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Biomedical subjects

A Hoffmann

Publications and source records attributed to A Hoffmann.

At least 163 records · Page 9Linked to original sources
PubMed1997

Experimental induction of liver fibrosis in young guinea pigs by combined application of copper sulphate and aflatoxin B1.

Aflatoxin B1 alone (0.05 mg resp. 0.037 mg/kg/d), copper alone (6.6 mg/kg/d or 200 mg/l drinking water) or a combination of both was administered orally for 6 months to young guinea pigs from the first/second day of life. In the copper group there were no pathomorphological changes. For the aflatoxin B1 group, liver damage was established. In the combined group, liver injury was more frequent and more severe compared to the aflatoxin B1 group and biliary copper excretion was diminished compared with the copper group. Histologically, only the livers of this group exhibited degeneration, atrophy and steatosis of liver cells, inflammatory processes and a more or less prominent fibrosis. For childhood cirrhosis (ICC and ICT) a combined etiology--a liver damaging agent plus elevated alimentary copper--is a plausible hypothesis.

Aflatoxin B1↗
PubMed1997

Considerations of transcriptional control mechanisms: do TFIID-core promoter complexes recapitulate nucleosome-like functions?

The general transcription initiation factor TFIID was originally identified, purified, and characterized with a biochemical assay in which accurate transcription initiation is reconstituted with multiple, chromatographically separable activities. Biochemical analyses have demonstrated that TFIID is a multiprotein complex that directs preinitiation complex assembly on both TATA box-containing and TATA-less promoters, and some TFIID subunits have been shown to be molecular targets for activation domains in DNA-binding regulatory proteins. These findings have most commonly been interpreted to support the view that transcriptional activation by upstream factors is the result of enhanced TFIID recruitment to the core promoter. Recent insights into the architecture and cell-cycle regulation of the multiprotein TFIID complex prompt both a reassessment of the functional role of TFIID in gene activation and a review of some of the less well-appreciated literature on TFIID. We present a speculative model for diverse functional roles of TFIID in the cell, explore the merits of the model in the context of published data, and suggest experimental approaches to resolve unanswered questions. Finally, we point out how the proposed functional roles of TFIID in eukaryotic class II transcription fit into a model for promoter recognition and activation that applies to both eubacteria and eukaryotes.

Animals↗
PubMed1997

Mouse model of GM2 activator deficiency manifests cerebellar pathology and motor impairment.

The GM2 activator deficiency (also known as the AB variant), Tay-Sachs disease, and Sandhoff disease are the major forms of the GM2 gangliosidoses, disorders caused by defective degradation of GM2 ganglioside. Tay-Sachs and Sandhoff diseases are caused by mutations in the genes (HEXA and HEXB) encoding the subunits of beta-hexosaminidase A. The GM2 activator deficiency is caused by mutations in the GM2A gene encoding the GM2 activator protein. For degradation of GM2 ganglioside by beta-hexosamindase A, the GM2 activator protein must participate by forming a soluble complex with the ganglioside. In each of the disorders, GM2 ganglioside and related lipids accumulate to pathologic levels in neuronal lysosomes, resulting in clinically similar disorders with an onset in the first year of life, progressive neurodegeneration, and death by early childhood. We previously have described mouse models of Tay-Sachs (Hexa -/-) and Sandhoff (Hexb -/-) diseases with vastly different clinical phenotypes. The Hexa -/- mice were asymptomatic whereas the Hexb -/- mice were severely affected. Through gene disruption in embryonic stem cells we now have established a mouse model of the GM2 activator deficiency that manifests an intermediate phenotype. The Gm2a -/- mice demonstrated neuronal storage but only in restricted regions of the brain (piriform, entorhinal cortex, amygdala, and hypothalamic nuclei) reminiscent of the asymptomatic Tay-Sachs model mice. However, unlike the Tay-Sachs mice, the Gm2a -/- mice displayed significant storage in the cerebellum and defects in balance and coordination. The abnormal ganglioside storage in the Gm2a -/- mice consisted of GM2 with a low amount of GA2. The results demonstrate that the activator protein is required for GM2 degradation and also may indicate a role for the GM2 activator in GA2 degradation.

Animals↗
PubMed1997

Regulation of apoptosis and cell cycle arrest by Zac1, a novel zinc finger protein expressed in the pituitary gland and the brain.

The proliferation rate of a cell population reflects a balance between cell division, cell cycle arrest, differentiation and apoptosis. The regulation of these processes is central to development and tissue homeostasis, whereas dysregulation may lead to overt pathological outcomes, notably cancer and neurodegenerative disorders. We report here the cloning of a novel zinc finger protein which regulates apoptosis and cell cycle arrest and was accordingly named Zac1. In vitro Zac1 inhibited proliferation of tumor cells, as evidenced by measuring colony formation, growth rate and cloning in soft agar. In vivo Zac1 abrogated tumor formation in nude mice. The antiproliferative activity of Zac1 was due to induction of extensive apoptosis and of G1 arrest, which proceeded independently of retinoblastoma protein and of regulation of p21(WAF1/Cip1), p27Kip1, p57Kip2 and p16INK4a expression. Zac1-mediated apoptosis was unrelated to cell cycle phase and G1 arrest was independent of apoptosis, indicating separate control of apoptosis and cell cycle arrest. Zac1 is thus the first gene besides p53 which concurrently induces apoptosis and cell cycle arrest.

Amino Acid Sequence↗
PubMed1997

A novel tetracycline-dependent expression vector with low basal expression and potent regulatory properties in various mammalian cell lines.

The tetracycline-dependent expression system has gained increasing popularity for the expression of any gene of interest. Careful choice of the expression vector has been suggested to exploit the full potential of this system. A novel tetracycline-sensitive expression vector based on a modified mouse mammary tumor virus promoter achieved considerably improved regulatory properties in a series of cell lines tested under transient and stable conditions. Therefore, the applicability of the tetracycline-dependent expression system can be largely enhanced by careful adaptation of the expression vector to the host cell line.

Animals↗
PubMed1997

[Late sequelae of lateral and central mid-facial fractures after osteosynthesis with miniplates].

Despite significant progress in the therapy of craniofacial injuries permanent consequences of the trauma are still likely to occur. It has been possible to follow-up 105 (65.2%) of the 161 patients who were treated for lateral and central midfacial fractures in our department between 1989 and 1991. Pathological findings on follow-up were found in 48.6% of our patients. Most frequent were persistent disturbances of the sensitivity in the area of the second branch of the trigeminal nerve (32.4%). Patients who were operated within the first week after trauma did have significantly less sensory disturbances than patients who underwent surgery later. 7.6% of our patients had permanent double vision (4.8% in their primary vision field). After subciliary incision 3% had an ectropium which was not found after transconjunctival incision. There was no significant difference in the cosmetic outcome of the two approaches. In one patient who received silicone for restoration of the orbital floor the plate did migrate. Other materials that were used for orbital floor reconstruction did not cause problems. Based on the post-operative results improvements for the therapeutic regimen are discussed.

Adolescent↗
PubMed1997

Pathological features of rectal cancer after preoperative radiochemotherapy.

The standard therapy for rectal carcinoma is surgical, however, preoperative radiochemotherapy will play an increasing role especially in locally advanced disease. To estimate the prognosis and the effect of radiochemotherapy the postradiochemotherapeutical pathological features are important to assess. We examined the surgical specimens of 17 patients after preoperative radiochemotherapy to estimate and grade the histological reactions. A proposal for a grading system for tumor regression (not yet available in the literature) has also been described. All but one of the carcinomas showed different degrees of tumor regression. A total regression was not observed after standardised pathological work up. In only one case a locally curative resection was not possible. We think that preoperative radiochemotherapy is able to reduce tumor mass thus achieving operability in non-curatively operable cases. We recommend standards of pathological work up and regression grading for further studies comparing surgery and radiochemotherapy of rectal carcinoma.

Adenocarcinoma, Mucinous↗
PubMed1997

Involvement of the cholinergic system and periaqueductal gray matter in the modulation of tonic immobility in the guinea pig.

Unilateral microinjection of carbachol (CCh, 1.0 microg/0.2 microl) into the ventrolateral periaqueductal gray matter (vPAG) increased the duration of tonic immobility (TI) episodes induced by postural inversion and by movement restriction maneuvers in adult male guinea pig (Cavia porcellus), while stimulation with the same drug at the same concentration into the dorsolateral and dorsomedial periaqueductal gray matter (dl/dmPAG) decreased the duration of TI. Pretreatment with atropine (7.6 microg/0.4 microl) showed that the action of CCh is mediated by muscarinic receptors in the ventrolateral PAG but not in the dorsomedial and dorsolateral regions. These data suggest that the PAG and the cholinergic system are involved in the modulation of TI episodes and that different regions of the guinea pig PAG play distinct roles in the organization of this behavior.

Animals↗
PubMed1997

Participation of the medial and anterior hypothalamus in the modulation of tonic immobility in guinea pigs.

Tonic immobility (TI) is an inhibitory behavioral response during which the animal presents profound physical inactivity and a relative lack of response to the environment. This response is induced in the laboratory by postural inversion of the animal and brief postural contention of its movements. In nature, the response occurs when there is physical contact between prey and predator. In this case, the physical inactivity of the prey may prevent the continuation of the attack. The neural substrate of this response is not well known and the objective of the present study was to investigate the effect of cholinergic stimulation of hypothalamic regions on TI modulation in guinea pigs (Cavia porcellus). Microinjection of carbachol (1.0 microg/0.2 microL) into the anterior hypothalamus promoted an increase in the duration of TI episodes. Microinjection of carbachol into the ventro- and dorsomedial hypothalamus, however, promoted a reduced duration of TI episodes. Pretreatment with atropine (0.5 microg/0.2 microL) showed that the action of carbachol is mediated by muscarinic receptors in the anterior and ventromedial hypothalamus but not in the dorsomedial hypothalamus. The results suggest that the hypothalamic regions may play different roles in the organization of defensive behavioral responses such as TI.

Animals↗
PubMed1997

Measurements of urinary prostaglandins in young ovulatory women during the menstrual cycle and in postmenopausal women.

The purpose of the present work was to study the prostaglandin excretion in young nonpregnant ovulatory women during the menstrual cycle on the one hand and in postmenopausal women on the other hand and to investigate the influence of female sex hormones (estradiol, progesterone) on urinary prostanoid excretion. Urinary excretion rates of prostaglandin E2 (PGE2), 6-keto-PGF1 alpha, thromboxane B2 (TxB2) and their metabolites PGE-M (11 alpha-hydroxy-9, 15-dioxo-2,3,4,5,20-pentanor-19-carboxyprostanoic acid), 2,3-dinor-6-keto-PGF1 alpha, 2,3-dinor-TxB2 and 11-dehydro-TxB2 were determined by gas chromatography-triple stage quadrupole mass spectrometry (GC/MS/MS) in 41 young non-pregnant women during the follicular phase and during the luteal phase and in 23 postmenopausal women. Excretion rates of all urinary prostanoids were not significantly different in the follicular phase when compared with the luteal phase. In contrast to the young ovulatory women, PGE2 and TxB2 were significantly higher in postmenopausal women. Concerning the other prostaglandins significant differences between these groups of women did not exist. Although serum levels of estradiol and progesterone were different in young and postmenopausal women, sex hormones have not been shown to correlate with prostaglandins. Our data do not suggest sex hormones to be responsible for the difference in the prostaglandin excretion in women of reproductive age and in women in the menopause. Further systematic investigations into age dependency of prostaglandin excretion in women are necessary.

6-Ketoprostaglandin F1 alpha↗
PubMed1997

Biologic allergen assay for in vivo test allergens with an in vitro model of the murine type I reaction.

BACKGROUND: The determination of the biologic activity of allergenic extracts in human beings is limited for ethical and practical reasons. The establishment of a simplified in vitro model, which mimics a main event of the type I reaction, should provide true benefit for manufactures, researchers, and clinicians. OBJECTIVE: This study was designed to develop and evaluate a mediator release assay based on rat bosophil leukemia cells for the purpose of investigating allergenic extracts. METHODS: Rat basophil leukemia cells were passively sensitized with murine IgE raised against allergens and stimulated by serial dilutions of allergenic extracts in a dose-related manner. The allergen-specific degranulation was monitored by measuring the release of beta-hexosaminidase. RESULTS: The investigation of standardized commercial allergen products for in vivo diagnostics (birch pollen, cat dander, and bee venom) allowed a quantitative description of differences in biologic activity in accordance with the declared activity units. The Fel d 1 content was determined in 17 cat dander extracts and correlated well with the results of a two-site binding ELISA (r = 0.93, log/log). Extremely low allergen amounts in the range of 10 to 100 pg/ml could be easily detected. Moreover, the cross-reactivity pattern of patients allergic to birch pollen could be reproduced with extracts of hazel, alder, apple, and celery. CONCLUSION: The assay is suitable for supplementing quality control of allergenic extracts and for the determination of biologic activity of final allergen products. As a research tool, it allows the study of IgE cross-linking properties of modified and recombinant allergens at an early stage before they are tested in human beings.

Allergens↗
PubMed1997

Angiotensin-I-converting enzyme DD genotype is a risk factor of coronary artery disease.

Coronary artery disease (CAD) is a polygenic disease whose phenotypic manifestation depends on the interaction of a number of environmental factors. A number of genes, including the angiotensin-I-converting enzyme (ACE) gene, have been implicated in the pathogenesis of CAD. ACE could affect smooth muscle cell and fibroblast migration and proliferation, low-density lipoprotein (LDL) oxidation and endothelial cell function; these are all important factors in atherosclerosis. A polymorphic variant of the ACE gene correlates with higher circulating ACE levels and carries an increased risk of myocardial infarction, and cardiomyopathies. In this study, we sought to determine the distribution of ACE genotypes and the frequency of allele D in patients undergoing coronary angiography at our institution. DNA from 196 patients with angiographically proven CAD and 96 controls without CAD was amplified by polymerase chain reaction (PCR). The primers flanked the region of the ACE gene (intron 16) where the insertion (I) or deletion (D) of a 287-bp fragment results in the I/D polymorphism. PCR amplification of alleles I and D resulted in 490- and 190-bp products, respectively. In the control group, the relative allele frequencies of the polymorphism were similar to those of previously published European studies. The ACE genotype DD was present in 37.3% of patients with CAD as compared to 23.4% in the controls (p < 0.001, odds ratio 1.95, 95% confidence intervals (CI) 1.06-3.57). There was no association with the history of prior myocardial infarction. The genotype distribution in patients with single-vessel involvement was not significantly different from controls (p = 0.14). However, the DD genotype was significantly more common in patients having multivessel CAD when compared to single-vessel disease, indicating an association of this polymorphism with the extent of CAD. ACE genotype DD is more common in patients with multivessel CAD as compared to controls and to patients with single-vessel involvement, indicating that genotype DD is a genetic risk factor for extensive, multivessel CAD.

Aged↗
PubMed1997

Molecular characterization of beta-trace protein in human serum and urine: a potential diagnostic marker for renal diseases.

We have isolated beta-trace protein from cerebrospinal fluid, serum, plasma, and urine samples of normal volunteers and sera and hemofiltrate of patients with chronic renal failure. Blood-derived and urinary beta-trace have significantly higher molecular weights than their cerebrospinal fluid counterpart, the amino acid sequences being identical. Oligosaccharide structural analysis revealed these molecular weight differences to be due to different N-glycosylation. beta-Trace from hemofiltrate and urine has larger sugar chains and concurrently significantly higher sialylation than cerebrospinal fluid-beta-trace which bears truncated "brain-type" oligosaccharide chains (published previously). beta-Trace concentrations were about 40 ng/ml for normal sera and plasma. 2000-6000 ng/ml were measured in sera of dialysis patients whereas in normal human cerebrospinal fluid, beta-trace concentration was about 8000 ng/ml. A reduced amount of 900 ng/ml was found in a single case of hydrocephalus cerebri. The sialylated glycoforms of beta-trace detected in the blood are presumably derived from resorbed cerebrospinal fluid protein whereas beta-TP-molecules bearing asialo-oligosaccharides are absent due to their hepatic clearance. The residual, sialylated beta-TP-species are probably eliminated from the blood via the kidney. This physiological clearance mechanism for the sialylated glycoforms is disturbed in hemodialysis patients resulting in about 100-fold elevated serum concentrations. These results let us suggest beta-trace may become a useful novel diagnostic protein in renal diseases.

Amino Acid Sequence↗
PubMed1997

Hypoglycosylation of a brain glycoprotein (beta-trace protein) in CDG syndromes due to phosphomannomutase deficiency and N-acetylglucosaminyl-transferase II deficiency.

Human beta-trace protein is a major intrathecally synthesized polypeptide constituent of human cerebrospinal fluid. We have previously shown that this protein is almost quantitatively modified with biantennary complex-type N-linked oligosaccharides which show "brain-type" glycosylation characteristics (Hoffmann,A. et al., J. Neurochem., 63, pp. 2185-2191, 1994). In the present study human beta-trace protein from the cerebrospinal fluid (CSF) of patients with carbohydrate-deficient glycoprotein syndrome (CDGS) due to phosphomannomutase (PMM) deficiency and N-acetyl-glucosaminyltransferase II (GlcNAc-T II) deficiency as well as from control individuals was studied by Western blot analysis. The protein from pooled CSFs was purified by immunoaffinity chromatography. The protein from the five patients with CDGS PMM deficiency showed three protein bands upon SDS-PAGE analysis corresponding to the di-, mono-, and unglycosylated polypeptide forms. Carbohydrate structural analysis of the enzymatically liberated N-glycans was performed applying mapping by HPAEC-PAD, methylation analysis as well as MALD/TOF-MS. Essentially identical oligosaccharide structures were detected in beta-TP from type I patients and control adult pooled CSF. The beta-trace protein from two patients with GlcNAc-T II deficiency showed a single di-N-glycosylated protein band with a significantly lower molecular weight than the di-glycosylated polypeptide from control patients and the beta-trace protein from pooled adult CSF. Beta-TP from GlcNAc-T II deficiency patients shared only three oligosaccharides out of the 13 observed in beta-TP from controls or patients with PMM deficiency. The major oligosaccharide structures of the glycoprotein from patients with GlcNAc-T II deficiency were found to be monoantennary asialo- or monosialylated lactosamine-type chains with proximal fucose and bisecting GlcNAc.

Adult↗
PubMed1997

DRINK: a biogeochemical source term model for low level radioactive waste disposal sites.

Interactions between element chemistry and the ambient geochemistry play a significant role in the control of radionuclide migration in the geosphere. These same interactions influence radionuclide release from near surface, low level radioactive waste, disposal sites once physical containment has degraded. In situations where LLW contains significant amounts of metal and organic materials such as cellulose, microbial degradation in conjunction with corrosion can significantly perturb the ambient geochemistry. These processes typically produce a transition from oxidising to reducing conditions and can influence radionuclide migration through changes in both the dominant radionuclide species and mineral phases. The DRINK (DRIgg Near field Kinetic) code is a biogeochemical transport code designed to simulate the long term evolution of the UK low level radioactive waste disposal site at Drigg. Drigg is the UK's principal solid low level radioactive waste disposal site and has been receiving waste since 1959. The interaction between microbial activity, the ambient geochemistry and radionuclide chemistry is central to the DRINK approach with the development of the ambient pH, redox potential and bulk geochemistry being directly influenced by microbial activity. This paper describes the microbial aspects of the code, site data underpinning the microbial model, the microbiology/chemistry interface and provides an example of the code in action.

Environmental Microbiology↗
PubMed1997

[Computer-based assessment of visual acuity--technical realization].

Testing of visual acuity for distant vision can be computerized by using monitor screens to present optotypes. Because of the limited spatial resolution of conventional monitors, measurement of visual acuity for near vision is not possible. This paper describes a new computer-aided method for the measurement of both near and distant visual acuity. Our approach to the assessment of visual acuity for near vision is based on a recently developed liquid crystal display (a screen, LCD) measuring 10.5 mm x 15 mm. The LCD permits the presentation of optotypes for the measurement of visual acuity between 0.063 and 1.25 at a viewing distance of 40 cm (near/distant). The presentation of optotypes for the assessment of the acuity of distant vision uses a standard 17" monitor that permits visual acuity figures of between 0.032 and 1.6 to be assessed.

Diagnosis, Computer-Assisted↗
PubMed1997

Bioavailability study with 2 different levonorgestrel-containing drugs in women.

In a randomized, single dose, open crossover study in 24 healthy women, aged between 20 and 28 years, the relative bioavailability of the test product Mini 30 (0.03 mg levonorgestrel) in comparison to a reference, Microval, was investigated after single dose administration. Because there was a difference in the in vitro dissolution test, it was of interest whether this difference had an influence on the extent and rate of absorption. Whereas 99.4% of the test were dissolved after 20 minutes, only 48.3% of the reference were dissolved after 45 minutes, 74.8% after 120 minutes and 95.5% after 240 minutes. Blood samples were taken from time 0-72 hours after administration. All serum samples were analyzed twice in a radioimmunoassay which was validated before the start of the study. The limit of quantitation was at 50 pg/ml. The AUC0 -infinity ratio test/reference and the 90% confidence interval were 104.8%, and 99.10%, respectively. The Cmax ratio test/reference and the 90% confidence interval were 175.5%, and 159.8%-192.8%, respectively. With regard to the extent of absorption (AUC0-infinity) the 2 preparations were within the acceptance range for bioequivalence whereas they were outside the acceptance range for the rate of absorption (Cmax). The elimination half-lives of LNG did not differ between the test and reference preparations (25.08 +/- 11.94 h, and 25.70 +/- 10.08 h, respectively). So, the in vitro results concerning the rate of dissolution were confirmed by the in vivo findings in Cmax whereas regarding the extent of absorption (AUC) there were no differences between the 2 preparations.

Absorption↗