Association of midregional proadrenomedullin with coronary artery stenoses, soft atherosclerotic plaques and coronary artery calcium

Midregional proadrenomedullin (MR-proADM) is elevated in patients with heart failure and myocardial infarction. The aim of this study was to evaluate the association of MR-proADM with the grade of coronary artery stenosis, presence of coronary artery soft plaques and coronary artery calcification score (CACS), determined by 64-multislice computed tomography (MSCT) in patients without known prior cardiovascular disease. This retrospective study included 107 patients undergoing MSCT for confirmation (or exclusion) of coronary artery disease. MR-proADM levels were measured in all patients. The assessment of coronary artery stenoses, CACS and soft coronary plaques was made by MSCT using known criteria. The MR-proADM [median (25th–75th percentiles)] level was 0.33 (0.21–0.43)?nmol/l. The MR-proADM level was 0.28 (0.22–0.40)?nmol/l in patients with coronary stenoses ≥50% (n?=?23) versus 0.33 (0.27–0.40)?nmol/l in patients with coronary stenoses <50% (n?=?83, P?=?0.59), 0.33 (0.26–0.40)?nmol/l in patients with soft plaques (n?=?56) versus 0.33 (0.25–0.41)?nmol/l in patients without soft plaques (n?=?50, P?=?0.73) and 0.33 (0.25–0.39)?nmol/l in patients with CACS?<200 (n?=?81) versus 0.32 (0.26–0.44)?nmol/l in patients with CACS?≥200 (n?=?26, P?=?0.77). In multivariate analysis, the MR-proADM level was a significant correlate of coronary artery stenoses [odds ratio (OR)?=?0.93; 95% confidence interval (CI) 0.86–0.99; P?=?0.026] and soft plaques (OR?=?0.94; 95% CI 0.90–0.99; P?=?0.015) but not of CACS (OR?=?0.98; 95% CI 0.93–1.03; P?=?0.36). A decreased MR-proADM level is an independent correlate of the presence of coronary artery disease and of soft atherosclerotic plaques. Patients with decreased MR-proADM levels may need invasive examinations to diagnose more severe forms of coronary artery disease.     

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.     

Development and evaluation of a simulator-based laparoscopic training program for surgical novices

Background

The use of simulation to train novice surgeons in laparoscopic skills is becoming increasingly popular. To maximize benefit from simulation, training needs to be delivered and assessed in a structured manner. This study aimed to define performance goals, demonstrate construct validity of the training program, and evaluate whether novice surgeons could reach the preset performance goals.

Methods

Nine expert laparoscopic surgeons established performance goals for three basic modules of an augmented-reality laparoscopic simulator. The three laparoscopic modules were used by 40 novice surgeons and 40 surgical trainees (postgraduate years [PGYs] 1–4). The performance outcomes were analyzed across the different groups (novice, PGYs 1 and 2, PGYs 3 and 4, expert) to determine construct validity. Then 26 recruited novices trained on the three modules with the aim of reaching the performance goals.

Results

The results demonstrated a significant difference in performance between all levels of experience for time (p < 0.001), motion analysis (p < 0.001), and error score (p < 0.001), thus demonstrating construct validity. All 26 novice surgeons significantly improved in performance with repetition for the metrics of time (p < 0.001) and motion analysis (p < 0.001). For two of the modules, the proficiency goals were reached in fewer than 10 trials by 80 % of the study participants.

Conclusion

Basic skills in laparoscopic surgery can be learned and improved using proficiency-based simulation training. It is possible for novice surgeons to achieve predefined performance goals in a reasonable time frame.     

In the Experimental Model of Acute Mesenteric Ischemia,The Correlation of Blood Diagnostic Parameters with the Duration of Ischemia and their Effects on Choice of Treatment

ABSTRACT

Purpose/Aim: Acute mesenteric ischemia is a syndrome characterized by sudden onset abdominal pain followed by intestinal necrosis. Morbidity and mortality increase with delayed diagnosis. Even with the latest radiological diagnostic methods, early diagnosis and initiation of treatment can be delayed. Using an experimental model, here we aim to determine the relationship between the laboratory parameters used to detect acute mesenteric ischemia and the duration of irreversible ischemia. Materials and Methods: A total of 30 male Wistar albino rats were divided into five groups, all of which underwent general anesthesia: (i) Superior mesenteric artery (SMA) dissection with laparotomy was performed, and blood samples and intestinal segment samples were taken after 2 hr (Sham group); (ii) volvulus of one-third of the small intestines was performed manually by laparotomy, and blood samples and intestinal segment samples were taken after 2 hr (Volvulus group); (iii) SMA was ligated with laparotomy, and blood samples and intestinal segment samples were taken after 2 hr (SMA+ligated 2-hr group); (iv) SMA was ligated with laparotomy, and blood samples and intestinal segment samples were taken after 4 hr (SMA+ligated 4-hr group); and (v) SMA was ligated with laparotomy, and blood samples and intestinal segment samples were taken after 6 hr (SMA+ligated 6-hr group). Results: The mean lactate dehydrogenase (LDH) activities of the SMA+ligated 2-hr and SMA+ligated 6-hr groups were statistically higher than the control group (p = .004). Compared to the Sham and Volvulus groups, the mean lactate level of the SMA+ligated 6-hr group was significantly higher (p = .004). Compared to the Sham and Volvulus groups, the mean D-dimer levels of the SMA+ligated 4-hr and SMA+ligated 6-hr groups were significantly higher (p = .004 and .003, respectively). By histopathological evaluation, we found that pathological damage increased as the ischemia lengthened. Conclusions: Mesenteric ischemia leads to an irreversible loss of intestinal perfusion and an increase in parameters of ischemia. Irreversible tissue damage occurs after 4 hr of ischemia and peaks after 6 hr, whereas parameters of ischemia (D-dimer, LDH, and L-Lactate levels) are highest at 2 hr after the onset of ischemia.