Histopathological correlates of the napkin-ring sign plaque in coronary CT angiography

ObjectiveThe purpose of this study was to identify histologic characteristics of advanced coronary atherosclerotic plaques that are related with the detection of the napkin-ring sign (NRS) in coronary CT angiography (CCTA).MethodsCCTA was performed in 7 human donor hearts. Histological slicing and stainings were performed in 1 mm increments of each major coronary artery. Histology was co-registered with the CT-data and classified according to the modified AHA classification.ResultsAdvanced plaques (types IV–VI) were present in 139 (23%) of 611 cross sections. Of these 33 (24%) demonstrated an NRS in CCTA. NRS plaques were associated with greater non-core plaque area (median 10.2 vs. 6.4 mm², p < 0.01) and larger vessel area (median 17.1 vs. 13.0 mm², p < 0.01). The area of the necrotic/lipid core was larger in plaques with NRS (median 1.1 vs. 0.5 mm², p = 0.05). Angiogenesis tended to be more frequent in plaques with NRS (48% vs. 30%) whereas micro-calcifications tended to be more frequent in plaques without NRS (27% vs. 46%) (p = 0.06 and 0.07 respectively). In a multivariate analysis, necrotic/lipid core area (OR = 1.9), non-core plaque area (OR = 1.6), and total vessel area (OR = 0.9) independently predicted the appearance of the NRS in coronary CT angiography.ConclusionDelineation of NRS in CCTA is independently linked to the size of the necrotic/lipid core, the size of the non-core plaque and to the vessel area as measured in histology of advanced coronary atherosclerotic plaques.     

Can computer tomography help predict feasibility of transseptal puncture after percutaneous closure of an interatrial septal communication?

Background

Transseptal puncture (TSP) is the first step in pulmonary vein isolation and catheter ablation, as well as in left atrial appendage closure in atrial fibrillation. Although TSP has been reported to be successful in patients with device closure of interatrial septal communications, questions pertinent to its feasibility in patients with large devices still remain. We sought to determine whether a ??safe zone?? for TSP could be visualised by computer tomography (CT), especially if larger device sizes for interatrial septal communication closure (IASC-C) had been used.

Methods

Retrospective observational study of 20 patients who underwent CT for de novo chest pain occurring after IASC-C or as a diagnostic test for suspected or proven coronary artery disease (CAD). Clinical follow-up was for 20.5?±?17.6 (6?C84) months. CT was done18?±?10 (2?C28) weeks after IASC-C. Device size and dimensions of both atria in the long and short axes were measured, as was the minimal distance of the device edge to the inferior and inferoposterior atrial floor.

Results

The calculated minimal distance from the device edge to the inferior aspect (at 6 o??clock) of the (right or left) atrial floor was 7.2?±?6.5 (0?C27) mm while that to the inferoposterior aspect (at 07:30 o??clock) was 5.3?±?4.2 (0?C15) mm. In both locations, a distance of >6?mm was documented in ten patients (50%) while in nine patients (45%) a space of <6?mm was shown in both locations. There was no correlation between atrial dimensions or device size and minimal device distance to either wall.

Conclusion

With the exception of cases with the smallest devices (18 and 20?mm), neither device size nor atrial dimensions allow us to predict the feasibility of TSP in patients with a clamshell-type interatrial septal device in place, so that CT may be of help in determining whether a safe puncture space does exist in these patients.     

In silico and in vitro metabolism of ribociclib: a mass spectrometric approach to bioactivation pathway elucidation and metabolite profiling

Ribociclib (RBC, Kisqali®) is a highly selective CDK4/6 inhibitor that has been approved for breast cancer therapy. Initially, prediction of susceptible sites of metabolism and reactivity pathways were performed by the StarDrop WhichP450™ module and the Xenosite web predictor tool, respectively. Later, in vitro metabolites and adducts of RBC were characterized from rat liver microsomes using LC-MS/MS. Subsequently, in silico data was used as a guide for the in vitro work. Finally, in silico toxicity assessment of RBC metabolites was carried out using DEREK software and structural modification was proposed to reduce their side effects and to validate the bioactivation pathway theory using the StarDrop DEREK module. In vitro phase I metabolic profiling of RBC was performed utilizing rat liver microsomes (RLMs). Generation of reactive metabolites was investigated using potassium cyanide (KCN) as a trapping nucleophile for the transient and reactive iminium intermediates to form a stable cyano adduct that can be identified and characterized using mass spectrometry. Nine phase I metabolites and one cyano adduct of RBC were characterized. The proposed metabolic pathways involved in generation of these metabolites are hydroxylation, oxidation and reduction. The reactive intermediate generation mechanism of RBC may provide an explanation of its adverse reactions. Aryl piperazine is considered a structural alert for toxicity as proposed by the DEREK report. We propose that the generation of only one reactive metabolite of RBC in a very small concentration is due to the decreased reactivity of the piperazine ring compared to previous reports of similar drugs. Docking analysis was performed for RBC and its proposed derivatives at the active site of the human CDK6 enzyme. Methyl-RBC exhibited the best ADMET and docking analysis and fewer side effects compared to RBC and fluoro-RBC. Further drug discovery studies can be conducted taking into account this concept allowing the development of new drugs with enhanced safety profiles that were confirmed by using StarDrop software. To the best of our knowledge, this is the first literature report of RBCin vitro metabolic profiling and structural characterization and toxicological properties of the generated metabolites.

Nine phase I metabolites and one product of KCN trapping of RBC were characterized. Aryl piperazine is considered a structural alert for toxicity as proposed by the DEREK report. Methyl-RBC exhibited less toxicity and more binding affinity to CDK6.     

Radioiodination and biodistribution of newly synthesized 3-benzyl-2-([3-methoxybenzyl]thio)benzo[g]quinazolin-4-(3H)-one in tumor bearing mice

3-Benzyl-2-((3-methoxybenzyl)thio)benzo[g]quinazolin-4(3H)-one was previously synthesized and proved by physicochemical analyses (HRMS, ¹H and ¹³C NMR). The target compound was examined for its radioactivity and the results showed that benzo[g]quinazoline was successfully labeled with radioactive iodine using NBS via an electrophilic substitution reaction. The reaction parameters that affected the labeling yield such as concentration, pH and time were studied to optimize the labeling conditions. The radiochemical yield was 91.2?±?1.22% and the in vitro studies showed that the target compound was stable for up to 24?h. The thyroid was among the other organs in which the uptake of ¹²⁵I-benzoquinazoline has increased significantly over the time up to 4.1%. The tumor uptake was 6.95%. Radiochemical and metabolic stability of the benzoquinazoline in vivo/in vitro and biodistribution studies provide some insights about the requirements for developing more potent radiopharmaceutical for targeting the tumor cells.     

Modified subpectoral biceps tenodesis

Purpose

The proximal part of the long head of the biceps muscle has become a recognized cause of significant shoulder pain. Tenodesis of the long head of the biceps has been advocated as a treatment for pain resulting from biceps tendonopathy, biceps instability, and biceps tendon tears. All of these pathologies may be encountered during rotator cuff, SLAP or Bankart surgery, or in isolation. Several techniques have been described for this tenodesis, including various arthroscopic and subpectoral methods.

Methods

We present a modified bone bridge technique of Mazzocca et al., for subpectoral biceps tenodesis. In this technique we tenodese the tendon through two bone tunnels back over the muscle itself without implants.

Results

Application of this technique on 30 patients (ages 25–48 years) with short-term follow-up of 12–18 months showed statistically significant improvement (P value < 0.05) of the mean Constant and Oxford shoulder scores (pre-operative mean scores were 39.03 and 21.3, respectively, while postoperative mean scores were 76.43 and 44.8, respectively).

Conclusion

This technique has potential advantages as it allows the possibility of adjusting the tension of the biceps tendon before final suturing, in addition to quicker soft tissue healing.     

F 16915 prevents heart failure-induced atrial fibrillation: a promising new drug as upstream therapy

Atrial fibrillation (AF) is a common complication of heart failure. The aim of the present study was to investigate the effects of a new pure docosahexaenoic acid derivative called F 16915 in experimental models of heart failure-induced atria dysfunction. The atrial dysfunction-induced AF was investigated (1) in a dog model of tachypacing-induced congestive heart failure and (2) in a rat model of heart failure induced by occlusion of left descending coronary artery and 2 months reperfusion. F 16915 (5 g/day for 4 weeks) significantly reduced the mean duration of AF induced by burst pacing in the dog model (989?±?111 s in the vehicle group to 79?±?59 s with F 16915, P?<?0.01). This dose of F 16915 also significantly reduced the incidence of sustained AF (5/5 dogs in the vehicle group versus 1/5 with F 16915, P?<?0.05). In the rat model, the percentage of shortening fraction in the F 16915 group (100 mg/kg p.o. daily) was significantly restored after 2 months (32.6?±?7.4 %, n?=?9 vs 17.6?±?3.4 %, n?=?9 in the vehicle group, P?<?0.01). F 16915 also reduced the de-phosphorylation of connexin43 from atria tissue. The present results show that treatment with F 16915 reduced the heart dilation, resynchronized the gap junction activity, and reduced the AF duration in models of heart failure. Thus, F 16915 constitutes a promising new drug as upstream therapy for the treatment of AF in patients with heart failure.     

OxNASH Score Correlates with Histologic Features and Severity of Nonalcoholic Fatty Liver Disease

Background and Aim

Oxidative stress is a core abnormality responsible for disease progression in nonalcoholic fatty liver disease (NAFLD). By employing a highly sensitive liquid chromatography–tandem mass spectrometry (LC/MS/MS) approach we recently were able to define the circulating profile of bioactive lipid peroxidation products characteristic of patients with nonalcoholic steatohepatitis (NASH) and developed the OxNASH score for NASH diagnosis. The aims of this study were to assess the utility of OxNASH as a predictor of NASH and study the association between OxNASH and specific histologic features of NAFLD.

Methods

Our cohort consisted of 122 patients undergoing liver biopsy for clinical suspicion of NAFLD. The NAFLD activity score (NAS) was calculated for each patient. Levels of fatty acid oxidation products were quantified using stable isotope dilution LC/MS/MS, and OxNASH was calculated.

Results

The mean age of our patients was 49.3 (±11.6) years, and the mean body mass index was 31.5 (±4.8) kg/m². The majority of patients were Caucasian (82 %) and 48 % were female. OxNASH correlated with NAS and with the individual histologic features of NAFLD, namely, steatosis, inflammation, and ballooning (P < 0.05), with the strongest association being with inflammation [rho (ρ) 0.40, 95 % confidence interval 0.23, 0.57, P < 0.001]. There was also a correlation between the stage of fibrosis and OxNASH (P = 0.001). These associations remained statistically significant after adjustment for multiple confounders.

Conclusions

Based on our results, in adult patients with NAFLD, OxNASH correlates with histologic features of NASH and appears to be a promising noninvasive marker.