PubMed Health⌕ Search

Biomedical subjects

B Schumacher

Publications and source records attributed to B Schumacher.

At least 19 recordsLinked to original sources
PubMed2001

The C. elegans homolog of the p53 tumor suppressor is required for DNA damage-induced apoptosis.

In mammals, one of the key regulators necessary for responding to genotoxic stress is the p53 transcription factor. p53 is the single most commonly mutated tumor suppressor gene in human cancers. Here we report the identification of a C. elegans homolog of mammalian p53. Using RNAi and DNA cosuppression technology, we show that C. elegans p53 (cep-1) is required for DNA damage-induced apoptosis in the C. elegans germline. However,cep-1 RNAi does not affect programmed cell death occurring during worm development and physiological (radiation-independent) germ cell death. The DNA binding domain of CEP-1 is related to vertebrate p53 members and possesses the conserved residues most frequently mutated in human tumors. Consistent with this, CEP-1 acts as a transcription factor and is able to activate a transcriptional reporter containing consensus human p53 binding sites. Our data support the notion that p53-mediated transcriptional regulation is part of an ancestral pathway mediating DNA damage-induced apoptosis and reveals C. elegans as a genetically tractable model organism for studying the p53 apoptotic pathway.

Amino Acid Sequence↗
PubMed2001

Role of vessel size as a predictor for the occurrence of in-stent restenosis in patients with diabetes mellitus.

Intracoronary stents have been shown to reduce the rate of restenosis when compared with balloon angioplasty, but in-stent restenosis continues to be an important clinical problem. It was therefore the aim of this registry to identify procedural and angiographic predictors for the occurrence of in-stent restenosis. We analyzed 368 patients with 421 lesions who underwent coronary stent implantation between January 1998 and February 2000. Indications for the placement of a coronary stent were severe dissections (37%), suboptimal angiographic results (38%), restenotic lesions (20%), and graft lesions (4%). Angiographic follow-up was obtained in 270 patients (73%) with 293 lesions after 6 months. Clinical and angiographic variables were analyzed by univariate and multivariate models for the ability to predict the occurrence of in-stent restenosis, defined as a diameter stenosis >50%. In-stent restenosis was angiographically documented in 67 patients and 68 lesions (23%). Under all tested variables the reference luminal diameter before stent implantation (p = 0.006) and diabetes mellitus (p = 0.023) were identified as independent predictors for the occurrence of in-stent restenosis. The comparison of diabetic and nondiabetic patients according to vessel size revealed a 2 times higher rate of in-stent restenosis in small vessels (44% vs 23%, p = 0.002), whereas in vessels >3.0 mm the rate of in-stent restenosis was not significantly different between the 2 groups. In this registry, the clinical variable diabetes and the procedural variable reference vessel size were independent predictors for the occurrence of in-stent restenosis. In these patients, the rate of in-stent restenosis was as high as 45%.

Analysis of Variance↗
PubMed2001

An alternative amino-terminus expressed in the central nervous system converts agrin to a type II transmembrane protein.

Agrin is a basal lamina-associated heparansulfate proteoglycan that is a key molecule in the formation of the vertebrate neuromuscular junction. The carboxy-terminal part of agrin is involved in its synaptogenic activity. The amino-terminal end of chick agrin consists of a signal sequence, required for the targeting of the protein to the secretory pathway, and the amino-terminal agrin (NtA) domain that binds to basal lamina-associated laminins. The cDNA encoding rat agrin lacks this NtA domain and instead codes for a shorter amino-terminal end. While the NtA domain is conserved in several species, including human, sequences homologous to the amino-terminus of rat agrin have not been described. In this work, we have characterized these amino-terminal sequences in mouse and chick. We show that they all serve as a noncleaved signal anchor that immobilizes the protein in a N(cyto)/C(exo) orientation in the plasma membrane. Like the secreted form, this transmembrane form of agrin is highly glycosylated indicative of a heparansulfate proteoglycan. The structure of the 5' end of the mouse agrin gene suggests that a distinct promoter drives expression of the transmembrane form. Agrin transcripts encoding this form are enriched in the embryonic brain, particularly in neurons. To our knowledge, this is the first example of a molecule that is synthesized both as a basal lamina and a plasma membrane protein.

Agrin↗
PubMed2001

[Electrophysiological characterization of connexin 40 deficient hearts--in vivo studies in mice].

Intercellular communication is not only mediated by extracellular transmitters, but also directly by gap junction channels. One channel is composed of two hexameric hemichannels which consist of six polypeptide subunits called connexines (Cx). In the mammalian heart the following connexines have been documented: Cx37, Cx40, Cx43, Cx45, Cx46, Cx50 and Cx57. The labeling by number represents the rounded, molecular mass of the amino acid sequences given in kD. If identical connexin-isotypes form both connexons of a gap junction channel, homotypic coupling exists and a homomeric gap junction channel is formed. Different connexin-isotypes within both connexons cause form heterotypic coupling and heteromeric gap junction channels. Each channel type has specific properties regarding permeability and electrical conductance. Beside a typical age-dependent alignment of gap junction channels on the surface of the cardiac myocytes, regional distribution of the different connexins is different at distinct parts of the mouse heart. Cx40 is not found in the ventricular working myocardium of mice. In the atria as well as in the conduction system, Cx40 is the most frequently expressed. In line with the localization and the conduction properties of distinct homotypic gap junction channels, the Cx40 deficient mouse is suitable for analysis of atrial arrhythmias. Cx40-deficiency in the mouse heart results in characteristic ECG changes like first degree atrioventricular block and prolongation of the QRS duration. Thus, an impairment of the sinuatrial, intraatrial and atrioventricular conduction properties is documented in Cx40 deficient mice. These observations are associated with an increased atrial vulnerability. The Cx40 deficient mouse provides a good example of the relevance of transgenic mouse models to clarify the mechanisms of arrhythmogenesis. The clinical impact of future transgenic mouse models depends on the cooperation of geneticists, basic researchers and clinicians.

Animals↗
PubMed2001

Imidazo-thiazine, -diazinone and -diazepinone derivatives. Synthesis, structure and benzodiazepine receptor binding.

In our search for new compounds acting on benzodiazepine receptors among the fused 2-thiohydantoin derivatives, a series of arylidene imidazo[2,1-b]thiazines was synthesized. The 1,2- and 2,3- cyclized derivatives of mono- and di-substituted Z-5-arylidene-2-thiohydantoins were examined (the X-ray crystal structure of Z-2-cinnamylidene-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazin-3(2H)-one was determined) and compared with the diphenyl derivatives. To investigate the influence of the type of annelated ring on the biological activity, imidazo[2,1-b]pyrimidinone and imidazo[2,1-b]diazepinone derivatives were obtained. The method used in annelation (1,2- and 2,3-cyclized isomers with the exception of fused arylidene imidazothiazines), the substitution pattern (arylidene towards diphenyl) as well as the character of the annelated ring had minor influence on the benzodiazepine receptor affinity of the investigated compounds. It appears that the greatest influence on the biological activity has the character and position of the substituents on the arylidene ring.

Animals↗
PubMed2001

Case report: regional cerebral hypoperfusion induced by ventricular tachycardia - short-term hippocampal hypoperfusion and its potential relationship to selective neuronal damage.

BACKGROUND: Focussing on regional cerebral hypoperfusion during hemodynamically stable, but borderline hypotensive, sustained ventricular tachycardia (VT) experimental studies show (1) a reduction of cerebral blood flow (CBF) during tachyarrhythmias in contrast to the concept of CBF autoregulation, (2) a mediation of hypoperfusion by neuronal and humoral mechanisms, and (3) an involvment of microcirculation due to an ischemic stress response of the cerebral tissue. The clinical relevance of these observations remains still unclear. CASE REPORTS: Two patients with coronary artery disease, left ventricular dysfunction and sustained monomorphic VT underwent electrophysiological study. VT was induced and the tracer (99m)Tc-HMPAO was injected after 3 minutes of ongoing VT. Regional CBF during this life threatening arrhythmia was determined with brain SPECT. A scanning protocol was performed after termination of VT. The measurements were repeated at baseline during normofrequent sinus rhythm (SR) one week later. CBF during SR was significantly reduced in the temporal lobe in comparison to the conditions during stable VT, particularly in the left hippocampus. CONCLUSION: The reduction of hippocampal CBF due to cerebrovascular vasoconstriction and neuronal reflex mechanism previously observed in experiments during stable, sustained VT can be confirmed in a clinical scenario by high resolution (99m)Tc-HMPAO brain SPECT. This supports the hypothesis that repetitive stable VT can play a role in the pathophysiology of cerebrovascular insufficiency. Further clinical studies are needed to analyze the impact of tachyarrhythmias on cognitive and mnemic function.

Aged↗
PubMed2001

The laminin-binding domain of agrin is structurally related to N-TIMP-1.

Agrin is the key organizer of postsynaptic differentiation at the neuromuscular junction. This organization activity requires the binding of agrin to the synaptic basal lamina. Binding is conferred by the N-terminal agrin (NtA) domain, which mediates a high-affinity interaction with the coiled coil domain of laminins. Here, we report the crystal structure of chicken NtA at 1.6 A resolution. The structure reveals that NtA harbors an oligosaccharide/oligonucleotide-binding fold with several possible sites for the interaction with different ligands. A high structural similarity of NtA with the protease inhibition domain in tissue inhibitor of metalloproteinases-1 (TIMP-1) supports the idea of additional functions of agrin besides synaptogenic activity.

Agrin↗
PubMed2001

Interference with cardiac pacemakers by magnetic resonance imaging: are there irreversible changes at 0.5 Tesla?

The safety and feasibility of magnetic resonance imaging (MRI) in patients with cardiac pacemakers is an issue of gaining significance. The effect of MRI on patients' pacemaker systems has only been analyzed retrospectively in some case reports. Therefore, this study prospectively investigated if MRI causes irreversible changes in patients' pacemaker systems. The effect of MRI at 0.5 Tesla on sensing and stimulation thresholds, lead impedance and battery voltage, current, and impedance was estimated during 34 MRI examinations in 32 patients with implanted pacemakers. After measurements at baseline and with documentation of intrinsic rhythm and modification of the pacing mode, patients underwent MRI. The rest of the function time of the pacemaker was calculated. Measurements were again performed after 99.5 +/- 29.6 minutes (mean +/- SD), immediately after MRI examination, and 3 months later. Lead impedance and sensing and stimulation thresholds did not change after MRI. Battery voltage decreased immediately after MRI and recovered 3 months later. Battery current and impedance tended to increase. The calculated rest of function time did not change immediately after MRI. MRI affected neither pacemaker programmed data, nor the ability to interrogate, program, or use telemetry. Surprisingly, in the gantry of the scanner, temporary deactivation of the reed switch occurred in 12 of 32 patients when positioned in the center of the magnetic field. Missing activation of the reed switch through the static magnetic field at 0.5 Tesla is not unusual. MRI at 0.5 Tesla does not cause irreversible changes in patients' pacemaker systems.

Contraindications↗
PubMed2001

Long-term follow-up of percutaneous transhepatic therapy (PTT) in patients with definite benign anastomotic strictures after hepaticojejunostomy.

BACKGROUND AND STUDY AIMS: Percutaneous transhepatic therapy (PTT) is a promising minimally invasive procedure for benign stenosis of the anastomosis after hepaticojejunostomy. In this prospective study, the effectiveness and safety of this technique were investigated. PATIENTS AND METHODS: Between October 1995 and May 2000 34 consecutive patients were referred for treatment of symptomatic cholestasis due to anastomotic strictures after hepaticojejunostomy. In all patients percutaneous transhepatic cholangioscopic (PTCS) drainage and bougienage of the stenosis up to 16 Fr were performed. Associated bile duct stones were fractured using PTCS laser lithotripsy and removed into the jejunum. Afterwards, patients received transhepatic drainage for 3 months initially. The tubes were replaced in case of persistent strictures every 3 months up to 1 year. Patients in whom treatment failed underwent surgery or received biliary metal stents, depending on risk factors and individual anatomy. RESULTS: The procedure was performed in 34 patients (mean age 57 +/- 15) with cholestasis (alkaline phosphatase 691 +/- 485 U/l, bilirubin level mean 3.2 +/- 3.1 mg/dl). The transhepatic tube was successfully positioned into the right hepatic bile duct (n = 25), into the left (n = 3), or into both (n = 3) after 4 +/- 1 sessions, except in two patients in whom an external drainage was used and another patient in whom the procedure had to be stopped due to a bleeding complication. In 14 patients bile duct stones were successfully treated by PTCS laser lithotripsy before the placement of a transhepatic tube. The 30-day morbidity and mortality rates were 23.5% and 0% respectively. In 23 patients, the transhepatic tube could be removed after 212 +/- 122 days, with no evidence of cholestasis during a further follow-up of 736 +/- 479 days. Four patients received metal stents because of persistent strictures after transhepatic intubation. Surgery had to be performed in a total of five patients, because of recurrent bile duct stones or recurrent strictures, in one patient with previous implantation of a metal stent, and in two patients with bile duct disconnection. Two patients died, one 1.5 years after surgery and one 427 days after metal stent implantation. None of these cases was related to the procedure. In two patients, the transhepatic tube is still in situ. CONCLUSIONS: Percutaneous transhepatic treatment of anastomotic strictures after hepaticojejunostomy is safe and highly effective in achieving internal biliary drainage. Temporary transhepatic intubation seems to be a promising minimally invasive alternative to surgery.

Adult↗
PubMed2000

Unique and shared functions of different connexins in mice.

BACKGROUND: Connexins are the protein subunits of intercellular gap junction channels. In mammals, they are encoded by a family of at least 15 genes, which show cell-type-specific but overlapping patterns of expression. Mice lacking connexin43 (Cx43) die postnatally from obstruction of the right ventricular outflow tract of the heart. To discriminate between the unique and shared functions of Cx43, Cx40 and Cx32, we generated two 'knock-in' mouse lines, Cx43KI32 and Cx43KI40, in which the coding region of the Cx43 gene was replaced, respectively, by the coding regions of Cx32 or Cx40. RESULTS: Heterozygous mutants were fertile and co-expressed the wild-type and the corresponding recombinant allele in all tissues analyzed. Heterozygous Cx43KI32, but not Cx43KI40, mutant mothers were unable to nourish their pups to weaning age, possibly reflecting a defect in milk ejection. Homozygous mutant males were sterile because of extensive germ-cell deficiency. The ovaries of homozygous Cx43KI32 neonates exhibited all stages of follicular development and ovulation. The hearts of homozygous Cx43KI32 neonates showed mild morphological defects, but the cardiac morphology of homozygous Cx43KI40 neonates was relatively normal. Spontaneous ventricular arrhythmias were observed in most Cx43KI40 and some Cx43KI32 mutant mice, suggesting increased ventricular vulnerability in these mice. CONCLUSIONS: The postnatal lethality of Cx43-deficient mice was rescued in Cx43KI32 or Cx43KI40 mice, indicating that Cx43, Cx40 and Cx32 share at least some vital functions. On the other hand, Cx43KI32 and Cx43KI40 mice differed functionally and morphologically from each other and from wild-type mice. Thus, these connexins also have unique functions.

Animals↗
PubMed2000

Radiofrequency ablation of atrioventricular nodal reentrant tachycardia: mechanisms and recurrence rate.

Radiofrequency catheter ablation is the treatment of choice in atrioventricular nodal reentrant tachycardia. Electrophysiologic investigations in 623 patients revealed eight mechanisms of tachycardia ablation: Ablation of fast (I) or slow (II), modification of fast (III) or slow AV nodal pathways (IV), modification of both pathways (V), ablation of fast and modification of slow (VI), ablation of slow and modification of fast pathways (VII) and ablation of both pathways (VIII). The criteria of diagnosis of these eight mechanisms of tachycardia ablation are described. Follow-up showed fewer relapses in patients with ablation (0-2%) in comparison to patients with modification of a single AV nodal pathway (8-12%). Alteration of both pathways includes an increasing risk of total AV nodal block, which occurred in 7 patients (1.1%). Detailed analysis of the mechanism of catheter ablation is recommended in all patients after radiofrequency current delivery for AV nodal reentrant tachycardia to estimate the risk of relapse during follow-up or development of total AV block in the particular patient in case of a further ablation procedure.

Catheter Ablation↗
PubMed2000

Clinical experience with implantable atrial and combined atrioventricular defibrillators.

UNLABELLED: The high prevalence of atrial fibrillation (AF) and its clinical complications, the poor efficacy of medical therapy for preventing recurrences, and dissatisfaction with alternative modes of therapy stimulated interest in implantable atrial and combined atrioventricular defibrillators. In a multicenter study, the safety and efficacy of a stand alone implantable atrial defibrillator, the Metrix system, were evaluated. The device was implanted in 51 patients with highly symptomatic episodes of AF refractory to pharmacological treatment. During a follow-up of 9 months, 96% of 227 spontaneous AF episodes were successfully converted to sinus rhythm in 41 patients. In 62 episodes (27%), several shocks and/or additional drug treatment were required to maintain stable sinus rhythm because of early recurrences of AF. A total of 3719 shocks were delivered and no induction of ventricular proarrhythmia or inaccurately synchronized shocks occurred. The AF detection algorithm exhibited a 100% specificity for the recognition of sinus rhythm and a 92.3% sensitivity for the detection of AF. The combined atrioventricular defibrillator, Jewel AF 7250, was evaluated in a multicenter, randomized, cross-over trial. The primary study objectives included: overall safety as determined by complications-free survival at 6 months, efficacy of tiered atrial pacing and defibrillation therapies for termination of spontaneous atrial tachycardias (AT) and AF, and relative sensitivity of a new dual-chamber detection algorithm. The device was implanted in 211 patients with either a history of ventricular tachyarrhythmias (VT/VF) alone or with a history of both AT/AF and VT/VF. During a mean follow-up of 4.5 months, it has been shown that the Jewel AF is safe and effective in treating atrial and ventricular tachyarrhythmias. Pace termination of 85% of AT episodes were achieved with painless delivery of antitachycardia pacing; additional 35% of AT episodes were terminated by high frequency burst pacing. CONCLUSIONS: The stand alone implantable atrial defibrillator may be safe and clinically useful in selected patients for the treatment of highly symptomatic, drug resistant recurrences of AF. The combined atrioventricular defibrillator may be particularly indicated in patients presenting with both a history of atrial and ventricular tachyarrhythmias.

Aged↗
PubMed2000

Predictors of success in radiofrequency catheter ablation of atrial flutter.

Radiofrequency catheter ablation of typical atrial flutter at the isthmus between the tricuspid annulus and the inferior vena cava is established. However in selected patients, the creation of a continuous linear lesion at the targeted isthmus requires a lengthened procedure or is not feasible at all and atrial flutter recurrences are common. In a retrospective analysis, we found that an intraoperatively determined distance between the tricuspid annulus and the inferior vena cava of <.2.5 cm is an independent predictor of a lengthened or failed ablation procedure. Additional equipment, e.g., long introducer sheaths, adapted ablation catheter design, or irrigated tip ablation, as well as alternative ablation approaches, e.g., linear lesions between the tricuspid annulus and Eustachian ridge, have been invented in order to increase the acute success rate or decrease fluoroscopy and procedure time. In a prospective study on the effects of various conduction properties at the isthmus between tricuspid annulus and inferior vena cava following radiofrequency ablation of atrial flutter, we showed previously that others than a complete bidirectional conduction block predicts a high recurrence rate of atrial flutter. For determination of transisthmal conduction properties following ablation, established mapping approaches are documentation of double potentials at the ablation line and right atrial activation sequence following posteroseptal and low lateral right atrial pacing. Novel threedimensional mapping systems, i.e., Carto(R) and EnSite(R), may further enhance the accuracy of conventional mapping techniques.

Atrial Flutter↗
PubMed2000

Popping phenomena in temperature-controlled radiofrequency ablation: when and why do they occur?

During temperature-controlled radiofrequency (RF) ablation a popping sound sometimes occurs. This popping phenomenon is known to be associated with unwanted effects like blood boiling, endocardial rupture, catheter dislocation, and impedance rise. The present in vitro study determined the influence of cooling, electrode contact, and tip temperature on the occurrence of popping phenomena. Pieces of porcine ventricle were immersed in a bath of saline solution at 37 degrees C. Forty-two RF ablations were performed with different electrode-tissue contact forces (i.e., 0.0-0.44 N) in a temperature-controlled mode (70 degrees C setpoint, 30 s, 50 W maximum power output, 4-mm tip, thermocouple). Half of the 42 ablations were performed with fluid flow (0.1 m/s, group I), the other half without flow (group II). In group I, mean tip temperature and power were 55.6 +/- 8.5 degrees C and 36.2 +/- 13.8 W, resulting in a lesion volume of 121 +/- 57 mm3. In group II, the respective values were 67.3 +/- 1.5 degrees C and 9.9 +/- 5.2 W resulting in a volume of 42 +/- 18 mm3. The differences between groups were statistically significant. Overall, ten popping phenomena occurred in group I and none in group II. Pops occurred significantly more often when the contact force was < 0.1 N (8/10) and the tip temperature was < 60 degrees C (8/10). Two endocardial ruptures occurred, both were associated with a popping phenomenon. Using temperature control, the probability of pops is significantly higher when the ablation electrode and the endocardial tissue surface are exposed to fluid flow and the electrode-tissue contact is poor. Under these conditions the tissue temperature can be much higher than the temperature measured at the tip electrode and can potentially reach 100 degrees C causing intramyocardial steam formation and a popping phenomenon.

Animals↗
PubMed2000

Bimodal RR interval distribution in chronic atrial fibrillation: impact of dual atrioventricular nodal physiology on long-term rate control after catheter ablation of the posterior atrionodal input.

INTRODUCTION: Radiofrequency (RF) catheter modification of the AV node in patients with atrial fibrillation (AF) is limited by an unpredictable decrease of the ventricular rate and a high incidence of permanent AV block. A bimodal RR histogram has been suggested to serve as a predictor for successful outcome but the corresponding AV node properties have never been characterized. We hypothesized that a bimodal histogram indicates dual AV nodal physiology and predicts a better outcome after AV node modification in chronic AF. METHODS AND RESULTS: Thirty-seven patients were prospectively subdivided into two groups according to the RR histogram of 24-hour ECG monitoring. Before to RF ablation, internal cardioversion and programmed stimulation were performed. Among the 22 patients (group I) with a bimodal RR histogram, dual AV nodal physiology was found in 17 (77%) patients. Ablation significantly decreased ventricular rate with loss of the peak of short RR cycles after ablation (mean and maximal ventricular rates: 32% and 35% rate reduction, respectively; P < 0.01). In 15 patients with a unimodal RR histogram (group II), dual AV nodal physiology was found in 2 (13%), and rate reductions were 16% and 17%, respectively. At 6 months, 3 (14%) patients in group I and 6 (40%) in group II underwent elective AV nodal ablation with pacemaker implantation due to intolerable rapid ventricular response to AF. CONCLUSION: Bimodal RR interval distribution during chronic AF suggests the presence of dual AV nodal physiology and predicts a better outcome of RF ablation of the posterior atrionodal input.

Adult↗
PubMed2000

[Theory and practical approaches in catheter ablation of atrial flutter].

Atrial flutter can be understood as atrial tachycardia due to a single intraatrial macroreentrant circuit that is determined by fixed or functional boundaries. In various types of atrial flutter, radiofrequency ablation became an established curative therapy. During the course of an ablation procedure, initially, the reentrant circuit has to be determined, e.g. by activation and entrainment mapping. Subsequently, the boundaries have to be identified. By connecting two appropriate boundaries with a linear lesion, the intraatrial reentrant circuit can be inhibited. Finally, it should be proven that the linear lesion results in a complete line of conduction block. Doing so, the acute and long-term results of atrial flutter ablation are comparable to those of other supraventricular tachycardias.

Atrial Flutter↗