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Purpose: d -Limonene is a natural monoterpene with pronounced chemotherapeutic activity and minimal toxicity in preclinical studies. A phase I clinical trial to assess toxicity, the maximum tolerated dose (MTD) and pharmacokinetics in patients with advanced cancer was followed by a limited phase II evaluation in breast cancer. Methods: A group of 32 patients with refractory solid tumors completed 99 courses of d-limonene 0.5 to 12 g/m2 per day administered orally in 21-day cycles. Pharmacokinetics were analyzed by liquid chromatography-mass spectrometry. Ten additional breast cancer patients received 15 cycles of d-limonene at 8 g/m2 per day. Intratumoral monoterpene levels were measured in two patients. Results: The MTD was 8 g/m2 per day; nausea, vomiting and diarrhea were dose limiting. One partial response in a breast cancer patient on 8 g/m2 per day was maintained for 11 months; three patients with colorectal carcinoma had prolonged stable disease. There were no responses in the phase II study. Peak plasma concentration (Cmax) for d-limonene ranged from 10.8 ± 6.7 to 20.5 ± 11.2 μ M. Predominant circulating metabolites were perillic acid (Cmax 20.7 ± 13.2 to 71 ± 29.3 μ M ), dihydroperillic acid (Cmax 16.6 ± 7.9 to 28.1 ± 3.1 μ M ), limonene-1,2-diol (Cmax 10.1 ± 8 to 20.7 ± 8.6 μ M ), uroterpenol (Cmax 14.3 ± 1.5 to 45.1 ± 1.8 μ M ), and an isomer of perillic acid. Both isomers of perillic acid, and cis and trans isomers of dihydroperillic acid were in urine hydrolysates. Intratumoral levels of d-limonene and uroterpenol exceeded the corresponding plasma levels. Other metabolites were trace constituents in tissue. Conclusions: d-Limonene is well tolerated in cancer patients at doses which may have clinical activity. The favorable toxicity profile supports further clinical evaluation. [ABSTRACT FROM AUTHOR]

Background: The registry-based randomized VALIDATE-SWEDEHEART trial (NCT02311231) compared bivalirudin vs. heparin in patients undergoing percutaneous coronary intervention (PCI) for myocardial infarction (MI). It showed no difference in the composite primary endpoint of death, MI, or major bleeding at 180 days. Here, we report outcomes at two years., Methods: Analysis of primary and secondary endpoints at two years of follow-up was prespecified in the study protocol. We report the study results for the extended follow-up time here., Results: In total, 6006 patients were enrolled, 3005 with ST-segment elevation MI (STEMI) and 3001 with Non-STEMI (NSTEMI), representing 70 % of all eligible patients with these diagnoses during the study. The primary endpoint occurred in 14.0 % (421 of 3004) in the bivalirudin group compared with 14.3 % (429 of 3002) in the heparin group (hazard ratio [HR] 0.97; 95 % confidence interval [CI], 0.85-1.11; P = 0.70) at one year and in 16.7 % (503 of 3004) compared with 17.1 % (514 of 3002), (HR 0.97; 95 % CI, 0.96-1.10; P = 0.66) at two years. The results were consistent in patients with STEMI and NSTEMI and across major subgroups., Conclusions: Until the two-year follow-up, there were no differences in endpoints between patients with MI undergoing PCI and allocated to bivalirudin compared with those allocated to heparin., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02311231., Competing Interests: Declaration of competing interest Elmir Omerovic reports grants from Astra Zeneca, personal fees from Astra Zeneca, MSD, Bayer, Janssen outside the submitted work. Stefan James reports grants from Astra Zeneca, grants from The Medicines Company, grants from Swedish Heart and Lung Foundation, and grants from Swedish Research Council during the conduct of the study; personal fees from Bayer and grants from Jansen outside the submitted work. Truls Råmunddal reports personal fees from Boston Scientific and personal fees from Abbot outside the submitted work. Ole Fröbert reports personal fees from GE Medical and from Astra Zeneca outside the submitted work. Pontus Lindroos reports personal fees from Astra Zeneca outside the submitted work. Anders Ulvenstam reports personal fees from Boston Scientific outside the submitted work. Matthias Götberg reports grants and personal fees from Volcano Corporation, personal fees from Boston Scientific, and personal fees from Medtronic Corporation outside the submitted work. Oskar Angerås Dr. reports personal fees from Astra Zeneca outside the submitted work. Olie Östlund reports grants from AstraZeneca, grants from The Medicines Company. Cleas Held reports grants and personal fees from AstraZeneca, grants from GlaxoSmithKline, grants from BristolMyers Squibb, and grants from Merck outside the submitted work. Sasha Koul reports personal fees from Pfizer, personal fees from BMS, and personal fees from Astra Zeneca outside the submitted work. David Erlinge reports personal fees from Astrazeneca and The Medicines Company outside the submitted work. All others co-authors have nothing to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The copepod Lernathropus kroyeri constitutes one of the major parasites for the Mediterranean aquaculture, infesting the sea bass Dicentrarchus labrax causing thus disruptions of growth performance and occasionally mortalities. Despite the large spread and the high frequency of this parasite in mariculture farms of Eastern Mediterranean, L. kroyeri genetic profile from aquaculture as well as the pathophysiological response of D. labrax have not been studied so far. Keeping this in mind, in the present study we investigated the L. kroyeri infestation on D. labrax from two farms in Greece, examining both healthy and heavy parasitized individuals. Assays included histopathology, phylogenetic reconstruction of the parasite and physiological response of the fish by the means of antioxidant, inflammatory metabolic and stress related gene expression analysis at both mRNA and protein levels. Genetic analysis indicated that L. kroyeri composes a monophyletic group, highly phylogenetically distant from other congeneric groups. Heavy infested D. labrax witnessed a significantly increased immune response that further led to oxidative stress and metabolic alterations. Overall, our results demonstrate the, seasonally independent, high infestation of this parasitic copepods, which continue to affect Mediterranean intensive aquaculture systems., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:John A. Theodorou reports financial support was provided by EU - Greece Operational Program. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the diagnostic performance of a novel deep learning attenuation correction software (DLACS) for myocardial perfusion imaging (MPI) using a cadmium-zinc-telluride (CZT) cardio dedicated camera with invasive coronary angiography (ICA) correlation for the diagnosis of coronary artery disease (CAD) in a high-risk population., Methods: Retrospective study of 300 patients (196 males [65%], mean age 68 years) from September 2014 to October 2019 undergoing MPI, followed by ICA and evaluated by means of quantitative angiography software, within six months after the MPI. The mean pre-test probability score for coronary disease according to the European Society of Cardiology criteria was 37% for the whole cohort. The MPI was performed in a dedicated CZT cardio camera (D-SPECT Spectrum Dynamics) with a two-day protocol, according to the European Association of Nuclear Medicine guidelines. MPI was retrospectively evaluated with and without the DLACS., Results: The overall diagnostic accuracy of MPI without DLACS to identify patients with any obstructive CAD at ICA was 87%, sensitivity 94%, specificity 57%, Positive Predictive Value 91% and Negative Predictive Value 64%. Using DLACS the overall diagnostic accuracy was 90%, sensitivity 91%, specificity 86%, Positive Predictive Value 97% and Negative Predictive Value 66%., Conclusion: Use of the novel DLACS enhances performance of the MPI using the CZT D-SPECT camera and achieves improved results, especially avoiding artefacts and reducing the number of false positive results., (Copyright © 2023 The Author(s). Published by Elsevier España, S.L.U. All rights reserved.)

Purpose: To evaluate the diagnostic performance of three different cardiac stress protocols for myocardial perfusion imaging (MPI) using a cadmium-zinc-telluride (CZT) camera with invasive coronary angiography (ICA) correlation for the diagnosis of coronary artery disease in a high risk population., Methods: Retrospective study of 263 patients (96 women and 167 males, mean age 68 years) from which 119 patients performed a bicycle stress test (BST), 113 pharmacological stress test (PST) and 31 a combination of the two (CST) between September 2014 and December 2018. The patients then underwent myocardial perfusion imaging (MPI), followed by ICA and evaluated by means of quantitative angiography software, within six months after the MPI. The mean pre-test probability score for coronary disease according to the European Society of Cardiology criteria was 36% for the whole population. The MPI was performed in a dedicated CZT cardio camera (D-SPECT Spectrum Dynamics) with a two-day protocol, according to the European Association of Nuclear Medicine guidelines., Results: No significant difference was observed between the three stress protocols in terms of diagnostic accuracy (BST 85%, PST 88%, CST 84%). The overall diagnostic accuracy of MPI to identify patients with any obstructive CAD at ICA was 86%, Sensitivity 93%, Specificity 54%, PPV 90% and NPV 63%., Conclusion: The CZT D-SPECT camera achieves overall satisfactory results in the diagnosis of CAD, observing no significant differences in the diagnostic performance when the stress test was performed as a BST, PST or CST., (Copyright © 2023 Sociedad Española de Medicina Nuclear e Imagen Molecular. Published by Elsevier España, S.L.U. All rights reserved.)

Purpose: Evaluate the prediction of quantitative coronary angiography (QCA) values from MPI, by means of deep learning., Methods: 546 patients (67% men) undergoing stress 99mTc-tetrofosmin MPI in a CZT camera in the upright and supine position were included (1092 MPIs). Patients were divided into two groups: ICA group included 271 patients who performed an ICA within 6 months of MPI and a control group with 275 patients with low pre-test probability for CAD and a normal MPI. QCA analyses were performed using radiologic software and verified by an expert reader. Left ventricular myocardium was segmented using clinical nuclear cardiology software and verified by an expert reader. A deep learning model was trained using a double cross-validation scheme such that all data could be used as test data as well., Results: Area under the receiver-operating characteristic curve for the prediction of QCA, with > 50% narrowing of the artery, by deep learning for the external test cohort: per patient 85% [95% confidence interval (CI) 84%-87%] and per vessel; LAD 74% (CI 72%-76%), RCA 85% (CI 83%-86%), LCx 81% (CI 78%-84%), and average 80% (CI 77%-83%)., Conclusion: Deep learning can predict the presence of different QCA percentages of coronary artery stenosis from MPIs., (© 2022. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.)

Objectives: The aim of this study was to conduct a nationwide all comer description of incidence, contemporary management and outcome in Swedish spontaneous coronary artery dissection (SCAD) patients. The incidence of SCAD as well as the management and outcome of these patients is not well described., Design: A nationwide observational study., Participants and Setting: All patients with SCAD registered in the Swedish Coronary Angiography and Angioplasty Register from 2015 to 2017 were included. The index angiographies of patients with registered SCAD were re-evaluated at each centre to confirm the diagnosis. Patients with non-SCAD myocardial infarction (MI) (n=32 601) were used for comparison., Outcome Measures: Outcomes included all-cause mortality, reinfarction or acute coronary reangiography., Results: This study found 147 SCAD patients, rendering an incidence of 0.74 per 100 000 per year and a prevalence of 0.43% of all MIs. The average age was 52.9 years, 75.5% were women and 47.6% presented with ST-segment elevation MI. Median follow-up time for major adverse cardiac event was 17.3 months. Percutaneous coronary intervention was attempted in 40.1% of SCAD patients and 30.6% received stent. The use of antithrombotic agents was similar between the groups and there was no difference regarding outcomes, 10.9% vs 13.4%, p=0.75. Mortality was lower in SCAD patients, 2.7% vs 8.0%, p=0.03, whereas SCAD patients more often underwent acute reangiography, 9.5% vs 4.6%, p<0.01., Conclusion: In this nationwide, all comer Swedish study, the overall incidence of SCAD was low, including 25% men which is more and in contrast to previous studies. Compared with non-SCAD MI, SCAD patients were younger, with lower cardiovascular risk burden, yet suffered substantial mortality and morbidity and more frequently underwent acute coronary reangiography., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Radial artery is the preferred access site in contemporary percutaneous coronary intervention (PCI). However, limited data exist regarding utilization pattern, safety, and long-term efficacy of transradial artery access (TRA) PCI in heavily calcified lesions using high-speed rotational atherectomy (HSRA)., Methods: All patients who underwent HSRA-PCI in Sweden between 2005 and 2016 were included. Outcomes were major adverse cardiac events (MACE, including death, myocardial infarction (MI) or target vessel revascularisation (TVR)), in-hospital bleeding and restenosis. Inverse probability of treatment weighting was used to adjust for the non-randomized access site selection., Results: We included 1479 patients of whom 649 had TRA and 782 transfemoral artery access (TFA) HSRA-PCI. The rate of TRA increased significantly by 18% per year but remained lower in HSRA-PCI (60%) than in the overall PCI population (85%) in 2016. TRA was associated with comparable angiographic success but significantly lower risk for major (adjusted OR 0.16; 95% CI 0.05-0.47) or any in-hospital bleeding (adjusted OR 0.32; 95% CI 0.13-0.78). At one year, the adjusted risk for MACE (HR 0.87; 95% CI 0.67-1.13) and its individual components did not differ between TRA and TFA patients. The risk for restenosis did not significantly differ between TRA and TFA HSRA-PCI treated lesions (adjusted HR 0.92; 95% CI 0.46-1.81)., Conclusion: HSRA-PCI by TRA was associated with significantly lower risk for in-hospital bleeding and equivalent long-term efficacy when compared with TFA. Our data support the feasibility and superior safety profile of TRA in HSRA-PCI., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Skin injuries may occur when radiation doses to the skin exceed 2 Gy. This study aimed to measure changes in skin microcirculation in patients undergoing chronic total occlusion percutaneous coronary interventions (CTO-PCI). In 14 patients, peak skin dose (PSD) was estimated with radiographic films and skin microcirculation was assessed with laser speckle contrast imaging (LSCI), before, 1 day after the intervention, and 4-6 weeks later. The mean PSD was 1.8 ± 0.9 Gy. Peak skin microcirculation increased by 12% from 45 ± 6 PU before to 50 ± 9 PU 1 day after the intervention (p = 0.01), and returned to 46 ± 8 PU after 4-6 weeks (p = 0.15). There was no significant correlation between PSD and the change in perfusion, neither 1 day (r = -0.13, p = 0.69) nor 4-6 weeks after the intervention (r = 0.33, p = 0.35). These results suggest that there are no radiation-induced microvascular changes in the skin after CTO-PCI at skin doses below 2 Gy., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: This study examines whether preceding assessment of periodontal status in patients with established coronary artery disease (CAD) can predict future CAD endpoints (myocardial infarction, new revascularization procedure, or CAD-related death) during 8-year follow-up and whether the changes in periodontal status over time differ in patients with CAD compared with healthy controls., Methods: In 2003, periodontal status was examined in 161 patients with CAD who underwent percutaneous coronary intervention or coronary artery bypass graft due to significant stenosis in the coronary arteries and 162 controls without CAD. Eight years later, 126 patients with CAD (102 males and 24 females, mean age: 68 ± 8.9 years) and 121 controls (101 males and 20 females, mean age: 69 ± 9.0 years) were reexamined periodontally. A standard classification of periodontal disease in three groups (mild, moderate, and severe) was used. CAD endpoints during follow-up were obtained by review of medical records. CAD as cause of death was confirmed from the Swedish Cause of Death Register., Results: No significant differences were found among patients with CAD, with or without CAD-related endpoints at 8-year follow-up, and severity of periodontitis at baseline (P = 0.7). CAD did not influence the incidence or severity of periodontitis. Significant differences were found at the final examination in periodontitis prevalence and severity (P = 0.001), number of teeth (P = 0.006), probing depth 4 to 6 mm (P = 0.016), bleeding on probing (P = 0.001), and radiographic bone level (P = 0.042) between CAD patients and controls, all in favor of controls., Conclusions: The study results did not show a significant association during 8 years among CAD endpoints and periodontal status at baseline. The progression of periodontitis was low in both groups, although the higher proportion of individuals with severe periodontitis among patients with CAD compared with controls remained unchanged over the 8-year follow-up. Further long-term prospective studies are needed to show whether periodontitis can be considered a risk or prognostic factor for CAD, in terms of endpoints including myocardial infarction, new revascularization procedure, and CAD-related death.

The depolarisation-induced release of dopamine from control rat striatal slices is inhibited by ethanol in vitro. The same parameter is enhanced in preparations from ethanol-treated rats. Under conditions of superfusion with normal physiological solutions we were unable to see similar results in noradrenaline (NA) release from cortical slices. Since we believed altered intracellular Ca2+ metabolism might underlie changes induced by ethanol in dopamine neurones, we superfused cortical slices with low K+ solutions which raise intracellular Ca2+. Under these conditions, ethanol in vitro inhibited depolarisation-induced NA release in control preparations. In preparations from ethanol tolerant animals, ethanol enhanced depolarisation-induced release. In cultures of adrenal chromaffin cells, similar alterations in coupling between Ca2+ and catecholamine release can be seen. Some of these changes may be a consequence of increased functional activity of dihydropyridine-sensitive Ca2+ channels.

Flavonoids are a class of phenolic plant pigments which impair the oxidative burst of neutrophils to an extent dependent on their hydrophobicity. The distribution of quercetin and of morin in nitrogen-cavitated neutrophils paralleled their respective hydrophobic characteristics and respiratory burst inhibition. While both flavonoids were localized primarily in the specific granule membrane of neutrophils, the amount of quercetin was considerably greater than that of morin. We here demonstrate inhibition of the initial stimulation response, depolarization of the membrane potential as monitored by fluorescence of the membrane probe diS-C3-(5), and of the respiratory burst, monitored by following the destruction of diS-C3-(5), a reaction mediated by the H2O2 produced in the burst. The flavonoids kaempferol, morin, quercetin, or fisetin were preincubated with human neutrophils at a concentration of 100 microM per 2 X 10(6) cells/ml for 2-3 min and subsequently stimulated with 1 microgram/ml of the tumor promoter phorbol myristate acetate (PMA) or with 60 micrograms/ml of immune complex. The effect of each compound differed, i.e. depolarization was enhanced by some and inhibited by others, while H2O2 generation was inhibited by each, supporting our previous findings that membrane potential depolarization and the respiratory burst are dissociable events. Concentration-response experiments, performed at flavonoid concentrations between 12.5 and 500 microM to determine the IC50 values of these compounds for depolarization and burst activation, indicated that none of the flavonoids affected the resting potential, while all perturbed the stimulus-coupled response, the direction and extent of the perturbation depending upon the stimulus, and the function assessed. These data show that the effects of flavonoids on human neutrophils are complex and suggest several sites of action depending upon the flavonoid's subcellular distribution and pathway of stimulation.