Biomedical subjects

M Begemann

Publications and source records attributed to M Begemann.

At least 19 recordsLinked to original sources

PubMed2001

Pneumococcal vaccine failure in an HIV-infected patient with fatal pneumococcal sepsis and HCV-related cirrhosis.

Pneumoccocal vaccination of HIV-positive individuals is recommended to prevent pneumococcal infection. We present a case of a 44-year-old HIV-infected male who came to the emergency room with bacterial pneumonia and sepsis. The patient also had a history of HBV and HCV infection. He expired in the emergency room and blood cultures were positive for Streptococcus pneumoniae. The autopsy confirmed the clinical diagnosis and, in addition, hepatitis C-related cirrhosis and splenic abnormalities. The patient had no history of opportunistic infections. His CD4 count 3 months prior to coming to the emergency room was 216 cells/microL with a viral load of 1,270 copies/mL. The patient had received Pneumovax two years before his death. The organism isolated from blood cultures was Streptococcus pneumoniae isotype 3, a strain included in Pneumovax. This is a case of pneumococcal vaccine failure with a fatal outcome in a person with an HIV infection and hepatitis C-related liver cirrhosis.

Adult↗

PubMed2000

Treatment of refractory complex-partial status epilepticus with propofol: case report.

PURPOSE: We report a case of a 65-year-old woman who had a subarachnoid and intraventricular hemorrhage secondary to rupture of an anterior communicating artery aneurysm and developed nonconvulsive status epilepticus of the complex-partial type, refractory to phenytoin (PHT), phenobarbital (PB), valproate (VPA), and lorazepam (LZP). METHODS: Three weeks after diagnosis of nonconvulsive status epilepticus, general anesthesia was induced with propofol and titrated to burst suppression on the electroencephalogram (EEG). RESULTS: During propofol infusion, the serum VPA level declined markedly, and despite >3 g daily doses, did not return to the therapeutic range, until several days after propofol was discontinued. Continuous propofol infusion was stopped after 7 days, and the patient recovered consciousness. Despite further complications, she gradually regained normal function and was discharged home 4 months after surgery. CONCLUSIONS: This is the first case of nonconvulsive status epilepticus successfully treated with propofol.

Aged↗

PubMed1999

Roles of cyclin D1 and related genes in growth inhibition, senescence and apoptosis.

It is now apparent that apoptosis is closely linked to the control of cell cycle progression. During the G1 to S progression, cyclin D1, p53, and the cyclin dependent kinase inhibitors p21WAF1 and p27kip1 can play roles in induction of apoptosis. During the G2 and M phases, premature activation of Cdk1 can cause cells to enter mitotic catastrophe, which results in apoptosis. In this review we focus on factors acting during G1 and S, particularly cyclin D1, and their effects on cell growth, senescence and apoptosis. We emphasize that cyclin D1 can have diverse effects on cells depending on its level of expression, the specific cell type, the cell context and other factors. Possible mechanisms by which cyclin D1 exerts these diverse effects, via cyclin dependent kinase-dependent and -independent pathways, are discussed.

Journal Article↗

PubMed1999

Acute testing of the rate-smoothed pacing algorithm for ventricular rate stabilization.

We evaluated the capability of a new pacemaker-based rate-smoothing algorithm (RSA) to reduce the irregular ventricular response of AF. RSA prevents sudden decreases in rate using a modified physiological band and flywheel feature. Twelve patients (51 +/- 21 years) with hemodynamically tolerated AF of 4 months to 20 years duration were studied. Atrial and ventricular leads were connected to the external pacemaker device in the electrophysiology laboratory. Consecutive RR intervals during AF were measured at baseline and after ventricular pacing with RSA ON. Ventricular pacing with the rate smoothing algorithm reduced maximum RR intervals (1,207 +/- 299 vs 855 +/- 148 ms, P = 0.0005), with no significant change in the minimum RR interval (401 +/- 55 vs 393 +/- 74 ms, P = 0.292). A small shortening of the mean RR interval (634 +/- 153 vs 594 +/- 135 ms, P = 0.007) was seen with no change in the median RR interval (609 +/- 153 vs 595 +/- 143 ms, P = 0.388). There was a 43% reduction in RR standard deviation (145 +/- 52 vs 82 +/- 28, P = 0.0005), 49% reduction in mean absolute RR interval difference (MAD) (152 +/- 64 vs 77 +/- 34, P = 0.0005) and MAD/mean RR ratio (0.23 +/- 0.05 vs 0.13 +/- 0.04, P = 0.0005). We conclude that rate-smoothed pacing effectively reduces RR variability of AF in the acute setting.

Adult↗

PubMed1998

Genomic changes in glioblastoma cell lines detected by comparative genomic hybridization.

Comparative genomic hybridization serves as a screening test for regions of copy number changes in tumor genomes. We have applied the technique to map DNA gains and losses in 5 cell lines derived from glioblastoma multiforme, the most common primary neoplasm of the central nervous system. The most frequent losses occurred on chromosomes 10 and 13. The most common gains were observed on chromosomes 5, 6, 7 and 20. Some novel sites of genomic alterations were also observed. Analysis of common areas of loss and gain in these cell lines provides a basis for future attempts to more finely map these genetic changes and for elucidation of genes involved in tumor progression.

Aged↗

PubMed1997

A K-ras oncogene increases resistance to sulindac-induced apoptosis in rat enterocytes.

BACKGROUND & AIMS: Mutations of c-K-ras occur commonly in colonic neoplasms. The aim of this study was to determine how c-K-ras mutations alter the responses to the chemopreventive agent sulindac. METHODS: The parental rat intestinal cell line IEC-18 and c-K-ras-transformed derivatives were treated with sulindac sulfide. Cell cycle distribution was determined by flow-cytometric analysis (fluorescence-activated cell sorter), apoptosis by DNA fragmentation (laddering), flow cytometry, and microscopy, and changes in gene expression by immunoblotting. RESULTS: Sulindac sulfide inhibited cell growth and induced apoptosis in a time- and dose-dependent manner more rapidly in and at lower concentrations in parental cells than ras-transformed cells. Expression of the sulindac sulfide arrested cells in G0/G1, but cells entered apoptosis throughout the cell cycle. Proapoptotic protein Bak was relatively high in untreated parental cells and increased markedly after sulindac sulfide but was low in untreated ras-transformed cells and did not increase after sulindac sulfide. Expression of other Bcl-2 family members was unchanged after sulindac sulfide. However, sulindac sulfide reduced levels of cyclin D1 protein and cyclin E- and cyclin D1-associated kinase activity. CONCLUSIONS: c-K-ras-transformed enterocytes are relatively resistant to sulindac sulfide-induced growth inhibition and apoptosis, which may result from specific reduction of bak expression.

Animals↗

PubMed1997

Disorders in cell circuitry associated with multistage carcinogenesis: exploitable targets for cancer prevention and therapy.

The development of a malignant tumor involves the progressive acquisition of mutations and epigenetic abnormalities in multiple genes that have highly diverse functions. Some of these genes code for pathways of signal transduction that mediate the action of growth factors. The enzyme protein kinase C plays an important role in these events and in the process of tumor promotion. Therefore, we examined the effects of three inhibitors of protein kinase C, CGP 41251, RO 31-8220, and calphostin C, on human glioblastoma cells. These compounds inhibited growth and induced apoptosis; these activities were associated with a decrease in the level of CDC2 and cyclin B1/CDC2-associated kinase activity. This may explain why the treated cells accumulated in G2-M. In a separate series of studies, we examined abnormalities in cell cycle control genes in human cancer. We have found that cyclin D1 is frequently overexpressed in a variety of human cancers. Mechanistic studies indicate that cyclin D1 can play a critical role in carcinogenesis because: overexpression enhances cell transformation and tumorigenesis; introduction of an antisense cyclin D1 cDNA into either human esophageal or colon cancer cells reverts their malignant phenotype; and overexpression of cyclin D1 can enhance the amplification of other genes. The latter finding suggests that cyclin D1 can enhance genomic instability and, thereby, the process of tumor progression. Therefore, inhibitors of the function of cyclin D1 may be useful in both cancer chemoprevention and therapy. We obtained evidence for the existence of homeostatic feedback loops between cyclins D1 or E and the cell cycle inhibitory protein p27Kip1. On the basis of these and other findings, we hypothesize that, because of their disordered circuitry, cancer cells suffer from "gene addiction" and "gene hypersensitivity," disorders that might be exploited in both cancer prevention and therapy.

Apoptosis↗

PubMed1996

Transforming activity of retroviral genomes encoding Gag-Axl fusion proteins.

Retroviral genomes encoding a portion of the Moloney murine leukemia virus Gag protein fused to portions of the murine axl cDNA were constructed so as to mimic naturally occurring transforming viruses. Virus MA1 retained 5 amino acids of the extracellular domain and the complete transmembrane and intracellular domains of Axl; virus MA2 retained only the intracellular Axl sequences beginning 33 amino acids downstream of the transmembrane region. Although both viruses could transform NIH 3T3 cells, they induced different morphological changes. MA1 transformants became elongated and assumed a cross-hatched pattern, while MA2 transformants were round and very refractile and grew to high density. Gag-Axl and Glyco-Gag-Axl proteins were detected in both types of transformed cells and were predominantly localized to the cytoplasmic compartment. When cell-free v-axl virus supernatants were introduced into wild-type BALB/c neonates, Rag-2-deficient mice, or c-myc transgenic mice, they did not cause tumors in a 3-month period. However, MA2-transformed NIH 3T3 cells, but not MA1 or control cells, could establish sarcomas by subcutaneous or intraperitoneal injection into BALB/c neonates. These results show that the transforming potential of the axl gene can be activated by truncation of the extracellular domain of the receptor and fusion of the remaining sequence to the gag gene.

3T3 Cells↗

PubMed1996

Increased expression of cyclin D1 in a murine mammary epithelial cell line induces p27kip1, inhibits growth, and enhances apoptosis.

Cyclin D1 is frequently amplified and/or overexpressed in human breast cancer and several other types of cancer. To examine the role of cyclin D1 in normal mammary epithelial cells, in the present study we have overexpressed human cyclin D1 in the mouse mammary epithelial cell line HC11, using retrovirus-mediated transduction. We found that the cyclin D1 overexpresser clones displayed a decrease in saturation density, a decrease in anchorage-independent growth, an increased fraction of cells in the G(zero)-G1 phase, and increased expression of beta-casein, when compared to the control cells. The latter finding suggested that they were more differentiated. Furthermore, the cyclin D1 overexpressers displayed a marked increase in susceptibility to induction of apoptosis by serum withdrawal or by treatment with hydroxyurea or the protein kinase C inhibitors CGP 41251 and Ro31-8220. Thus, in some mammary epithelial cells, increased expression of cyclin D1 can inhibit growth, induce differentiation, and enhance apoptosis. These effects might be due, at least in part, to the fact that these derivatives displayed increased expression of the p27kip1 inhibitory protein.

Animals↗

PubMed1996

Inhibition of the growth of glioblastomas by CGP 41251, an inhibitor of protein kinase C, and by a phorbol ester tumor promoter.

Protein kinase C (PKC) plays a central role in signal transduction pathways that mediate the action of certain growth factors, tumor promoters, and cellular oncogenes. To explore whether PKC might be an appropriate target for the chemotherapy of human brain tumors, cell lines were established from five glioblastomas, one mixed gliosarcoma and glioblastoma, two astrocytomas, and one choroid plexus carcinoma. The staurosporine derivative CGP 41251, an inhibitor of PKC, inhibited cell proliferation in all nine cell lines with an IC50 in the range of 0.4 micrometer. Drug withdrawal and clonogenicity assays showed that CGP 41251 induced an irreversible growth arrest. Three cell lines were examined in detail: two human glioblastoma cell lines, GB-1 and GB-2, and one gliosarcoma cell line, GS-1. All of these three cell lines were highly aneuploid and displayed morphologies and immunohistochemical markers characteristic of the glial lineage. The compound 12-O-tetradecanoylphorbol-13-acetate (TPA), a tumor promoter and activator of PKC, also inhibited the growth of these cell lines. CGP 41251 in combination with TPA caused further growth inhibition. Cultures treated with CGP 41251 displayed an increase in the fraction of cells in G2-M, a decrease of cells in S phase, and no consistent effect on G0-G1. Immunohistochemical analyses demonstrated that growth inhibition by CGP 41251 was associated with the formation of giant nuclei with extensive fragmentation and apoptotic bodies. These effects of CGP 41251 were abrogated by withdrawal of serum from the medium or by exposure of these cells to aphidicolin, actinomycin D, cycloheximide, or TPA. In contrast to the effects seen with the glioblastoma cell lines, nontransformed astrocyte lines remained viable in the presence of 0.4 and 0.8 micrometer CGP 41251 and displayed only a slight increase in the fraction of giant nuclei with fragmentation. The antitumor activity of CGP 41251 was demonstrated in vivo against xenografts of the glioblastoma cell lines U87 MG and U373 MG. These findings suggest that CGP 41251 might be a useful agent for the treatment of glioblastomas.

Aged↗

PubMed1994

The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest.

The retinoblastoma tumor suppressor protein (RB) binds several cellular proteins involved in cell cycle progression. Using the yeast two-hybrid system, we found that RB bound specifically to the protein BRG1. BRG1 shares extensive sequence similarity to Drosophila brahma, an activator of homeotic gene expression, and the yeast transcriptional activator SNF2/SW12. BRG1 contains an RB-binding motif found in viral oncoproteins and bound to the A/B pocket and the hypophosphorylated form of RB. BRG1 did not bind RB in viral oncoprotein-transformed cells. Coimmunoprecipitation experiments suggested BRG1 associates with the RB family in vivo. In the human carcinoma cell line SW13, BRG1 exhibited tumor suppressor activity by inducing formation of flat, growth-arrested cells. This activity depended on the ability of BRG1 to cooperate and complex with RB, as both an RB-nonbinding mutant of BRG1 and the sequestration of RB by adenovirus E1A protein abolished flat cell formation.

Amino Acid Sequence↗

PubMed1991

One-year follow-up of automatic adaptation of the rate response algorithm of the QT sensing, rate adaptive pacemaker.

Optimal functioning of a rate adaptive pacemaker depends upon reliable sensing of the sensor and appropriate programming of the rate of response algorithm. QT sensing pacemakers use data derived from the endocardial electrogram in the programming of the rate response algorithm. In the latest versions of these pacemakers, programming of the rate response algorithm may be performed using either a semiautomatic Fast Learn (FL) procedure or by using the newly developed, fully Automatic Slope Adaptation (ASA) mechanism. We report our experience in a prospective study of 17 patients in the first year postimplantation. ASA was characterized by significant changes only in the values of the slope settings at the lower rate limit (3.7 msec/msec at time 0 to 5.77 msec/msec at 2 weeks, P less than 0.001) during the first 2 weeks after its enablement. Further adaptation between weeks 2 to 4 was observed (5.77 msec/msec to 6.4 msec/msec, P = 0.2) but this was not significant. The slope settings derived using the FL procedure were also checked at 2 and 4 weeks and were reproducible. They were closest in value to the values attained by the automated mechanism at 4 weeks. This suggests that the final value of the slope setting at the lower rate limit using ASA is reached between weeks 2 to 4. Both methods of slope determination result in satisfactory and similar rate response profiles but the time to achieve slope stability will necessarily be slower with ASA.

Algorithms↗

PubMed1991

Applicability of the stimulus-T interval for antitachycardia pacing.

UNLABELLED: At the onset of tachycardia, the refractory period (RP) changes together with the tachycardia termination window. We evaluated dogs with total atrioventricular (AV) block to determine if stimulus-T interval (STI) can be used to adjust the coupling interval(s) of an antitachycardia pacemaker in relation to changes in RP. Endocardial STI was recorded continuously together with six surface ECG leads. Steady-state (greater than 2 min) RP was determined for drive cycle lengths (DCL) 400 msec and 900 msec. The test pulse (TP) coupling interval, with DCL 900 msec, was chosen to be equal to the RP of DCL 400 msec. DCL was then changed to 400 msec until TP captured. STI of DCL of beat before capture was gained was measured. DCL was then changed back to 900 msec and the interval determined when capture was lost. TP was then lengthened by 5 msec and the procedure repeated until TP captured immediately upon changing to DCL 400 msec. RESULTS: The difference between RP at onset of pacing at DCL of 400 msec and RP when capture was achieved with the shortest coupling interval was 35-50 (mean 40) msec. This required 35-90 (mean 62) seconds. The correlation coefficient RP to STI was greater than 0.95. CONCLUSIONS: (1) RP changed by as much as 35-50 msec at the onset of an abrupt increase in rate in a 35-90-second period; and (2) STI enables estimation of RP on a beat-to-beat basis. Capture can therefore be predicted from the previous beat and the coupling interval adjusted accordingly in an antitachycardia pacing mode.

Animals↗

PubMed1991

Amplitude and direction of atrial depolarization using a multipolar floating catheter: principles for a single lead VDD pacing.

VDD stimulation using a single catheter for atrial sensing and ventricular sensing and pacing has become a reality. In order to compare the quality of the cavitary atrial electrogram (AEG) and to determine the intraatrial P wave direction and conduction time (CT), we compared, in an acute study, three different types of atrial electrode systems using four different leads, in 53 patients in sinus rhythm. The three electrode systems were: (1) one experimental system with quadripolar orthogonal electrodes using the Goldreyer concept; (2) one experimental system with quadripolar whole ring electrodes; (3) two systems with diagonally oriented half-ring electrodes, one experimental quadripolar and one bipolar CCS commercial (Polysafe A-Track lead). For the experimental systems, the four electrodes forming two independent bipolar pairs were situated on the intraatrial floating portion of a single lead and one supplemental electrode was distally positioned in the right ventricular apex. Bipolar AEGs were recorded at the high and at the low levels of the right atrium. For the CCS lead, the single bipolar AEG was recorded at the high level of the right atrium only. The highest AEG amplitude and the highest values for ventricular far-field rejection were provided by both diagonally oriented half-ring electrodes at the high atrial level and by the whole ring electrodes at the low atrial level. For both atrial levels, the orthogonal electrode system provided the smallest AEG amplitudes, the highest ventricular electrogram amplitudes, and therefore, the smallest values for ventricular far-field rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1990

Expression of chicken liver cell adhesion molecule fusion genes in transgenic mice.

The tissue-specific expression of the chicken liver cell adhesion molecule (L-CAM) was studied by generating transgenic mice. The rat insulin II promoter was fused to a chicken L-CAM cDNA or to chicken genomic L-CAM sequences. Mice carrying the cDNA showed no expression of L-CAM. Mice carrying L-CAM genomic sequences showed expression in the beta cells of the pancreas, suggesting that sequences in introns or in flanking regions are required for expression. Murine L-CAM was undetectable in the beta cells of the pancreas of those transgenic mice expressing chicken L-CAM and thus appeared to be down-regulated, but expression of the mouse protein was not altered at other sites. Chicken L-CAM was also found in extrapancreatic tissues such as skin, kidney, liver, lung, intestine, blood vessels, and the choroid plexus and leptomeninges of the central nervous system. These findings raised the possibility that the chicken L-CAM gene contains cis regulatory elements that interfere with the specificity of a tissue-specific promoter such as the rat insulin promoter. To test this hypothesis, transgenic mice were produced with a construct containing the murine neurofilament promoter fused to genomic chicken L-CAM sequences. Chicken L-CAM was expressed in the brain and spinal cord, where L-CAM is not normally found, but it was also found in some nonneural tissues (kidney, liver, intestine, lung) in which L-CAM is normally expressed. The combined results suggest that tissue-specific cis-acting elements in the chicken L-CAM gene, when combined with heterologous promoters/enhancers, can generate novel patterns of gene expression.

Animals↗

PubMed1988

Differences between normal and transformed murine fibroblasts in the expression of various promoter/enhancer-chloramphenicol acetyltransferase constructs.

High levels of poly(A)+ RNAs homologous to certain endogenous retrovirus-related DNA sequences are frequently seen in carcinogen-transformed rodent cells. To explore the underlying mechanism, transient expression assays were done to determine whether carcinogen- or radiation-transformed C3H 10T 1/2 cell lines differ from normal 10T 1/2 cells in terms of their ability to express the chloramphenicol acetyltransferase (CAT) gene when it is linked to various promoter/enhancer sequences, including two independently isolated intracisternal A particle (IAP) long terminal repeat sequences designated prcm and pMIA6. We found that with several constructs, CAT activity was always 3- to 10-fold higher in the transformed 10T 1/2 cell lines than in the normal 10T 1/2 cells. The prcm-CAT construct displayed the highest CAT activity in both the normal and transformed C3H 10T 1/2 cells. Studies with 32P-labeled prcm-CAT DNA and Southern blot analyses indicated that the differences in CAT activity between normal and transformed cells were not due to greater uptake or retention of the transfected DNA by the transformed cells. Competition studies provided evidence that factors required for the expression of the prcm-CAT construct are present in limited amounts in normal 10T 1/2 cells and in excess amounts in transformed 10T 1/2 cells. These putative factors may play a role in the increased expression of endogenous retrovirus-related sequences in the transformed cells.

Animals↗

PubMed1988

Hydrocortisone-induced accumulation of fibronectin mRNA and cell surface-associated fibronectin.

A Morris hepatoma 7777-derived cell line, DTH-3, was used to study the control of fibronectin gene expression. In cultures of DTH-3 cells in conventional medium supplemented with serum or in chemically defined MX-83 medium supplemented with insulin no cell surface fibronectin was detectable by indirect immunofluorescence techniques using specific polyclonal antibodies. By Northern blot hybridization analysis a dose- and time-dependent accumulation of 8 kb fibronectin mRNA in response to hydrocortisone treatment was demonstrated. Furthermore, 24 h after addition of hydrocortisone an extensive fibrillar fibronectin network was established. The results suggest that the hydrocortisone-dependent induction of fibronectin production might, at least in part, be controlled at the transcriptional level.

Animals↗

PubMed1988

Nonlinear relationship between pacing and evoked QT intervals.

The paced evoked response is an established biosensor which has been used in the design of a rate responsive pacemaker. The unit is capable of sensing the interval between the delivery of a pacing stimulus and the downslope of the evoked T wave. With fixed rate pacing this interval has been shown to shorten with exercise and the main cause of this effect is thought to be mediated by the increase in the plasma catecholamines which are released on exertion. The detection of a reduction in the stimulus-T interval results in an increase in pacing rate. The rate of change of pacing rate is referred to as the slope setting and this must be determined for each individual patient so that optimal rate responsive pacing can be effected. The algorithm underlying the slope setting is the pacing rate-evoked QT interval relationship. This relationship was implemented as a linear function, but this study, which was conducted to reevaluate it, has demonstrated nonlinearity between the pacing and evoked QT intervals. The degree of QT shortening is least at low heart rates. This finding has resulted in the development of a new algorithm for the pacemaker in the form of a new program for the pacing system. This should result in a more physiological rate of change of heart rate with exercise and less chance of sudden changes in rate. These postulates are the subject of current clinical trials.

Adolescent↗