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Biomedical subjects

G Laux

Publications and source records attributed to G Laux.

At least 37 records · Page 2Linked to original sources
PubMed2001

The transcriptional program of a human B cell line in response to Myc.

The proto-oncogene c-myc (myc) encodes a transcription factor (Myc) that promotes growth, proliferation and apoptosis. Myc has been suggested to induce these effects by induction/repression of downstream genes. Here we report the identification of potential Myc target genes in a human B cell line that grows and proliferates depending on conditional myc expression. Oligonucleotide microarrays were applied to identify downstream genes of Myc at the level of cytoplasmic mRNA. In addition, we identified potential Myc target genes in nuclear run-on experiments by changes in their transcription rate. The identified genes belong to gene classes whose products are involved in amino acid/protein synthesis, lipid metabolism, protein turnover/folding, nucleotide/DNA synthesis, transport, nucleolus function/RNA binding, transcription and splicing, oxidative stress and signal transduction. The identified targets support our current view that myc acts as a master gene for growth control and increases transcription of a large variety of genes.

B-Lymphocytes↗
PubMed2001

Cloning of phospholipid hydroperoxide glutathione peroxidase (PHGPx) as an anti-apoptotic and growth promoting gene of Burkitt lymphoma cells.

Burkitt Lymphoma (BL) cells are highly sensitive to suboptimal growth conditions and undergo apoptosis when seeded at low cell density or reduced serum concentration. Irradiated fibroblasts or a mix of pruvate, alpha-thioglycerol, and bathocuproine disulfonate can protect BL cells from apoptosis induced by lowering cell density or serum concentration by promoting cystine uptake in the cells. The availability of cystine is the limiting factor for glutathione biosynthesis in BL cells and thus for the ability of the cells to cope with oxidative stress. We have set up an expression cloning strategy to clone genes that protect BL cells from apoptosis induced by low cell density and/or serum. Using this approach we have cloned among others the cDNA for Phospholipid Hydroperoxide Glutathione Peroxidase (PHGPx).

Apoptosis↗
PubMed2001

Cost-benefit analysis of newer versus older antidepressants--pharmacoeconomic studies comparing SSRIs/SNRIs with tricyclic antidepressants.

Changes in the social and health services over the last years have forced doctors to concern themselves with cost benefit calculations and budget forecasting. Cost considerations are a (co-) determinant in the choice of antidepressants as well as neuroleptics and/or antipsychotics. In recent years, pharmacoeconomic studies have been performed to answer the question as to what extent treatment with new antidepressants, in particular SSRIs, is actually less expensive than treatment with (generic) tricyclic antidepressants due to better safety profiles and higher compliance in spite of the considerably higher retail price. Following descriptions of the methodological principles, the currently available studies are presented and discussed critically in this report. It can be stated that the economic value of different antidepressants can not be decided definitively at the present time. The available data do not allow the conclusion that SSRIs should be preferred over tricyclic antidepressants with the argument that the treatment as a whole is more cost effective in spite of the higher costs.

Antidepressive Agents, Second-Generation↗
PubMed1999

Functional genomics in cancer research: identification of target genes of the Epstein-Barr virus nuclear antigen 2 by subtractive cDNA cloning and high-throughput differential screening using high-density agarose gels.

In the past, the identification and isolation of phenotype-associated genes was a difficult and time-consuming task. However, recent improvements of methods that are designed to isolate differentially expressed genes have remarkably speeded up the process of target gene isolation. The ultimate goal of functional genomics is to apply these technologies to clone phenotype-associated genes irrespective of the availability of probes (e.g., antibodies) and an intimate knowledge of biological background. We demonstrate the use of a novel subtractive cDNA cloning approach for the isolation and characterization of target genes of the Epstein-Barr virus nuclear antigen 2 (EBNA2). Two different subtractive cDNA libraries specific for two different time periods following activation of a conditional estrogen receptor/EBNA2 (ER/EBNA2) fusion protein were generated. Comparison of the two libraries by cross-hybridization experiments allowed the differentiation between direct and indirect target genes of EBNA2 and led to the identification of a novel direct target gene of EBNA2.

Cloning, Molecular↗
PubMed1999

SPECT patterns in probable Alzheimer's disease.

The primary objective of this study was to test hypotheses about the relationship between HMPAO-SPECT findings and probable Alzheimer's disease (DAT) in a relatively large sample of patients diagnosed according to DSM-III-R. SPECT patterns of 20 controls and 116 DAT patients were investigated. Left and right frontal, temporal, parietal and occipital regions of the brain were rated as showing a hypoperfusion or not. A wide variety of patterns were found and these are described in detail below. In DAT patients, temporal and/or parietal regions were affected significantly more often (88%, p > 0.001) than frontal and/or occipital regions (70%). A bilateral temporoparietal pattern, which has been repeatedly reported as typical for DAT, was observed in 48% of DAT patients, but also in 25% of controls, and did not differentiate significantly between these two groups (p > 0.05). Conversely, more than three regions with hypoperfusion were observed significantly more often in DAT patients (48%, p < 0.01) than in controls (10%). In DAT patients, the number of regions with hypoperfusion correlated significantly with the score of the Mini Mental State Examination (MMSE, r = 0.33, p < 0.001). The frequency of at least one hypoperfusion was approximately equal in left and right hemispheres (77% vs. 73%, p = 0.2). The hypothesis that cognitive decline in DAT starts in the temporal regions was tested in 14 SPECT patterns showing only one region with hypoperfusion. In 12 of these patterns, a temporal region was in fact affected (p < 0.001). Whereas hypoperfusion in frontal areas was not accompanied by a significantly lower MMSE than when only temporoparietal regions were affected, MMSE scores were significantly lower when occipital regions were affected in addition to temporoparietal regions (p < 0.05). The clinical use of SPECT findings was tested in discriminating analyses with the MMSE and a delayed recall test as additional predictors of DAT. Whereas the MMSE and the delayed recall test differentiated significantly between DAT patients and controls, SPECT findings yielded no further differentiation. In conclusion, the theoretical and clinical implications of SPECT findings and their relationships to other physiological and psychological variables deserve further investigation.

Aged↗
PubMed1999

Undesirable blood pressure changes under naturalistic treatment with moclobemide, a reversible MAO-A inhibitor--results of the drug utilization observation studies.

Blood pressure decrease, associated with postural hypotension, as well as spontaneous hypertension are considered to be typical side-effects of conventional, irreversible and nonselective MAO (A+B) inhibitors. The new generation of reversible MAO-A inhibitors is, however, expected to have negligible cardiovascular effects and low propensity to induce either blood pressure increases or decreases. But, the true incidence of such changes is largely unknown since observation studies, specifically assessing the frequency of blood pressure changes, in unselected population of patients treated in the practice, are lacking.

Adult↗
PubMed1999

Activated mouse Notch1 transactivates Epstein-Barr virus nuclear antigen 2-regulated viral promoters.

Epstein-Barr virus nuclear antigen 2 (EBNA2) is essential for B-cell immortalization by EBV, most probably by its ability to transactivate a number of cellular and viral genes. EBNA2-responsive elements (EBNA2REs) have been identified in several EBNA2-regulated viral promoters, each of them carrying at least one RBP-Jkappa recognition site. RBP-Jkappa recruits EBNA2 to the EBNA2RE and, once complexed to EBNA2, is converted from a repressor into an activator. An activated form of the cellular receptor Notch also interacts with RBP-Jkappa, providing a link between EBNA2 and Notch signalling. To determine whether activated Notch is able to transactivate EBNA2-responsive viral promoters, we performed cotransfection experiments with activated mouse Notch1 (mNotch1-IC) and luciferase constructs of the BamHI C, LMP1, and LMP2A promoters. We present here evidence that mNotch1-IC transactivates viral promoters known to be regulated by EBNA2. As shown for EBNA2, mutations or deletions of the RBP-Jkappa sites diminish or eliminate mNotch1-IC-mediated transactivation of the promoters, pointing to an essential role for Notch-RBP-Jkappa interaction. In addition to RBP-Jkappa, other cellular factors may bind within the EBNA2REs of viral promoters. While some factors appear to play an important role in both EBNA2- and mNotch1-IC-mediated transactivation, others are only important for the activity of either EBNA2 or mNotch1-IC. We could observe specific mNotch1-IC-responsive regions, thereby throwing more light upon which cofactors interact with EBNA2 and mNotch1-IC, thus enabling them to become functionally transactivators in vivo.

Animals↗
PubMed1999

The proto-oncogene c-myc is a direct target gene of Epstein-Barr virus nuclear antigen 2.

Epstein-Barr virus (EBV) infects and transforms primary B lymphocytes in vitro. Viral infection initiates the cell cycle entry of the resting B lymphocytes. The maintenance of proliferation in the infected cells is strictly dependent on functional EBNA2. We have recently developed a conditional immortalization system for EBV by rendering the function of EBNA2, and thus proliferation of the immortalized cells, dependent on estrogen. This cellular system was used to identify early events preceding induction of proliferation. We show that LMP1 and c-myc are directly activated by EBNA2, indicating that all cellular factors essential for induction of these genes by EBNA2 are present in the resting cells. In contrast, induction of the cell cycle regulators cyclin D2 and cdk4 are secondary events, which require de novo protein synthesis.

Cell Line, Transformed↗
PubMed1999

The influence of clozapine and typical neuroleptics on information processing of the central nervous system under clinical conditions in schizophrenic disorders: implications for fitness to drive.

The present study investigates the psychomotor performance of schizophrenic inpatients receiving neuroleptic medication and comedication according to their clinical demands in regard to their fitness to drive. The hypothesis was tested that even under polydrug medication, the clozapine-treated patients (n = 10) would have a superior performance compared to the patients taking classical neuroleptics (n = 18). The data were collected by technical equipment (Act and React Testsystem) measuring reaction time, vigilance, visual perception and stress tolerance. The patients' driving ability turned out to be equally impaired in both treatment groups; 11% of the patients passed all tests without major impairment; 32% of the patients showed some impairments that required individual evaluation of their driving ability; 57% were considered to be severely impaired and driving could not be recommended. Except for one test, no significant group differences in psychomotor reaction performance were obtained. These results are discussed concerning limitations and consequences.

Adult↗
PubMed1998

Neuroleptic malignant syndrome under treatment with antidepressants? A critical review.

Neuroleptic malignant syndrome (NMS) is a rare complication of treatment with neuroleptics. The pathophysiology is not fully known. A dopaminergic transmission block in the basal ganglia and hypothalamus is thought to be the pathophysiological mechanism of NMS. Several cases of NMS have been reported, precipitated by medication without a direct effect on the dopaminergic system. This Medline analysis concerns 23 cases of antidepressant-induced NMS reported in the literature with the differing pathophysiological hypotheses on the precipitation of NMS. The results indicate no hard evidence of an antidepressant-evoked NMS. However, various hypotheses assuming an disturbed balance of the dopaminergic and non-dopaminergic system may be relevant in animal studies, but are without clinically relevant proof presently. An antidepressant-induced NMS is a very rare complication on the basis of pretreatment with neuroleptics causing chronic dopamine blockade and elevated plasma level of neuroleptics due to comedicated antidepressants.

Antidepressive Agents↗
PubMed1998

The influence of polypharmacological antidepressive treatment on central nervous information processing of depressed patients: implications for fitness to drive.

Antidepressive medication may cause impairment of psychomotor functioning relevant to psychosocial adaptation and fitness to drive. This impairment seems to be less severe by activating antidepressants (SSRI, MAOI). In clinical settings, however, polypharmacological treatment of depressive disorders is frequent. This study evaluates the influence of antidepressants and common comedications on central nervous information processing concerning the ability to drive. Inpatients (n = 44) with major depression (ICD-10) were investigated under steady state plasma level condition. The data were recorded by the Act & React Testsystem ART-90 and analyzed according to medication, severity of illness and age. 88.6% of the patients failed to pass all the tests. With respect to different groups of antidepressants, no differences in psychomotor reaction performance were observed in polydrug treatment. The impact of these results on the patients' fitness to drive is discussed.

Adult↗
PubMed1997

Relation of echocardiographic preload indices to stroke volume in critically ill patients with normal and low cardiac index.

OBJECTIVE: To examine the usefulness of preload indices obtained by transoesophageal echocardiography (TOE) for estimating stroke volume at various levels of cardiac index. DESIGN: Prospective clinical study. SETTING: Intensive care unit with surgical patients. PATIENTS: 16 ventilated patients monitored via Swan-Ganz catheterization and TOE. INTERVENTIONS: Echocardiographic images of left ventricular cross-sectional short-axis areas were analysed for the preload indices end-diastolic area (EDA), stroke area and end-diastolic wall stress. The relation between these indices and stroke volume, calculated from thermodilution cardiac output, was analysed in all patients and in nine patient groups discriminated by various ranges in heart rate (< or = 70 to > 110 beats/min), pulmonary artery occlusion pressure (< or = 8 to > 12 mmHg) and cardiac index (< or = 3.0 to > 4.2 l/min per m2). MEASUREMENTS AND RESULTS: Overall stroke volume (n = 155) correlated significantly (p < 0.0001) with EDA (r = 0.89) and stroke area (r = 0.80). The correlation with end-diastolic wall stress was non-significant (r = 0.51). Linearity in the relation between stroke volume and EDA or stroke area was independent of variations in heart rate and pulmonary artery occlusion pressure. Stroke volume correlated well with EDA and stroke area, when cardiac index was normal or high, but the relation slightly deteriorated (r = 0.63 to < or = 0.72) when the cardiac index was low. Changes in EDA and stroke area by more than 1, 2 or 3 cm2 were weak predictors for changes in stroke volume greater than 20%. CONCLUSIONS: Stability of the relation between echocardiographic preload indices and stroke volume emphasize the potential of TOE for continuous preload monitoring in the critically ill.

Cardiac Output↗
PubMed1997

Both Epstein-Barr viral nuclear antigen 2 (EBNA2) and activated Notch1 transactivate genes by interacting with the cellular protein RBP-J kappa.

The Epstein-Barr viral nuclear antigen 2 (EBNA2) plays a key role during establishment and maintenance of B cell immortalization after Epstein-Barr virus (EBV) infection. EBNA2 acts as a transactivator of cellular and viral genes. We studied two EBNA2 regulated viral promoters (TP1 promoter and LMP/TP2 promoter) in detail to learn more about the molecular mechanisms of EBNA2-mediated transactivation. In both promoters we could identify at least one binding site for the cellular repressor protein RBP-J kappa. EBNA2 is tethered to the EBNA2 responsive promoter elements by interaction with this cellular protein. Although necessary, the binding of RBP-J kappa is not sufficient for EBNA2-mediated transactivation. At least two further cellular proteins, which are different in the studied promoters are important for efficient transactivation. The identification of RBP-J kappa as central mediator of EBNA2 transactivation suggested an interference of EBNA2 with the highly conserved Notch receptor signal transduction pathway. We could show that an activated form of the Notch receptor can transactivate a reporter construct containing a hexamer of the two RBP-J kappa binding sites of the TP1 promoter supporting the idea that EBNA2 acts as a functional equivalent of an activated Notch receptor.

DNA-Binding Proteins↗
PubMed1997

The relation between left ventricular wall stress shortening and preload changes in ventilated patients.

The relation between left ventricular end-systolic wall stress (ESWS) and the velocity of circumferential fibre shortening (Vcfs) was examined in four non-random groups with 12 patients each. In group A, preload was increased by the administration of hydroxyethylstarch 30 mL min-1. In group B, preload was reduced by administering nitroglycerine 4.0 +/- 0.8 mg h-1. A change in pulmonary capillary wedge pressure by 3 mmHg was taken to be the end point for preload manipulation. To assess a change in the relation between ESWS and Vcfs, patients in group C received adrenaline at an infusion rate of 4 g min-1. Patients in group D served as the controls. Geometric variables of ESWS and Vcfs were determined by transoesophageal echocardiography. A linear model was used to assess the relation between ESWS and Vcfs within each group by regression analysis, and analysis of covariance performed to detect significance of intragroup and intergroup differences (P < 0.005). No significant changes were found during preload intervention. With adrenaline, Vcfs increased significantly for a given ESWS. It is concluded that the relation between ESWS and Vcfs, in a multiple patient setting, is independent of modest preload changes and may have the potential to indicate inotropic effects.

Adult↗
PubMed1997

Serotonin syndrome after lithium add-on medication to paroxetine.

A 59-year-old female patient was hospitalized on account of a depressive episode in the course of a long-standing bipolar disorder. On a combination of lithium (400 mg/day) and paroxetine (30 mg/day) she developed symptoms of shivering, high-frequency tremor of the upper and lower limbs, skin flush in the face, agitation, and slight impairment of mental focusing, suggestive of a serotonin syndrome. At this stage serum lithium and paroxetine levels were 0.63 mmol/l, and 693 ng/ml, respectively; the latter was six times higher than the upper concentrations seen in patients on this dosage of the drug. Consequently, the dosage of paroxetine was reduced to 10 mg/day, and lithium was continued. This regimen resulted in a steady-state paroxetine serum level of 390 ng/ml. The patient became symptom-free and the depressive episode attenuated, thus enabling us to discharge the patient.

Antidepressive Agents, Second-Generation↗
PubMed1997

Quality-monitoring of psychotropic drug therapy in post-marketing surveillance. Results of a drug utilization observation (DUO) study on moclobemide.

Thanks to their non-intervening nature, post-marketing drug utilization observation (DUO) studies reflect both the properties of the substance under investigation and doctors' treatment decisions, thus-in contrast with clinical trials-allowing the interactions of these two factors to be investigated. A DUO study involving the administration of moclobemide to 9419 patients investigated the prescribing behavior of about two-thirds of all general practitioners and internists in Germany prescribing moclobemide during the study period. The results obtained suggest that, on the whole, moclobemide is being prescribed knowledgeably and correctly for the treatment of the full spectrum of depressive disorders. The management of these patients tended to adhere strictly to existing treatment recommendations while at the same time revealing a certain degree of latitude for treatment optimization. This applies particularly to the utilization of the recommended dosage range, especially in severely depressed states, and the consistent, syndrome-based combination treatment with hypnotics/sedatives or neuroleptics in the respective patient groups indicated. Potential interactions-though comparatively few are known for moclobemide-were taken into account in most cases. The safety profile closely matches the experience gained from clinical trials. Despite the large sample size involved there was no evidence of any hitherto unknown serious events. The experience gained during this survey suggests that the DUO study is a suitable instrument for monitoring the use of an antidepressant in the early post-registration period, enabling action to be taken at an early stage to correct any systematic deviations from the conditions of registration.

Adolescent↗