Antibody-mediated activation of a defective beta-D-galactosidase. II. Immunological relationship between the normal and the defective enzyme.

Two closely related protein antigens were used to study immunogenic competition. Namely, normal beta-D-galactosidase of Escherichia coli (Z) and a genetically defective beta-D-galactosidase (AMEF) which seems to differ from the normal in one amino acid substitution. A unique characteristic of this pair of antigens is that, although they are indistinguishable in precipitation and absorption tests with antibodies, the enzymatic activity of AMEF is specifically increased several-hundredfold in the presence of antibodies directed against Z. The following results show that Z and AMEF also differ in their immunogenic ability: (a) antibodies directed against Z activated AMEF; antibodies directed against AMEF did not activate, but competed specifically with activating antibodies. (b) Animals immunized with AMEF failed to produce activating antibodies when they were subsequently challenged with Z, although the presence of some cells primed to produce activating antibodies could be demonstrated by adoptive transfer. (c) Animals preimmunized with Z were stimulated in their production of activating antibodies by AMEF challenge, although not as efficiently as with Z. A model explaining these observations by competition for the immunogenic site among antigen-sensitive cells carrying cross-reacting receptors is presented.

Covalent attachment of enzyme as a membrane-label for viable eucaryotic cells.

An enzyme, beta-D-galactosidase, was covalently coupled to mammalian cells by means of a bifunctional reagent. The coupling procedure did not cause appreciable loss of cell viability (less than 6%) as measured by plating efficiently and membrane integrity. After 24 h in culture, the cells exhibited an average of 2.6 x 10(4) molecules of beta-D-galactosidase per cell. Histological evidence indicated that the enzyme was localized on the cell surface and distributed uniformly among the cell population. Considerations for choosing enzyme-label include sensitivity of assay by enzymatic, immunologic and histochemical methods, and the possibility of isolating labeled membrane components by enzyme-specific affinity chromatography.

A quantitative cytotoxicity assay using whole blood: application to H-2 tissue typing.

A fluorochromatic cytotoxicity assay featuring direct use of whole blood and quantitative evaluation is described. Its application to tissue typing for H-2 antigens together with data indicating reproducibility specificity of the assay are presented. Procedures for visual and automated quantification are included.

Frequency of magnetic resonance signal abnormalities of the brain in patients aged less than 50 years with idiopathic dilated cardiomyopathy.

Twenty patients with idiopathic dilated cardiomyopathy (IDC) aged less than 50 years (mean 41) and an age-matched group of 20 healthy volunteers were studied. All subjects were free of cerebrovascular symptoms and risk factors for stroke. Magnetic resonance imaging of the brain, extracranial Doppler ultrasonography, heart catheterization and echocardiography were performed. In patients with IDC, a higher frequency of ventricular enlargement (p less than 0.02), cortical atrophy (p less than 0.01) and white matter lesions (p less than 0.05) was observed. Cerebral infarcts were found in 4 patients (p less than 0.05) who showed clinically severe limitation of functional capacity (New York Heart Association class III or IV). The extent of cortical atrophy, and the duration of clinical evidence of IDC showed a significant correlation (p less than 0.04). The data indicate a high incidence of parenchymal abnormalities of the brain in young, neurologically asymptomatic patients with IDC.

Aborted sudden death in a patient with a structurally normal heart: the Brugada syndrome.

We report a 37-year-old man with documented aborted sudden death. After resuscitation, the patient showed no structural heart disease but the ECG showed a right bundle-branch block with a descending ST segment elevation in leads V(1) and V(2). After transient normalization of the ECG, the administration of ajmaline led to spontaneous development of the distinct descending ST segment elevation in the right precordial leads and therefore to the diagnosis of Brugada syndrome. The incidence of sudden cardiac death among these patients is high. The only treatment is an implantable cardioverter-defibrillator (ICD). The Brugada syndrome should therefore be borne in mind in the differential diagnosis of sudden death.

A randomized controlled trial of a computer-based physician workstation in an outpatient setting: implementation barriers to outcome evaluation.

OBJECTIVE: A research prototype Physician Workstation (PWS) incorporating a graphical user interface and a drug ordering module was compared with the existing hospital information system in an academic Veterans Administration General Medical Clinic. Physicians in the intervention group received recommendations for drug substitutions to reduce costs and were alerted to potential drug interactions. The objective was to evaluate the effect of the PWS on user satisfaction, on health-related outcomes, and on costs. DESIGN: A one-year, two-period, randomized controlled trial with 37 subjects. MEASUREMENTS: Differences in the reliance on noncomputer sources of information, in user satisfaction, in the cost of prescribed medications, and in the rate of clinically relevant drug interactions were assessed. RESULTS: The study subjects logged onto the workstation an average of 6.53 times per provider and used it to generate 2.8% of prescriptions during the intervention period. On a five-point scale (5 = very satisfied, 1 = very dissatisfied), user satisfaction declined in the PWS group (3.44 to 2.98 p = 0.008), and increased in the control group (3.23 to 3.72, p < 0.0001). CONCLUSION: The intervention physicians did not use the PWS frequently enough to influence information-seeking behavior, health outcomes, or cost. The study design did not determine whether the poor usage resulted from satisfaction with the control system, problems using the PWS intervention, or the functions provided by the PWS intervention. Evaluative studies should include provisions to improve the chance of successful implementation as well as to yield maximum information if a negative study occurs.

Coronary revascularization: influence on ventricular arrhythmias.

Myocardial ischemia may cause severe cardiac arrhythmias. In the present study, the influence of revascularization on ventricular arrhythmias was investigated. A total of 68 patients (61 male, 7 female; mean age 53 years) with coronary artery disease was divided into three groups: Group A (21 patients) underwent percutaneous transluminal coronary angioplasty (PTCA); Group B (37 patients) had coronary artery bypass grafting (CABG); and Group C were 10 patients who served as controls, who had simple coronary angiography. All patients had a Holter ECG on the day before angiography. PTCA patients and controls were restudied on the day after the procedure, while in Group B, Holter ECG was repeated three weeks after surgery. Groups A and B were again studied 18 months after the first Holter ECG. The PTCA group showed a slight reduction in complex arrhythmias immediately following PTCA, which increased again after 18 months; the CABG group, however, revealed a significant increase in complex arrhythmias three weeks after bypass surgery, but a decrease after 18 months. There was no significant change in the control group before or after angiography. Thus, successful revascularization has no influence on ventricular arrhythmias after 18 months.

Atrioventricular nodal reentry tachycardia: electrophysiologic comparisons in patients with and without 2:1 infra-His block.

Patients with atrioventricular nodal reentry tachycardia (AVNRT) occasionally may demonstrate a 2:1 infra-His block during tachycardia. However, the electrophysiologic background of this phenomenon has not been established so far. In the present study we compared the electrophysiologic parameters of 10 consecutive patients with a transient 2:1 infra-His block during AVNRT of the common type (Group A) with those of 17 consecutive patients without this phenomenon during tachycardia (Group B). Transient 2:1 infra-His block occurred without termination of the tachycardia in all 10 patients of Group A. The tachycardia sustained despite intermittent or permanent conduction disturbance of the infrahisian tissue in 8 of these 10 patients. In comparison, the electrophysiologic parameters of 17 patients without 2:1 block during AVNRT of the common type (Group B) were analyzed. A significantly longer antegrade (318 +/- 58 ms vs. 259 +/- 50 ms) and retrograde (308 +/- 59 ms vs. 239 +/- 20 ms) AV conduction capacity could be demonstrated in these patients. The tachycardia cycle length did not differ significantly between the two groups, although the mean tachycardia cycle length was 48 ms longer in patients of Group B. These observations demonstrate an advanced conduction capacity in patients with a transient infra-His block during AVRNT of the common type. This study underlines that the reentry circuit in AVNRT is not necessarily dependent on infrahisian tissue.

Comparative effects of digoxin and xamoterol on arrhythmias in patients with mild to moderate heart failure.

The prognosis of heart failure patients is poor and as many as half of the deaths are sudden and thereby presumably attributable to arrhythmias. In the present study the effect of traditional therapy of mild heart failure with digoxin on arrhythmias was compared with the effect of xamoterol, a cardioselective beta 1 partial agonist, which has in addition beta-blocking properties at higher levels of sympathetic tone. Fifteen patients (NYHA class II-III) were included in the study. After a two-week baseline period they were randomized to digoxin or xamoterol for four weeks followed by a two-week washout and another four weeks of crossover therapy. Heart rate, blood pressure, and the number of complex ventricular premature beats remained essentially unchanged with digoxin. With xamoterol heart rate increased from 86 to 93 (ns) but was significantly higher during the night in comparison with digoxin. The number of ventricular premature beats decreased from 186 +/- 317 to 110 +/- 137 and increased to 130 +/- 175 after treatment. The number of runs decreased from 11 +/- 35 to 2.7 +/- 5 and increased to 5.6 +/- 9 after therapy. In conclusion, no significant effect of digoxin or xamoterol on ventricular arrhythmias was found. However, xamoterol showed a tendency to reduce simple and complex ventricular arrhythmias in patients with mild to moderate heart failure.

Evaluation of the antihypertensive effect of lisinopril compared with nifedipine in patients with mild to severe essential hypertension.

For several reasons, increasing numbers of patients with hypertension are treated with angiotensin-converting enzyme inhibitors and calcium channel blockers. In a twenty-four week, double-blind, randomized, parallel study, the antihypertensive effect of lisinopril (20 to 80 mg qd) and nifedipine (20 to 80 mg bid) were compared in 21 patients. Fourteen patients received lisinopril (mean dose 35 mg), and 7 patients received nifedipine (mean dose 54 mg). By the end of week 12, 8 patients had responded (supine diastolic pressure less than or equal to 90 mg) to lisinopril and 5 to nifedipine. At the end of the study supine systolic/diastolic blood pressure was reduced from 172/104 to 149/92 mmHg with lisinopril and from 171/102 to 158/94 mmHg with nifedipine. No significant difference between the two treatments was detected. Three patients were reported to have at least one clinical adverse experience during the active treatment period, 1 in the lisinopril group and 2 in the nifedipine group. No serious clinical adverse experiences were recorded. In conclusion, lisinopril and nifedipine are both effective in reducing blood pressure in patients with mild to severe hypertension. Lisinopril qd and nifedipine slow release bid produce similar decreases in blood pressure after twelve weeks of therapy and the safety profiles of the two drugs are similar.

Noninvasive and invasive diagnosis of a huge congenital aneurysm of the left atrium: a case report.

An intrapericardial aneurysm of the left atrium in a twenty-eight-year old asymptomatic woman is reported. The aneurysm was diagnosed by two-dimensional echocardiography and the specific intraaneurysmatic flow pattern was described by color blood flow imaging. To the authors' knowledge such a noninvasive diagnosis of a left atrial aneurysm has never been reported in the literature before. The diagnosis was confirmed by angiocardiography. The aneurysm was successfully resected. The patient was discharged without medication and continues to do well.

Circadian blood pressure pattern in patients with treated hypertension and left ventricular hypertrophy.

Left ventricular hypertrophy in hypertensives is an important determinant of prognosis. In the present study 45 patients with treated essential hypertension were divided into two groups: 23 patients had normal left ventricular dimension and 22 patients had echocardiographic signs of left ventricular hypertrophy (LVH). All patients were adequately treated during daytime, but ambulatory blood pressure monitoring showed a distinct abnormal pattern in the LVH group characterized by a lack of blood pressure reduction during the night; 16 of 22 patients with LVH had no blood pressure decline during the night, whereas 17 of 23 patients without hypertrophy showed this reduction (P less than 0.01). In conclusion, patients with hypertension and LVH often reveal a lack of blood pressure decline during the night, which may be the reason for the development of left ventricular hypertrophy (and thus should be managed by a different circadian blood pressure therapy) or which may be the consequence of progressive structural changes in the resistance vessels, along with the development of left ventricular hypertrophy. It is suggested that patients with hypertension and left ventricular hypertrophy should have ambulatory twenty-four hour blood pressure monitoring.

[Redilatation with the trefoil balloon catheter in 2 patients with a high degree of aortic stenosis]. / Redilatation mit dem Trefoil-Ballonkatheter bei 2 Patienten mit hochgradiger Aortenstenose.

Percutaneous transluminal balloon valvuloplasty (PTBV) is successfully applied in the treatment of calcified aortic stenosis. However, results following redilatation have not yet been dealt with in the literature. This method was successfully used in two patients (62a m/70a f) suffering from severe sclerotic aortic stenoses. Redilatation was undertaken in the first case after one month and after four in the second. A second redilatation by balloon catheter was done upon request of the patients after a further nine months. Following this third dilatation both patients suffered from femoral thrombosis which was treated surgically in the second case, while in the first local thrombolysis was done. In the management of the first patient valve replacement had to be performed four months after the last dilatation due to renewed complaints, while the second patient showed no evidence of recurrence within three months after the last dilatation.

Socio-economic effects and cost saving potential of remote patient monitoring (SAVE-HM trial).

OBJECTIVE: In the SAVE-trial we evaluated the safety, reliability and improvements of patient management using the BIOTRONIK Home Monitoring®-System (HM) in pacemaker (PM) and implanted cardioverter defibrillator (ICD) patients. DESIGN: 115 PM (Module A) and 36 ICD-patients (Module B) were recruited 3 months after implantation. PATIENTS: 65 patients in Module A were randomised to HM-OFF and had one scheduled outpatient clinic follow-up(FU) per year, whereas patients randomised to HM-ON were equipped with the mobile transmitter and discharged without any further scheduled in-office FU. In Module B 18 patients were randomised to HM-OFF and followed by standard outpatient clinic controls every 6 months; 18 patients were randomised to HM-ON receiving remote monitoring plus one outpatient clinic visit per year; unscheduled follow-ups were performed when necessary. RESULTS: The average follow-up period was 17.1 ± 9.2 months in Module A and 26.3 ± 8.6 months in Module B. In both modules, the number of FUs per year was significantly reduced (Module A HM-ON 0.29 ± 0.6 FUs/year vs HM-OFF 0.53 ± 0.5 FUs/year; p b 0.001; Module B HM-ON 0.87 ± 0.25 vs HM-OFF 1.73 ± 0.53 FU/year,p b 0.001). Cost analysis was significantly lower in the HM-ON group compared to the HM-OFF group (18.0 ± 41.3 and 22.4 ± 26.9 € respectively; p b 0.003). 93% of the unscheduled visits in Module B were clinically indicated,whereas 55% of the routine FUs were classified as clinically unnecessary. CONCLUSION: Remote home monitoring of pacemaker and ICD devices was safe, reduced overall hospital visits, and detected events that mandated unscheduled visits.

Initial experiences with a telemedicine framework for remote pacemaker follow-up.

According to international guidelines implanted cardiac pacemakers (PM) have to be checked periodically to ensure that they are working correctly. To spare a significant number of patients the burden of traveling to specialized PM clinics a telemedicine framework has been developed prototypically. A mobile, personal digital assistant (PDA) based PM follow-up unit provides the caregiver at the point-of-care with the necessary infrastructure to perform a basic PM follow-up examination remotely. In case of detected malfunction of the PM the patient is ordered to the hospital for further examination. The system has been evaluated in a clinical pilot trial on 44 patients with a total of 23 different PM models from 8 different manufacturers. The initial results indicate the potential of the concept to work as an efficient, manufacturer independent screening method with the ultimate goal to increase the safety, quality and efficiency of PM therapy.

Genetic control of immunologic unresponsiveness to adjuvant-free solutions of beta-D-galactosidase. I. Inheritance of the Ir-Z1 and ir-Z2 loci in mice.

Two genetic loci, Ir-Z1 and ir-Z2, controlling the immune response to adjuvant-free bacterial beta-D-galactosidase (Z) are present in inbred mouse strains SJL/J and CE/J, respectively. Each locus segregates as a single, autosomal gene: Ir-Z1 as dominant and ir-Z2 as recessive. The response is characterized by production of activating and precipitating IgG. Maximal levels of circulating IgG occur between 16 and 20 days after immunization with a single, 50-microgram dose of enzyme. Failure of proteins other than Z to elicit an immune response indicates that the Ir-Z control is specific for determinant(s) of this enzyme. The immunogenicity of beta-D-galactosidase preparations cannot be attributed to either the catalytic activity of the enzyme or adjuvant contamination. Non-responder mice acquire immunologic memory without detectable increase in circulating specific IgG under the same conditions that elicit antibody production in responder strains.