The detection and sensory perception of inspiratory resistive loads in people with chronic tetraplegia

This study investigated sensations of breathing following tetraplegia. Fifteen people with chronic tetraplegia and fifteen healthy able-bodied controls matched for age, sex, height, and weight participated. Sensations of breathing were quantified by determining the threshold for detecting an added resistance during inspiration. In a separate task, the perceived magnitudes of six suprathreshold resistive loads were determined with a modified Borg scale. The detection threshold of 0.34 cmH2O/L/s [standard deviation (SD) 0.14] in the tetraplegia group was higher than the 0.23 cmH2O/L/s (SD 0.10) threshold for able-bodied controls (P = 0.004). Both participant groups perceived larger loads to be more effortful, with the Borg effort rating increasing linearly with the peak inspiratory pressure generated at each load. The relationship between Borg effort rating and peak inspiratory pressure was steeper in participants with tetraplegia than in able-bodied controls (P = 0.001), but there was no difference when pressure was divided by maximal inspiratory pressure (P = 0.95). Despite a higher detection threshold, the findings suggest that the perceived magnitude of a suprathreshold inspiratory load is not impaired in chronic tetraplegia and that load magnitude perception is related to the maximal, and not absolute, inspiratory muscle force. NEW & NOTEWORTHY Sensations of breathing are thought to be impaired following chronic tetraplegia. The detection threshold for an added resistive load during inspiration was higher in people with tetraplegia than in healthy able-bodied participants. However, for inspiratory loads above the detection threshold, the perceived magnitude of a resistive load as a function of the peak inspiratory pressure was greater in tetraplegia. Load magnitude perception was comparable between participant groups when peak pressure was divided by maximal inspiratory pressure

Supraspinal fatigue in human inspiratory muscles with repeated sustained maximal efforts

To investigate the involvement of supraspinal fatigue in the loss of maximal inspiratory pressure (PImax), we fatigued the inspiratory muscles. Six participants performed 5 sustained maximal isometric inspiratory efforts (15-s contractions, duty cycle ~75%) which reduced PImax, as measured from esophageal and mouth pressure, to around half of their initial maximums. Transcranial magnetic stimulation (TMS) delivered over the motor cortex near the beginning and end of each maximal effort evoked superimposed twitch-like increments in the ongoing PImax, increasing from ~1.0% of PImax in the unfatigued contractions to ≥40% of ongoing PImax for esophageal and mouth pressures. The rate of increase in the superimposed twitch as PImax decreased with fatigue was not significantly different between the esophageal and mouth pressure measures. The inverse relationship between superimposed twitch pressure and PImax indicates a progressive decline in the ability of motor cortical output to drive the inspiratory muscles maximally, leading to the development of supraspinal fatigue. TMS also evoked silent periods in the electromyographic recordings of diaphragm, scalenes, and parasternal intercostal. The duration of the silent period increased with fatigue in all three muscles, which suggests greater intracortical inhibition, with the largest change observed in the diaphragm. The peak rate of relaxation in pressure during the silent period slowed as fatigue developed, indicating peripheral contractile changes in the active inspiratory muscles. These changes in the markers of fatigue show that both central and peripheral fatigue contribute to the loss in PImax when inspiratory muscles are fatigued with repeated sustained maximal efforts. NEW & NOTEWORTHY When the inspiratory muscles are fatigued with repeated sustained maximal efforts, supraspinal fatigue, a component of central fatigue, contributes to the loss in maximal inspiratory pressure. The presence of supraspinal fatigue was confirmed by the increase in amplitude of twitch-like increments in pressure evoked by motor cortical stimulation during maximal efforts, indicating that motor cortical output was not maximal as extra muscle force could be generated to increase inspiratory pressure

Tongue acceleration in humans evoked with intramuscular electrical stimulation of genioglossus

Genioglossus was stimulated intramuscularly to determine the effect of regional activation of the muscle on tongue movement in eight healthy adults. Stimulation at motor threshold was delivered with a needle electrode inserted to different depths in the anterior and posterior regions of genioglossus. The current amplitude that induced muscle contraction was ∼80% higher for anterior than posterior sites. Evoked tongue movements were determined from stimulus-triggered averages (150 pulses) of the outputs from an accelerometer fixed to the posterosuperior surface of the tongue. The median amplitude [95% confidence intervals] for the resultant acceleration was 0.0 m/s2 [0.0, 0.2] for anterior and 0.6 m/s2 [0.1, 2.8] for posterior sites. There was a positive relationship between acceleration amplitude and stimulation depth in the posterior of genioglossus (p < 0.001), but acceleration amplitude did not vary with stimulation depth in the anterior region (p = 0.83). This heterogeneity in acceleration responses between muscle regions may contribute to differences in collapsibility of the upper airway

Short-term outcomes of pubertal suppression in a selected cohort of 12 to 15 year old young people with persistent gender dysphoria in the UK

BACKGROUND: In adolescents with severe and persistent gender dysphoria (GD), gonadotropin releasing hormone analogues (GnRHa) are used from early/middle puberty with the aim of delaying irreversible and unwanted pubertal body changes. Evidence of outcomes of pubertal suppression in GD is limited. METHODS: We undertook an uncontrolled prospective observational study of GnRHa as monotherapy in 44 12-15 year olds with persistent and severe GD. Prespecified analyses were limited to key outcomes: bone mineral content (BMC) and bone mineral density (BMD); Child Behaviour CheckList (CBCL) total t-score; Youth Self-Report (YSR) total t-score; CBCL and YSR self-harm indices; at 12, 24 and 36 months. Semistructured interviews were conducted on GnRHa. RESULTS: 44 patients had data at 12 months follow-up, 24 at 24 months and 14 at 36 months. All had normal karyotype and endocrinology consistent with birth-registered sex. All achieved suppression of gonadotropins by 6 months. At the end of the study one ceased GnRHa and 43 (98%) elected to start cross-sex hormones. There was no change from baseline in spine BMD at 12 months nor in hip BMD at 24 and 36 months, but at 24 months lumbar spine BMC and BMD were higher than at baseline (BMC +6.0 (95% CI: 4.0, 7.9); BMD +0.05 (0.03, 0.07)). There were no changes from baseline to 12 or 24 months in CBCL or YSR total t-scores or for CBCL or YSR self-harm indices, nor for CBCL total t-score or self-harm index at 36 months. Most participants reported positive or a mixture of positive and negative life changes on GnRHa. Anticipated adverse events were common. CONCLUSIONS: Overall patient experience of changes on GnRHa treatment was positive. We identified no changes in psychological function. Changes in BMD were consistent with suppression of growth. Larger and longer-term prospective studies using a range of designs are needed to more fully quantify the benefits and harms of pubertal suppression in GD

Turing instabilities in a mathematical model for signaling networks

GTPase molecules are important regulators in cells that continuously run through an activation/deactivation and membrane-attachment/membrane-detachment cycle. Activated GTPase is able to localize in parts of the membranes and to induce cell polarity. As feedback loops contribute to the GTPase cycle and as the coupling between membrane-bound and cytoplasmic processes introduces different diffusion coefficients a Turing mechanism is a natural candidate for this symmetry breaking. We formulate a mathematical model that couples a reaction-diffusion system in the inner volume to a reaction-diffusion system on the membrane via a flux condition and an attachment/detachment law at the membrane. We present a reduction to a simpler non-local reaction-diffusion model and perform a stability analysis and numerical simulations for this reduction. Our model in principle does support Turing instabilities but only if the lateral diffusion of inactivated GTPase is much faster than the diffusion of activated GTPase.Comment: 23 pages, 5 figures; The final publication is available at http://www.springerlink.com http://dx.doi.org/10.1007/s00285-011-0495-

Expansion of Human Airway Basal Stem Cells and Their Differentiation as 3D Tracheospheres

Although basal cells function as human airway epithelial stem cells, analysis of these cells is limited by in vitro culture techniques that permit only minimal cell growth and differentiation. Here, we report a protocol that dramatically increases the long-term expansion of primary human airway basal cells while maintaining their genomic stability using 3T3-J2 fibroblast coculture and ROCK inhibition. We also describe techniques for the differentiation and imaging of these expanded airway stem cells as three-dimensional tracheospheres containing basal, ciliated, and mucosecretory cells. These procedures allow investigation of the airway epithelium under more physiologically relevant conditions than those found in undifferentiated monolayer cultures. Together these methods represent a novel platform for improved airway stem cell growth and differentiation that is compatible with high-throughput, high-content translational lung research as well as human airway tissue engineering and clinical cellular therapy

Dopamine receptor D4 (DRD4) polymorphisms with reduced functional potency intensify atrophy in syndrome-specific sites of frontotemporal dementia.

ObjectiveWe aimed to understand the impact of dopamine receptor D4 (DRD4) polymorphisms on neurodegeneration in patients with dementia. We hypothesized that DRD4dampened-variants with reduced functional potency would be associated with greater atrophy in regions with higher receptor density. Given that DRD4 is concentrated in anterior regions of the limbic and cortical forebrain we anticipated genotype effects in patients with a more rostral pattern of neurodegeneration.Methods337 subjects, including healthy controls, patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) underwent genotyping, structural MRI, and cognitive/behavioral testing. We conducted whole-brain voxel-based morphometry to examine the relationship between DRD4 genotypes and brain atrophy patterns within and across groups. General linear modeling was used to evaluate relationships between genotype and cognitive/behavioral measures.ResultsDRD4 dampened-variants predicted gray matter atrophy in disease-specific regions of FTD in anterior cingulate, ventromedial prefrontal, orbitofrontal and insular cortices on the right greater than the left. Genotype predicted greater apathy and repetitive motor disturbance in patients with FTD. These results covaried with frontoinsular cortical atrophy. Peak atrophy patterned along regions of neuroanatomic vulnerability in FTD-spectrum disorders. In AD subjects and controls, genotype did not impact gray matter intensity.ConclusionsWe conclude that DRD4 polymorphisms with reduced functional potency exacerbate neuronal injury in sites of higher receptor density, which intersect with syndrome-specific regions undergoing neurodegeneration in FTD

Autocrine IGF-1 Action in Adipocytes Controls Systemic IGF-1 Concentrations and Growth

OBJECTIVE—IGF-1 and the IGF-1 receptor (IGF-1R) have been implicated in the regulation of adipocyte differentiation and lipid accumulation in vitro