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.

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.

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.

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.

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.

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.

Longterm follow-up of patients with pulmonary thromboembolism. Late prognosis and evolution of hemodynamic and respiratory data.

Seventy-six patients with various forms of pulmonary thromboembolic disease were followed-up for 1 to 15 years. All were free of other cardiopulmonary disease at the time of the first examination which was performed at least two months after the last pulmonary embolism. Catheterization was repeated in all survivors on average 4.8 years later. Severe chronic pulmonary hypertension (mean pulmonary artery pressure (PPA greater than 30 mm Hg) did not occur after a single episode of acute embolism, was infrequent after single subacute or recurrent emboli (8 of 9 patients), and was common after occult emboli (12 of 13 patients). Mortality in all clinical groups correlated with PPA and with the presence of right heart failure. In survivors, no correlation was found between the longterm changes of PPA and age, duration of disease, interval between catheterizations, PaO2, or cardiac output. Pulmonary hypertension progressed further in patients with initial PPA greater than 30 mm Hg. In contrast, none of the patients with normal or borderline PPA at the initial examination developed severe pulmonary hypertension during the follow-up. Since the future course of patients could be predicted from the first examination, repeated hemodynamic investigation proved to be of minor prognostic value.

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.

Precordial isopotential electrocardiographic mapping and its clinical use in patients with ischaemic heart disease.

After ten years of experience, the authors present an overview of the possible clinical uses of precordial isopotential electrocardiographic mapping in patients with ischaemic heart disease. The resting Q wave and ST segment maps have most often been found useful in the early phases of myocardial infarction. They are a helpful tool for monitoring progression of the disease, the effect of drugs, or the therapeutic effect of fibrinolytic therapy, etc. R wave mapping provides an excellent opportunity for following up patients after orthotopic heart transplantation and monitoring cardiac rejection. Stress tests are usually performed under a workload; alternative loads may be mental, pharmacological, stimulation-induced or under hypoxaemic stress. To evaluate a test, resting values are compared with those obtained during exercise. It is mainly exercise ST segment maps which have proved to be most informative; their use in the chronic phase of ischaemic heart disease helps to make the diagnosis of coronary insufficiency more accurate. In clinical practice, stress tests are recommended mostly in the follow-up of drug therapy, monitoring of the therapeutic effect of cardiac surgery or coronary angioplasty.

[Further experimental investigations on the therapy of gas gangrene with ozone and oxygen (author's transl)]. / Weitere experimentelle Untersuchungen zur Therapie des Gasbrandes mit Ozon und Sauerstoff

In continuation of a recently-published investigation on the effect of intramuscular injections of an ozone-oxygen mixture on experimental gas gangrene in the guinea pig, 2 additional experiments were performed in order to establish the efficacy of the therapy when given twice daily instead of only once. Futhermore, the effect of an analogous therapy was investigated with the use of pure oxygen. The ozone-oxygen therapy reduced the death rate from 100% in untreated control animals to 73.6 and 70.0%, respectively, in the 2 series of experiments. The median survival times were prolonged from 0.56 and 1.33 days to 5.50 and 6.66 days. The use of oxygen twice daily reduced the death rates significantly even further to 57.0 and 47.9%. With this therapy the median survival time was increased to 8 and more than 12 days. The differences in therapeutic effect of the 2 gases were not, however, statistically significant. On account of its simple applicability previous experiments on animals it is proposed that this therapy be employed also in cases of human gas gangrene. In addition, the bactericidal effect of CaCl2, as used in this experimental study, on vegetative forms of Clostridia is demonstrated.

[Thromboembolic incidents in the cardiology department]. / Tromboembolické príhody na kardiologickém pracovisti.

The authors evaluate the incidence of pulmonary embolism (PE) and its impact in patients who died in the cardiological department of the Institute of Clinical and Experimental Medicine during two five-year periods (1979-1983 and 1984-1988). These two periods are compared with the period 1974-1978 in the same department. The purpose was to assess the trend of fundamental findings (number of post-mortem examinations, number of PE, number of fatal PE, source of thrombosis in PE etc.). Based on the assembled findings it may be said that the number of p.m. examinations is increasing and thus also the number of PE. There was an obvious rise of the number of women with embolic, attacks in the cardiological department. Correct clinical diagnoses are equal in all periods.

[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.

[The early phase of development of myocardial infarction in diabetics]. / Prubeh casné fáze infarktu myokardu u diabetiku.

The authors evaluated retrospectively the course of the early stage of symptomatic myocardial infarction (IM) with regard to the incidence and character of infarction pain and the clinical course of IM during hospitalization at the coronary unit (CU) in a group of diabetic patients (D, n = 67) and a group of non-diabetic controls (ND, n = 63). In the group D there was a higher incidence of painless IM (D 7.5%, ND 0%, p less than 0.05). The interval between the development of the first symptoms of IM and admission to the CU was significantly longer in diabetics (D 20 +/- 35 hours, ND 9 +/- 16 hours, p less than 0.05). IM in diabetics was more frequently complicated by left-sided cardiac failure (D 48%, ND 27%, p less than 0.05). As to other investigated complications the two groups did not differ significantly. Nor did they differ in the mortality during hospitalization at the CU.

[Computer-assisted electrocardiographic mapping and left ventricular function in patients with acute myocardial infarct]. / Pocítacové elektrokardiografické mapování a funkce levé komory u nemocných s cerstvým srdecním infarktem.

In 22 patients with a first myocardial infarction the authors assessed the relationship between morphological changes of the QRS complex and systolic left ventricular function. Using a 56-lead computer-assisted electrocardiogram from the precordium in the form of a map (apparatus Cardiomap-1), the authors prepared a record during the first days after initiating treatment with a thrombolytic agent and again after a period of three weeks. They found only one correlation between the decrement of Q waves and the increase of the left ventricular ejection fraction (p less than 0.05). This correlation, however, is of no practical importance due to the low correlation coefficient. The relationship is moreover markedly influenced by the time of the first record. After the third day of thrombolytic treatment it is not expedient to make the initial record. No relationship between the change of R waves, ST segments and left ventricular function was found. Similarly, due to the great dispersal of values it is not possible to differentiate between patients with inferior infarctions of the heart muscle and anterior myocardial infarctions.

[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.

[Precordial S-T stress mapping in the evaluation of the effects of percutaneous transluminal coronary angioplasty]. / Prekordiální zátezové S-T mapy pri hodnocení úcinku perkutánní transluminální koronární angioplastiky.

The morphological impact of percutaneous transluminal angioplasty (PTCA) on the treated artery is closely checked by coronary arteriography. Indirect non-invasive evaluations are made possible by electrocardiography, isotope methods and echocardiography which are the commonest visualization methods. The authors used a precordial S-T load map. After complete revascularization following PTCA there was a significant drop of the sum of S-T depressions and in some members of the group it reached normal values. The S-T load map is a suitable non-invasive procedure for monitoring the effect of PTCA.

[Topography of foci of perfusion defects after myocardial infarct on standard ECG and thallium stress scintigraphy]. / Topografie loziska perfúzní poruchy po infarktu myokardu podle standardního EKG a zátezové thaliové scintigrafie.

65 patients after previous myocardial infarction well documented by electrocardiography were investigated by 201-Tl scintigraphy after submaximal ergometry. Topographic results of the scintigraphy in three planes were compared with the location of previous infarction demonstrated by standard electrocardiography. 30% of disagreements and partial agreements in more than half the patients were caused predominantly by inability of electrocardiography to qualify a true ischaemic necrosis in the interventricular septum, by limited ability to localize exactly the site of myocardial infarction and by underestimating its size, in particular in the posterior left ventricular wall, where the lesion often extends to the lateral wall. Some principal disagreements of both methods in different findings on the anterior and posterior left ventricular walls stress the low value of standard electrocardiography for exact topographic diagnosis of the infarct site. The authors express their opinion that the size of myocardial infarction and its influence on left ventricular function measured by non-invasive methods in the acute state would be more important for the prognosis of the patient.