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Biomedical subjects

D Scholz

Publications and source records attributed to D Scholz.

At least 55 records · Page 3Linked to original sources
PubMed1994

Altered expression of titin and contractile proteins in failing human myocardium.

Our own previous ultrastructural studies in human hearts with dilated cardiomyopathy and heart failure showed sarcomeric and cytoskeletal disarrangement. On the basis of these findings we tested the hypothesis that in cardiomyopathic failing hearts not only the sarcomere structure but also the organization and the amount of numerous contractile proteins are disturbed. Titin was included in this study because it is the elastic "third" filament of the sarcomere and also plays an important role as template for myosin and actin filaments in sarcomerogenesis. Human cardiac tissue obtained at the time of transplantation surgery was investigated using immunohistochemistry with monoclonal antibodies against titin, myosin, actin, tropomyosin, and troponin T. Additionally, isolated myocytes from rat or pig heart were used for the standardization of the localization pattern. In normal tissue, myosin and the thin filament complex showed a regular cross striation that was wider in myosin staining than for actin, troponin T, and tropomyosin corresponding with the different width of the A and I bands in the sarcomere. Titin localization in normal human and animal myocardium showed a regular cross striation pattern. In diseased cardiac tissue titin fluorescence intensity was reduced and frequently disorganization or almost complete loss of titin from many myocytes were present. Severe abnormalities of contractile proteins consisting of disarrangement or lack of filaments were also observed. Double staining procedures showed that in the same myocyte defects of the contractile apparatus were accompanied by a simultaneous reduction of titin indicating that the "third" sarcomeric filament system is involved in heart failure. Abnormalities of titin expression may be especially important because titin significantly influences sarcomeric elastic behaviour and is necessary as template for the organization of newly synthesized myosin and actin filaments. The loss of titin may contribute to the altered compliance in failing hearts. It is concluded that disorganization and loss of titin, myosin, and the thin filament complex are severe in the failing human heart because of dilated cardiomyopathy and that these changes may represent several of the most important components of the structural correlate of reduced cardiac function.

Adult↗
PubMed1994

HIV proteinase inhibitors containing 2-aminobenzylstatine as a novel scissile bond replacement: biochemical and pharmacological characterization.

Derivation of the 2-aminobenzylstatine containing HIV-1 proteinase (PR) inhibitor I led to a series of compounds with considerably improved antiviral activity, the most potent derivatives inhibiting HIV-1 with IC50 values below 25 nM. This was achieved by the combination of several structural modifications, most prominently by introduction of a benzimidazole heterocycle into the inhibitor. The mode of action of the 2-aminobenzylstatine PR inhibitors was demonstrated to be inhibition of gag precursor processing. The antiviral efficacy of the PR inhibitors was demonstrated in various cell lines, in primary T4 lymphocytes and in monocytes. The most potent compound (XI) inhibited replication of several HIV-1 clinical isolates in primary cells with IC50 values of 8 to 23 nM. The analysis of the pharmacokinetic behaviour of compounds I and VII revealed blood half-lives in rodents in the range of about 1.5 h. Compound I also showed appreciable oral uptake in mice (18%), but yielded no detectable blood levels in rats after oral administration. Benzimidazole containing compounds like VII were not orally bioavailable to a significant extent, neither in mice nor in rats. Thus, while introduction of a benzimidazole group into the PR inhibitors was a successful structural modification with regard to antiviral activity in cell culture, it completely abolished oral bioavailability.

Amino Acid Sequence↗
PubMed1994

Altered nucleus/cytoplasm relationship and degenerative structural changes in human dilated cardiomyopathy.

We investigated systematically the structure of the myocardium obtained from patients with dilated cardiomyopathy undergoing transplantation because of intractable heart failure. Hearts were explanted at the time of surgery from 12 patients (10 men and 2 women, aged 31-57 years, ejection fraction < 20%) and numerous samples were taken for light and electron microscopy. Biopsies from the left ventricle of 8 patients during operations for atrial septal defect served as control tissue. The most obvious qualitative findings were focal hypertrophy and atrophy of myocytes, enlargement and bizarre shape of nuclei, lack of contractile material and occurrence of numerous small mitochondria. On a quantitative level, the nuclear density was reduced (18%, p < 0.05) but the nuclear profile area was significantly increased (85%, p < 0.001). Thus the nucleus/cytoplasm relationship was altered. The volume density of the contractile filaments was decreased (25%, p < 0.001), but the mitochondrial volume density was unchanged. There was an increase in cell width (39%, p < 0.01) and of the connective tissue content (= fibrosis) (112%, p < 0.001). It is suggested that the nuclear abnormalities may be the primary event in the pathogenesis of dilated cardiomyopathy. These may then lead to a reduced transcriptional rate which most probably is the cause of the lack of myofilaments and other degenerative changes. The deterioration of the structural quality of the hypertrophied myocytes results finally in atrophy and fibrosis and may be the structural correlate of functional disturbances in dilated cardiomyopathy.

Adult↗
PubMed1993

Comparison of somatosensory evoked potentials with striatal glucose consumption measured by positron emission tomography in the early diagnosis of Huntington's disease.

Both somatosensory evoked potentials (SEP) and striatal glucose consumption (rCMRGlc) measured by positron emission tomography (PET) have been reported to be abnormal early in the course of Huntington's disease (HD). To compare their diagnostic value, SEP and rCMRGlc were measured in a group of 18 first degree off-spring of HD families: 6 had manifest HD with chorea and the remaining 12 individuals were chorea-free subjects at risk for HD. In five patients with manifest disease, both SEP and striatal rCMRGlc were significantly abnormal, defined in SEP as having either a bilaterally absent frontal N30 amplitude or a reduction of the parietal N20/P25 amplitude below 1 microV on at least one side; in PET as exhibiting a reduction of the cerebellar ratio (CR) of both caudate and lentiform rCMRGlc below the 99% confidence limits of these variables determined in 20 normal volunteers. The remaining patient with manifest HD had questionably abnormal SEP and significantly reduced indices of striatal rCMRGlc. The five persons at risk for HD who had normal SEP also had normal striatal rCMRGlc; those three at-risk patients with abnormal SEP also had a reduction of the CR of both caudate and lentiform rCMRGlc. Of the remaining four individuals at risk for HD who had questionably abnormal SEP, three had CR values of striatal rCMRGlc in the normal range and one a reduction of the CR of lentiform rCMRGlc. In at-risk patients, the SEP diagnosis correlated significantly with caudate (r = -0.8; p < 0.002) and lentiform (r = -0.76; p < 0.005) rCMRGlc. These data indicate a parallel deterioration of SEP and striatal rCMRGlc early in the course of HD even before the development of chorea.

Adult↗
PubMed1993

Increased striatal glucose consumption in Sydenham's chorea.

Positron emission tomography and 18F-fluorodeoxyglucose were used to measure the regional cerebral glucose consumption in a 15-year-old choreatic girl with classical Sydenham's chorea shortly after the onset of hyperkinetic movements and 5 months later after chorea had resolved and in a 74-year-old hemichoreatic woman with long-standing hyperkinesia as a residuum of Sydenham's chorea in adolescence. Whereas cerebellar, thalamic, and cortical glucose consumption was within normal limits in both patients, lentiform and caudate glucose consumption was significantly increased in both hemispheres of the 15-year-old patient and in the hemisphere contralateral to the chorea in the 74-year-old patient. In the younger patient, striatal glucose consumption returned to normal after her hyperkinesia had disappeared with antibiotic therapy. The observation of an increase in striatal glucose consumption in Sydenham's chorea, in contrast to the decrease of this variable encountered in the vast majority of other choreatic disorders, leads to questioning the pathophysiology of chorea in humans and suggests the use of emission tomographic measurement of variables related to cerebral energy metabolism for differential diagnosis in choreatic disorders.

Adolescent↗
PubMed1992

Enzymatic synthesis and comparative biological evaluation of a phosphonate analogue of the lipid A precursor.

Phosphonate analogue 5 of the lipid A precursor 4 has been prepared from phosphonate 2 and nucleotide 3 with the help of lipid A synthase, isolated from the overproducing Escherichia coli mutant MC 1061 (delta 2512) or JB1104 (delta 2514). The biological properties of phosphonate 5 and phosphate 4 are quite similar to each other as compared in the limulus amoebocyte lysate assay, by the activation of the RAW264 murine macrophagelike cell line (determined by stimulation of ornithine decarboxylase), and by the pyrogenicity in rabbits. Hydrolytic removal of the 1-phosphate group of 4 is thus not a prerequisite for its biological activity.

Animals↗
PubMed1992

Regional cerebral glucose consumption measured by positron emission tomography in patients with Wilson's disease.

Using positron emission tomography (PET), the regional cerebral metabolic rate of glucose consumption (rCMRGlc) was measured in 14 patients with Wilson's disease (WD) and 23 normal subjects. In WD patients, cerebellar, striatal and--to a lesser extent--cortical and thalamic rCMRGlc were significantly decreased compared with controls. Striatal rCMRGlc was significantly reduced in those 4 patients who had recently started decoppering therapy as compared with striatal rCMRGlc measured in those 10 patients with longer duration of medication. Caudate rCMRGlc correlated significantly with various signs of extrapyramidal dysfunction. Cerebellar, thalamic and cortical rCMRGlc correlated significantly with the severity of pyramidal signs. These data indicate that the PET measurement of rCMRGlc may be a useful tool to evaluate cerebral involvement in WD and to monitor the response to treatment.

Adult↗
PubMed1992

[Disasters in former East Germany--experiences and problems of the Leipzig "Identification" Task Group].

Mass-disasters with high numbers of victims are a real challenge to the specialists. The role of forensic experts is generally emphasized. The missions of the Leipzig Taskgroup for identification and the experience gained during them confirm, that special training necessary staff members is. Compared with the general signs of identity, like clothing, jewelry and accessories, scars etc., the marks of ears and observations of forensic odonto-stomatology provide good chances for identification. For forensic odonto-stomatology, we developed computer programs.

Accidents, Aviation↗
PubMed1991

Structural analysis of the lipid A component of Campylobacter jejuni CCUG 10936 (serotype O:2) lipopolysaccharide. Description of a lipid A containing a hybrid backbone of 2-amino-2-deoxy-D-glucose and 2,3-diamino-2,3-dideoxy-D-glucose.

The chemical structure of Campylobacter jejuni CCUG 10936 lipid A was elucidated. The hydrophilic backbone of the lipid A was shown to consist of three (1----6)-linked bisphosphorylated hexosamine disaccharides. Neglecting the phosphorylation pattern, a D-glucosamine (2-amino-2-deoxy-D-glucose) disaccharide [beta-D-glucosaminyl-(1----6)-D-glucosamine], a hybrid disaccharide of 2,3-diamino-2,3-dideoxy-D-glucose and D-glucosamine [2,3-diamino-2,3-dideoxy-beta-D-glucopyranosyl-(1----6)-D-glucosamine], and a 2,3-diamino-2,3-dideoxy-D-glucose disaccharide were present in a molar ratio of 1:6:1.2. Although the backbones are bisphosphorylated, heterogeneity exists in the substitution of the polar head groups. Phosphorylethanolamine is alpha-glycosidically bound to the reducing sugar residue of the backbone, though C-1 is also non-stoichiometrically substituted by diphosphorylethanolamine. Position 4' of the non-reducing sugar residue carries an ester-bound phosphate group or is non-stoichiometrically substituted by diphosphorylethanolamine. By methylation analysis it was shown that position 6' is the attachment site for the polysaccharide moiety in lipopolysaccharide. These backbone species carry up to six molecules of ester- and amide-bound fatty acids. Four molecules of (R)-3-hydroxytetradecanoic acid are linked directly to the lipid A backbone (at positions 2, 3, 2', and 3'). Laser desorption mass spectrometry showed that both (R)-3-hydroxytetradecanoic acids linked to the non-reducing sugar unit carry, at their 3-hydroxyl group, either two molecules of hexadecanoic acid or one molecule of tetradecanoic and one of hexadecanoic acid. It also suggested that the (R)-3-(tetradecanoyloxy)-tetradecanoic acid was attached at position 2', whereas (R)-3-(hexadecanoyloxy)-tetradecanoic acid was attached at position 3', or at positions 2' and 3'. Therefore, the occurrence of three backbone disaccharides differing in amino sugar composition and presence of a hybrid disaccharide differentiate the lipid A of this C. jejuni strain from enterobacterial and other lipids A described previously.

Campylobacter jejuni↗
PubMed1991

Biological activity in the human system of isotype variants of oligosaccharide-Y-specific murine monoclonal antibodies.

The capacity of isotype variants of BR55-2, an anti-tumor monoclonal antibody directed against Y oligosaccharide, to mediate antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in the human system was evaluated using freshly isolated peripheral blood mononuclear cells, lymphocytes, monocytes and complement. The ADCC activities of the BR55-2 IgG3 isotype and its switch variants (IgG1, IgG2b, and IgG2a) with human monocytes were high for all isotypes, whereas the activity of all isotypes was lower with freshly isolated lymphocytes, IgG1 being the least effective. The CDC on the other hand was strong with IgG3, IgG2b and IgG2a and negative with the IgG1 variant. The IgG3 and IgG2a isotypes were selected for further development. Their strong ADCC and CDC activity against mammary carcinoma, colon carcinoma and small-cell lung tumor cell lines was confirmed quantitatively using proteins highly purified from tissue-culture supernatants. Significant variations in ADCC and CDC competence was observed among human donors.

Antibodies, Monoclonal↗
PubMed1991

RETRACTED: Does the preparation of heparin influence anticoagulation during cardiopulmonary bypass?

Various preparations of heparin from different manufacturers are commercially available. The influence of bovine lung heparin (BLH) and porcine mucosal heparin (PMH) on anticoagulation and heparin plasma concentration was investigated in four groups of 10 patients undergoing elective aortocoronary bypass grafting either after single dose or repetitive dose (after 60 minutes) of one of these heparin preparations. Heparin plasma concentration increased significantly after injection of heparin (BLH: minimum, 1.67 U/mL; maximum, 2.10 U/mL; PMH: minimum, 1.69 U/mL; maximum, 2.15 U/mL). Sixty minutes after the initial dose, heparin plasma levels were higher in the patients who received PMH. Supplemental heparin doses 60 minutes after the loading dose increased plasma heparin concentration only with porcine mucosal heparin. Elimination of heparin in the urine was not different among the groups. Fibrinogen and antithrombin III concentrations, as well as activated clotting time (ACT; always greater than 400 seconds) and partial thromboplastin time (PTT; always greater than 300 seconds), did not differ among the groups, indicating effective anticoagulation during the bypass period with both types of heparin. It can be concluded that sufficient anticoagulation can be achieved with either kind of heparin. PMH seems to be longer acting and a repeat dose in these patients seems to be necessary only if cardiopulmonary bypass lasts longer than 90 minutes.

Aged↗
PubMed1991

C-glycosidic analogues of lipid A and lipid X: synthesis and biological activities.

The synthesis of a series of novel analogues of lipid A, the lipophilic terminal of lipopolysaccharides (LPS), and lipid X, the reducing monosaccharide unit in lipid A, is reported. In these compounds, the native 1-O-phosphate group has been replaced by a "bioisosteric" CH2COOH substituent. The new N,O-acylated monosaccharide C-glycosides were obtained by Wittig reaction of suitably protected glucosamine derivatives. These lipid X analogues were recognized as substrates by the enzyme lipid A synthase and could be coupled with UDP-lipid X to afford the corresponding disaccharide analogues of the lipid A precursor on preparative scale. All compounds were characterized by NMR, MS, and elemental analysis, and were tested for their ability to enhance nonspecific resistance to infection in mice and also for endotoxicity. The results clearly show that the new compounds express biological activities similar to those of their O-phosphorylated natural counterparts. Furthermore, these compounds exhibit a better therapeutic index in mouse models than the standard LPS obtained from Salmonella abortus equi.

Animals↗
PubMed1991

[Risk of CMV infection and illness after kidney transplantation].

Between 1980 and 1986 465 cadaveric kidney transplants were performed at the Kidney Transplant Centre Berlin-Friedrichshain. The post-transplant risk to acquire a cytomegalovirus (CMV) infection depended on the preoperative CMV antibody status of donor and recipient, on the nettoimmunosuppression and on the recipient's age. The highest infection rate and the most serious courses showed seronegative recipients from seropositive donors. The typical time interval of clinical manifestation included the postoperative months 1-3. A significant dependence of the frequency of infection on different immunosuppressive protocols could not be proven. But there was a significant coincidence between CMV infection and rejection crises. In spite of the raised frequency of rejection crises an influence of the CMV infection on the 1-year-graft and patient survival rates could not be demonstrated. Both an early diagnosis and an adequate therapy are of particular importance.

Age Factors↗
PubMed1990

Oligosaccharide Y specific monoclonal antibody and its isotype switch variants.

Isotype switch variants of the IgG3 secreting hybridoma BR55-2 were developed with gamma 1, gamma 2b and gamma 2a heavy chains. The variants have the same affinity for antigen and expected affinities for the Fc receptor. The Y antigen defined by MAb BR55-2 has a restricted distribution to breast, colorectal, pancreatic, gastric and small cell lung carcinomas. The MAb BR55-2 also bound to prostatic and laryngeal carcinomas. The BR55-2 defined epitope is expressed by gastrointestinal cancer cell lines as a glycolipid, while the breast carcinoma cells express the same epitope on glycoproteins. These differences may influence tumor cell susceptibility to lysis by MAb BR55-2 and its isotype switch variants.

Animals↗
PubMed1990

[Effect of recombinant gamma interferon on allergic skin reaction and bronchoconstriction].

Gamma-interferon (IFN-gamma) has immunosuppressive and immunostimulatory effects. Net results in clinical disease are difficult to predict. We studied possible anti-allergic effects of IFN-gamma in a double blind study in 30 patients with bronchial asthma. We performed quantitative skin prick and bronchial allergen provocation tests using each patient's main allergen prior to and after 20 injections of either recombinant IFN-gamma (100 micrograms each) or placebo, measuring skin wheal area, specific airway resistance (SRaw) and the maximal expiratory flow at 50% of vital capacity (MEF50). IFN-gamma reduced skin wheal area significantly but had no effect on allergic bronchoconstriction.

Asthma↗