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Biomedical subjects

R Müller

Publications and source records attributed to R Müller.

At least 19 recordsLinked to original sources
PubMed2007

Fluoxetine treatment increases trabecular bone formation in mice.

Mounting evidence exists for the operation of a functional serotonin (5-HT) system in osteoclasts and osteoblasts, which involves both receptor activation and 5-HT reuptake. In previous work we showed that the serotonin transporter (5-HTT) is expressed in osteoclasts and that its activity is required by for osteoclast differentiation in vitro. The purpose of the current study was to determine the effect of treatment with fluoxetine, a specific serotonin reuptake inhibitor, on bone metabolism in vivo. Systemic administration of fluoxetine to Swiss-Webster mice for 6 weeks resulted in increased trabecular BV and BV/TV in femurs and vertebrae as determined by micro-computed tomography (microCT). This correlated with an increase in trabecular number, connectivity, and decreased trabecular spacing. Fluoxetine treatment also resulted in increased volume in vertebral trabecular bone. However, fluoxetine-treated mice were not protected against bone loss after ovariectomy, suggesting that its anabolic effect requires the presence of estrogen. The effect of blocking the 5-HTT on bone loss following an LPS-mediated inflammatory challenge was also investigated. Subcutaneous injections of LPS over the calvariae of Swiss-Webster mice for 5 days resulted in increased numbers of osteoclasts and net bone loss, whereas new bone formation and a net gain in bone mass was seen when LPS was given together with fluoxetine. We conclude that fluoxetine treatment in vivo leads to increased bone mass under normal physiologic or inflammatory conditions, but does not prevent bone loss associated with estrogen deficiency. These data suggest that commonly used anti-depressive agents may affect bone mass.

Animals↗
PubMed2006

Chemotherapy of brain tumour using doxorubicin bound to surfactant-coated poly(butyl cyanoacrylate) nanoparticles: revisiting the role of surfactants.

Poly(butyl cyanoacrylate) nanoparticles coated with poloxamer 188 (Pluronic) F68) and also, as shown previously, polysorbate 80 (Tween 80) considerably enhance the anti-tumour effect of doxorubicin against an intracranial glioblastoma in rats. The investigation of plasma protein adsorption on the surface of the drug-loaded nanoparticles by two-dimensional electrophoresis (2-D PAGE) revealed that both surfactants, besides other plasma components, induced a considerable adsorption of apolipoprotein A-I (ApoA-I). It is hypothesized that delivery of doxorubicin to the brain by means of nanoparticles may be augmented by the interaction of apolipoprotein A-I that is anchored on the surface of the nanoparticles with the scavenger receptor class B type I (SR-BI) located at the blood-brain barrier. This is the first study that shows a correlation between the adsorption of apolipoprotein A-I on the nanoparticle surface and the delivery of the drug across the blood-brain barrier.

Adsorption↗
PubMed2006

Impaired scaling of responses to vestibular stimulation in incomplete SCI.

Patients with incomplete spinal cord injury (iSCI) have impaired postural control leading to a high danger of falling. Clinically, it is impossible to assess the extent to which postural instability due to sensorimotor deficit is influenced by a disturbance in the vestibulospinal pathways. Galvanic vestibular stimulation (GVS) was applied to investigate changes in the vestibular spinal responses and their potential influence on postural stability in iSCI patients. Six chronic iSCI patients and age-matched controls were stimulated with a bipolar binaural stimulus. The centre of pressure (CoP) and soleus EMG responses during free standing with closed eyes on firm and compliant ground were measured. The impairment in postural stability was assessed by the mean amplitude of CoP deflections during two minutes undisturbed standing. Although iSCI patients were significantly less stable than controls, direct GVS responses of the soleus EMG and postural sways tended to be increased on firm ground. The GVS responses increased when changing from firm to compliant ground, showing a close correlation between the extent of postural instability and the response amplitudes. Therefore, challenging proprioceptive feedback induced a significant up-modulation of the GVS responses. However, when we took the postural instability in iSCI patients into account, the EMG and CoP responses to GVS were reduced compared to controls. The combined assessment of EMG and CoP responses to GVS complements the clinical examination and permits evaluation of the preservation and modulation of vestibulospinal responses in iSCI.

Aged↗
PubMed2006

Specimen-specific beam models for fast and accurate prediction of human trabecular bone mechanical properties.

Direct assessment of bone competence in vivo is not possible, hence, it is inevitable to predict it using appropriate simulation techniques. Although accurate estimates of bone competence can be obtained from micro-finite element models (muFE), it is at the expense of large computer efforts. In this study, we investigated the application of structural idealizations to represent individual trabeculae by single elements. The objective was to implement and validate this technique. We scanned 42 human vertebral bone samples (10 mm height, 8 mm diameter) with micro-computed tomography using a 20 microm resolution. After scanning, direct mechanical testing was performed. Topological classification and dilation-based algorithms were used to identify individual rods and plates. Two FE models were created for each specimen. In the first one, each rod-like trabecula was modeled with one thickness-matched beam; each plate-like trabecula was modeled with several beams. From a simulated compression test, assuming one isotropic tissue modulus for all elements, the apparent stiffness was calculated. After reducing the voxel size to 40 microm, a second FE model was created using a standard voxel conversion technique. Again, one tissue modulus was assumed for all elements in all models, and a compression test was simulated. Bone volume fraction ranged from 3.7% to 19.5%; Young's moduli from 43 MPa to 649 MPa. Both models predicted measured apparent moduli equally well (R2 = 0.85), and were in excellent agreement with each other (R2 = 0.97). Tissue modulus was estimated at 9.0 GPa and 10.7 GPa for the beam FE and voxel FE models, respectively. On average, the beam models were solved in 219 s, reducing CPU usage up to 1150-fold as compared to 40 microm voxel FE models. Relative to 20 microm voxel models 10,000-fold reductions can be expected. The presented beam FE model is an abstraction of the intricate real trabecular structure using simple cylindrical beam elements. Nevertheless, it enabled an accurate prediction of global mechanical properties of microstructural bone. The strong reduction in CPU time provides the means to increase throughput, to analyze multiple loading configuration and to increase sample size, without increasing computational costs. With upcoming in vivo high-resolution imaging systems, this model has the potential to become a standard for mechanical characterization of bone.

Biomechanical Phenomena↗
PubMed2006

Modulation of locomotor activity in complete spinal cord injury.

The aim of this study was to evaluate the modulation of muscle activity during locomotor-like movements by different walking speeds in subjects with a motor complete spinal cord injury (SCI) compared to actively--and passively-walking control subjects without neurological deficit. Stepping movements on a treadmill were induced and assisted by a driven gait orthosis. Electromyographic (EMG) muscle activity of one leg (rectus and biceps femoris, tibialis anterior and gastrocnemius) was recorded and analyzed at three stepping velocities with similar body weight support in both subject groups. In SCI subjects, the EMG amplitude of biceps femoris, tibialis anterior and gastrocnemius was in general similar or weaker than in passively- and actively-stepping control subjects, but that of rectus femoris was larger. The degree of co-activation between tibialis anterior and gastrocnemius was higher in SCI than in control subjects. A significant velocity-dependent EMG modulation was present in all four-leg muscles in both subject groups. In SCI subjects, this EMG modulation was similar to that in actively stepping control subjects. It is concluded that in complete spastic SCI subjects, spinal neuronal circuits underlying locomotion can to a large extent adequately respond to a change in external drive to adapt the neuronal pattern to a new locomotion speed. The application of various speeds might enhance the effect of locomotor training in incomplete SCI subjects.

Adult↗
PubMed2006

Underweight in ski jumping: The solution of the problem.

Underweight is becoming increasingly prevalent in many sports. Among world class ski jumpers, the body mass index BMI has decreased by 4 units since 1970. The BMI ignores different body properties of individuals. Particular care should be taken in groups with unusual leg length to avoid classifying them inappropriately as thin or overweight (WHO). The improved measure MI (mass index) for relative body weight overcomes this shortcoming. Anthropometric data of ski jumpers was collected during the Olympic Games in Salt Lake City (2002; participation 81 %, n = 57), during the Summer Grand Prix in Hinterzarten (2000; participation 100 %, n = 92), and during the World Cup in Planica (2000; n = 56). The BMI and the MI were determined. The MI considers the individual leg length: A person with longer legs than average has an MI > BMI, and vice versa: MI = 0.28 m/s2 (m: mass in kg, s: sitting height in meters). BMI classes of ski jumpers in the season 2004/2005 were calculated from their official individual ski length limitation which is a function of their BMI. BMI means were 19.84 in Planica, 19.58 in Hinterzarten, and 19.43 kg m(-2) in SLC. Lowest BMI was 16.4 kg m(-2). The percentage of underweight ski jumpers (BMI < 18.5 kg m(-2)) decreased from 22.8 % at the Olympic Games 2002 to 8.7 % in the season 2004/2005 due to the new ski jumping regulations. The ratio s/h = C (s = sitting height, h = height, C = cormic index) ranged from 0.49 to 0.57. Accordingly, the MI values (which are leg length corrected BMI values according to MI = BMI (C /C) (k) with k = 2 and C = 0.53) deviated remarkably from BMI values. For the 49 cases with BMI or MI or both below 18.5 kg m(-2), the classification to be underweight or not changed in 69 % when the MI was used instead of the BMI. Underweight or overweight is not only a question of cut-off points; the measure used determines the classification accuracy. A substantial improvement of weight analyses in sports medicine, public health, and general medicine as well can be obtained by using the MI instead of the BMI.

Adult↗
PubMed2006

Fibroblast growth factor 16 and 18 are expressed in human cardiovascular tissues and induce on endothelial cells migration but not proliferation.

Endothelial cells line the blood vessel and precursor endothelial cells appear to have a pivotal effect on the organ formation of the heart, the embryonic development of the kidney, and the liver. Several growth factors including the fibroblast growth factors (FGF) seem to be involved in these processes. Ligands such as basic FGF produced and secreted by endothelial cells may also coordinate cellular migration, differentiation, and proliferation under pathological conditions including wound healing, tumorgenesis, and fibrogenesis in the adult. Recently we demonstrated the expression of two secreted FGFs, FGF16, and FGF18, in HUVEC and in rat aortic tissue. In the present report, we confirmed by RT-PCR analysis that FGF18 is wildly expressed in the cardiovascular tissue, while FGF16 showed a more restricted expression pattern. HUVEC clearly demonstrated chemotaxis towards FGF16 and FGF18. Both FGFs also enhanced cell migration in response to mechanical damage. However, recombinant FGF16 and FGF18 failed to induce endothelial cell proliferation or sprouting in a three-dimensional in vitro angiogenesis assay. Fgf18 expression was earlier reported in the liver, and we detected FGF18 expression in liver vascular and liver sinusoidal endothelial cells (LSECs), but not in hepatic parenchymal cells. Recombinant FGF18 stimulated DNA synthesis in primary hepatocytes, suggesting, that endothelial FGF18 might have a paracrine function in promoting growth of the parenchymal tissue. Interestingly, FGF2, which is mitogenic on endothelial cells and hepatocytes stimulates a sustained MAPK activation in both cell types, while FGF18 causes a short transient activation of the MAPK pathway in endothelial cells but a sustained activation in hepatocytes. Therefore, the difference in the time course of MAPK activation by the different FGFs appears to be the cause for the different cellular responses.

Animals↗
PubMed2006

Neuronal function in chronic spinal cord injury: divergence between locomotor and flexion- and H-reflex activity.

OBJECTIVE: Knowledge about the long-term course of spinal neuronal function after spinal cord injury (SCI) is important if regeneration therapies become available in the future. The objective of this study was to examine the behavior of locomotor EMG activity and of spinal reflexes in patients with chronic motor-complete SCI. METHODS: EMG activity from rectus femoris (RF), biceps femoris (BF), medial gastrocnemius (GM) and tibialis anterior (TA) of both sides was investigated during locomotor movements assisted by a robotic device in 10 chronic (>1 year after accident) complete SCI and 5 healthy subjects. H-reflexes (recorded from GM) were induced during the onset and flexion reflexes (recorded from BF and TA) at the end of the stance phase. RESULTS: Only in the chronic SCI subjects an exhaustion of EMG activity--i.e. a decrease in amplitude--occurred within a few minutes in all leg muscles. The EMG exhaustion was not associated with a change in the H- or flexion reflex amplitude during a walking session. CONCLUSIONS: Exhaustion of neuronal function in chronic complete SCI might be restricted to unused motor tasks, i.e. locomotion. The fact that H- and flexion reflexes show a normal behavior might be due to the fact that they still become activated. SIGNIFICANCE: Training/pharmalogical approaches may be required to maintain neuronal function of unused tasks as a basis for future successful regeneration therapies.

Adult↗
PubMed2006

Time-lapsed investigation of three-dimensional failure and damage accumulation in trabecular bone using synchrotron light.

Synchrotron radiation micro-computed tomography (SRmicroCT) is a very useful technique when it comes to three-dimensional (3D) imaging of complex internal and external geometries. Being a fully non-destructive technique, SRmicroCT can be combined with other experiments in situ for functional imaging. We are especially interested in the combination of SRmicroCT with mechanical testing in order to gain new insights in the failure mechanism of trabecular bone. This interest is motivated by the immense costs in health care due to patients suffering from osteoporosis, a systemic skeletal disease resulting in decreased bone stability and increased fracture risk. To better investigate the different failure mechanisms on the microlevel, we have developed a novel in situ mechanical compression device, capable of exerting both static and dynamic displacements on experimental samples. The device was calibrated for mechanical testing using solid aluminum and bovine trabecular bone samples. To study different failure mechanisms in trabecular bone, we compared a fatigued and a non-fatigued bovine bone sample with respect to failure initiation and propagation. The fatigued sample failed in a burst-like fashion in contrast to the non-fatigued sample, which exhibited a distinct localized failure band. Moreover, microscopic cracks - microcracks and microfractures - were uncovered in a 3D fashion illustrating the failure process in great detail. The majority of these cracks were connected to a bone surface. The data also showed that the classification of microcracks and -fractures from 2D section can sometimes be ambiguous, which is also true for the distinction of diffuse and distinct microdamage. Detailed investigation of the failure mechanism in these samples illustrated that trabecular bone often fails in delamination, providing a mechanism for energy dissipation while conserving trabecular bone architecture. In the future, this will allow an even better understanding of bone mechanics related to its hierarchical structural organization.

Animals↗
PubMed2006

ATRA can enhance apoptosis that is induced by Flt3 tyrosine kinase inhibition in Flt3-ITD positive cells.

Among activating Flt3 mutations that have been shown in 25-30% of acute myeloid leukaemia (AML) Flt3-internal tandem duplication (ITD) mutations are predominant. We investigated the influence of all-trans-retinoic acid (ATRA) and granulocyte colony stimulating factor (G-CSF) for their effects on differentiation and apoptosis in human cell lines with different Flt3 variants (THP-1 versus MV4-11 and MOLM13) dependent on the inhibition of Flt3 tyrosine kinase by the bis(lH-2-indolyl)methanone D-65476. While myeloid differentiation was not observed in both Flt3-ITD cell lines (MV4-11 and MOLM13), we demonstrate an enhanced proapoptotic effect of D-65476 in the presence of ATRA that was restricted to the Flt3-ITD expressing cells. The combined treatment with ATRA and D-65476 also led to a pronounced down-regulation of surviv in on mRNA and protein level in Flt3-ITD but not in Flt3 wildtype expressing cells (THP-1). Surprisingly, there was no differential expression of important proteins like Bcl-X(L), Bcl-2 or Bax that might explain enhanced apoptosis. Furthermore, Akt phosphorylation after stimulation with Flt3 ligand dependent on D-65476 was not affected by pretreatment with ATRA. We suggest that regulation of inhibitors of apoptosis might play a crucial role how ATRA can increase the proapoptotic effect of Flt3 inhibitors in myeloid leukemia cells expressing Flt3-ITD. This effect can potentially be exploited for the treatment of Flt3-ITD positive acute myeloid leukemia.

Apoptosis↗
PubMed2006

Budesonide foam versus budesonide enema in active ulcerative proctitis and proctosigmoiditis.

BACKGROUND: Rectal budesonide is an effective treatment of active ulcerative proctitis or proctosigmoiditis. AIM: To compare the therapeutic efficacy, tolerability and safety, and patient's preference of budesonide foam vs. budesonide enema. METHODS: Patients with active ulcerative proctitis or proctosigmoiditis (clinical activity index > 4 and endoscopic index > or = 4) were eligible for this double-blind, double-dummy, randomized, multicentre study. They received 2 mg/25 mL budesonide foam and placebo enema (n = 265), or 2 mg/100 mL budesonide enema and placebo foam (n = 268) for 4 weeks. Primary endpoint was clinical remission (clinical activity index < or = 4) at the final/withdrawal visit (per protocol). RESULTS: A total of 541 patients were randomized--533 were evaluable for intention-to-treat analysis and 449 for per protocol analysis. Clinical remission rates (per protocol) were 60% for budesonide foam and 66% for budesonide enema (P = 0.02362 for non-inferiority of foam vs. enema within a predefined non-inferiority margin of 15%). Both formulations were safe and no drug-related serious adverse events were observed. Because of better tolerability and easier application most patients preferred foam (84%). CONCLUSION: Budesonide foam is as effective as budesonide enema in the treatment of active ulcerative proctitis or proctosigmoiditis. Both budesonide formulations are safe, and most patients prefer foam.

Administration, Rectal↗
PubMed2006

Identification of novel tumour-associated genes differentially expressed in the process of squamous cell cancer development.

Chemically induced mouse skin carcinogenesis represents the most extensively utilized animal model to unravel the multistage nature of tumour development and to design novel therapeutic concepts of human epithelial neoplasia. We combined this tumour model with comprehensive gene expression analysis and could identify a large set of novel tumour-associated genes that have not been associated with epithelial skin cancer development yet. Expression data of selected genes were confirmed by semiquantitative and quantitative RT-PCR as well as in situ hybridization and immunofluorescence analysis on mouse tumour sections. Enhanced expression of genes identified in our screen was also demonstrated in mouse keratinocyte cell lines that form tumours in vivo. Self-organizing map clustering was performed to identify different kinetics of gene expression and coregulation during skin cancer progression. Detailed analysis of differential expressed genes according to their functional annotation confirmed the involvement of several biological processes, such as regulation of cell cycle, apoptosis, extracellular proteolysis and cell adhesion, during skin malignancy. Finally, we detected high transcript levels of ANXA1, LCN2 and S100A8 as well as reduced levels for NDR2 protein in human skin tumour specimens demonstrating that tumour-associated genes identified in the chemically induced tumour model might be of great relevance for the understanding of human epithelial malignancies as well.

Animals↗
PubMed2006

[Retrospective evaluation of the results of the microbiological meat examination (MFU) from calves and cows].

The microbiological meat examination (MFU), consisting of a bacteriological analysis and a testing for antibiotic residues, is one of several additional analyses used for an edibility rating of carcasses made during meat inspection. Reasons for performing a microbiological meat examination and procedures in the laboratory are defined in the Swiss ordinance for meat examination (FUV). The aim of this study was to analyze the data of 313 microbiological meat examinations from calves and 2882 microbiological meat examinations from cows carried out at the Institute for Food Safety and Hygiene during a period of 8 years. Reasons for microbiological meat examinations as reported by the meat inspectors were mainly classified to the category of "inflammation and necroses" (FUV, Annex 4, Pt 1.2; calves: 73%, cows: 48%). As declarations of the age of the pathological-anatomical changes (that influences directly the probability of detection of pathogens) were generally missing, it is not surprising that the compliance between a particular pathological-anatomical change and a specific detection of pathogens is poor (calves: 19%, cows: 18% of all MFU). About 18% (calves) and 45% (cows) of the reasons for microbiological meat examinations did not correspond to one of the reasons mentioned in the ordinance for meat examination. However, according to the data set, some reasons require a microbiological meat examination due to an often-found specific detection of pathogens. Otherwise, a remarkable number of reasons mentioned were missing the link to bacteriological etiology. Moreover, 14% (calf) and 7% (cow) of microbiological meat examinations with the declaration "no pretreatment" as well as 15% (calf) and 11% (cow) of microbiological meat examinations without declaration showed a positive result in the testing for antibiotic residues.

Animals↗
PubMed2006

[Also a reform effect? An explorative analysis of increasing hospitalization due to mental disorders].

The present prospective longitudinal study describes and explores the impact of demographic change and political reforms on the growing risk of suffering from mental disorders and subsequent hospitalization. The statistical analysis is based on all insured individuals who were 50 years and older during the years 1993 to 2003 (n = 453 609) from a statutory sickness fund, the Gmünder Ersatzkasse. Event-history analyses show no linear but a rather u-shaped relationship between age and the risk to be given in-patient treatment for mental disorders. However, the age effect shrinks significantly when the number of previous hospital stays, the proximity to death, and the marital status are statistically controlled. On the other hand, the number of psychic disorders as a minor diagnosis has grown robustly after the legal requirement for fully documenting hospital cases according to section sign 301 SGB V and after the legal decision to introduce DRG refunding in 2000. Since the risk of in-hospital treatment of a psychic minor diagnosis increases most in somatic and not in psychiatric clinics, we suspect an up-grading effect.

Age Distribution↗
PubMed2006

[Retrospective analysis of falls in an inpatient rehabilitation centre for rheumatic and orthopaedic diseases].

AIM: To analyse the frequency and circumstances of falls in an inpatient rehabilitation centre. METHODS: In a survey all falls reported to the Austrian accident insurance carrier were analysed and external circumstances of falls were evaluated. The survey covers a period of 64 months (Jan 2000 to April 2005): 10 820 inpatients (234 502 patient days); mean age 52.8 years; 1,252 patients aged >/= 70 years; 47 % male, 53 % female. RESULTS: Of 223 accidents registered, 140 (62.8 %) were falls. Of these, 17 patients had to be referred to a surgical unit for further treatment. In total, 1.29 % of all patients fell during their stay (with report to the accident insurance carrier), 0.16 % suffered major injuries from falls (with referral to surgical unit). Females fell more frequently than males. 39 % of the falls were associated with physical therapy. Most falls occurred in daytime. The location in the centre or the day of week showed no major influence on the frequency of falls. Falls occurred slightly more often in the first part of the three-week inpatient stay. CONCLUSION: The high total number of falls shows that falls are important in an inpatient rehabilitation centre for rheumatic and orthopaedic diseases. The analysis did not reveal any special location inside the rehabilitation centre with an increased risk of falls calling for urgent interventions. The active and activating physical therapies do not seem to increase the number of falls significantly.

Accidental Falls↗
PubMed2006

Biochemical characterization of MelJ and MelK.

Melithiazol and myxothiazol are two myxobacterial metabolites that are highly efficient electron transport inhibitors of the respiratory chain. MelJ and MelK encoded in the melithiazol biosynthetic gene cluster were recently shown to be involved in the formation of the methyl ester from a hypothetical amide intermediate. In vivo studies suggest that the structurally highly similar amide myxothiazol A can be used as a substrate mimic of the hypothetical melithiazol amide to characterize the hydrolase MelJ. Both enzymes were produced in Escherichia coli as intein chitin fusion proteins and were purified using affinity chromatography. MelJ was found to catalyse the conversion of the amide myxothiazol to free myxothiazol acid. The formerly unknown myxothiazol acid was purified and used as a substrate for the methyl transferase MelK which methylates the compound using S-adenosyl-methionine as cosubstrate. Sequence analyses suggest that MelJ and MelK are members of the amidase signature family and of a new subclass of methyltransferases, respectively. Kinetic analyses point at a very high substrate specificity for both enzymes. Furthermore, the in vitro reconstitution of a unique mechanism of methyl ester formation found in myxobacteria is reported.

Acrylates↗
PubMed2006

Treponema denticola in disseminating endodontic infections.

Treponema denticola is a consensus periodontal pathogen that has recently been associated with endodontic pathology. In this study, the effect of mono-infection of the dental pulp with T. denticola and with polymicrobial "red-complex" organisms (RC) (Porphyromonas gingivalis, Tannerella forsythia, and T. denticola) in inducing disseminating infections in wild-type (WT) and severe-combined-immunodeficiency (SCID) mice was analyzed. After 21 days, a high incidence (5/10) of orofacial abscesses was observed in SCID mice mono-infected with T. denticola, whereas abscesses were rare in SCID mice infected with the red-complex organisms or in wild-type mice. Splenomegaly was present in all groups, but only mono-infected SCID mice had weight loss. T. denticola DNA was detected in the spleen, heart, and brain of mono-infected SCID mice and in the spleen from mono-infected wild-type mice, which also had more periapical bone resorption. The results indicate that T. denticola has high pathogenicity, including dissemination to distant organs, further substantiating its potential importance in oral and linked systemic conditions.

Alveolar Bone Loss↗