Biomedical subjects
Publications and source records attributed to T Hofmann.
The possibility of reducing the number of animals in sensitization studies (maximization method) is discussed on the basis of results from 20 sensitization tests. It appears that the number of test animals in sensitization studies may be reduced to ten treated animals and five control animals without prejudice to the quality of the test.
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The synthesis of two new analogues of statine are reported corresponding to analogues with the lysine side chain and the ornithine side chain. These analogues were designed on the basis of substrate specificity and molecular modeling of three-dimensional structures of the penicillopepsin: Iva-Val-Sta-OEt crystal structure. 4,8-Diamino-3-hydroxyoctanoic acid [LySta] and 4,7-diamino-3-hydroxyheptanoic acid [OrnSta] were synthesized respectively from Boc-Lys(Z)-al and Boc-Orn(Bzl,Z)-al by addition of lithio ethyl acetate to the aldehyde group. The [LySta] derivative was converted to the trichloroethoxycarbonyl derivative and separated into the corresponding 3S,4S and 3R,4R diastereomers. The [OrnSta] derivative was used as a mixture of 3-position diastereomers. These new amino acids were used to prepare the following inhibitors: Iva-Val-Val-[LySta]-OEt and Iva-Val-Val-[OrnSta]-OEt as well as the corresponding synthetic intermediates. Inhibition constants (Ki values) were measured for inhibition of porcine pepsin and penicillopepsin. Both compounds were potent inhibitors of penicillopepsin with Ki values 10-100 times smaller (2.1 and 1.1 nM, respectively) than the Ki of Iva-Val-Val-Sta-OEt (47 nM). In contrast both inhibitors are exceptionally weak inhibitors of porcine pepsin with Ki values greater than 1 microM. These results are correlated with the ability of the basic group in the new inhibitors to bind to aspartic acid-77 in penicillopepsin.
We previously reported a family with apolipoprotein C-II (apoC-II) deficiency characterized by the presence of a mutant apoC-II, apoC-IIToronto. We now report the purification and primary structure of apoC-IIToronto. The sequence of apoC-IIToronto is identical to that of normal apoC-II from residues 1-68. It differs from residue 69, where Asp69-Gln70-Val71-Leu72-Ser73-Val74- Leu75-Lys76-Gly77-Glu78-Glu79 is replaced by Thr69-Lys70-Phe71-Phe72-Leu73-Cys74. This is consistent with the deletion of a nucleotide in the codon for either Thr68 or Asp69 and a translation reading frame shift.
The complete amino acid sequence of the alpha chains of both isolectins found in pea seeds has been determined using automated Edman degradation. We show that the alpha chains of these two proteins differ only at their C-termini: isolectin B is two amino acids longer than isolectin A. Furthermore, the alpha chains of both isolectins are shorter than would be predicted from the nucleotide sequence of a cDNA clone for pea lectin. We suggest, therefore, that these proteins arise from differential C-terminal processing. Amino acid composition data and C-terminal analysis show that the beta chains have also been processed at their C-termini, but in this case identical chains for both isolectins are produced.
50 consecutive patients with acute myocardial infarction and symptoms of less than 4 hours duration were treated with anisoylated plasminogen streptokinase activator complex (APSAC) 30U intravenously as a bolus injection over 5 minutes. An open infarct-related artery was found in 32 patients (64%) when the first coronary angiography was taken 66 +/- 21 minutes after APSAC. Complete reperfusion was subsequently seen in 10 of 18 patients with an occluded infarct-related artery 74 +/- 16 minutes after injection of APSAC. Thus, a patient infarct-related artery was seen in 42 patients (84%) within 68 +/- 20 minutes. A control coronary angiography was performed in 37 patients (74%) after 25 +/- 19 days. Reocclusion was found in 5 patients. The minimal cross-sectional area of the residual coronary stenosis increased from 1.3 +/- 0.9 mm2 to 1.8 +/- 1.9 mm2. Patients with residual thrombi after coronary thrombolysis (n = 13) demonstrated an increase of the minimal cross-sectional area of the residual stenosis from 1.2 +/- 0.8 to 2.6 +/- 2.3 mm2, whereas those without residual thrombi showed only minor changes of the minimal cross-sectional area (1.3 +/- 0.9 to 1.2 +/- 1.2 mm2). Thus, APSAC demonstrated a high patency rate and a low reocclusion rate after intravenous administration. The prolonged fibrinolytic activity of APSAC leads to a further regression of the residual coronary stenosis among patients with coronary thrombi after reperfusion.
In a prospective study, 267 patients with invasively diagnosed coronary artery disease were studied by programmed electrical stimulation (PES) and induced ventricular arrhythmias were compared to spontaneous arrhythmias occurring during 24 h Holter registration. In 89 patients (33%) no evidence of myocardial infarction was present, 61 patients (23%) were studied for 6 weeks to 3 months, 36 patients (13%) for 3-6 months and 81 patients (31%) for more than 6 months after myocardial infarction. PES was performed in the right ventricular apex with 1 and 2 extrastimuli during pacing with 100, 120 and 140 beats/min. Endpoint of the study was defined by the induction of 4 repetitive ventricular responses (RVR). Within 72 hours after PES a 24 h Holter registration was performed in all patients. During PES, 15 patients (6%) were not inducible for any RVR. Single RVR (1-2) were induced in 146 patients (55%) and 3-5 RVR in 68 patients (25%). Ventricular tachycardia and ventricular fibrillation were induced in 38 patients (14%); 6 patients showed a sustained, monomorphic tachycardia. Altogether, the incidence of RVR was higher when a history of myocardial infarction was present. With increasing time after infarction the incidence of inducible 3-5 RVR remained stable; however, the number of greater than 6 RVR decreased. During Holter registration, 54/255 patients (21%) showed no spontaneous ventricular arrhythmias, 70 patients (28%) had arrhythmias of Lown-class I/II, 84 patients (33%) of Lown-class III. Complex arrhythmias were observed in 47 patients (18%) (Lown-class IVA: 33 patients, IVB: 14 patients).(ABSTRACT TRUNCATED AT 400 WORDS)
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The incidence and severity of ventricular arrhythmias were compared with hemodynamic findings of cardiac catheterization, in 160 patients with mitral and aortic valve disease. All patients underwent right and left heart catheterization, as well as M-mode and 2D-echocardiography, and 24-hour ambulatory electrocardiographic monitoring. Out of 160 patients, 68 had mitral valve disease and 92 had aortic valve disease. In mitral regurgitation the degree and frequency of ventricular arrhythmias showed a positive correlation to the degree of regurgitation (rs = 0.44, rs = 0.56, respectively) and a negative correlation to left ventricular ejection fraction (rs = -0.49, rs = -0.57) and to cardiac index (rs = 0.48, rs = 0.53). In aortic valve disease the incidence and severity of ventricular arrhythmias were not related to the type of valve lesion, to the transvalvular pressure gradient nor to the degree of regurgitation. In aortic stenosis, the degree of arrhythmia showed a negative correlation to left ventricular ejection fraction (rs = 0.55) and a positive correlation to left ventricular endsystolic volume index (rs = 0.40) and to peak systolic left ventricular wall stress (rs = 0.59). In aortic regurgitation the number of ventricular arrhythmias showed a negative correlation to left ventricular ejection fraction (rs = -0.43) and a positive correlation to left ventricular endsystolic volume index (rs = 0.43) and to peak systolic left ventricular wall stress (rs = 0.37). These data demonstrate that the incidence and severity of ventricular arrhythmias, in patients with aortic valve disease and mitral regurgitation, are strongly associated with the impairment of left ventricular function.
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Intestinal calcium binding proteins (ICaBP's) constitute a group of small vitamin D inducible proteins considered to play an important role in the absorption of dietary calcium. The mammalian ICaBP's are representatives of the "EF-hand" family of calcium binding proteins. As a first step in the application of protein engineering techniques to the study of structure-function relationships in mammalian ICaBP's, we have synthesized a gene encoding the minor A form (the native form lacking the two N-terminal amino acids) of bovine ICaBP employing a rapid, microscale gene synthesis technique based on "shotgun ligation" of sets of oligonucleotides. Expression of the synthetic gene from a plasmid containing the tac promoter in a lon protease deficient strain of Escherichia coli yielded the desired product at a level of about 1-2 wt % of total protein. During the purification of the ICaBP expressed in E. coli, a contaminant was strongly adhering to it but was efficiently removed by gel filtration after denaturation with urea. The minor A form of ICaBP produced in E. coli was characterized by its mobility during sodium dodecyl sulfate-polyacrylamide gel electrophoresis and by its total amino acid composition, partial amino acid sequence, UV absorption spectrum, and 360-MHz 1H NMR spectrum, showing beyond reasonable doubt its identity with the minor A form of ICaBP obtained from bovine intestines.
The safety and fibrinolytic efficacy of a new anisoylated plasminogen-streptokinase activator complex (APSAC) was tested in 50 patients with acute myocardial infarction (AMI) less than 4 hours in duration. APSAC (30 mg) was given intravenously as a bolus injection 151 +/- 47 minutes after clinical symptoms. Coronary angiography was then performed to assess coronary artery patency: 28 patients had an inferior AMI and 22 an anterior AMI. A patent infarct-related artery was found in 32 patients (64%) on first coronary angiography 66 +/- 21 minutes after administration of APSAC. Subsequent reperfusion was observed in 10 patients after 74 +/- 16 minutes (84%). Bleeding complications or hematomas were observed in 18 patients, of whom 3 required blood transfusions. Marked hypofibrinogenemia was observed within 24 hours in most patients. A control coronary angiogram was recorded in 37 patients (74%) after 25 +/- 19 days and showed reocclusion in 5 patients.
The complete amino acid sequences of two basic proline-rich proteins, IB-1 and IB-6, from human parotid saliva have been determined. Fragments for sequence analysis were obtained by enzymatic digestions. The proteins have molecular weights of 9571 (IB-1) and 11,530 (IB-6) and contain 34 and 39 mol % proline, respectively. IB-1 and IB-6 contain an identical sequence of 54 residues except for an alanine in position 52 of IB-6, where IB-1 has proline. An unusually high number of repeated sequences occurs in both molecules. IB-1 has a blocked amino-terminal residue, pyroglutamic acid, and also contains one phosphoserine residue in position 8. The relationship of these proteins to the basic proline-rich protein IB-9 [Kauffman, D., Wong, R., Bennick, A., & Keller, P. (1982) Biochemistry 21, 6558-6562] and to other salivary proline-rich proteins is discussed.
Echocardiographic studies were performed in 105 patients with acute and recurrent pulmonary emboli. Pulmonary embolism was confirmed by pulmonary angiography (n = 48), autopsy (n = 6), and lung perfusion scintigraphy (n = 51). Seventy of 93 patients (75%) displayed a dilated right ventricle, 38 of 91 patients (42%) had reduced left ventricular cavity dimension, 41 of 82 patients (50%) had a decreased EF slope of the mitral valve, and 78 of 101 patients (77%) showed dilatation of the right pulmonary artery. The motion of the interventricular septum was abnormal in 41 of 93 patients (44%). Right-sided thrombi were seen in 13 patients within the right pulmonary artery (n = 11) and in the right ventricle (n = 3); in one patient they were found in the superior vena cava, in the innominate vein, and the right atrium. Two patients suffered from right-sided endocarditis. Thus echocardiographic changes were frequently found in patients with proved pulmonary emboli. The echocardiographic findings of right-sided cardiac and pulmonary artery abnormalities indicate hemodynamically active pulmonary emboli.
The study of recessive oncogenes such as those responsible for retinoblastoma and Wilms tumor is difficult because the gene products involved are unknown and because the diseases are not associated with unique cellular or molecular phenotypes suitable for genetic manipulation. Since the gene for esterase D (ESD) is known to be tightly linked to the retinoblastoma locus (RB1) in the q14.1 band of chromosome 13, we have cloned the ESD gene from a human cDNA library by using oligonucleotides specific for a partial amino acid sequence of the purified enzyme to provide a genetic marker for further studies on retinoblastoma. The putative ESD gene codes for a message of 1.2 kilobases, which is present in all cell types examined, and maps to 13q14.1, thus confirming that it is the ESD gene. Restriction enzyme analysis reveals a restriction fragment length polymorphism with Apa I; this polymorphism results from the heterozygosity of 32% of the individuals tested and is shown to be useful in identifying carriers of the mutation responsible for retinoblastoma. A preliminary screen of 24 retinoblastoma tumors by Southern blot did not reveal any homologous deletions or rearrangements of the ESD locus.