Studies on the mechanism of action of penicillopepsin.
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Amino Acid Sequence↗
Biomedical subjects
T Hofmann
Publications and source records attributed to T Hofmann.
In vivo regulation of surfactant proteins by glucocorticoids.
Surfactant proteins have key roles in regulating surfactant secretion, in recycling, and in the assembly of the surfactant monolayer but little is known about their regulation in vivo. Surfactant proteins SP-A, SP-B, and SP-C have been shown to be upregulated by glucocorticoids in vitro, but the role of glucocorticoids in the physiologic regulation of surfactant protein synthesis remains unknown. We have studied the effects of exogenously administered glucocorticoids on the regulation of steady-state surfactant protein mRNA accumulation. We have also studied the effects of adrenalectomy on the accumulation of the surfactant protein mRNAs. Surfactant protein genes appear to have quantitatively different responses to exogenously administered glucocorticoids, with SP-C mRNA increasing at the lowest dose, SP-A and SP-B mRNA increasing in response to similar glucocorticoids doses but with SP-B yielding the highest maximum response. Adrenalectomy, however, does not alter surfactant protein mRNA levels. These observations support a minor role for glucocorticoids in maintaining the steady-state accumulation of surfactant protein mRNA. Adrenalectomy decreases total pulmonary SP-A when compared to sham-operated animals in the absence of changes in its mRNA. Therefore, glucocorticoids may have translational or post-translational effects that regulate total pulmonary SP-A accumulation, but the effects appear to be minor. These findings support a potential role for the adrenal in the pulmonary response to stress and demonstrate for the first time differential accumulation of the surfactant protein mRNAs to glucocorticoids in vivo.
Adrenalectomy↗
Can we predict sudden cardiac death?
Up to now only 30 to 40% of patients who die suddenly can be identified as likely candidates before the event. Risk factors in these asymptomatic subjects include a familial history of coronary artery disease, high blood cholesterol levels, hypertension, smoking and, more importantly, an abnormal ECG at rest or during exercise. The predictive value of these abnormalities is too low to justify more detailed clinical investigations in most of these asymptomatic subjects. Exceptions might be the group of patients with multiple risk factors and competitive sportsmen. Sudden cardiac death is a well known complication in patients with hypertrophic and dilated cardiomyopathy. Risk factors in hypertrophic cardiomyopathy include a familial history of this disease, syncope and increasing age. Furthermore, in the adult, the presence of nonsustained episodes of ventricular tachycardia during Holter monitoring seems to indicate an increased risk of sudden cardiac death. In idiopathic dilated cardiomyopathy, the presence of frequent episodes of ventricular pairs and/or episodes of ventricular tachycardia during Holter monitoring, together with a reduced left ventricular ejection fraction, characterises the patient at risk of sudden cardiac death. In patients with coronary artery disease, the patient at risk of sudden cardiac death can be identified by investigating the following: coronary anatomy; global and regional left ventricular function; the presence of ischaemia during rest and/or exercise; the presence of late potentials, by means of the signal-averaged ECG; the presence of spontaneous ventricular arrhythmias (especially sustained and nonsustained ventricular tachycardia); and the results of electrophysiological testing. On the basis of these investigations, 3 subgroups can be distinguished: patients at low risk, medium risk, and high risk of sudden cardiac death.
Death, Sudden↗
[The determination of left ventricular flow rates using single-probe radiocardiography in the steady-state distribution phase].
A new procedure of extracting data from measurements by single-probe radionuclide ventriculography is presented which reduces the phase differences during summation of single-beat actions and permits the use of a greater number of single actions for summation. Sum curves so determined are better suited for measurements of ejection fractions, compliance and ventricular blood flow rates.
Angina, Unstable↗
[Role of cephalometry in orthodontic treatment planning. A study with case report with various considerations of the Quick Ceph Image programs].
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Adolescent↗
[Arrhythmia and anti-arrhythmia therapy as prognostic risks].
The incidence of sudden death is estimated to be 0.25%/year in the industrialized world. 30 to 40% of patients are known to be at major risk before they succumb sudden death. Etiology is usually coronary heart disease (75%), dilated and hypertensive cardiomyopathy as well as valvular disease. 75% of patients dying suddenly die from ventricular fibrillation. The most common mechanism of sudden cardiac death in heart failure is sustained ventricular tachycardia deteriorating into ventricular fibrillation, the initiating factors being single ventricular beats, ventricular pairs or nonsustained ventricular tachycardia (trigger mechanism). At least 50% of patients dying during Holter monitoring have been on antiarrhythmic treatment during the time of sudden death and this percentage is increased to 70% in patients dying from torsade de pointes ventricular tachycardia. The question that has arisen is whether suppression of such arrhythmias by antiarrhythmic agents will reduce the incidence of sudden cardiac death. Unfortunately, the patient group at highest risk - low ventricular ejection fraction and high incidence of nonsustained ventricular tachycardia episodes during 24 hour-monitoring and thus, the group most in need of arrhythmia suppression - has the lowest responder rate as well as the highest incidence of serious toxicity. Until the suppression of those arrhythmias by antiarrhythmic agents is demonstrated to improve prognosis in this patient group, routine use of antiarrhythmic agents cannot be recommended in this patient population.
Anti-Arrhythmia Agents↗
[Progress in clinical cardiology. Echocardiography].
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Blood Flow Velocity↗
Rate-determining steps in penicillopepsin-catalysed reactions.
The hydrolysis of Ac-(Ala)2-Lys-Nph-(Ala)2-amide (II) by penicillopepsin is characterized by a solvent isotope effect of 2.11, whereas the hydrolysis of Ac-Lys-Nph-amide (I) shows no solvent isotope effect. The dependence of the isotope effect on the concentration of D2O in H2O for substrate II is not linear and suggests that two or more protons are involved in its rate-determining step. We propose that for substrate I the rate-determining step is the distortion of the scissile bond towards a tetrahedral configuration, and for substrate II a conformational change induced by the occupation of the S3 pocket in the enzyme.
Amino Acid Sequence↗
Echocardiographic evaluation of patients with clinically suspected arterial emboli.
153 patients (mean age 42 years, range 16-60) who had arterial embolic events were examined prospectively by transthoracic and transoesophageal echocardiography. Patients older than 60 years and those with evidence of extracranial carotid artery occlusive disease were excluded. 84 patients had a cerebral ischaemic event, 50 patients had embolic events in an abdominal organ or limb, and 19 patients had acute retinal ischaemia. The transthoracic echocardiographic examination was normal in 92 patients (60%), whereas only 65 patients (42%) had normal findings after both transthoracic and transoesophageal examination (p less than 0.005). Intracardiac masses, including valvular vegetations, were found in 39 patients (25%), including 27% of patients with cerebral embolism and 32% of these with peripheral embolism, but in none of the patients with retinal ischaemia (p less than 0.001). 47 patients (31%) had valvular disease, 10 (7%) had wall motion abnormalities, 23 (15%) had abnormalities of the interatrial septum, and 9 patients (6%) had diseases of the thoracic aorta. Cardiovascular abnormalities were frequently found by echocardiography in patients with arterial emboli. The transesophageal technique significantly increased the chance of detecting such abnormalities, especially intracardiac masses.
Adolescent↗
A ligand-induced, temperature-dependent conformational Change in penicillopepsin. Evidence from nonlinear Arrhenius plots and from circular dichroism studies.
The effect of temperature on the rate constants of hydrolysis of various substrates by penicillopepsin is dependent on the length of the substrate. For the series Ac-(Ala)m-Lys-Nph-(Ala)n-amide (where Ac- is acetyl- and Nph- is p-nitrophenylalanyl-), where m and n = 0-2, substrates lacking both P'2 and P3 residues give linear Arrhenius plots with an energy of activation of about 55 kJ.mol-1. The Arrhenius plots of substrates in which an alanine residue occupies P'2 show a sharp break at an average transition temperature of 10.5 degrees C. The activation energies are approximately 90 kJ.mol-1 below and approximately 54 kJ.mol-1 above the transition temperature, respectively. For substrates in which P3 is occupied, the average transition temperature is 14.2 degrees C. In this case, the activation energies are 66 kJ.mol-1 below and from 26 to 39 kJ.mol-1 above the transition point. The most probable explanation of these phenomena is that substrate interaction at subsites S3 and/or S'2 of the enzyme induces a temperature-dependent conformational change. Physical evidence for this comes from the observation that the temperature dependence of a CD absorption band at 242 nm of a penicillopepsin-pepstatin complex shows a sharp break that corresponds to those observed in the Arrhenius plots of substrates with alanine at P'2 and P3, whereas the same CD band in the free enzyme is linearly dependent on temperature.
Amino Acid Sequence↗
Repeat determination of left ventricular wall thickness from mass and volume during one cardiac cycle for the calculation of left ventricular wall stress parameters.
Left ventricular end-diastolic wall stress, end-systolic wall stress, and systolic stress-time integral are important parameters to characterize left ventricular load and function. To obtain these parameters, left ventricular pressure, volume, and wall thickness data must be determined at short time intervals throughout one cardiac cycle. However, the measurement of wall thickness at short intervals (i.e., 20 ms) throughout a cardiac cycle is tedious. Furthermore, measurements of wall thickness are less accurate at end-systole compared with end-diastole. For these reasons we developed a computer program for calculating wall thickness at short intervals (20 ms) throughout the cardiac cycle from one single determination of left ventricular wall mass and repetitive measurements of left ventricular (LV) volume.
Computer Simulation↗
Purification and characterization of the Dr hemagglutinins expressed by two uropathogenic Escherichia coli strains.
The fibrillar Dr hemagglutinins expressed by two uropathogenic Escherichia coli isolates were mechanically sheared from whole cells and subsequently purified by using anion-exchange high-pressure liquid chromatography. The isolated hemagglutinins were proteins with apparent subunit molecular masses of 14,500 daltons by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and isoelectric points of 5.4 in denaturing isoelectric focusing gels. The two proteins were serologically related to each other but distinct from P fimbriae, as assessed by bacterial agglutination and immunoblotting. The amino acid compositions of the two hemagglutinins were highly similar both to each other and to other Dr hemagglutinins. N-terminal amino acid sequencing of the major hemagglutinin subunit proteins demonstrated homology with afimbrial E. coli adhesins.
Adhesins, Escherichia coli↗
Beta-blocking agents vs. antiarrhythmic interventions in heart failure complicated by arrhythmias.
Approximately 40-50% of the patients with end-stage cardiac failure (either ischemic or nonischemic) die suddenly and unexpectedly, most probably from ventricular fibrillation. It is unclear whether the complex ventricular arrhythmias observed in large numbers of these patients were related to the mode of death. Theoretically, it seems quite reasonable to attempt to suppress the development of life-threatening ventricular arrhythmias (e.g., sustained ventricular tachycardia or ventricular fibrillation) in those patients. If antiarrhythmic drug therapy is ineffective, alternative antiarrhythmic interventions (antiarrhythmic surgery or implantation of an automatic implantable cardioverter defibrillator) should be considered. In patients with so-called potentially malignant ventricular arrhythmias (e.g., nonsustained ventricular tachycardia), antiarrhythmic drug therapy remains controversial as presently there is no definitive proof that this therapy prolongs life or reduces the incidence of sudden cardiac death. In patients with end-stage cardiac failure, beta-blockade can result in a decrease in resting tachycardia, improvement in clinical heart failure symptoms, and increase in work load capacity. It remains controversial whether treatment with these agents can also improve prognosis and prevent sudden cardiac death. Therefore, at this time, only patients in the earlier stages of this clinical syndrome and with clinical signs of markedly increased sympathetic tone can be treated with low doses of beta-blockers.
Adrenergic beta-Antagonists↗
[How are tachycardic cardiac arrhythmias modified by therapy of congestive heart failure?].
Previous studies have demonstrated the high prevalence of frequent and complex ventricular arrhythmias in patients with severe congestive heart failure. It has been claimed that these arrhythmias are independent risk factors of prognosis. Moreover in severely depressed left ventricular function frequent and repetitive arrhythmias may deteriorate the hemodynamic situation. Recent clinical studies have drawn increasing attention to the possibility that the desired therapeutic effect of Class I antiarrhythmic agents may be complicated by their ability to aggravate the arrhythmia or to provoke new arrhythmias. These "proarrhythmical effects" were more frequent in patients with life-threatening arrhythmias and in those with severely depressed left ventricular function. Prevention trials with Class I antiarrhythmic agents have failed to show beneficial effects on the arrhythmia profile and on the prognosis of those patients. On the other hand, it is now well recognized that the incidence of cardiac death can be reduced by the use of ACE-inhibitors in this patient population. Accordingly, there is evidence of a reduced incidence of complex ventricular arrhythmias during treatment with these drugs in some of the patients with congestive heart failure. The influence of digitalis on the arrhythmia profile and the cardiac mortality in these patients is still a matter of debate. On the other hand, there is evidence that newer positive inotropic agents such as phosphodiesterase-inhibitors rather increase the number of arrhythmias and the prevalence of sudden cardiac death in this patient population.
Angiotensin-Converting Enzyme Inhibitors↗
[Transesophageal echocardiography in the assessment of the severity of aortic valve stenosis].
The aortic valve orifice area was measured in 95 patients with valvular aortic stenosis by means of transthoracic and transesophageal echocardiography. These results were compared to invasively determined measurements. The aortic-valve orifice area could be measured by transesophageal echocardiography in 87 patients (92%), and in 13 patients (14%) by the transthoracic approach. A comparison of the valve-orifice area determined by transthoracic and transesophageal echocardiography revealed a correlation coefficient of r = 0.91. There was also a good agreement when the aortic-valve orifice area determined by transesophageal echocardiography was compared to the invasive findings (r = 0.82; p less than 0.001). The morphology of the aortic valve could be better delineated with the transesophageal approach.
Adult↗
[Elimination of secretions in CF patients under amiloride inhalation].
Inhaled amiloride reduces active absorption of sodium of respiratory epithelium in CF patients and so, transiently, diminishes loss of water. 10 CF patients, 8 to 28 years of age, were examined on two days. First day, they inhaled in a randomised order isotonic saline and a solution of amiloride hydrochloride (0.3 mg/ml) one after another, each inhalation taking twenty minutes. Second day, inhalations were performed in an inverse order. To intensify the effect of inhalation, the inhalation procedure was combined with "autogenic drainage", a special kind of physiotherapy. Main criterion for evaluation was the amount of expectorated sputum. Mean increase of sputum during amiloride inhalation in comparison to saline was +50.4%. Patients and physiotherapist observed a liquefaction of secretion and a decrease of coughing by amiloride and a support of physiotherapy. These results suggest a beneficial clinical effect of regular amiloride inhalation in CF patients.
Absorption↗
Identification of an isoaspartyl linkage formed upon deamidation of bovine calbindin D9k and structural characterization by 2D 1H NMR.
Preparations of recombinant bovine calbindin D9k (r-calbindin) that appear homogeneous on SDS electrophoresis gels have been shown by isoelectric focusing to be mixtures of proteins differing in net charge. The production of two isoforms with increased negative charge occurs during a routine urea denaturation step and can be effectively suppressed by replacing this procedure with thermal denaturation. The two isoforms have been separated from the native protein by DEAE-Sephacel ion-exchange chromatography. Amino acid sequencing of tryptic peptide fragments and two-dimensional (2D) 1H NMR studies establish that the isoforms correspond to calbindin D9k deamidated at Asn56 and that the major product has an isoaspartate (beta-linked peptide) residue at this position. The minor deamidated component is found to have a normal Asp-Gly alpha-linkage. A detailed analysis of proton chemical shifts, phi backbone dihedral angles, and nuclear Overhauser effects indicates that the global conformation of r-calbindin is not perturbed upon deamidation and that all elements of secondary structure are intact. The Asp56 form is nearly identical with the intact protein, whereas the structure of the iso-Asp56 form is perturbed, predominantly in the polypeptide segment Lys55-Asp58. These studies demonstrate that 2D 1H NMR techniques can be used to identify and quantitate the two isoforms produced upon deamidation of a protein and to assess changes in the local and global conformation.
Amino Acids↗
1H NMR studies of porcine calbindin D9k in solution: sequential resonance assignment, secondary structure, and global fold.
The 1H nuclear magnetic resonance (NMR) spectrum of Ca2+-saturated porcine calbindin D9k (78 amino acids, Mr 8800) has been assigned. Greater than 98% of the 1H resonances, including spin systems for each amino acid residue, have been identified by using an approach that integrates data from a wide range of two-dimensional scalar correlated NMR experiments [Chazin, Rance, & Wright (1988) J. Mol. Biol. 202, 603-626]. Due to the limited quantity of sample and conformational heterogeneity of the protein, two-dimensional nuclear Overhauser effect (NOE) experiments also played an essential role in the identification of spin systems. On the basis of the pattern of scalar connectivities, 43 of the 78 spin systems could be directly assigned to the appropriate residue type. This provided an ample basis for obtaining the sequence-specific resonance assignments. The elements of secondary structure are identified from sequential and medium-range NOEs, values of 3JNH alpha, and the location of slowly exchanging backbone amide protons. Four well-defined helices and a mini beta-sheet between the two calcium binding loops are present in solution. These elements of secondary structure and a few key long-range NOEs provided sufficient information to define the global fold of the protein in solution. Generally good agreement is found between the crystal structure of the minor A form of bovine calbindin D9k and the solution structure of intact porcine calbindin D9k. The only significant difference is a short one-turn helix in the loop between helices II and III in the bovine crystal structure, which is clearly absent in the porcine solution structure.
Amino Acid Sequence↗