COVID-19-mediated patient delay caused increased total ischaemic time in ST-segment elevation myocardial infarction

Netherlands Heart Journal - The current study aimed to evaluate changes in treatment delay and outcome for ST-segment elevation myocardial infarction (STEMI) in the Netherlands during the first...     

Seminal plasma induces the expression of IL-1α in normal and neoplastic cervical cells via EP2/EGFR/PI3K/AKT pathway

Background

Cervical cancer is a chronic inflammatory disease of multifactorial etiology usually presenting in sexually active women. Exposure of neoplastic cervical epithelial cells to seminal plasma (SP) has been shown to promote the growth of cancer cells in vitro and tumors in vivo by inducing the expression of inflammatory mediators including pro-inflammatory cytokines. IL-1α is a pleotropic pro-inflammatory cytokine induced in several human cancers and has been associated with virulent tumor phenotype and poorer prognosis. Here we investigated the expression of IL-1α in cervical cancer, the role of SP in the regulation of IL-1α in neoplastic cervical epithelial cells and the molecular mechanism underlying this regulation.

Methods and results

Real-time quantitative RT-PCR confirmed the elevated expression of IL-1α mRNA in cervical squamous cell carcinoma and adenocarcinoma tissue explants, compared with normal cervix. Using immunohistochemistry, IL-1α was localized to the neoplastically transformed squamous, columnar and glandular epithelium in all cases of squamous cell carcinoma and adenocarcinomas explants studied. We found that SP induced the expression of IL-α in both normal and neoplastic cervical tissue explants. Employing HeLa (adenocarcinoma) cell line as a model system we identified PGE₂ and EGF as possible ligands responsible for SP-mediated induction of IL-1α in these neoplastic cells. In addition, we showed that SP activates EP2/EGFR/PI3kinase-Akt signaling to induce IL-1α mRNA and protein expression. Furthermore, we demonstrate that in normal cervical tissue explants the induction of IL-1α by SP is via the activation of EP2/EGFR/PI3 kinase-Akt signaling.

Conclusion

SP-mediated induction of IL-1α in normal and neoplastic cervical epithelial cells suggests that SP may promote cervical inflammation as well as progression of cervical cancer in sexually active women.

     

Acute myocardial infarction in adolescents: reappraisal of underlying mechanisms

Worldwide, a myocardial infarction (MI) is an important cause of death. Acute MI occurs most commonly at an older age. However, the incidence of acute     

Life-threatening bilateral aorto-ostial coronary artery disease in an octogenarian

Aorto-ostial disease is difficult to approach percutaneously; therefore, a surgical option may be more desirable. We describe a case of an octogenarian in which the clinical arguments and technical approach have been summarised for a successful percutaneous therapeutic strategy. (Neth Heart J 2009;17:30-2.)     

Specificity in lipases: a computational study of transesterification of sucrose

Computational conformational searches of putative transition states of the reaction of sucrose with vinyl laurate catalyzed by lipases from Candida antarctica B and Thermomyces lanuginosus have been carried out. The dielectric of the media have been varied to understand the role of protein plasticity in modulating the observed regioselective transesterification. The binding pocket of lipase from Candida adapts to the conformational variability of the various substates of the substrates by small, local adjustments within the binding pocket. In contrast, the more constrained pocket of the lipase from Thermomyces adapts by adjusting through concerted global motions between subdomains. This leads to the identification of one large pocket in Candida that accommodates both the sucrose and the lauroyl moieties of the transition state, whereas in Thermomyces the binding pocket is smaller, leading to the localization of the two moieties in two distinct pockets; this partly rationalizes the broader specificity of the former relative to the latter. Mutations have been suggested to exploit the differences towards changing the observed selectivities.     

Restenosis begets restenosis: implications for stent selection

Background. Identifying the risk for restenosis is of critical importance in the stent selection process of patients undergoing percutaneous coronary intervention (PCI). Therefore, we sought to determine if a history of clinical recurrence (CR) after PCI increases the risk of CR after treatment of a de novo lesion in another coronary artery. Methods. We retrospectively analysed all 12,763 patients who underwent PCI between 1993 and 2004 and selected patients with two or more interventions in two different native vessels. These patients were divided into two groups: patients without CR, and patients with CR after the first PCI. Clinical recurrence was defined as revascular-isation of the target vessel by either PCI or CABG within one year. Results. A total of 1010 patients with two or more interventions in two different native vessels were identified: 727 patients without and 283 patients with CR after the first PCI. Baseline patient characteristics and conventional risk factors were comparable between the two groups. Patients with a history of CR had a higher risk of CR after a second intervention in a second vessel (OR=3.4, 95% CI=2.3 to 4.9). A total of 112 patients also had a third intervention in a third native vessel: 12 patients with two CR, 30 patients with one CR and 70 patients with no CR after the first two interventions. CR rates in these patients were 50, 17 and 3%, respectively (p<;0.001). Conclusion. Patients with a history of CR have a markedly increased risk of developing CR after a second or third PCI in a different coronary artery. Therefore, in the decision-making process on whether to use a bare metal stent or drug-eluting stent, the history of CR is a simple and powerful aid. (Neth Heart J 2008;16:376-81.)     

Quantification of an C-labelled β-adrenoceptor ligand, S-(−)CGP 12177, in plasma of humans and rats

β-Adrenoceptors in human lungs and heart can be imaged with the radioligand 4-[3-[(1,1-dimethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-¹¹C-one (CGP 12177, [¹¹C]I). For quantification of receptor density with compartment models by adjustment of rate constants, an ‘input function’ is required which consists of the integral of the concentration of unmodified ligand in arterial plasma over time. A discrepancy in the literature regarding metabolic stability of [¹¹C]I prompted us to study metabolism in rats by reversed-phase HPLC (RP-HPLC) of trichloroacetic acid extracts of arterial plasma after i.v. injection of [¹¹C]I (> 11.1 TBq/mmol, 11 MBq/kg). Some plasma samples were also directly applied to an internal-surface reversed-phase (ISRP) column. In parallel experiments, tritiated [¹¹C]I was employed and methanol extracts of arterial plasma were analyzed by straight-phase TLC. The three methods were in excellent agreement. Unmodified [¹¹C]I decreased from > 98.5% (³H) or > 99.9% (¹¹C) initially to 57 ± 7% at 80 min post injection to formation of two polar metabolites. Using the RP-HPLC method, no metabolism was detectable in humans up to 30 min after injection of [¹¹C]I (1851 MBq). Deproteinization of plasma with acetonitrile resulted in the formation of a radioactive species (artifact) which eluted immediately after the void volume in RP-HPLC and which could be mistakenly interpreted as a metabolite. Plasma protein binding was low (ca. 30%) in both humans and rats. Association of the radioligand to blood cells suggested that equilibrium between receptor-bound and free radioligand was reached within 15 min after high-specific-activity injections, but only after more than 30 min after low-specific-activity injections.     

Quantification of the β-adrenoceptor ligand S-1′-[F]fluorocarazolol in plasma of humans, rats and sheep

Myocardial and pulmonary β-adrenoceptors can be imaged with 2-(S)-(−)-(9H-carbazol-4-yl-oxy)-3-[1-(fluoromethyl)ethyl]amino-2- propanol (S-1′-[¹⁸F]fluorocarazolol, I). Quantification of unmodified fluorocarazolol in plasma is necessary for analysis of PET images in terms of receptor densities. We have determined I and its radioactive metabolites in rat, sheep and human plasma, using (1) solid-phase extraction (C₁₈) followed by reversed-phase HPLC and (2) direct injection of untreated plasma samples on an internal-surface reversed-phase (ISRP) column. The two methods were in good agreement. Unmodified I decreased from over 99% initially to less than 5%, 5–10% and 20% at 60 min post-injection in rats, sheep and human volunteers, respectively. Protein binding in sheep and human plasma was determined by ultrafiltration. The fraction of total plasma radioactivity bound to protein and the fraction representing unmodified radioligand were linearly correlated, suggesting that fluorocarazolol was more than 70% protein-bound, whereas its metabolites showed negligible protein binding. Direct injection of plasma on an ISRP column seems a convenient method for quantification of lipophilic radioligands such as fluorocarazolol.