Reliability of an Automatic Sensing Algorithm

Automatic adaptation of the atrial sensitivity was evaluated in 18 patients with dual chamber pacemakers (Intermedics, Inc., Relay) in the unipolar mode. After atrial sensitivity was stabilized in the upright position, patients underwent a 1.0 W/kg body weight exercise for 5 minutes. A 24-hour Holter EGG was recorded, and the maximum and minimum atrial sensitivity values reached were stored in the memory of the pulse generator. In a second series of 12 patients, Holter ECGs were recorded twice, starting with the same sensitivity but with automatic adaptation alternately switched "on" or "off." Results of the exercise test: mean atrial sensitivity declined from 2.30 ± 0.77 mV to 2.03 ± 0.68 mV. There was no change in five patients, a slight increase in two patients, and lowering of the atrial sensitivity was observed in 11 patients, the difference ranging from 0.2 to 1.0 mV. A total of two P waves in two patients were missed by the atrial amplifier. The minimum and maximum sensitivity reached during Holter monitoring averaged 2.31 ± 0.67 mV versus 1.72 ± 0.71 mV (difference 0-1.7 mV). Normal pacemaker function was found in six patients, including one patient without any intrinsic atrial activity. Malsensing of less than five P waves occurred in four patients. More than 50 sensing defects resulted from ectopic atrial beats (four patients). We observed atrial oversensing in three cases; one patient showed atrial over- and undersensing. The comparison between fixed and variable sensitivity did not reveal any superiority of automatic adaptation. Conclusion: earlier findings of atrial signal variation during daily life are confirmed. Although quite reliable during exercise studies, automatic adaptation of atrial sensitivity is not able to compensate for sudden changes in atrial electrogram or to sufficiently suppress extracardiac noise.     

Cyclic disulfide analogues of the complement component C3a Synthesis and conformational investigations

The flexible C-terminal region of the anaphylatoxic peptide C3a was reported to contain the receptor binding site. To elucidate the receptor binding conformation of the C-terminus, as well as to examine a synthetic approach to potential C3a-antagonists, 26 cyclic disulfide bridged C3a analogues were synthesized. Solid phase peptide synthesis was performed on different polymeric supports by individual peptide synthesis, with Fmoc strategy, and simultaneous multiple peptide synthesis, using Boc and Fmoc strategies. Both strategies gave open-chain peptides in comparable yields. Syntheses using the Boc strategy employed the HF-labile 4(methoxy)benzyl group (Mob) for β-thiol protection of cysteine; in contrast, the TFA-stable protecting groups, acetamidomethyl (Acm) and trityl (Trt), were chosen for syntheses employing Fmoc strategy. Ring closure reactions by iodine oxidation were carried out starting from protected (Acm/Acm, Trt/Acm) or unprotected dithiols. The resulting cyclic C3a analogues were characterized by HPLC, amino acid analysis, and FAB-MS. Conformational investigations using CD spectroscopy and theoretical structural investigations by means of molecular dynamics calculations revealed that slight variations in sequence result in pronounced conformational consequences. The potential of cyclic C3a analogues to activate or to desensitize guinea pig platelets, a standard test system for biological activities of anaphylatoxic peptides like C3a, revealed relatively low activities for cyclic peptides (<0.1% C3a activity). N-terminal acylation with cationic, arginine-rich sequences like YRRGR- led to amplified biological effects. Three of the synthesized peptides, namely CAALCLAR (P1), YRRGR°CGGLCLAR (P5) and YRRGRAhx°CGGLCLAR (P8), point in the direction of C3a antagonists.     

Immunogenicity of recombinant Plasmodium falciparum rhoptry associated proteins 1 and 2

Mice and rabbits immunized with recombinant forms of malaria vaccine candidate antigens rhoptry-associated proteins 1 and 2 (RAP-1, RAP-2 and rRAP-l, rRAP-2) produce antibodies at litres equivalent to monoclonal antibody ascites fluid raised against the native proteins. Sera from animals immunized with rRAP-l contain antibodies which recognize the native protein by indirect immunofluorescence and immunoblotting, partially inhibit erythrocyte invasion in vitro and are long lasting. Epitope mapping shows these antibodies predominantly recognize epitopes in the N-terminal third of rRAP-l, some of which coincide with the targets of inhibitory monoclonal antibodies. By contrast, sera from animals immunized with rRAP-2 contain antibodies which recognize the recombinant but not the native protein     

Clinical Significance of Sleep-Related Breathing Disorders in Patients with Implantable Cardioverter Defibrillators

The prevalence and clinical significance of sleep-related breathing disorders (SRBDs) in patients with cardiac disease and a history of life-threatening ventricular tachyarrhythmias is unclear. Forty consecutive recipients of implantable cardioverter defibrillators (ICDs) with cardiac disease and a documented history of spontaneous, life-threatening, ventricular tachyarrhythmias underwent full night polysomnography. SRBDs were diagnosed if the apnea/hypopnea index was > 10. SRBD were diagnosed in 16 of 40 patients (40%): central sleep apnea (CSA) was present in 9 of these 16 patients (56%), 8 of whom had associated Cheyne-Stoke respiration. Seven of the 16 patients with SRBD (44%) had obstructive sleep apnea (OSA). Patients with and without SRBDs were comparable with respect to left ventricular ejection fraction, NYHA classification, underlying heart disease, ICD indications, and concomitant antiarrhythmic drug and beta-blocker therapy. Patients were followed prospectively for 2 years. ICD-treated ventricular tachyarrhythmias occurred in 10 of 24 patients (42%) without SRBD, in 4 of 9 patients (44%) with CSA, and in 3 of 7 patients (44%) with OSA (NS). The numbers and circadian distributions of episodes recorded during follow-up in patients without SRBD versus with CSA or OSA were not significantly different (14 ± 25, median = 4 vs 4 ± 5, median = 2.5 vs 15 ± 15, median = 7, respectively). The 2-year mortality, which was entirely attributable to nonsudden cardiac events, was highest in patients with CSA (4/9 [44%], vs 0/7 [0%] with OSA, vs 3/24 patients (12.5%) without SRBD; P < 0.05).     

Antibodies to cytoskeletal proteins in patients with Crohn''s disease

The immunologic basis of inflammatory bowel disease has been the focus of interest of a series of studies on Crohn's disease and the process of immune sensitization at the gastrointestinal mucosal level is functionally poorly understood. To date only few contradictory reports concerning the incidence of autoantibodies in patients with this disease exist. The aim of this study was to investigate the sera drawn from 60 patients suffering from biopsy-proven Crohn's disease to evaluate the prevalence of autoantibodies against nuclear antigens and cytoskeletal proteins. Using standard methods, no anti-nuclear antibodies or antibodies to extractable nuclear antigens could be detected. All sera were also negative for antibodies to double-stranded DNA, anti-mitochondrial antibodies, and antibodies to gastric parietal cells. Using sensitive enzyme-linke immunosorbent assays with purified antigens and Western blotting with cytoskeletal proteins of human intestinal cells, the following antibodies could be demonstrated: cytokeratin 18 autoantibodies (IgG 20.0%; IgM 6.7%; IgA 13.3%), actin antibodies (IgG 36.7%; IgM 48.3%, IgA 26.7%), desmin antibodies (IgG 6.7%; IgM 15.08%; IgA 5.0%), vimentin antibodies (IgG 3.3%; IgM 16.7%; IgA 10.0%) and tropomyosin antibodies (IgG 3.3%; IgM 3.3%, IgA 5.0%). Statistically significant correlations could be found for levels of cytokeratin 18 antibodies (IgM-type) and the BEST index of activity, and for levels of desmin antibodies (IgM-type) and the van HEES index of activity. Highest levels could be measured for actin antibodies (IgG-type) in patients with isolated disease manifestation in the colon. The mechanism of induction of autoantibodies against cytoskeletal components in Crohn's disease still remains obscure. Unmasking of hidden antigens after cell injury during the inflammatory process of disease might lead to sensitization and antibody production. The pattern of antibodies in patients with Crohn's disease seems to be different compared with that of connective tissue diseases.     

Determinants of the Natural Course of Ventricular Late Potentials After Thrombolytic Therapy for Acute Myocardial Infarction

The intraindividual changes of ventricular late potentials and their possible determinants were examined prospectively in 88 consecutive patients (male: 75; mean age: 58 ± 9 years) after thrombolytic therapy for acute myocardial infarction. Late potential analysis was performed 4 weeks and 12 months after acute myocardial infarction. At the same time, a left heart catheterization was performed to assess the extent of coronary heart disease and left ventricular ejection fraction. The incidence of late potential 4 weeks after acute myocardial infarction was 15% (13/88 patients). Eighteen percent (16/88) of the patients revealed changing results of late potential analysis: 9 patients lost late potential (late potential pos./neg.) 1 year after acute myocardial infarction and 7 patients presented new formation of late potential (late potential neg./pos.). Preserved late potentials were found in four patients (late potential pos./pos.). Late potential analysis remained negative in 68 patients (late potential neg./neg.). There was no influence of age, gender, site of infarction, clinical course, and medical treatment on the natural course of late potential. Changing results of late potential analysis seemed to be correlated with the evolution of left ventricular ejection fraction and the dynamics of coronary heart disease. In the group late potential pos./pos., comparable values for left ventricular ejection fraction were measured at both examinations, whereas late potential neg./neg. had a significant increase in ejection fraction. In the group late potential pos./neg., a significant improvement in left ventricular function was also measured. In contrast, the late potential neg./pos. group tended to have lower left ventricular ejection fractions 1 year after infarction. In the late potential neg./pos. and late potential pos./pos. groups, the extent of coronary artery disease returned to conditions comparable to baseline despite an initial reduction after coronary revascularization performed 4 weeks after infarction. Late potential neg./neg. and late potential pos./neg. revealed a stable benefit gained from coronary revascularization with a persistent reduction in the number of diseased vessels. Dynamic changes in the results of the signal-averaged ECG 1 year after thrombolytic therapy for acute myocardial infarction were observed in 18% of the patients. These changes seem to be correlated with the evolution of left ventricular function and the dynamics of coronary artery disease.     

A phase I/II trial of recombinant human interleukin-6 in patients with aplastic anaemia

Summary. In a phase I/II study, 11 patients with marrow failure (10 with acquired aplastic anaemia and one with pancytopenic Fanconi anaemia) were treated with recombinant human interleukin-6 (rhIL-6) to assess the safety and tolerability of rhIL-6 and its effects on peripheral blood counts, bleeding complications and transfusion requirements. All patients with acquired aplastic anaemia were refractory to immunosuppressive treatment or had relapsed after immunosuppressive therapy and were not bone marrow transplantation candidates. Recombinant hIL-6 was to be given as a once-daily subcutaneous injection for 28 d at doses ranging from 0-5 to 5-0βg/kg. After an observation period of 2 weeks, five patients received a second treatment course of 28 d.
Only one patient had a sustained increase in platelet count from 18 000 to 72 000/ fA. Bleeding occurred in four patients and caused premature discontinuation of rhIL-6 therapy in three patients. A deterioration of pre-existing anaemia was observed in nine patients. No significant changes of leucocyte counts were observed during the first cycle. During the second cycle the peripheral blood monocyte counts decreased significantly. No significant changes in bone marrow cellularity were observed. Recombinant hIL-6 induced a dose-dependent increase in acute-phase reactants in all patients. Other adverse events included fever, headache, arthralgia, tachycardia and hypertension. In conclusion, rhIL-6 given alone at low doses does not increase platelet counts in the majority of patients with aplastic anaemia and can precipitate a sudden worsening of pre-existing anaemia and thrombocytopenia. This study was discontinued prematurely on account of the toxicity of rhIL-6 seen in patients with aplastic anaemia.     

NCI-Black-Reiter (NBR) Male Rats Fail to Develop Renal Disease following Exposure to Agents That Induce {alpha}-2u-Globulin ({alpha}2u) Nephropathy

NCI-Black-Reiler (NBR) Male Rats Fail to Develop Renal Diseasefollowing Exposure to Agents That Induce _2u-Globulin (_2u) Nephropathy.Dietrich, D. R., and Swenberg, J. A. (1991). Fundam. Appl. Toxicol16, 749–762. The NCI-Black-Reiter (NBR) rat is the onlystrain of male rat known not to synthesize the hepatic formof the low molecular weight protein, _2u-globulin. In previousstudies, NBR rats were shown not to develop renal disease whenexposed to decalin, a compound known to induce _2u-globulin nephropathyin other rat strains. The objective of this study was to showthat the presence of _2u-globulin (_2u-) is essential for thedevelopment of this syndrome in rats exposed to 2,2,4-trimethylpentane(TMP), 1,4-dichlorobenzene (DCB), isopho-rone (IP), PS-6 unleadedgasoline (UG), and d-limonene (d-L). The induction of _2u-nephropathyin F344 male rats with lindane was used as a positive controland this response was contrasted to male NBR and female F344rats treated with lindane. Five to seven 11-week-old male NBRrats were exposed to TMP (500 mg/kg/day), DCB (500 mg/kg/day),IP (1000 mg/kg/day), UG (500 mg/kg/day), d-L (1650 mg/kg/day),or lindane (10 mg/kg/day) and five 11-week-old male and femaleF344 rats were exposed to lindane (10 mg/kg/day) by oral gavageon 4 consecutive days. NBR male and F344 male and female ratsgavaged with corn oil were incorporated in the study as vehiclecontrols. The presence of hyaline droplets was assessed in perfusion-fixedkidneys by staining paraffin sections with Mallory-Heidenheinstain and in GMA sections with Lee's methylene basic blue fuchsinstain. Paraffin sections were also analyzed immunohistochemicallyfor the presence of _2u-. Under exposure conditions that clearlyinduce _2u-nephropathy in male F344 rats, no lesions, hyalinedroplets, or _2u- were detectable in treated or control maleNBR and female F344 rats. It is thus concluded that the presenceof _2u is causal to the development of renal disease in ratsexposed to TMP, DCB, IP, UG, d-L, and lindane.