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Biomedical subjects

J Berger

Publications and source records attributed to J Berger.

At least 19 recordsLinked to original sources

Activation of an inducible c-FosER fusion protein causes loss of epithelial polarity and triggers epithelial-fibroblastoid cell conversion.

As a novel approach to studying the modulation of the polarized epithelial phenotype, we have expressed c-Fos and c-Myc estrogen receptor fusion proteins (c-FosER and c-MycER) in mammary epithelial cells. The hybrid proteins could be activated by estrogen for defined time periods and after the cells had achieved their fully polarized organization. Activation of c-MycER deregulated proliferation but did not affect epithelial polarity. Short-term activation of c-FosER induced the reversible loss of morphological and functional cell polarity. In contrast, long-term stimulation of c-FosER caused the cells to depolarize irreversibly, to invade collagen gels, and to undergo epithelial-fibroblastoid cell conversion. Our data suggest that Fos proteins are important in modulating the epithelial phenotype both in normal tissue development and in invasive processes.

Animals

Cancer of the stomach and the colon-rectum among workers in a coke gas plant.

Four thousand nine hundred and eight male workers of the Hamburg gas plant, employed for 10 or more years during the period from January 1, 1900 to December 31, 1989, have been traced for cancer mortality. Based on their jobs, they were grouped into three subcohorts: gas furnace workers, workers in other parts of the plant, and white-collar workers. Despite the general "healthy worker effect," gas furnace workers showed a significant incidence of cancer of all sites (standardized mortality ratio [SMR] = 186), particularly cancers of the lung (SMR = 288), stomach (SMR = 177), and the colon-rectum (SMR = 184). In comparison to the death rates of white-collar workers, the manual workers in other parts of the plant also showed an excess of cancer mortality for cancer of these sites. The reason for this excess in cancer mortality seems to be due to the working conditions. The results contribute to the current evidence that exposure to coal carbonization fumes causes not only lung cancer, but also cancers of the stomach and colon-rectum.

Adult

Transoesophageal echocardiography during removal of a caval filter in a patient at high risk of massive pulmonary thromboembolism.

A new type of vena caval filter was to be removed from a woman who had a high risk of massive pulmonary thromboembolism because of extensive thrombus in the iliac vein incorporating the filter. The removal was performed under general anaesthesia in the cardiac operating theatre using transoesophageal echocardiography to monitor the right heart and the pulmonary artery during the critical phase of removal. The manoeuvre succeeded with only insignificant embolisation occurring, and that was identified by transoesophageal echocardiography.

Echocardiography

Dominant-negative mutants are clustered in a domain of the human T-cell leukemia virus type I Rex protein: implications for trans dominance.

The 27-kDa Rex trans-acting protein appears to be essential for replication of human T-cell leukemia virus type I. Mutations introduced outside of the Rex RNA-binding domain-nucleolar localization signal display either wild-type activity or, conversely, yield dominant-negative proteins. We generated missense mutations in a particular domain of the Rex protein (amino acid residues 54 to 69) which is characterized by a cluster of dominant-negative mutants. Our results indicate that amino acids 57 to 67 are critically important for Rex function mediated through the RxRE cis-acting RNA sequence. Within this domain, only amino acids 61 to 63 could be mutated without loss of function. All other missense and deletion mutants yielded dominant-negative proteins. In vitro RNA-binding studies performed with glutathione S-transferase-Rex fusion proteins demonstrated that all of the mutant Rex proteins interacted specifically with RxRE RNA. Analysis of chimeric Rex-Rev proteins suggests that this Rex domain is important for oligomerization.

Amino Acid Sequence

Controlling Stroop effects by manipulating expectations for color words.

An important characteristic of automatic processing is its uncontrollability. The Stroop phenomenon is regarded as a prototypical example of this characteristic of automatic processing, hence, the Stroop effect should not change when the percentages of color words versus neutral stimuli are manipulated to induce controlled processing. We found that Stroop interference decreased as the percentage of color words increased. Furthermore, the magnitude of the inhibitory component of the Stroop effect was negatively correlated with the percentage of color words; the facilitatory component was insensitive to the manipulation. These results suggest that the Stroop effect is controllable (see Logan, 1980) and that the locus of control is postlexical. The results also suggest that facilitation and inhibition are produced by different mechanisms and challenge those models of the Stroop phenomenon (e.g., Cohen, Dunbar, & McClelland, 1990; Phaf, Van der Heijden, & Hudson, 1990) that assume that a single processing mechanism causes facilitation and inhibition and that control affects facilitation and inhibition alike (Logan, 1980).

Adult

[Treatment of ischemic cerebrovascular accidents with hyperbaric oxygenation].

The authors present eleven year's experience with comprehensive treatment of patients who suffered an ischemic cerebrovascular attack. This comprises so-called conventional treatment of cerebrovascular attacks and also hyperbaroxia, i.e. administration of oxygen under high partial pressure. The authors used a therapeutic pressure of 0.2 MPa for 90 minutes in individual exposures. Of 31 treated patients 23 improved, i.e. 76%; eight improved slightly, eight significantly and seven substantially. The condition of the remainder did not change. Hyperbaroxia should therefore be used everywhere where this method is available.

Adult

ROENTGEN: case-based reasoning and radiation therapy planning.

ROENTGEN is a design assistant for radiation therapy planning which uses case-based reasoning, an artificial intelligence technique. It learns both from specific problem-solving experiences and from direct instruction from the user. The first sort of learning is the normal case-based method of storing problem solutions so that they can be reused. The second sort is necessary because ROENTGEN does not, initially, have an internal model of the physics of its problem domain. This dependence on explicit user instruction brings to the forefront representational questions regarding indexing, failure definition, failure explanation and repair. This paper presents the techniques used by ROENTGEN in its knowledge acquisition and design activities.

Artificial Intelligence

[Prognostication of chronic Ph+ myeloid leukemia using the PHCML.EXE computer program].

In 193 patients with Ph-positive chronic myeloid leukaemia (CML) Sokal's calculation formulae prognosticating initial risk status were applied, using the computer program PHCML. The aim of this study was to the prognostic reproducibility of these prognostic staging systems in our patient population. Our results confirm the previous conclusions that prognostic discrimination is possible at the time of diagnosis of CML but in our patients with poorer prognosis the stratification seems to be more accurate. No significant advantage was achieved when we prognosticated our patients younger than 46 years using the formula recommended by Sokal et al. specifically for younger patients. We analyzed different criteria when segregating patients in groups with better or poorer prognosis. We found that the coefficient of the patient's relative risk as the boundary, was 1.9 our patient's group contrary to 1.2 in Sokal's studies.

Adolescent

[Quality control in hematology].

Qualified quality control is a necessary part of modern haematology: we cannot deem laboratory results reliable until effective quality checking is included. Quality assessment includes external (national, regional) and internal (intra-laboratory) control. We suggest to found a Czech national external quality control agency for haematology based on principles which were declared by the World Health Organization. Internal control includes correct identification of samples, analytical control (standardization of test, evaluation of accuracy and precision) and biological quality control (history of patient's characteristics, relation to other laboratory results in clinical context). The deviation index, which is expressed either as a number or verbally 'excellent', 'good', 'satisfactory', or 'unsatisfactory', can supply rapid information on the quality of results in the haematological laboratory.

Hematology

Cancer mortality among workers in chemical plant contaminated with dioxin.

Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin or TCDD) can arise as a contaminant in the production of herbicides. It causes chloracne in those exposed to it but its human carcinogenicity has been a matter of dispute. We report here a mortality follow-up of 1583 workers (1184 men, 399 women) employed in a chemical plant in Germany that produced herbicides, including processes contaminated with TCDD. Production of TCDD was reduced from 1954 after an outbreak of chloracne. Vital status up to 1989 was determined for 97.1% of workers hired between 1952 and 1984, and 367 deaths (313 men, 54 women) were recorded. A malignant neoplasm was the underlying cause of death in 93 men and 20 women. Standardised mortality ratios (SMR) were calculated with, as references, national mortality statistics for West Germany and deaths in a cohort of male gas workers; for total cancer mortality they were 1.24 (95% confidence interval 1.00-1.52) and 1.39 (1.10-1.75), respectively, among men. Cancer mortality was increased among men with 20 or more years of employment (SMR = 1.87 [Germany] and 1.82 [gas workers]) and among men who began employment before 1955 (SMR = 1.61 and 1.87). The group with suspected highest exposure to TCDD had SMRs of 1.42 and 1.78. Only 7% of cohort women worked in the high exposure locations in the plant, compared with 39.6% of men, and no increased risk of cancer mortality was observed among women; but breast cancer mortality was raised (SRM = 2.15). These results, together with a US occupational study and a German investigation of accidental exposure, support the hypothesis that TCDD is a human carcinogen.

Cause of Death

Thioredoxin reductase activity at the surface of human primary cutaneous melanomas and their surrounding skin.

Plasma membrane-associated thioredoxin reductase activities have been determined on primary melanoma tissues and their surrounding skin in 29 patients. Compared to patient's normal skin, enzyme activities in melanoma were higher in some patients (n = 24) and lower in others (n = 5). Those melanomas with high TR activities yielded low activities in the adjacent epidermis, reaching normal activity 3 to 5 cm away from each primary site (n = 4). Tumors with low activities showed higher than normal activities on the immediate surrounding skin (i.e., 1 cm away from the tumor) compared to the normal skin (n = 3). Earlier it was shown that in both keratinocytes and melanoma cells, calcium regulates thioredoxin reductase activity by an allosteric mechanism. The differences in TR activities within the high and low groups may be caused by a calcium flux between the primary tumor and the surrounding epidermis, and vice versa. A comparison of TR activities to tumor invasiveness (Breslow level) in 28 primary melanomas showed a significant correlation using regression analysis (p = 0.031). A 4-fold difference in TR activity corresponds to a one-unit change in Breslow determination. These preliminary results suggest that TR activity may be another useful and sensitive assay for melanoma spread.

Biomarkers, Tumor

Positive phase II study in the treatment of advanced malignant melanoma with fotemustine.

To date, dacarbazine (DTIC) has been the most effective drug in the treatment of advanced metastatic melanoma, achieving response rates of up to 28% (mean, 21%). Multidrug responses were generally no better than those obtained using monotherapy. A quite promising clinical trial was conducted using the new nitrosourea fotemustine. A total of 19 patients presenting with advanced malignant melanoma (clinical stage IV according to the 1987 UICC classification system) underwent treatment involving a more rapid infusion of the drug and a reduction in the rest period from 5 to 3 weeks. This monotherapy with fotemustine yielded two complete responses and seven partial responses; in addition, four patients showed no change and six cases progressed after the induction cycle (median duration of response to date, 7.6 months, including four cases that have not relapsed). Fotemustine was well tolerated by the patients, with the only mild side effects being thrombocytopenia, leukocytopenia and easily controlled nausea/vomiting. Preclinical studies performed previously indicated that fotemustine inhibits enzymes involved in the ribonucleotide reduction pathway (i.e. DNA synthesis), whereby responding patients (n = 3) appeared to favor the thioredoxin reductase/thioredoxin electron transfer to ribonucleotide reductase, whereas non-responders (n = 4) expressed the alternate glutathione reductase/glutaredoxin mechanism. The 47% response rate obtained in these studies vs the 24% reported previously for fotemustine may reflect variations in enzymes in the ribonucleotide reduction pathway in different patients. However, the efficacy of fotemustine against advanced melanoma warrants more extensive trials of this drug, especially since the quality of life of the patients during and after chemotherapy was not severely affected.

Adult

Evaluation of a commercial latex test for serological diagnosis of Helicobacter pylori infection in treated and untreated patients.

The value of a commercially available latex test (Pyloriset) for the diagnosis of Helicobacter pylori infection by demonstration of specific antibodies was compared with that of direct diagnostic methods such as culture, biopsy-urease test and microscopy of fuchsin-stained smears. The sera were from 136 patients who prior to this study either had or had not been treated for Helicobacter pylori-infection simultaneously with amoxicillin (3 x 750 mg/day) and metronidazole (3 x 500 mg/day) for 12 days. On average, the sensitivity of the test was 90%. The specificity with sera from untreated patients was 75.9%; with sera from treated patients specificity was 22.2%, 28% and 20% 1, 3 and 6 months respectively after start of treatment. Only as late as one year after the onset of chemotherapy did the specificity return to 67%. Because of its low specificity this test does not offer any advantage over other tests in the detection of Helicobacter pylori-infection or in monitoring the chemotherapeutic success.

Amoxicillin

Hepatocellular oxidant stress following intestinal ischemia-reperfusion injury.

Reperfusion of ischemic intestine results in acute liver dysfunction characterized by hepatocellular enzyme release into plasma, reduction in bile flow rate, and neutrophil sequestration within the liver. The pathophysiology underlying this acute hepatic injury is unknown. This study was undertaken to determine whether oxidants are associated with the hepatic injury and to determine the relative value of several indirect methods of assessing oxidant exposure in vivo. Rats were subjected to a standardized intestinal ischemia-reperfusion injury. Hepatic tissue was assayed for lipid peroxidation products and oxidized and reduced glutathione. There was no change in hepatic tissue total glutathione following intestinal ischemia-reperfusion injury. Oxidized glutathione (GSSG) increased significantly following 30 and 60 min of reperfusion. There was no increase in any of the products of lipid peroxidation associated with this injury. An increase in GSSG within hepatic tissue during intestinal reperfusion suggests exposure of hepatocytes to an oxidant stress. The lack of a significant increase in products of lipid peroxidation suggests that the oxidant stress is of insufficient magnitude to result in irreversible injury to hepatocyte cell membranes. These data also suggest that the measurement of tissue GSSG may be a more sensitive indicator of oxidant stress than measurement of products of lipid peroxidation.

Animals

Mutational analysis of functional domains in the HIV-1 Rev trans-regulatory protein.

HIV-1 replication depends on the expression of trans-regulatory genes (tat, rev) encoded in the 3' part of the retroviral genome. HIV-1 Rev trans-activator protein allows the cytoplasmic translocation of incompletely spliced retroviral mRNA which is required for the translational switch from regulatory (Tat, Rev, Nef) to structural proteins (Gag, Pol, Env). The HIV-1 Rev regulatory protein comprises an activation domain (RAD) and a RNA binding domain (RBD). Both functional domains are not well defined and the RBD appears to overlap with the nuclear localization signal (NLS). Our mutational analysis localized the Rev protein domain important for RRE (nucleotide 7781 to 8000) binding in vitro to amino acid residues 31 to 50. Mutations in this domain always resulted in exclusion from the nucleoli. Furthermore, these mutants did not support Rev-dependent p24 Gag production in vivo. Sequences immediately upstream of this domain (RevM4, RevM19) were attenuated in their in vivo activity possibly indicating a role in Rev protein oligomerization. The observed tight correlation between subcellular localization and RNA binding in vitro indicates that this short stretch of amino acids supports two essential functions required for HIV-1 replication.

Amino Acid Sequence

Structure-affinity relationships of 12-sulfonyl derivatives of 5,8,8a,9,10,11,12,12a,13,13a-decahydro-6H-isoquino[2,1-g][1 ,6] naphthyridines at alpha-adrenoceptors.

Analogues of the potent alpha 2-adrenoceptor antagonist (8aR,12aS,13aS)-5,8,8a,9,10,11,12,12a,13,13a- decahydro-3-methoxy-12-(methylsulfonyl)- 6H-isoquino[2,1-g][1,6]naphthyridine (1b) were prepared and evaluated for alpha 1- and alpha 2-adrenoceptor affinity. Affinity for alpha 2-adrenoceptors was assessed by displacement of [3H]yohimbine from rat cerebral cortical membranes and although 1b and close structural analogues demonstrated high affinity, none were selective for the alpha 2A or alpha 2B subtypes reputedly present in this tissue. All of the high affinity alpha 2-adrenoceptor ligands were, however, selective with respect to [3H]prazosin (alpha 1) binding. Affinity for [3H]yohimbine-labeled alpha 2-adrenoceptors was found to be highly dependent on the stereochemistry of the tetracyclic system. The 8a beta,12a alpha,13a alpha diastereomer of 1 (56) had moderate affinity for alpha 2-adrenoceptors while the 8a beta,12a beta,13a alpha diastereomer (55) had very low affinity. The affinity and selectivity of these agents for alpha 2-adrenoceptors was found to correspond to that observed for several isomeric yohimbine analogues which have similar relative and absolute stereochemistries. Deviation from the structure of 1 by opening the B ring, changing the position of the sulfonamide nitrogen, or changing the attachment of the D ring led to a dramatic decrease in alpha 2-adrenoceptor affinity. High binding affinity was found to correlate with functional antagonism in the guinea pig ileum. The reversal of clonidine-induced mydriasis in the rat was used to assess bioavailability and indicated that 1b was a potent alpha 2-adrenoceptor antagonist in vivo.

Adrenergic alpha-Antagonists

Large skull defect in aplasia cutis congenita treated by pericranial flap: long-term follow-up.

Nine patients with aplasia cutis congenita were treated in our department during the past 30 years. Of these, 1 patient died due to uncontrolled hemorrhage and 1 patient was operated on by using a pericranial flap to cover a 7 x 5-cm scalp defect with large bony involvement. After 5 years of follow-up, the skull defect closed completely by normal bone that can be palpated on examination and seen on radiographs.

Ectodermal Dysplasia