Tissue Specific Distribution and Activation of Sapindaceae Toxins in Horses Suffering from Atypical Myopathy.

peer reviewedEquine atypical myopathy is caused by hypoglycin A (HGA) and methylenecyclopropylglycine (MCPrG), the known protoxins of sycamore maple (Acer pseudoplatanus). Various tissues from five atypical myopathy cases were analyzed but only HGA was found. Whether deamination of MCPrG has already occurred in the intestine as the first stage of metabolization has not been investigated. Activation of the protoxins to methylenecyclopropylacetyl (MCPA)-CoA and methylenecyclopropylformyl (MCPF)-CoA, respectively, occurred mainly in the skeletal muscles, as evidenced by very high concentrations of MCPA-carnitine and MCPF-carnitine in this tissue. Inhibition of the acyl-CoA dehydrogenases of short- and medium-chain as well as branched-chain fatty acids by the toxins led to a strong increase in the corresponding acylcarnitines, again preferentially in skeletal muscles. An accumulation of the long-chain acylcarnitines beyond the level of the control samples could not be detected in the tissues. As a high amount of HGA was always found unmetabolized in the organs, we speculate that targeting the interruption of further metabolization might be a way to stop the progression of intoxication. Inhibition of the mitochondrial branched-chain amino acid aminotransferase, i.e., the first enzyme responsible for the activation of sycamore maple protoxins, could be a therapeutic approach

Monitoring tyrosinaemia type I: Blood spot test for nitisinone (NTBC).

Background: Quantification of nitisinone, 2-(nitro-4-trifluoromethylbenzoyl)1,3-cyclohexanedione (NTBC) has been repeatedly described. Nevertheless monitoring of NTBC has not yet become part of routine therapy surveillance in tyrosinaemia type I (OMIM 276700)

Towards newborn screening for ornithine transcarbamylase deficiency: fast non-chromatographic orotic acid quantification from dried blood spots by tandem mass spectrometry.

Background: Orotic acid (OA) is the key parameter in the detection of ornithine transcarbamylase deficiency (OTC-D). Inclusion of OA into newborn screening compatibility with existing analytical procedures is necessary

TMF: Laser Application for a Close-to-Reality Simulation of Thermo-Mechanical Fatigue Processes in Rocket Engines

The concept of a thermo-mechanical fatigue (TMF) - test bench is discussed in this paper. Motivation for the TMF tests are two-fold: to assess the life expectation of structures being exposed to extreme thermo-mechanical loads first on subcomponent or panel level, and to serve as validation experiment for life-prediction models. In Europe, the concept of TMF-panel testing has been first very successfully applied to rocket thrust chamber structures in the frame of the Ariane 5 Flight Recovery Programme in 2003 and 2004. These encouraging results have motivated the partners DLR Lampoldshausen and EADS Astrium to jointly investigate again the TMF-bench concept with special focus on meeting relevant requirements for future liquid propulsion needs. The following key elements of a TMF test bench are presented in the paper: • the TMF heating device – a diode Laser, which is available already at DLR Lampoldshausen, • the design of the panel housing, • a tentative design of the TMF panel. Furthermore, numerical analyses of this tentative TMF panel – such as a CFD analysis of the coolant flow in the core part of the TMF panel and a thermal as well as a structural Finite Element analysis of the sandwich part of the TMF panel during the hot run are shown

Detection of MCPG metabolites in horses with atypical myopathy.

Atypical myopathy (AM) in horses is caused by ingestion of seeds of the Acer species (Sapindaceae family). Methylenecyclopropylacetyl-CoA (MCPA-CoA), derived from hypoglycin A (HGA), is currently the only active toxin in Acer pseudoplatanus or Acer negundo seeds related to AM outbreaks. However, seeds or arils of various Sapindaceae (e.g., ackee, lychee, mamoncillo, longan fruit) also contain methylenecyclopropylglycine (MCPG), which is a structural analogue of HGA that can cause hypoglycaemic encephalopathy in humans. The active poison formed from MCPG is methylenecyclopropylformyl-CoA (MCPF-CoA). MCPF-CoA and MCPA-CoA strongly inhibit enzymes that participate in β-oxidation and energy production from fat. The aim of our study was to investigate if MCPG is involved in Acer seed poisoning in horses. MCPG, as well as glycine and carnitine conjugates (MCPF-glycine, MCPF-carnitine), were quantified using high-performance liquid chromatography-tandem mass spectrometry of serum and urine from horses that had ingested Acer pseudoplatanus seeds and developed typical AM symptoms. The results were compared to those of healthy control horses. For comparison, HGA and its glycine and carnitine derivatives were also measured. Additionally, to assess the degree of enzyme inhibition of β-oxidation, several acyl glycines and acyl carnitines were included in the analysis. In addition to HGA and the specific toxic metabolites (MCPA-carnitine and MCPA-glycine), MCPG, MCPF-glycine and MCPF-carnitine were detected in the serum and urine of affected horses. Strong inhibition of β-oxidation was demonstrated by elevated concentrations of all acyl glycines and carnitines, but the highest correlations were observed between MCPF-carnitine and isobutyryl-carnitine (r = 0.93) as well as between MCPA- (and MCPF-) glycine and valeryl-glycine with r = 0.96 (and r = 0.87). As shown here, for biochemical analysis of atypical myopathy of horses, it is necessary to take MCPG and the corresponding metabolites into consideration

Pitch perception for mixtures of spectrally overlapping harmonic complex tones

This study measured difference limens for fundamental frequency (DLF0s) for a target harmonic complex in the presence of a simultaneous spectrally overlapping harmonic masker. The resolvability of the target harmonics was manipulated by bandpass filtering the stimuli into a low (800–2400 Hz) or high (1600–3200 Hz) spectral region, using different nominal F0s for the targets (100, 200, and 400 Hz), and different masker F0s (0, +9, or −9 semitones) relative to the target. Three different modes of masker presentation, relative to the target, were tested: ipsilateral, contralateral, and dichotic, with a higher masker level in the contralateral ear. Ipsilateral and dichotic maskers generally caused marked elevations in DLF0s compared to both the unmasked and contralateral masker conditions. Analyses based on excitation patterns revealed that ipsilaterally masked F0 difference limens were small (<2%) only when the excitation patterns evoked by the target-plus-masker mixture contained several salient (>1 dB) peaks at or close to target harmonic frequencies, even though these peaks were rarely produced by the target alone. The findings are discussed in terms of place- or place-time mechanisms of pitch perception

Auditory-nerve responses predict pitch attributes related to musical consonance-dissonance for normal and impaired hearing

Human listeners prefer consonant over dissonant musical intervals and the perceived contrast between these classes is reduced with cochlear hearing loss. Population-level activity of normal and impaired model auditory-nerve (AN) fibers was examined to determine (1) if peripheral auditory neurons exhibit correlates of consonance and dissonance and (2) if the reduced perceptual difference between these qualities observed for hearing-impaired listeners can be explained by impaired AN responses. In addition, acoustical correlates of consonance-dissonance were also explored including periodicity and roughness. Among the chromatic pitch combinations of music, consonant intervals/chords yielded more robust neural pitch-salience magnitudes (determined by harmonicity/periodicity) than dissonant intervals/chords. In addition, AN pitch-salience magnitudes correctly predicted the ordering of hierarchical pitch and chordal sonorities described by Western music theory. Cochlear hearing impairment compressed pitch salience estimates between consonant and dissonant pitch relationships. The reduction in contrast of neural responses following cochlear hearing loss may explain the inability of hearing-impaired listeners to distinguish musical qualia as clearly as normal-hearing individuals. Of the neural and acoustic correlates explored, AN pitch salience was the best predictor of behavioral data. Results ultimately show that basic pitch relationships governing music are already present in initial stages of neural processing at the AN level. © 2011 Acoustical Society of America