DNA-damage and NAD(+)-depletion are initial events in oxygen radical induced islet cell death.
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Animals↗
Biomedical subjects
M Müller
Publications and source records attributed to M Müller.
Chemical mechanisms of formation of DNA-carcinogen adducts, elucidation of potential of adducts for mutagenicity, and mechanisms of polymerase fidelity and mutation in the presence of adducts.
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Aflatoxin B1↗
Interactions of TCDD with signal transduction and neoplastic development in c-myc transgenic and TGF-alpha transgenic mice.
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Animals↗
Expression of CD44V2 in transitional cell carcinoma of the urinary bladder and in urine.
CD44 is the principal cell surface receptor for hyaluronate. Variant forms of the receptor, produced by alternative splicing, have been found to be associated with tumor progression in a variety of cancers. Based on investigations at the RNA level, it has recently been proposed that expression of CD44 variant V2 was present in urothelial cancer but not in normal urothelium. Since a distinctive marker for urothelial cancer would be extremely useful, frozen sections of normal urothelium and urothelial cancer were examined for expression of standard CD44 and CD44V2. Frozen sections of specimens of 35 patients with transitional cell carcinoma of the bladder, 16 specimens of normal bladder and 5 ureters were examined. Immunohistochemical staining was performed using a polyclonal antibody to CD44V2 (PAB CD44V2), a monoclonal antibody to CD44V2 (MAB CD44V2) and a monoclonal antibody to CD44S (MAB CD44S). CD44V2 and CD44S were also measured in lysates of urine sediments from 21 patients by enzyme-linked immunoabsorbent assay (ELISA). All investigated transitional cell carcinomas expressed CD44V2. There was no differentiation between invasive and noninvasive carcinoma. CD44V2 was also expressed in normal urothelium. Standard CD44 was expressed by the transitional cell carcinoma, normal urothelium, musculature and interstitial tissue. The amount of CD44V2 and CD44S in lysates of urine sediments is not correlated to diagnosis. In contrast to investigations at the RNA level, CD44V2 on the protein level seems not to be a distinctive marker for urothelial cancer. Therefore, CD44V2 will not be a useful diagnostic marker for detection of transitional cell carcinoma.
Antibody Specificity↗
[The effects of dopexamine. Transpulmonary shunt volume in thoracic surgical procedures with one-lung respiration].
OBJECTIVE: To study the influence of dopexamine on pulmonary shunt and hypoxic pulmonary vasoconstriction during major thoracic surgery with one-lung ventilation (OLV). DESIGN: Prospective, randomised, placebo-controlled study. SETTING: University hospital. PATIENTS: Twenty adult patients undergoing elective pulmonary resection. ANAESTHESIA: General anaesthesia was performed using propofol, fentanyl, N2O and vecuronium. Volume-controlled ventilation was performed to maintain normocapnia over the whole investigation period. During OLV, the tidal volume was reduced and the respiratory rate was increased to avoid a peak airway pressure exceeding 40 cm H2O. Furthermore the FiO2 was increased to 1.0 and the external PEEP was removed during OLV. INTERVENTIONS: The patients received either dopexamine at 2 micrograms/kg/min (group A, n = 10) or 0.9% saline as control (group B, n = 10) after assessing the baseline values. MEASUREMENT AND RESULTS: The following cardiorespiratory variables were recorded: Heart rate, mean arterial pressure and mean pulmonary arterial pressure. Cardiac output was measured by thermodilution using a continuous cardiac output thermodilution catheter. Arterial and mixed venous blood gas analysis were measured from simultaneously drawn samples. Cardiac index (CI), systemic vascular resistance index, pulmonary vascular resistance index, oxygen delivery index (DO2I), oxygen consumption index and the venous admixture were calculated using standard formula. Furthermore, pressure-flow-curves were constructed to analyse flow independent changes in the pulmonary vascular resistance. Data were recorded at the following times: After induction of anaesthesia in stable haemodynamics during two-lung ventilation (baseline values, T0), intraoperatively during one-lung ventilation (T1) and postoperatively after re-establishing two-lung ventilation (T2). Patients characteristics, data from the preoperative lung function testing and surgical procedures did not differ significantly between the groups. CI increased in the dopexamine group from 2.5 +/- 1.2 1.min-1.m-2 (T0) to 3.6 +/- 0.9 l.min-1.m-2 (T1) and 4.0 +/- 1.3 l.min-1.m-2 (T2). The course of the intrapulmonary right-to-left shunting did not differ between the groups. In the dopexamine-treated group the DO2I increased from 430 +/- 143 ml.min.m-2 (T0) to 652 +/- 255 ml.min.m-2 (T1) and 653 +/- 207 ml.min.m-2 (T2). Regarding the pressure-flow-curves there was no difference during OLV between the two groups indicating no major blocking effect of dopexamine on hypoxic pulmonary vasoconstriction. CONCLUSION: It is concluded that dopexamine can be used to improve haemodynamics and oxygen delivery during thoracic surgery without increasing venous admixture during one-lung ventilation.
Aged↗
[Cerebral perfusion reserve and collateral circulation in patients with internal carotid stenosis].
The cerebral hemodynamics in patients with carotid disease is influenced by a network of extra- and intracranial collaterals. The purpose of this study was to compare the findings of regional cerebral perfusion reserve (rCPR) with angiographically proven collateral circulation. In 41 patients (28 men, 13 women, age 63 +/- 10 years) with angiographically proven carotid stenoses or occlusions (30 stenoses, 11 occlusions) 24 99mTc-HMPAO-SPECT and 25 dynamic Xe-CT investigations were conducted, both before and after acetazolamide stimulation. rCPR was quantified as the ratio (1) of the absolute rCBF values obtained by Xe-CT and (2) of the count density measured by HMPAO-SPECT of the acetazolamide administration. A rCPR of less than 95% in a vascular territory was classified as compromised rCPR. A recent CT examination was available in all cases. According to the angiographic findings the patients could be classified into (1) group A (n = 9) with residual carotid perfusion, (2) Group B (n = 8) with collateralization via the circle of Willis, and (3) group C (n = 24) with leptomeningeal or ophthalmic artery collateral circulation. The rCPR values were significantly different in groups B and C with both methods, Xe-CT (P = 0.0035) and HMPAO-SPECT (P = 0.0014). rCPR was decreased in 13/14 group C patients investigated with Xe-CT and in 11/14 examined with HMPAO-SPECT. All patients in group B showed normal rCPR according to Xe-CT and HMPAO-SPECT. In group A, six of seven revealed decreased rCPR on Xe-CT, while rCPR values were normal in all four group A-patients examined with HMPAO-SPECT. The cerebral hemodynamics depend on a collateralization network and not only on the degree of internal carotid artery (ICA) stenosis. A decreased CPR in a vascular territory ipsilateral to an ICA stenosis or occlusion correlates strongly with the angiographic finding of leptomeningeal or ophthalmic artery collateral circulation.
Aged↗
Does continuous heparinization influence platelet function in the intensive care patient?
OBJECTIVE: To study the influence of continuous administration of heparin on platelet function in intensive care patients. DESIGN: Prospective, serial investigation. SETTING: Clinical investigation on a surgical and neurosurgical intensive care unit in a university hospital. PATIENTS: The study included 45 patients: 15 postoperative with patients sepsis (Acute Physiology and Chronic Health Evaluation II score between 15 and 25), 15 trauma patients (Injury Severity Score 15 to 25), and 15 neurosurgical patients. INTERVENTIONS: Management of the patients was carried out according to the guidelines for modern intensive care therapy. Sepsis and trauma patients received standard (unfractionated) heparin continuously [aim: an activated partial thromboplastin time (aPTT) approximately 2.0 times normal value; sepsis-heparin and trauma-heparin patients], whereas neurosurgical patients received no heparin (neurosurgical patients). MEASUREMENTS AND RESULTS: From arterial blood samples, platelet aggregation was measured by the turbidimetric method. Platelet aggregation was induced by adenosine diphosphate (ADP; 2.0 mumol/l), collagen (10 micrograms/ml), and epinephrine (25 mumol/l). Measurements were carried out on the day of diagnosis of sepsis or 12 h after hemodynamic stabilization (trauma and neurosurgery patients) (baseline) and during the next 5 days at 12.00 noon. Standard coagulation parameters [platelet count and fibrinogen and antithrombin III (AT III) plasma concentrations] were also monitored. Heparin 4-10 U/kg per h (mean dose: approximately 500 U/h) was necessary to reach an aPTT of about 2.0 times normal. Platelet count was highest in the neurosurgical patients, but it did not decrease after heparin administration to the trauma and sepsis patients. AT III and fibrinogen plasma levels were similar in the three groups of patients. In the sepsis group, platelet aggregation variables decreased significantly (e.g., epinephrine-induced maximum platelet aggregation:-45 relative % from baseline value). Platelet function recovered during the study and even exceeded baseline values (e.g., ADP-induced maximum platelet aggregation: +42.5 relative % from baseline value). Continuous heparinization did not blunt this increase of platelet aggregation variables. In the heparinized trauma patients, platelet aggregation variables remained almost stable and were no different to platelet aggregation data in the untreated neurosurgical patients. CONCLUSIONS: Continuous administration of heparin with an average dose of approximately 500 U/h did not negatively influence platelet function in the trauma patients. Recovery from reduced platelet function in the sepsis group was not affected by continuous heparinization. Thus, continuous heparinization with this dose appears to be safe with regard to platelet function in the intensive care patient.
APACHE↗
[Corneal topography after cataract surgery with tunnel incision on a steeper meridian in inverse and oblique astigmatism].
Scleral tunnel incision at the 12 o'clock-position for no-stitch cataract surgery can increase preexisting against-the-rule astigmatism by flattening the vertical corneal meridian. An oblique axis can change by operative induction. We investigated, in a prospective study, whether reduction of such a preoperative astigmatism could be induced by locating the tunnel incision on the steeper meridian. Eighteen eyes with senile cataract and against-the-rule or oblique astigmatism of at least 0.7 diopters were operated with a standardized 5 x 6 mm scleral tunnel incision and a 6 mm PMMA posterior chamber lens. We evaluated the astigmatism with a videokeratoscopy TMS-I preoperatively and about 6 months after the surgery. The mean corneal astigmatism was 1.8 diopters pre- and 1.5 diopters postoperatively. A reduction of keratometric astigmatism was reached in 72% of cases; 17% remained unchanged. The surgically induced astigmatism calculated by Jaffer's and Clayman's vector analysis was 0.68 diopters. The technique of scleral tunnel incision with lateral or oblique approach can reduce a preexisting against-the-rule or oblique astigmatism.
Astigmatism↗
[Keratoplasty of pseudophakic eyes with posterior chamber lenses in Fuchs' dystrophy and secondary bullous keratopathy. Long-term outcome].
UNLABELLED: Penetrating keratoplasties in pseudophakia were added to a group with limited prognosis. This was especially valuable, if iris-supported and anterior chamber intraocular lenses were implanted. Since today mainly posterior chamber lenses are implanted, the question of the long-term prognosis in this type of lens is important. PATIENTS AND METHOD: From 1985 to 1994, 62 penetrating keratoplasties in pseudophakic eyes with posterior chamber IOL were performed: group I: decompensated Fuchs dystrophy (26 patients), group II: secondary surgery-related bullous keratopathy (36 patients) exclusively. Minimal follow-up was 18 months, mean age was 73.7 years. RESULTS: The mean follow-up period was 32 months. The mean visual acuity on delivery was 0.11. After 6 months it was 0.23, after 1 year 0.3, after 2 years 0.35 and after 3 years 0.41 without significant differences in either group. Two years after transplantation 52.8% gained a visual acuity (VA) of > or = 0.3, after 3 years 58.6% of which 41.1% had a VA of > or = 0.5. There was a visual improvement in 83.4%; the mean spherical equivalent was -0.29 D. Refractive errors within 2 D of emmetropia were found in 56.7%; 95.1% of the grafts remained clear. Five patients had a reversible graft rejection. Extracorneal factors of impaired vision were observed in 25 patients. CONCLUSION: Despite a different VA before surgery, the visual outcome in the two groups was identical. Penetrating keratoplasty in Fuchs dystrophy and secondary bullous keratopathy with posterior chamber IOL have a much better long-term prognosis than those with iris-supported and anterior chamber IOL. Postoperative complications and graft rejections are rare.
Aged↗
Differential expression of CD44s and CD44v10 proteins and syndecan in normal and irradiated mouse epidermis.
The role of the CD44s adhesion molecule, its epithelial isoforms and its relationship to epidermal proteoglycans such as syndecan was studied in normal and irradiated mouse skin. In normal mouse skin, only 10% of basal cells are strongly CD44s-immunopositive, with a cytoplasmic expression pattern. Double-label experiments with the basal cell marker keratin 14 confirmed the epithelial nature of the strongly CD44s-positive cell type in the basal layer. Some spinous keratinocytes and the majority of the remaining basal cells exhibited a weak membranous staining pattern. In contrast, the epithelial isoform, CD44v10, was strongly present in all basal and suprabasal epithelial cells of the epidermis, with a membranous staining pattern. Syndecan was found in the granular layer of the normal epidermis only. After 1 week of daily irradiation, the entire basal cell layer of the epidermis expressed CD44s in the membrane, but with a varying degree of staining intensity. This reactivity spread to the upper spinous layer after 3 weeks of treatment. In hyperproliferative epidermis, there was no difference in the staining patterns between CD44s and CD44v10. The expression of syndecan switched from the granular layer to the basal and lower spinous layers after 2 weeks of daily irradiation. Immunoreactivity for syndecan was also strongly enhanced in the dermis of irradiated samples. The results suggest an important role for syndecan and CD44 in proliferative processes during radiation-induced accelerated repopulation.
Animals↗
Cellular distribution of c-Jun and c-Fos in rat lung before and after bleomycin induced injury.
C-Jun and c-Fos transcription factors have been associated with enhanced cellular proliferation. We studied their cellular distribution in normal and fibrotic rat lung. Pulmonary fibrosis was induced by intratracheal administration of bleomycin. In normal rat lung, c-Jun and c-Fos are present in alveolar macrophages and type II pneumocytes, in the bronchiolar epithelium and in smooth muscle cells of bronchioli and blood vessels. Subcellular fractionation of proteins revealed a predominant presence of both c-Jun and c-Fos in the heavy membrane fraction containing mitochondria and secretory granules. This was confirmed by immunoelectron microscopy, which also revealed a different localization of c-Jun and c-Fos in different cell types. Whereas in type II pneumocytes and in macrophages cytoplasmic c-Jun and c-Fos is associated with mitochondria, in Clara cells of the bronchial epithelium only secretory granules contain c-Jun and c-Fos. In addition, c-Jun is strongly present in the nuclear fraction. In the fibrotic rat lung c-Jun and c-Fos are located in the same cell types as in control lungs. In addition, fibroblasts contain c-Jun and c-Fos in areas of proliferation whereas in areas of complete fibrosis there is only a very weak expression of c-Jun and c-Fos.
Animals↗
Neuroarchitecture of the lower division of the central body in the brain of the locust (Schistocerca gregaria).
We have investigated the anatomical organization of the lower division of the central body in the brain of the locust Schistocerca gregaria. Bodian preparations, Golgi impregnations, and intracellular filling with Lucifer yellow have revealed that the lower division of the central body is organized into six horizontal layers and sixteen vertical columns. Neurons of the lower division of the central body have been classified into five types of tangential neuron (TL1-TL5) and two types of columnar neuron (CL1, CL2). TL1-TL4 neurons ramify in specific layers in the lower division of the central body and in the lateral triangle (TL1, TL2 neurons), the median olive (TL3 neurons), or the dorsal shell (TL4 neurons) of the lateral accessory lobe. TL5 neurons ramify in the protocerebral bridge, in the lateral accessory lobe, and in all layers of the lower division of the central body. The two types of columnar neurons have arborizations in the protocerebral bridge and in the lower division of the central body and project to the lateral triangle of the lateral accessory lobe (CL1 neurons) or to the lower subunit of the nodulus (CL2 neurons). Possible functional implications for the processing of neuronal information in the central complex are discussed.
Animals↗
Diclofenac concentrations in defined tissue layers after topical administration.
INTRODUCTION: To date it is unclear whether therapeutic concentrations are attained in target tissues after topical administration of nonsteroidal anti-inflammatory drugs. Therefore this study in healthy volunteers was undertaken to measure diclofenac concentrations attained in defined tissue layers directly underlying the site of topical diclofenac application by in vivo microdialysis. METHODS: In each experiment two microdialysis probes were inserted, one into a superficial (3.9 +/- 0.3 mm) and one into a deep (9.3 +/- 0.5 mm) tissue layer, in 20 healthy volunteers and calibrated in vivo. The distance between the surface of the skin and the tips of the microdialysis probes was measured by 7.5 MHz ultrasound. Diclofenac was administered topically as a single dose of approximately 300 mg/100 cm2. Concentration versus time profiles in tissue layers were monitored for 5 hours. RESULTS: Concentration versus time profiles were obtained in 11 of 20 experiments. However, there was no correlation between area under the concentration-time curve (AUC) in a defined layer and the depth of probe insertion. In those experiments where concentration versus time profiles were obtained for both probes mean AUC was 532 +/- 197 microg x min x ml(-1) for superficial layers, and 438 +/- 249 microg x min x ml(-1) for deep layers. CONCLUSION: We conclude that transdermal penetration of diclofenac, at least after single doses, is not predictable and may strongly be influenced by individual skin properties.
Administration, Cutaneous↗
In vivo drug-response measurements in target tissues by microdialysis.
To study the suitability of the microdialysis technique for the measurement of target tissue pharmacodynamics in humans, the model compounds theophylline, milrinone, and compound 48/80 were administered locally by means of reversed microdialysis to the interstitial space of skeletal muscle or skin in 24 healthy volunteers. Simultaneously, interstitial concentrations of cyclic adenosine monophosphate (cAMP; as an indicator of phosphodiesterase activity) were measured in skeletal muscle, and interstitial concentrations of histamine (as an indicator of mast cell release) were measured in skin. In muscle, reversed microdialysis with milrinone led to a dose-dependent increase in interstitial cAMP concentrations (n = 8), whereas no significant effect on cAMP was observed for theophylline versus placebo (1.63 +/- 0.53 nmol/L; n = 6), even at local concentrations exceeding those attained after therapeutic doses. In skin, reversed microdialysis with compound 48/80 increased interstitial histamine concentration dose dependently versus placebo (5.99 +/- 2.74 nmol/L; n = 10). From our experiments in human skeletal muscle and skin, we concluded that microdialysis was a suitable technique for the characterization of in vivo drug response at the relevant target site. Extension of these measurements to several other human tissues is readily feasible.
Adult↗
Microwave CO2 plasma-initiated vapour phase graft polymerization of acrylic acid onto polytetrafluoroethylene for immobilization of human thrombomodulin.
The functionalization of polytetrafluoroethylene (PTFE) for human thrombomodulin (hTM) binding has been achieved by CO2 plasma activation and subsequent vapour phase graft polymerization of acrylic acid (AA). The PTFE surfaces after CO2 plasma treatment, AA grafting and hTM immobilization were characterized by attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS) and electron spin resonance (ESR) spectroscopy, as well as by zeta potential and wetting measurements to quantitatively control each step of modification. The activity of immobilized hTM was estimated by the protein C activation test.
Acrylates↗
Hepatic bile salt flux does not modulate level and activity of the sinusoidal Na+-taurocholate cotransporter (ntcp) in rats.
BACKGROUND/AIMS: Efficient uptake at the basolateral plasma membrane of hepatocytes is required for maintenance of the enterohepatic circulation of bile salts. Uptake occurs mainly via a Na+-dependent process mediated by ntcp, a recently cloned and characterized 51 kDa glycoprotein. The aim of this study was to evaluate the role of variations in hepatic bile salt flux through the liver in the regulation of ntcp activity and expression under non-cholestatic conditions. METHODS: We determined the kinetics of Na+-dependent taurocholate transport in isolated basolateral plasma membrane vesicles as well as hepatic ntcp protein and ntcp mRNA levels in long-term (8 days) bile-diverted rats, with a transhepatic bile salt flux of 0, and in streptozotocin-induced diabetic rats with a 2.5-fold increased bile salt flux. RESULTS: We found no changes in the kinetics of taurocholate transport in the absence of transhepatic bile salt flux due to bile diversion. Ntcp protein and ntcp mRNA levels were also unaffected in bile-diverted rats. Likewise, no changes in taurocholate transport kinetics, ntcp protein or ntcp mRNA levels were detected in streptozotocin-diabetic rats when compared to non-diabetic controls. Thus, variation in hepatic bile salt flux from 0 to 250% of normal values had no effect on hepatic ntcp expression or taurocholate transport activity in basolateral plasma membrane vesicles in rats. In contrast, 4 days of bile duct ligation resulted in a strong decrease in ntcp mRNA and protein levels, as recently also reported by others. CONCLUSIONS: Our data indicate that ntcp is not regulated by the transhepatic flux of bile acids under non-cholestatic conditions.
Animals↗
Evolutionary origins of trichomonad hydrogenosomes.
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Journal Article↗
What are the microsporidia?
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Journal Article↗