A nucleosynthetic origin for the Earth's anomalous (142)Nd composition.

A long-standing paradigm assumes that the chemical and isotopic compositions of many elements in the bulk silicate Earth are the same as in chondrites. However, the accessible Earth has a greater (142)Nd/(144)Nd ratio than do chondrites. Because (142)Nd is the decay product of the now-extinct (146)Sm (which has a half-life of 103 million years), this (142)Nd difference seems to require a higher-than-chondritic Sm/Nd ratio for the accessible Earth. This must have been acquired during global silicate differentiation within the first 30 million years of Solar System formation and implies the formation of a complementary (142)Nd-depleted reservoir that either is hidden in the deep Earth, or lost to space by impact erosion. Whether this complementary reservoir existed, and whether or not it has been lost from Earth, is a matter of debate, and has implications for determining the bulk composition of Earth, its heat content and structure, as well as for constraining the modes and timescales of its geodynamical evolution. Here we show that, compared with chondrites, Earth's precursor bodies were enriched in neodymium that was produced by the slow neutron capture process (s-process) of nucleosynthesis. This s-process excess leads to higher (142)Nd/(144)Nd ratios; after correction for this effect, the (142)Nd/(144)Nd ratios of chondrites and the accessible Earth are indistinguishable within five parts per million. The (142)Nd offset between the accessible silicate Earth and chondrites therefore reflects a higher proportion of s-process neodymium in the Earth, and not early differentiation processes. As such, our results obviate the need for hidden-reservoir or super-chondritic Earth models and imply a chondritic Sm/Nd ratio for the bulk Earth. Although chondrites formed at greater heliocentric distances and contain a different mix of presolar components than Earth, they nevertheless are suitable proxies for Earth's bulk chemical composition.

Design study of a miniaturized displacement transducer (MDT) for an active middle ear implant system.

People suffering from moderate to severe hearing loss can be treated with active middle ear implants. A new approach in this field is to implant an electromechanical transducer onto the round window membrane in order to improve coupling and be able to treat patients with middle-ear problems. In this paper the design study for a miniaturized displacement transducer (MDT) for the round window is presented. Based on a requirement analysis, the basic principle and analytical modeling of the actuator is shown. A parameter variation study results in an optimized actuator configuration that is able to generate an amplification of 110 dB SPL theoretically. As a next step this actuator has to be manufactured and tested.

3-D analysis of bacterial cell-(iron)mineral aggregates formed during Fe(II) oxidation by the nitrate-reducing Acidovorax sp. strain BoFeN1 using complementary microscopy tomography approaches.

The formation of cell-(iron)mineral aggregates as a consequence of bacterial iron oxidation is an environmentally widespread process with a number of implications for processes such as sorption and coprecipitation of contaminants and nutrients. Whereas the overall appearance of such aggregates is easily accessible using 2-D microscopy techniques, the 3-D and internal structure remain obscure. In this study, we examined the 3-D structure of cell-(iron)mineral aggregates formed during Fe(II) oxidation by the nitrate-reducing Acidovorax sp. strain BoFeN1 using a combination of advanced 3-D microscopy techniques. We obtained 3-D structural and chemical information on different cellular encrustation patterns at high spatial resolution (4-200 nm, depending on the method): more specifically, (1) cells free of iron minerals, (2) periplasm filled with iron minerals, (3) spike- or platelet-shaped iron mineral structures, (4) bulky structures on the cell surface, (5) extracellular iron mineral shell structures, (6) cells with iron mineral filled cytoplasm, and (7) agglomerations of extracellular globular structures. In addition to structural information, chemical nanotomography suggests a dominant role of extracellular polymeric substances (EPS) in controlling the formation of cell-(iron)mineral aggregates. Furthermore, samples in their hydrated state showed cell-(iron)mineral aggregates in pristine conditions free of preparation (i.e., drying/dehydration) artifacts. All these results were obtained using 3-D microscopy techniques such as focused ion beam (FIB)/scanning electron microscopy (SEM) tomography, transmission electron microscopy (TEM) tomography, scanning transmission (soft) X-ray microscopy (STXM) tomography, and confocal laser scanning microscopy (CLSM). It turned out that, due to the various different contrast mechanisms of the individual approaches, and due to the required sample preparation steps, only the combination of these techniques was able to provide a comprehensive understanding of structure and composition of the various Fe-precipitates and their association with bacterial cells and EPS.

Biocompatible molecularly imprinted polymers for the voltage regulated uptake and release of L-glutamate in neutral pH solutions.

A biocompatible device for the voltage dependent uptake and release of the neural transmitter L-glutamate in neutral pH solutions is demonstrated. The device consists of a gold electrode coated with molecularly imprinted, overoxidised polypyrrole (oPPy). It is shown here that oPPy can behave as an anion exchanger in neutral pH. The voltage dependent uptake and release of glutamate from the oPPy as well as the enantioselectivity of the polymer layer for L-glutamate over D-glutamate are investigated in neutral pH solutions using electrochemical quartz crystal microbalance techniques. The biocompatibility of the oPPy layer is demonstrated using retinae from young rats. The retinae were isolated and the dissociated cells were kept in culture for up to 1-week. The cells were exposed to the oPPy layers for 3 days, and there is no significant difference in the survival rate between the cells cultured on the oPPy layers and the control samples. Additionally the cell-polymer interface from cells grown directly on the oPPy layers is investigated using electron microscopy.

Influence of repeated treadmill exercise on quality and freezability of stallion semen.

The objective of this study was to investigate changes of quality and freezability of stallion semen in response to repeated acute treadmill exercise. Ejaculates from 11 stallions were collected, evaluated and frozen weekly during four periods of 4 weeks each defined as before (period 1), during (period 2) and after (periods 3 and 4) intense exercise. In fresh semen the gel-free volume, sperm concentration, motility, normal sperm and sperm with major defects (acrosome defects, nuclear vacuoles, abnormal heads, midpiece defects and proximal droplets) were evaluated. In frozen-thawed semen, motility as well as viability (SYBR-14/PI) were examined. In period 2, all stallions were exercised on an indoor high speed treadmill twice a week (total of eight sessions) using an incremental workload test. Heart rate was monitored telemetrically during exercise and blood samples were taken for determination of cortisol, testosterone and lactate. Results of our investigation demonstrate that heart rate and the plasma concentrations of cortisol, testosterone and lactate significantly (P < 0.05) increased during each exercise session. Furthermore, significantly more major sperm defects were present in periods 3 (69.5+/-2.1%) and 4 (66.8+/-2.1%) than in periods 1 (62.2+/-2.4%) and 2 (62.5+/-2.2%). Acrosome defects increased towards the end of exercise but improved 3 weeks later to values observed before exercise. In frozen-thawed semen, motility was significantly lower in period 2 (45.4+/-2.3%) compared to period 4 (51.6+/-1.7%) and viability was significantly lower in period 2 (49.2+/-2.0%) than in periods 1 (53.8+/-2.1%) and 4 (53.7+/-1.6%). Our results clearly demonstrate that in the stallion repeated strenuous treadmill exercise can negatively influence semen quality and freezability.

Patch-clamping of primary cardiac cells with micro-openings in polyimide films.

Patch-clamping is a powerful method for investigating the function and regulation of ionic channels. Currently, great efforts are being made to automate this method. As a step towards this goal, the feasibility of patch-clamping primary cells with a microscopic opening in a planar substrate was tested. Using standard microfabrication and ion beam technology, small-diameter openings (2 and 4 microm) were formed in polyimide films (thickness 6.5 microm). Single cells (sheep Purkinje heart cells, Chinese hamster ovary cells) in a suspension were positioned on top of the opening and sucked towards the opening to improve adhesion of the cell to the planar substrate, hence increasing the seal resistance. Voltage/current measurements yielded a median seal resistance of 1.3 Mohms with 4 microm openings (n=24) and 26.0 Mohms with 2 microm openings (n = 75), respectively. With 2 microm openings, successful loose-patch recordings of TTX-sensitive inward currents and action potentials in sheep Purkinje heart cells (n = 18) were made. In rare cases, gigaseals (n = 4) were also measured, and a whole-cell configuration (n = 1) could be established. It was concluded that the simple planar patch approach is suitable for automated loose-patch recordings from cells in suspension but will hardly be suitable for high-throughput whole-cell patch-clamping with high-resistance seals.

Modelling ion binding to AA platform motifs in RNA: a continuum solvent study including conformational adaptation.

Binding of monovalent and divalent cations to two adenine-adenine platform structures from the Tetrahymena group I intron ribozyme has been studied using continuum solvent models based on the generalised Born and the finite-difference Poisson-Boltzmann approaches. The adenine-adenine platform RNA motif forms an experimentally characterised monovalent ion binding site important for ribozyme folding and function. Qualitative agreement between calculated and experimental ion placements and binding selectivity was obtained. The inclusion of solvation effects turned out to be important to obtain low energy structures and ion binding placements in agreement with the experiment. The calculations indicate that differences in solvation of the isolated ions contribute to the calculated ion binding preference. However, Coulomb attraction and van der Waals interactions due to ion size differences and RNA conformational adaptation also influence the calculated ion binding affinity. The calculated alkali ion binding selectivity for both platforms followed the order K(+) > Na(+) > Rb(+) > Cs(+) > Li(+) (Eisenman series VI) in the case of allowing RNA conformational relaxation during docking. With rigid RNA an Eisenman series V was obtained (K(+) > Rb(+) > Na(+) > Cs(+) > Li(+)). Systematic energy minimisation docking simulations starting from several hundred initial placements of potassium ions on the surface of platform containing RNA fragments identified a coordination geometry in agreement with the experiment as the lowest energy binding site. The approach could be helpful to identify putative ion binding sites in nucleic acid structures determined at low resolution or with experimental methods that do not allow identification of ion binding sites.

Dynamics of middle ear prostheses - simulations and measurements.

The efficient and systematic development of a middle ear prosthesis necessitates the use of computer models for the prosthesis itself and the reconstructed middle ear. The structure and parameters of the computer model have to be verified by specific measurements of the implant and the reconstructed ear. To obtain a realistic model of a reconstructed ear, three steps of modeling and measurements have been carried out. To get a first approach of the coupling elements a mechanical test rig representing a simplified reconstructed middle ear was built. The velocity of the stapedial footplate was measured with a laser Doppler vibrometer. The corresponding computer model was formulated, and the respective parameters were determined using the measured dynamical transfer functions. In the second step, a prosthesis was implanted into a human temporal bone without inner ear. Exciting this system with noise, the velocity of the stapes footplate was measured with the laser Doppler vibrometer. Based on the multibody system approach, a mechanical computer model was generated to describe the spatial motions of the reconstructed ossicular chain. Varying some significant parameters, simulations have been carried out. To describe the dynamical behavior of the system consisting of middle and inner ear, the computer model used in the second step has been enlarged by adding a simplified structure of the inner ear. The results were compared with in situ measurements taken from living humans.

Conditional gene targeting in macrophages and granulocytes using LysMcre mice.

Conditional mutagenesis in mice has recently been made possible through the combination of gene targeting techniques and site-directed mutagenesis, using the bacteriophage P1-derived Cre/loxP recombination system. The versatility of this approach depends on the availability of mouse mutants in which the recombinase Cre is expressed in the appropriate cell lineages or tissues. Here we report the generation of mice that express Cre in myeloid cells due to targeted insertion of the cre cDNA into their endogenous M lysozyme locus. In double mutant mice harboring both the LysMcre allele and one of two different loxP-flanked target genes tested, a deletion efficiency of 83-98% was determined in mature macrophages and near 100% in granulocytes. Partial deletion (16%) could be detected in CD11c+ splenic dendritic cells which are closely related to the monocyte/macrophage lineage. In contrast, no significant deletion was observed in tail DNA or purified T and B cells. Taken together, LysMcre mice allow for both specific and highly efficient Cre-mediated deletion of loxP-flanked target genes in myeloid cells.

[First comparisons with laser vibrometry measurements and computer simulation of ear ossicle movements]. / Erste Vergleiche von Laservibrometriemessungen und Computersimulationen der Gehörknöchelchenbewegungen.

The dynamic behavior of the ossicular chain is very complex and is frequency-dependent. To date, this has still not been fully investigated or understood. There remains a lack of measurement procedures to pick up the motion of the ossicles and ear drum simultaneously with sufficient resolution. The presented paper reports simultaneous measurements with laser-Doppler vibrometry at two points of the ossicular chain of cadaver specimens. Motions not observed were derived using mechanical simulation models on a computer and then evaluating appropriate mathematical equations. Using a sound stimulus, the displacement velocities of the umbo and stapes footplate were measured, and the corresponding transfer functions were derived by Fourier transform. Results were used for verification of the computer models. In the current investigations these models were refined and allow for the detailed investigation of the dynamic behavior of the ossicular chain, facilitating the optimal design of passive and active middle-ear implants.

[Laser vibrometry. A middle ear and cochlear analyzer for noninvasive studies of middle and inner ear function disorders]. / Laservibrometrie. Ein Mittelohr- und Kochleaanalysator zur nicht-invasiven Untersuchung von Mittel- und Innenohrfunktionsstörungen.

A complete battery of audiometric methods is required for the differential diagnosis of different hearing disabilities (including puretone audiometry, impedance, stapes reflex, speech audiometry, brainstam evoked response audiometry, otoacoustic emissions, etc.). In many cases, a comprehensive diagnosis is not possible. Here we describe a new technique based on a laser-Doppler vibrometer that has the potential for non-invasive diagnosis not only middle ear disease but also cochlear pathologies. Disturbance of cochlear function can be ascertained because the input impedance of the cochlea acts as a mechanical load on the middle ear and therefore influences motion of the umbo. In the present study vibration of the umbo and eardrum were measured with a commercially available laser-Doppler vibrometer coupled directly into a standard surgical microscope. The use of the microscope allowed non-invasive measurements of vibrations without having to introduce reflecting material onto the tympanic membrane. Sound pressure was measured with a calibrated probe microphone placed near the tympanic membrane. The displacement response and the specific acoustic impedance of the umbo were calculated from the velocity and sound pressure measured. For normal hearing subjects, the amplitude of the umbo's displacement for frequencies from 0.1 kHz to 1 kHz was 1 nm at 60 dB SPL and decreased with a slope of 6 dB/octave for frequencies between 1 and 5 kHz. A strong correlation was found between the specific acoustic impedance of the umbo and hearing thresholds for hearing-impaired subjects (having otosclerosis or sensorineural hearing losses). The frequency response of the umbo proved to be a means for evaluating the function of both the middle ear and the cochlea under pathological conditions. The measurement technique described is also suitable for intraoperative investigation of the frequency response of the opened middle ear, as well as for the in situ frequency response of partial and total ossicular replacement prostheses.

An HLA-DRB alpha-helix motif shared by DR11 and DR8 alleles is implicated in the pluriallelic restriction of peptide-specific T-cell lines.

The T-cell recognition of HLA-DR-peptide complexes is generally restricted by the polymorphism of the DRB molecules but pluriallelic restriction has been described. The molecular basis of restriction and promiscuity of such peptide-specific responses is poorly understood. We isolated a panel of T-cell lines specific for the tetanus toxin peptide p2 (TT830-843) exhibiting pluriallelic restriction by DR11 and DR8 alleles. Fine restriction specificity of the T-cell lines was examined in functional assays against DR oligotyped APCs expressing different variants of DR11 and DR8 alleles. Our results show that (a) polymorphisms between serologically related alleles are relevant in terms of restriction of the peptide-specific T-cell response; in some instances, a single amino acid substitution can determine the restriction of a T-cell line; (b) different patterns of restriction are not the result of specific differences in DR-p2 binding as p2 peptide binds to all DR11 and DR8 alleles tested (DRB1* 1101, -1102, -1103, -1104, 110X, -0801, -0802, -0803, and -0806); and (c) pluriallelic restriction of the peptide-specific T-cell response correlates with the presence of a DRB1 alpha-helix motif (67-71-86) shared by some DR11 and DR8 alleles. Possible implications of pluriallelic restriction of peptide-specific T-cell response in autoimmune disorders associated with DR11 and DR8 are discussed.

Parkinson's disease: a chronic, low-grade antioxidant deficiency?

The cause of Parkinson's disease (PD) is aggressively being pursued. Several hypotheses have been advanced, yet none of these completely explains the large body of evidence research has already uncovered. A new hypothesis, that PD is caused by a chronic antioxidant deficiency state, is outlined in this article. Oxidative stress, mitochondrial abnormalities, epidemiology, genetics, toxins, history of PD and diet are discussed.

Neuroleptic medications inhibit complex I of the electron transport chain.

Neuroleptic medications are prescribed to millions of patients, but their use is limited by potentially irreversible extrapyramidal side effects. Haloperidol shows striking structural similarities to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which produces parkinsonism apparently through inhibition of NADH:ubiquinone oxidoreductase (complex I) of the mitochondrial electron transport chain. We now report that haloperidol, chlorpromazine, and thiothixene inhibit complex I in vitro in rat brain mitochondria. Clozapine, an atypical antipsychotic reported to have little or no extrapyramidal toxicity, also inhibits complex I, but at a significantly higher concentration. Neuroleptic treated patients have significant depression of platelet complex I activity similar to that seen in idiopathic Parkinson's disease. Complex I inhibition may be associated with the extrapyramidal side effects of these drugs.

Diffuse Lewy body disease and progressive dementia.

Thirty cases of diffuse Lewy body disease (DLBD) have been reported, primarily by neuropathologists, but an associated clinical syndrome has not been clearly defined. Four recent cases have led us to examine the clinicopathologic correlations. Patients are usually elderly, with symptoms lasting from 1 to 20 years. Progressive dementia or psychosis is typically the first and most prominent feature. Parkinsonian signs, initially mild or absent, become common eventually, and rigidity is usually severe. Involuntary movements, myoclonus, quadriparesis in flexion, orthostatic hypotension, and dysphagia have also been noted. Classic, concentric Lewy bodies are found profusely in the brainstem, basal forebrain, and hypothalamic nuclei, while less well defined "Lewy-like" bodies occur in limbic structures and in deep neocortical layers. In addition, focal spongiform changes in the mesial temporal lobe were found in two of our cases. We suggest that DLBD may be another specific cause of progressive dementia.

Constant infusions of morphine and intakes of sweetened ethanol solution among rats.

Previous studies have indicated that injections of small doses of morphine increase rats' intake of solutions containing ethanol when rats have a choice of either water or a solution containing ethanol. In this experiment, rats which were implanted with osmotic pumps that delivered constant infusions of morphine (0.6 mg/kg/hr across 24 days) had elevated daily intakes of ethanol, as compared to controls, from the second day of opportunity to take the alcoholic beverage until the pumps were removed. In addition, half of the rats with pumps infusing morphine also received injections of morphine (1.0 mg/kg) just before the 1.5-hr opportunity to take alcoholic beverage or water every day for 8 days. Across this 8-day period, these rats took a mean of 5.18 g of pure ethanol/kg of body weight (g/kg) during the 1.5-hr opportunity to take the alcoholic beverage. This was reliably more than the mean of 4.02 g/kg that their counterparts (having morphine pumps and receiving injections of saline) took across the same period. These data support the hypothesis that a surfeit of opioidergic ligand may potentiate drinking of alcoholic beverages.

A small dose of morphine increases intake of and preference for isotonic saline among rats.

Water-deprived rats were given hourly opportunities to ingest physiological saline and water for a number of days until they were taking substantial amounts of both solutions. Prior to some opportunities to ingest, they were injected with either morphine (2.0 mg/kg) or a placebo. Across a variety of procedures, morphine increased intake of and, in 1-hr tests, increased preference for 0.9% NaCl. Intake of 1.5% NaCl also increased after administration of morphine. These data suggest that endogenous opioids are involved in sodium intake. These data also provide further support for the idea that one or more of the endogenous opioid systems are involved in the regulation of ingestion.

Metkephamid (Tyr-D-ala-Gly-Phe-N(Me)Met-NH2), a potent opioid peptide: receptor binding and analgesic properties.

The interaction of metkephamid (Tyr-D-Ala-Gly-Phe-N(Me)Met-NH2) with 3H-dihydromorphine and 3H-D-Ala2-D-Leu5-enkephalin binding has been examined in rat brain homogenates. Displacements of both 3H-ligands by metkephamid indicate that metkephamid interacts competitively with greatest potency to the high affinity binding component for both ligands (mu1 site). Unlike most enkephalins and opiates, metkephamid binds equipotently to both morphine-selective (mu2) and enkephalin-selective (delta) binding sites. Metkephamid is differentiated from morphine by its better than 12-fold higher affinity for the delta receptor. Blockade of the high affinity (mu1) binding in vivo with high doses of naloxazone dramatically reduces metkephamid's analgesic potency.

[Craniolacunia ("Lückenschädel") as an isolated finding (author's transl)]. / Isolierter Lückenschädel bei Neugeborenem.

Case report of congenital craniolacunia ("Lückenschädel" or lacunar skull) only associated with several noncerebral malformations but lacking the CNS findings usually associated with this condition, such as dysraphism. Presentation and discussion of etiology and prognosis of this anomaly and its differential diagnosis.