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Biomedical subjects

M Müller

Publications and source records attributed to M Müller.

At least 307 records · Page 17Linked to original sources
PubMed2001

IP(3) receptor function and localization in myotubes: an unexplored Ca(2+) signaling pathway in skeletal muscle.

We present evidence for an unexplored inositol 1,4,5-trisphosphate-mediated Ca(2+) signaling pathway in skeletal muscle. RT-PCR methods confirm expression of all three known isotypes of the inositol trisphosphate receptor in cultured rodent muscle. Confocal microscopy of cultured mouse muscle, doubly labeled for inositol receptor type 1 and proteins of known distribution, reveals that the receptors are localized to the I band of the sarcoplasmic reticulum, and this staining is continuous with staining of the nuclear envelope region. These results suggest that the receptors are positioned to mediate a slowly propagating Ca(2+) wave that follows the fast Ca(2+) transient upon K(+) depolarization. This slow wave, imaged using fluo-3, resulted in an increase in nucleoplasmic Ca(2+) lasting tens of seconds, but not contraction; the slow wave was blocked by both the inositol trisphosphate receptor inhibitor 2-aminoethoxydiphenyl borate and the phospholipase C inhibitor U-73122. To test the hypothesis that these slow Ca(2+) signals are involved in signal cascades leading to regulation of gene expression, we assayed for early effects of K(+) depolarization on mitogen-activated protein kinases, specifically extracellular-signal related kinases 1 and 2 and the transcription factor cAMP response element-binding protein (CREB). Within 30-60 seconds following depolarization, phosphorylation of both the kinases and CREB was evident and could be inhibited by 2-aminoethoxydiphenyl borate. These results suggest a signaling system mediated by Ca(2+) and inositol trisphosphate that could regulate gene expression in muscle cells.

Actinin↗
PubMed2001

Biophysical characterization of lipopolysaccharide and lipid A inactivation by lactoferrin.

The interaction of bacterial endotoxins (LPS Re and lipid A, the 'endotoxic principle' of LPS) with the endogenous antibiotic lactoferrin (LF) was investigated using various physical techniques and biological assays. By applying Fourier-transform infrared (FTIR) spectroscopy, we find that LF binds to the phosphate group within the lipid A part and induces a rigidification of the acyl chains of LPS. The secondary structure of the protein - as monitored by the amide I band - is, however, not changed. Concomitant with the IR data, scanning calorimetric data indicate a sharpening of the acyl chain phase transition. From titration calorimetric and zeta potential data, saturation of LF binding to LPS was found to lie at a [LF]:[LPS] ratio of 1:3 to 1:5 M from the former and 1:10 M from the latter technique. X-ray scattering data indicate a change of the lipid A aggregate structure from inverted cubic to multilamellar, and with fluorescence (FRET) spectroscopy, LF is shown to intercalate by itself into phospholipid liposomes and may also block the lipopolysaccharide-binding protein (LBP)-induced intercalation of LPS. The LPS-induced cytokine production of human mononuclear cells exhibits a decrease due to LF binding, whereas the coagulation of amebocyte lysate in the Limulus test exhibited concentration-dependent changes. Based on these results, a model for the mechanisms of endotoxin inactivation by LF is proposed.

Animals↗
PubMed2001

Use of automated external defibrillators in a Brazilian airline. A 1-year experience.

After the incorporation of automated external defibrillators by other airlines and the support of the Brazilian Society of Cardiology, Varig Airlines began the onboard defibrillation program with the initial purpose of equipping wide-body aircrafts frequently used in international flights and that airplanes use in the Rio - São Paulo route. With all flight attendants trained, the automated external defibrillation devices were incorporated to 34 airplanes of a total fleet of 80 aircrafts. The devices were installed in the baggage compartments secured with velcro straps and 2 pairs of electrodes, one or which pre-connected to the device to minimize application time. Later, a portable monitor was address to the resuscitation kit in the long flights. The expansion of the knowledge of the basic life support fundamentors and the corrected implantation of the survival chain and of the automated external defibrillators will increase the extense of recovery of cardiorespiratory arrest victims in aircrafts.

Adult↗
PubMed2001

Bioequivalence and relative bioavailability of three estradiol and norethisterone acetate-containing hormone replacement therapy tablets.

OBJECTIVE: The primary objective was to demonstrate bioequivalence between the estrogen components ofActivelle (1 mg estradiol (E2) + 0.5 mg norethisterone acetate (NETA)) and the combined phase of Novofem (1 mg E2 + 1 mg NETA) and between the NETA components of the combined phase of Novofem (1 mg E2 + 1 mg NETA) and Trisequens (2 mg E2 + 1 mg NETA). SUBJECTS, MATERIALS AND METHODS: The study design was double-blind, randomized, three-way, balanced six-sequence cross-over. The washout period was 14 days between treatments. Single doses of the above-described tablets were administered in the morning following an overnight fast to 24 healthy postmenopausal or bilaterally oophorectomized women. Plasma concentration profiles of E2, estrone (E1; pharmacologically active metabolite of E2) and norethindrone (NET: NET was determined since NETA is very rapidly metabolized to NET) were measured over 72 h, and 36 h, respectively. For the two former substances a baseline correction was performed by subtracting the mean of two predose measurements from the concentrations measured after dosing. RESULTS: One subject dropped out of the study, completing only one treatment sequence; therefore, the results are based on 23 subjects. The baseline-corrected E2 and E1 AUC0-t (Novofem)/AUC0-t (Activelle) ratios were 105% and 100%, respectively; and the Cmax ratios 100% and 105%, respectively. Identical median tmax was observed for E2 (6 h) and for E1 (5 h). The NET AUC0-t (Novofem)/AUC0-t (Trisequens) ratio was 95%, and the corresponding Cmax ratio 98%. The median tmax for Novofem was 0.75 h and for Trisequens 1.0 h. CONCLUSION: Bioequivalence was demonstrated for E2, E1 and NET in accordance with the study objectives.

Administration, Oral↗
PubMed2001

Osteoporosis and mild metabolic acidosis in the rat after orchiectomy and their prevention: should prophylactic therapy be administered to patients with androgen deprivation?

PURPOSE: To date there has been little research on the etiology and prophylaxis of osteopenia during androgen deprivation. This condition is gaining increasing attention, partially due to the considerable osteoporosis related side effects of hormone withdrawal symptoms in patients with prostate cancer. We characterized androgen deprivation and its prophylaxis. MATERIALS AND METHODS: A total of 36 male Sprague-Dawley rats underwent laparotomy, orchiectomy or orchiectomy with subsequently treatment with calcium acetate and sodium citrate via the water supply. Postoperative observation was 19 weeks. Test parameters were weight development, testosterone, parathyroid hormone, vitamin D, osteocalcin, cross links, hydroxyproline and cyclic adenosine monophosphate as well as bone density, tensile strength, mineral content and histomorphometry. RESULTS: Animals subjected to orchiectomy had a reduction in bone mineral content and fracture energy with mild metabolic acidosis. The markers of bone metabolism were statistically unchanged, while the ratio of trabeculae-to-tissue area decreased. Animals treated with orchiectomy, calcium acetate and sodium citrate had moderately compensated metabolic alkalosis and increased bone minerals. Fracture energy was likewise normal and there was a tendency toward higher bone metabolism. CONCLUSIONS: Castration led to a reduced increase in body mass, considerable standard deviation from biochemical and histological criteria for tubular bone and, thus, an increased fracture risk. A possible cause may be reduced formation and unchanged bone loss combined with mild metabolic acidosis. Calcium and alkalization seem to be effective prophylaxis for androgen deprivation. Considering the large number of osteoporotic complications after androgen deprivation, further clinical studies are justified to show the benefits of prophylactic therapy.

Acetates↗
PubMed2001

Comparison of "type I" and "type II" organic cation transport by organic cation transporters and organic anion-transporting polypeptides.

Previous inhibition studies with taurocholate and cardiac glycosides suggested the presence of separate uptake systems for small "type I" (system1) and for bulky "type II" (system2) organic cations in rat hepatocytes. To identify the transport systems involved in type I and type II organic cation uptake, we compared the organic cation transport properties of the rat and human organic cation transporter 1 (rOCT1; hOCT1) and of the organic anion-transporting polypeptides 2 and A (rat Oatp2; human OATP-A) in cRNA-injected Xenopus laevis oocytes. Based on characteristic cis-inhibition patterns of rOCT1-mediated tributylmethylammonium and Oatp2-mediated rocuronium uptake, rOCT1 and Oatp2 could be identified as the organic cation uptake systems1 and 2, respectively, in rat liver. While hOCT1 exhibited similar transport properties as rOCT1, OATP-A- but not Oatp2-mediated rocuronium uptake was inhibited by the OATP-A substrate N-methyl-quinidine. The latter substrate was also transported by rOCT1 and hOCT1, demonstrating distinct organic cation transport activities for rOCT1 and Oatp2 and overlapping organic cation transport activities for hOCT1 and OATP-A. Finally, the data demonstrate that unmethylated quinidine is transported by rOCT1, hOCT1, and OATP-A at pH 6.0, but not at pH 7.5, indicating that quinidine requires a positive charge for carrier-mediated uptake into hepatocytes. In conclusion, the studies demonstrate that in rat liver the suggested organic cation uptake systems1 and 2 correspond to rOCT1 and Oatp2, respectively. However, the rat-based type I and II organic cation transporter classification cannot be extended without modification from rat to human.

Androstanols↗
PubMed2001

Late confirmation of acute methyl bromide poisoning using S-methylcysteine adduct testing.

Methyl bromide poisoning is difficult to confirm because routine laboratory testing has not been reliable. Measurable levels of the parent agent are rapidly reduced, probably as a result of direct tissue chemical reaction. Serum bromide levels have been used as an indirect measure of exposure and/or toxicity but are inconsistent. Recently special testing has shown that protein adducts formed after exposure to methyl bromide may be a better measure of significant exposure. The S-methylcysteine adduct was used to confirm acute methyl bromide toxicity 10 weeks after an exposure. Additionally, genotyping of the glutathione-S-transferase TI enzyme in erthyrocytes from this case characterized a predisposition to the neurotoxic effects of methyl bromide.

Adult↗
PubMed2001

Increased incidence of luteinizing hormone-releasing hormone receptor gene messenger RNA expression in hormone-refractory human prostate cancers.

There are few options for treating hormone-refractory prostate cancer (PC). Various studies indicate that luteinizing hormone-releasing hormone (LHRH) agonists may have a direct inhibitory effect on prostate tumors mediated by specific LHRH receptors. One study evaluated LHRH receptors in hormone-dependent PC tissue, but no data have thus far been obtained on the presence of LHRH receptors in benign prostatic hyperplasia (BPH) and especially hormone-refractory PC in patients. Thus, it is not yet clear whether LHRH receptors indicate tumor-related differentiation or even hormone-refractory dedifferentiation or are likewise associated with BPH. The aim of this study was to determine the rate of LHRH receptor mRNA expression in BPH and in primary, potentially androgen-dependent and in hormone-refractory PC with clinical progression. Multiplex reverse transcription-PCR was used to simultaneously detect the expression of mRNA for LHRH receptors and beta-actin in 48 patients with BPH, 14 with a primary, possibly hormone-dependent, prostate carcinoma (PPC), and 18 with a hormone-refractory prostate carcinoma (HRPC). Sixteen of 18 samples with HRPC showed intact RNA and expressed mRNA for LHRH receptors (100%). However, the RNA-intact PPC and BPH showed significantly lower expression of mRNA for LHRH receptors (46.2 and 55.3%, respectively; variance analysis: P = 0.0017). The significantly higher expression of mRNA for LHRH receptors in HRPC indicates that therapeutic concepts should be developed that target this site of action. In addition to possible direct effects of LHRH agonists or antagonists demonstrated previously in vitro, it seems useful to apply targeted cytotoxic LHRH analogues or monoclonal antibodies.

Aged↗
PubMed2001

Lipid analysis of human HDL and LDL by MALDI-TOF mass spectrometry and (31)P-NMR.

The analysis of HDL and LDL is important for the further understanding of atherosclerosis because changes of the protein and lipid moieties occur under pathological conditions. Because destruction of lipids leads to the formation of well-defined products such as lysophospholipids or chlorohydrins, methods that allow their fast and reliable determination would be useful. In this study, matrix-assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI-TOF MS) was applied for the analysis of the lipid composition of human lipoproteins. These data were compared with high resolution (31)P-NMR spectroscopy. Differences between LDL and HDL in sphingomyelin and phosphatidylcholine content could be monitored by NMR and mass spectrometry, and differences with respect to the extraction efficiency were found by MALDI-TOF MS. Additionally, treatment of LDL with hypochlorite and phospholipase A(2) resulted in marked changes (formation of chlorohydrines and lysolipids). Lysophosphatidylcholines were detectable by both methods, whereas MALDI-TOF MS failed to detect chlorohydrines of phospholipids. We conclude that MALDI-TOF MS provides rapidly a reliable lipid profile of lipoproteins. However, a previous lipid separation must be performed to detect lipid oxidation products. NMR can be directly applied, but suffers from lower sensitivity, and provides only limited information on fatty acid composition.

Chlorohydrins↗
PubMed2001

A K+ channel is involved in LPS signaling.

We previously showed a clear correlation between the molecular conformation of the lipid A moiety of endotoxin molecules and their cytokine-inducing capacity in mononuclear cells. While conically shaped lipid A moieties exhibit a high agonistic activity, a shift to a more cylindrically shaped lipid A leads to a decrease in agonistic and increase in antagonistic activity of the endotoxin molecules. Here, we show the involvement of a high-conductance Ca2+-activated potassium (MaxiK) channel in LPS signaling in macrophages. Corresponding to their biological activity, endotoxins activate a MaxiK channel as shown in outside-out patch-clamp experiments. LPS antagonists and anti-CD14 antibodies inhibit the LPS-induced activation of the channel. Blocking of the channel by specific channel blockers in macrophage cultures leads to inhibition of cytokine mRNA production. In particular, this result implies that there is no other independent transmembrane signaling pathway operative in macrophages. A shift of the molecular conformation of an a priori antagonistic lipid A from a cylindrical to a conical shape by adding the membrane-active compound chlorpromazine increases the activity of the MaxiK channel and the biological activity of the lipid A. We conclude that the activation of the MaxiK channel is a very early step in LPS-induced signaling in macrophages.

Cells, Cultured↗
PubMed2001

Using questions and interests to guide data mining for medical quality management.

The healthcare sector is currently facing both the economic necessity and the technical opportunity of a data based approach to quality management. Against this background, a process model for such a data based medical quality management is proposed and intelligent data mining methods are applied to patient data. Intelligent data mining incorporates advantages of both knowledge acquisition from data and from experts. A controlled language for business questions is presented which abstracts from database and data mining terminology to allow high-level interaction. Objective and subjective interestingness of results is measured and used to filter and sort.

Artificial Intelligence↗
PubMed2001

Quantification of human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) mRNA in testicular tissue of infertile patients.

AIM: To evaluate the quantitative detection of human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) mRNA as diagnostic parameters in the workup of testicular tissue specimens from patients presenting with non-obstructive azoospermia. METHODS: hTR and hTERT mRNA expression were quantified in 38 cryopreserved testicular tissue specimens by fluorescence real-time reverse transcription-polymerase chain reaction (RT-PCR) in a LightCycler(r). This was paralleled by conventional histological workup in all tissue specimens and additional semithin sectioning preparation in cases with maturation arrest (n = 12) and Sertoli-cell-only syndrome (n = 12). RESULTS: The average normalized hTERT expression (N(hTERT)) was 131.9 +/- 48.0 copies (mean +/- SD) in tissue specimens with full spermatogenesis, N(hTERT) = 51.2 +/- 17.2 copies in those with maturation arrest and N(hTERT) = 2.7 +/- 2.4 copies in those with Sertoli-cell-only syndrome (SCOS). The discriminant analysis showed that detection of N(hTERT) (N(hTR)) had a predictive value of 86.8% (55.3%) for correct classification in one of the three histological subgroups. CONCLUSION: Our results demonstrate that quantitative detection of hTERT mRNA expression in testicular tissue enables a molecular-diagnostic classification of gametogenesis. Quantitative detection of hTERT in testicular biopsies is thus well suited for supplementing the histopathological evaluation.

DNA-Binding Proteins↗
PubMed2001

Computational aspects of protein identification by mass spectrometry.

Recent developments in proteomics and genomics provide huge quantities of data to analyze. Automatic interpretation of mass spectrometry data has become essential for high-throughput processes aiming to study complete proteomes. There exist two main sources of mass spectrometric data: peptide mass fingerprint and fragmentation spectra, both of which require specific bioinformatic algorithms. We present a survey of these algorithms and discuss the efficiency of the different approaches and the possible improvements that may lead to a complete automatic high-throughput identification process.

Computational Biology↗
PubMed2001

[Multi-slice spiral CT of the coronary arteries: clear vascular imaging using standard software].

OBJECTIVE: To visualize the coronary arteries with a clear view and over a long distance by using data sets from contrast-enhanced computed tomography of the heart. MATERIAL AND METHODS: Image data of 151 patients suffering from coronary artery disease were calculated by means of retrospective triggering at four different diastolic delay times in contrast-enhanced CT. The large coronary segments were subsequently reconstructed in two planes with multiplanar volume reconstruction (MPVR)--a non-dedicated postprocessing software. RESULTS: On the pre-condition that data sets were acquired at sinus rhythm and at a heart beat rate lower than 65/min coronary arteries could be depicted over a long distance in single or double angulated reconstruction planes with the help of multiplanar volume reconstruction (MPVR). Time consumption for image reconstruction was reasonable. Additionally to the anatomy of the coronary arteries in two different planes, typical CT findings in occluding coronary artery disease are presented. CONCLUSION: Multiplanar volume reconstruction (MPVR) implemented on most workstations is a powerful and ideal postprocessing tool in reconstructing coronary arteries from contrast-enhanced CT data sets.

Coronary Angiography↗
PubMed2000

Microdialysis in clinical drug delivery studies.

The introduction of in vivo microdialysis (MD) to clinical pharmacological studies has opened the opportunity to obtain previously inaccessible information about the drug distribution process to the clinically relevant target site. The aim of this review is to provide a comprehensive overview of the current literature about MD in drug delivery studies from a clinical perspective. In particular the application of MD in clinical--antimicrobial, oncological and transdermal--and neurological research will be described and the scope of MD in pharmacokinetic-pharmacodynamic (PK-PD) studies will be discussed. It is concluded that MD has a great potential for both academic and industrial research, and may become the method of choice for drug distribution studies in humans.

Anti-Bacterial Agents↗
PubMed2000

Stereoselective formation of Bis(alpha-hydroxy ketones) via enzymatic carboligation.

The enzymatic approach to a novel class of chiral bis(alpha-hydroxy ketones) of type 5 and 8, which enable the synthesis of new multidentate ligands for asymmetric transition metal catalysis, is described. The key step is the second benzoylformate decarboxylase catalyzed C-C-bond formation between an aromatic dialdehyde and acetaldehyde, which proceeds with complete stereocontrol. Transformation of enantiomerically enriched monoadduct (S)-4 (ee 88%) and (S)-7 (ee 79%) resulted in optical pure (S,S)-5 and (S,S)-8 besides minor amounts of the corresponding diastereomeric meso-forms.

Journal Article↗