Neural circuits of long-term thermoregulatory adaptations to cold temperatures and metabolic demands.

The mammalian brain controls heat generation and heat loss mechanisms that regulate body temperature and energy metabolism. Thermoeffectors include brown adipose tissue, cutaneous blood flow and skeletal muscle, and metabolic energy sources include white adipose tissue. Neural and metabolic pathways modulating the activity and functional plasticity of these mechanisms contribute not only to the optimization of function during acute challenges, such as ambient temperature changes, infection and stress, but also to longitudinal adaptations to environmental and internal changes. Exposure of humans to repeated and seasonal cold ambient conditions leads to adaptations in thermoeffectors such as habituation of cutaneous vasoconstriction and shivering. In animals that undergo hibernation and torpor, neurally regulated metabolic and thermoregulatory adaptations enable survival during periods of significant reduction in metabolic rate. In addition, changes in diet can activate accessory neural pathways that alter thermoeffector activity. This knowledge may be harnessed for therapeutic purposes, including treatments for obesity and improved means of therapeutic hypothermia.

SARS-CoV-2 infection in free-ranging white-tailed deer.

Humans have infected a wide range of animals with SARS-CoV-21-5, but the establishment of a new natural animal reservoir has not been observed. Here we document that free-ranging white-tailed deer (Odocoileus virginianus) are highly susceptible to infection with SARS-CoV-2, are exposed to multiple SARS-CoV-2 variants from humans and are capable of sustaining transmission in nature. Using real-time PCR with reverse transcription, we detected SARS-CoV-2 in more than one-third (129 out of 360, 35.8%) of nasal swabs obtained from O. virginianus in northeast Ohio in the USA during January to March 2021. Deer in six locations were infected with three SARS-CoV-2 lineages (B.1.2, B.1.582 and B.1.596). The B.1.2 viruses, dominant in humans in Ohio at the time, infected deer in four locations. We detected probable deer-to-deer transmission of B.1.2, B.1.582 and B.1.596 viruses, enabling the virus to acquire amino acid substitutions in the spike protein (including the receptor-binding domain) and ORF1 that are observed infrequently in humans. No spillback to humans was observed, but these findings demonstrate that SARS-CoV-2 viruses have been transmitted in wildlife in the USA, potentially opening new pathways for evolution. There is an urgent need to establish comprehensive 'One Health' programmes to monitor the environment, deer and other wildlife hosts globally.

Recent Advances in Melanoma Diagnosis and Prognosis Using Machine Learning Methods.

PURPOSE OF REVIEW: The purpose was to summarize the current role and state of artificial intelligence and machine learning in the diagnosis and management of melanoma. RECENT FINDINGS: Deep learning algorithms can identify melanoma from clinical, dermoscopic, and whole slide pathology images with increasing accuracy. Efforts to provide more granular annotation to datasets and to identify new predictors are ongoing. There have been many incremental advances in both melanoma diagnostics and prognostic tools using artificial intelligence and machine learning. Higher quality input data will further improve these models' capabilities.

Mediobasal hypothalamic neurons contribute to the control of brown adipose tissue sympathetic nerve activity and cutaneous vasoconstriction.

The mediobasal hypothalamus (MBH) contains heterogeneous neuronal populations that regulate food intake and energy expenditure. However, the role of MBH neurons in the neural control of thermoeffector activity for thermoregulation is not known. This study sought to determine the effects of modulating the activity of MBH neurons on the sympathetic outflow to brown adipose tissue (BAT), BAT thermogenesis, and cutaneous vasomotion. Pharmacological inhibition of MBH neurons by local administration of muscimol, a GABAA receptor agonist, reduced skin cooling-evoked BAT thermogenesis, expired CO2, body temperature, heart rate, and mean arterial pressure, while blockade of GABAA receptors by nanoinjection of bicuculline in the MBH induced large increases in BAT sympathetic nerve activity (SNA), BAT temperature, body temperature, expired CO2, heart rate, and cutaneous vasoconstriction. Neurons in the MBH send projections to neurons in the dorsal hypothalamic area and dorsomedial hypothalamus (DMH), which excite sympathetic premotor neurons in the rostral raphe pallidus area (rRPa) that control sympathetic outflow to BAT. The increases in BAT SNA, BAT temperature, and expired CO2 elicited by blockade of GABAA receptors in the MBH were reversed by blocking excitatory amino acid receptors in the DMH or in the rRPa. Together, our data show that MBH neurons provide a modest contribution to BAT thermogenesis for cold defense, while GABAergic disinhibition of these neurons produces large increases in the sympathetic outflow to BAT, and cutaneous vasoconstriction. Activation of glutamate receptors on BAT thermogenesis-promoting neurons of the DMH and rRPa is necessary for the increased sympathetic outflow to BAT evoked by disinhibition of MBH neurons. These data demonstrate neural mechanisms that contribute to the control of thermoeffector activity, and may have important implications for regulating body temperature and energy expenditure.

Dynamic 13 C MR spectroscopy as an alternative to imaging for assessing cerebral metabolism using hyperpolarized pyruvate in humans.

PURPOSE: This study is to investigate time-resolved 13 C MR spectroscopy (MRS) as an alternative to imaging for assessing pyruvate metabolism using hyperpolarized (HP) [1-13 C]pyruvate in the human brain. METHODS: Time-resolved 13 C spectra were acquired from four axial brain slices of healthy human participants (n = 4) after a bolus injection of HP [1-13 C]pyruvate. 13 C MRS with low flip-angle excitations and a multichannel 13 C/1 H dual-frequency radiofrequency (RF) coil were exploited for reliable and unperturbed assessment of HP pyruvate metabolism. Slice-wise areas under the curve (AUCs) of 13 C-metabolites were measured and kinetic analysis was performed to estimate the production rates of lactate and HCO3- . Linear regression analysis between brain volumes and HP signals was performed. Region-focused pyruvate metabolism was estimated using coil-wise 13 C reconstruction. Reproducibility of HP pyruvate exams was presented by performing two consecutive injections with a 45-minutes interval. RESULTS: [1-13 C]Lactate relative to the total 13 C signal (tC) was 0.21-0.24 in all slices. [13 C] HCO3- /tC was 0.065-0.091. Apparent conversion rate constants from pyruvate to lactate and HCO3- were calculated as 0.014-0.018 s-1 and 0.0043-0.0056 s-1 , respectively. Pyruvate/tC and lactate/tC were in moderate linear relationships with fractional gray matter volume within each slice. White matter presented poor linear regression fit with HP signals, and moderate correlations of the fractional cerebrospinal fluid volume with pyruvate/tC and lactate/tC were measured. Measured HP signals were comparable between two consecutive exams with HP [1-13 C]pyruvate. CONCLUSIONS: Dynamic MRS in combination with multichannel RF coils is an affordable and reliable alternative to imaging methods in investigating cerebral metabolism using HP [1-13 C]pyruvate.

Neural control of the spleen as an effector of immune responses to inflammation: mechanisms and treatments.

Immune system responses are a vital defense mechanism against pathogens. Inflammatory mediators finely regulate complex inflammatory responses from initiation to resolution. However, in certain conditions, the inflammation is initiated and amplified, but not resolved. Understanding the biological mechanisms underlying the regulation of the immune response is critical for developing therapeutic alternatives, including pharmaceuticals and bioelectronic tools. The spleen is an important immune effector organ since it orchestrates innate and adaptive immune responses such as pathogen clearance, cytokine production, and differentiation of cells, therefore playing a modulatory role that balances pro- and anti-inflammatory responses. However, modulation of splenic immune activity is a largely unexplored potential therapeutic tool that could be used for the treatment of inflammatory and life-threatening conditions. This review discusses some of the mechanisms controlling neuroimmune communication and the brain-spleen axis.

Neural circuits mediating circulating interleukin-1ß-evoked fever in the absence of prostaglandin E2 production.

Infectious diseases and inflammatory conditions recruit the immune system to mount an appropriate acute response that includes the production of cytokines. Cytokines evoke neurally-mediated responses to fight pathogens, such as the recruitment of thermoeffectors, thereby increasing body temperature and leading to fever. Studies suggest that the cytokine interleukin-1ß (IL-1ß) depends upon cyclooxygenase (COX)-mediated prostaglandin E2 production for the induction of neural mechanisms to elicit fever. However, COX inhibitors do not eliminate IL-1ß-induced fever, thus suggesting that COX-dependent and COX-independent mechanisms are recruited for increasing body temperature after peripheral administration of IL-1ß. In the present study, we aimed to build a foundation for the neural circuit(s) controlling COX-independent, inflammatory fever by determining the involvement of brain areas that are critical for controlling the sympathetic outflow to brown adipose tissue (BAT) and the cutaneous vasculature. In anesthetized rats, pretreatment with indomethacin, a non-selective COX inhibitor, did not prevent BAT thermogenesis or cutaneous vasoconstriction (CVC) induced by intravenous IL-1ß (2 µg/kg). BAT and cutaneous vasculature sympathetic premotor neurons in the rostral raphe pallidus area (rRPa) are required for IL-1ß-evoked BAT thermogenesis and CVC, with or without pretreatment with indomethacin. Additionally, activation of glutamate receptors in the dorsomedial hypothalamus (DMH) is required for COX-independent, IL-1ß-induced BAT thermogenesis. Therefore, our data suggests that COX-independent mechanisms elicit activation of neurons within the DMH and rRPa, which is sufficient to trigger and mount inflammatory fever. These data provide a foundation for elucidating the brain circuits responsible for COX-independent, IL-1ß-elicited fevers.

Carotid Arterial Compliance and Aerobic Exercise Training in Chronic Traumatic Brain Injury: A Pilot Study.

OBJECTIVE: Decreased carotid arterial compliance (CAC) is associated with cerebral microvascular damage, cerebral blood flow (CBF) dysregulation, and increased risk for stroke and dementia, which are reported to be prevalent after traumatic brain injury (TBI). However, the effect of TBI on CAC has not been reported. The purposes of this pilot study were to (1) compare CAC between participants with chronic traumatic brain injury (cTBI) and age-matched healthy control (HC) subjects and (2) to examine whether CAC changed after 3 months of exercise training in those with cTBI. SETTING: Community based. PARTICIPANTS: Nineteen participants with cTBI (6-72 months postinjury) and 19 HC matched for age and sex were tested at baseline. The same cTBI cohort was enrolled in a proof-of-concept randomized controlled exercise training program to investigate the effects of 3 months of aerobic exercise training (AET) or nonaerobic stretching and toning (SAT) on cerebrovascular parameters. DESIGN: Cross-sectional study and randomized controlled trial. MAIN MEASURES: CAC was measured by tonometry and ultrasonography at the common carotid artery; CBF was measured by ultrasonography at the bilateral internal carotid and vertebral arteries, and pulsatile CBF was measured by transcranial Doppler ultrasonography at the middle cerebral arteries. Cerebrovascular resistance (CVR) was calculated as mean arterial pressure divided by total CBF. RESULTS: Relative to HC, the participants with cTBI had lower CAC (0.10 ± 0.03 vs 0.12 ± 0.03 mm 2 /mm Hg, P = .046) and higher CVR (0.17 ± 0.03 vs 0.15 ± 0.03 mm Hg/mL/min, P = .028). CAC tended to increase after AET compared with SAT ( P = .080). Increases in CAC were associated with decreased pulsatile CBF ( r = -0.689, P = .003). CONCLUSION: These findings suggest that the individuals with cTBI have decreased CAC, which may potentially be improved by AET.

Dopaminergic input from the posterior hypothalamus to the raphe pallidus area inhibits brown adipose tissue thermogenesis.

Systemic administration of dopamine (DA) receptor agonists leads to falls in body temperature. However, the central thermoregulatory pathways modulated by DA have not been fully elucidated. Here we identified a source and site of action contributing to DA's hypothermic action by inhibition of brown adipose tissue (BAT) thermogenesis. Nanoinjection of the type 2 and type 3 DA receptor (D2R/D3R) agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), in the rostral raphe pallidus area (rRPa) inhibits the sympathetic activation of BAT evoked by cold exposure or by direct activation of N-methyl-d-aspartate (NMDA) receptors in the rRPa. Blockade of D2R/D3R in the rRPa with nanoinjection of SB-277011A increases BAT thermogenesis, consistent with a tonic release of DA in the rRPa contributing to inhibition of BAT thermogenesis. Accordingly, D2Rs are expressed in cold-activated and serotonergic neurons in the rRPa, and anatomical tracing studies revealed that neurons in the posterior hypothalamus (PH) are a source of dopaminergic input to the rRPa. Disinhibitory activation of PH neurons with nanoinjection of gabazine inhibits BAT thermogenesis, which is reduced by pretreatment of the rRPa with SB-277011A. In conclusion, the rRPa, the site of sympathetic premotor neurons for BAT, receives a tonically active, dopaminergic input from the PH that suppresses BAT thermogenesis.

A proof-of-concept trial of a community-based aerobic exercise program for individuals with traumatic brain injury.

Objective: To assess the feasibility of conducting an aerobic exercise training study in a community setting for individuals with traumatic brain injury (TBI)Methods: This is a prospective, randomized, and controlled study. Nine participants (three moderate-to-severe and six mild TBI) were randomized to a community-based 3-month individualized aerobic exercise training program (AET). Seven participants (four moderate-to-severe, three mild TBI) were randomized to a stretching and toning program (SAT). Cardiorespiratory fitness (CRF) level was assessed with peak oxygen uptake (VO2peak) testing.Results: After 3 months of training, the AET trended toward improved VO2peak when compared with the SAT group (8% vs - 4%, p = .059) with a large effect size of 1.27. Only 50% of participants in the AET group completed more than 70% of the assigned exercise sessions. No adverse events were reported. Both the AET and SAT groups reported small improvements in self-reported mood symptoms, including depression, anxiety, and anger.Conclusions: It is feasible to conduct an exercise training study and improve CRF for persons with TBI in community settings with structured exercise protocols. However, exploring methods to enhance adherence is crucial for future exercise clinical trials to improve brain health in this population.

Reversible and Selective Interconversion of Hydrogen and Carbon Dioxide into Formate by a Semiartificial Formate Hydrogenlyase Mimic.

The biological formate hydrogenlyase (FHL) complex links a formate dehydrogenase (FDH) to a hydrogenase (H2ase) and produces H2 and CO2 from formate via mixed-acid fermentation in Escherichia coli. Here, we describe an electrochemical and a colloidal semiartificial FHL system that consists of an FDH and a H2ase immobilized on conductive indium tin oxide (ITO) as an electron relay. These in vitro systems benefit from the efficient wiring of a highly active enzyme pair and allow for the reversible conversion of formate to H2 and CO2 under ambient temperature and pressure. The hybrid systems provide a template for the design of synthetic catalysts and surpass the FHL complex in vivo by storing and releasing H2 on demand by interconverting CO2/H2 and formate with minimal bias in either direction.

Preoptic area cooling increases the sympathetic outflow to brown adipose tissue and brown adipose tissue thermogenesis.

Modest cold exposures are likely to activate autonomic thermogenic mechanisms due to activation of cutaneous thermal afferents, whereas central thermosensitive neurons set the background tone on which this afferent input is effective. In addition, more prolonged or severe cold exposures that overwhelm cold defense mechanisms would directly activate thermosensitive neurons within the central nervous system. Here, we examined the involvement of the canonical brown adipose tissue (BAT) sympathoexcitatory efferent pathway in the response to direct local cooling of the preoptic area (POA) in urethane-chloralose-anesthetized rats. With skin temperature and core body temperature maintained between 36 and 39°C, cooling POA temperature by ~1-4°C evoked increases in BAT sympathetic nerve activity (SNA), BAT temperature, expired CO2, and heart rate. POA cooling-evoked responses were inhibited by nanoinjections of ionotropic glutamate receptor antagonists or the GABAA receptor agonist muscimol into the median POA or by nanoinjections of ionotropic glutamate receptor antagonists into the dorsomedial hypothalamic nucleus (bilaterally) or into the raphe pallidus nucleus. These results demonstrate that direct cooling of the POA can increase BAT SNA and thermogenesis via the canonical BAT sympathoexcitatory efferent pathway, even in the face of warm thermal input from the skin and body core.

Activation of TRPV1 in nucleus tractus solitarius reduces brown adipose tissue thermogenesis, arterial pressure, and heart rate.

The sympathetic nerve activity (SNA) to brown adipose tissue (BAT) regulates BAT thermogenesis to defend body temperature in cold environments or to produce fever during immune responses. The vagus nerve contains afferents that inhibit the BAT SNA and BAT thermogenesis evoked by skin cooling. We sought to determine whether activation of transient receptor potential vanilloid 1 (TRPV1) channels in the nucleus tractus solitarius (NTS), which are prominently expressed in unmyelinated vagal afferents, would affect cold-evoked BAT thermogenesis, cardiovascular parameters, or their vagal afferent-evoked responses. In urethane-chloralose-anesthetized rats, during skin cooling, nanoinjection of the TRPV1-agonist resiniferatoxin in NTS decreased BAT SNA (from 695 ± 195% of baseline during cooling to 103 ± 8% of baseline after resiniferatoxin), BAT temperature (-0.8 ± 0.1°C), expired CO2 (-0.3 ± 0.04%), mean arterial pressure (MAP; -20 ± 5 mmHg), and heart rate (-44 ± 11 beats/min). Pretreatment of NTS with the TRPV1 antagonist capsazepine prevented these resiniferatoxin-mediated effects. Intravenous injection of the TRPV1 agonist dihydrocapsaicin also decreased all the measured variables (except MAP). Bilateral cervical or subdiaphragmatic vagotomy attenuated the decreases in BAT SNA and thermogenesis evoked by nanoinjection of resiniferatoxin in NTS but did not prevent the decreases in BAT SNA and BAT thermogenesis evoked by intravenous dihydrocapsaicin. We conclude that activation of TRPV1 channels in the NTS of vagus nerve intact rats inhibits BAT SNA and decreases BAT metabolism, blood pressure, and heart rate. In contrast, the inhibition of BAT thermogenesis following systemic administration of dihydrocapsaicin does not require vagal afferent activity, consistent with a nonvagal pathway through which systemic TRPV1 agonists can inhibit BAT thermogenesis.

Glucagon-like peptide-1 regulates brown adipose tissue thermogenesis via the gut-brain axis in rats.

Endogenous intestinal glucagon-like peptide-1 (GLP-1) controls satiation and glucose metabolism via vagal afferent neurons (VANs). Recently, VANs have received increasing attention for their role in brown adipose tissue (BAT) thermogenesis. It is, however, unclear whether VAN GLP-1 receptor (GLP-1R) signaling affects BAT thermogenesis and energy expenditure (EE) and whether this VAN mechanism contributes to energy balance. First, we tested the effect of the GLP-1R agonist exendin-4 (Ex4, 0.3 µg/kg ip) on EE and BAT thermogenesis and whether these effects require VAN GLP-1R signaling using a rat model with a selective Glp1r knockdown (kd) in VANs. Second, we examined the role of VAN GLP-1R in energy balance during chronic high-fat diet (HFD) feeding in VAN Glp1r kd rats. Finally, we used viral transsynaptic tracers to identify the possible neuronal substrates of such a gut-BAT interaction. VAN Glp1r kd attenuated the acute suppressive effects of Ex4 on EE and BAT thermogenesis. Consistent with this finding, the VAN Glp1r kd increased EE and BAT activity, diminished body weight gain, and improved insulin sensitivity compared with HFD-fed controls. Anterograde transsynaptic viral tracing of VANs infected major hypothalamic and hindbrain areas involved in BAT sympathetic regulation. Moreover, retrograde tracing from BAT combined with laser capture microdissection revealed that a population of VANs expressing Glp1r is synaptically connected to the BAT. Our findings reveal a novel role of VAN GLP-1R signaling in the regulation of EE and BAT thermogenesis and imply that through this gut-brain-BAT connection, intestinal GLP-1 plays a role in HFD-induced metabolic syndrome.

Salinity pulses interact with seasonal dry-down to increase ecosystem carbon loss in marshes of the Florida Everglades.

Coastal wetlands are globally important sinks of organic carbon (C). However, to what extent wetland C cycling will be affected by accelerated sea-level rise (SLR) and saltwater intrusion is unknown, especially in coastal peat marshes where water flow is highly managed. Our objective was to determine how the ecosystem C balance in coastal peat marshes is influenced by elevated salinity. For two years, we made monthly in situ manipulations of elevated salinity in freshwater (FW) and brackish water (BW) sites within Everglades National Park, Florida, USA. Salinity pulses interacted with marsh-specific variability in seasonal hydroperiods whereby effects of elevated pulsed salinity on gross ecosystem productivity (GEP), ecosystem respiration (ER), and net ecosystem productivity (NEP) were dependent on marsh inundation level. We found little effect of elevated salinity on C cycling when both marsh sites were inundated, but when water levels receded below the soil surface, the BW marsh shifted from a C sink to a C source. During these exposed periods, we observed an approximately threefold increase in CO2 efflux from the marsh as a result of elevated salinity. Initially, elevated salinity pulses did not affect Cladium jamaicense biomass, but aboveground biomass began to be significantly decreased in the saltwater amended plots after two years of exposure at the BW site. We found a 65% (FW) and 72% (BW) reduction in live root biomass in the soil after two years of exposure to elevated salinity pulses. Regardless of salinity treatment, the FW site was C neutral while the BW site was a strong C source (-334 to -454 g C·m-2 ·yr-1 ), particularly during dry-down events. A loss of live roots coupled with annual net CO2 losses as marshes transition from FW to BW likely contributes to the collapse of peat soils observed in the coastal Everglades. As SLR increases the rate of saltwater intrusion into coastal wetlands globally, understanding how water management influences C gains and losses from these systems is crucial. Under current Everglades' water management, drought lengthens marsh dry-down periods, which, coupled with saltwater intrusion, accelerates CO2 loss from the marsh.

Tonic inhibition of brown adipose tissue sympathetic nerve activity via muscarinic acetylcholine receptors in the rostral raphe pallidus.

KEY POINTS: A tonically active, muscarinic cholinergic inhibition of rostral raphe pallidus (rRPa) neurons influences thermogenesis of brown adipose tissue (BAT) independent of ambient temperature conditions. The tonically active cholinergic input to rRPa originates caudal to the hypothalamus. Muscarinic acetylcholine receptor (mAChR) activation in rRPa contributes to the inhibition of BAT sympathetic nerve activity (SNA) evoked by activation of neurons in the rostral ventrolateral medulla (RVLM). The RVLM is not the sole source of the muscarinic cholinergic input to rRPa. Activation of GABA receptors in rRPa does not mediate the cholinergic inhibition of BAT SNA. ABSTRACT: We sought to determine if body temperature and energy expenditure are influenced by a cholinergic input to neurons in the rostral raphe pallidus (rRPa), the site of sympathetic premotor neurons controlling thermogenesis of brown adipose tissue (BAT). Nanoinjections of the muscarinic acetylcholine receptor (mAChR) agonist, oxotremorine, or the cholinesterase inhibitor, neostigmine (NEOS), in the rRPa of anaesthetized rats decreased cold-evoked BAT sympathetic nerve activity (SNA, nadirs: -72 and -95%), BAT temperature (Tbat, -0.5 and -0.6°C), expired CO2 (Exp. CO2 , -0.3 and -0.5%) and heart rate (HR, -22 and -41 bpm). NEOS into rRPa reversed the increase in BAT SNA evoked by blockade of GABA receptors in rRPa. Nanoinjections of the mAChR antagonist, scopolamine (SCOP), in the rRPa of warm rats increased BAT SNA (peak: +1087%), Tbat (+1.8°C), Exp. CO2 (+0.7%), core temperature (Tcore, +0.5°C) and HR (+54 bpm). SCOP nanoinjections in rRPa produced similar activations of BAT during cold exposure, following a brain transection caudal to the hypothalamus, and during the blockade of glutamate receptors in rRPa. We conclude that a tonically active cholinergic input to the rRPa inhibits BAT SNA via activation of local mAChR. The inhibition of BAT SNA mediated by mAChR in rRPa does not depend on activation of GABA receptors in rRPa. The increase in BAT SNA following mAChR blockade in rRPa does not depend on the activity of neurons in the hypothalamus or on glutamate receptor activation in rRPa.

Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase-II: A Phase II Randomized Trial.

OBJECTIVES: A relationship between reduced brain tissue oxygenation and poor outcome following severe traumatic brain injury has been reported in observational studies. We designed a Phase II trial to assess whether a neurocritical care management protocol could improve brain tissue oxygenation levels in patients with severe traumatic brain injury and the feasibility of a Phase III efficacy study. DESIGN: Randomized prospective clinical trial. SETTING: Ten ICUs in the United States. PATIENTS: One hundred nineteen severe traumatic brain injury patients. INTERVENTIONS: Patients were randomized to treatment protocol based on intracranial pressure plus brain tissue oxygenation monitoring versus intracranial pressure monitoring alone. Brain tissue oxygenation data were recorded in the intracranial pressure -only group in blinded fashion. Tiered interventions in each arm were specified and impact on intracranial pressure and brain tissue oxygenation measured. Monitors were removed if values were normal for 48 hours consecutively, or after 5 days. Outcome was measured at 6 months using the Glasgow Outcome Scale-Extended. MEASUREMENTS AND MAIN RESULTS: A management protocol based on brain tissue oxygenation and intracranial pressure monitoring reduced the proportion of time with brain tissue hypoxia after severe traumatic brain injury (0.45 in intracranial pressure-only group and 0.16 in intracranial pressure plus brain tissue oxygenation group; p < 0.0001). Intracranial pressure control was similar in both groups. Safety and feasibility of the tiered treatment protocol were confirmed. There were no procedure-related complications. Treatment of secondary injury after severe traumatic brain injury based on brain tissue oxygenation and intracranial pressure values was consistent with reduced mortality and increased proportions of patients with good recovery compared with intracranial pressure-only management; however, the study was not powered for clinical efficacy. CONCLUSIONS: Management of severe traumatic brain injury informed by multimodal intracranial pressure and brain tissue oxygenation monitoring reduced brain tissue hypoxia with a trend toward lower mortality and more favorable outcomes than intracranial pressure-only treatment. A Phase III randomized trial to assess impact on neurologic outcome of intracranial pressure plus brain tissue oxygenation-directed treatment of severe traumatic brain injury is warranted.

Glycinergic inhibition of BAT sympathetic premotor neurons in rostral raphe pallidus.

The rostral raphe pallidus (rRPa) contains sympathetic premotor neurons controlling thermogenesis in brown adipose tissue (BAT). We sought to determine whether a tonic activation of glycineA receptors (GlyAR) in the rRPa contributes to the inhibitory regulation of BAT sympathetic nerve activity (SNA) and of cardiovascular parameters in anesthetized rats. Nanoinjection of the GlyAR antagonist, strychnine (STR), into the rRPa of intact rats increased BAT SNA (peak: +495%), BAT temperature (TBAT, +1.1°C), expired CO2, (+0.4%), core body temperature (TCORE, +0.2°C), mean arterial pressure (MAP, +4 mmHg), and heart rate (HR, +57 beats/min). STR into rRPa in rats with a postdorsomedial hypothalamus transection produced similar increases in BAT thermogenic and cardiovascular parameters. Glycine nanoinjection into the rRPa evoked a potent inhibition of the cooling-evoked increases in BAT SNA (nadir: -74%), TBAT (-0.2°C), TCORE (-0.2°C), expired CO2 (-0.2%), MAP (-8 mmHg), and HR (-22 beats/min) but had no effect on the increases in these variables evoked by STR nanoinjection into rRPa. Nanoinjection of GABA into the rRPa inhibited the STR-evoked BAT SNA (nadir: -86%) and reduced the expired CO2 (-0.4%). Blockade of glutamate receptors in rRPa reduced the STR-evoked increases in BAT SNA (nadir: -61%), TBAT (-0.5°C), expired CO2 (-0.3%), MAP (-9 mmHg), and HR (-33 beats/min). We conclude that a tonically active glycinergic input to the rRPa contributes to the inhibitory regulation of the discharge of BAT sympathetic premotor neurons and of BAT thermogenesis and energy expenditure.

Reliability of the NINDS common data elements cranial tomography (CT) rating variables for traumatic brain injury (TBI).

BACKGROUND: Non-contrast head computer tomography (CT) is widely used to evaluate eligibility of patients after acute traumatic brain injury (TBI) for clinical trials. The NINDS Common Data Elements (CDEs) TBI were developed to standardize collection of CT variables. The objectives of this study were to train research assistants (RAs) to rate CDEs and then to evaluate their performance. The aim was to assess inter-rater reliability (IRR) of CDEs between trained RAs and a neurologist and to evaluate applicability of CDEs in acute and sub-acute TBI to test the feasibility of using CDE CT ratings in future trials and ultimately in clinical practice. The second aim was to confirm that the ratings of CDEs reflect pathophysiological events after TBI. METHODS AND RESULTS: First, a manual was developed for application of the CDEs, which was used to rate brain CTs (n = 100). An excellent agreement was found in combined kappas between RAs on admission and on 24-hour follow-up CTs (Iota = 0.803 and 0.787, respectively). Good IRR (kappa > 0.61) was shown for six CDEs on admissions and for seven CDEs on follow-up CTs. Low IRR (kappa < 0.4) was determined for five CDEs on admission and for four CDEs on follow-up CT. Combined IRR of each assistant with the neurologist were good on admission (Iota = 0.613 and 0.787) and excellent on follow-up CT (Iota = 0.906 and 0.977). Second, Principal Component Analysis (PCA) was applied to cluster the rated CDEs (n = 255) and five major components were found that explain 53% of the variance. CONCLUSIONS: CT CDEs are useful in clinical studies of TBI. Trained RAs can reliably collect variables. PCA identifies CDE clusters with clinical and biologic plausibility. ABBREVIATIONS: RA, research assistant; CT, Cranial Tomography; TBI, Traumatic Brain Injury; CDE, Common Data Elements; IRR, inter-rater reliability; PCA, Principal Component Analysis; GCS, Glasgow Coma Scale; R, rater; CI, confidence interval; CCC, Concordance correlation coefficient; IVH, Intraventricular haemorrhage; DCA, Discriminant Component analysis; SAH, Subarachnoid Haemorrhage.

A high-fat diet impairs cooling-evoked brown adipose tissue activation via a vagal afferent mechanism.

In dramatic contrast to rats on a control diet, rats maintained on a high-fat diet (HFD) failed to activate brown adipose tissue (BAT) during cooling despite robust increases in their BAT activity following direct activation of their BAT sympathetic premotor neurons in the raphe pallidus. Cervical vagotomy or blockade of glutamate receptors in the nucleus of the tractus solitarii (NTS) reversed the HFD-induced inhibition of cold-evoked BAT activity. Thus, a HFD does not prevent rats from mounting a robust, centrally driven BAT thermogenesis; however, a HFD does alter a vagal afferent input to NTS neurons, thereby preventing the normal activation of BAT thermogenesis to cooling. These results, paralleling the absence of cooling-evoked glucose uptake in the BAT of obese humans, reveal a neural mechanism through which consumption of a HFD contributes to reduced energy expenditure and thus to weight gain.