Aging alters signaling properties in the mouse spinal dorsal horn.

A well-recognized relationship exists between aging and increased susceptibility to chronic pain conditions, underpinning the view that pain signaling pathways differ in aged individuals. Yet despite the higher prevalence of altered pain states among the elderly, the majority of preclinical work studying mechanisms of aberrant sensory processing are conducted in juvenile or young adult animals. This mismatch is especially true for electrophysiological studies where patch clamp recordings from aged tissue are generally viewed as particularly challenging. In this study, we have undertaken an electrophysiological characterization of spinal dorsal horn neurons in young adult (3-4 months) and aged (28-32 months) mice. We show that patch clamp data can be routinely acquired in spinal cord slices prepared from aged animals and that the excitability properties of aged dorsal horn neurons differ from recordings in tissue prepared from young animals. Specifically, aged dorsal horn neurons more readily exhibit repetitive action potential discharge, indicative of a more excitable phenotype. This observation was accompanied by a decrease in the amplitude and charge of spontaneous excitatory synaptic input to dorsal horn neurons and an increase in the contribution of GABAergic signaling to spontaneous inhibitory synaptic input in aged recordings. While the functional significance of these altered circuit properties remains to be determined, future work should seek to assess whether such features may render the aged dorsal horn more susceptible to aberrant injury or disease-induced signaling and contribute to increased pain in the elderly.

UX007 for the treatment of long chain-fatty acid oxidation disorders: Safety and efficacy in children and adults following 24weeks of treatment.

BACKGROUND: Long-chain fatty acid oxidation disorders (LC-FAOD) lead to accumulation of high concentrations of potentially toxic fatty acid intermediates. Newborn screening and early intervention have reduced mortality, but most patients continue to experience frequent hospitalizations and significant morbidity despite treatment. The deficient energy state can cause serious liver, muscle, and heart disease, and may be associated with an increased risk of sudden death. Triheptanoin is a medium odd-chain fatty acid. Anaplerotic metabolites of triheptanoin have the potential to replace deficient tricarboxylic acid (TCA) cycle intermediates, resulting in net glucose production as a novel energy source for the treatment of LC-FAOD. STUDY DESIGN: A single-arm, open-label, multicenter Phase 2 safety and efficacy study evaluated patients with severe LC-FAOD evidenced by ongoing related musculoskeletal, cardiac, and/or hepatic events despite treatment. After a four-week run-in on current regimen, investigational triheptanoin (UX007) was titrated to a target dose of 25-35% of total daily caloric intake. Patients were evaluated on several age/condition-eligible endpoints, including submaximal exercise tests to assess muscle function/endurance (12-minute walk test; 12MWT) and exercise tolerance (cycle ergometry), and health related quality of life (HR-QoL). Results through 24weeks of treatment are presented; total study duration is 78weeks. RESULTS: Twenty-nine patients (0.8 to 58years) were enrolled; most qualified based on severe musculoskeletal disease. Twenty-five patients (86%) completed the 24-week treatment period. At Week 18, eligible patients (n=8) demonstrated a 28% increase (LS mean=+181.9 meters; p=0.087) from baseline (673.4meters) in 12MWT distance. At Week 24, eligible patients (n=7) showed a 60% increase in watts generated (LS mean=+409.3W; p=0.149) over baseline (744.6W) for the exercise tolerance test. Improvements in exercise tests were supported by significant improvements from baseline in the adult (n=5) self-reported SF-12v2 physical component summary score (LS mean=+8.9; p<0.001). No difference from baseline was seen in pediatric parent-reported (n=5) scores (SF-10) at Week 24. Eighteen patients (62%) had treatment-related adverse events, predominantly gastrointestinal (55%), mild-to-moderate in severity, similar to that seen with prior treatment with medium chain triglyceride (MCT) oil. One patient experienced a treatment-related serious adverse event of gastroenteritis. One patient discontinued from study due to diarrhea of moderate severity; the majority of patients (25/29; 86%) elected to continue treatment in the extension period. CONCLUSIONS: In patients with severe LC-FAOD, UX007 interim study results demonstrated improved exercise endurance and tolerance, and were associated with positive changes in self-reported HR-QoL.

Fabrication and tunable reinforcement of net-shaped aluminum matrix composite parts via 3D printing.

Advanced materials, such as metal matrix composites (MMCs), are important for innovation, national security, and addressing climate change. MMCs are used in military, aerospace, and automotive applications because of their exceptional mechanical and thermal properties, however adoption has been slow due to costly and onerous manufacturing processes. A new process using fused filament fabrication 3D printing has been developed to make net shape MMCs without tooling or machining. The process involves printing an alumina preform and then using pressure-less infiltration with a molten aluminum alloy to form the composite. Arbitrary shapes can be formed in this process-a brake lever and a flange are demonstrated-and the properties can be tuned by varying the ceramic infill geometric pattern and ceramic loading. By using 35 vol% continuous fiber reinforcement over 800 MPa strength and 140 GPa modulus are achieved for the aluminum composite, 3.4 × and 2 × the matrix aluminum properties.

Purinergic modulation of glutamate transmission: An expanding role in stress-linked neuropathology.

Chronic stress has been extensively linked to disturbances in glutamatergic signalling. Emerging from this field of research is a considerable number of studies identifying the ability of purines at the pre-, post-, and peri-synaptic levels to tune glutamatergic neurotransmission. While the evidence describing purinergic control of glutamate has continued to grow, there has been relatively little attention given to how chronic stress modulates purinergic functions. The available research on this topic has demonstrated that chronic stress can not only disturb purinergic receptors involved in the regulation of glutamate neurotransmission, but also perturb glial-dependent purinergic signalling. This review will provide a detailed examining of the complex literature relating to glutamatergic-purinergic interactions with a focus on both neuronal and glial contributions. Once these detailed interactions have been described and contextualised, we will integrate recent findings from the field of stress research.

Rapid diagnosis of anaerobic infections by direct gas-liquid chromatography of clinical speciments.

Current methods to isolate and identify anaerobic bacteria are laborious and time consuming. It was postulated that the short-chain fatty acids (SCFA) produced by these organisms might serve as microbial markers in clinical material. 98 specimens of pus or serous fluid were analyzed by gas-liquid chromatography, and findings were compared with culture results. Good correlations were found for the recovery of anaerobic Gram-negative bacilli and the presence of isobutyric, butyric, and succinic acids. 19 of 20 specimens with significant amounts of these acids (greater than 0.01 mumol/ml) yielded bacteroides or fusobacteria. Culture of the single "false-positive" specimen failed to grow anaerobic Gram-negative bacilli, although clinical data and Gram-stain suggested their presence. 77 of 78 specimens which has insignificant concentrations of the marker acids failed to yield anaerobic, Gram-negative bacilli in culture. The single "false-negative" specimen yielded Bacteroides pneumosintes, an organism which does not ferment carbohydrates. It is concluded that direct gas-liquid chromatographic analysis of clinical specimens provides a rapid presumptive test for the presence of anaerobic, Gram-negative bacilli.

Cocaine preferentially enhances sensory processing in the upper layers of the primary sensory cortex.

Sensory systems are believed to play an important role in drug addiction, particularly in triggering craving and relapse, and it has been shown in previous studies that administration of cocaine can enhance evoked responses in the primary sensory cortex of experimental animals. Primary sensory cortex comprises a multi-layered structure to which a variety of roles have been assigned; an understanding of how cocaine affects evoked activity in these different layers may shed light on how drug-associated sensory cues gain control over behavior. The aim of the present study was to examine how cocaine affects whisker sensory responses in different layers of the primary sensory (barrel) cortex. Field potential and multi-unit activity were recorded from the cortex of anesthetized rats using 16 channel linear probes during repetitive (air puff) stimulation of the whiskers. In control conditions (under saline, i.v.), responses strongly adapted to the repeated sensory stimulation. Following an i.v. injection of cocaine (0.5 mg/kg, i.v.), this adaptation was strongly attenuated, giving each stimulus a more equal representation and weight. Attenuation of adaptation was more marked in the upper cortical layers in both field potential and multi-unit data. Indeed, in these layers, not only was adaptation attenuated but multi-unit response amplitudes under cocaine exceeded those under saline for stimuli occurring early in the train. The results extend our previous findings concerning the enhancement by cocaine of primary sensory responses. Insofar as enhanced neural responses equate to enhanced stimulus salience, the results indicate that cocaine may play a previously under-appreciated role in the formation of associations between drug and drug-related environmental cues by enhancing stimulus salience. The associative process itself may be assisted by a preferential action in the upper cortical layers, thought to be involved in learning and plasticity.

Enzymatic methylation of microsomal metabolites of benzo(a)pyrene.

These studies suggest that the microsomal metabolism of benzo(a)pyrene (BP) produces metabolites which can be methylated by the catechol-o-methyltransferase (COMT)/S-adenosylmethionine (SAM) enzyme/donor combination. Induced microsomes converted 12 to 15% of substrate BP to polar products. Approximately 0.06% of substrate BP was recovered as COMT/SAM-reactive substances. In tests for specificity, COMT/SAM was found to react with catechols, but not with dihydrodiols, quinones, a phenol, an epoxide, or 1,4-hydroquinone. Organic extracts of COMT/[14C]SAM incubations with BP were fractionated by high-performance liquid chromatography. The appearance of radiolabeled chromatographic bands required the presence of substrate BP, microsomes, and COMT/[14C]SAM. When the Ames mutagenesis assay was supplemented with COMT/SAM, a 36% reduction was observed in the number of revertant colonies induced by the microsomal oxidation of BP. In contrast, the mutagenic properties of 2-aminofluorene were not affected by COMT/SAM. These observations indicate that COMT/SAM does not generally inhibit mixed-function oxidase activity but rather reacts with substances which are activated by ring oxygenations.

Cocaine administration produces a protracted decoupling of neural and haemodynamic responses to intense sensory stimuli.

Evidence suggests that for relatively weak sensory stimuli, cocaine elevates background haemodynamic parameters but still allows enhanced neural responses to be reflected in enhanced haemodynamic responses. The current study investigated the possibility that for more intense stimuli, the raised background may produce a protracted attenuation of the haemodynamic response. Three experiments were performed to measure effects of i.v. cocaine administration (0.5 mg/kg) or saline on responses in rat barrel cortex to electrical stimulation of the whisker pad. The first experiment used optical imaging spectroscopy (OIS) and laser Doppler flowmetry (LDF) to measure haemodynamic changes. Cocaine caused an increase in baseline blood flow (peak approximately 90%), which lasted for the duration of the test period (25 min). Haemodynamic responses to whisker stimulation were substantially reduced throughout. The second experiment used a 16-channel multi-electrode to measure evoked potentials at 100 mum intervals through the barrel cortex. Summed neural responses (collapsed across the spatial dimension) after cocaine administration were similar to those after saline. The third experiment extended experiment 1 by examining the effects of cocaine on whisker sensory responses using functional magnetic resonance imaging (and concurrent OIS or LDF). Cocaine caused a similar increase in baseline and reduction in the evoked response to that seen in experiment 1. Together, the results of these three experiments show that cocaine produces a protracted decoupling of neural activity and haemodynamic responses to intense sensory stimulation, which suggests that imaging techniques based on changes in haemodynamic parameters may be unsuitable for studying the effects of cocaine on sensory processing in humans.

Astrocyte and microglial control of glutamatergic signalling: a primer on understanding the disruptive role of chronic stress.

It is now well established that chronic stress can induce significant structural remodelling of astrocytes and microglia. Until recently, however, the full significance of these morphological disturbances has remained unclear. Clues to the significance of astroglial re-organisation following stress are beginning to emerge from a compelling literature describing how astrocytes contribute to glutamatergic neurotransmission. The present review briefly summarises these two fields of research, identifies points of overlap and, in doing so, pin-points future research directions for stress neurobiology. Ultimately, understanding how chronic stress can disrupt the interactions of astrocytes and microglia with neurones has the potential in the future to improve the development of therapeutics designed to treat stress-related illnesses such as depression.

Pseudo-random procedures for rapid presentation rates using optical imaging and spectroscopy.

Optical imaging of rat barrel cortex has provided detailed spatio-temporal maps of functional cortical architecture. We describe an event-related procedure (ERP) for optical imaging based on selective signal averaging as reported by Burock et al., using an anti-correlative pseudo-random event sequence. The sequence used 1 s vibrissal stimulation at 5 Hz, with an interevent interval of 2 s. This rapid presentation rate allows for greater statistical power per unit time, and allows for direct comparison of event-related studies with other imaging modalities. The spatio-temporal characteristics of single wavelength and spectrographic results were found to be comparable with those obtained by standard techniques, although a general lessening of haemodynamic response function (HRF) was noted. We also describe a method of locating barrel activity by spectral analysis of summed event data. Using this technique, the power spectrum of remitted light from the barrel region was found to peak within +/- 0.12 Hz of the inter-event interval frequency.

Integration of neural responses originating from different regions of the cortical somatosensory map.

The neural pathways responsible for detecting peripheral tactile stimuli are well known; however, the interactions between different somatosensory regions have been less well investigated. This study demonstrates how the contralateral sensory response of rat barrel cortex to whisker stimulation is affected by stimulation of contralateral forepaw and ipsilateral whisker and forepaw. The barrel cortex in the right hemisphere was located using optical imaging. A 16-channel multielectrode was used to measure field potentials evoked by contralateral electrical stimulation of the whisker pad. A standard response in the right barrel cortex to single pulse electrical stimulation of the contralateral whisker pad was modulated by applying conditioning stimulation to one of three other regions of the body (the ipsilateral whisker pad, the ipsilateral or contralateral forepaws). In conditions where the standard contralateral whisker stimulus preceded the conditioning pulse, the size of response was identical to when it was stimulated alone. However, when the ipsilateral whisker and contralateral forepaw conditioning stimuli preceded the contralateral whisker pad stimulation, up to a 35% reduction in the contralateral whisker response was observed. These results confirm and extend previous studies [Proc. Natl. Acad. Sci. U. S. A. 97 (2000) 11026-11031; J. Neurosci. 21 (2001) 5251-5261], which show bilateral integration of neural activity within the rat somatosensory system. Furthermore, the longer latency of the inhibition following stimulation of the contralateral forepaw suggests the possible involvement of extracortical circuitry.

Stereopsis, vertical disparity and relief transformations.

The pattern of retinal binocular disparities acquired by a fixating visual system depends on both the depth structure of the scene and the viewing geometry. This paper treats the problem of interpreting the disparity pattern in terms of scene structure without relying on estimates of fixation position from eye movement control and proprioception mechanisms. We propose a sequential decomposition of this interpretation process into disparity correction, which is used to compute three-dimensional structure up to a relief transformation, and disparity normalization, which is used to resolve the relief ambiguity to obtain metric structure. We point out that the disparity normalization stage can often be omitted, since relief transformations preserve important properties such as depth ordering and coplanarity. Based on this framework we analyse three previously proposed computational models of disparity processing; the Mayhew and Longuet-Higgins model, the deformation model and the polar angle disparity model. We show how these models are related, and argue that none of them can account satisfactorily for available psychophysical data. We therefore propose an alternative model, regional disparity correction. Using this model we derive predictions for a number of experiments based on vertical disparity manipulations, and compare them to available experimental data. The paper is concluded with a summary and a discussion of the possible architectures and mechanisms underling stereopsis in the human visual system.

Interaction of stereo and texture cues in the perception of three-dimensional steps.

A computational method for calibrating stereo using shape-from-texture is described together with five experiments that tested whether the human visual system implements the method. The experiments all tested the prediction that the perceived size of a step between two planar and slanted real surfaces should be affected by texture slant cues projected on to them that are inconsistent with the disparity cues. The predicted effect was observed but the results could be accounted for by a new phenomenon revealed in control conditions: the perceived size of a step between two slanted planes is in part determined by the size of the slants even when texture and stereo cues are held consistent. We conclude that the hypothesis that human stereo is calibrated by texture is not confirmed.

Blind signal separation from optical imaging recordings with extended spatial decorrelation.

Optical imaging is the video recording of two-dimensional patterns of changes in light reflectance from cortical tissue evoked by stimulation. We derived a method, extended spatial decorrelation (ESD), that uses second-order statistics in space for separating the intrinsic signals into the stimulus related components and the nonspecific variations. The performance of ESD on model data is compared to independent component analysis algorithms using statistics of fourth and higher order. Robustness against sensor noise is scored. When applied to optical images, ESD separates the stimulus specific signal well from biological noise and artifacts.

Effect of root canal sealers and irrigation agents on retention of preformed posts luted with a resin cement.

This study examined the effect of three sealers and four irrigants on retention of Dentatus preformed posts luted with Panavia 21 resin cement. Gutta-percha with one of the following sealers--EWT, AH26, Nogenol, or no sealer (control)--was used to fill the root canals of 160 autoclaved incisor and premolar tooth roots. After 72 hr 8 mm post spaces were created with Dentatus Probos Pathfinders and Dentatus reamers. After irrigating the post spaces with saline, 5.25% NaOCl, 50% citric acid followed by NaOCl, or 40% H3PO4, followed by NaOCl, Panavia 21 TC cement was introduced into the canal on the Dentatus #4 stainless steel post's threads. An up-and-down and counterclockwise motion and then a forward twist seated the posts without engaging dentin. Mesiodistal and faciolingual radiographs visualized the chambers. After 72 hr posts were removed axially with an Instron at 5 mm/min. Surprisingly, using Nogenol sealer reduced post retention whereas EWT and AH26 increased retention compared with no sealer. Post retention improved after acid etchants, especially for AH26.

Stress analysis of human tooth root using various root canal instruments.

This study compared external root stresses from instrumentation by several motor-driven nickel-titanium instruments to stresses developed by hand files. Twelve curved first molar mesial roots were invested in PLM-9 photoelastic material to disclose net stress transmitted from the canal through the dentin. Minimal fringe patterns were observed during instrumentation with all techniques. Light-speed yielded the least change. In no case was a complete 60 psi fringe change noted.

Experience with vascular control before excision of giant, highly vascular sacrococcygeal teratomas in neonates.

Sacrococcygeal teratomas (SCT) are the most common neoplasms in newborns with a reported occurrence of 1 in 35,000 live births. Highly vascularized tumors in which the ratio of tumor weight to patient weight approaches 1:1 are frequently associated with hyperdynamic states, prenatal hydrops, placentamegaly, postnatal high-output cardiac failure, and carry a high perinatal mortality rate. Operative management of giant, highly-vascular sacrococcygeal teratomas in neonates can be complicated by life-threatening hemorrhage. Laparotomy, control of the aorta, and the arterial blood supply to these tumors before resection has been advocated as a safer alternative. The authors report their experience with three infants successfully treated using this approach. Hemodynamic stability was maintained during the operations. All tumors were resected successfully. The patients are alive without evidence of recurrence, 8.5 months to 18 months (average, 14.3 months) after the operation. Alpha-fetoprotein levels dropped to normal range after the removal of SCT and have remained normal in follow-up. Vascular control before excision of giant, highly-vascular SCT in neonates is safe, decreases intraoperative blood loss, and postoperative morbidity.

Effect of signal length on the performance of independent component analysis when extracting the lambda wave.

The aim of the study was to investigate the effect of signal length on the performance of a signal source separation method, independent component analysis (ICA), when extracting the visual evoked potential (EP) lambda wave from saccade-related electro-encephalogram (EEG) waveforms. A method was devised that enabled the effective length of the recorded EEG traces to be increased prior to processing by ICA. This involved abutting EEG traces from an appropriate number of successive trials (a trial was a set of waveforms recorded from 64 electrode locations in a study investigating saccade performance). ICA was applied to the saccade-related EEG and electro-oculogram (EOG) waveforms recorded from the electrode locations. One spatial and five temporal features of the lambda wave were monitored to assess the performance of ICA applied to both abutted and non-abutted waveforms. ICA applied to abutted trials managed to extract all six features across all seven subjects included in the study. This was not the case when ICA was applied to the non-abutted trials. It was quantitatively demonstrated that the process of abutting EEG waveforms was useful for ICA preprocessing when extracting lambda waves.

Comparison of three methods of assessing strength imbalances at the knee.

Three strength measurement methods for determining muscle imbalances at the knee were compared in 24 male athletes. Peak quadriceps extensions and hamstring flexions were measured isotonically, isometrically, and isokinetically. Isokinetic measurement was performed at 60, 180, and 300 degrees /sec. Repeated measures ANOVA revealed no significant difference among the three methods for bilateral imbalance ratio measurement. However, hamstring/quadricep ratios were significantly greater when measured isokinetically than when measured by the other methods. It was concluded that strength measurement methods may be used interchangeably when determining bilateral strength imbalance ratios at the knee but they may not be used interchangeably when assessing hamstring/quadricep ratios. Determinations of excess imbalance ratios (>10%) showed no consistent pattern across methods and may indicate problems associated with attempts to identify safety limits from muscle testing.J Orthop Sports Phys Ther 1988;10(4):134-137.