Freeform production of cartilage structures using aerosol methods

This project dealt with the construction of freeform structures embedded with cartilage cells. Cells were delivered in 18 wt% Pluronic? solution via a pressure atomizer onto a heated surface. The structure was constructed by adding subsequent layers after drying. Structures were analyzed for cell viability, total cell count and axial cell distribution using Trypan blue dye. We determined that 67.7% of total cells survived the process and that they were evenly distributed throughout the structure

Brain moderators supporting the relationship between depressive mood and pain.

Pain and depressive mood commonly exhibit a comorbid relationship. Yet, the brain mechanisms that moderate the relationship between dysphoric mood and pain remain unknown. An exploratory analysis of functional magnetic resonance imaging, behavioral, and psychophysical data was collected from a previous study in 76 healthy, nondepressed, and pain-free individuals. Participants completed the Beck Depression Inventory-II (BDI), a measure of negative mood/depressive symptomology, and provided pain intensity and pain unpleasantness ratings in response to noxious heat (49°C) during perfusion-based, arterial spin-labeled functional magnetic resonance imaging. Moderation analyses were conducted to determine neural mechanisms involved in facilitating the hypothesized relationship between depressive mood and pain sensitivity. Higher BDI-II scores were positively associated with pain intensity (R = 0.10; P = 0.006) and pain unpleasantness (R = 0.12; P = 0.003) ratings. There was a high correlation between pain intensity and unpleasantness ratings (r = 0.94; P < 0.001); thus, brain moderation analyses were focused on pain intensity ratings. Individuals with higher levels of depressive mood exhibited heightened sensitivity to experimental pain. Greater activation in regions supporting the evaluation of pain (ventrolateral prefrontal cortex; anterior insula) and sensory-discrimination (secondary somatosensory cortex; posterior insula) moderated the relationship between higher BDI-II scores and pain intensity ratings. This study demonstrates that executive-level and sensory-discriminative brain mechanisms play a multimodal role in facilitating the bidirectional relationship between negative mood and pain

Neural mechanisms supporting the relationship between dispositional mindfulness and pain

Inter-individual differences in pain sensitivity vary as a function of interactions between sensory, cognitive-affective and dispositional factors. Trait mindfulness, characterized as the innate capacity to non-reactively sustain attention to the present moment, is a psychological construct that is associated with lower clinical pain outcomes. Yet, the neural mechanisms supporting dispositional mindfulness are unknown. In an exploratory data analysis obtained during a study comparing mindfulness to placebo-analgesia, we sought to determine if dispositional mindfulness is associated with lower pain sensitivity. We also aimed to identify the brain mechanisms supporting the postulated inverse relationship between trait mindfulness and pain in response to noxious stimulation. We hypothesized that trait mindfulness would be associated with lower pain and greater deactivation of the default mode network. Seventy-six, meditation-naïve and healthy volunteers completed the Freiburg Mindfulness Inventory (FMI) and were administered innocuous (35°C) and noxious stimulation (49°C) during perfusion-based functional magnetic resonance imaging. Higher FMI ratings were associated with lower pain intensity (p =.005) and pain unpleasantness ratings (p =.005). Whole brain analyses revealed that higher dispositional mindfulness was associated with greater deactivation of a brain region extending from the precuneus to posterior cingulate cortex (PCC) during noxious heat. These novel findings demonstrate that mindful individuals feel less pain and evoke greater deactivation of brain regions supporting the engagement sensory, cognitive and affective appraisals. We propose that mindfulness and the PCC should be considered as important mechanistic targets for pain therapies

Mindfulness Meditation-Based Pain Relief Employs Different Neural Mechanisms Than Placebo and Sham Mindfulness Meditation-Induced Analgesia

Mindfulness meditation reduces pain in experimental and clinical settings. However, it remains unknown whether mindfulness meditation engages pain-relieving mechanisms other than those associated with the placebo effect (e.g., conditioning, psychosocial context, beliefs). To determine whether the analgesic mechanisms of mindfulness meditation are different from placebo, we randomly assigned 75 healthy, human volunteers to 4 d of the following: (1) mindfulness meditation, (2) placebo conditioning, (3) sham mindfulness meditation, or (4) book-listening control intervention. We assessed intervention efficacy using psychophysical evaluation of experimental pain and functional neuroimaging. Importantly, all cognitive manipulations (i.e., mindfulness meditation, placebo conditioning, sham mindfulness meditation) significantly attenuated pain intensity and unpleasantness ratings when compared to rest and the control condition (p < 0.05). Mindfulness meditation reduced pain intensity (p = 0.032) and pain unpleasantness (p < 0.001) ratings more than placebo analgesia. Mindfulness meditation also reduced pain intensity (p = 0.030) and pain unpleasantness (p = 0.043) ratings more than sham mindfulness meditation. Mindfulness-meditation-related pain relief was associated with greater activation in brain regions associated with the cognitive modulation of pain, including the orbitofrontal, subgenual anterior cingulate, and anterior insular cortex. In contrast, placebo analgesia was associated with activation of the dorsolateral prefrontal cortex and deactivation of sensory processing regions (secondary somatosensory cortex). Sham mindfulness meditation-induced analgesia was not correlated with significant neural activity, but rather by greater reductions in respiration rate. This study is the first to demonstrate that mindfulness-related pain relief is mechanistically distinct from placebo analgesia. The elucidation of this distinction confirms the existence of multiple, cognitively driven, supraspinal mechanisms for pain modulation. SIGNIFICANCE STATEMENT Recent findings have demonstrated that mindfulness meditation significantly reduces pain. Given that the “gold standard” for evaluating the efficacy of behavioral interventions is based on appropriate placebo comparisons, it is imperative that we establish whether there is an effect supporting meditation-related pain relief above and beyond the effects of placebo. Here, we provide novel evidence demonstrating that mindfulness meditation produces greater pain relief and employs distinct neural mechanisms than placebo cream and sham mindfulness meditation. Specifically, mindfulness meditation-induced pain relief activated higher-order brain regions, including the orbitofrontal and cingulate cortices. In contrast, placebo analgesia was associated with decreased pain-related brain activation. These findings demonstrate that mindfulness meditation reduces pain through unique mechanisms and may foster greater acceptance of meditation as an adjunct pain therapy

Voxel-based morphometry and arterial spin labeling fMRI reveal neuropathic and neuroplastic features of brain processing of itch in end-stage renal disease

Pruritus of end-stage renal disease (ESRD) is a multifactorial symptom of complex etiology not yet fully understood. In this study we have investigated the cerebral perfusion patterns at rest in ESRD patients on hemodialysis, compared with those in healthy volunteers. We have also studied the brain responses evoked by experimental itch induction in ESRD, after stimulating the two distinct histamine and cowhage itch pathways, and compared them with the responses evoked in healthy volunteers. To identify potential structural alterations in ESRD patients compared with a group of age-matched healthy volunteers, we calculated the density of gray matter for the entire brain using a voxel-based morphometric analysis. Our results indicated that gray matter density was significantly reduced in ESRD patients in the frontal, parietal, temporal, and occipital cortices, as well as in the S1, precuneus, and insula, whereas the brain stem, hippocampus, amygdala, midcingulate cortex, and nucleus accumbens displayed an increased gray matter density. Functionally, we found a significantly higher brain perfusion at baseline associated with ESRD pruritus in the anterior cingulate, insula, claustrum, hippocampus, and nucleus accumbens. The brain responses evoked by cowhage itch, which are mediated by protease-activated receptors (PAR2), displayed significant differences compared with responses in healthy individuals and were correlated with perceived itch intensity in a dual, complex manner. The inverse correlations in particular suggested that a negative feedback mechanism modulated itch intensity, when elicited in a preexistent chronic itch background

Relationships between Psychological Factors and Experimental Pain Outcomes in Healthy Individuals: Results from 8 Studies

Psychological factors, such as anxiety, depression, and pain catastrophizing, may affect how healthy individuals experience experimental pain. However, current literature puts forth contradictory results, possibly due to differing study methodologies, such as the type of psychophysical measure or survey. To better understand such results, this paper analyzed the relationships between psychological factors and experimental pain outcomes across eight different studies (total n= 595) conducted in different populations of healthy adult and adolescent participants. Analyses were conducted with and without controlling for sex, age, and race. Each study was analyzed separately and as part of an aggregate analysis. Even without correction for multiple comparisons, only a few significant relationships were found for the individual studies. Controlling for demographic factors had minimal effect on the results. Importantly, even the few statistically significant models showed relatively small effect sizes; psychological factors explained no more than 20% of the variability in experimental pain sensitivity of healthy individuals. The aggregate analyses revealed relationships between anxiety and PPT / cold pain ratings and between pain catastrophizing and PPT. Sample size calculations based on the aggregate analyses indicated that several hundred participants would be required to correctly detect relationships between these psychological factors and pain measures. These overall negative findings suggest that anxiety, depression, and pain catastrophizing in healthy individuals may not be meaningfully related to experimental pain outcomes. Furthermore, positive findings in the literature may be subject to small group effects and publication bias towards positive findings

Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease

BACKGROUND: Atherosclerotic peripheral artery disease (PAD) affects 8–12% of Americans over 65 and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE is an NHLBI-sponsored, randomized, double-blind, placebo-controlled phase 2, exploratory clinical trial designed to assess safety and efficacy of autologous bone marrow–derived aldehyde dehydrogenase bright (ALDHbr) cells in PAD patients and to explore associated claudication physiologic mechanisms. METHODS: All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by ten injections into the thigh and calf of the index leg. The co-primary endpoints were: change from baseline to six months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging (MRI); as well as safety. RESULTS: A total of 82 patients with claudication and infra-inguinal PAD were randomized at nine sites, of which 78 had analyzable data (57 male, 21 female; mean age 66±9 years). The mean differences in the change over six months between study groups for PWT (mean ± standard error of the mean [SEM]) (0.9±0.8 minutes; 95% CI −0.6 to 2.5; p=0.238), collateral count (0.9±0.6 arteries; 95% CI −0.2 to 2.1; p=0.116), peak hyperemic popliteal flow (0.0±0.4 mL/sec; 95% CI −0.8 to 0.8; p=0.978), and capillary perfusion (−0.2±0.6%; 95% CI −1.3 to 0.9; p=0.752) were not significant. Additionally, there were no significant differences for the secondary endpoints, including quality of life measures. There were no adverse safety outcomes. Correlative relationships between MRI measures and PWT were not significant. A post-hoc exploratory analysis suggested that ALDHbr cell administration might be associated with an increase in the number of collateral arteries (1.5±0.7; 95% CI 0.1 to 2.9; p=0.047) in participants with completely occluded femoral arteries. CONCLUSIONS: ALDHbr cell administration did not improve PWT or MR outcomes, and the changes in PWT were not associated with the anatomic or physiologic MRI endpoints. Future PAD cell therapy investigational trial design may be informed by new anatomic and perfusion insights

\u3ci\u3eDrosophila\u3c/i\u3e Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu