Biomedical subjects

M Müller

Publications and source records attributed to M Müller.

At least 289 records · Page 16Linked to original sources

PubMed2001

Grand mal convulsion and plasma concentrations after intravascular injection of ropivacaine for axillary brachial plexus blockade.

We report a patient to whom ropivacaine 1.1 mg kg(-1) was administered for brachial plexus blockade and who developed grand mal convulsions because of inadvertent i.v. injection. No symptoms of cardiovascular toxicity occurred. Venous blood samples were taken 15, 45, 75 and 155 min after the injection. The measured total plasma concentrations of ropivacaine were 3.3, 1.6, 1.2 and 1.0 mg litre(-1) respectively. Initial plasma concentration after the end of the injection period was estimated at 5.75 mg litre(-1) using a two-compartment pharmacokinetic model.

Aged↗

PubMed2001

Mitochondrial type iron-sulfur cluster assembly in the amitochondriate eukaryotes Trichomonas vaginalis and Giardia intestinalis, as indicated by the phylogeny of IscS.

Pyridoxal-5'-phosphate-dependent cysteine desulfurase (IscS) is an essential enzyme in the assembly of FeS clusters in bacteria as well as in the mitochondria of eukaryotes. Although FeS proteins are particularly important for the energy metabolism of amitochondrial anaerobic eukaryotes, there is no information about FeS cluster formation in these organisms. We identified and sequenced two IscS homologs of Trichomonas vaginalis (TviscS-1 and TviscS-2) and one of Giardia intestinalis (GiiscS). TviscS-1, TviscS-2, and GiiscS possess the typical conserved regions implicated in cysteine desulfurase activity. N-termini of TviscS-1 and TviscS-2 possess eight amino acid extensions, which resemble the N-terminal presequences that target proteins to hydrogenosomes in trichomonads. No presequence was evident in GiiscS from Giardia, an organism that apparently lacks hydrogenosmes or mitochondria. Phylogenetic analysis showed a close relationship among all eukaryotic IscS genes including those of amitochondriates. IscS of proteobacteria formed a sister group to the eukaryotic clade, suggesting that isc-related genes were present in the proteobacterial endosymbiotic ancestor of mitochondria and hydrogenosomes. NifS genes of nitrogen-fixing bacteria, which are IscS homologs required for specific formation of FeS clusters in nitrogenase, formed a more distant group. The phylogeny indicates the presence of a common mechanism for FeS cluster formation in mitochondriates as well as in amitochondriate eukaryotes. Furthermore, the analyses support a common origin of Trichomonas hydrogenosomes and mitochondria, as well as secondary loss of mitochondrion/hydrogenosome-like organelles in Giardia.

Amino Acid Sequence↗

PubMed2001

Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock.

OBJECTIVE: Current guidelines for adjusting antimicrobial therapy regimens commonly are based on drug concentrations measured in plasma. In septic patients, however, the interstitial space of soft tissues in addition to the central compartment represents the target site of infection. We thus hypothesized that one explanation for therapeutic failure during antibiotic treatment might be the inability to achieve effective antimicrobial concentrations in the interstitial space fluid of soft tissues. This is corroborated by the fact that piperacillin, a frequently administered beta-lactam antibiotic, often fails to be effective despite documented susceptibility of the causative pathogen in vitro. DESIGN: Prospective comparative study of two groups. SETTING: The intensive care unit and research ward of an university hospital. SUBJECTS: Six patients with septic shock and a control group of six gender- and age-matched healthy volunteers. INTERVENTIONS: To measure piperacillin penetration into the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue, we employed microdialysis after a single intravenous administration of 4.0 g of piperacillin to patients and healthy volunteers. Piperacillin concentrations were assayed by using reversed-phase high-pressure liquid chromatography. MEASUREMENTS AND MAIN RESULTS: In septic shock patients, interstitial piperacillin concentrations in skeletal muscle and subcutaneous adipose tissue were five- to ten-fold lower than corresponding free plasma concentrations (p <.03). Mean piperacillin concentrations in subcutaneous adipose tissue never exceeded 11 microg/mL, which is below the minimal inhibitory concentration for a range of relevant pathogens in patients with septic shock. CONCLUSION: The results of the present study demonstrate that in septic shock patients, piperacillin concentrations in the interstitial space may be subinhibitory, even though effective concentrations are attained in plasma. The lack of success of antimicrobial therapy in these patients thus might be attributable to inadequate target site penetration of antibiotics.

Adipose Tissue↗

PubMed2001

Real-time quantitative PCR of telomerase mRNA is useful for the differentiation of benign and malignant pancreatic disorders.

The presence of telomerase activity has been proposed as a specific and sensitive marker for malignant tissue, and positivity rates of up to 95% have been reported in pancreatic cancer. In the present study telomerase activity analysis was reevaluated in 29 pancreatic cancer tissues compared with 36 chronic pancreatitis tissues and 21 normal controls, and a study was made of whether malignant and benign pancreatic disorders can be better differentiated using a novel technique real-time quantitative PCR analysis-analyzing telomerase mRNA expression. Telomerase activity was present in 35% (10 of 29) of pancreatic cancer samples, 3% (one of 36) of chronic pancreatitis samples, and none of the normal pancreatic tissue samples in the TRAP assay. Real-time quantitative PCR analysis revealed the presence of telomerase mRNA expression in 50% (10 of 20) of normal, 86% (31 of 36) of chronic pancreatitis, and 90% (26 of 29) of pancreatic cancer samples. However, quantification of the expression data revealed that the relative increase above normal was 5.5 (range, 3.5-8.6) for chronic pancreatitis and 23.9 (range, 18.6-30.7) for pancreatic cancer samples (p < 0.01). No relationship was found between telomerase activity and the fold increase of telomerase mRNA above normal and gender, patient age, tumor stage, or tumor grade. These data indicate that detection of telomerase activity using the TRAP assay has limitations in differentiating benign and malignant pancreatic disorders. However, telomerase mRNA analysis by real-time quantitative PCR analysis allows a highly sensitive detection and differentiation of pancreatic cancer from normal pancreas and chronic pancreatitis and thereby may serve as a new reliable, easy, and effective diagnostic tool for cancer diagnosis.

Adult↗

PubMed2001

Fluvoxamine but not sertraline inhibits the metabolism of olanzapine: evidence from a therapeutic drug monitoring service.

Therapeutic drug monitoring data of the new atypical neuroleptic drug olanzapine were used to study interactions with the selective serotonin reuptake inhibitors fluvoxamine and sertraline. The distribution of the ratio of concentration/daily dose (C/D; ng/mL per mg/d) of olanzapine was compared in three groups: patients treated with olanzapine (n = 134), patients treated with olanzapine plus fluvoxamine (n = 10) concomitantly, and patients treated with olanzapine plus sertraline (n = 21) concomitantly. No significant difference was seen between the olanzapine and the olanzapine plus sertraline groups. Patients receiving fluvoxamine in addition to olanzapine had C/D ratios that were in the mean 2.3-fold higher than patients receiving olanzapine without additional fluvoxamine. This indicated that fluvoxamine inhibits the metabolism of olanzapine, probably because of inhibition of cytochrome P450 (CYP) 1A2, whereas sertraline is unlikely to interfere with the metabolism of olanzapine. Combination therapy of olanzapine and fluvoxamine should be used cautiously, and therapeutic drug monitoring should be instituted to avoid olanzapine-induced adverse effects or intoxications.

Adult↗

PubMed2001

Differential release of interleukines 6, 8, and 10 in cerebrospinal fluid and plasma after traumatic brain injury.

Traumatic brain injury (TBI) is characterized by a high mortality which is largely determined by the initial cerebral trauma, secondary brain injury or indirectly during a Multiple Organ Dysfunction Syndrome (MODS). Therefore, we analyzed IL-6, IL-8, and IL-10 in cerebrospinal fluid (CSF) and in plasma with respect to blood-brain barrier (BBB) integrity in 29 patients suffering from isolated TBI. IL-6 and IL-8 were significantly increased compared to baseline levels early after trauma in CSF and plasma. In all patients CSF IL-6 and IL-8 were found to be higher than corresponding plasma levels. IL-10 in plasma was significantly increased above control plasma values, however, without a significant difference to the corresponding CSF values. BBB dysfunction was temporary present in 23 patients. Significant correlations between BBB dysfunction and cytokines were not found. Thus, alterations of the BBB seems not to influence the distribution pattern of interleukines in CSF and plasma after trauma.

Adolescent↗

PubMed2001

The use of clinical scales in depicting cerebrovascular complications in bacterial meningitis.

To evaluate the utility of different scales for clinical assessment, over time, in acute bacterial meningitis, the authors investigated 53 consecutive patients (mean age 53 +/- 17 years). Clinical status on days 1, 3, 5, 8, and 14 after admission was determined by the Scandinavian Stroke Scale (SSS), Glasgow Coma Scale (GCS), and Hunt and Hess Scale (HH), and, on day 21, by the Glasgow Outcome Scale (GOS). Transcranial Doppler examinations were performed serially to assess for disease-related arterial narrowing. This was observed in 27 patients (51%) within 2 weeks of admission. All scales were observed to correlate with the 21-day GOS. Patients with cerebral arterial narrowing had significantly decreased SSS scores between days 1 and 8 and worse GCS and HH scores between days 3 and 5. Mean blood flow velocity in the middle cerebral artery on days 5 and 8 significantly correlated with GOS (r = 0.268, P < .008; r = -0.324, P < .003, respectively). The use of such clinical scales allows standardized assessment of patients with bacterial meningitis and provides prognostic information. Cerebral arterial narrowing was observed to correlate with neurologic impairment.

Acute Disease↗

PubMed2001

Increased acid and bile reflux in Barrett's esophagus compared to reflux esophagitis, and effect of proton pump inhibitor therapy.

OBJECTIVES: Barrett's metaplasia is an acquired condition resulting from longstanding gastroesophageal reflux disease. Approximately 10% of esophagitis patients develop Barrett's esophagus. There is increasing evidence that duodenogastroesophageal reflux plays a role in the progression of disease. We further analyzed the correlation of acid and biliary reflux with reflux esophagitis and Barrett's esophagus and tested the effects of proton pump inhibitor therapy. METHODS: Patients with either reflux esophagitis (group 1) or Barrett's esophagus (group 2) prospectively underwent simultaneous 24-h esophageal pH and bile reflux testing without any therapy affecting acid secretion or GI motility. A total of 16 patients in group 1 and 18 patients in group 2 were tested again under proton pump inhibitor therapy. RESULTS: Acid and bile exposure were significantly increased in Barrett's patients (n = 23) compared to 20 esophagitis patients (median percentage of time that pH was <4 was 24.6% vs 12.4%, p = 0.01, median percentage of time that bilirubin absorbance was >0.2 was 34.7% vs 12.8%, p < 0.05). During therapy, both acid and bile reflux decreased significantly in both groups. Median percentage of time that pH was <4 and bilirubin absorbance was >0.2 before and during therapy was 18.2%/2.3% and 29.8%/0.7% (p = 0.001 and p = 0.001) in Barrett's esophagus patients versus 14.5%/3.6% and 21.5%/0.9% (p = 0.002 and p = 0.011) in esophagitis patients. There was no significant difference between the groups. In two esophagitis patients, bile reflux increased during therapy. CONCLUSIONS: There is a good correlation of the duration of esophageal exposure to acid and bile with the severity of pathological change in the esophagus. Both acid and bile reflux is significantly suppressed by proton pump inhibitor therapy with exceptions among individual esophagitis patients. The prolonged simultaneous attack of bile and acid may play a key role in the development of Barrett's metaplasia.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed2001

Factor XIII prevents development of myocardial edema in children undergoing surgery for congenital heart disease.

In a prospective investigation of perioperative cardiac edema formation requiring a delayed sternal closure, we identified thrombin increase combined with a simultaneous decrease of factor XIII as a probable cause. After experimental studies additionally revealed that factor XIII could protect endothelial barrier function, we did another prospective randomized trial in which factor XIII or placebo was preoperatively substituted. The substitution finally showed distinct effects minimizing the incidence of myocardial swelling. Therefore, the clinical application of factor XIII may have a valuable therapeutic benefit in cases of leakage syndrome during extracorporeal circulation in congenital heart surgery.

Cardiomyopathies↗

PubMed2001

DNA-based detection of prostate cancer in blood, urine, and ejaculates.

BACKGROUND: Methylation-specific polymerase chain reaction (MSP) targeting promoter hypermethylation of the glutathione S transferase P1 gene (GSTP1), as the most frequent DNA alteration in prostatic carcinoma, was used for the molecular detection of cell-bound and cell-free prostate tumor DNA in various human bodily fluids. MATERIALS AND METHODS: We investigated GSTP1 promoter hypermethylation in DNA isolated from plasma, serum, nucleated blood cells, ejaculates, urines after prostate massage, and prostate tissue from 33 patients with prostate cancer and 26 control patients with benign prostatic hyperplasia (BPH). Using a viral DNA extraction kit specifically recommended for DNA isolation from urine samples, GSTP1 promoter hypermethylation in urine sediments after prostatic massage was investigated in a cohort of 29 patients with prostate cancer and 40 controls with BPH. Fluorescently labeled MSP products were analyzed on an automated gene sequencer. RESULTS: GSTP1 promoter hypermethylation was found in 90% of tumors (18 of 20), 72% of plasma or serum samples (23 of 32), 50% of ejaculates (4 of 8), and between 36% (4 of 11; normal DNA isolation kit) and 76% (22 of 29; viral kit) of exprimated urines from patients with prostate cancer. Also, MSP identified circulating tumor cells in 30% (10 out of 33) of prostate cancer patients. Except for one urine sample, GSTP1 promoter hypermethylation was not found in tissue and body fluids from patients with BPH. CONCLUSION: GSTP1 promoter methylation analysis provides a highly specific tool for DNA-based diagnosis of prostate cancer in body fluids.

Aged↗

PubMed2001

Dual role of lipopolysaccharide (LPS)-binding protein in neutralization of LPS and enhancement of LPS-induced activation of mononuclear cells.

The lipopolysaccharide (LPS)-binding protein (LBP) has a concentration-dependent dual role in the pathogenesis of gram-negative sepsis: low concentrations of LBP enhance the LPS-induced activation of mononuclear cells (MNC), whereas the acute-phase rise in LBP concentrations inhibits LPS-induced cellular stimulation. In stimulation experiments, we have found that LBP mediates the LPS-induced cytokine release from MNC even under serum-free conditions. In biophysical experiments we demonstrated that LBP binds and intercalates into lipid membranes, amplified by negative charges of the latter, and that intercalated LBP can mediate the CD14-independent intercalation of LPS into membranes in a lipid-specific and temperature-dependent manner. In contrast, prior complexation of LBP and LPS inhibited binding of these complexes to membranes due to different binding of LBP to LPS or phospholipids. This results in a neutralization of LPS and, therefore, to a reduced production of tumor necrosis factor by MNC. We propose that LBP is not only present as a soluble protein in the serum but may also be incorporated as a transmembrane protein in the cytoplasmic membrane of MNC and that the interaction of LPS with membrane-associated LBP may be an important step in LBP-mediated activation of MNC, whereas LBP-LPS complexation in the serum leads to a neutralization of LPS.

Acute-Phase Proteins↗

PubMed2001

Presence of prokaryotic and eukaryotic species in all subgroups of the PP(i)-dependent group II phosphofructokinase protein family.

Inorganic pyrophosphate-dependent phosphofructokinase (PP(i)-PFK) of the amitochondriate eukaryote Mastigamoeba balamuthi was sequenced and showed about 60% identity to PP(i)-PFKs from two eubacteria, Propionibacterium freudenreichii and Sinorhizobium meliloti. These gene products represent a newly recognized lineage of PFKs. All four lineages of group II PFKs, as defined by phylogenetic analysis, contained both prokaryotic and eukaryotic species, underlining the complex evolutionary history of this enzyme.

Amoeba↗

PubMed2001

Enhancement of capsid gene expression: preparing the human papillomavirus type 16 major structural gene L1 for DNA vaccination purposes.

Expression of the structural proteins L1 and L2 of the human papillomaviruses (HPV) is tightly regulated. As a consequence, attempts to express these prime-candidate genes for prophylactic vaccination against papillomavirus-associated diseases in mammalian cells by means of simple DNA transfections result in insufficient production of the viral antigens. Similarly, in vivo DNA vaccination using HPV L1 or L2 expression constructs produces only weak immune responses. In this study we demonstrate that transient expression of the HPV type 16 L1 and L2 proteins can be highly improved by changing the RNA coding sequence, resulting in the accumulation of significant amounts of virus-like particles in the nuclei of transfected cells. Data presented indicate that, in the case of L1, adaptation for codon usage accounts for the vast majority of the improvement in protein expression, whereas translation-independent posttranscriptional events contribute only to a minor degree. Finally, the adapted L1 genes demonstrate strongly increased immunogenicity in vivo compared to that of unmodified L1 genes.

Capsid Proteins↗

PubMed2001

Therapeutic vaccines for human papillomaviruses.

Although papillomavirus infections are not very immunogenic there is evidence that the immune system controls the spread of virus and the development of diseases associated with such infections. Certain types of human papillomaviruses (HPV) are the major cause of premalignant and malignant diseases of the anogenital tract, most notably cancer of the uterine cervix, a major health care problem worldwide. Since the viral oncoproteins E6 and E7 are constitutively expressed within the tumor cells, they are considered as suitable targets for attack by T lymphocytes. Several approaches to specifically trigger a cell-mediated immune response have been successful in experimental animals, leading to suppression of HPV-induced tumors. First clinical trials have been completed which raise hopes that a similar effect can also be achieved by therapeutic vaccination of humans.

Cancer Vaccines↗

PubMed2001

Molecular markers in testicular germ cell tumors--objects of clinical research or close to becoming clinical tools?

The aim of this short review is to critically evaluate hitherto investigated molecular markers for testicular germ cell tumors. Molecular parameters have been clinically established as diagnostic and prognostic markers for a number of tumors; this has not yet been achieved for germ cell tumors. There are interesting prospects, however. Studies on the ribonucleoprotein telomerase, for example, have demonstrated a correlation between enzyme activity and chemotherapeutic drug sensitivity. Moreover, innovative treatment approaches target this reverse transcriptase via telomerase antisense RNA. Another potential diagnostic marker is the detection of circulating tumor cells, which correlated with an increased relapse rate in initial studies. There are also interesting possibilities for the germ-cell-tumor-specific isochromosome [i(12)p], which is helpful in the differential diagnosis of mediastinal masses. Here initial studies demonstrated a correlation between the copy number and resistance against chemotherapeutic drugs. Without prospective studies to validate data obtained thus far, neither these nor other parameters can be assessed as diagnostic and prognostic factors. Irrespective of their immediate clinical applicability, however, investigations on molecular alterations in testicular germ cell tumors will become the basis for a molecular-diagnostically oriented subclassification of tumors as well as for novel therapeutic approaches.

Chromosome Aberrations↗

PubMed2001

Differential regulation of cathepsin B and prorenin gene expression in renal juxtaglomerular cells.

Cathepsin B (cathB) is a lysosome cysteine proteinase. It has been suggested to process prorenin to renin in the renin producing juxtaglomerular (JG) cells of the afferent arterioles (AA) of the kidney. Whether cathB expression is regulated similarly to prorenin production is yet unknown. We have measured prorenin and cathB mRNA levels as well as cathB protein levels in renal AA of Sprague-Dawley rats subjected to low (0.02% w/w) salt diet and ramipril treatment (10 mg/kg/day), or to normal (0.6%) or high (4%) salt diet. Prorenin and cathB expression were also analyzed in the JG cell line As4.1. Prorenin mRNA levels in animals on normal (plus ramipril), low or high salt diet correlated as 1:10:0.5, respectively, while cathB mRNA levels correlated as 1:1:0.6, respectively. Treatment of the As4.1 cells with 100 nM phorbol-12-myristate-13-acetate (PMA) for 16 h inhibited prorenin mRNA expression 3-fold relative to the control conditions. CathB mRNA abundance was not different between the PMA treated and the control As4.1 cells. Western analysis of the cathB protein abundance has shown no difference between the rats on normal and low salt diet, and decrease by 50% in the rats on high salt diet. The results of this study suggest that prorenin and cathB gene expression in renal JG cells are differentially regulated.

Angiotensin II↗

PubMed2001

Impact of chemotherapy on male fertility.

Testicular tumors and malignant lymphomas are, with increasing incidence, the most frequent malignant diseases in men between the age of 15 and 34. With the introduction of cisplatin-based polychemotherapy, cure rates rose to over 90% in patients with germ cell tumors and were comparably favorable at around 80% in those with malignant lymphomas. In view of these high cure rates, increasing clinical importance is attached to chemotherapy induced fertility disorders. One problem involved in assessing the influence of chemotherapy on fertility is the fact that the malignant disease itself strongly alters spermatogenesis. This complicates an evaluation of the effect of cytostatic therapy on fertility disorders. There are significant cytostatic- and dose-specific differences. Longterm infertility due to cytostatic therapy may be expected in more than 50% of the patients at a cumulative dose of cisplatin > 0.6 g/m(2), cyclophosphamide > 6 g/m(2), and procarbazine >/= 4 g/m(2). However, it takes up to 3 years or more for spermatogenesis to recover after the termination of chemotherapy. An individual assessment of the post-therapeutic fertility status is extremely limited, since variance of the pretherapeutic fertility status causes interindividual differences, and the numerical data mentioned above only permit a vague estimation. Before patients undergo cytostatic therapy, cryopreservation of germ cells should thus be suggested or, in some cases, testicular extraction of spermatozoa.

Adolescent↗

PubMed2001

Spontaneous echo contrast caused by platelet and leukocyte aggregates?

BACKGROUND AND PURPOSE: Spontaneous echocardiographic contrast (SEC) is correlated to clinical thromboembolic events. We sought to determine the origin of SEC by utilizing direct analysis of left atrial blood. METHODS: We examined the blood of 13 patients with and 19 without SEC. Blood samples were taken from the femoral vein and artery and from the right and left atria after transseptal puncture. Samples were incubated with fluorescence-labeled antibodies directed against the platelet (CD41a-PE, CD42b-PE, and CD62p-FITC) and leukocyte membrane epitopes (CD45-APC and CD14-FITC). The expressed epitopes were analyzed by dual laser flow cytometry immediately after blood withdrawal. RESULTS: In the peripheral blood of both groups, more activation and aggregation were found in the venous blood than in the arterial blood (CD41a, P=0.007; CD14neutro, P=0.017; and leukocyte-platelet aggregates [LTAg], P=0.002). In patients without SEC, the degree of activation and aggregation of the cardiac samples closely resembled the results of the peripheral samples. The degree of activation and aggregation was significantly higher in the right atrium than in the left atrium (LTAg, P<0.01; leukocyte activation, P<0.01; CD41a, P<0.01; CD62p, P<0.02). In contrast, in patients with SEC the parameters of platelet and leukocyte activation as well as LTAg was significantly higher in the left atrium than in the right atrium of the same patient (all P<0.01). A correlation between the amount of SEC and platelet-monocyte aggregates could be found (r=0.92, P<0.0001). CONCLUSIONS: The hypothesis that platelet aggregates are involved in the pathogenesis of SEC is supported by the fact that platelets in the left atrium of patients with SEC showed more activation.

Adult↗