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INTRODUCTION - Recent studies on comatose survivors of cardiac arrest undergoing targeted temperature management (TTM) have shown similar outcomes at multiple target temperatures. However, details regarding core temperature variability during TTM and its prognostic implications remain largely unknown. We sought to assess the association between core temperature variability and neurological outcomes in patients undergoing TTM following cardiac arrest.
METHODS - We analyzed a prospectively collected cohort of 242 patients treated with TTM following cardiac arrest at a tertiary care hospital between 2007 and 2014. Core temperature variability was defined as the statistical variance (i.e. standard deviation squared) amongst all core temperature recordings during the maintenance phase of TTM. Poor neurological outcome at hospital discharge, defined as a Cerebral Performance Category (CPC) score>2, was the primary outcome. Death prior to hospital discharge was assessed as the secondary outcome. Multivariable logistic regression was used to examine the association between temperature variability and neurological outcome or death at hospital discharge.
RESULTS - A poor neurological outcome was observed in 147 (61%) patients and 136 (56%) patients died prior to hospital discharge. In multivariable logistic regression, increased core temperature variability was not associated with increased odds of poor neurological outcomes (OR 0.38, 95% CI 0.11-1.38, p=0.142) or death (OR 0.43, 95% CI 0.12-1.53, p=0.193) at hospital discharge.
CONCLUSION - In this study, individual core temperature variability during TTM was not associated with poor neurological outcomes or death at hospital discharge.
Copyright © 2017 Elsevier Inc. All rights reserved.
Sensing and responding to environmental cues is critical to the lifestyle of filamentous fungi. How environmental variation influences fungi to produce a wide diversity of ecologically important secondary metabolites (SMs) is not well understood. To address this question, we first examined changes in global gene expression of the opportunistic human pathogen, Aspergillus fumigatus, after exposure to different temperature conditions. We found that 11 of the 37 SM gene clusters in A. fumigatus were expressed at higher levels at 30° than at 37°. We next investigated the role of the light-responsive Velvet complex in environment-dependent gene expression by examining temperature-dependent transcription profiles in the absence of two key members of the Velvet protein complex, VeA and LaeA We found that the 11 temperature-regulated SM gene clusters required VeA at 37° and LaeA at both 30 and 37° for wild-type levels of expression. Interestingly, four SM gene clusters were regulated by VeA at 37° but not at 30°, and two additional ones were regulated by VeA at both temperatures but were substantially less so at 30°, indicating that the role of VeA and, more generally of the Velvet complex, in the regulation of certain SM gene clusters is temperature-dependent. Our findings support the hypothesis that fungal secondary metabolism is regulated by an intertwined network of transcriptional regulators responsive to multiple environmental factors.
Copyright © 2016 Lind et al.
INTRODUCTION - This study sought to provide a preliminary assessment of whether spinally mediated afferent hyperactivity (i.e., central sensitization) might contribute to manifestations of overactive bladder syndrome (OAB) in women as indexed by elevated temporal summation of evoked heat pain stimuli.
METHODS - We recruited 20 adult women with OAB who were planning to undergo interventional therapy for OAB with either onabotulinumtoxinA injection or sacral neuromodulation and 23 healthy controls without OAB symptoms to undergo quantitative sensory testing with cutaneous thermal pain temporal summation. The primary study outcome was the degree of temporal summation, as reflected in the magnitude of positive slope of the line fitted to the series of 10 stimuli at the 49°C target temperatures. Linear regression and analysis of covariance were utilized to compare the degree of temporal summation between study groups.
RESULTS - The standardized slope of temporal summation trials for women with OAB was significantly higher than for controls (β = 3.43, 95% confidence interval = 0.6-6.2, P = 0.017). The adjusted means ±SE of the standardized temporal summation slopes for the full OAB and control groups were 3.0 ± 0.5 (95% confidence interval = 2.0, 4.1) and 1.7 ± 0.5 (95% confidence interval = 0.7, 2.7), respectively.
CONCLUSION - In this preliminary study, we demonstrated that women with OAB refractory to primary and secondary therapies exhibited greater thermal cutaneous temporal summation than women without OAB symptoms. This suggests that central sensitization, indexed by temporal summation, may be an underlying factor contributing to OAB in some women. Neurourol. Urodynam. 36:1108-1112, 2017. © 2016 Wiley Periodicals, Inc.
© 2016 Wiley Periodicals, Inc.
Activated brown adipose tissue (BAT) plays an important role in thermogenesis and whole body metabolism in mammals. Positron emission tomography (PET)-computed tomography (CT) imaging has identified depots of BAT in adult humans, igniting scientific interest. The purpose of this study is to characterize both active and inactive supraclavicular BAT in adults and compare the values to those of subcutaneous white adipose tissue (WAT). We obtained [(18)F]fluorodeoxyglucose ([(18)F]FDG) PET-CT and magnetic resonance imaging (MRI) scans of 25 healthy adults. Unlike [(18)F]FDG PET, which can detect only active BAT, MRI is capable of detecting both active and inactive BAT. The MRI-derived fat signal fraction (FSF) of active BAT was significantly lower than that of inactive BAT (means ± SD; 60.2 ± 7.6 vs. 62.4 ± 6.8%, respectively). This change in tissue morphology was also reflected as a significant increase in Hounsfield units (HU; -69.4 ± 11.5 vs. -74.5 ± 9.7 HU, respectively). Additionally, the CT HU, MRI FSF, and MRI R2* values are significantly different between BAT and WAT, regardless of the activation status of BAT. To the best of our knowledge, this is the first study to quantify PET-CT and MRI FSF measurements and utilize a semiautomated algorithm to identify inactive and active BAT in the same adult subjects. Our findings support the use of these metrics to characterize and distinguish between BAT and WAT and lay the foundation for future MRI analysis with the hope that some day MRI-based delineation of BAT can stand on its own.
BACKGROUND - Compared to healthy controls, people with Alzheimer's disease (AD) have been shown to receive less pain medication and report pain less frequently. It is unknown if these findings reflect less perceived pain in AD, an inability to recognize pain, or an inability to communicate pain.
METHODS - To further examine aspects of pain processing in AD, we conducted a cross-sectional study of sex-matched adults ≥65 years old with and without AD (AD: n = 40, female = 20, median age = 75; control: n = 40, female = 20, median age = 70) to compare the psychophysical response to contact-evoked perceptual heat thresholds of warmth, mild pain, and moderate pain, and self-reported unpleasantness for each percept.
RESULTS - When compared to controls, participants with AD required higher temperatures to report sensing warmth (Cohen's d = 0.64, p = 0.002), mild pain (Cohen's d = 0.51, p = 0.016), and moderate pain (Cohen's d = 0.45, p = 0.043). Conversely, there were no significant between-group differences in unpleasantness ratings (p > 0.05).
CONCLUSIONS - The between-group findings demonstrate that when compared to controls, people with AD are less sensitive to the detection of thermal pain but do not differ in affective response to the unpleasant aspects of thermal pain. These findings suggest that people with AD may experience greater levels of pain and potentially greater levels of tissue or organ damage prior to identifying and reporting injury. This finding may help to explain the decreased frequency of pain reports and consequently a lower administration of analgesics in AD.
IL-15 is currently undergoing clinical trials to assess its efficacy for treatment of advanced cancers. The combination of IL-15 with soluble IL-15Rα generates a complex termed IL-15 superagonist (IL-15 SA) that possesses greater biological activity than IL-15 alone. IL-15 SA is considered an attractive antitumor and antiviral agent because of its ability to selectively expand NK and memory CD8(+) T (mCD8(+) T) lymphocytes. However, the adverse consequences of IL-15 SA treatment have not been defined. In this study, the effect of IL-15 SA on physiologic and immunologic functions of mice was evaluated. IL-15 SA caused dose- and time-dependent hypothermia, weight loss, liver injury, and mortality. NK (especially the proinflammatory NK subset), NKT, and mCD8(+) T cells were preferentially expanded in spleen and liver upon IL-15 SA treatment. IL-15 SA caused NK cell activation as indicated by increased CD69 expression and IFN-γ, perforin, and granzyme B production, whereas NKT and mCD8(+) T cells showed minimal, if any, activation. Cell depletion and adoptive transfer studies showed that the systemic toxicity of IL-15 SA was mediated by hyperproliferation of activated NK cells. Production of the proinflammatory cytokine IFN-γ, but not TNF-α or perforin, was essential to IL-15 SA-induced immunotoxicity. The toxicity and immunological alterations shown in this study are comparable to those reported in recent clinical trials of IL-15 in patients with refractory cancers and advance current knowledge by providing mechanistic insights into IL-15 SA-mediated immunotoxicity.
Copyright © 2015 by The American Association of Immunologists, Inc.
Mesoscale local functional organizations of the primate spinal cord are largely unknown. Using high-resolution fMRI at 9.4 T, we identified distinct interhorn and intersegment fMRI activation patterns to tactile versus nociceptive heat stimulation of digits in lightly anesthetized monkeys. Within a spinal segment, 8 Hz vibrotactile stimuli elicited predominantly fMRI activations in the middle part of ipsilateral dorsal horn (iDH), along with significantly weaker activations in ipsilateral (iVH) and contralateral (cVH) ventral horns. In contrast, nociceptive heat stimuli evoked widespread strong activations in the superficial part of iDH, as well as in iVH and contralateral dorsal (cDH) horns. As controls, only weak signal fluctuations were detected in the white matter. The iDH responded most strongly to both tactile and heat stimuli, whereas the cVH and cDH responded selectively to tactile versus nociceptive heat, respectively. Across spinal segments, iDH activations were detected in three consecutive segments in both tactile and heat conditions. Heat responses, however, were more extensive along the cord, with strong activations in iVH and cDH in two consecutive segments. Subsequent subunit B of cholera toxin tracer histology confirmed that the spinal segments showing fMRI activations indeed received afferent inputs from the stimulated digits. Comparisons of the fMRI signal time courses in early somatosensory area 3b and iDH revealed very similar hemodynamic stimulus-response functions. In summary, we identified with fMRI distinct segmental networks for the processing of tactile and nociceptive heat stimuli in the cervical spinal cord of nonhuman primates. Significance statement: This is the first fMRI demonstration of distinct intrasegmental and intersegmental nociceptive heat and touch processing circuits in the spinal cord of nonhuman primates. This study provides novel insights into the local functional organizations of the primate spinal cord for pain and touch, information that will be valuable for designing and optimizing therapeutic interventions for chronic pain management.
Copyright © 2015 the authors 0270-6474/15/3510493-10$15.00/0.
We evaluated the performance of time to clinical stability (TCS), a longitudinal outcome measure using 4 physiologic parameters (temperature, heart rate, respiratory rate, and use of supplemental oxygen), among children enrolled in a prospective study of pneumonia hospitalizations. We calculated the time from admission to normalization for each of the 4 parameters individually along with various combinations of these parameters (≥2 parameters). We assessed for agreement between the combined TCS measures and both hospital length of stay and an ordinal severity scale (nonsevere, severe, and very severe). Overall, 323 (96.7%) of 334 included children had ≥1 parameter abnormal on admission; 70 (21%) children had ≥1 parameter abnormal at discharge. For the 4 combined measures, median TCS decreased with increasing age. Increasing TCS was associated with both longer length of stay and increasing disease severity. The simplest combined measure incorporating only respiratory rate and need for supplemental oxygen performed similarly to more complex measures including additional parameters. Our study demonstrates that longitudinal TCS measures may be useful in children with pneumonia, both in clinical settings to assess recovery and readiness for discharge, and as an outcome measure in research and quality assessments. Additional study is needed to further validate our findings.
© 2015 Society of Hospital Medicine.
Recent demonstrations of correlated low-frequency MRI signal variations between subregions of the spinal cord at rest in humans, similar to those found in the brain, suggest that such resting-state functional connectivity constitutes a common feature of the intrinsic organization of the entire central nervous system. We report our detection of functional connectivity within the spinal cords of anesthetized squirrel monkeys at rest and show that the strength of connectivity within these networks is altered by the effects of injuries. By quantifying the low-frequency MRI signal correlations between different horns within spinal cord gray matter, we found distinct functional connectivity relationships between the different sensory and motor horns, a pattern that was similar to activation patterns evoked by nociceptive heat or tactile stimulation of digits. All horns within a single spinal segment were functionally connected, with the strongest connectivity occurring between ipsilateral dorsal and ventral horns. Each horn was strongly connected to the same horn on neighboring segments, but this connectivity reduced drastically along the spinal cord. Unilateral injury to the spinal cord significantly weakened the strength of the intrasegment horn-to-horn connectivity only on the injury side and in slices below the lesion. These findings suggest resting-state functional connectivity may be a useful biomarker of functional integrity in injured and recovering spinal cords.