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Biomedical subjects

T Hofmann

Publications and source records attributed to T Hofmann.

At least 37 records · Page 2Linked to original sources
PubMed1996

Clinical pharmacokinetics of tacrolimus in rescue therapy after renal transplantation.

Tacrolimus, a potent new immunosuppressive drug, was introduced for rescue therapy in 25 renal transplant recipients with ongoing rejection (n = 24) or severe cyclosporine toxicity (n = 1). A highly significant (p < 0.001) rise in serum creatinine from 138 +/- 14 (3 months before conversion) to 295 +/- 26 mumol/l preceded conversion to tacrolimus. Tacrolimus rescue therapy started 73 +/- 9 months after transplantation, the follow-up was 8 +/- 1 months. Outcome, pharmacokinetics, and side-effects were analyzed. Patient survival was 100% on tacrolimus therapy. Graft survival was 88% after 3 months, and 70% after 8 months. Serum creatinine remained stable during the observation period (Crea after 8 months: 271 +/- 26 mumol/l). Starting with an initial dose of 9.6 +/- 0.3 mg/day (0.14 +/- 0.01 mg/kg/day) we could reduce tacrolimus dose to 6.0 +/- 0.9 mg/day (0.09 +/- 0.02 mg/kg/day; p < 0.001) after 1 month. Tacrolimus trough levels were adjusted to a therapeutic window of 5-8 ng/ml. We had to perform 3.4 +/- 0.5 dose adjustments per patient mainly within the first month after conversion (70%). A high variability in interindividual tacrolimus dose was noted. Last cyclosporine dose was a good predictor of required tacrolimus dose after 1 month (r = 0.88; p < 0.001). Overall, 82 adverse events were noted, of which 29 (35%) were associated with high trough levels (> 10 ng/ml). In contrast, 3 patients with trough levels < 4 ng/ml had ongoing rejection. Blood pressure and routine laboratory data remained unchanged. Steroid dose could be tapered from 12 +/- 2 to 5 +/- 0.3 mg/day (p < 0.02). Gingival hyperplasia and hirsutism improved after conversion. We conclude: Tacrolimus conversion for rescue therapy after renal transplantation is efficient and safe with target trough levels between 5 -8 ng/ml. Frequent drug monitoring is necessary, especially within the first month after conversion. Previous cyclosporine dose can be used as a guideline for starting dose.

Adult↗
PubMed1995

Chimeric envelope glycoproteins constructed between amphotropic and xenotropic murine leukemia retroviruses.

A set of chimeric envelope proteins between amphotropic and xenotropic murine leukemia retroviruses (MuLV), two closely related members in the MuLV family, were constructed. The purpose was to examine the regions that could be successfully exchanged between these two similar viral envelope proteins. The data indicate that fully active chimeras can be built when the junction is either at the EcoRI site (amino acid 169) 42 amino acids N-terminal to the polyproline hinge of gp70 (named CH4) or at the ScaI site (aa 593) in the membrane spanning portion of p15E (CH1). However, a chimera at the AflII site (aa 125, CH5) and two in the C-terminal end of gp70 (aa 418, CH2; aa 326, CH3) were inactive. These results, taken together with other data from our laboratory and others, suggest that the entire gp70/p15E structure is sensitive to alterations and that even envelope proteins that are very similar have only a limited ability to exchange sequences.

3T3 Cells↗
PubMed1995

Chiari's network: normal anatomic variant or risk factor for arterial embolic events?

OBJECTIVES: This study was performed to assess the prevalence of Chiari's network in patients undergoing transesophageal echocardiography and to determine whether this anomaly is associated with other cardiac lesions or is characterized by typical clinical findings. BACKGROUND: Chiari's network is a congenital remnant of the right valve of the sinus venosus. It has been found in 1.3% to 4% of autopsy studies and is believed to be of little clinical consequence. METHODS: Video recordings of 1,436 consecutive adult patients evaluated by transesophageal echocardiography over a 30-month period were reviewed for the presence of Chiari's network. Echocardiographic contrast studies had been performed in all patients with Chiari's network and were compared with those of 160 consecutive patients without a Chiari net, serving as a control group. RESULTS: Chiari's network was present in 29 of 1,436 patients (prevalence 2%). A frequently associated finding was a patent foramen ovale in 24 (83%) of the 29 patients with Chiari's network versus 44 (28%) of 160 control patients (p < 0.001). Intense right-to-left shunting occurred significantly more often in patients with Chiari's network than in control patients (16 [55%] of 29 patients vs. 19 [12%] of 160 control patients, p < 0.001). Another frequent association was an atrial septal aneurysm in 7 (24%) of 29 patients. The indication for transesophageal echocardiography was a suspected cardiac source of arterial embolism in 24 (83%) of 29 patients with a Chiari net, 13 of whom (54%) had recurrent embolic events. Chiari's network was significantly more common in patients with unexplained arterial embolism than in patients evaluated for other indications (24 [4.6%] of 522 patients vs. 5 [0.5%] of 914 patients, p < 0.001). Potential causes for arterial embolism were present in 9 of the 24 patients with a Chiari net and embolic events (atrial septal aneurysm in 7, cerebrovascular lesion in 2). In 15 (62%) of 24 patients only a patent foramen ovale could be identified. Three patients had deep venous thrombosis and pulmonary embolism at the time of arterial embolism; none had a thrombus detected within the network. CONCLUSIONS: In patients undergoing transesophageal echocardiography, the prevalence of Chiari's network was 2%, which is consistent with autopsy studies. By maintaining an embryonic right atrial flow pattern into adult life and directing the blood from the inferior vena cava preferentially toward the interatrial septum, Chiari's network may favor persistence of a patent foramen ovale and formation of an atrial septal aneurysm and facilitate paradoxic embolism.

Abnormalities, Multiple↗
PubMed1995

Simultaneous measurement of pulmonary venous flow by intravascular catheter Doppler velocimetry and transesophageal Doppler echocardiography: relation to left atrial pressure and left atrial and left ventricular function.

OBJECTIVES: The aim of our study was to compare measurements of pulmonary venous flow velocity obtained either by transesophageal Doppler echocardiography or by intravascular catheter Doppler velocimetry. Furthermore, the relation among pulmonary venous flow velocity, left atrial compliance and left atrial pressure was evaluated. BACKGROUND: Data about the relation between left atrial pressure and pulmonary venous flow velocity are controversial. METHODS: A total of 32 patients undergoing elective open heart surgery for coronary artery bypass grafting were included prospectively in the study. Pulmonary venous flow velocity (Doppler catheter) and left atrial pressure (microtip pressure transducer) were recorded simultaneously with recordings of pulmonary venous flow velocity obtained by transesophageal Doppler echocardiography. RESULTS: Agreement between Doppler catheter and Doppler echocardiographic measurements of pulmonary venous flow velocity (n = 18 patients) was analyzed using the Bland-Altmann technique. The 95% limits of agreement were -0.16 to +0.11 m/s for systolic peak velocity, -0.14 to +0.09 m/s for diastolic peak velocity and -0.12 to +0.10 m/s for atrial peak velocity. The closest agreement between both methods was found for the ratio of systolic to diastolic peak velocity, the ratio of systolic to diastolic flow duration and the time from Q deflection on the electrocardiogram to maximal flow velocity. Mean left atrial pressure was strongly correlated with the ratio of systolic to diastolic peak velocity (r = -0.829), systolic velocity-time integral (r = -0.653), time to maximal flow velocity (r = 0.844) and the ratio of systolic to diastolic flow duration (r = -0.556). The ratio of systolic to diastolic peak velocity and the time to maximal flow velocity were identified as strong independent predictors of mean left atrial pressure. Left atrial compliance was not found to be an independent predictor of mean left atrial pressure. CONCLUSIONS: Flow velocity in the left upper pulmonary vein can be reliably recorded by transesophageal pulsed wave Doppler echocardiography. Our data reveal further evidence that mean left atrial pressure can be estimated by the pattern of pulmonary venous flow velocity.

Aged↗
PubMed1995

[In vitro studies of the effect of vasoconstrictor nose drops on ciliary epithelium of human nasal mucosa].

We investigated the influence of four nasal decongestants and one preservative on ciliated cells, using cell cultures of human nasal mucosa. These cells were exposed to nasal decongestants in vitro. A fast decrease in ciliary beat frequency was seen during naphazoline and oxymethazoline application which was fully reversible after naphazoline. There was only a minimal decrease in ciliary beat frequency during application of phenylephrine and xylomethazoline decongestants. The preservative benzalkoniumchloride caused an irreversible decrease in ciliary beat frequency which was concentration dependent. We therefore recommend nasal decongestants which contain xylomethazoline or phenylephrine. If the preservative benzalkoniumchloride can not be substituted by newer less harmful substances, it should be added in minimal concentrations.

Dose-Response Relationship, Drug↗
PubMed1995

The amphotropic and ecotropic murine leukemia virus envelope TM subunits are equivalent mediators of direct membrane fusion: implications for the role of the ecotropic envelope and receptor in syncytium formation and viral entry.

The murine leukemia virus (MuLV) envelope protein was examined to determine which sequences are responsible for the differences in direct membrane fusion observed with the ecotropic and amphotropic MuLV subtypes. These determinants were studied by utilizing amphotropic-ecotropic chimeric envelope proteins that have switched their host range but retain their original fusion domain (TM subunit). Fusion was tested both in rodent cells and in 293 cells bearing the human homolog of the ecotropic MuLV receptor. The results demonstrate that the amphotropic TM is able to mediate cell-to-cell fusion to an extent equivalent to that mediated by the ecotropic TM, indicating that their fusion domains are equivalent. The "murinized" human homolog of the ecotropic receptor supports syncytium formation as well as the native murine receptor. These findings suggest that interactions between the ecotropic envelope protein and conserved sequences in the ecotropic receptor are the principal determinants of syncytium formation. The relationship of the fusion phenotype to pH-dependent infection and the route of viral entry was examined by studying virions bearing the chimeric envelope proteins. Such virions appear to enter cells via a pathway that is directed by the host range-determining region of their envelope rather than by sequences that confer pH dependence. Therefore, the pH dependence of infection may not reflect the initial steps in viral entry. Thus, it appears that both the syncytium phenotype and the route of viral entry are properties of the viral receptor, the amino-terminal half of the ecotropic envelope protein, or the interaction between the two.

3T3 Cells↗
PubMed1994

Respiratory allergy: hazard identification and risk assessment.

Various chemicals and proteins of industrial importance are known to cause respiratory allergy, with occupational asthma being the most important manifestation of the disease. This paper describes clinical syndromes, mechanisms associated with occupational respiratory hypersensitivity, and methods available currently for the prospective identification of potential respiratory allergens. Certain classes of chemicals are commonly associated with occupational respiratory allergy. There is insufficient information, however, to predict respiratory sensitization potential from analysis of structure alone, although reactivity with proteins is likely to be relevant. As yet there exist no fully validated or widely applied predictive methods or internationally harmonized guidelines. The most promising predictive animal methods are the mouse IgE test and guinea pig models. Work in mice has focused upon events occurring during the induction phase of sensitization following primary encounter with the test chemical. In contrast, guinea pig models have been used primarily to identify respiratory allergens (chemicals or proteins) as a function of elicitation reactions induced in previously sensitized animals. Given the possible serious health manifestations of respiratory allergy, early identification of respiratory sensitizers is urgently required. The two methods should, as a priority, be developed further and the production of a detailed protocol for these methods be undertaken to facilitate further validation. Together, this information will allow for two types of risk assessment associated with respiratory allergy: the risk that exposure to a material will (1) induce sensitization in an individual and (2) elicit allergic reactions in a previously sensitized individual.

Allergens↗
PubMed1994

Mechanism of pepsin-catalyzed aminotranspeptidation reactions.

1. The tetrapeptide Ala2-Nph2 (where Nph = p-nitrophenylalanyl) is treated by porcine pepsin to study the mechanism of aminotranspeptidation reactions. 2. The major initial product is Ala2-Nph and the major transpeptidation products are Nph2 and Nph3 accompanied by some Nph, a little Nph4, Ala2-Nph3 and Ala2-Nph4. 3. Oligomers of Nph greater than tetramers are formed near the end of the reaction. 4. In presence of [3H]Nph, no incorporation of Nph into the transpeptidation products is observed. 5. 18O-labeling shows extensive incorporation of 18O atoms from [18O]water in the carbonyl oxygens of Nph residues.

Amino Acid Sequence↗
PubMed1993

Secondary substrate binding in aspartic proteinases: contributions of subsites S3 and S'2 to kcat.

The kinetic parameters kcat and Km were determined at 25 degrees C and pH 5.5 for endothiapepsin and rhizopuspepsin acting on the series of substrates Ac-Ala(m)-Lys-Nph-Ala(n)-amide where Nph is p-nitrophenylalanine, and m and n equal 0-4. Kinetic parameters were also determined at 25 degrees C and pH 3.5 for pig pepsin acting on the series of substrates Ac-Ala(m)-Phe-Nph-Argn-Ala(n)-amide, where m equals 0 to 2 and n equals 0 or 1, and another series based on -Ile-Glu-Phe-Nph-Arg-, which is the core of a series of peptides designed by Dunn et al. (1986, Biochem. J. 237, 899-906). Km values were found to be largely independent of increases in the chain length of the substrates whereas kcat values showed large increases with increasing chain length. With endothiapepsin and rhizopuspepsin the largest increases (between 13-fold and over 150-fold) were obtained when alanine residues were added in positions P3 and P'2 and thus are similar to those observed previously with penicillopepsin. Additions of alanines to positions P2, P'3, and P'4 gave much smaller increases. In the case of pig pepsin the results were not as clearcut. Whereas the largest increases were seen for positions P3 and P'2 only with some of the peptides, the increases were strongly dependent on the length of the peptides. With some of the longer peptides the increases were comparable to those seen for positions P2 and P'3. Thus, whereas the addition of two alanines in position P3 to the dipeptide Ac-Phe-Nph-amide caused a large proportional increase in kcat, the increase was much smaller when the addition was made to the homologous tetrapeptide and even smaller when made to the pentapeptide Ac-Ala-Phe-Nph-Arg-Ala-amide. Additions of arginine in position P'2 gave large increases in kcat for all three peptides of the series.

Amino Acid Sequence↗
PubMed1993

The primary structure of carboxypeptidase S1 from Penicillium janthinellum.

The complete amino acid sequence of carboxypeptidase S1 from Penicillium janthinellium has been determined by N-terminal sequencing of the reduced and vinylpyridinated protein and of peptides obtained by cleaved with cyanogen bromide, iodosobenzoic acid, hydroxylamine, endoproteinase LysC, endoproteinase AspN and Glu-specific proteinase from B. licheniformis. The enzyme consists of a single peptide chain of 433 amino acid residues and contains 9 half-cystine residues and one glycosylated asparagine residue. A comparison to other carboxypeptidases shows that the enzyme is homologous to carboxypeptidase-Y and carboxypeptidase-MIII from malt. Specificity and binding of substrates are discussed from a three-dimensional model based on the known structure of carboxypeptidase-Y from Saccharomyces cereviciae and carboxypeptidase II from wheat.

Amino Acid Sequence↗
PubMed1993

Studies on the effects of a high dose UVA-1 radiation therapy on surface markers and function of epidermal Langerhans cells.

Recently, high-dose UVA-1 therapy (340-400 nm) was introduced as an effective treatment of severe exacerbated atopic dermatitis. Since the target of this type of radiation in the skin is not known we investigated using the mouse model whether surface markers of the antigen-presenting function of epidermal Langerhans cells are affected by UVA-1 radiation. Even repeated high doses of UVA-1 radiation (up to 50 J/cm2) had no detectable effect on surface ATPase activity and Ia antigen expression on Langerhans cells. Also, the contact allergen oxazolone was presented normally in skin treated with UVA-1 radiation. In contrast, if the mice were injected 1 h before irradiation with 8-methoxypsoralen a dramatic reduction in ATPase activity and Ia antigen expression on Langerhans cells was observed and the induction of contact sensitivity was suppressed (PUVA effect). These results show that epidermal Langerhans cells are not impaired either in structure or function and that these cells probably do not represent the primary target of UVA-1 radiation in the skin. No side effects resulting from a diminished Langerhans cell function should result from high-dose UVA-1 therapy.

Adenosine Triphosphatases↗
PubMed1993

Investigation of possible metabolism of pigment yellow 17, a 3,3'-dichlorobenzidine-based pigment, after inhalation exposure in rats.

Rats were exposed by inhalation to the technically highest administrable concentration of 230 mg Pigment Yellow 17/m3 air for 4 h. Inhalability of the dust was guaranteed by a mass-median aerodynamic diameter of 1.0-1.1 microns. For 14 days after exposure, urine and serum samples were analysed for 3,3'-dichlorobenzidine, the parent carcinogenic amine of the test compound. No 3,3'-dichlorobenzidine could be detected either in urine or blood, the detection limit being 5 ng/ml for both media. Based on the results of this study there is no evidence for metabolic cleavage of Pigment Yellow 17 to 3,3'-dichlorobenzidine in the rat.

3,3'-Dichlorobenzidine↗
PubMed1993

Detection of left-to-right shunt in atrial septal defect by negative contrast echocardiography: a comparison of transthoracic and transesophageal approach.

The occurrence of a right atrial negative contrast effect as an indicator of left-to-right shunt was studied in 101 patients with atrial septal defect by peripheral venous contrast injection during transthoracic and transesophageal echocardiography. Confirmation of the diagnosis was provided by cardiac catheterization or by autopsy in 72 (72%) patients. The defect could be visualized directly in 57 (57%) patients during the transthoracic and in 93 (93%) during the transesophageal examination (p < 0.001). A negative right atrial echo contrast effect was observed in 53 of 92 (58%) patients from the transthoracic and in 86 of 92 (93%) patients from the transesophageal approach (p < 0.001). Among these were seven (7%) patients with an aneurysmal interatrial septum but no directly visible defect during conventional transesophageal imaging. Appearance of contrast in the left atrium indicating right-to-left shunting was seen in 70 of 92 (76%) patients from the transthoracic and in 91 of 92 (99%) patients from the transesophageal approach (p < 0.001). Contrast injection during transesophageal imaging also helped identify additional malformations in 12 (12%) patients. Thus transesophageal echocardiography with echo contrast injection is a very reliable diagnostic method in patients with suspected atrial septal defect.

Adolescent↗
PubMed1993

[Transesophageal echocardiography in patients with systemic arterial embolism].

The percentage of ischemic strokes or peripheral arterial embolism attributed to cardiogenic embolism is about 30% and 75%, respectively. Diagnostic work-up in patients with prior arterial embolism is of prognostic importance, because embolic events are often recurrent. Cardioembolic sources with major risk of embolism are atrial fibrillation, mechanical or biological heart valve prosthesis, left ventricular or left atrial thrombi, left atrial myxomas, bacterial endocarditis, nonbacterial thrombotic endocarditis and nonischemic dilative cardiomyopathies. Cardioembolic sources with minor risk of embolism are mitral valve prolapse, isolated mitral annular calcification, patent foramen ovale, atrial septal aneurysm and calcific aortic valve stenosis. Studies have shown that two-dimensional transthoracic echocardiography yields little useful information in patients with arterial embolism. The advent of transesophageal echocardiography in the late 1980s allowed a more reliable identification of potential cardioembolic sources. The close contact of the echoprobe in the esophagus to the heart allows better resolution of intracardiac structures, particularly when cardiovascular abnormalities at the atrial level, the base of the heart and the thoracic aorta are sought. We studied 153 patients with clinically suspected arterial embolism by transthoracic and transesophageal echocardiography. Patients with extracranial carotide occlusive disease and patients older than 60 years were excluded from the study. In 88 out of 153 patients (58%) a cardioembolic mechanism could be detected by the combination of transthoracic and transesophageal echocardiography. Using the transthoracic method alone, a cardioembolic source could only be found in 55 patients (36%). Valvular heart disease and regional or global wall motion abnormalities could be visualized by both methods with similar results. However, only two out of 22 left atrial thrombi detected by transesophageal echocardiography could be documented also with the transthoracic approach. Transesophageal echocardiography was superior in the evaluation of valvular vegetations, intracardiac tumors, diseases of the thoracic aorta and abnormalities of the interatrial septum. Only left ventricular thrombi could be better evaluated by the transthoracic method, because visualization of the left ventricular apex by the transesophageal approach is problematic. In patients with systemic arterial embolism the combination of transthoracic and transesophageal echocardiography is the diagnostic method of choice to detect a cardioembolic source. Randomized studies in the future must prove, whether the echocardiographic findings can lead to better therapeutic strategies to improve the prognosis of patients with embolic disease.

Adult↗
PubMed1992

Domain flexibility in aspartic proteinases.

Comparison of the three-dimensional structures of native endothiapepsin (EC 3.4.23.6) and 15 endothiapepsin oligopeptide inhibitor complexes defined at high resolution by X-ray crystallography shows that endothiapepsin exists in two forms differing in the relative orientation of a domain comprising residues 190-302. There are relatively few interactions between the two parts of the enzyme; consequently, they can move as separate rigid bodies. A translational, librational, and screw analysis of the thermal parameters of endothiapepsin also supports a model in which the two parts can move relative to each other. In the comparison of different aspartic proteinases, the rms values are reduced by up to 47% when the two parts of the structure are superposed independently. This justifies description of the differences, including those between pepsinogen and pepsin (EC 3.4.34.1), as a rigid movement of one part relative to another although considerable distortions within the domains also occur. The consequence of the rigid body movement is a change in the shape of the active site cleft that is largest around the S3 pocket. This is associated with a different position and conformation of the inhibitors that are bound to the two endothiapepsin forms. The relevance of these observations to a model of the hydrolysis by aspartic proteinases is briefly discussed.

Aspartic Acid Endopeptidases↗