Damage-associated molecular patterns in resuscitated hemorrhagic shock are mitigated by peritoneal fluid administration.

Conventional resuscitation (CR) of hemorrhagic shock (HS), a significant cause of trauma mortality, is intravenous blood and fluids. CR restores central hemodynamics, but vital organ flow can drop, causing hypoperfusion, hypoxia, damage-associated molecular patterns (DAMPs), and remote organ dysfunction (i.e., lung). CR plus direct peritoneal resuscitation (DPR) prevents intestinal and hepatic hypoperfusion. We hypothesized that DPR prevents lung injury in HS/CR by altering DAMPs. Anesthetized male Sprague-Dawley rats were randomized to groups ( n = 8/group) in one of two sets: 1) sham (no HS, CR, or DPR), 2) HS/CR (HS = 40% mean arterial pressure (MAP) for 60 min, CR = shed blood + 2 volumes normal saline), or 3) HS/CR + DPR. The first set underwent whole lung blood flow by colorimetric microspheres. The second set underwent tissue collection for Luminex, ELISAs, and histopathology. Lipopolysaccharide (LPS) and DAMPs were measured in serum and/or lung, including cytokines, hyaluronic acid (HA), high-mobility group box 1 (HMGB1), Toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 protein (MYD88), and TIR-domain-containing adapter-inducing interferon-ß (TRIF). Statistics were by ANOVA and Tukey-Kramer test with a priori P < 0.05. HS/CR increased serum LPS, HA, HMGB1, and some cytokines [interleukin (IL)-1α, IL-1ß, IL-6, and interferon-γ]. Lung TLR4 and MYD88 were increased but not TRIF compared with Shams. HS/CR + DPR decreased LPS, HA, cytokines, HMGB1, TLR4, and MYD88 levels but did not alter TRIF compared with HS/CR. The data suggest that gut-derived DAMPs can be modulated by adjunctive DPR to prevent activation of lung TLR-4-mediated processes. Also, DPR improved lung blood flow and reduced lung tissue injury. Adjunctive DPR in HS/CR potentially improves morbidity and mortality by downregulating the systemic DAMP response.

Electrical stimulation of the parabrachial nucleus induces reanimation from isoflurane general anesthesia.

Clinically, emergence from general anesthesia is viewed as a passive process where anesthetics are discontinued at the end of surgery and anesthesiologists wait for the drugs to wear off. The mechanisms involved in emergence are not well understood and there are currently no drugs that can actively reverse the state of general anesthesia. An emerging hypothesis states that brain regions that control arousal become active during emergence and are a key part of the return to wakefulness. In this study, we tested the hypothesis that electrical activation of the glutamatergic parabrachial nucleus (PBN) in the brainstem is sufficient to induce reanimation (active emergence) during continuous isoflurane general anesthesia. Using c-Fos immunohistochemistry as a marker of neural activity, we first show a selective increase in active neurons in the PBN during passive emergence from isoflurane anesthesia. We then electrically stimulated the PBN to assess whether it is sufficient to induce reanimation from isoflurane general anesthesia. Stimulation induced behavioral arousal and restoration of the righting reflex during continuous isoflurane general anesthesia. In contrast, stimulation of the nearby central inferior colliculus (CIC) did not restore the righting reflex. Spectral analysis of the electroencephalogram (EEG) revealed that stimulation produced a significant decrease in EEG delta power during PBN stimulation. The results are consistent with the hypothesis that the PBN provides critical arousal input during emergence from isoflurane anesthesia.

Delta frequency optogenetic stimulation of the thalamic nucleus reuniens is sufficient to produce working memory deficits: relevance to schizophrenia.

BACKGROUND: Low-frequency (delta/theta) oscillations in the thalamocortical system are elevated in schizophrenia during wakefulness and are also induced in the N-methyl-D-asparate receptor hypofunction rat model. To determine whether abnormal delta oscillations might produce functional deficits, we used optogenetic methods in awake rats. We illuminated channelrhodopsin-2 in the thalamic nucleus reuniens (RE) at delta frequency and measured the effect on working memory (WM) performance (the RE is involved in WM, a process affected in schizophrenia [SZ]). METHODS: We injected RE with adeno-associated virus to transduce cells with channelrhodopsin-2. An optical fiber was implanted just dorsal to the hippocampus in order to illuminate RE axon terminals. RESULTS: During optogenetic delta frequency stimulation, rats displayed a strong WM deficit. On the following day, performance was normal if illumination was omitted. CONCLUSIONS: The optogenetic experiments show that delta frequency stimulation of a thalamic nucleus is sufficient to produce deficits in WM. This result supports the hypothesis that delta frequency bursting in particular thalamic nuclei has a causal role in producing WM deficits in SZ. The action potentials in these bursts may "jam" communication through the thalamus, thereby interfering with behaviors dependent on WM. Studies in thalamic slices using the N-methyl-D-asparate receptor hypofunction model show that delta frequency bursting is dependent on T-type Ca(2+) channels, a result that we confirmed here in vivo. These channels, which are strongly implicated in SZ by genome-wide association studies, may thus be a therapeutic target for treatment of SZ.

Ambulance personnel perceptions of near misses and adverse events in pediatric patients.

OBJECTIVE: To identify emergency medical services (EMS) provider perceptions of factors that may affect the occurrence, identification, reporting, and reduction of near misses and adverse events in the pediatric EMS patient. METHODS: This was a subgroup analysis of a qualitative study examining the nature of near misses and adverse events in EMS as it relates to pediatric prehospital care. Complementary qualitative methods of focus groups, interviews, and anonymous event reporting were used to collect results and emerging themes were identified and assigned to specific analytic domains. RESULTS: Eleven anonymous event reports, 17 semistructured interviews, and two focus groups identified 61 total events, of which 12 were child-related. Eight of those were characterized by participants as having resulted in no injury, two resulted in potential injury, and two involved an ultimate fatality. Three analytic domains were identified, which included the following five themes: reporting is uncommon, blaming errors on others, provider stress/discomfort, errors of omission, and limited training. Among perceived causes of events, participants noted factors relating to management problems specific to pediatrics, problems with procedural skill performance, medication problems/calculation errors, improper equipment size, parental interference, and omission of treatment related to providers' discomfort with the patient's age. Few participants spoke about errors they had committed themselves; most discussions centered on errors participants had observed being made by others. CONCLUSIONS: It appears that adverse events and near misses in the pediatric EMS environment may go unreported in a large proportion of cases. Participants attributed the occurrence of errors to the stress and anxiety produced by a lack of familiarity with pediatric patients and to a reluctance to cause pain or potential harm, as well as to inadequate practical training and experience in caring for the pediatric population. Errors of omission, rather than those of commission, were perceived to predominate. This study provides a foundation on which to base additional studies of both a qualitative and quantitative nature that will shed further light on the factors contributing to the occurrence, reporting, and mitigation of adverse events and near misses in the pediatric EMS setting.

A small molecule inhibitor of the Wnt antagonist secreted frizzled-related protein-1 stimulates bone formation.

Canonical Wnt signaling has been demonstrated to increase bone formation, and Wnt pathway components are being pursued as potential drug targets for osteoporosis and other metabolic bone diseases. Deletion of the Wnt antagonist secreted frizzled-related protein (sFRP)-1 in mice activates canonical signaling in bone and increases trabecular bone formation in aged animals. We have developed small molecules that bind to and inhibit sFRP-1 in vitro and demonstrate robust anabolic activity in an ex vivo organ culture assay. A library of over 440,000 drug-like compounds was screened for inhibitors of human sFRP-1 using a cell-based functional assay that measured activation of canonical Wnt signaling with an optimized T-cell factor (TCF)-luciferase reporter gene assay. One of the hits in this screen, a diarylsulfone sulfonamide, bound to sFRP-1 with a K(D) of 0.35 microM in a tryptophan fluorescence quenching assay. This compound also selectively inhibited sFRP-1 with an EC(50) of 3.9 microM in the cell-based functional assay. Optimization of this high throughput screening hit for binding and functional potency as well as metabolic stability and other pharmaceutical properties led to improved lead compounds. One of these leads (WAY-316606) bound to sFRP-1 with a K(D) of 0.08 microM and inhibited it with an EC(50) of 0.65 microM. Moreover, this compound increased total bone area in a murine calvarial organ culture assay at concentrations as low as 0.0001 microM. This work demonstrates the feasibility of developing small molecules that inhibit sFRP-1 and stimulate canonical Wnt signaling to increase bone formation.

Emergency medical services provider perceptions of the nature of adverse events and near-misses in out-of-hospital care: an ethnographic view.

OBJECTIVES: The objectives were to examine the perceptions of emergency medical services (EMS) providers regarding near-misses and adverse events in out-of-hospital care. METHODS: This study uses qualitative methods (focus groups, interviews, event reporting) to examine the perceptions of EMS providers regarding near-misses and adverse events in out-of-hospital care. Results were reviewed by five researchers; analytic domains were assigned and emerging themes were identified. Descriptive statistics were calculated. RESULTS: Fifteen in-depth interviews (73% advanced life support [ALS], 40% volunteer, and 87% male) resulted in 50 event descriptions. Eleven additional event reports were obtained from the anonymous reporting system. Of the 61 total events, 27 (44%) were near-misses and 34 (56%) were adverse events. Fourteen (23%) involved a child (< 19 years). Types of error included 33 clinical judgment (54%), 13 skill performance (21%), 9 medication event (15%), 3 destination choice (5%), and 3 others (5%). For the 21 cases where the provider discussed the event, 10 (48%) were reported to a physician, and 9 (43%) to a supervisor; 4 (19%) were not reported, and none were reported to the patient. Focus groups supported interview and event report data. Emerging themes included a focus on the errors of others and a "blame-and-shame" culture. CONCLUSIONS: Adverse events and near-misses were common among the EMS providers who participated in this study, but the culture discourages sharing of this information. Participants attributed many events to systems issues and to inadequacies of other provider groups. Further study is necessary to investigate whether these hypothesis-generating themes are generalizable to the EMS community as a whole.

Jugular foramen schwannomas: diagnosis, management, and outcomes.

OBJECTIVES/HYPOTHESIS: To describe the presentation, radiographic findings, and surgical management of seven patients who have been diagnosed and treated with jugular foramen schwannomas at the University of Utah. STUDY DESIGN: Retrospective chart review. METHODS: The charts of seven patients diagnosed with jugular foramen schwannomas were reviewed for presentation symptoms, radiographic findings, and physical examination findings. For the six who underwent surgical excision, the surgical procedure used, cranial nerve function results, audiometric results, perioperative complications, and other follow-up data are presented. RESULTS: Seven patients were identified from ages 24 to 69 years. Six of the seven underwent surgical excision. Primary presentation symptoms included dizziness, hearing loss, dysphagia, diplopia, tongue paresis, and hoarseness. The choice of surgical approach was based on the size and location of the tumor. All patients had complete excision of their tumors. The nerve of origin included the glossopharyngeal, vagus, and spinal accessory nerves. Preoperative cranial nerve dysfunction continued postoperatively for lower cranial nerves but resolved in patients who were noted to have preoperative dysfunction of cranial nerve V and VI. The rate of new lower cranial nerve injury was 15% and was only seen in the cranial nerves that were determined to be the nerve of origin. In two cases, a temporary feeding tube was required. No recurrences have been noted to date. CONCLUSIONS: Jugular foramen schwannomas can be successfully diagnosed preoperatively with computed tomography and magnetic resonance imaging. These tumors can be successfully managed with surgery and low morbidity.