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The distribution, density and activation of Langerhans cells (LC) has been established in biopsies of normal human buccal mucosa, hard palate, lateral border and dorsum of tongue, floor of mouth and lip taken from sudden death post mortems. LC were identified in cryostat sections with monoclonal antibodies agains CD1, HLADR, HLADQ and HLADP using an immunoalkaline phosphatase technique. The use of post mortem material was validated by comparison with biopsies taken from volunteers. LC were predominantly situated in the basal and immediately suprabasal layers of the epithelium. In floor of mouth, lip, lateral border and dorsum of tongue the cells were found along the length of the epithelium. In buceal mucosa, although LC showed fundamentally a similar distribution, a tendency to cluster around the connective tissue papillae was also noted. In hard palate LC were found parallel to the surface in the mid zone of the epithelium. No evidence of LC free areas was found. Dorsum of tongue had the highest density of LC per mm epithelial surface length (28.3 cells per mm) which was significantly greater (P < 0.05) than buccal mucosa (25.2) which in turn had signficantly more cells (P< 0.05) than lip (22.4). The lowest density of LC was found in lateral border of tongue (17.6), hard palate (17.6) and floor of mouth (16.7). These sites had significantly fewer cells than lip, buccal mucosa and dorsum of tongue (P< 0.05). Class II MHC molecules are necessary for antigen presentation and in all sites except buceal mucosa there was no significant difference between the number of cells expressing CD1, HLADR, HLADQ and HLADP. In buccal mueosa there were no differences between CDI, HLADR and HLADQ expression but significantly fewer cells expressed HLADP (P< 0.005). The results indicate that although there are regional differences in LC distribution and density, normal oral mucosal LC may be capable of acting as fully functional and efficient antigen presenting cells. [ABSTRACT FROM AUTHOR]

Specimens from Jour regions of oral mucosa (palate, buccal mucosa, lateral border of the tongue, and the floor of the mouth) and of abdominal skin were taken from 58 individuals at autopsy, for determination of permeability constants (Kp) to tritium-labeled water. Comparisons between fresh specimens and those stored at --80°C revealed no significant effect on Kp as a result of freezing; similar results were found with use of specimens from corresponding regions of the pig. Values for Kp were significantly different for all of the tissue regions examined and ranged from 44 ± 4 x 10-7 cm/min for skin to 973 ± 33 x 10-7 cm/min for the floor of the mouth, which was the most permeable region. Similar differences were evident among corresponding regions of porcine oral mucosa and skin. Moreover, the Kp values obtained for human tissues were not significantly different from those of the pig, except for the floor of the mouth, which was more permeable in human than in pig tissue. The results reveal interesting differences in the permeability of human oral mucosa that might be related to susceptibility to mucosal disease in those conditions where local extrinsic etiological agents are implicated. [ABSTRACT FROM AUTHOR]

Evaluates the effects of 3-isobutyl-gamma-aminobutyric acid (GABA), a GABA derivative, against indomethacin-induced gastric damage. Pharmacologic effect of the GABA derivative on the central nervous system.

Aim: To investigate the impact of total pancreatectomy (TP) on oncological outcomes for patients at high-risk of local recurrence or secondary progression in the remnant gland after partial pancreatectomy (PP) for IPMN-associated cancer., Summary Background Data: Major risk factors for invasive progression in the remnant gland include multifocality, diffuse main duct dilation, and the presence of invasive cancer. In these high-risk patients, a TP may be oncologically beneficial. However, current guidelines discourage TP, especially in elderly patients., Methods: This international multicenter study compares TP versus PP in patients with adenocarcinoma arising from multifocal or diffuse IPMN (2002-2022). Log-rank test and multivariable Cox-analysis with interaction analysis was performed to assess overall survival (OS), disease-free survival (DFS), and local-DFS., Results: Of 359 included patients, 162 (45%) were treated with TP, whereas 197 (55%) underwent PP. Despite TP and PP having similar R0-rates (59% vs. 58%, P=0.866), patients undergoing a TP had significantly longer local-DFS compared to PP (P=0.039). However, no difference in OS was observed between the two surgical approaches (P=0.487). In a multivariable analysis, young age (optimal cut-off ≤63.6 yrs) was associated with an OS benefit derived from TP (HR:0.44, 95%CI:0.22-0.89), whereas no significant difference was observed in elderly patients (HR:1.24, 95%CI:0.92-1.67, Pinteraction=0.007)., Conclusion: Since overall, patients with diffuse or multifocal IPMN with an invasive component do not benefit from TP in terms of OS, the indication for TP may be individualized to young patients who have sufficient life expectancy to benefit from the prevention of secondary progression or local recurrence., Competing Interests: Conflicts of Interest: None declared. Disclosures: There are no conflicts of interest for any of the authors., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Evidence to support cryoprecipitate for reversal of alteplase-related hemorrhagic conversion of acute ischemic stroke is limited. Guidelines recommend cryoprecipitate as first line treatment, followed by aminocaproic acid as a conditional recommendation with very low-quality evidence. The purpose of this case series was to describe the use of cryoprecipitate for alteplase-related hemorrhagic conversion of acute ischemic stroke. Methods: This was an IRB-approved retrospective case series of adults who received cryoprecipitate for an alteplase-related hemorrhagic conversion of acute ischemic stroke at two comprehensive stroke centers within a large academic medical center. Thromboembolism at 14 days and hemostasis within 24 hours were collected. The outcomes of cryoprecipitate alone vs cryoprecipitate with aminocaproic acid (C + A) were also described. Results: A total of 19 patients were included. Thrombosis occurred in 1/19 (5%) and hemostasis occurred in 4/14 (29%) of evaluable patients. In-hospital mortality was seen in 9/19 (47%) patients. Seventy four percent (14/19) of patients received concomitant blood products other than cryoprecipitate and 63% received a concomitant reversal agent. Thirteen patients received cryoprecipitate alone and six received C + A. Thrombosis was seen in 1/13 (8%) vs 0/6 (0%) and hemostasis occurred in 2/11 (18%) and 2/3 (67%) evaluable cryoprecipitate vs C + A patients respectively. Conclusion: Cryoprecipitate was associated with a low rate of thrombosis and hemostasis for alteplase-associated hemorrhagic conversion of acute ischemic stroke. There was significant heterogeneity in treatment regimens, including the use of and dosing of adjunctive aminocaproic acid and monitoring of fibrinogen levels.

Aim: Hernia repair strengthens the abdominal wall with a textile mesh. Recurrence and pain indicate weak bonds between mesh and tissue. It remains a question which biomechanical factors strengthen the mesh-tissue interface, and whether surgeons can enhance the bond between mesh and tissue. Material and Methods: This study assessed the strength of the mesh-tissue interface by dynamic loads. A self-built bench test delivered dynamic impacts. The test simulated coughing. Porcine and bovine tissue were used for the bench test. Tissue quality, mesh adhesiveness, and fixation intensity influenced the retention power. The influences were condensed in a formula to assess the durability of the repair. The formula was applied to clinical work. The relative strength of reconstruction was related to the individual human abdominal wall. From computerized tomography at rest and during Valsalva's Maneuver, the tissue quality of the individual patient was determined before surgery. Results: The results showed that biomechanical parameters observed in porcine, bovine, and human tissue were in the same range. Tissues failed in distinct patterns. Sutures slackened or burst at vulnerable points. Both the load duration and the peak load increased destruction. Stress concentrations elevated failure rates. Regional areas of force contortions increased stress concentrations. Hernia repair improved strain levels. Measures for improvement included the closure of the defect, use of higher dynamic intermittent strain (DIS) class meshes, increased mesh overlap, and additional fixation. Surgeons chose the safety margin of the reconstruction as desired. Conclusion: The tissue quality has now been introduced into the concept of a critical and a gained resistance toward pressure-related impacts. A durable hernia repair could be designed from available coefficients. Using biomechanical principles, surgeons could minimize pain levels. Mesh-related complications such as hernia recurrence can potentially be avoided in incisional hernia repair., Competing Interests: FK has received research grants from Baxter®, Dahlhausen®, and Medtronic® not related to the research perspective described in the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kallinowski, Ludwig, Gutjahr, Gerhard, Schulte-Hörmann, Krimmel, Lesch, Uhr, Lösel, Voß, Heuveline, Vollmer, Görich and Nessel.)

Purpose: Current guidelines favor 4F-PCC over plasma for warfarin reversal. Uncertainty remains on its thrombotic risk and hemostatic effectiveness when used for direct-acting oral anticoagulants (DOACs), transplants, massive transfusion protocols (MTP), and non-anticoagulated patients. This study sought to evaluate the tolerability and effectiveness of 4F-PCC in a real-world setting., Materials and Methods: This was a retrospective study of adults who received 4F-PCC from March 2014 to December 2015. The primary outcome was thromboembolic events within 14 days. The secondary outcome was hemostatic effectiveness within 24 h., Results: The final analysis included 212 patients. Primary reversal indication was major bleed in 165 patients (77.8%) and emergent surgery in 47 patients (22.2%). Thromboembolism occurred in 22 patients (10.4%), more in emergent surgery than major bleed reversals (17% and 8.5%, respectively). MTP and heart transplant patients had the highest thromboembolic event rates (44.4% and 28.6%, respectively). Hemostatic effectiveness was 65.8% (68% in major bleed and 58.1% in emergent surgery). DOAC patients achieved hemostasis most often (78.9%). Administration of any reversal agent, major surgery within 14 days, and MTP activation were significant predictors of thromboembolism., Conclusions: Use of 4F-PCC in this real-world setting was associated with variable thromboembolic and hemostatic effectiveness rates based on the indication for reversal., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Little data exist regarding the practice of sodium management in acute neurologically injured patients. This study describes the practice variations, thresholds for treatment, and effectiveness of treatment in this population., Methods: This retrospective, multicenter, observational study identified 400 ICU patients, from 17 centers, admitted for ≥48 h with subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), intraparenchymal hemorrhage, or intracranial tumors between January 1, 2011 and July 31, 2012. Data collection included demographics, APACHE II, Glascow Coma Score (GCS), serum sodium (Na+), fluid rate and tonicity, use of sodium-altering therapies, intensive care unit (ICU) and hospital length of stay, and modified Rankin score upon discharge. Data were collected for the first 21 days of ICU admission or ICU discharge, whichever came first. Sodium trigger for treatment defined as the Na+ value prior to treatment with response defined as an increase of ≥4 mEq/L at 24 h., Results: Sodium-altering therapy was initiated in 34 % (137/400) of patients with 23 % (32/137) having Na + >135 mEq/L at time of treatment initiation. The most common indications for treatment were declining serum Na + (68/116, 59 %) and cerebral edema with mental status changes (21/116, 18 %). Median Na + treatment trigger was 133 mEq/L (IQR 129-139) with no difference between diagnoses. Incidence and treatment of hyponatremia was more common in SAH and TBI [SAH (49/106, 46 %), TBI (39/97, 40 %), ICH (27/102, 26 %), tumor (22/95, 23 %); p = 0.001]. The most common initial treatment was hypertonic saline (85/137, 62 %), followed by oral sodium chloride tablets (42/137, 31 %) and fluid restriction (15/137, 11 %). Among treated patients, 60 % had a response at 24 h. Treated patients had lower admission GCS (12 vs. 14, p = 0.02) and higher APACHE II scores (12 vs. 10, p = 0.001). There was no statistically significant difference in outcome when comparing treated and untreated patients., Conclusion: Sodium-altering therapy is commonly employed among neurologically injured patients. Hypertonic saline infusions were used first line in more than half of treated patients with the majority having a positive response at 24 h. Further studies are needed to evaluate the impact of various treatments on patient outcomes.

Study Objective: To describe the effectiveness and tolerability of conivaptan and tolvaptan for the correction of hyponatremia in neurocritically ill patients., Design: Retrospective cohort study., Setting: Neurointensive care units at two academic medical centers., Patients: Thirty-six adults admitted to the neurocritical care unit who received at least one dose of conivaptan (5 patients) or tolvaptan (31 patients) between June 2012 and May 2013., Measurements and Main Results: A single oral dose or intravenous bolus was administered to 23 (74%) patients who received tolvaptan and 2 (40%) patients who received conivaptan, respectively. The mean maximal increase in serum sodium level at 24 hours following the last dose compared with baseline was 5.2 mEq/L for conivaptan (p=0.05) and 7.9 mEq/L for tolvaptan (p<0.001). The mean ± SD maximal increases in serum sodium level at 48, 72, and 96 hours following the last dose of vaptan therapy compared with baseline were 5.5 ± 2.2 mEq/L (p=0.01), 5.6 ± 2.0 mEq/L (p=0.005), and 4.8 ± 2.2 mEq/L (p=0.03), respectively. Sodium overcorrection occurred in six patients (19%) receiving tolvaptan and none of the patients receiving conivaptan. Hypotension occurred in 20% of patients receiving conivaptan and 52% of patients receiving tolvaptan, whereas hypokalemia was observed in 40% of patients receiving conivaptan., Conclusion: Use of vaptans in neurocritically ill patients led to a significant increase in serum sodium level at 24 hours after the last dose, which was sustained for 96 hours, with the majority of patients receiving a single dose. Risk of sodium overcorrection was high and necessitates appropriate patient selection and frequent monitoring., (© 2017 Pharmacotherapy Publications, Inc.)

Purpose: Recently published practice guidelines and research reports on pharmacotherapy in critical care patient populations are summarized., Summary: The Critical Care Pharmacotherapy Literature Update (CCPLU) Group is composed of over 50 experienced critical care pharmacists who evaluate 31 peer-reviewed journals monthly to identify literature pertaining to pharmacotherapy in critical care populations. Articles are chosen for summarization in a monthly CCPLU Group publication on the basis of applicability and relevance to clinical practice and strength of study design. From January to December 2015, a total of 121 articles were summarized; of these, 3 articles presenting clinical practice guidelines and 12 articles presenting original research findings were objectively selected for inclusion in this review based on their potential to change or reinforce current evidence-based practice. The reviewed guidelines address the management of intracranial hemorrhage (ICH), adult advanced cardiac life support (ACLS) and post-cardiac arrest care, and the management of supraventricular tachycardia (SVT). The reviewed research reports address topics such as nutrition in critically ill adults, administration of β-lactams for severe sepsis, anticoagulant selection in the context of continuous renal replacement therapy, early goal-directed therapy in septic shock, magnesium use for neuroprotection in acute stroke, and progesterone use in patients with traumatic brain injury., Conclusion: Important recent additions to the critical care pharmacy literature include updated joint clinical practice guidelines on the management of spontaneous ICH, ACLS, and SVT., (Copyright © 2017 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

T-cell activation requires increased ATP and biosynthesis to support proliferation and effector function. Most models of T-cell activation are based on in vitro culture systems and posit that aerobic glycolysis is employed to meet increased energetic and biosynthetic demands. By contrast, T cells activated in vivo by alloantigens in graft-versus-host disease (GVHD) increase mitochondrial oxygen consumption, fatty acid uptake, and oxidation, with small increases of glucose uptake and aerobic glycolysis. Here we show that these differences are not a consequence of alloactivation, because T cells activated in vitro either in a mixed lymphocyte reaction to the same alloantigens used in vivo or with agonistic anti-CD3/anti-CD28 antibodies increased aerobic glycolysis. Using targeted metabolic (13)C tracer fate associations, we elucidated the metabolic pathway(s) employed by alloreactive T cells in vivo that support this phenotype. We find that glutamine (Gln)-dependent tricarboxylic acid cycle anaplerosis is increased in alloreactive T cells and that Gln carbon contributes to ribose biosynthesis. Pharmacological modulation of oxidative phosphorylation rapidly reduces anaplerosis in alloreactive T cells and improves GVHD. On the basis of these data, we propose a model of T-cell metabolism that is relevant to activated lymphocytes in vivo, with implications for the discovery of new drugs for immune disorders., (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.)

Introduction: Seizures refractory to third-line therapy are also labeled super-refractory status epilepticus (SRSE). These seizures are extremely difficult to control and associated with poor outcome. We aimed to characterize efficacy and side-effects of continuous infusions of pentobarbital (cIV-PTB) treating SRSE., Methods: We retrospectively reviewed continuous electroencephalography (cEEG) reports for all adults with RSE treated with cIV-PTB between May 1997 and April 2010 at our institution. Patients with post-anoxic SE and those receiving cIV-PTB for reasons other than RSE were excluded. We collected baseline information, cEEG findings, side-effects and functional outcome at discharge and one year., Results: Thirty one SRSE patients treated with cIV-PTB for RSE were identified. Mean age was 48 years old (interquartile range (IQR) 28,63), 26% (N = 8) had a history of epilepsy. Median SE duration was 6.5 days (IQR 4,11) and the mean duration of cIV-PTB was 6 days (IQR 3,14). 74% (N = 23) presented with convulsive SE. Underlying etiology was acute symptomatic seizures in 52% (N = 16; 12/16 with encephalitis), remote 30% (N = 10), and unknown 16% (N = 5). cIV-PTB controlled seizures in 90% (N = 28) of patients but seizures recurred in 48% (N = 15) while weaning cIV-PTB, despite the fact that suppression-burst was attained in 90% (N = 28) of patients and persisted >72 hours in 56% (N = 17). Weaning was successful after adding phenobarbital in 80% (12/15 of the patients with withdrawal seizures). Complications during or after cIV-PTB included pneumonia (32%, N = 10), hypotension requiring pressors (29%, N = 9), urinary tract infection (13%, N = 4), and one patient each with propylene glycol toxicity and cardiac arrest. One-third (35%, N = 11) had no identified new complication after starting cIV-PTB. At one year after discharge, 74% (N = 23) were dead or in a state of unresponsive wakefulness, 16% (N = 5) severely disabled, and 10% (N = 3) had no or minimal disability. Death or unresponsive wakefulness was associated with catastrophic etiology (p = 0.03), but none of the other collected variables., Conclusions: cIV-PTB effectively aborts SRSE and complications are infrequent; outcome in this highly refractory cohort of patients with devastating underlying etiologies remains poor. Phenobarbital may be particularly helpful when weaning cIV-PTB.

Objective: This study compares 2 treatment protocols allowing low vs high continuous IV midazolam (cIV-MDZ) doses., Methods: We compared adults with refractory status epilepticus treated with a protocol allowing for high-dose cIV-MDZ (n = 100; 2002-2011) with those treated with the previous lower-dose cIV-MDZ (n = 29; 1996-2000). We collected data on baseline characteristics, cIV-MDZ doses, seizure control, hospital course, and outcome., Results: Median maximum cIV-MDZ dose was 0.4 mg/kg/h (interquartile range [IQR] 0.2, 1.0) for the high-dose group and 0.2 mg/kg/h (IQR 0.1, 0.3) for the low-dose group (p < 0.001) with similar duration of infusion. Median time from status epilepticus onset to cIV-MDZ start was 1 day (IQR 1, 3) for the high-dose group and 2 days (IQR 1, 5) for the low-dose group (p = 0.016). "Withdrawal seizures" (occurring within 48 hours of discontinuation of cIV-MDZ) were less frequent in the high-dose group (15% vs 64%, odds ratio 0.10, 95% confidence interval 0.03-0.27). "Ultimate cIV-MDZ failure" (patients requiring change to a different cIV antiepileptic medication) and hospital complications were not different between groups. Hypotension was more frequent with higher cIV-MDZ doses but was not associated with worse outcome. Discharge mortality was lower in the high-dose group (40% vs 62%, odds ratio 0.34, 95% confidence interval 0.13-0.92 in multivariate analysis)., Conclusions: High-dose cIV-MDZ treatment of refractory status epilepticus can be performed safely, is associated with a lower seizure rate after cIV-MDZ discontinuation, and may be associated with lower mortality than traditional lower-dose protocols., Classification of Evidence: This study provides Class III evidence that midazolam at higher infusion rates is associated with a reduction in seizure recurrence within 48 hours after discontinuation and may be associated with lower mortality.

Purpose: Recent impactful additions to the professional literature on the role of pharmacotherapy in treating the critically ill are summarized., Summary: An unusually large number of updated practice guidelines and other publications with broad critical care pharmacotherapy ramifications appeared in the primary biomedical literature during the designated review period (February 2012-February 2013). Hundreds of relevant articles were evaluated by the Critical Care Pharmacotherapy Literature Update group (CCPLU), a national group of pharmacists who routinely monitor 25 peer-reviewed journals for emerging evidence that pertains to rational medication use in the intensive care unit (ICU) setting. From among those articles, 64 were summarized for dissemination to CCPLU members; the 8 publications deemed to have the greatest utility for critical care practitioners, as determined by CCPLU through a voting process, were selected for inclusion in this review, with preference given to evidence meeting high standards of methodological quality. The summaries presented here include (1) important new recommendations on management of pain, agitation, and delirium in critically ill patients, (2) a comprehensive update of a practice guideline issued in 2008 by the Surviving Sepsis Campaign, (3) novel strategies for the prevention and/or treatment of hyperglycemia in critical care, and (4) reports on clinical trials of promising alternative methods of sedation for use in weaning patients from mechanical ventilation., Conclusion: This review provides synopses of practice guidelines and other recent additions to the professional literature pertaining to rational medication use in the ICU practice setting.

Seizures are a well-described complication of acute brain injury and neurosurgery. Antiepileptic drugs (AEDs) are frequently utilized for seizure prophylaxis in neurocritical care patients. In this review, the Neurocritical Care Society Pharmacy Section describes the evidence associated with the use of AEDs for seizure prophylaxis in patients with intracerebral tumors, traumatic brain injury, aneurysmal subarachnoid hemorrhage, craniotomy, ischemic stroke, and intracerebral hemorrhage. Clear evidence indicates that the short-term use of AEDs for seizure prophylaxis in patients with traumatic brain injury and aneurysmal subarachnoid hemorrhage may be beneficial; however, evidence to support the use of AEDs in other disease states is less clear., (© 2013 American College of Clinical Pharmacy.)

Background: Nicardipine and labetalol are two commonly used antihypertensives for treating elevated blood pressures in the setting of intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH). There are no studies comparing these two agents as continuous infusions., Methods: A retrospective chart review was conducted of patients admitted between November 2009 and January 2011 with ICH and SAH to compare effectiveness and safety between both agents. Percent time spent at goal was set as the primary outcome. The secondary outcomes included blood pressure variability, time to goal, incidence of bradycardia, tachycardia, and hypotension., Results: A total of 81 patients were available for analysis, 10 initiated on labetalol (LAB), 57 on nicardipine (NIC), and 14 required the combination of these agents (COMB) to reach goal. We found no difference between NIC, LAB, and the COMB groups in the median percent time at goal [88 % (61-98); 93 % (51-99); 66 % (25-95), (p = NS)]. Median percentage of blood pressure variability, hypotension, and bradycardia were also comparable between groups, however, more tachycardia was observed in the COMB group versus both LAB and NIC groups (45 vs. 0 vs. 3 %; p < 0.001). Mean time to goal SBP in 24 patients who had BP readings available at 1st h of initiation was 32 ± 34 min in the NIC group and 53 ± 42 min in the LAB group (p = 0.03)., Conclusions: Both agents appear equally effective and safe for blood pressure control in SAH and ICH during the initial admission hours. A prospective study is needed to validate these findings.

Background: Numerous anticonvulsant agents are now available for treating status epilepticus (SE). However, a paucity of data is available to guide clinicians in the initial treatment of seizures or SE. This study describes the current strategies being employed to treat SE in the U.S.A., Methods: Fifteen American academic medical centers completed a retrospective, multicenter, observational study by reviewing 10-20 of the most recent cases of SE at their institution prior to December 31, 2009. A multivariate analysis was performed to determine factors associated with cessation of seizures., Results: A total of 150 patients were included. Most patients with SE had a seizure disorder (58%). SE patients required a median of 3 AEDs for treatment. Three quarters of patients received a benzodiazepine as first-line therapy (74.7%). Phenytoin (33.3%) and levetiracetam (10%) were commonly used as the second AED. Continuous infusions of propofol, barbiturate, or benzodiazepine were used in 36% of patients. Median time to resolution of SE was 1 day and was positively associated with presence of a complex partial seizure, AED non-compliance prior to admission, and lorazepam plus another AED as initial therapy. Prolonged ICU length of stay and topiramate therapy prior to admission were negatively associated with SE resolution. Mortality was higher in patients without a history of seizure (22.2 vs. 6.9%, p = 0.006)., Conclusions: The use of a benzodiazepine followed by an AED, such as phenytoin or levetiracetam, is common as first and second-line therapy for SE and appears to be associated with a shorter time to SE resolution. AED selection thereafter is highly variable. Patients without a history of seizure who develop SE had a higher mortality rate.

Background: As the practice of aggressive temperature control has become more commonplace, new clinical problems are arising, of which shivering is the most common. Treatment for shivering while avoiding the negative consequences of many anti-shivering therapies is often difficult. We have developed a stepwise protocol that emphasizes use of the least sedating regimen to achieve adequate shiver control., Methods: All patients treated with temperature modulating devices in the neurological intensive care unit were prospectively entered into a database. Baseline demographic information, daily temperature goals, best daily GCS, and type and cumulative dose of anti-shivering agents were recorded., Results: We collected 213 patients who underwent 1388 patient days of temperature modulation. Eighty-nine patients underwent hypothermia and 124 patients underwent induced normothermia. In 18% of patients and 33% of the total patient days only none-sedating baseline interventions were needed. The first agent used was most commonly dexmeditomidine at 50% of the time, followed by an opiate and increased doses of propofol. Younger patients, men, and decreased BSA were factors associated with increased number of anti-shivering interventions., Conclusions: A significant proportion of patients undergoing temperature modulation can be effectively treated for shivering without over-sedation and paralysis. Patients at higher risk for needing more interventions are younger men with decreased BSA.

Robust mechanisms for tissue repair are critical for survival of multicellular organisms. Efficient cutaneous wound repair requires the migration of cells at the wound edge and farther back within the epidermal sheet, but the genes that control and coordinate these migrations remain obscure. This is in part because a systematic screening approach for in vivo identification and classification of postembryonic wound closure genes has yet to be developed. Here, we performed a proof-of-principle reporter-based in vivo RNAi screen in the Drosophila melanogaster larval epidermis to identify genes required for normal wound closure. Among the candidate genes tested were kinases and transcriptional mediators of the Jun N-terminal kinase (JNK) signaling pathway shown to be required for epithelial sheet migration during development. Also targeted were genes involved in actin cytoskeletal remodeling. Importantly, RNAi knockdown of both canonical and noncanonical members of the JNK pathway caused open wounds, as did several genes involved in actin cytoskeletal remodeling. Our analysis of JNK pathway components reveals redundancy among the upstream activating kinases and distinct roles for the downstream transcription factors DJun and DFos. Quantitative and qualitative morphological classification of the open wound phenotypes and evaluation of JNK activation suggest that multiple cellular processes are required in the migrating epidermal cells, including functions specific to cells at the wound edge and others specific to cells farther back within the epidermal sheet. Together, our results identify a new set of conserved wound closure genes, determine putative functional roles for these genes within the migrating epidermal sheet, and provide a template for a broader in vivo RNAi screen to discover the full complement of genes required for wound closure during larval epidermal wound healing.

Objective: To better define the activity of soluble CXCL16 in the recruitment of polymorphonuclear neutrophils (PMNs) in vivo, utilizing a novel animal model of gout involving engraftment of SCID mice with normal human synovial tissue (ST) injected intragraft with gouty human synovial fluid (SF)., Methods: For in vitro studies, a modified Boyden chemotaxis system was used to identify CXCL16 as an active recruitment factor for PMNs in gouty SF. Migration of PMNs could be reduced by neutralization of CXCL16 activity in gouty SF. For in vivo analyses, fluorescent dye-tagged PMNs were injected intravenously into SCID mice while, simultaneously, diluted gouty SF containing CXCL16, or depleted of CXCL16 by antibody blocking, was administered intragraft. In addition, the receptor for CXCL16, CXCR6, was inhibited by incubating PMNs with a neutralizing anti-CXCR6 antibody prior to injection into the mouse chimeras. Recruitment of PMNs to the gouty SF-injected normal human ST was then examined in this SCID mouse chimera system., Results: CXCL16 concentrations were highly elevated in gouty SF, and PMNs were observed to migrate in response to CXCL16 in vitro. Normal human ST-SCID mouse chimeras injected intragraft with gouty SF that had been depleted of CXCL16 during PMN transfer showed a significant reduction of 50% in PMN recruitment to engrafted tissue as compared with that after administration of sham-depleted gouty SF. Similar findings were achieved when PMNs were incubated with a neutralizing anti-CXCR6 antibody before injection into chimeras., Conclusion: Overall, the results of this study outline the effectiveness of the human-SCID mouse chimera system as a viable animal model of gout, serving to identify the primary function of CXCL16 as a significant mediator of in vivo recruitment of PMNs to gouty SF.

Introduction: The function of interleukin-18 (IL-18) was investigated in pertinent animal models of rodent rheumatoid arthritis (RA) to determine its proinflammatory and monocyte recruitment properties., Methods: We used a modified Boyden chemotaxis system to examine monocyte recruitment to recombinant human (rhu) IL-18 in vitro. Monocyte recruitment to rhuIL-18 was then tested in vivo by using an RA synovial tissue (ST) severe combined immunodeficient (SCID) mouse chimera. We defined monocyte-specific signal-transduction pathways induced by rhuIL-18 with Western blotting analysis and linked this to in vitro monocyte chemotactic activity. Finally, the ability of IL-18 to induce a cytokine cascade during acute joint inflammatory responses was examined by inducing wild-type (Wt) and IL-18 gene-knockout mice with zymosan-induced arthritis (ZIA)., Results: We found that intragraft injected rhuIL-18 was a robust monocyte recruitment factor to both human ST and regional (inguinal) murine lymph node (LN) tissue. IL-18 gene-knockout mice also showed pronounced reductions in joint inflammation during ZIA compared with Wt mice. Many proinflammatory cytokines were reduced in IL-18 gene-knockout mouse joint homogenates during ZIA, including macrophage inflammatory protein-3alpha (MIP-3alpha/CCL20), vascular endothelial cell growth factor (VEGF), and IL-17. Signal-transduction experiments revealed that IL-18 signals through p38 and ERK1/2 in monocytes, and that IL-18-mediated in vitro monocyte chemotaxis can be significantly inhibited by disruption of this pathway., Conclusions: Our data suggest that IL-18 may be produced in acute inflammatory responses and support the notion that IL-18 may serve a hierarchic position for initiating joint inflammatory responses.