Persistent neuroinflammation and functional deficits in a murine model of decompression sickness.

We hypothesized that early intra-CNS responses in a murine model of decompression sickness (DCS) would be reflected by changes in the microparticles (MPs) that exit the brain via the glymphatic system, and due to systemic responses the MPs would cause inflammatory changes lasting for many days leading to functional neurological deficits. Elevations on the order of 3-fold of blood-borne inflammatory MPs, neutrophil activation, glymphatic flow and neuroinflammation in cerebral cortex and hippocampus were found in mice at 12 days after exposure to 760 kPa of air for 2 hours. Mice also exhibited a significant decline in memory and locomotor activity, as assessed by novel object recognition and rotarod testing. Similar inflammatory changes in blood, neuroinflammation and functional impairments were initiated in naïve mice by injection of filamentous (F-) actin-positiveMPs, but not F-actin-negative MPs,obtained from decompressed mice. We conclude that high pressure/decompression stress establishes a systemic inflammatory process that results in prolonged neuroinflammation and functional impairments in the mouse decompression model.

Practical Recommendations for the Evaluation and Management of Cardiac Injury Due to Carbon Monoxide Poisoning.

Carbon monoxide (CO) is a relatively frequent cause of poisoning evaluated in emergency departments. The risk of neurologic injuries, such as cognitive, psychological, vestibular, and motor deficits, is 25% to 50%. However, the risk of cardiac injuries should also be considered. Among patients with CO poisoning, the mortality in patients with myocardial injury is approximately 3 times greater than that in patients without myocardial injury. In large-scale studies, up to 69.2% of patients with acute CO poisoning exhibiting elevated troponin I levels and no underlying cardiovascular illnesses had late gadolinium enhancement on cardiac magnetic resonance, suggesting covert CO-induced myocardial fibrosis. Myocardial damage can be evaluated using electrocardiography, echocardiography, computed tomography, and cardiac magnetic resonance. This paper offers recommendations for cardiac evaluations based on our collective experience of managing >2,000 cases of acute CO poisoning with supporting information taken from peer-reviewed published reports on CO poisoning.

An Improved Clinical and Genetics-Based Prediction Model for Diabetic Foot Ulcer Healing.

Objective: The goal of this investigation was to use comprehensive prediction modeling tools and available genetic information to try to improve upon the performance of simple clinical models in predicting whether a diabetic foot ulcer (DFU) will heal. Approach: We utilized a cohort study (n = 206) that included clinical factors, measurements of circulating endothelial precursor cells (CEPCs), and fine sequencing of the NOS1AP gene. We derived and selected relevant predictive features from this patient-level information using statistical and machine learning techniques. We then developed prognostic models using machine learning approaches and assessed predictive performance. The presentation is consistent with TRIPOD requirements. Results: Models using baseline clinical and CEPC data had an area under the receiver operating characteristic curve (AUC) of 0.73 (0.66-0.80). Models using only single nucleotide polymorphisms (SNPs) of the NOS1AP gene had an AUC of 0.67 (95% confidence interval, CI: [0.59-0.75]). However, models incorporating baseline and SNP information resulted in improved AUC (0.80, 95% CI [0.73-0.87]). Innovation: We provide a rigorous analysis demonstrating the predictive potential of genetic information in DFU healing. In this process, we present a framework for using advanced statistical and bioinformatics techniques for creating superior prognostic models and identify potentially predictive SNPs for future research. Conclusion: We have developed a new benchmark for which future predictive models can be compared against. Such models will enable wound care experts to more accurately predict whether a patient will heal and aid clinical trialists in designing studies to evaluate therapies for subjects likely or unlikely to heal.

Dissolved gases from pressure changes in the lungs elicit an immune response in human peripheral blood.

Conventional dogma suggests that decompression sickness (DCS) is caused by nitrogen bubble nucleation in the blood vessels and/or tissues; however, the abundance of bubbles does not correlate with DCS severity. Since immune cells respond to chemical and environmental cues, we hypothesized that the elevated partial pressures of dissolved gases drive aberrant immune cell phenotypes in the alveolar vasculature. To test this hypothesis, we measured immune responses within human lung-on-a-chip devices established with primary alveolar cells and microvascular cells. Devices were pressurized to 1.0 or 3.5 atm and surrounded by normal alveolar air or oxygen-reduced air. Phenotyping of neutrophils, monocytes, and dendritic cells as well as multiplexed ELISA revealed that immune responses occur within 1 hour and that normal alveolar air (i.e., hyperbaric oxygen and nitrogen) confer greater immune activation. This work strongly suggests innate immune cell reactions initiated at elevated partial pressures contribute to the etiology of DCS.

Elevations of Extracellular Vesicles and Inflammatory Biomarkers in Closed Circuit SCUBA Divers.

Blood-borne extracellular vesicles and inflammatory mediators were evaluated in divers using a closed circuit rebreathing apparatus and custom-mixed gases to diminish some diving risks. "Deep" divers (n = 8) dove once to mean (±SD) 102.5 ± 1.2 m of sea water (msw) for 167.3 ± 11.5 min. "Shallow" divers (n = 6) dove 3 times on day 1, and then repetitively over 7 days to 16.4 ± 3.7 msw, for 49.9 ± 11.9 min. There were statistically significant elevations of microparticles (MPs) in deep divers (day 1) and shallow divers at day 7 that expressed proteins specific to microglia, neutrophils, platelets, and endothelial cells, as well as thrombospondin (TSP)-1 and filamentous (F-) actin. Intra-MP IL-1ß increased by 7.5-fold (p < 0.001) after day 1 and 41-fold (p = 0.003) at day 7. Intra-MP nitric oxide synthase-2 (NOS2) increased 17-fold (p < 0.001) after day 1 and 19-fold (p = 0.002) at day 7. Plasma gelsolin (pGSN) levels decreased by 73% (p < 0.001) in deep divers (day 1) and 37% in shallow divers by day 7. Plasma samples containing exosomes and other lipophilic particles increased from 186% to 490% among the divers but contained no IL-1ß or NOS2. We conclude that diving triggers inflammatory events, even when controlling for hyperoxia, and many are not proportional to the depth of diving.

Neuroinflammation with increased glymphatic flow in a murine model of decompression sickness.

This project investigated glial-based lymphatic (glymphatic) function and its role in a murine model of decompression sickness (DCS). DCS pathophysiology is traditionally viewed as being related to gas bubble formation from insoluble gas on decompression. However, a body of work implicates a role for a subset of inflammatory extracellular vesicles, 0.1 to 1 µm microparticles (MPs) that are elevated in human and rodent models in response to high gas pressure and rise further after decompression. Herein, we describe immunohistochemical and Western blot evidence showing that following high air pressure exposure, there are elevations of astrocyte NF-κB and microglial-ionized calcium-binding adaptor protein-1 (IBA-1) along with fluorescence contrast and MRI findings of an increase in glymphatic flow. Concomitant elevations of central nervous system-derived MPs coexpressing thrombospondin-1 (TSP) drain to deep cervical nodes and then to blood where they cause neutrophil activation. A new set of blood-borne MPs are generated that express filamentous actin at the surface that exacerbate neutrophil activation. Blood-brain barrier integrity is disrupted due to activated neutrophil sequestration that causes further astrocyte and microglial perturbation. When postdecompression node or blood MPs are injected into naïve mice, the same spectrum of abnormalities occur and they are blocked with coadministration of antibody to TSP. We conclude that high pressure/decompression causes neuroinflammation with an increased glymphatic flow. The resulting systemic liberation of TSP-expressing MPs sustains the neuroinflammatory cycle lasting for days.NEW & NOTEWORTHY A murine model of central nervous system (CNS) decompression sickness demonstrates that high gas pressure activates astrocytes and microglia triggering inflammatory microparticle (MP) production. Thrombospondin-expressing MPs are released from the CNS via enhanced glymphatic flow to the systemic circulation where they activate neutrophils. Secondary production of neutrophil-derived MPs causes further cell activation and neutrophil adherence to the brain microvasculature establishing a feed-forward neuroinflammatory cycle.

Blood-Borne Microparticles Are an Inflammatory Stimulus in Type 2 Diabetes Mellitus.

The proinflammatory state associated with diabetes mellitus (DM) remains poorly understood. We found patients with DM have 3- to 14-fold elevations of blood-borne microparticles (MPs) that bind phalloidin (Ph; Ph positive [+] MPs), indicating the presence of F-actin on their surface. We hypothesized that F-actin-coated MPs were an unrecognized cause for DM-associated proinflammatory status. Ph+MPs, but not Ph-negative MPs, activate human and murine (Mus musculus) neutrophils through biophysical attributes of F-actin and membrane expression of phosphatidylserine (PS). Neutrophils respond to Ph+MPs via a linked membrane array, including the receptor for advanced glycation end products and CD36, PS-binding membrane receptors. These proteins in conjunction with TLR4 are coupled to NO synthase 1 adaptor protein (NOS1AP). Neutrophil activation occurs because of Ph+MPs causing elevations of NF-κB and Src kinase (SrcK) via a concurrent increased association of NO synthase 2 and SrcK with NOS1AP, resulting in SrcK S-nitrosylation. We conclude that NOS1AP links PS-binding receptors with intracellular regulatory proteins. Ph+MPs are alarmins present in normal human plasma and are increased in those with DM and especially those with DM and a lower-extremity ulcer.

Hyperbaric oxygen should be used for carbon monoxide poisoning.

This short review addresses the mechanisms of injury mediated by carbon monoxide (CO) and current information on efficacy of hyperbaric oxygen therapy (HBOT). Recent clinical series involving large, country-wide databases and prospective randomized trials are summarized. We conclude that there is an abundance of basic science and preclinical and clinical research supporting the use of HBOT for acute CO poisoning. With appropriate consideration for pathology and therapeutic mechanisms, HBOT at a dose of 2.5-3.0 atm absolute is a necessary treatment for this toxidrome.

Varying Oxygen Partial Pressure Elicits Blood-Borne Microparticles Expressing Different Cell-Specific Proteins-Toward a Targeted Use of Oxygen?

Oxygen is a powerful trigger for cellular reactions, but there are few comparative investigations assessing the effects over a large range of partial pressures. We investigated a metabolic response to single exposures to either normobaric (10%, 15%, 30%, 100%) or hyperbaric (1.4 ATA, 2.5 ATA) oxygen. Forty-eight healthy subjects (32 males/16 females; age: 43.7 ± 13.4 years, height: 172.7 ± 10.07 cm; weight 68.4 ± 15.7 kg) were randomly assigned, and blood samples were taken before and 2 h after each exposure. Microparticles (MPs) expressing proteins specific to different cells were analyzed, including platelets (CD41), neutrophils (CD66b), endothelial cells (CD146), and microglia (TMEM). Phalloidin binding and thrombospondin-1 (TSP), which are related to neutrophil and platelet activation, respectively, were also analyzed. The responses were found to be different and sometimes opposite. Significant elevations were identified for MPs expressing CD41, CD66b, TMEM, and phalloidin binding in all conditions but for 1.4 ATA, which elicited significant decreases. Few changes were found for CD146 and TSP. Regarding OPB, further investigation is needed to fully understand the future applications of such findings.

Astrocyte-derived microparticles initiate a neuroinflammatory cycle due to carbon monoxide poisoning.

We hypothesized that carbon monoxide (CO) establishes an inflammatory cycle mediated by microparticles (MPs). Mice exposed to a CO protocol (1000 â€‹ppm for 40 â€‹min and then 3000 â€‹ppm for 20 â€‹min) that causes neuroinflammation exhibit NF-κB activation in astrocytes leading to generation of MPs expressing thrombospondin-1(TSP-1) that collect in deep cervical lymph nodes draining the brain glymphatic system. TSP-1 bearing MPs gain access to the blood stream where they activate neutrophils to generate a new family of MPs, and also stimulate endothelial cells as documented by leakage of intravenous 2000 â€‹kDa dextran. At the brain microvasculature, neutrophil and MPs sequestration, and myeloperoxidase activity result in elevations of the p65 subunit of NF-κB, serine 536 phosphorylated p65, CD36, and loss of astrocyte aquaporin-4 that persist for at least 7 days. Knock-out mice lacking the CD36 membrane receptor are resistant to all CO inflammatory changes. Events triggered by CO are recapitulated in naïve wild type mice injected with cervical node MPs from CO-exposed mice, but not control mice. All MPs-mediated events are inhibited with a NF-κB inhibitor, a myeloperoxidase inhibitor, or anti-TSP-1 antibodies. We conclude that astrocyte-derived MPs expressing TSP-1 establish a feed-forward neuroinflammatory cycle involving endothelial CD36-to-astrocyte NF-κB crosstalk. As there is currently no treatment for CO-induced neurological sequelae, these findings pose several possible sites for therapeutic interventions.

Plasma gelsolin modulates the production and fate of IL-1ß-containing microparticles following high-pressure exposure and decompression.

Plasma gelsolin (pGSN) levels fall in association with diverse inflammatory conditions. We hypothesized that pGSN would decrease due to the stresses imposed by high pressure and subsequent decompression, and repletion would ameliorate injuries in a murine decompression sickness (DCS) model. Research subjects were found to exhibit a modest decrease in pGSN level while at high pressure and a profound decrease after decompression. Changes occurred concurrent with elevations of circulating microparticles (MPs) carrying interleukin (IL)-1ß. Mice exhibited a comparable decrease in pGSN after decompression along with elevations of MPs carrying IL-1ß. Infusion of recombinant human (rhu)-pGSN into mice before or after pressure exposure abrogated these changes and prevented capillary leak in brain and skeletal muscle. Human and murine MPs generated under high pressure exhibited surface filamentous actin (F-actin) to which pGSN binds, leading to particle lysis. In addition, human neutrophils exposed to high air pressure exhibit an increase in surface F-actin that is diminished by rhu-pGSN resulting in inhibition of MP production. Administration of rhu-pGSN may have benefit as prophylaxis or treatment for DCS.NEW & NOTEWORTHY Inflammatory microparticles released in response to high pressure and decompression express surface filamentous actin. Infusion of recombinant human plasma gelsolin lyses these particles in decompressed mice and ameliorates particle-associated vascular damage. Human neutrophils also respond to high pressure with an increase in surface filamentous actin and microparticle production, and these events are inhibited by plasma gelsolin. Gelsolin infusion may have benefit as prophylaxis or treatment for decompression sickness.

Physiologic and biochemical rationale for treating COVID-19 patients with hyperbaric oxygen.

The SARS-Cov-2 (COVID-19) pandemic remains a major worldwide public health issue. Initially, improved supportive and anti-inflammatory intervention, often employing known drugs or technologies, provided measurable improvement in management. We have recently seen advances in specific therapeutic interventions and in vaccines. Nevertheless, it will be months before most of the world's population can be vaccinated to achieve herd immunity. In the interim, hyperbaric oxygen (HBO2) treatment offers several potentially beneficial therapeutic effects. Three small published series, one with a propensity-score-matched control group, have demonstrated safety and initial efficacy. Additional anecdotal reports are consistent with these publications. HBO2 delivers oxygen in extreme conditions of hypoxemia and tissue hypoxia, even in the presence of lung pathology. It provides anti-inflammatory and anti-proinflammatory effects likely to ameliorate the overexuberant immune response common to COVID-19. Unlike steroids, it exerts these effects without immune suppression. One study suggests HBO2 may reduce the hypercoagulability seen in COVID patients. Also, hyperbaric oxygen offers a likely successful intervention to address the oxygen debt expected to arise from a prolonged period of hypoxemia and tissue hypoxia. To date, 11 studies designed to investigate the impact of HBO2 on patients infected with SARS-Cov-2 have been posted on clinicaltrials.gov. This paper describes the promising physiologic and biochemical effects of hyperbaric oxygen in COVID-19 and potentially in other disorders with similar pathologic mechanisms.

Early Predictors of Near-Shore Spinal Injuries Among Emergency Department Patients.

BACKGROUND: Spinal injuries (SIs) can pose a significant burden to patients and family; delayed surgical intervention, associated with interhospital transfer, results in worse outcomes. OBJECTIVE: This study aimed to identify early patient-centered factors associated with risk for near-shore SIs to assist clinicians with expeditious medical decision-making. METHODS: We performed a multicenter retrospective study of all adults transported from Ocean City, Maryland to two emergency departments (EDs) and one regional trauma center for evaluation of suspected SIs from 2006 to 2017. Outcomes were any SI and any spinal cord injury (SCI). Multivariable logistic regression was performed for association of environmental and clinical factors with outcomes. RESULTS: We analyzed 278 records, 102 patients (37%) were diagnosed with any SI and 41 (15%) were diagnosed with SCIs. Compared with patients without SI, patients with SI were more likely to be older (48 vs. 39 years), male (90% vs. 70%), with pre-existing spinal condition (62% vs. 33%), and injury caused by diving (11% vs. 2%). Multivariable logistic regression showed age (odd ratio [OR] 1.07; 95% confidence interval [CI] 1.04-1.11), diving (OR 3.5; 95% CI 3-100+), and wave height (OR 4.5; 95% CI 1.35-15.2) were associated with any SI, and a chief complaint of extremity numbness or tingling (OR 5.73; 95% CI 1.2-27.9) was associated with SCI. CONCLUSIONS: We identified older age, diving, and higher wave height as risk factors for any SI and symptoms of numbness and tingling were associated with SCIs. Clinicians should consider expediting these patients' transfers to a trauma center with neurosurgical capability.

The Effects of Hyperbaric Oxygen on Rheumatoid Arthritis: A Pilot Study.

BACKGROUND/OBJECTIVE: This case series pilot study assessed the effects of hyperbaric oxygen therapy (HBO2) for treating rheumatoid arthritis (RA). METHODS: Ten RA subjects received 30 HBO2 treatments over 6 to 10 weeks. Serial rheumatologic evaluations (ie, the Disease Activity Scale [DAS28], the Routine Assessment of Patient Index Data 3, and the Pain and Sleep Quality Questionnaire) were completed at baseline, throughout the course of the study, and at the 6-month follow-up. RESULTS: There was a statistically significant effect of HBO2 therapy over time on the DAS28-Global Health (p = 0.01), the DAS28-C-reactive protein (p = 0.002), and the DAS28-erythrocyte sedimentation rate (p = 0.008) measures; these analyses excluded 2 patients who were in clinical remission at baseline. Selected post hoc comparisons showed significantly lower DAS28-Global Health, DAS28-C-reactive protein, and DAS28-erythrocyte sedimentation rate scores at 3 and 6 months relative to baseline. In addition, statistically significant decreases in pain as measured by the Routine Assessment of Patient Index Data 3 and Pain and Sleep Quality Questionnaire were observed at the end of HBO2 relative to baseline. CONCLUSIONS: Hyperbaric oxygen therapy is effective for joint pain in patients with RA based on data from multiple, validated clinical measures. Further research with more subjects and the use of a control group is necessary.

The Role of Hyperbaric Oxygen Treatment for COVID-19: A Review.

The recent coronavirus disease 2019 (COVID-19) pandemic produced high and excessive demands for hospitalizations and equipment with depletion of critical care resources. The results of these extreme therapeutic efforts have been sobering. Further, we are months away from a robust vaccination effort, and current therapies provide limited clinical relief. Therefore, several empirical oxygenation support initiatives have been initiated with intermittent hyperbaric oxygen (HBO) therapy to overcome the unrelenting and progressive hypoxemia during maximum ventilator support in intubated patients, despite high FiO2. Overall, few patients have been successfully treated in different locations across the globe. More recently, less severe patients at the edge of impending hypoxemia were exposed to HBO preventing intubation and obtaining the rapid resolution of symptoms. The few case descriptions indicate large variability in protocols and exposure frequency. This summary illustrates the biological mechanisms of action of increased O2 pressure, hoping to clarify more appropriate protocols and more useful application of HBO in COVID-19 treatment.

Effects of Adjunctive Therapeutic Hypothermia Combined With Hyperbaric Oxygen Therapy in Acute Severe Carbon Monoxide Poisoning.

OBJECTIVE: To determine the effects of adjunctive therapeutic hypothermia, by comparing hyperbaric oxygen therapy versus hyperbaric oxygen therapy combined with therapeutic hypothermia in acute severe carbon monoxide poisoning. DESIGN: Retrospective analysis of data from our prospectively collected carbon monoxide poisoning registry. SETTING: A single academic medical center in Wonju, Republic of Korea. PATIENTS: Patients with acute severe carbon monoxide poisoning older than 18 years. Acute severe carbon monoxide poisoning was defined as mental status showing response to painful stimulus or unresponsive at the emergency department, and a continuation of this depressed mental status even after the first hyperbaric oxygen therapy. Patients were classified into the no-therapeutic hypothermia and therapeutic hypothermia groups. Hyperbaric oxygen therapy was performed up to twice within 24 hours after emergency department arrival, whereas therapeutic hypothermia was performed at a body temperature goal of 33°C for 24 hours using an endovascular cooling device after the first hyperbaric oxygen therapy. INTERVENTIONS: Hyperbaric oxygen therapy versus hyperbaric oxygen therapy combined with therapeutic hypothermia. MEASUREMENTS AND MAIN RESULTS: We investigated the difference in the Global Deterioration Scale score at 1 and 6 months after carbon monoxide exposure, between the no-therapeutic hypothermia and therapeutic hypothermia groups. Global Deterioration Scale scores were classified as follows: 1-3 points (favorable neurocognitive outcome) and 4-7 points (poor neurocognitive outcome). During the study period, 37 patients were treated for acute severe carbon monoxide poisoning, with 16 and 21 patients in the no-therapeutic hypothermia and therapeutic hypothermia groups, respectively. The therapeutic hypothermia group demonstrated significantly higher number of patients with favorable outcomes (p = 0.008) at 6 months after carbon monoxide exposure and better improvement of the 6-month Global Deterioration Scale score than the 1-month score (p = 0.006). CONCLUSIONS: Our data suggest that in acute severe carbon monoxide poisoning, patients who were treated using therapeutic hypothermia combined with hyperbaric oxygen therapy had significantly more favorable neurocognitive outcomes at 6 months after carbon monoxide exposure than those treated with hyperbaric oxygen therapy alone.

Transport Blood Pressures and Outcomes in Stroke Patients Requiring Thrombectomy.

OBJECTIVE: Mechanical thrombectomy is the treatment of choice for acute ischemic strokes from large vessel occlusions. Absolute blood pressure and blood pressure variability (BPV) may affect patients' outcome. We hypothesized that patients' outcomes were not associated with BPV during transport between hospitals in the era of effective thrombectomy. METHODS: We performed a retrospective observational review of adult patients admitted to our comprehensive stroke center who underwent mechanical thrombectomy between January 1, 2015, and December 31, 2018. Data were collected from our stroke registry and transportation records. Outcomes were defined as 90-day modified Rankin Scale (mRS) ≤2 and any acute kidney injury (AKI) during hospitalization. RESULTS: We analyzed 134 eligible patients. The mean age was 66 years (standard deviation = 14 years). Forty percent achieved mRS ≤2, and 16% had an AKI. BPV and maximum systolic blood pressures during transport were examined as variables to determine outcome. We found BPV was similar between patients with good and bad functional independence. Furthermore, the maximum systolic blood pressure during transport (odds ratio = 0.98; 95% confidence interval, 0.96-0.99; P = .038), not BPV, was associated with a lower likelihood of mRS ≤2. No similar correlation of analyzed blood pressure variables could be found for AKI as an outcome. CONCLUSION: The maximum systolic blood pressure was associated with worse functional outcomes in stroke patients transported for thrombectomy. Prehospital clinicians should be cognizant of high blood pressure among patients with acute ischemic stroke from large vessel occlusion during transport and treat accordingly.

Transportation Management Affecting Outcomes of Patients With Spontaneous Intracranial Hemorrhage.

OBJECTIVE: Patients with spontaneous intracranial hemorrhage (sICH) have poor outcomes, in part because of blood pressure variability (BPV). Patients with sICH causing elevated intracranial pressure (ICP) are frequently transferred to tertiary centers for neurosurgical interventions. We hypothesized that BPV and care intensity during transport would correlate with outcomes in patients with sICH and elevated ICP. METHODS: We analyzed charts from adult sICH patients who were transferred from emergency departments to a quaternary academic center from January 1, 2011, to September 30, 2015, and received external ventricular drainage. Outcomes were in-hospital mortality and the Glasgow Coma Scale on day 5 (HD5GCS). Multivariable and ordinal logistic regressions were used for associations between clinical factors and outcomes. RESULTS: We analyzed 154 patients, 103 (67%) had subarachnoid hemorrhage and 51 (33%) intraparenchymal hemorrhage; 38 (25%) died. BPV components were similar between survivors and nonsurvivors and not associated with mortality. Each additional intervention during transport was associated with a 5-fold increase in likelihood to achieve a higher HD5GCS (odds ratio = 5.4; 95% confidence interval, 1.7-16; P = .004). CONCLUSION: BPV during transport was not associated with mortality. However, high standard deviation in systolic blood pressure during transport was associated with lower HD5GCS in patients with intraparenchymal hemorrhage. Further studies are needed to confirm our observations.

Blood-borne and brain-derived microparticles in morphine-induced anti-nociceptive tolerance.

We hypothesized that elevations of microparticles (MPs) would occur with morphine administration to mice. Repetitive dosing to induce anti-nociceptive tolerance increases blood-borne MPs by 8-fold, and by 10-fold in deep cervical lymph nodes draining brain glymphatics. MPs express proteins specific to cells including neutrophils, microglia, astrocytes, neurons and oligodendrocytes. Interleukin (IL)-1ß content of MPs increases 68-fold. IL-1ß antagonist administration diminishes blood-borne and cervical lymph node MPs, and abrogates tolerance induction. Intravenous polyethylene glycol Telomer B, a surfactant that lyses MPs, and intraperitoneal methylnaltrexone also inhibit MPs elevations and tolerance. Critically, neutropenic mice do not develop anti-nociceptive tolerance, elevations of blood-borne or cervical node MPs. Immunohistochemical evidence for microglial activation by morphine does not correlated with the MPs response pattern. Neutrophil-derived MPs appear to be required for morphine-induced anti-nociceptive tolerance. Further, patients entering treatment for opioid use disorder exhibit similar MPs elevations as do tolerant mice.

Vascular dysfunction following breath-hold diving.

The pathogenesis of predominantly neurological decompression sickness (DCS) is multifactorial. In SCUBA diving, besides gas bubbles, DCS has been linked to microparticle release, impaired endothelial function, and platelet activation. This study focused on vascular damage and its potential role in the genesis of DCS in breath-hold diving. Eleven breath-hold divers participated in a field study comprising eight deep breath-hold dives with short surface periods and repetitive breath-hold dives lasting for 6 h. Endothelium-dependent vasodilation of the brachial artery, via flow-mediated dilation (FMD), and the number of microparticles (MPs) were assessed before and after each protocol. All measures were analyzed by two-way within-subject ANOVA (2 × 2 ANOVA; factors: time and protocol). Absolute FMD was reduced following both diving protocols (p < 0.001), with no interaction (p = 0.288) or main effect of protocol (p = 0.151). There was a significant difference in the total number of circulating MPs between protocols (p = 0.007), where both increased post-dive (p = 0.012). The number of CD31+/CD41- and CD66b+ MP subtypes, although different between protocols (p < 0.001), also increased by 41.0% ± 56.6% (p = 0.050) and 60.0% ± 53.2% (p = 0.045) following deep and repetitive breath-hold dives, respectively. Both deep and repetitive breath-hold diving lead to endothelial dysfunction that may play an important role in the genesis of neurological DCS.