Biomedical subjects

E Unger

Publications and source records attributed to E Unger.

At least 19 recordsLinked to original sources

PubMed2007

Atrophy, but not necrosis, in rabbit skeletal muscle denervated for periods up to one year.

Our understanding of the effects of long-term denervation on skeletal muscle is heavily influenced by an extensive literature based on the rat. We have studied physiological and morphological changes in an alternative model, the rabbit. In adult rabbits, tibialis anterior muscles were denervated unilaterally by selective section of motor branches of the common peroneal nerve and examined after 10, 36, or 51 wk. Denervation reduced muscle mass and cross-sectional area by 50-60% and tetanic force by 75%, with no apparent reduction in specific force (force per cross-sectional area of muscle fibers). The loss of mass was associated with atrophy of fast fibers and an increase in fibrous and adipose connective tissue; the diameter of slow fibers was preserved. Within fibers, electron microscopy revealed signs of ultrastructural disorganization of sarcomeres and tubular systems. This, rather than the observed transformation of fiber type from IIx to IIa, was probably responsible for the slow contractile speed of the muscles. The muscle groups denervated for 10, 36, or 51 wk showed no significant differences. At no stage was there any evidence of necrosis or regeneration, and the total number of fibers remained constant. These changes are in marked contrast to the necrotic degeneration and progressive decline in mass and force that have previously been found in long-term denervated rat muscles. The rabbit may be a better choice for a model of the effects of denervation in humans, at least up to 1 yr after lesion.

Animals↗

PubMed2006

Risk factors for diabetes insipidus in langerhans cell histiocytosis.

BACKGROUND: Diabetes insipidus (DI) is the most frequent central nervous system (CNS)-related permanent consequence in Langerhans cell histiocytosis (LCH), which mostly requires life-long hormone replacement therapy. In an attempt to define the population at risk for DI, 1,741 patients with LCH registered on the trials DALHX 83 and DALHX 90, LCH I and LCH II were studied. RESULTS: Overall 212 of 1,741 patients (12%) was reported to have DI. In 102 of 1,741 patients (6%) DI was present at diagnosis of LCH. One thousand one hundred eighty three of 1,539 patients without DI at diagnosis had follow up information. One hundred ten of these (9%) later developed DI. The risk of developing DI was 20% at 15 years after diagnosis. Multisystem disease patients at diagnosis carried a 4.6-fold risk for DI compared to single system patients. Craniofacial lesions, in particular in the "ear," "eye," and oral region were associated with a significantly increased risk for DI (relative hazard rate, RHR 1.7), independent of the extent of disease. No influence of the duration of therapy could be determined, but the duration of initial disease activity (RHR 1.5) and the occurrence of reactivations (RHR 3.5) significantly increased the risk for DI. CONCLUSIONS: Patients with multisystem disease and craniofacial involvement at diagnosis, in particular of the "ear," "eye," and the oral region carry a significantly increased risk to develop DI during their course. This risk is augmented when the disease remains active for a longer period or reactivates.

Clinical Trials as Topic↗

PubMed2005

Implantable device for long-term electrical stimulation of denervated muscles in rabbits.

Although denervating injuries produce severe atrophic changes in mammalian skeletal muscle, a degree of functional restoration can be achieved through an intensive regime of electrical stimulation. An implantable stimulator was developed so that the long-term effects of different stimulation protocols could be compared in rabbits. The device, which is powered by two lithium thionyl chloride batteries, is small enough to be implanted in the peritoneal cavity. All stimulation parameters can be specified over a wide range, with a high degree of resolution; in addition, up to 16 periods of training (10-180 min) and rest (1-42 h) can be set in advance. The microcontroller-based device is programmed through a bidirectional radiofrequency link. Settings are entered via a user-friendly computer interface and annotated to create an individual study protocol for each animal. The stimulator has been reliable and stable in use. Proven technology and rigorous quality control has enabled 55 units to be implanted to date, for periods of up to 36 weeks, with only two device failures (at 15 and 29 weeks). Changes in the excitability of denervated skeletal muscles could be followed within individual animals. Chronaxie increased from 3.24 +/- 0.54 ms to 15.57 +/- 0.85 ms (n = 55, p < 0.0001) per phase in the 2 weeks following denervation.

Animals↗

PubMed2005

Sub-20 nm short channel carbon nanotube transistors.

Carbon nanotube field-effect transistors with sub-20 nm long channels and on/off current ratios of >10(6) are demonstrated. Individual single-walled carbon nanotubes with diameters ranging from 0.7 to 1.1 nm grown from structured catalytic islands using chemical vapor deposition at 700 degrees C form the channels. Electron beam lithography and a combination of HSQ, calix[6]arene, and PMMA e-beam resists were used to structure the short channels and source and drain regions. The nanotube transistors display on-currents in excess of 15 microA for drain-source biases of only 0.4 V.

Journal Article↗

PubMed2005

Improved outcome of treatment-resistant high-risk Langerhans cell histiocytosis after allogeneic stem cell transplantation with reduced-intensity conditioning.

Children with multisystem Langerhans cell histiocytosis (LCH) and risk organ involvement who fail to respond to conventional chemotherapy have an extremely poor prognosis. Myeloablative stem cell transplantation (SCT) as a possible salvage approach for these patients has been associated with a high risk of transplant-related mortality. Therefore, allogeneic stem cell transplantation following a reduced-intensity conditioning regimen (RIC-SCT) has recently been performed as an alternative salvage approach. We report on the experience with allogeneic RIC-SCT in nine pediatric high-risk LCH patients. Conditioning regimen included fludarabine in all patients, melphalan in eight patients, total lymphoid irradiation in six patients, total body irradiation in two, antithymocyte globulin in five, and Campath in four patients. RIC-SCT was well tolerated with regard to common procedure-related complications. Two patients died 50 and 69 days after RIC-SCT, respectively. Seven out of the nine patients survived and showed no signs of disease activity (including one with nonengraftment and full autologous hematopoietic recovery) after median follow-up of 390 days post-SCT. Based on this observation, we conclude that RIC-SCT is a feasible procedure with low transplant-related morbidity and mortality and a promising new salvage approach for high-risk LCH patients with resistant risk organ involvement.

Female↗

PubMed2005

Directed binding: a novel physical mechanism that describes the directional motion of two-headed kinesin motor proteins.

We propose a novel physical mechanism to describe the mode of processive propagation of two-headed kinesin motor proteins along microtubule (MT) filaments. Binding and unbinding of the kinesin heads to and from the MT filament play a crucial role in producing movement. The chemical energy of adenosine triphosphate hydrolysis is used in large part for the unbinding process of kinesin from the MT filament. Importantly, in our model, the binding of each head is to be directionally oriented to the MT filament. Therefore, we treat the two motor domains (heads) as extended objects that are connected with each other by a neck region that contains the kinesin dimerization domain. The head domains recognize tubulin binding sites by feeling the two-dimensional periodic potential from the MT surface and are also subjected to thermal noise. Using experimentally determined results regarding physical parameters of the walk, we develop a simple mathematical and mechanical model in which directed binding of the heads to tubulin results in a directed twist of the molecule, probably in the neck linker region, away from its relaxed state. Unbinding of the head from the filament relaxes the twist and defines the propagation direction. We showed that there must be at least two torsional springs (one for every head) involved that can store elastic energy. Consequently, in our model, it is the internal structure both of the relaxed and tensed-up state and the transition mode between them that define the walking direction of kinesin. We present calculations based on the model that are in good quantitative agreement with experimental observations for kinesin.

Binding Sites↗

PubMed2004

Pineal gland abnormalities in Langerhans cell histiocytosis.

BACKGROUND: The most common types of central nervous system (CNS) disease in Langerhans cell histiocytosis (LCH) comprise involvement of the hypothalamic-pituitary region (HPR) and neurodegenerative changes in the cerebellum, basal ganglia or pons. In the review process of magnetic resonance images (MRI) from 129 LCH patients a high frequency of cysts within or large pineal glands was noted by chance. PROCEDURE: To prove whether this observation was specific for LCH or not, we compared MRI findings of the HPR in LCH patients with a control group of 55 non-LCH patients with the same age and sex distribution. RESULTS: In LCH patients, the pineal gland was significantly larger and also the number of pineal cysts was significantly higher as compared to the control group. No difference was found regarding the size or frequency of cystic changes between patients who had received chemotherapy prior to the MRI and untreated patients. In the LCH patients, we further found a significant correlation of pineal gland enlargement with involvement of the HPR, but not with neurodegenerative changes. Analysis of melatonin (the principal hormone of the pineal gland) levels in 24 hr urine in 14 LCH patients did not reveal a melatonin deficiency or overproduction in the LCH group as compared to 6 normal controls. CONCLUSIONS: The pineal gland is another site of possible CNS involvement in LCH. LCH CNS patients did not show an overt disturbance in melatonin levels. The role of the pineal gland in CNS LCH remains to be defined.

Adolescent↗

PubMed2003

Role of cytokines in photodynamic therapy-induced local and systemic inflammation.

Photodynamic therapy (PDT) of tumour results in the rapid induction of an inflammatory response that is considered important for the activation of antitumour immunity, but may be detrimental if excessive. The response is characterised by the infiltration of leucocytes, predominantly neutrophils, into the treated tumour. Several preclinical studies have suggested that suppression of long-term tumour growth following PDT using Photofrin((R)) is dependent upon the presence of neutrophils. The inflammatory pathways leading to the PDT-induced neutrophil migration into the treated tumour are unknown. In the following study, we examined, in mice, the ability of PDT using the second-generation photosensitiser 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) to induce proinflammatory cytokines and chemokines, as well as adhesion molecules, known to be involved in neutrophil migration. We also examined the role that these mediators play in PDT-induced neutrophil migration. Our studies show that HPPH-PDT induced neutrophil migration into the treated tumour, which was associated with a transient, local increase in the expression of the chemokines macrophage inflammatory protein (MIP)-2 and KC. A similar increase was detected in functional expression of adhesion molecules, that is, E-selectin and intracellular adhesion molecule (ICAM)-1, and both local and systemic expression of interleukin (IL)-6 was detected. The kinetics of neutrophil immigration mirrored those observed for the enhanced production of chemokines, IL-6 and adhesion molecules. Subsequent studies showed that PDT-induced neutrophil recruitment is dependent upon the presence of MIP-2 and E-selectin, but not on IL-6 or KC. These results demonstrate a PDT-induced inflammatory response similar to, but less severe than obtained with Photofrin((R)) PDT. They also lay the mechanistic groundwork for further ongoing studies that attempt to optimise PDT through the modulation of the critical inflammatory mediators.

Animals↗

PubMed2003

Interaction of metal salts with cytoskeletal motor protein systems.

Interactions of chemicals with the microtubular network of cells may lead to genotoxicity. Micronuclei (MN) might be caused by interaction of metals with tubulin and/or kinesin. The genotoxic effects of inorganic lead and mercury salts were studied using the MN assay and the CREST analysis in V79 Chinese hamster fibroblasts. Effects on the functional activity of motor protein systems were examined by measurement of tubulin assembly and kinesin-driven motility. Lead and mercury salts induced MN dose-dependently. The no-effect-concentration for MN induction was 1.1 microM PbCl(2), 0.05 microM Pb(OAc)(2) and 0.01 microM HgCl(2). The in vitro results obtained for PbCl(2) correspond to reported MN induction in workers occupationally exposed to lead, starting at 1.2 microM Hg(II) (Vaglenov et al., 2001, Environ. Health Perspect. 109, 295-298). The CREST Analysis indicate aneugenic effects of Pb(II) and aneugenic and additionally clastogenic effects of Hg(II). Lead (chloride, acetate, and nitrate) and mercury (chloride and nitrate) interfered dose-dependently with tubulin assembly in vitro. The no-effect-concentration for lead salts in this assay was 10 microM. Inhibition of tubulin assembly by mercury started at 2 microM. The gliding velocity of microtubules along immobilised kinesin molecules was affected by 25 microM Pb(NO(3))(2) and 0.1 microM HgCl(2) in a dose-dependent manner. Our data support the hypothesis that lead and mercury genotoxicity may result, at least in part, via disturbance of chromosome segregation via interaction with cytoskeletal proteins.

Animals↗

PubMed2002

Analysis of the migration behaviour of single microtubules in electric fields.

By video contrast microscopy, individual microtubules formed from pure tubulin in the presence of taxol were studied in constant electric fields. At nearly physiological conditions, i.e., in a buffer at pH 6.8 and 120 mM ionic strength, suspended microtubules moved towards the anode with an electrophoretic mobility of approximately 2.6 x 10(-4) cm(2)/V s, corresponding to an unbalanced negative charge of 0.19 electron charges per tubulin dimer. Strikingly, this value is lower by a factor of at least 50 than that calculated from crystallographic data for the non-assembled tubulin dimer. Moreover, the taxol-stabilized microtubules had an isoelectric point of about pH 4.2 which is significantly lower than that known for the tubulin monomers. This indicates that microtubule formation is accompanied by substantial changes of charge distribution within the tubulin subunits. Constant electric fields were shown to affect also the orientation of microtubules gliding across a kinesin-coated surface at pH 6.8.

Animals↗

PubMed2001

Basic design and construction of the Vienna FES implants: existing solutions and prospects for new generations of implants.

We can distinguish 3 generations of FES implants for activation of neural structures: 1. RF-powered implants with antenna displacement dependent stimulation amplitude; 2. RF-powered implants with stabilised stimulation amplitude; and 3. battery powered implants. In Vienna an 8-channel version of the second generation type has been applied clinically to mobilisation of paraplegics and phrenic pacing. A 20-channel implant of the second generation type for mobilisation of paraplegics and an 8-channel implant of the third generation type for cardiac assist have been tested in animal studies. A device of completely new design for direct stimulation of denervated muscles is being tested in animal studies. There is a limited choice of technologically suitable biocompatible and bioresistant materials for implants. The physical design has to be anatomically shaped without corners or edges. Electrical conductors carrying direct current (D.C.) have to be placed inside a hermetic metal case. The established sealing materials, silicone rubber and epoxy resin, do not provide hermeticity and should only embed DC-free components. For electrical connections outside the hermetic metal case welding is preferable to soldering; conductive adhesives should be avoided. It is advisable to use a hydrophobic oxide ceramic core for telemetry antenna coils embedded in sealing polymer. Cleaning of all components before sealing in resin is of the utmost importance as well as avoidance of rapid temperature changes during the curing process.

Animals↗

PubMed2001

Selection and orientation of adjacent genes influences DAM-mediated male sterility in transformed maize.

Anther-targeted expression of E. coli DNA (Adenosine-N6-)-Methyltransferase (DAM) in maize was tested as a means to produce male-sterile plants. A high frequency of male-sterile plants with reduced anther size was observed when DAM was regulated by the maize anther-specific promoter 5126 (5126:DAM) and placed upstream of the herbicide resistance gene, pat, regulated by the cauliflower mosaic virus (CaMV) 35S promoter (35S:PAT). In contrast, placement of 5126:DAM upstream of a pat gene regulated by either the maize ubiquitin (UBI:PAT) or rice actin (rACTIN:PAT) promoters resulted in male-fertile plants. Based on these observed differences, DAM-mediated sterility was used as a phenotypic marker to assess the contribution of factors affecting gene expression such as orientation of the transcription units, choice of regulatory sequences mediating expression of adjacent genes, and effects of varying the anther-specific promoter regulating DAM. Constructs that place a portion of the CaMV 35S promoter, including the native AS-1 sequences, between 5126:DAM and UBI:PAT yielded a high frequency of male-sterile plants with reduced anther size. Significant differences in the frequency of male-sterile events and the associated anther size were also observed when the position of 35S:PAT was changed relative to 5126:DAM. These data provide evidence that gene expression in transformed maize plants can be impacted by simply altering the order, orientation or regulatory sequences of adjacent genes.

Acetyltransferases↗

PubMed2001

Functional and biological test of a 20 channel implantable stimulator in sheep in view of functional electrical stimulation walking for spinal cord injured persons.

A newly developed implantable stimulator with 20 output channels, mainly intended for the stimulation of lower extremities in paraplegics, was implanted in 6 sheep over a time period of 26 weeks. Five epineural electrodes each were used to contact various nerves at different locations to elicit hip and knee extension and flexion and to make carrousel and selective stimulation possible. Different electrode application strategies in view of paraplegic standing and walking were investigated. Additional implanted electrodes allowed M-wave monitoring for selectivity investigations in 3 sheep. Stimulator, electrode leads, and electrodes proved to be reliable. Selective stimulation with electrodes placed on the trunk of the sciatic nerve could be demonstrated but with bad reproducibility. Histological investigation of the tissues surrounding electrodes and leads showed the expected stable foreign body response. Strong hip and knee extension could be gained in all cases while only weak flexion forces could be elicited in most cases. Muscle biopsies showed that daily stimulation for 8 h at threshold level caused an increase in muscle Type I fibers and a decrease in Type IIc fibers. Implants and electrodes fulfill the most important functional and biological criteria for their clinical application for paraplegic walking. The intention to provide selective flexion functions via epineural stimulation could not be demonstrated sufficiently in this animal model.

Animals↗

PubMed2001

Video-EEG monitoring in respiratory chain disorders.

Subclinical epileptiform activity in patients with respiratory chain disorders (RCDs) has not been previously investigated by video-EEG monitoring. The purpose of this study was to look for the type and frequency of epileptiform activity during a 24 h-video-EEG recording in RCD patients. Eleven patients with RCD, 7 women and 4 men, aged 24-72 years, underwent a clinical neurologic examination, blood tests, CT/MRI scans of the brain, routine scalp EEG and continuous video-EEG monitoring over 24 consecutive hours. Ten patients had normal 24 h-video-EEG recordings. One of these patients had no CNS involvement; her resting EEGs showed diffuse background slowing. In one patient, automatic spike detection revealed 12 spikes during a 6 hour period. Resting scalp EEG in this patient showed extensive, bilaterally synchronous, pseudoperiodic polyspike-waves. In conclusion, subclinical epileptiform activity could be recorded by 24 h-video-EEG monitoring in only 1 of 11 RCD patients. The single patient with subclinical epileptiform activity presented with intermittent myoclonic jerks.

Adult↗

PubMed2001

Determination of the net exchange rate of tubulin dimer in steady-state microtubules by fluorescence correlation spectroscopy.

The microtubule cytoskeleton plays an important role in eukaryotic cells, e. g., in cell movement or morphogenesis. Microtubules, formed by assembly of tubulin dimers, are dynamic polymers changing randomly between periods of growing and shortening, a property known as dynamic instability. Another process characterizing the dynamic behaviour is the so-called treadmilling due to different binding constants of tubulin at both microtubule ends. In this study, we used tetramethylrhodamine (TMR)-labeled tubulin added to microtubule suspensions to determine the net exchange rate (NER) of tubulin dimers by fluorescence correlation spectroscopy (FCS) as a measure for microtubule dynamics. This approach, which seems to be suitable as a screening system to detect compounds influencing the NER of tubulin dimers into microtubules at steady-state, showed that taxol, nocodazole, colchicine, and vinblastine affect microtubule dynamics at concentrations as low as 10(-9)-10(-10) M.

Animals↗

PubMed2001

Pruritometer 2: portable recording system for the quantification of scratching as objective criterion for the pruritus.

Studies to evaluate therapies for itching (pruritus) related diseases often require the quantification of the itch sensation. Like all subjective symptoms the evaluation of itching is difficult and can only be done indirectly. With the Pruritometer 2 a measuring system is introduced that evaluates itching by detecting scratching movements. Based on the Pruritometer 1, that processes the signals of a piezoelectric vibration sensor, fixed on the midfinger of the patients dominant hand, and triggers a simple counter, the Pruritometer 2 allows to store the scratch activity during a 24 hours period. For each adjustable time slice of this time period, the amount of scratches and the scratch intensity are recorded. All data can be transferred to a PC via infrared link for further processing with a standard software package. An additional PC-software allows to set various parameters for optimal scratch detection and to test the patient attached system, also via the infrared link. All electronic components are shockproof encapsulated in a milled housing and are attached to a textile watchstrap that is worn by the patient like a wristwatch.

Equipment Design↗

PubMed2000

Effect of temperature on kinesin-driven microtubule gliding and kinesin ATPase activity.

DeCuevas et al. [J. Cell Biol. 116 (1992) 957-965] demonstrated by circular dichroism spectroscopy for the kinesin stalk fragment that shifting temperature from 25 to 30 degrees C caused a conformational transition. To gain insight into functional consequences of such a transition, we studied the temperature dependence of a full-length kinesin by measuring both the velocity of microtubule gliding across kinesin-coated surfaces and microtubule-promoted kinesin ATPase activity in solution. The corresponding Arrhenius plots revealed distinct breaks at 27 degrees C, corroborating the temperature-dependent conformational transition for a motility-competent full-length kinesin. Microtubules were found to glide up to 45 degrees C; at higher temperatures, kinesin was irreversibly damaged.

Animals↗

PubMed2000

Speeding up kinesin-driven microtubule gliding in vitro by variation of cofactor composition and physicochemical parameters.

So far, there has been a discrepancy between the velocities of kinesin-dependent microtubule motility measured in vitro and within cells. By changing ATP, Mg(2+), and kinesin concentrations, pH and ionic strength, we tried to find conditions that favour microtubule gliding across kinesin-covered glass surfaces. For porcine brain kinesin, we found that raising the molar Mg(2+)/ATP ratio can substantially elevate gliding velocity. Gliding became also faster after temperature elevation or lowering the number of kinesin molecules bound to the glass surface. The highest mean gliding velocity (1.8 microm/s+/-0.09 microm/s), approaching velocities measured for anterograde transport in vivo, was achieved by combination of favourable factors (2.5 m m ATP, 12.5 m m Mg(2+), 37 degrees C, 450 kinesin molecules/microm(2)).

Adenosine Diphosphate↗