Hochsensitives C-reaktives Protein in Schlaganfallkohorten

Introduction: Patients with ischemic stroke have a high risk of recurrent stroke and other vascular events. Currently, an accurate prediction of vascular risk in these patients is made difficult by the lack of markers with high prognostic value. High-sensitivity C-reactive protein (hs-CRP) has shown promise as a prognostic marker in both primary and secondary prevention of cardiovascular disease. Furthermore, as colchicine is emerging as a promising agent in secondary prevention in coronary disease, the association between inflammation and cerebrovascular disease needs to be examined more closely before similar interventions are applied for secondary stroke prevention. We systematically reviewed the existing literature to determine whether hs-CRP was associated with long-term vascular risk in ischemic stroke and transient ischemic attacks(TIA). Additionally, we conducted our own cohort study in Berlin to add to the available data. Methods: The EMBASE and Medline databases were searched on 21 February 2021 for case-control or cohort studies composed of ischemic stroke or TIA patients that measured hs- CRP levels at baseline, and recorded vascular events or death during ≥ 12 months of follow-up. For the cohort study, first-ever ischemic stroke patients were consecutively enrolled at the three Charité university hospitals and followed up for 3 years. Hs-CRP was measured at admission. Recorded vascular endpoints included myocardial infarcts, recurrent ischemic strokes, and allcause death. Results: 27 studies (15752 patients) were included in the meta-analysis. In the cohort study, 533 ischemic stroke patients were included. When the highest quartile was compared against the lowest, hs-CRP was associated with vascular events during follow-up (adjusted HR: 2.04, CI:1.01-4.14). Conclusion: There is evidence of an association between higher hs-CRP levels and increased vascular risk in patients with ischemic stroke or TIA, similar to the association seen in cardiovascular disease. This study adds to the evidence supporting the role of inflammation in the progression of cerebrovascular disease.Einleitung Patient(inn)en mit ischämischem Schlaganfall haben ein hohes Risiko für weitere Schlaganfälle und andere vaskuläre Ereignisse. Derzeit wird eine genaue Einschätzung des Rezidivrisikos bei diesen Patient(inn)en durch das Fehlen von Markern mit hohem prognostischen Wert erschwert. High-sensitivity C-reaktives Protein (hs-CRP) hat sich als prognostischer Marker sowohl bei der primären als auch bei der sekundären Prävention von Herz-Kreislauf-Erkrankungen als vielversprechend erwiesen. In dieser Studie wurde die vorhandene Literatur systematisch überprüft, um festzustellen, ob hs-CRP mit einem langfristigen vaskulären Risiko bei ischämischem Schlaganfall- und TIA-Patient(inn)en assoziiert ist. Zusätzlich haben wir in Berlin eine eigene Kohortenstudie durchgeführt, um die bereits verfügbaren Daten zu diesem Thema zu ergänzen. Methoden EMBASE- und Medline-Datenbanken wurden am 21. Februar 2021 nach Fallkontroll- oder Kohortenstudien durchsucht, die sich aus Patient(inn)en mit ischämischem Schlaganfall zusammensetzten, die den hs-CRP-Spiegel zu Studienbeginn gemessen haben und vaskuläre Ereignisse oder Todesfälle während einer Nachbeobachtungszeit von ≥ 12 Monaten aufgezeichnet haben. Für die Kohortenstudie wurden Patient(inn)en mit ischämischem Schlaganfall an unseren drei Standorten eingeschlossen, und 3 Jahre lang nachverfolgt. Der hs-CRP-Spiegel wurde bei Aufnahme gemessen. Zu den aufgezeichneten vaskulären Endpunkten gehörten Myokardinfarkte, wiederkehrende ischämische Schlaganfälle und Tod. Ergebnisse In die Meta-Analyse wurden 27 Studien mit 15752 Patient(inn)en eingeschlossen. In die Kohortenstudie wurden 533 Patient(inn)en mit ischämischem Schlaganfall eingeschlossen. Wenn das höchste hs-CRP-Quartil mit dem niedrigsten verglichen wurde, war hs-CRP mit vaskulären Ereignissen während des Follow-Ups assoziiert (adjustierte HR 4. vs. 1. Quartil: 2,06, CI: 1,01-4,14). Schlussfolgerung Es gibt Hinweise für einen Zusammenhang zwischen höheren hs-CRP-Spiegeln und einem erhöhten vaskulären Rezidivrisiko bei Patient(inn)en mit ischämischem Schlaganfall oder TIA, ähnlich der Assoziation bei Koronarerkrankungen. Diese Studie ergänzt die Evidenz, die die Rolle von Entzündungen beim Fortschreiten von zerebrovaskulären Erkrankungen unterstützt

3-(3-Chloro­phenyl­sulfin­yl)-2,4,6-trimethyl-1-benzofuran

In the title compound, C17H15ClO2S, the 3-chloro­phenyl ring makes a dihedral angle of 71.46 (4)° with the mean plane of the benzofuran fragment. In the crystal, mol­ecules are linked by weak C—H⋯O hydrogen bonds and a slipped π–π inter­action between the 3-chloro­phenyl rings of adjacent mol­ecules [centroid–centroid distance = 3.630 (2) Å, inter­planar distance = 3.375 (2) Å and slippage = 1.337 (2) Å]

2-(3-Fluoro­phen­yl)-5-iodo-7-methyl-3-methyl­sulfinyl-1-benzofuran

In the title compound, C16H12FIO2S, the 3-fluoro­phenyl ring makes a dihedral angle of 34.93 (7)° with the mean plane [r.m.s. deviation = 0.019 (1) Å] of the benzofuran fragment. In the crystal, mol­ecules are linked via pairs of I⋯O contacts [3.088 (2) Å] into inversion dimers. These dimers are connected by weak C—H⋯O hydrogen bonds

Sp1 up-regulates cAMP-response-element-binding protein expression during retinoic acid-induced mucous differentiation of normal human bronchial epithelial cells.

CREB [CRE (cAMP-response element)-binding protein] is an important transcription factor that is differentially regulated in cells of various types. We recently reported that RA (retinoic acid) rapidly activates CREB without using RARs (RA receptors) or RXRs (retinoid X receptors) in NHTBE cells (normal human tracheobronchial epithelial cells). However, little is known about the role of RA in the physiological regulation of CREB expression in the early mucous differentiation of NHTBE cells. In the present study, we report that RA up-regulates CREB gene expression and that, using 5\u27-serial deletion promoter analysis and mutagenesis analyses, two Sp1 (specificity protein 1)-binding sites located at nt -217 and -150, which flank the transcription initiation site, are essential for RA induction of CREB gene transcription. Furthermore, we found that CREs located at nt -119 and -98 contributed to basal promoter activity. Interestingly, RA also up-regulated Sp1 in a time- and dose-dependent manner. Knockdown of endogenous Sp1 using siRNA (small interfering RNA) decreased RA-induced CREB gene expression. However, the converse was not true: knockdown of CREB using CREB siRNA did not affect RA-induced Sp1 gene expression. We conclude that RA up-regulates CREB gene expression during the early stage of NHTBE cell differentiation and that RA-inducible Sp1 plays a major role in up-regulating human CREB gene expression. This result implies that co-operation of these two transcription factors plays a crucial role in mediating early events of normal mucous cell differentiation of bronchial epithelial cells

Methyl 2-(5-methyl-3-methyl­sulfinyl-1-benzofuran-2-yl)acetate

The title compound, C13H14O4S, was prepared by oxidation of methyl 2-(5-methyl-3-methyl­sulfanyl-1-benzofuran-2-yl)acetate with 3-chloro­peroxy­benzoic acid. The O atom and methyl group of the methyl­sulfinyl substituent lie on opposite sides of the plane of the benzofuran system. The crystal structure is stabilized by inter­molecular aromatic π–π inter­actions between the benzene rings of neighbouring mol­ecules, with a centroid–centroid separation of 3.841 (3) Å

5-Bromo-2-phenyl-3-phenyl­sulfinyl-1-benzofuran

In the title compound, C20H13BrO2S, the O atom and the phenyl group of the phenyl­sulfinyl substituent are located on opposite sides of the plane of the benzofuran system. The S-bound phenyl ring is almost perpendicular to this plane [80.35 (8)°]. The phenyl ring in the 2-position is twisted with respect to the benzofuran plane, making a dihedral angle of 16.0 (1)°

Ethyl 2-(5-bromo-3-ethyl­sulfinyl-1-benzofuran-2-yl)acetate

The title compound, C14H15BrO4S, was prepared by the oxidation of ethyl 2-(5-bromo-3-ethyl­sulfanyl-1-benzofuran-2-yl)acetate with 3-chloro­peroxy­benzoic acid. The crystal structure is stabilized by aromatic π–π inter­actions between the benzene rings of neighbouring mol­ecules [centroid–centroid distance = 3.814 (9) Å], and possibly by weak C—H⋯π inter­actions. In addition, the crystal structure exhibits three inter­molecular C—H⋯O non-classical hydrogen bonds. The ethyl group bonded to carboxyl­ate O atom is disordered over two positions, with refined site-occupancy factors of 0.686 (18) and 0.314 (18)

2-(3-Fluoro­phen­yl)-3-methyl­sulfanyl-5-phenyl-1-benzofuran

In the title compound, C21H15FOS, the dihedral angles between the mean plane of the benzofuran fragment and the pendant 3-fluoro­phenyl and phenyl rings are 1.76 (5) and 32.29 (5)°, respectively. In the crystal, mol­ecules are linked by a slipped π–π inter­action between the furan and benzene rings of neighbouring mol­ecules [centroid–centroid distance = 3.665 (2) Å, inter­planar distance = 3.391 (2) Å and slippage = 1.390 (2) Å]

2-Methyl-3-(phenyl­sulfon­yl)naphtho[1,2-b]furan

In the title mol­ecule, C19H14O3S, the phenyl ring forms a dihedral angle of 69.13 (6)° with the plane of the naphthofuran fragment, being slightly tilted towards it. The crystal packing exhibits π–π inter­actions between the benzene rings from neighbouring mol­ecules [centroid–centroid distance = 3.616 (4) Å] and weak C—H⋯O and C—H⋯π inter­actions

2-(5-Cyclo­hexyl-3-methyl­sulfanyl-1-benzofuran-2-yl)acetic acid

In the title compound, C17H20O3S, the cyclo­hexyl ring adopts a chair conformation. In the crystal, the carboxyl groups are involved in inter­molecular O—H⋯O hydrogen bonds, which link the mol­ecules into centrosymmetric dimers. These dimers are further stabilized by weak inter­molecular C—H⋯O hydrogen bonds. In addition, the crystal structure also exhibits aromatic π–π inter­actions between the furan rings of adjacent mol­ecules [centroid–centroid distance = 3.505 (2) Å, inter­planar distance = 3.385 (2) Å and slippage = 0.909 (2) Å], and inter­molecular C—H⋯π inter­actions