[Natriuretic peptides in patients with aortic stenosis]. / Nátriuretické peptidy pri aortovej stenóze.

INTRODUCTION: The aim of this research was to, in patients with severe (tight) aortic stenosis (AoS), evaluate a) an association between clinical and some haemodynamic characteristics and natriuretic peptides (ANP, BNP) concentrations and b) usefulness of these hormones in the decision making on the next therapeutic steps. METHODS: Echocardiography and 6-minut exertion walking test were performed in 23 consecutive patients (12 men, 11 women; age 67 +/- 7 years) and 20 controls together with ANP and BNP measurements from three plasma samples before, immediately after and 20 minutes after the exertion test. RESULTS: There was high inter-individual variability in the ANP and BNP concentrations in patients with AoS. All ANP and BNP were significantly higher than in the controls (ANP 1, 2, 3, p < 0.001; BNP 1, 2, 3, p < 0.001). Only the ANP levels increased significantly after the exercise (ANP 1 vs. ANP 2 = 0.011; ANP 2 vs. ANP 3 p = 0.037). We identified significant correlations between aortic peak gradient and BNP 1, 2 (r = 0.821, p < 0.001) and ANP 1, with BNP correlations being stronger. We did not find any correlations with aortic valve area and the left ventricle mass. The hormone levels were non-significantly increased depending on NYHA classification. Exercise did not improve validity ofANP and BNP measurement. Their values had high sensitivity but low specificity in detecting critical AoS. CONCLUSION: ANP and mainly BNP helped to exclude severe AoS but they were not useful in detecting lower, orderline gradients. We did not prove ANP and BNP to be significant factors in decision making about the timing of AoS surgery.

Natriuretic peptides and endothelin-1 in patients undergoing coronary artery bypass grafting.

Off-pump coronary artery bypass grafting (CABG) is an alternative to conventional CABG using cardiopulmonary bypass. Off-pump technique reduces the complications of CABG performed with extracorporeal circulatory assistance (Lancey et al. 2000; Mack et al. 2004a,b). The object of this study was to compare peri- and postoperative time courses of vasoactive peptides - atrial natriuretic poptide (ANP), brain natriuretic poptide (BNP) and endothelin-1 (ET-1) in off-pump versus on-pump CABG. 22 patients, who underwent on-pump (group A, n = 11) or off-pump CABG (group B, n = 11) were studied. The peri- and postoperative time courses of plasma ANP and BNP were similar in both groups. A statistically significant difference between ET-1 plasma level 2 h after surgery in the group A and ET-1 plasma level 2 h after surgery in the group B (2.46 + or - 1.14 pg/ml/Ht versus 0.74 + or - 0.09 pg/ml/Ht, p < 0.0001) was found. Different CABG techniques were not associated with significant changes in peri- and postoperative plasma ANP and BNP. By contrast, plasma ET-1 significantly rose in the group A 2 h after surgery, indicating endothelial damage.

An acute toxic neuropathy caused by organo-phosphate poisoning in hens.

OBJECTIVE: Organophosphorus compounds can induce an acute toxic peripheral neuropathy. In hens, the acute peripheral neuropathy was induced by poisoning with organo-phosphorus compound (OPC)--tri-ortho-cresyl phosphate (TOCP). METHODS: In the course of an acute TOCP-induced toxic neuropathy in hens the activity of following enzymes was analysed: asparaginase, glutaminase, glutamat-dehydrogenase, AMP and adenosine deaminases and 5'nucleotidase; ALT (SGPT), AST (SGOT) and proteins levels were estimated. RESULTS: A decrease in activity of all analysed enzymes was observed; the amount of proteins was increased. CONCLUSION: The biochemical changes display the slowing or stoppage in axonal transport of proteins. The disturbance of axoplasmic flow and the axonal demyelination may be considered as an attribute of peripheral neuropathy. (Tab. 1, Fig. 1, Ref. 32.).

Antioxidant status of patients after on-pump and off-pump coronary artery bypass grafting.

BACKGROUND: It has been convincingly established that cardiopulmonary bypass routinely used in cardiac surgery induces an oxidative stress. The extensive production of reactive oxygen species occurring during cardiopulmonary bypass has a deleterious effect on the endogenous antioxidant defense pool. The recovery of antioxidant enzyme activities as well as other antioxidatively substances is one of the important tasks for the effective defense of patients in the postoperative period. AIM OF THE STUDY: Oxidative stress markers and the antioxidant status and the activities of some antioxidant enzymes were studied in patients during one-week period after cardiac revascularization performed using cardiopulmonary bypass and the results were compared with patients operated by off-pump technique. PATIENTS AND METHODS: Thirty-nine patients undergoing elective surgical revascularization (coronary artery bypass grafting) were divided in two groups: twenty-two patients operated using cardiopulmonary bypass (group A) and a group B of seventeen patients undergoing pump-off surgery. Blood samples were drawn before operation and then in course of the first week after surgery. The following biochemical parameters were estimated: plasma levels of total antioxidant status (TAS) and of thiobarbituric acid reactive substances (TBARS) as well as erythrocyte activities of two antioxidant enzymes--superoxide dismutase (SOD) and glutathione peroxidase (GPx). RESULTS: There was a significantly decreased preoperative and also postoperative levels of TAS associated with a preoperatively increased level of TBARS in group A only. In both groups of patients (especially in group B), markedly decreased activity of SOD was observed. The increase of GPx activity--especially on the third postoperative day--was not significant. CONCLUSIONS: Regardless of the surgical technique, both groups of patients had a markedly decreased antioxidant capacity with a significantly increased production of lipid peroxides especially in patients operated with cardiopulmonary bypass. The decreased antioxidant status was connected with decreased erythrocyte activity of SOD. Therefore, we recommend the regular supply of antioxidant acting substances (antioxidant vitamins and coenzyme Q10) be included in their standard therapeutic strategy especially in the preoperative period. (Tab. 2, Fig. 4, Ref: 22.)

Protection of newborn organism against effect of oxidative stress.

OBJECTIVE: The aim of the present study was to investigate influence of oxidative stress on newborn organism, in terms of the dynamics of malondialdehyde (MDA) concentration changes and of the activities of selected antioxidants in asphyxial newborns on the 1st and 5th day of life. METHOD: In the group of 62 preterm and term asphyxial newborns, characterized by the presence of asphyxial criteria and admitted within 24 hours of life, the plasma concentration of MDA and level of total antioxidant status (TAS) were followed. RESULTS: Dynamic changes of MDA signalized active process of lipoperoxidation (LP) and values of TAS were decreased in comparison with the capacity of adult patients.

[The influence of chloroquine on some biochemical and hematological parameters in patients with critical limb ischemia]. / Vplyv chlorochinu na niektoré biochemické a hematologické parametre u pacientov s kritickou koncatinovou ischémiou.

CLI represents a major medical and social problem. The incidence is increasing and currently it was estimated 500-1000 per 1 million inhabitants. We carried out a clinical study (2000-2004) concerning monitoring of some hematological and biochemical markers during reperfusion in patients with CLI. The subject of our interest included possibilities to influence PMNL elastase by medical means and neutrophil-lymphocyte ratio which is considered a reliable and simple parameter to assess severity of clinical conditions.

[Regional biochemical and hematologic changes in patients after revascularization of the lower extremities in ischemia of the extremities]. / Regionálne biochemické a hematologické zmeny u pacientov po revaskularizácii dolných koncatín pre koncatinovú ischémiu.

INTRODUCTION: Surgical treatment of PAOD is related to iatrogenic ischaemia caused by arterial clamping and ischaemia which is result of natural development of the disease. The pathway of skeletal muscle reperfusion injury is complex and one of the most important factors related to injury is endothelial damage. The expected reason of endothelial damage is increased production of oxygen free radicals by prematurely activated PMN (polymorphonuclear) leukocytes (direct injury). Non-specific tissue injury is related to releasing of PMN elastase. Endothelial dysfunction, hypercoagulable state and microcirculation stasis are responsible for indirect injury and no-reflow fenomena. STUDY DESIGN: Observational pilot study. METHODS: 10 patients underwent surgery because of PAOD (all suffering from critical limb ischaemia). During reperfusion period in defined intervals following parameters were measured (samples were taken from ipsilateral femoral vein): PMN elastase, lactate, total antioxidant status, malondialdehyd, minerals, acid-base balance, blood count, APTT, prothrombin time, fibrinogen and HTI (heparin tolerance index). RESULTS: Patients with PAOD are threatened by hypercoagulable state with its clinical and surgical consequences. Maximal grade of local acidosis is reached 2 hours from the beginning of reperfusion. Tissue damage is expressed by maximum activity of PMN elastase 18-24 hours during reperfusion and represents non-specific tissue damage. Low total antioxidant status reveals high sensibility to oxygen free radicals. MDA does not achieve the pathological range in observed series. CONCLUSION: Our results confirmed inevitable importance of prevention of hypercoagulability, oxygen free radical tissue damage and PMN elastase activation to avoid of non-specific tissue damage.

Cytokine levels in patients with a very low left ventricular ejection fraction after open heart surgery.

INTRODUCTION: Cardiopulmonary bypass and cardiac operations are obligatorily connected with systemic inflammatory reaction. Production of proinflammatory cytokines is responsible also for negative effects on the myocardial function. OBJECTIVE OF STUDY: Follow-up of the dynamic changes of proinflammatory and antiinflammatory cytokine levels in patients with left ventricular dysfunction during the first week after cardiac surgery. PATIENTS AND METHODS: A total of nine patients with a very low left ventricular ejection fraction (22.75 +/- 0.65%) who had undergone cardiac surgery (for coronary artery bypass grafting or aortic valve reconstruction) were investigated during the first after week operation. The preoperative and postoperative plasma levels of tumor necrosis factor (TNF), interleukin-8 (IL-8) and interleukin-10 (IL-10) were estimated by means of ELISA technique. RESULTS: With respect to the preoperative levels, on the first postoperative day the levels IL-8 (from 9.36 to 16.65 pg/ml) (p < 0.05) and of IL-10 (from 6.93 to 28.09 pg/ml) (p < 0.02) significantly rose with a stepwise decrease down to the seventh day after surgery. From the third to seventh day an insignificant increase in TNF level was also noted. CONCLUSIONS: The results have shown that open heart surgery in patients with a severe left ventricular dysfunction evoked a systemic inflammatory response demonstrated by early increase in proinflammatory cytokine IL-8 and was accompanied by increased level of antiinflammatory cytokine IL-10. Despite stepwise decrease in IL-8 levels, they did not reach the preoperative levels, not even on the seventh postoperative day. (Tab. 1, Fig. 3, Ref. 21.)

[Biochemical markers of perioperative myocardial infarct in non-cardiac surgery]. / Biochemické markery perioperacného infarktu myokardu v nesrdcovej chirurgii.

Perioperative myocardial infarction as well as other major cardiac events induced by myocardial ischemia during and after a more complex or long-lasting operation represents a permanent threat for a successful outcome. High number of cardiac ischemic events especially following major vascular surgery and in elder subjects requires early, sensitive and specific diagnostic markers. This review paper presents conventional as well as novel biochemical methods fulfilling the above mentioned criteria. Until now used estimations of traditional enzyme activities (aspartate aminotransferase and lactate dehydrogenase) are either entirely discarded or subsequently lose their importance (i.e. activities of total creatine kinase and its MB-isoenzyme) an instead modern methods that estimate the amounts of specific cardiac proteins--troponins T and I, constituents of myocardial contractile apparatus--released from ischemized heart are used. Patient's monitoring by means of these cardiac markers allows an early, rapid and reliable estimation of perioperative myocardial infarction enabling possible to arrange an immediate effective treatment. Recently the myocardial regulatory protein troponin I is considered the most specific cardiac marker the plasma level of which does not increase in acute damage and chronic diseases of skeletal muscles, nor in chronic renal failure. (Ref. 52.)

Coenzyme Q10 depletion and mitochondrial energy disturbances in rejection development in patients after heart transplantation.

UNLABELLED: Sixty endomyocardial biopsies (EMB) and whole blood or plasma samples from 34 patients after heart transplantation (HTx-pts) were studied. Acute rejection of the transplanted heart was histologically graded as: 0 (without), 0-1 (incipient), 1 (mild), 2 (moderate). The level of coenzyme Q10 (CoQ10) in 28 EMB was estimated by HPLC. Mitochondrial respiratory chain function and energy production were measured in 60 EMB. This study is the first report showing a correlation between: (a) histological signs of rejection in the human transplanted heart and (b) CoQ10 level of EMB, CoQ10 blood level, and mitochondrial bioenergetic processes: inhibition in FAD-part, but not in NAD-part of respiratory chain. In all patients after heart transplantation (HTx-pts) the dynamic balance between total antioxidant status and degree of oxidative stress was disturbed. CONCLUSIONS: CoQ10 level and mitochondrial bioenergetic functions of EMB contribute to the explanation of pathobiochemical mechanisms of origin and development rejection of human transplanted heart. We suppose that estimation of EMB CoQ10 level could be used as a bioenergetic marker of rejection development in human transplanted heart. CoQ10 therapy could contribute to the prevention of rejection of the transplanted heart.

[Parameters of energy metabolism in patients after vascular reconstructive surgical procedures]. / Niektoré parametre energetického metabolizmu u pacientov pocas cievneho rekonstrukcného chirurgického výkonu.

Revascularization surgery in patients with peripheral arterial occlusive disease presents an acceptable clinical model for studying the rate of ischaemia-reperfusion injury of cells and other structures of skeletal muscle of the affected extremity. Validity of carefully chosen set of biochemical parameters for determination of this injury during and after surgery as well as in the early and late reperfusion periods and during the readaptation to situation after restoration of blood circulation was verified. Blood samples were taken from the regional common femoral vein which allowed to obtain information directly from the ischaemized extremity. Analyzed biochemical parameters have given useful information about the situation in acid-base regulation, in energy metabolism as well as antioxidant capacity. These parameters were estimated in four time intervals: before aorta cross-clamping (preischaemic phase), then 30 min (early reperfusion) and 18 hours (readaptation period) after aorta-declamping. In the early reperfusion period a marked acidosis and raised carbon dioxide tension, significant increase of lactate and pyruvate levels as well as increased hypoxanthine plasma level were observed. On the contrary, in this period the lowest lipoperoxide level was found, evident in the wake of relative stability of concentration of endogenous antioxidants documented by a constant glutathione redox status that at the first postoperative day even significantly decreased as a consequence of a drop of oxidized and increased of reduced form of glutathione. Therefore, the applied biochemical parameters allow to monitor the ischaemia-reperfusion damage of afflicted region and could be used even in the study of compounds with a protective effect against possible injury of ischaemized and reoxygenized tissues. (Tab. 3, Fig. 4, Ref. 32.)

[The effect of uric acid, creatine phosphate and carnitine on lipid peroxidation in cerebral cortex and myocardium homogenates]. / Vplyv kyseliny mocovej, kreatínfosfátu a karnitínu na lipoperoxidáciu v homogenátoch mozgovej kôry a myokardu.

BACKGROUND: Uric acid as the product of purine nucleotide degradation is an integrate component of blood plasma. This metabolite is considered to be one of the important naturally occurring antioxidants building up the antioxidation system of the organism. Creatine phosphate and carnitine are important substances participating in energy metabolism of the cells. Energy production is closely related to the level of reduction systems and thus also to the antiradical ability of the cell. By this mechanism could creatine phosphate and carnitine improve the antioxidative capacity of the cell. METHODS: In homogenates of rat brain cortex and myocardium was the production of oxygen radicals stimulated by mixture of Fe2+ ions and ascorbate. Oxygen radicals may induce lipid peroxidation by the means of the reaction with lipid structures. We tried to inhibit the process of lipid peroxidation by addition of uric acid, creatine phosphate and carnitine into the incubation medium. Intensity of lipoperoxidation was measured by detection of substances giving positive reaction with thiobarbituric acid (TBA) in homogenates of brain cortex and myocardium. RESULTS: Uric acid in concentrations of 1 and 0.5 mmol.l-1 markedly inhibits the production of compounds reacting with TBA. This effect was not found in 0.05 mmol.l-1 concentration. Creatine phosphate and carnitine in 1 mmol.l-1 concentrations also decreased the value of lipid peroxides in homogenates of brain cortex, but their effect was lower than the effect of uric acid. This effect was not seen in myocardium homogenates.

[Prognostic significance of biochemical markers in acute coronary syndromes]. / Prognostický význam biochemických markerov pri akútnych koronárnych syndrómoch.

The article reviews the possibilities of biochemical markers in coincidence with the assessment of prognosis in acute coronary syndromes and in the revealing of effectivity of their therapy. The current options of clinical biochemistry in many cases allow to supplement, confirm, or exclude the results of modern physical and other clinical examination methods and in this way to contribute to the accuracy of the diagnostic process, and enable to comment the prognosis and the risk measure of the patient. A significant progress has been achieved in the assessment of effectivity in thrombolytic therapy in acute myocardial infarction, where especially the series assessment of myoglobin levels or specific troponin cardiomarkers can facilitate the process of physician's decision as to the assessment of the subsequent procedure in the treatment of patients. The assessment of levels of both specific and partly less specific cardiomarkers becomes one of the criteria of the decision in coincidence with ischaemic episodes in the peri and postoperative periods (the diagnosis of peri-operative myocardial infarction). Specific troponin cardiomarkers acquire an extraordinary significance in the prediction of the measure of risk in patients with unstable angina pectoris where already one single assessment of the level of these markers is sufficient for hospitalization of the patient and thus enables to change the physician's strategy of further therapy. (Ref. 95.)

Prognosticky vyznam biochemickych markerov pri akutnych koronarnych syndromoch.

The article reviews the possibilities of biochemical markers in coincidence with the assessment of prognosis in acute coronary syndromes and in the revealing of effectivity of their therapy. The current options of clinical biochemistry in many cases allow to supplement, confirm, or exclude the results of modern physical and other clinical examination methods and in this way to contribute to the accuracy of the diagnostic process, and enable to comment the prognosis and the risk measure of the patient. A significant progress has been achieved in the assessment of effectivity in thrombolytic therapy in acute myocardial infarction, where especially the series assessment of myoglobin levels or specific troponin cardiomarkers can facilitate the process of physician's decision as to the assessment of the subsequent procedure in the treatment of patients. The assessment of levels of both specific and partly less specific cardiomarkers becomes one of the criteria of the decision in coincidence with ischaemic episodes in the peri and postoperative periods (the diagnosis of peri-operative myocardial infarction). Specific troponin cardiomarkers acquire an extraordinary significance in the prediction of the measure of risk in patients with unstable angina pectoris where already one single assessment of the level of these markers is sufficient for hospitalization of the patient and thus enables to change the physician's strategy of further therapy. (Ref. 95.).

Participation of coenzyme Q10 in the rejection development of the transplanted heart: a clinical study.

Coenzyme Q10 and alpha-tocopherol concentrations were assessed in 28 endomyocardial biopsies from 22 patients and in 61 blood samples from 31 patients after heart transplantation with histologically confirmed signs of rejection. The values were compared to the group of 14 patients with cardiomyopathies of unclear etiology as candidates for heart transplantation. Blood analyses were also compared with 50 healthy persons. Myocardial and blood coenzyme Q10 concentrations were already significantly decreased in the incipient phase of rejection (degree 0-1) and also in rejection phase 1 and 2. In patients without rejection signs myocardial and blood coenzyme Q10 values were similar to those of cardiomyopathic patients. No significant differences were found in alpha-tocopherol concentrations in relation to signs of rejection. Increased plasma lipid peroxidation quantified as malondialdehyde production was detected in all groups of transplanted patients. The results contribute to the explanation of some pathobiochemical mechanisms participating in the rejection development of the transplanted heart.

[Coenzyme Q10 and alpha-tocopherol in patients after heart transplantation]. / Koenzým Q10 a alfatokoferol u pacientov po transplantácii srdca.

Pathobiochemical mechanisms which participate in the rejection of transplanted heart are not fully clarified. A significant role in this process can be played by endogenous antioxidants, especially coenzyme Q10 which aside from its antioxidative properties is inevitable for cellular bioenergy. The authors investigated the concentration of Q10 alpha-tocopherol in endomyocardial biopsies in the blood in 11 patients from 1 to 9 years of age after transplantation of the heart (HTx-pat) examined in UKVCH in Bratislava who were compared with the group of 13 patients with cardiopathies of unclear origin (KPNP-pat) as possible candidates for transplantation. They detected a decreased concentration of coenzyme Q10 in the myocardium and blood of HTx-patients. Levels of alpha-to-copherol in the myocardium were identical in both groups, in plasma they were higher in patients after HTx. The authors suppose that the levels of coenzyme Q10 in patients after HTx can be influenced by an increased production of free oxygen radicals during rejection episodes, as well as immunosuppressive therapy, and indicate to the possible consequences of this decrease. The presented results provide the first information on the levels of coenzyme Q14 and alpha-tocopherol in patients after transplantation of the heart, registered and controlled in the Slovak Republic. They can contribute to the clarification of some pathobiochemical mechanisms of rejection, respectively to their therapeutic effect. (Fig. 2, Ref. 16.).

[Mitochondrial bioenergetics in patients before and after heart transplantation]. / Bioenergetika mitochondrií u pacientov pred transplantáciou a po transplantácii srdca.

BACKGROUND: The results of the study of biochemical and genetic characteristics of mitochondria in human medicine become widely used in practice. This is confirmed also by the Nobel Symposium which took place in 1994, and was dedicated to the problem of mitochondrial diseases and the effect of their therapy. Relatively rare is the information on the pathobiochemistry of heart muscle mitochondria in patients with cardiomyopathies. No information, so far, is available on oxidative phosphorylation in cases of myocardium transplantation in patients. MAIN PURPOSE AND OBJECTIVES: To bring early metabolic changes in mitochondria within EMB (endomyocardial biopsy) under control in patients after transplantation of the heart (Htx). These detected metabolic changes can contribute to the clarification of the mechanisms participating in the rejection of the transplanted myocardium. PATIENTS AND METHODS: The investigated group of patients included: a) patients with cardiopathies of unclear origin (NYHA II, NYHAIII) b) patients after transplantation of the heart (NYHAI-II) The authors assessed the properties of the respiratory chain and ATP production in mitochondria of EMB. CONCLUSIONS: The new methodical approach to the study of bioenergy of mitochondria of the myocardium in patients allows an early recognition of pathobiochemical changes in myocardium. Supplementing studies are going to reveal wether the presented methodical approach bear diagnostic value. (Fig. 3, Ref. 25.).

[Biochemical markers in acute myocardial infarct]. / Biochemické markery pri akútnom infarkte myokardu.

Exact and early diagnosis of acute myocardial infarction is essential for the subsequent routine management of this frequent cardiovascular disease. At present, the clinical biochemistry possesses a set of more or less cardiospecific protein markers for early detection of myocardial ischemic damage. After the admission of patient to the hospital, serial estimations of rather non-specific enzyme activities (creatine kinase, its MB-izoenzyme, lactate dehydrogenase, hydroxybutyrate dehydrogenase) are currently used for the detection of acute myocardial infarction and for the further monitoring of the patient and managing his therapy. In the past decade, many cardiospecific biochemical markers were discovered and gradually introduced into the routine clinical practice. The most perspective markers are some molecules of contractile proteins of heart myofibrils (troponins, myosin chains) as well as "rediscovered" myoglobin. The aim of this review article is to inform about the commonly used, as well as about the new biochemical markers, to discuss some problems of diagnostic strategy in the early and exact detection of ischemic myocardial damage and to attract attention to the difficulties. However its disadvantage resides in its presence in both myocardium and skeletal muscles which arise when the diagnosis of acute myocardial infarction is prematurely excluded from consideration and such patients are discharged too soon from hospital. (Fig. 1, Tab. 1, Ref. 72.)

[Cardiopathies of unknown origin--a cooperative interdisciplinary study]. / Kardiopatie nejasného pôvodu--kooperatívna interdisciplinárna stúdia.

The authors described aim. objectives, design and criteria of the study which is oriented to the clinical and research problems of heart diseases of uncertain origin. The paper presents the preliminary experience with invasive cardiological techniques in this field. At the same time the authors discuss the potential impact of the basic research on the prevention and effective treatment of cardiopathy which is until now of unknown origin.

[Echocardiography of cardiopathies]. / Echokardiografia kardiopatií.

The authors deal with the relation of echocardiography and diseases of the cardiac muscle, draftly classified as cardiopathies. The author's starting point is issued from the presumption that heart diseases which lack the characteristic diagnostic signs in echocardiographic picture affect the heart's systolic and diastolic functions. Echocardiography enables to quantify the extent of affliction of both functions. On the basis of analysis of a set of 22 prospectively examined patients the authors judge as to wether the results of individual volume measurements by means of echocardiographic imaging (one dimensional, two dimensional, Doppler) are correct. In the frame of systolic and diastolic functions examination they highlight the Doppler evaluation due to its technical simplicity and good correlations with literal documents dealing with invasive examinations.