Behaviour of simple thymic cysts over time; is surveillance required?

AIM: Anterior mediastinal lesions can be a source of uncertainty on imaging, and thymic cysts present a unique diagnostic challenge. Differentiation of non-simple fluid-containing benign simple thymic cysts from small thymic neoplasms is challenging with computed tomography (CT) alone. Additionally, the malignant potential of simple thymic cysts is unclear and guidelines for imaging surveillance are not established. MATERIALS AND METHODS: All imaging studies containing the phrase "thymic cyst" were identified at our institution between October 2012 and October 2022. Studies were excluded if the main radiological diagnosis was anything other than a thymic cyst. This yielded 107 individual patient records, of which 11 did not meet inclusion criteria, leaving 96 unique patients. RESULTS: While most cysts evaluated remained stable throughout the period of surveillance (53%; n=51), some increased in size (13%), some decreased in size (6%), and some fluctuated (5%). Some cysts changed in internal attenuation/signal characteristics in keeping with interval haemorrhage (6%). 34% of cysts (n=31) demonstrate internal average attenuation values of more than 20HU. Of the entire cohort of patients studied over 10 years, none developed malignancy within the period of surveillance. CONCLUSION: Unilocular thymic cysts are most often discovered incidentally but their imaging characteristics can be difficult to interpret on CT, as they are commonly hyperdense and may change in size and internal content. Once simple thymic cysts are adequately characterised with magnetic resonance imaging (MRI) then extended radiological surveillance may not be required.

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.

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.

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.

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.

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.

Pentoxifylline as a rescue treatment for DMD: a randomized double-blind clinical trial.

OBJECTIVE: To determine whether pentoxifylline (PTX) slows the decline of muscle strength and function in ambulatory boys with Duchenne muscular dystrophy (DMD). METHODS: This was a multicenter, randomized, double-blinded, controlled trial comparing 12 months of daily treatment with PTX or placebo in corticosteroid-treated boys with DMD using a slow-release PTX formulation (~20 mg/kg/day). The primary outcome was the change in mean total quantitative muscle testing (QMT) score. Secondary outcomes included changes in QMT subscales, manual muscle strength, pulmonary function, and timed function tests. Outcomes were compared using Student t tests and a linear mixed-effects model. Adverse events (AEs) were compared using the Fisher exact test. RESULTS: A total of 64 boys with DMD with a mean age of 9.9 ± 2.9 years were randomly assigned to PTX or placebo in 11 participating Cooperative International Neuromuscular Research Group centers. There was no significant difference between PTX and the placebo group in total QMT scores (p = 0.14) or in most of the secondary outcomes after a 12-month treatment. The use of PTX was associated with mild to moderate gastrointestinal or hematologic AEs. CONCLUSION: The addition of PTX to corticosteroid-treated boys with DMD at a moderate to late ambulatory stage of disease did not improve or halt the deterioration of muscle strength and function over a 12-month study period. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that treatment with PTX does not prevent deterioration in muscle function or strength in corticosteroid-treated boys with DMD.

Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy.

OBJECTIVE: To perform a double-blind, randomized study comparing efficacy and safety of daily and weekend prednisone in boys with Duchenne muscular dystrophy (DMD). METHODS: A total of 64 boys with DMD who were between 4 and 10 years of age were randomized at 1 of 12 centers of the Cooperative International Neuromuscular Research Group. Efficacy and safety of 2 prednisone schedules (daily 0.75 mg/kg/day and weekend 10 mg/kg/wk) were evaluated over 12 months. RESULTS: Equivalence was met for weekend and daily dosing of prednisone for the primary outcomes of quantitative muscle testing (QMT) arm score and QMT leg score. Secondary strength scores for QMT elbow flexors also showed equivalence between the 2 treatment groups. Overall side effect profiles of height and weight, bone density, cataract formation, blood pressure, and behavior, analyzed at 12 months, did not differ between weekend and daily dosing of prednisone. CONCLUSIONS: Weekend dosing of prednisone is equally beneficial to the standard daily dosing of prednisone. Analysis of side effect profiles demonstrated overall tolerability of both dosing regimens. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that weekend prednisone dosing is as safe and effective as daily prednisone in preserving muscle strength and preventing body mass index increases in boys with DMD over a 12-month period.

Model estimation of cerebral hemodynamics between blood flow and volume changes: a data-based modeling approach.

It is well known that there is a dynamic relationship between cerebral blood flow (CBF) and cerebral blood volume (CBV). With increasing applications of functional MRI, where the blood oxygen-level-dependent signals are recorded, the understanding and accurate modeling of the hemodynamic relationship between CBF and CBV becomes increasingly important. This study presents an empirical and data-based modeling framework for model identification from CBF and CBV experimental data. It is shown that the relationship between the changes in CBF and CBV can be described using a parsimonious autoregressive with exogenous input model structure. It is observed that neither the ordinary least-squares (LS) method nor the classical total least-squares (TLS) method can produce accurate estimates from the original noisy CBF and CBV data. A regularized total least-squares (RTLS) method is thus introduced and extended to solve such an error-in-the-variables problem. Quantitative results show that the RTLS method works very well on the noisy CBF and CBV data. Finally, a combination of RTLS with a filtering method can lead to a parsimonious but very effective model that can characterize the relationship between the changes in CBF and CBV.

Fine detail of neurovascular coupling revealed by spatiotemporal analysis of the hemodynamic response to single whisker stimulation in rat barrel cortex.

The spatial resolution of hemodynamic-based neuroimaging techniques, including functional magnetic resonance imaging, is limited by the degree to which neurons regulate their blood supply on a fine scale. Here we investigated the spatial detail of neurovascular events with a combination of high spatiotemporal resolution two-dimensional spectroscopic optical imaging, multichannel electrode recordings and cytochrome oxidase histology in the rodent whisker barrel field. After mechanical stimulation of a single whisker, we found two spatially distinct cortical hemodynamic responses: a transient response in the "upstream" branches of surface arteries and a later highly localized increase in blood volume centered on the activated cortical column. Although the spatial representation of this localized response exceeded that of a single "barrel," the spread of hemodynamic activity accurately reflected the neural response in neighboring columns rather than being due to a passive "overspill." These data confirm hemodynamics are capable of providing accurate "single-condition" maps of neural activity.

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.

Neurovascular coupling investigated with two-dimensional optical imaging spectroscopy in rat whisker barrel cortex.

Optical imaging slit spectroscopy is a powerful method for estimating quantitative changes in cerebral haemodynamics, such as deoxyhaemoglobin, oxyhaemoglobin and blood volume (Hbr, HbO2 and Hbt, respectively). Its disadvantage is that there is a large loss of spatial data as one image dimension is used to encode spectral wavelength information. Single wavelength optical imaging, on the other hand, produces high-resolution spatiotemporal maps of brain activity, but yields only indirect measures of Hbr, HbO2 and Hbt. In this study we perform two-dimensional optical imaging spectroscopy (2D-OIS) in rat barrel cortex during contralateral whisker stimulation to obtain two-dimensional maps over time of Hbr, HbO2 and Hbt. The 2D-OIS was performed by illuminating the cortex with four wavelengths of light (575, 559, 495 and 587 nm), which were presented sequentially at a high frame rate (32 Hz). The contralateral whisker pad was stimulated using two different durations: 1 and 16 s (5 Hz, 1.2 mA). Control experiments used a hypercapnic (5% CO2) challenge to manipulate baseline blood flow and volume in the absence of corresponding neural activation. The 2D-OIS method allowed separation of artery, vein and parenchyma regions. The magnitude of the haemodynamic response elicited varied considerably between different vascular compartments; the largest responses in Hbt were in the arteries and the smallest in the veins. Phase lags in the HbO2 response between arteries and veins suggest that a process of upstream signalling maybe responsible for dilating the arteries. There was also a consistent increase in Hbr from arterial regions after whisker stimulation.

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.

Retinotopy within rat primary visual cortex using optical imaging.

The purpose of this study was to determine the retinotopic organization of rat primary visual cortex (area 17) using optical imaging technology. Stimulating discrete regions of visual space resulted in localised changes in the remitted light during optical imaging of visual cortex in rat. From these localised changes, our results confirm previous electrophysiological studies on the location, size and organization of rat primary visual cortex. Small differences in the cortical magnification factor (CMF) were found between visual field areas with the highest CMF confined to the upper nasal region. No significant CMF differences were found within the horizontal and vertical visual field axes. No secondary visual areas were activated either anterior or medial to area 17 with the pattern stimuli used in the current study. However, there was evidence of activity to upper nasal stimulation on the posterior lateral extrastriate area. The location of area 17 from optical imaging activity was confirmed anatomically using conventional immunohistochemical techniques. This study shows the retinotopic organization of rat primary visual cortex and serves as a precursor before examining animal models of retinal degeneration and the effectiveness of potential therapies to stem retinal disease.

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.

Haemodynamic responses to sensory stimulation are enhanced following acute cocaine administration.

Cocaine enhances neural activity in response to sensory stimulation, an effect that may play a role in the development of drug craving. However, cocaine-induced sensory enhancement may be difficult to study in humans using neuroimaging if the global increases in baseline haemodynamic parameters, which cocaine produces, interfere with the ability of enhanced sensory-related neural activity to lead to enhanced haemodynamic responses. To investigate the effect of cocaine-induced baseline haemodynamic changes on sensory-related haemodynamic (and electrophysiological) responses, field potential (FP) and haemodynamic responses (obtained using optical imaging spectroscopy and laser-Doppler flowmetry) in the barrel cortex of the anaesthetised rat were measured during mechanical whisker stimulation following cocaine (0.5 mg/kg) or saline administration. During cocaine infusion, the relationship between blood flow and volume transiently decoupled. Following this, cocaine caused large baseline increases in blood flow (133%) and volume (33%), which peaked after approximately 6 min and approached normal levels again after 25 min. During the peak baseline increases, FP responses to whisker stimulation were similar to saline whereas several haemodynamic response parameters were slightly reduced. After the peak, significant increases in FP responses were observed, accompanied by significantly enhanced haemodynamic responses, even though the haemodynamic baselines remained elevated. Hence, the haemodynamic response to sensory stimulation is transiently reduced in the presence of large increases in baseline but, after the baseline peak, enhanced neural responses are faithfully accompanied by enhanced haemodynamic responses. The findings suggest that any cocaine-induced enhancement of sensory-related neural activity in humans is likely to be detectable by neuroimaging.

Validation of the NFL-225 test for predicting 1-RM bench press performance in college football players.

BACKGROUND: The purpose of this study was to evaluate the accuracy of repetitions-to-fatigue (RTF) using an absolute load of 102.3 kg (225 lbs) to estimate one-repetition maximum (1-RM) bench press performance in college football players using various prediction equations. EXPERIMENTAL DESIGN: a prospective study on the association between muscular endurance and muscular strength. PARTICIPANTS: 260 players from NCAA Division IA (n=43), IAA (n=63), II (n=129), and red-shirts (n=25) were evaluated at the conclusion of a minimum of eight weeks of heavy-resistance training during the off-season. MEASURES: all subjects performed a 1-RM bench press and RTF using an absolute load of 102.3 kg. RESULTS: The Mayhew et al. NFL-225 equation nonsignificantly overestimated 1-RM from RTF by 0.5 kg, while the Chapman et al. NFL-225 equation significantly underpredicted by 3.2 kg, although both equations were comparable in the number of players predicted within +/-4.5 kg of actual 1-RM (52% vs 51%, respectively). Only two of nine RTF equations currently in use produced predicted 1-RM values that were not significantly different from actual 1-RM performance. CONCLUSIONS: Specific NFL-225 equations are more accurate in estimating 1-RM bench press from absolute muscle endurance in college football players than previous published RTF equations. The accuracy of prediction decreases at higher repetitions.