Biomedical subjects
Publications and source records attributed to M Zabel.
A case of a 38-year-old patient with severe renovascular hypertension high serum zinc concentration and ceroidlipofuscinosis was presented. The diagnosis of ceroidlipofuscinosis was based on electron microscope picture of mucosus tissue of rectum where the secondary lisosoms, so characteristic of this disease, were found in cells of connective tissue.
The study aimed at employing the Immunomax technique to detect the markers of HBV replication (HBcAg and HBV-DNA) in liver biopsy material, obtained from children with chronic hepatitis type B. In line with the currently modified classification of chronic hepatitis and with the increasing potential of antiviral therapy it seemed purposeful to supplement routine staining techniques with studies at the molecular level. Our studies demonstrated the effective detection of both the core antigen and HBV-DNA in liver tissue in children using immunocytochemical techniques and in situ hybridization, amplified with the Immunomax technique. HBcAg was detected in 26 out of 27 liver biopsies from patients with chronic hepatitis type B and with replication of the virus. HBV-DNA was detected in all study children with HBV infection and in 2 out of 5 cases of chronic hepatitis of a distinct etiology. No significant relationships could be found between the detection of tissue HBV markers on the one hand and the intensity of inflammatory lesions or severity of fibrosis on the other.
BACKGROUND: Risk stratification by means of analysis of QT dispersion (QTD) in the 12-lead surface ECG is under intense investigation in various patient populations. The aim of the present prospective study was to evaluate the prognostic value of QTD and other ECG variables reflecting dispersion of ventricular repolarization in comparison with established risk stratifiers during long-term follow-up in a large cohort of post-myocardial infarction patients treated according to contemporary therapeutic guidelines. METHODS AND RESULTS: In 280 consecutive infarct survivors, the 12-lead ECG was optically scanned and digitized for analysis of QTD (QTmax-QTmin) and 25 other repolarization variables, including recently developed and validated parameters such as the T peak-to-T end interval and the area under the T wave. In addition, a variety of established risk stratifiers were assessed. After a mean follow-up period of 32+/-10 months, 30 patients reached one of the prospectively defined study end points (death, ventricular tachycardia, or resuscitated ventricular fibrillation). Comparisons between event and nonevent patients by means of Kaplan-Meier event probability analyses revealed that none of the ECG dispersion variables were of discriminative value. In contrast, variables such as left ventricular ejection fraction (P=0.007), mean 24-hour heart rate (P=0.022), or heart rate variability (P=0.007) proved to be potentially useful risk stratifiers in this patient population. On multivariate analysis, only LVEF, heart rate variability, and a history of thrombolysis were independent predictors of outcome. CONCLUSIONS: Determination of QTD from the surface ECG even when performed with the best available methodology failed to predict subsequent risk in this large series of infarct survivors.
Heart rate variability (HRV) has been established as an important risk parameter in patients surviving myocardial infarction. Recently, analysis of HRV-particularly of the standard deviation of NN intervals (SDNN)--from short term ECG recordings has been proposed as an alternative to that from 24 hour Holter monitorings. The present study is the first to compare SDNN from short term recordings to that from 24 hour recordings with respect to risk stratification after myocardial infarction. In 60 patients at the time of discharge from the hospital, SDNN from Holter monitoring averaged 93 +/- 30 ms compared to 39 +/- 18 determined from short term recordings. Patients with a prospectively defined clinical endpoint differed significantly from those with an uneventful course with respect to age, left ventricular ejection fraction, mean RR interval from Holter recording (753 +/- 153 vs 921 +/- 132 ms), mean RR from short term recording (783 +/- 153 vs 914 +/- 163 ms), and SDNN from the Hotler recording (71 +/- 27 vs 97 +/- 29 ms; p < 0.001). However, patients with and without a clinical event could not be separated by means of SDNN measured from short term ECG registrations (35 +/- 22 vs 41 +/- 19 ms; p = NS). Thus, SDNN measured from short term ECG recordings does not seem to be useful regarding risk stratification of patients after myocardial infarction. Analysis of HRV should be performed using 24 hour Holter monitoring, which provides more information and reflects circadian fluctuation in autonomic tone.
Studies were performed on adrenal glands of 7 human embryos between 6 and 8 weeks of intra-uterine life using clone PC-10 mouse serum (Dako, No. M879). During the 6th week, immunoreactivity for the proliferating-cell nuclear antigen (PCNA) was observed only in the central and medial parts of the developing fetal zone of the adrenal gland (75.2 +/- 3.1% of adrenocortical cells showed nuclei stained with anti-PCNA), while the peripheral part was immunonegative. One week later the second outer layer, i.e. the permanent cortex appeared. During the 8th week, the cortex formed two distinct zones: a relatively large and centrally located fetal zone and a thin rim of definitive (permanent) cortex, the later adult adrenal cortex. PCNA-positive cells were present throughout the surface of the gland being most numerous in the center (76.4 +/- 1.4%) and less numerous in the peripheral part (16.6 +/- 2.6%). A very thin layer of permanent cortex surrounding the fetal zone showed less numerous cells stained for PCNA (36.4 +/- 3.4%) as compared with the inner fetal zone. During the 8th week the proliferative cells activity was similar in both zones. The middle proliferative center of the fetal zone disappeared, and all cells of this zone had similar PCNA reactivity.
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Although it is well established that haemoglobin can be taken up by kidney tubular epithelium, the exact mechanism of the process has not been elucidated so far. We have undertaken a study to determine whether any specific binding sites for haemoglobin are present on the membranes of renal tubular cells. Paraffin sections of rat kidney cortex were incubated with haemoglobin, and the bound molecules were detected by means of a combined avidin-peroxidase and ImmunoMax method. Haemoglobin binding sites were observed in the apical membrane of distal tubules. Binding occurred for both rat haemoglobin and swine and human haemoglobins, and the proteins could compete with each other. Competition experiments with other proteins showed that the binding is specific for haemoglobin and that the net charge of the protein is not critical for the interaction. We failed to detect the binding sites in proximal tubules, where most of the filtered proteins are reabsorbed. The role of the binding sites in the distal nephron is unclear. Our findings may be essential for the further understanding of the pathomechanism of haemoglobin-induced acute renal failure.
INTRODUCTION: The current standard for arrhythmic risk stratification is electrophysiologic (EP) testing, which, due to its invasive nature, is limited to patients already known to be at high risk. A number of noninvasive tests, such as determination of left ventricular ejection fraction (LVEF) or heart rate variability, have been evaluated as additional risk stratifiers. Microvolt T wave alternans (TWA) is a promising new risk marker. Prospective evaluation of noninvasive risk markers in low- or moderate-risk populations requires studies involving very large numbers of patients, and in such studies, documentation of the occurrence of ventricular tachyarrhythmias is difficult. In the present study, we identified a high-risk population, recipients of an implantable cardioverter defibrillator (ICD), and prospectively compared microvolt TWA with invasive EP testing and other risk markers with respect to their ability to predict recurrence of ventricular tachyarrhythmias as documented by ICD electrograms. METHODS AND RESULTS: Ninety-five patients with a history of ventricular tachyarrhythmias undergoing implantation of an ICD underwent EP testing, assessment of TWA, as well as determination of LVEF, baroreflex sensitivity, signal-averaged ECG, analysis of 24-hour Holter monitoring, and QT dispersion from the 12-lead surface ECG. The endpoint of the study was first appropriate ICD therapy for electrogram-documented ventricular fibrillation or tachycardia during follow-up. Kaplan-Meier survival analysis revealed that TWA (P < 0.006) and LVEF (P < 0.04) were the only significant univariate risk stratifiers. EP testing was not statistically significant (P < 0.2). Multivariate Cox regression analysis revealed that TWA was the only statistically significant independent risk factor. CONCLUSIONS: Measurement of microvolt TWA compared favorably with both invasive EP testing and other currently used noninvasive risk assessment methods in predicting recurrence of ventricular tachyarrhythmias in ICD recipients. This study suggests that TWA might also be a powerful tool for risk stratification in low- or moderate-risk patients, and needs to be prospectively evaluated in such populations.
INTRODUCTION: QT dispersion (QTD) from the 12-lead ECG has been widely adopted as a noninvasive index of dispersion of ventricular repolarization (DVR). QTD, however, has never been validated by direct comparison with myocardial DVR in the human heart. METHODS AND RESULTS: Monophasic action potential (MAP) recordings obtained in an earlier study were retrospectively matched with 12-lead ECGs available from within 24 hours of the invasive procedure. MAPs were available from an average of 8+/-3 left endocardial sites in 4 patients with left ventricular hypertrophy (LVH) and 7 patients with normal ECGs, and 6+/-2 epicardial sites in 3 patients of each group during normal ventricular activation. Local repolarization time (RT) was determined as MAP duration at 90% repolarization plus the local activation time. Dispersion of RT was calculated as the difference between the earliest and latest RT. ECGs were digitized and analyzed with recently described interactive QTD analysis software. In addition to standard QTD (defined as QTmax-QTmin), all currently proposed ECG dispersion variables were compared and correlated with the invasive measurements of DVR. QTD exhibited a reasonable correlation with dispersion of RT (R = 0.67; P < 0.01). Several other variables designed to measure DVR exhibited a similar, but not better, correlation. Among them, the QT peak/QT end ratio in V3 (R = -0.72; P < 0.01) and averaged over all analyzable leads (R = -0.59; P < 0.01) exhibited a good correlation with dispersion of RT, which was further improved when endocardial measurements were considered alone. T area measures did not correlate with dispersion of RT, but discriminated LVH. CONCLUSION: DVR can be assessed by means of a 12-lead surface ECG. Several of the variables under study exhibit a similar accuracy in determination of true myocardial dispersion of repolarization. Variables involving the terminal part of repolarization, such as the QT peak/QT ratio, even from a single lead, may add to the determination of DVR from the human heart.
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The aim of the present study was to compare parafollicular cells in the bison thyroid and its ultimobranchial remnants. The thyroid of 26 European bisons was fixed in Bouin's fluid, 5 microns thick paraffin sections were stained with hematoxylin and eosin. Azan or silver Grimelius methods. For immunocytochemical analysis specific rabbit antisera were used against human calcitonin (CT), human calcitonin gene-related peptide (CGRP), bovine (b) or rat (r) neuron-specific enolase (NSE), human synthetic somatostatin (ST), and porcine chromogranin. Strongly positive reactions in the majority of parafollicular cells were observed after application of antisera against CT, CGRP, bNSE and rNSE only. ST-immunopositive cells were found in small numbers. Immunopositive parafollicular cells were also present outside typical structures of the thyroid within persistent ultimobranchial remnants. In persistent ultimobranchial bodies, parafollicular cells were frequently observed in groups between ultimobranchial follicles in form of solid cell nests. Many of these cells did not react with any of the antisera used and showed features of immature cells. It is concluded that histomorphologic analysis and immunocytochemical examination reveals a heterogeneous population of parafollicular cells in the bison thyroid, and this heterogeneity was particularly clear in persistent ultimobranchial bodies.
QT dispersion has been adopted as a new index for the noninvasive assessment of the inhomogeneity of repolarization and has been evaluated in several clinical studies as an index of arrhythmia propensity. In most of these studies, indices of dispersion of repolarization were rate corrected by the Bazett formula calculating QT dispersion as QT cmax-QT cmin or JT dispersion as JT cmax-JT cmin, implying that dispersion of repolarization also changes with heart rate. This study aimed to determine in the electrically paced isolated heart whether dispersion of ventricular repolarization is rate dependent. Multiple (5-7) monophasic action potentials (MAPs) were recorded simultaneously from the epicardium and endocardium of both ventricles in 18 isolated Langendorff-perfused rabbit hearts. Hearts were paced from a right ventricular site at basic cycle lengths (CL) between 1,200 and 300 ms in 100-ms decrements. Action potential duration was measured at 90% repolarization (APD90), and recovery time (RT) was defined as the sum of APD90 and activation time in each of the simultaneous MAP recordings. The dispersion of APD90 and RT, respectively, were calculated as the maximal difference among all recordings. APD90 and RT shortened continuously throughout the range of paced steady-state CLs from 1,200 to 300 ms. APD90 was 197.6 +/- 6.1 ms at a CL of 1,200 ms and decreased to 148.5 +/- 2.5 ms at a CL of 300 ms (P < 0.0001). RT was 228.2 +/- 6.2 ms at a CL of 1,000 ms and decreased to 175.9 +/- 2.9 at a CL of 300 ms (P < 0.0001). In contrast, dispersion of APD90 and RT did not change significantly. Dispersion of APD90 was 24.8 +/- 2.3 ms at a CL of 1,200 ms, 26.1 +/- 1.9 msec at a CL of 1,000 ms, and 21.6 +/- 2.1 at a CL of 300 ms (NS). Dispersion of RT was 29.7 +/- 3.4 ms at a CL of 1,200 ms, 29.0 +/- 3.0 ms at a CL of 1,000 ms, and 32.7 +/- 3.2 ms at a CL of 300 ms (NS). In contrast to the duration of the QT interval, dispersion of ventricular repolarization does not change significantly with pacing induced changes in CL. Assuming that the rate-dependent behavior of action potential duration is similar between the rabbit and human heart, a rate correction of parameters of dispersion of repolarization is probably unnecessary.
Heart rate variability (HRV) is considered to represent a noninvasive tool to assess cardiac autonomic tone at the level of the sinus node. It has been shown to have predictive power for risk assessment in patients surviving acute myocardial infarction. For this purpose, HRV should be assessed from 24-hour Holter recordings obtained 7-10 days following the infarction. Although there is some recovery of HRV during the first 3 months after infarction, HRV remains reduced in postinfarction patients compared to values obtained in healthy individuals. Compared to assessment of left ventricular function as a risk marker, HRV is superior with respect to prediction of arrhythmic events and sudden death whereas both parameters yield comparative power for prediction of total cardiac mortality. Since the predictive power of HRV analysis alone is relatively low, the combined use of HRV measurements together with traditional risk markers (such as ventricular ectopic beats, signal-averaged ECG, or left ventricular function) results in improved risk prediction with positive predictive accuracy in the range of 30%-50%.
INTRODUCTION: Evidence is accumulating that microvolt T wave alternans (TWA) is a marker of increased risk for ventricular tachyarrhythmias. Initially, atrial pacing was used to elevate heart rate and elicit TWA. More recently, a noninvasive approach has been developed that elevates heart rate using exercise. METHODS AND RESULTS: In 30 consecutive patients with a history of ventricular tachyarrhythmias, the spectral method was used to detect TWA during both atrial pacing and submaximal exercise testing. The concordance rate for the presence or absence of TWA using the two measurement methods was 84%. There was a patient-specific heart rate threshold for the detection of TWA that averaged 100 +/- 14 beats/min during exercise compared with 97 +/- 9 beats/min during right atrial pacing (P = NS). Beyond this threshold, there was a significant and comparable increase in level of TWA with decreasing pacing cycle length and increasing exercise heart rates. CONCLUSIONS: The present study is the first to demonstrate that microvolt TWA can be assessed reliably and noninvasively during exercise stress. There is a patient-specific heart rate threshold beyond which TWA continues to increase with increasing heart rates. Heart rate thresholds for the onset of TWA measured during atrial pacing and exercise stress were comparable, indicating that heart rate alone appears to be the main factor of determining the onset of TWA during submaximal exercise stress.
INTRODUCTION: The exact electrophysiologic mechanism of torsades de pointes (TdP) is under intense investigation. No isolated animal heart model of this particular arrhythmia exists. METHODS AND RESULTS: In isolated rabbit hearts, TdP was induced by means of bradycardia in the presence of a high concentration of d-sotalol (10(-4) M) and shortly after lowering the concentration of potassium and magnesium in the perfusate. Multiple simultaneous epicardial and endocardial monophasic action potentials (MAPs) and volume-conducted 12-lead ECGs were recorded. d-Sotalol prolonged repolarization and increased dispersion of ventricular repolarization compared to baseline recordings. With the onset of low potassium and magnesium concentrations, repolarization was further prolonged and dispersion of repolarization was further increased followed by the occurrence of early afterdepolarizations (EADs) in the majority of MAP recordings, i.e., at both endocardial and epicardial locations of both ventricles. Upon increase of EAD amplitude, triggered arrhythmias with TdP of up to 42 beats ensued in 10 of 11 hearts studied. MAP duration at 90% repolarization (APD90), dispersion of APD90, and the incidence of EADs as well as dispersion of the QT interval and T wave area were significantly higher in beats triggering bigemini, couplets, or runs of TdP. CONCLUSION: TdP observed in this new isolated heart model was associated with markedly increased dispersion of ventricular repolarization and the occurrence of EADs in multiple locations of the heart. TdP is initiated when the amplitude of an EAD reaches threshold for initiation of the first beat of an episode.
INTRODUCTION: Increased dispersion of ventricular repolarization has been suggested as a cause of proarrhythmic effects of Class IA or III antiarrhythmic drugs, such as d-sotalol, quinidine, and amiodarone. METHODS AND RESULTS: The influence of d-sotalol, quinidine, and amiodarone on the dispersion of monophasic action potential (MAP) durations was studied in 55 isolated Langendorff-perfused rabbit hearts at different pacing cycle lengths (CLs). MAP duration measured at 90% repolarization (APD90) was determined from 6 to 8 endocardial and epicardial MAP recordings with dispersion of ventricular repolarization defined as the range of APD90. The protocol was repeated 60 minutes after initiation of a perfusate containing increasing concentrations of d-sotalol (n = 12, 10[-6] M, 10[-5] M, and 5 x 10[-5] M) and quinidine (n = 8, 10[-6] M and 10[-5] M). Seventeen rabbits were fed with an aqueous solution of amiodarone (50 mg/kg per day over 4 weeks). The data of these experiments (n = 17) were compared with a series of 18 untreated control rabbits. Dispersion of ventricular repolarization was unchanged with the low concentration of d-sotalol (10[-6] M) but was increased-particularly at long CLs-with higher d-sotalol concentrations. With both concentrations of quinidine, dispersion of ventricular repolarization was increased in a rate-independent manner. Amiodarone did not affect dispersion of ventricular repolarization. CONCLUSIONS: Rate-dependent and concentration-dependent increases in dispersion of ventricular repolarization by d-sotalol and quinidine in this isolated rabbit heart model may help explain their proarrhythmic effects while the absence of an increase in dispersion of ventricular repolarization with amiodarone correlates with its clinically observed lower incidence of proarrhythmia.
TT cell line is the best known stabilized cell line derived from the human medullary thyroid carcinoma. The ultrastructural characteristics of these cells include well developed rough endoplasmic reticulum, a prominent Golgi apparatus and a considerable number of secretory granules. Numerous hormones were immunocytochemically demonstrated in TT cells of which calcitonin and calcitonin gene-related peptide (CGRP) are the products of the same gene but an alternative RNA processing. TT cells were found to produce some other hormones as well, namely ACTH, neurotensin, enkephalin, PTHrP, gastrin-releasing peptide (GRP), serotonin but also functional proteins of the chromogranin group, synaptophysin, NSE, calbindin and tyrosine hydroxylase. Some marker proteins have been detected in the cytosol (CEA) and in the cytoskeleton (alpha-tubulin, cytokeratin). The influence of numerous factors on the secretory activity of these cells has been demonstrated so far, including effects of 1,25-dihydroxycholecalciferol, glucocorticoids, sex steroids, cAMP, gastrin-releasing peptide, sodium butyrate, phorbol esters, ionomycin and forskolin. The investigators performed on the TT cell line demonstrate that this is the most reliable model system for the human parafollicular cells developed so far, in comparison to other cell lines derived from the medullary carcinoma of the thyroid.
Histological studies were performed on 24 pancreases of normal human embryos and fetuses aged 7 to 38 weeks. For immunocytochemistry, the avidin-biotin-peroxidase method was used to identify and localize insulin, glucagon, somatostatin, and pancreatic polypeptide (PP) cells. In 7 wk old embryos, cells containing somatostatin and PP are observed. One week later appear single glucagon-positive cells. In the 9th wk, insulin producing cells are visible. During the fetal period two populations of the investigated cells are found: Langerhans islets and dispersed cells. The latter cells containing insulin, glucagon or somatostatin are localized in the walls of pancreatic ducts throughout the whole gland, while PP-positive cells are seen mainly in the part of the pancreas, which develops from the ventral anlage (anteroinferior part of the head and adjacent part of the main pancreatic duct). During the development of islets we have observed four stages: (1) scattered cells (7 to 10 weeks); (2) grouping cells (11 to 15 weeks); (3) mantle and zonular islets (10 to 29 weeks), in which B cells located inside are surrounded by a thick zone of A, PP and somatostatin-producing cells; (4) mixed islets (from 30 weeks on) - all cells are scattered over the whole transverse section of the islet. In the developing pancreas, the glucagon- and somatostatin-containing cells are the most numerous, while the insulin and PP-containing cells occur in lesser quantities.