Publications by authors named "Alan D"

17 Publications

  • Page 1 of 1

Noncanonical open reading frames encode functional proteins essential for cancer cell survival.

Nat Biotechnol 2021 Jun 28;39(6):697-704. Epub 2021 Jan 28.

Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Although genomic analyses predict many noncanonical open reading frames (ORFs) in the human genome, it is unclear whether they encode biologically active proteins. Here we experimentally interrogated 553 candidates selected from noncanonical ORF datasets. Of these, 57 induced viability defects when knocked out in human cancer cell lines. Following ectopic expression, 257 showed evidence of protein expression and 401 induced gene expression changes. Clustered regularly interspaced short palindromic repeat (CRISPR) tiling and start codon mutagenesis indicated that their biological effects required translation as opposed to RNA-mediated effects. We found that one of these ORFs, G029442-renamed glycine-rich extracellular protein-1 (GREP1)-encodes a secreted protein highly expressed in breast cancer, and its knockout in 263 cancer cell lines showed preferential essentiality in breast cancer-derived lines. The secretome of GREP1-expressing cells has an increased abundance of the oncogenic cytokine GDF15, and GDF15 supplementation mitigated the growth-inhibitory effect of GREP1 knockout. Our experiments suggest that noncanonical ORFs can express biologically active proteins that are potential therapeutic targets.
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http://dx.doi.org/10.1038/s41587-020-00806-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195866PMC
June 2021

Predictors of long-term survival in patients treated with targeted temperature management after cardiac arrest.

Arch Med Sci 2020 18;16(5):1250-1253. Epub 2019 Feb 18.

2 Medical School, Charles University, Motol University Hospital, Prague, Czech Republic.

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http://dx.doi.org/10.5114/aoms.2019.81397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444699PMC
February 2019

Effects of menaquinone-7 supplementation in patients with aortic valve calcification: study protocol for a randomised controlled trial.

BMJ Open 2018 08 23;8(8):e022019. Epub 2018 Aug 23.

Centre for Individualized Medicine in Arterial Diseases, Odense Universitetshospital, Odense, Denmark.

Introduction: Aortic stenosis is a common heart valve disease, and due to the growing elderly population, the prevalence is increasing. The disease is progressive with increasing calcification of the valve cusps. A few attempts with medical preventive treatment have failed; thus, presently, the only effective treatment of aortic stenosis is surgery. This study will examine the effect of menaquinone-7 (MK-7) supplementation on progression of aortic valve calcification (AVC). We hypothesise that MK-7 supplementation will slow down the calcification process.

Methods And Analysis: In this multicenter and double-blinded, placebo-controlled study, 400 men aged 65-74 years with substantial AVC are randomised (1:1) to treatment with MK-7 (720 µg/day) supplemented by the recommended daily dose of vitamin D (25 µg/day) or placebo treatment (no active treatment) for 2 years. Exclusion criteria are treatment with vitamin K antagonist or coagulation disorders. To evaluate AVC score, a non-contrast CT scan is performed at baseline and repeated after 12 and 24 months of follow-up. Primary outcome is difference in AVC score from baseline to follow-up at 2 years. Intention-to-treat principle is used for all analyses.

Ethics And Dissemination: There are no reported adverse effects associated with the use of MK-7. The protocol is approved by the Regional Scientific Ethical Committee for Southern Denmark (S-20170059) and the Data Protection Agency (17/19010). It is conducted in accordance with the Declaration of Helsinki. Positive as well as negative findings will be reported.

Trial Registration Number: NCT03243890.
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http://dx.doi.org/10.1136/bmjopen-2018-022019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112404PMC
August 2018

History and current use of mild therapeutic hypothermia after cardiac arrest.

Arch Med Sci 2016 Oct 25;12(5):1135-1141. Epub 2016 Aug 25.

Department of Cardiology, 2 Medical School, Charles University, University Hospital Motol, Prague, Czech Republic.

In spite of many years of development and implementation of pre-hospital advanced life support programmes, the survival rate of out-of-hospital cardiac arrest (OHCA) used to be very poor. Neurologic injury from cerebral hypoxia is the most common cause of death in patients with OHCA. In the past two decades, post-resuscitation care has developed many new concepts aimed at improving the neurological outcome and survival rate of patients after cardiac arrest. Systematic post-cardiac arrest care after the return of spontaneous circulation, including induced mild therapeutic hypothermia (TH) in selected patients, is aimed at significantly improving rates of long-term neurologically intact survival. This review summarises the history and current knowledge in the field of mild TH after OHCA.
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http://dx.doi.org/10.5114/aoms.2016.61917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5016592PMC
October 2016

Ectopic gynaecomastia on the inner aspect of the thigh in an otherwise healthy man.

J Surg Case Rep 2012 Dec 11;2012(12). Epub 2012 Dec 11.

Breast Unit, Aberdeen Royal Infirmary, Aberdeen, UK

Gynaecomastia is a common examination finding in adult men. Supernumery breasts along the milk line are also identified frequently in the adult population. Here we report a case of ectopic gynaecomastia, away from the milk line. A 28-year-old man with no other health problems attended the general surgical clinic with a lump on the inner aspect of his left leg. This was thought to be a lipoma by the referring General Practitioner. It was however noted to have an associated nipple areolar complex and ultrasound confirmed mixed density breast tissue with no evidence of malignancy. Excision was undertaken and histopathology confirmed this to be breast tissue. In this case report, we report the first case of ectopic gynaecomastia in this region in an otherwise healthy man.
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http://dx.doi.org/10.1093/jscr/rjs025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3855010PMC
December 2012

Combined percutaneous treatment of atrial septal defect and pulmonic or aortic stenosis in adult patients.

Arch Med Sci 2010 Dec 29;6(6):976-80. Epub 2010 Dec 29.

Cardiology Department, Cardiovascular Center, University Hospital Motol, Prague, Czech Republic.

Combined atrial septal defect and pulmonic or aortic stenosis are relatively uncommon conditions in adult patients, with few reported cases of percutaneous treatment. We present two patients with secundum type atrial septal defect and concomitant pulmonic or aortic stenosis and their treatment by transcatheter techniques.
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http://dx.doi.org/10.5114/aoms.2010.19312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3302714PMC
December 2010

Alterations in serum selenium levels and their relation to troponin I in acute myocardial infarction.

Mol Cell Biochem 2010 Dec 1;345(1-2):23-7. Epub 2010 Aug 1.

Department of Cardiology, Cardiovascular Center, Na Homolce Hospital, Prague, Czech Republic.

Selenium (Se) is an essential trace element with antioxidant function. The aim of the present study was to estimate the alterations of Se serum level during the acute phase of myocardial infarction and its relation to biomarkers of myocardial necrosis. Serum Se levels were measured at admission and after 24 h in 60 consecutive patients with acute coronary syndrome (both with and without ST elevation). Troponin I (TnI) was assessed at admission and then twice daily for 3 days; patients with normal levels were excluded. Fifty-five patients with acute MI (positive TnI) were included into the analysis. During the first day of hospitalization, patients received standard therapy, including acetylsalicylic acid, clopidogrel, and heparin or enoxaparin; all underwent urgent coronary angiography and percutaneous intervention, when appropriate. Mean Se levels at baseline and 24 h later were comparable (67.1 ± 2.1 vs. 67.2 ± 1.8 μg/L, ns). Linear regression has shown significant correlation between baseline Se levels and peak TnI (y = 3.4x - 116, r (2) = 0.13, P = 0.008). Positive correlation was found also between the peak TnI and the difference from baseline to 24 h (y = 2.2x + 115, r (2) = 0.08, P = 0.04). Moreover, close negative correlation was observed between baseline Se levels and the difference from baseline to 24 h (y = -0.9x + 62.7, r (2) = 0.55, P<0.001). Our results have shown marked individual changes in Se levels during the acute phase of MI as well as correlation between Se levels and peak TnI. These results suggest that alterations in serum Se may be related to the extent of myocardial infarction.
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http://dx.doi.org/10.1007/s11010-010-0555-xDOI Listing
December 2010

Fluvastatin in the first-line therapy of acute coronary syndrome: results of the multicenter, randomized, double-blind, placebo-controlled trial (the FACS-trial).

Trials 2010 May 25;11:61. Epub 2010 May 25.

Heart Center, Department of Cardiology, Na Homolce Hospital, Prague, Czech Republic.

Background: Statins have been proved to be effective in reduction of mortality and morbidity when started in the early secondary prevention in stabilized patients after acute coronary syndrome (ACS). The safety and efficacy of statin administration directly in the first-line therapy in unstable ACS patients is not clear. The aim of our study was, therefore, to assess the effect of statin treatment initiated immediately at hospital admission of patients with ACS.

Methods: The trial was stopped prematurely after enrollment of one hundred and fifty-six patients with ACS that were randomized at admission to fluvastatin 80 mg (N = 78) or placebo (N = 78). Study medication was administered immediately after randomization and then once daily for 30 days; all patients were then encouraged to continue in open-label statin therapy and at the end of one-year follow-up 75% in the fluvastatin group and 78% in the placebo group were on statin therapy.

Results: We did not demonstrate any difference between groups in the level of C-reactive protein, interleukin 6, and pregnancy-associated plasma protein A on Day 2 and Day 30 (primary endpoint). Fluvastatin-therapy, however, significantly reduced one-year occurrence of major adverse cardiovascular events (11.5% vs. 24.4%, odds ratio (OR) 0.40, 95% CI 0.17-0.95, P = 0.038). This difference was caused mainly by reduction of recurrent symptomatic ischemia (7.7% vs. 20.5%, OR 0.32, 95% CI 0.12-0.88, P = 0.037).

Conclusions: This study failed to prove the effect of fluvastatin given as first-line therapy of ACS on serum markers of inflammation and plaque instability. Fluvastatin therapy was, however, safe and it may reduce cardiovascular event rate that supports immediate use of a statin in patients admitted for ACS.

Trial Registration: NCT00171275.
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http://dx.doi.org/10.1186/1745-6215-11-61DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2886041PMC
May 2010

Sonographic assessment of renal growth in patients with Beckwith-Wiedemann syndrome: the Beckwith-Wiedemann syndrome renal nomogram.

Clinics (Sao Paulo) 2009 ;64(1):41-4

Alberta Children's Hospital, Toronto, Ontario, Canada.

Background: Beckwith-Wiedemann syndrome is a disorder of somatic overgrowth. Evidence of kidney overgrowth is a diagnostic criterion that may be used to help identify those patients who are at the greatest risk of developing Wilms tumors. In such subjects, kidney size is typically larger than that of age-matched normal controls.

Objective: The purpose of our study was to generate a nomogram that could be used to measure renal dimensions in children with Beckwith-Wiedemann syndrome in a clinical setting.

Materials & Methods: All of the Beckwith-Wiedemann syndrome patients followed at our institution from 1996 to 2004 were eligible for inclusion in our study. Renal length was measured with a curvilinear transducer and with the patient supine. Renal lengths were measured for both kidneys using real-time ultrasound for all patients. Their data were compared with those of age-matched controls reported in the 1984 study by Rosenbaum et al.

Results: Ninety-six children with Beckwith-Wiedemann syndrome were followed from 1996 to 2004. Forty-three of these patients met our criteria for inclusion in the study: 28 girls (65%) and 15 boys (35%). We identified a linear relationship between kidney length and patient age. No statistically significant differences in renal length were found between boys and girls (p=0.2153) or between the kidneys on either side of the body (p=0.9613).

Conclusion: Our study provides a practical, simple renal growth chart that offers a reasonable, sensitive method for evaluating kidney size in children with Beckwith-Wiedemann syndrome.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2671979PMC
http://dx.doi.org/10.1590/s1807-59322009000100008DOI Listing
August 2009

Treatment of a large left main coronary artery thrombus by aspiration thrombectomy.

J Thromb Thrombolysis 2009 Apr 10;27(3):352-4. Epub 2008 Mar 10.

Cardiovascular Center, Department of Cardiology, 1st Medical School of Charles University and University Hospital Motol, Prague, Czech Republic.

A left main coronary artery thrombosis is a life-threatening condition demanding immediate therapeutic management. Traditional treatment options include thrombolysis, percutaneous coronary intervention (PCI) with stenting or cardiac bypass surgery. The number of reported cases in which aspiration thrombectomy has been used is limited. Indications for this therapeutic approach are determined by coronary anatomy, clinical stability, and hemodynamic condition of the patient. We present the case of an acute left main coronary artery thrombosis leading to progressive deterioration of left ventricle function that was successfully treated with aspiration thrombectomy.
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http://dx.doi.org/10.1007/s11239-008-0209-yDOI Listing
April 2009

Anti-Xa activity of enoxaparin and nadroparin in patients with acute coronary syndrome.

Exp Clin Cardiol 2008 ;13(4):175-8

Department of Cardiology, Charles University in Prague, 2nd Faculty of Medicine & University Hospital Motol, Prague, Czech Republic.

Background: Clinical studies have clearly revealed that low-molecular-weight heparins (LMWHs) are an effective alternative to unfractionated heparin in the therapy of acute coronary syndrome (ACS); however, data on the comparison of different LMWHs are sparse.

Aim: To compare the inhibition of coagulation factor Xa by enoxaparin and nadroparin in the therapy of ACS.

Methods: Thirty-eight consecutive patients with ACS were randomly assigned to enoxaparin (group E, n=18) or nadroparin (group N, n=20) in the recommended dose. Anti-Xa activity was measured 3 h after administering the first dose of LMWH.

Results: Baseline demographics (age, sex) and clinical (type of ACS, pain-to-door time, elevation of troponin, percutaneous coronary intervention performed, smoking status, and history of diabetes, hypertension and hyperlipoproteinemia) characteristics were similar in both groups. Anti-Xa activity was significantly higher in group E than in group N (0.65+/-0.05 U/mL versus 0.30+/-0.03 U/mL; P<0.001). Moreover, the therapeutic target (0.5 U/mL to 0.8 U/mL) was achieved in 66.7% of patients in group E; on the other hand, effective therapy was observed in 10.0% of patients in group N (P<0.001).

Conclusions: The results of the present study demonstrate a highly significant difference in anti-Xa activity of enoxaparin and nadroparin in their recommended dosing regimens, in the therapy of ACS 3 h after subcutaneous administration; the anticoagulant effect of enoxaparin was markedly stronger than that of nadroparin.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663480PMC
July 2011

Multiple mobile aortic thrombosis treated by thrombolysis. A case report.

J Thromb Thrombolysis 2007 Dec 20;24(3):315-6. Epub 2007 Sep 20.

Department of Cardiology, Cardiovascular Center, University Hospital Motol, V Uvalu 84, Prague 5 150 06, Czech Republic.

Mobile aortic thrombosis is a relatively rare condition with a high morbidity particularly due to peripheral embolisation. The most frequent management is anticoagulant or surgical therapy but the number of cases reported is limited and therapeutic approaches are still not well established. We present a case of large multiple mobile pedunculated thrombosis in descending aorta treated by thrombolysis.
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http://dx.doi.org/10.1007/s11239-007-0091-zDOI Listing
December 2007

Immediate effect of fluvastatin on lipid levels in acute coronary syndrome.

Mol Cell Biochem 2007 Dec 25;306(1-2):19-23. Epub 2007 Jul 25.

Department of Cardiology, Charles University in Prague, 2nd Faculty of Medicine & University Hospital Motol, Prague, Czech Republic.

It is widely assumed that acute benefit of statin therapy is mediated especially by non-lipid effects. The immediate influence of statins on lipid levels in patients with acute coronary syndrome (ACS) is, however, not clear. A total of 64 consecutive patients with ACS were randomized at admission to fluvastatin 80 mg (Group 1, N = 32) or standard therapy without statin (Group 2, N = 32). The levels of total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), high-density-lipoprotein cholesterol (HDL-C), and triglycerides (TG) were examined at admission and after 24 h. Baseline characteristics were comparable in both groups. In Group 1, fluvastatin significantly decreased the levels of TC by 14.5%, LDL-C by 17.2%, and HDL-C by 10.0% (P < 0.001); TG were not influenced. In Group 2 only marginal reductions in TC (by 4.1%, P = 0.03) and HDL-C (by 7.5%, P < 0.01) were detected; the levels of LDL-C and TG were not changed. As compared with Group 2, in Group 1 the final levels of TC (P = 0.02) and LDL-C (P = 0.01) were significantly lower. Fluvastatin therapy, when started at admission in patients with ACS, significantly reduces TC and LDL-C already after 24 h. We suggest that the lipid-lowering effect of statins in the therapy of ACS is probably as prompt as non-lipid effects.
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http://dx.doi.org/10.1007/s11010-007-9549-8DOI Listing
December 2007

Pregnancy-associated plasma protein A and proform eosinophilic major basic protein in the detection of different types of coronary artery disease.

Physiol Res 2008 2;57(1):23-32. Epub 2007 Jan 2.

Department of Cardiology, Second Medical School and University Hospital of Charles University Prague, CzechRepublic.

Kryptor system was proven to be a rapid, standard method for pregnancy-associated plasma protein A and proform eosinophilic major basic protein (PAPP-A/proMBP) complex detection in coronary artery disease (CAD). No age and/or gender differences in 51 controls and 110 stable coronary artery disease (SCAD) patients were found. SCAD patients did not differ from controls and no difference in PAPP-A/proMBP levels with regards to the number of affected vessels was found. In 21 unstable angina pectoris (UAP), in 35 without and 66 with ST elevation acute myocardial infarctions (NSTEMI, STEMI respectively) patients PAPP-A/proMBP levels were increased (P=0.004 and P<0.0005, respectively). PAPP-A/proMBP levels did not correlate with cardiac troponin I (cTnI) in STEMI and NSTEMI patients. PAPP-A/ proMBP increase was more frequent than cTnI (P=0.036) within the early phase of STEMI. In NSTEMI patients PAPP-A/proMBP positivity was present in 50% of cTnI negative cases. Receiver operating characteristic (ROC) analysis revealed the highest diagnostic accuracy of PAPP-A/proMBP (0.919) in STEMI cTnI positive cases. The highest specificity/sensitivity PAPP-A/proMBP levels for particular acute coronary syndrome (ACS) types were 10.65-14.75 mIU/l. Combination of PAPP-A/proMBP with cTnI increases their diagnostic efficacy within the early phase of ACS. Our results suggest that PAPP-A/proMBP complex is involved in processes preceding vulnerable plaque development in ACS.
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http://dx.doi.org/10.33549/physiolres.930986DOI Listing
October 2008

Statins in the first-line therapy of acute coronary syndrome - similar to aspirin?

Exp Clin Cardiol 2005 ;10(1):9-16

Department of Cardiology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.

Statins are cholesterol-lowering drugs, highly effective in the primary and secondary prevention of coronary artery disease. It has been found, however, that statins also have nonlipid effects; they can influence different pathways, which have been described to participate in the pathogenesis of acute coronary syndrome (ACS). Inflammation or decreased production of nitric oxide are obvious targets for statin therapy. Recently, several large clinical trials have been published, showing safety and, in some areas, efficacy of administration of statins early after ACS. Furthermore, there is growing evidence from both experimental and small clinical studies that statin therapy may have favourable effects when started as soon as possible after the development of ACS. Confirmation of this approach by large randomized trials is needed; however, based on currently available data, statins have high chance of achieving a similar place in the first-line therapy of ACS as the pillar of contemporary therapeutic strategy, aspirin.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716222PMC
July 2011

Fluvastatin in the therapy of acute coronary syndrome: Rationale and design of a multicenter, randomized, double-blind, placebo-controlled trial (The FACS Trial)[ISRCTN81331696].

Curr Control Trials Cardiovasc Med 2005 Mar 24;6(1). Epub 2005 Mar 24.

Department of Cardiology, University Hospital Motol and Charles University, 2nd Faculty of Medicine, Prague, Czech Republic.

BACKGROUND: Activation of inflammatory pathways plays an important contributory role in coronary plaque instability and subsequent rupture, which can lead to the development of acute coronary syndrome (ACS). Elevated levels of serum inflammatory markers such as C-reactive protein (CRP) represent independent risk factors for further cardiovascular events. Recent evidence indicates that in addition to lowering cholesterol levels, statins also decrease levels of inflammatory markers. Previous controlled clinical trials reporting the positive effects of statins in participants with ACS were designed for very early secondary prevention. To our knowledge, no controlled trials have evaluated the potential benefits of statin therapy, beginning immediately at the time of hospital admission. A previous pilot study performed by our group focused on early initiation of cerivastatin therapy. We demonstrated a highly significant reduction in levels of inflammatory markers (CRP and interleukin-6). Based on these preliminary findings, we are conducting a clinical trial to evaluate the efficacy of another statin, fluvastatin, as an early intervention in patients with ACS. METHODS: The FACS-trial (Fluvastatin in the therapy of Acute Coronary Syndrome) is a multicenter, randomized, double-blind, placebo-controlled study evaluating the effects of fluvastatin therapy initiated at the time of hospital admission. The study will enroll 1,000 participants admitted to hospital for ACS (both with and without ST elevation). The primary endpoint for the study is the influence of fluvastatin therapy on levels of inflammatory markers (CRP and interleukin-6) and on pregnancy associated plasma protein A (PAPP-A). A combined secondary endpoint is 30-day and one-year occurrence of death, nonfatal myocardial infarction, recurrent symptomatic ischemia, urgent revascularization, and cardiac arrest. CONCLUSION: The primary objective of the FACS trial is to demonstrate that statin therapy, when started immediately after hospital admission for ACS, results in reduction of inflammation and improvement of prognosis. This study may contribute to new knowledge regarding therapeutic strategies for patients suffering from ACS and may offer additional clinical indications for the use of statins.
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http://dx.doi.org/10.1186/1468-6708-6-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC555952PMC
March 2005

The effect of early treatment by cerivastatin on the serum level of C-reactive protein, interleukin-6, and interleukin-8 in the patients with unstable angina and non-Q-wave myocardial infarction.

Mol Cell Biochem 2003 Apr;246(1-2):45-50

Department of Internal Medicine, University Hospital Motol, 2nd Medical Faculty, Charles University, Prague, Czech Republic.

The aim of our study was to evaluate whether a single dose of cerivastatin at the time of admission of patients with unstable angina pectoris (UAP) or non-Q-wave myocardial infarction (NQMI) can influence the serum level of C-reactive protein (CRP), interleukin-6 (IL-6) and interleukin-8 (IL-8) 24 h later. Forty-four patients with rest chest pain and subendocardial ischemia on ECG were randomized to receive cerivastatin 0.3 mg at the time of admission (group C+) to standard therapy or to remain just on standard therapy (group C-). Blood samples for determination of troponin I (TI), CRP, IL-6 and IL-8 were collected at admission (entry level) and 24 h later (final level). Patients with non-physiological baseline levels of TI, as well as patients with progression to Q wave MI were excluded. All baseline, clinical and demographic data and final values of TI were comparable in the two groups. In patients treated with cerivastatin (group C+, n = 13) we observed decrease in the CRP level (-6.73 +/- 3.93 mg/L); on the other hand, in group C- (n = 17) the CRP level increased (+7.92 +/- 2.77 mg/L, p = 0.004). Similar differences were observed also in IL-6: in group C+ the level was significantly reduced as compared with the increase in group C- (-0.76 +/- 0.52 vs. 4.58 +/- 1.49 ng/L, p = 0.005). The level of IL-8 was not affected. Our results suggest that early treatment with cerivastatin can decrease the serum level of CRP and IL-6 in patients with UAP/NQMI; this might positively influence their prognosis. Nevertheless, further studies are needed to support this hypothesis.
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