% scored echocardiographic and CMR image quality as excellent. For both modalities (echocardiographic and then CMR results), intramodality inter-reader MWT percentage variability was large (range -59% to 117% [SD ±20%] and -61% to 52% [SD ±11%], respectively). Agreement between modalities was low (SE of measurement 4.8 mm; 95% CI 4.3 mm-5.2 mm; r = 0.56 [modest correlation]). In the multicenter HCM cohort, this estimated echocardiographic MWT percentage variability (±20%) applied to the European Society of Cardiology algorithm reclassified risk in 19.5% of patients, which would have led to inappropriate ICD decision making in 1 in 7 patients with HCM (8.7% would have had ICD placement recommended despite potential low risk, and 6.8% would not have had ICD placement recommended despite intermediate or high risk). CONCLUSIONS: Using the best available images and experienced readers, MWT as a biomarker in HCM has a high degree of inter-reader variability and should be applied with caution as part of decision making for ICD insertion. Better standardization efforts in HCM recommendations by current governing societies are needed to improve clinical decision making in patients with HCM