Efficacy and safety of switching between biologics in chronic rhinosinusitis with nasal polyps or N-ERD.

BACKGROUND AND OBJECTIVE: The effectiveness of biologics in chronic rhinosinusitis with nasal polyps (CRSwNP) is well-established. However, real-world experience on the effectiveness of transitioning between two monoclonal antibodies is scarce. Therefore, we aimed to analyze the safety and efficacy of antibody switching in treatment of chronic rhinosinusitis. METHODS: All patients with CRSwNP or nonsteroidal anti-inflammatory drugs-exacerbated respiratory disease (N-ERD) requiring a switch between biologics were retrospectively studied. Analysis included changes in polyp size, quality of life parameters, asthma control, and side effects. RESULTS: Out of 195 patients treated with biologics for CRSwNP or N-ERD in our center, 23 (11.8%) required transition to a different monoclonal antibody. The majority switched from omalizumab to dupilumab (17/23, 73.9%), mostly due to inadequate symptom control. Nine out of these 17 patients (52.9%) were switched without a washout period. All patients showed significant improvement in nasal polyp score, asthma control test and sino-nasal outcome test-22 after changing to dupilumab. Keratoconjunctivitis sicca was the side-effect (4.3%) reported after the switch from omalizumab to dupilumab, which lead to termination of therapy in one patient. Due to limited sample size, other antibody transitions were reported in a descriptive manner. CONCLUSION: The transition to dupilumab is an effective option in patients with inadequate treatment response or side-effects of omalizumab in nasal polyposis. Our preliminary results indicate that a wash-out period may not be necessary when switching between biologics, however, these findings require further investigations. Other monoclonal antibody transitions also show promising results, but warrant validations in larger cohorts due to small patient samples in our study.

Traditional risk factors of acute coronary syndrome in four different male populations - total cholesterol value does not seem to be relevant risk factor.

Cardiovascular diseases are the most common cause of mortality and morbidity in most populations. As the traditional modifiable risk factors (smoking, hypertension, dyslipidemia, diabetes mellitus, and obesity) were defined decades ago, we decided to analyze recent data in patients who survived acute coronary syndrome (ACS). The Czech part of the study included data from 999 males, and compared them with the post-MONICA study (1,259 males, representing general population). The Lithuanian study included 479 male patients and 456 age-matched controls. The Kazakhstan part included 232 patients and 413 controls. In two countries, the most robust ACS risk factor was smoking (OR 3.85 in the Czech study and 5.76 in the Lithuanian study), followed by diabetes (OR 2.26 and 2.07) and hypertension (moderate risk elevation with OR 1.43 and 1.49). These factors did not influence the ACS risk in Kazakhstan. BMI had no significant effect on ACS and plasma cholesterol was surprisingly significantly lower (P<0.001) in patients than in controls in all countries (4.80+/-1.11 vs. 5.76+/-1.06 mmol/l in Czechs; 5.32+/-1.32 vs. 5.71+/-1.08 mmol/l in Lithuanians; 4.88+/-1.05 vs. 5.38+/-1.13 mmol/l in Kazakhs/Russians). Results from our study indicate substantial heterogeneity regarding major CVD risk factors in different populations with the exception of plasma total cholesterol which was inversely associated with ACS risk in all involved groups. These data reflect ethnical and geographical differences as well as changing pattern of cardiovascular risk profiles.

Gene variants at FTO, 9p21, and 2q36.3 are age-independently associated with myocardial infarction in Czech men.

AIM: Cardiovascular disease (CVD) is a major cause of morbidity and mortality in developed countries. This study aimed to confirm the effect of common putative CVD-associated gene variants (FTO rs17817449, KIF6 rs20455, 9p21 rs10757274 and 2q36.3 rs2943634) on CVD manifestation, and determine whether this effect differs between younger (< 50 years) and older CVD patients. METHODS: 1191 controls and 1889 MI patients were analyzed. All participants were Caucasian Czech males aged <65 years (532 were <50 years) who were examined at cardiology clinics in Prague, Czech Republic. Variants of FTO, 9p21, 2q36.3, and KIF-6 were genotyped using PCR-RFLP or TaqMan assay. RESULTS: Variants of FTO (OR 1.48; 95% CI, 1.19-1.84 in a TT vs. GG comparison, p=0.0005); 9p21 (OR 1.74; 95% CI, 1.41-2.14 in an AA vs. GG comparison, p=0.0001); and 2q36.3 (OR 1.34; 95%CI, 1.09-1.65 in an AA vs. +C comparison, p=0.006) were significantly associated with MI in the male Czech population. In contrast, genotype frequencies of KIF-6 (rs20455) were the same in patients and controls (P=1.00). Nearly identical results were observed when a subset of young MI patients (N=532, aged <50 years) was analyzed. CONCLUSION: We confirmed the importance of determining FTO, 9p21, and 2q36.3 variants as part of the genetic determination of MI risk in the Czech male population.

Rs6922269 marker at the MTHFD1L gene predict cardiovascular mortality in males after acute coronary syndrome.

Myocardial infarction (MI) is the leading cause of death in industrialized countries. All the traditional risk factors for MI are responsible for approximately 50% of cases of MI cases. Attention therefore has recently focused on genetic variants that are not associated with conventional risk factors. One of them is the marker rs6922269, which has been suggested as a risk factor for development of MI in Western populations. We analyzed the relationship between rs6922269 variant on MTHFD1L gene and (i) risk of the acute coronary syndrome (ACS) in the Czech population and (ii) mortality in 7 years follow up. Rs6922269 (G>A) variant was analyzed (CR 99.3% for patients and 98.0% for controls) by PCR-RFLP in consecutively examined 1614 men and 503 women with ACS (age below 65 years) and in population-based controls--1191 men and 1368 women (aged up to 65 years). ANOVA and Chi square were used for statistical analysis. The genotype frequencies were almost identical (P=0.87) in the ACS patients and in controls and no differences were observed, if males (P=0.73) and females (P=0.93) were analysed separately. In addition, rs6922269 polymorphism was not associated with the classical risk factors (dyslipidemia, hypertension, obesity, smoking, diabetes) in control population. Cardiovascular mortality was significantly higher in males, carriers of the AA genotype (P<0.001, OR 2.52, 95% CI 1.40-4.55, for AA vs. +G). We conclude, that rs6922269 variant at MTHFD1L gene could be an important prognostic factor for cardiovascular mortality in patients after ACS.

Association between a marker on chromosome 9 and acute coronary syndrome. confirmatory study on Czech population.

Myocardial infarction (MI) is the leading cause of death in industrialized countries. All the classical risk factors for MI are responsible for approximately 50 % of MI cases. Attention has therefore recently been attracted to those genetic variants that are not associated with conventional risk factors. One of them is the marker rs10757274 in the "genefree" zone on chromosome 9, which has been repeatedly recognized as a risk factor for development of MI in Western populations. We analysed the relationship between the rs10757274 variant on chromosome 9 and risk of the acute coronary syndrome (ACS) in Czech population. The rs10757274 (A > G) variant was successfully analysed (CR = 99.4 % for patients and 98.4 % for controls) by PCR-RFLP in consecutively examined 1,046 men and 281 women with ACS (age below 65 years) and in population-based controls - 1,162 men and 1,355 women (aged up to 65 years). ANOVA and χ2 were used for statistical analysis. We confirmed that GG homozygotes are more frequent (codominant model of analysis) among patients with myocardial infarction than in the control group both in men (28.5 % vs. 22.0 %, P = 0.0001, OR 1.73, 95 % CI 1.36-2.19) and women (32.0 % vs. 24.6 %, P = 0.02, OR 1.62, 95 % CI 1.13-2.34). However, rs10757274 polymorphism was not associated with the classical risk factors either in control population or in ACS patients. We conclude that the rs10757274 variant at 9p23.1 is an important genetic risk factor for ACS development in the Czech population.

Sudden cardiac death thirty years ago and at present. The role of autonomic disturbances in acute myocardial infarction revisited.

The most common cause of sudden cardiac death is ventricular fibrillation (VF). In addition to the status, size and location of the ventricular focus, a major pathogenic mechanism triggering VF is autonomic dysbalance (disturbance). This term refers to a wide range of reflex changes in the ratio of sympathetic to vagal ventricular activation over time, occurring immediately after coronary artery occlusion at the onset of acute myocardial infarction (AMI). Another trigger of VF is autonomic disturbance due to emotional stress. Experimental and clinical research into autonomic disturbances associated with coronary artery occlusion and emotional stress was given considerable attention as early as some 30 years ago when researchers were already searching for ways of inhibiting autonomic disturbances using predominant sympathetic and vagal activation by beta-blockers (BB) and atropine, respectively. The aim of our paper is to compare results obtained 30 years ago with current status of experimental and clinical research into SCD prevention. Another aim is to identify questions that have remained unanswered to date; answers to these outstanding questions could help further reduce the risk of SCD.

Why we are not able to find the coronary heart disease gene - apoE as an example.

The apoprotein E gene ranks among the most discussed candidate genes for cardiovascular disease. We studied whether the association between apoprotein E gene polymorphism and manifestation of acute coronary syndrome is modulated by the presence/absence of traditional cardiovascular risk factors. The population under study were 1066 patients (men under 65 years) admitted between 2006- 2009 to five coronary care units in Prague (GENetic DEtermination of Myocardial Infarction in Prague) and the control population (1066 age-matched men selected from the Czech population sample). The frequency of disadvantage genotype E4+ was significantly higher (P < 0.01) in acute coronary syndrome patients (22.38 %) than in controls (16.76 %). When the acute coronary syndrome group was step by step limited to non-smokers, non-diabetics and normotensive individuals, the odds ratio displayed a gradual increase from 1.35 (for the entire group) through 1.48 (non-smokers), 1.53 (non-smokers+non-diabetics) to 1.71 (non-smokers+non-diabetics+normotensives). The effect of the apoprotein E gene on the individual risk of acute coronary syndrome is nonhomogenous within the patient groups. This association of apoprotein E gene with acute coronary syndrome is strongly modified by the presence/absence of traditional cardiovascular factors of atherosclerosis in a high-risk Czech population.

Apolipoprotein E Arg136 --> Cys in individuals with premature myocardial infarction.

Coronary artery disease is a serious health problem worldwide caused by interactions between genetic and environmental risk factors. One of the candidate genes is the gene for apolipoprotein E. We present a case report of two young smoking and obese carriers (man 45 years and woman 32 years old) of the apolipoprotein E (p.Arg136Cys) mutation, but with no severe dyslipidaemias detected among 1,671 survivors (1,483 men, 188 women, aged 21-75 years) of acute coronary syndrome screened for genetic and traditional cardiovascular risk factors. Between acute coronary syndrome survivors, the mutation has not yet been described. Even though this mutation raises suspicion to be a risk factor for cardiovascular disease (based on previous publications), its frequency was very low and similar to the control population (12 detected carriers of the mutation within the 9,386 screened individuals). Therefore, whether this rare mutation is causal for the development of myocardial infarction needs to be further evaluated.

Effects of substituted cyclodextrins on the separation of aromatic sulphonic acids by capillary zone electrophoresis.

Effects of the addition of various additives in the working electrolyte on the selectivity of capillary electrophoretic separation of naphthalenesulphonic acids used as intermediates in the production of synthetic dyes were investigated. Cyclodextrins form inclusion complexes with various compounds and are not only excellent chiral selectors, but have been also successfully applied for separations of positional isomers. In this work, methyl-beta-cyclodextrin, heptakis(2,6-di-O-methyl)-beta-cyclodextrin, heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin, (2-hydroxypropyl)-beta-cyclodextrin and (2-hydroxypropyl)-gamma-cyclodextrin were studied as isomeric selector additives and compared with unsubstituted beta-cyclodextrin. In addition to the size of the cyclodextrin cavity, the number and type of the substituents in the cyclodextrin molecules strongly affect the separation of isomeric naphthalenesulphonic acids, but the effect of the substituted cyclodextrins on the separation selectivity is different for various types of sulphonic acids. Best separations of non-substituted naphthalenesulphonic acids were achieved in a borate buffer with methyl-beta-cyclodextrin, whereas the running buffer with non-substituted beta-cyclodextrin provides superior separation of amino and hydroxynaphthalenesulphonic acids.

Percutaneous coronary intervention in the current era compared with 1985-1986: the National Heart, Lung, and Blood Institute Registries.

BACKGROUND: Although refinements have occurred in coronary angioplasty over the past decade, little is known about whether these changes have affected outcomes. METHODS AND RESULTS: Baseline features and in-hospital and 1-year outcomes of 1559 consecutive patients in the 1997-1998 Dynamic Registry who were having first coronary intervention were compared with 2431 patients in the 1985-1986 National Heart, Lung, and Blood Institute Registry. Compared with patients in the 1985-1986 Registry, Dynamic Registry patients were older (mean age, 62 versus 58 years; P:<0.001) and more often female (32.1% versus 25.5%; P:<0.001). In the Dynamic Registry, procedures were more often performed for acute myocardial infarction (22.9% versus 9.9%; P:<0.001) and treated lesions were more severe (84.5% versus 82.5% diameter reduction; P:<0.001), thrombotic (22.1% versus 11.3%; P:<0.001) or calcified (29.5% versus 10.8%; P:<0.001). Stents were used in 70.5% of Dynamic Registry patients, whereas 1985-1986 patients received balloon angioplasty alone. Procedural success was higher in the Dynamic Registry (92.0% versus 81.8%; P:<0.001) and the rate of in-hospital death, myocardial infarction, and emergency coronary bypass surgery combined was lower (4.9% versus 7.9%; P:=0.001) than in the 1985-1986 Registry. The 1-year rate for CABG was lower in the Dynamic Registry (6.9% versus 12.6%; P:<0.001). CONCLUSIONS: Although Dynamic Registry patients had more unstable and complex coronary disease than those in the 1985-1986 Registry, their rate of procedural success was higher whereas rates of complications and subsequent CABG were lower. Results of percutaneous coronary intervention have improved substantially over the past decade.

C(-260)-->T polymorphism in the promoter of the CD14 monocyte receptor gene as a risk factor for myocardial infarction.

BACKGROUND: The CD14 receptor of monocytes is an important mediator for the activation of monocytes/macrophages by endotoxins from the envelope of Gram-negative bacteria (lipopolysaccharides). We identified a polymorphism in the CD14 receptor and examined whether this genetic marker influenced the expression of the CD14 receptor on monocytes and affected the predisposition to myocardial infarction. METHODS AND RESULTS: We identified a C(-260)-->T nucleotide change, creating a HaeIII polymorphism in the promoter of the CD14 gene. The polymorphism was determined in 178 male patients <65 years old (cases; average age, 55.9+/-6.3 years) at the time of their first myocardial infarction and in 135 representative selected male control subjects (controls; average age, 55.2+/-11.5 years). The frequency of the T allele (absence of the cutting site) was 0.49 in cases and 0.35 in controls (P=0.0005; OR, 1.781; 95% CI, 1.286 to 2.465). Subsequently, we measured the expression of monocyte CD14 by flow cytometry in 18 volunteers with different CD14 genotypes. A significantly higher density of the CD14 receptor was shown in the T/T homozygotes than in the others (P=0.0028). CONCLUSIONS: A higher frequency of allele T(-260) in the promoter of the CD14 receptor gene was found in myocardial infarction survivors than in controls. At the same time, this variation was associated with a higher density of CD14 receptors in healthy volunteers. Therefore, we can conclude that in addition to the well-established risk factors, a genetically determined reaction of monocytes/macrophages to infectious stimuli could play an important role in the process of atherosclerosis.

Catheter-based fixation of the mitral valve after acute papillary muscle rupture: a new technique for temporary hemodynamic stabilization.

We describe a new, catheter-based method for temporary management of hemodynamic instability after papillary muscle rupture in a patient with an acute myocardial infarction.

[Congenital coronary artery aneurysm: a rare cause of acute myocardial infarct]. / Kongenitales Koronararterienaneurysma: Eine seltene Ursache des akuten Myokardinfarktes.

An 18-year-old female presented with acute posterior wall infarction after exercise stress. Coronary angiography showed an aneurysm of the proximal right coronary artery partially occluded with thrombi, followed by a complete occlusion of the vessel. The left coronary artery was normal. Despite immediate intracoronary thrombolysis she developed a large posterior wall necrosis. Angiographic follow-up revealed worsening left ventricular function but not progression of the aneurysmatic ectasia. The diagnosis congenital coronary artery aneurysm was made since there was no evidence for an atherosclerotic, infectious or inflammatory vascular disease. The patient was treated conservatively and within 2 years of follow-up the clinical course was uneventful.

[Heart transplantation at the Institute of Clinical and Experimental Medicine in Prague]. / Transplantace srdce v Institutu klinické a experimentální medicíny v Praze.

In the Institute of Clinical and Experimental Medicine in Prague 101 orthotopic allotransplantations of the heart were performed in 100 patients (87 men and 13 women). The reason for transplantation were terminal stages in the first place dilated cardiomyopathies and ischaemic heart disease. 58% of the patients survive after transplantation, the mortality rate is 42%. The highest mortality is in the early postoperative period (within two weeks after operation)--21 cases (50%). The longest survival period is nine years and six months. All patients have cyclosporin immunosuppressive treatment (in combination with another drug, later with another two drugs). In the authors' group in particular incipient acute rejections are encountered, "mild" rejections are less frequent and "moderate" rejections least frequent. The patients do not reach the stage of advanced acute rejection, i.e. "severe" rejection. Acute rejections are treated as a rule with 3 g Urbason. After this treatment acute rejection improves as a rule completely after one or two weeks therapy.

[Pericardial puncture under echocardiographic control]. / Punkce perikardu pod echokardiografickou kontrolou.

The authors summarize their hitherto assembled experience with pericardiocentesis under echocardiographic control. From May 1986 to December 1991 they made these punctures 55 times in 49 patients. In the majority therapeutic puncture was involved, only seven times puncture was used for diagnostic purposes. Echocardiography can evaluate not only the presence of an exudate and assess its haemodynamic impact but it is the optimal method for finding an optimal site for puncture and it is very suitable for checking the course of the operation. In smaller operations and in biopsies of pathological pericardial tissue it is advisable to use special instruments which make the procedure safe. The authors recorded a total of three failures, in one instance the exudate was removed with the assistance of a surgeon, in one instance the situation was coped with by repeated puncture and in one instance by a conservative procedure. None of the patients developed complications. A list of the latter is discussed. The method is nowadays part of therapeutic procedures of the cardiologist.

[History of heart transplantation]. / Historie srdecní transplantace.

The article examines the history of heart transplantation in experiment and in clinical practice. The part focusing on experimental transplantation covers the period from the very first attempts in 1905 up to the introduction of the current technique. The second part provides an outline of the history of transplantation in clinical practice including immunosuppressive therapy and rejection control. The first heart transplantation in the Czech Republic was performed in 1984.

[Noninvasive diagnosis of myocardial rejection using echocardiography]. / Neinvazivní diagnostika rejekce myokardu pomocí echokardiografie.

The potential of echocardiography in evaluating myocardial rejection was determined in 56 patients (8 females) following orthotopic heart transplantation. The patients' average age was 42.3 (range 18-67) years. Endomyocardial biopsy was used as the reference method. The study included a total of 254 results of biopsy: 137 specimens were free of any signs of rejection while 51 showed incipient rejection and mild rejection was found in 54 specimens. Moderate rejection was detected in 12 specimens; severe rejection was not present in any case. Echocardiography was used to determine ventricular size, wall thickness, left ventricular function, pericardial effusion, mitral and tricuspid flow and isovolumic relaxation time. Rejection has been found to be associated with ventricular wall thickening; the appearance of or an increase in pericardial effusion seems to be a relatively specific feature (a very low-sensitivity marker though); change in isovolumic relaxation time is believed to be the most sensitive marker. No relation between rejection and mitral and tricuspid flow was demonstrated. Echocardiography may alert the cardiologist to a rejection episode; isovolumic relaxation time and its alterations are the most informative features in this respect. The method may help postpone the intervals of biopsy which, however, must be performed on the slightest suspicion of rejection. Still, it cannot be regarded as a replacement for endomyocardial biopsy at the moment.

[The patient after heart transplantation]. / Obraz nemocného po srdecní transplantaci.

The data of the first 100 patients undergoing heart transplantation in the period between January 1984 and May 1993 were analyzed. Of this group, 57 patients are alive. Out of the total of 43 deaths, 14 patients died from graft failure within the first postoperative days, 6 died from surgical complications, 11 from infection, 10 deaths were due to accelerated coronary atherosclerosis, and 2 patients died from tumours. Early mortality rates (within 30 days since surgery) were 37% and 17% in patients operated on between 1984-88 and between 1989-93, respectively. The health condition of heart transplant recipients is affected by side effects of immunosuppressive therapy. Forty per cent of patients re-develop systemic hypertension within the first post-transplantation year. Five years after transplantation, hypertension is detected in 60% of patients. Elevated serum creatinine levels are present in 70% of patients by the end of the first post-transplantation year. In the ensuing period, there is no progression in renal function impairment, which does not require cyclosporin withdrawal and is not associated with the development of hypertension. In the first post-transplantation year, 45% of patients are markedly obese. All patients with overweight and obesity show markedly raised levels of serum cholesterol. Another undesirable effect (mainly due to corticosteroid therapy) is the development of ulcers in 16% of patients. Heart transplantation has become an established method at the Institute for Clinical and Experimental Medicine in Prague. Despite the above pitfalls, heart transplantation substantially prolongs the life of patients and dramatically alters the quality of their life.

[Infectious complications in patients after heart transplantation]. / Infekcní komplikace nemocných po transplantaci srdce.

The incidence of infectious complications was monitored in a group of the first 100 patients undergoing orthotopic heart transplantation at the Institute for Clinical and Experimental Medicine from January 1984 through May 1993. The definition of an infectious complication was a clinically manifest infection requiring treatment. Cytomegalovirus infection and Epstein-Barr virus infection were evaluated by the development of antibody against IgM. A total of 168 infectious complications were detected in 80 patients. The infectious complications were fatal in 11 patients; hence, infections were implicated in 26% of all deaths following heart transplantation. The spectrum of infections markedly varies depending on the interval since the procedure. The most frequent infections within the 30 postoperative days are bacterial (often nosocomial) infections. In the later period (30 days onward), viral infections account for 72% of cases. Of the rarer types of infections, the pulmonary form of aspergillosis was identified in 3 cases, nocardiosis and legionellosis in one case each. Infectious complications were the main cause of deaths in the period of 1 to 4 months post-transplantation, and the spectrum and rate of complications were not different from data reported by other centres.