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Plastic bronchitis is a rare condition characterized by the formation of airway casts occluding the lower respiratory tract. It is described more commonly in children, especially following correction of congenital heart disease. It involves lymphatic abnormalities leading to endobronchial lymph precipitating airway cast formation. When it presents acutely, it can lead to acute airway obstruction, which can be life-threatening. Plastic bronchitis has been rarely described in adults and is potentially underdiagnosed. The purpose of this case report is to emphasize, for the adult anesthesiologist and adult critical care physician, the importance of prompt diagnosis and respiratory support in a case of plastic bronchitis.A 40-yr-old female with severe aortic stenosis underwent a Ross procedure. The surgery was uneventful, but within two hours of arrival in the intensive care unit, the patient developed severe hypoxemia. Despite attempts to optimize her respiratory status, the patient remained severely hypoxemic, and veno-venous extracorporeal membrane oxygenation (ECMO) was initiated using a percutaneous femoro-femoral cannulation. A bronchoscopy showed bronchial secretions casting the proximal bronchus, suggestive of plastic bronchitis. After numerous bronchoscopies, we were able to clean the airways and wean the ECMO support on postoperative day 3.Plastic bronchitis can present in adult patients and be life-threatening when associated with acute respiratory failure. We report an unusual case of an adult patient treated with veno-venous ECMO for plastic bronchitis following cardiac surgery. Use of ECMO support while providing airway cleaning can be lifesaving in patients with respiratory failure secondary to plastic bronchitis.RéSUMé: OBJECTIF: La bronchite plastique est une affection rare caractérisée par la formation de bouchons muqueux qui moulent et obstruent les voies aériennes inférieures. Elle est plus fréquemment décrite chez les enfants, en particulier après la correction d’une cardiopathie congénitale. Elle découle d’anomalies lymphatiques conduisant à l’accumulation de lymphe endobronchique, précipitant la formation de bouchons muqueux dans les voies aériennes. Lorsqu’elle se présente de manière aiguë, la bronchite plastique peut entraîner une obstruction aiguë des voies aériennes, une complication potentiellement fatale. La bronchite plastique a rarement été décrite chez l’adulte et est potentiellement sous-diagnostiquée. L’objectif de cette présentation de cas est de souligner, pour l’anesthésiologiste et l’intensiviste s’occupant d’une population adulte, l’importance d’un diagnostic rapide et d’un support respiratoire en cas de bronchite plastique. CARACTéRISTIQUES CLINIQUES: Une femme de 40 ans souffrant d’une sténose aortique sévère a bénéficié d’une procédure de Ross. La chirurgie s’est déroulée sans incident, mais dans les deux heures suivant son arrivée à l’unité de soins intensifs, la patiente a présenté une hypoxémie sévère. Malgré les tentatives d’optimisation de son état respiratoire, la patiente est restée gravement hypoxémique et une oxygénation par membrane extracorporelle (ECMO) veino-veineuse a été amorcée à l’aide d’une canulation fémoro-fémorale percutanée. Une bronchoscopie a montré des sécrétions bronchiques moulant les bronches proximales, évoquant une bronchite plastique. Après de nombreuses bronchoscopies, nous avons pu nettoyer les voies aériennes et sevrer la patiente du soutien ECMO au 3ème jour postopératoire. CONCLUSION: La bronchite plastique peut se présenter chez les patients adultes et être potentiellement fatale lorsqu’elle est associée à une insuffisance respiratoire aiguë. Nous rapportons un cas inhabituel d’une patiente adulte traitée par ECMO veino-veineuse pour une bronchite plastique après une chirurgie cardiaque. L’utilisation du soutien par ECMO simultanément au nettoyage des voies aériennes peut être nécessaire chez les patients atteints d’insuffisance respiratoire secondaire à une bronchite plastique.

To categorize, quantify and interpret findings documented in feedback letters of monitoring or auditing visits for an investigator-initiated, peer-review funded multicenter randomized trial testing probiotics for critically ill patients.In 37 Canadian centers, monitoring and auditing visits were performed by 3 trained individuals; findings were reported in feedback letters. At trial termination, we performed duplicate content analysis on letters, categorizing observations first into unique findings, followed by 10 pre-determined trial quality management domains. We further classified each observation into a) missing operational records, b) errors in process, and potential threats to c) data integrity, d) patient privacy or e) safety.Across 37 monitoring or auditing visits, 75 unique findings were categorized into 10 domains. Most frequently, observations were in domains of training documentation (180/566 [32%]) and the informed consent process (133/566 [23%]). Most observations were missing operational records (438/566 [77%]) rather than errors in process (128/566 [23%]). Of 75 findings, 13 (62/566 observations [11%]) posed a potential threat to data integrity, 1 (1/566 observation [0.18%]) to patient privacy, and 9 (49/566 observations [8.7%]) to patient safety.Monitoring and auditing findings predominantly concerned missing documentation with minimal threats to data integrity, patient privacy or safety.PROSPECT (Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial): NCT02462590.

Background In randomized clinical controlled trials, the choice of usual care as the comparator may be associated with better clinician uptake of the study protocol and lead to more generalizable results. However, if care processes evolve to resemble the intervention during the course of a trial, differences between the intervention group and usual care control group may narrow. We evaluated the effect on mean arterial pressure of an unblinded trial comparing a lower mean arterial pressure target to reduce vasopressor exposure, vs. a clinician-selected mean arterial pressure target, in critically ill patients at least 65 years old. Methods For this multicenter observational study using data collected both prospectively and retrospectively, patients were recruited from five of the seven trial sites. We compared the mean arterial pressure of patients receiving vasopressors, who met or would have met trial eligibility criteria, from two periods: [1] at least 1 month before the trial started, and [2] during the trial period and randomized to usual care, or not enrolled in the trial. Results We included 200 patients treated before and 229 after trial initiation. There were no differences in age (mean 74.5 vs. 75.2 years; p = 0.28), baseline Acute Physiology and Chronic Health Evaluation II score (median 26 vs. 26; p = 0.47) or history of chronic hypertension (n = 126 [63.0%] vs. n = 153 [66.8%]; p = 0.41). Mean of the mean arterial pressure was similar between the two periods (72.5 vs. 72.4 mmHg; p = 0.76). Conclusions The initiation of a trial of a prescribed lower mean arterial pressure target, compared to a usual clinician-selected target, was not associated with a change in mean arterial pressure, reflecting stability in the net effect of usual clinician practices over time. Comparing prior and concurrent control groups may alleviate concerns regarding drift in usual practices over the course of a trial or permit quantification of any change.

IMPORTANCE: Growing interest in microbial dysbiosis during critical illness has raised questions about the therapeutic potential of microbiome modification with probiotics. Prior randomized trials in this population suggest that probiotics reduce infection, particularly ventilator-associated pneumonia (VAP), although probiotic-associated infections have also been reported. OBJECTIVE: To evaluate the effect of Lactobacillus rhamnosus GG on preventing VAP, additional infections, and other clinically important outcomes in the intensive care unit (ICU). DESIGN, SETTING, AND PARTICIPANTS: Randomized placebo-controlled trial in 44 ICUs in Canada, the United States, and Saudi Arabia enrolling adults predicted to require mechanical ventilation for at least 72 hours. A total of 2653 patients were enrolled from October 2013 to March 2019 (final follow-up, October 2020). INTERVENTIONS: Enteral L rhamnosus GG (1 × 10(10) colony-forming units) (n = 1321) or placebo (n = 1332) twice daily in the ICU. MAIN OUTCOMES AND MEASURES: The primary outcome was VAP determined by duplicate blinded central adjudication. Secondary outcomes were other ICU-acquired infections including Clostridioides difficile infection, diarrhea, antimicrobial use, ICU and hospital length of stay, and mortality. RESULTS: Among 2653 randomized patients (mean age, 59.8 years [SD], 16.5 years), 2650 (99.9%) completed the trial (mean age, 59.8 years [SD], 16.5 years; 1063 women [40.1%.] with a mean Acute Physiology and Chronic Health Evaluation II score of 22.0 (SD, 7.8) and received the study product for a median of 9 days (IQR, 5-15 days). VAP developed among 289 of 1318 patients (21.9%) receiving probiotics vs 284 of 1332 controls (21.3%; hazard ratio [HR], 1.03 (95% CI, 0.87-1.22; P = .73, absolute difference, 0.6%, 95% CI, –2.5% to 3.7%). None of the 20 prespecified secondary outcomes, including other ICU-acquired infections, diarrhea, antimicrobial use, mortality, or length of stay showed a significant difference. Fifteen patients (1.1%) receiving probiotics vs 1 (0.1%) in the control group experienced the adverse event of L rhamnosus in a sterile site or the sole or predominant organism in a nonsterile site (odds ratio, 14.02; 95% CI, 1.79-109.58; P

IntroductionVasodilatory hypotension is common among intensive care unit (ICU) patients; vasopressors are considered standard of care. However, optimal mean arterial pressure (MAP) targets for vasopressor titration are unknown. The objective of the Optimal VAsopressor TitraTION in patients 65 years and older (OVATION-65) trial is to ascertain the effect of permissive hypotension (vasopressor titration to achieve MAP 60–65 mm Hg) versus usual care on biomarkers of organ injury in hypotensive patients aged ≥65 years.Methods and analysisOVATION-65 is an allocation-concealed randomised trial in 7 Canadian hospitals. Eligible patients are ≥65 years of age, in an ICU with vasodilatory hypotension, receiving vasopressors for ≤12 hours to maintain MAP ≥65 mm Hg during or after adequate fluid resuscitation, and expected to receive vasopressors for ≥6 additional hours. Patients are excluded for any of the following: active treatment for spinal cord or acute brain injury; vasopressors given solely for bleeding, ventricular failure or postcardiopulmonary bypass vasoplegia; withdrawal of life-sustaining treatments expected within 48 hours; death perceived as imminent; previous enrolment in OVATION-65; organ transplant within the last year; receiving extracorporeal life support or lack of physician equipoise. Patients are randomised to permissive hypotension versus usual care for up to 28 days. The primary outcome is high-sensitivity troponin T, a biomarker of cardiac injury, on day 3. Secondary outcomes include biomarkers of injury to other organs (brain, liver, intestine, skeletal muscle); lactate (a biomarker of global tissue dysoxia); resource utilisation; adverse events; mortality (90 days and 6 months) and cognitive function (6 months). Assessors of biomarkers, mortality and cognitive function are blinded to allocation.Ethics and disseminationThis protocol has been approved at all sites. Consent is obtained from the eligible patient, the substitute decision-maker if the patient is incapable, or in a deferred fashion where permitted. End-of-grant dissemination plans include presentations, publications and social media platforms and discussion forums.Trial registration numberNCT03431181.

KEY POINTS An 81-year-old man presented to our hospital with signs and symptoms suggestive of a left middle cerebral artery stroke. The patient had a history of stable coronary artery disease, ischemic cardiomyopathy with a left ventricular ejection fraction of 45%, well-controlled hypertension

IntroductionVentilator-associated pneumonia (VAP) is a common healthcare-associated infection in the intensive care unit (ICU). Probiotics are defined as live microorganisms that may confer health benefits when ingested. Prior randomised trials suggest that probiotics may prevent infections such as VAP and Clostridioides difficile–associated diarrhoea (CDAD). PROSPECT (Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial) is a multicentre, double-blinded, randomised controlled trial comparing the efficacy of the probiotic Lactobacillus rhamnosus GG with usual care versus usual care without probiotics in preventing VAP and other clinically important outcomes in critically ill patients admitted to the ICU.Methods and analysisThe objective of E-PROSPECT is to determine the incremental cost-effectiveness of L. rhamnosus GG plus usual care versus usual care without probiotics in critically ill patients. E-PROSPECT will be performed from the public healthcare payer’s perspective over a time horizon from ICU admission to hospital discharge.We will determine probabilities of in-ICU and in-hospital events from all patients alongside PROSPECT. We will retrieve unit costs for each resource use item using jurisdiction-specific public databases, supplemented by individual site unit costs if such databases are unavailable. Direct costs will include medications, personnel costs, radiology/laboratory testing, operative/non-operative procedures and per-day hospital ‘hoteling’ costs not otherwise encompassed. The primary outcome is the incremental cost per VAP prevented between the two treatment groups. Other clinical events such as CDAD, antibiotic-associated diarrhoea and in-hospital mortality will be included as secondary outcomes. We will perform pre-specified subgroup analyses (medical/surgical/trauma; age; frailty status; antibiotic use; prevalent vs no prevalent pneumonia) and probabilistic sensitivity analyses for VAP, then generate confidence intervals using the non-parametric bootstrapping approach.Ethics and disseminationStudy approval for E-PROSPECT was granted by the Hamilton Integrated Research Ethics Board of McMaster University on 29 July 2019. Informed consent was obtained from the patient or substitute decision-maker in PROSPECT. The findings of this study will be published in peer-reviewed journals.Trial registration numberNCT01782755; Pre-results.

Management of asymptomatic small well-differentiated (panNET)2 cm remains controversial. A consensus conference was held on this topic. The impact of attending the conference and participating in the audience response survey on surgeon's clinical approach to pancreatic neuroendocrine tumors was assessed.Audience members were surveyed using a smartphone real-time response system at the beginning and end of the conference.The majority of 75 attendees underwent fellowship training, and 30% had10 years experience as attending surgeons. Previously published consensus statements on the topic were considered insufficient to guide surgical practice by 82% of attendees, and over 96% desired additional data. After review of the data, consensus statements, and decision-making process, a significant number of participants changed their opinions regarding indications for tissue biopsy (p = 0.001), size thresholds for excision (p = 0.002), and regional lymph node dissection (p = 0.002) independent of whether a consensus was reached by the content-expert panel.This represented the first Delphi process consensus on the topic, and the survey confirmed the topic as well-chosen and timely. Attendees changed opinions on management of panNET regardless of whether formal consensus was reached. Therefore, statements of consensus combined with presentation of literature and live discussion served to impact attendees' approach to this disease.

Tumor-specific antigens (TSAs) represent ideal targets for cancer immunotherapy, but few have been identified thus far. We therefore developed a proteogenomic approach to enable the high-throughput discovery of TSAs coded by potentially all genomic regions. In two murine cancer cell lines and seven human primary tumors, we identified a total of 40 TSAs, about 90% of which derived from allegedly noncoding regions and would have been missed by standard exome-based approaches. Moreover, most of these TSAs derived from nonmutated yet aberrantly expressed transcripts (such as endogenous retroelements) that could be shared by multiple tumor types. Last, we demonstrated that, in mice, the strength of antitumor responses after TSA vaccination was influenced by two parameters that can be estimated in humans and could serve for TSA prioritization in clinical studies: TSA expression and the frequency of TSA-responsive T cells in the preimmune repertoire. In conclusion, the strategy reported herein could considerably facilitate the identification and prioritization of actionable human TSAs.

Mechanisms underlying sepsis-associated encephalopathy remain unclear, but reduced cerebral blood flow, alone or in conjunction with altered autoregulation, is reported as a potential contributor. We compared cerebral blood flow of control subjects and vasopressor-dependent septic patients.Randomized crossover study.MRI with arterial spin labeling.Ten sedated septic patients on mechanical ventilation (four with controlled chronic hypertension) and 12 control subjects (six with controlled chronic hypertension) were enrolled. Mean ± SD ages were 61.4 ± 10.2 and 44.2 ± 12.8 years, respectively (p = 0.003). Mean Acute Physiology and Chronic Health Evaluation II score of septic patients at ICU admission was 27.7 ± 6.6.To assess the potential confounding effects of sedation and mean arterial pressure, we measured cerebral blood flow with and without sedation with propofol in control subjects and at a target mean arterial pressure of 65 mm Hg and greater than or equal to 75 mm Hg in septic patients. The sequence of sedation versus no sedation and mean arterial pressure targets were randomized.In septic patients, cerebral blood flow measured at a mean arterial pressure target of 65 mm Hg (40.4 ± 10.9 mL/100 g/min) was not different from cerebral blood flow measured at a mean arterial pressure target of greater than or equal to 75 mm Hg (41.3 ± 9.8 mL/100 g/min; p = 0.65). In control subjects, we observed no difference in cerebral blood flow measured without and with sedation (24.8 ± 4.2 vs 24.9 ± 5.9 mL/100 g/min; p = 0.93). We found no interaction between chronic hypertension and the effect of sedation or mean arterial pressure targets. Cerebral blood flow measured in sedated septic patients (mean arterial pressure target 65 mm Hg) was 62% higher than in sedated control subjects (p = 0.001).In septic patients, cerebral blood flow was higher than in sedated control subjects and did not vary with mean arterial pressure targets. Further research is required to understand the clinical significance of cerebral hyperperfusion in septic patients on vasopressors and to reassess the neurologic effects of current mean arterial pressure targets in sepsis.

BACKGROUNDThe optimal approach to titrate vasopressor therapy is unclear. Recent sepsis guidelines recommend a mean arterial pressure (MAP) target of 65 mmHg and higher for chronic hypertensive patients. As data emerge from clinical trials comparing blood pressure targets for vasopressor therapy, an accurate description of usual care is required to interpret study results. Our aim was to measure MAP values during vasopressor therapy in Canadian intensive care units (ICUs) and to compare these with stated practices and guidelines.METHODIn a multicenter prospective cohort study of critically ill adults with severe hypotension, we recorded MAP and vasopressor doses hourly. We investigated variability across patients and centres using multivariable regression models and Analysis of variance (ANOVA), respectively.RESULTSWe included data from 56 patients treated in 6 centers. The mean (standard deviation [SD]) age and Acute Physiology and Chronic Health Evaluation (APACHE) II score were 64 (14) and 25 (8). Half (28 of 56) of the patients were at least 65 years old, and half had chronic hypertension. The patient-averaged MAP while receiving vasopressors was 75 mm Hg (6) and the median (1st quartile, 3rd quartile) duration of vasopressor therapy was 43 hours (23, 84). MAP achieved was not associated with history of underlying hypertension (p = 0.46) but did vary by center (pCONCLUSIONSIn this multicenter, prospective observational study, the patient-level average MAP while receiving vasopressors for severe hypotension was 75 mmHg, approximately 10 mmHg above current recommendations and stated practices. Moreover, our results do not support the notion that clinicians tailor vasopressor therapy to individual patient characteristics such as underlying chronic hypertension but MAP achieved while receiving vasopressors varied by site.

The outcome of necrotizing soft tissue infections (NSTI) remains unchanged despite advances in care. Reasons cited are changing patterns of causative factors, delays in diagnosis, and inadequate antibiotic coverage and surgical treatment. To document outcomes of NSTI after aggressive management and to identify risk factors of mortality and prolonged hospital stay, we reviewed all our patients with NSTI admitted from January 2000 to January 2002. Causative factors, comorbid conditions, site of NSTI, physiologic parameters, symptoms, diagnostic tests, therapeutic interventions, and outcomes were analyzed. Patients were treated aggressively with antibiotics, admission to ICU, and frequent surgical debridements. Of 46 patients identified, 28 (61%) were admitted in ICU, and eight (17%) died. The patients who died had higher admission white blood cell counts (46 ± 22 vs 22 ± 10 x 103/mm3, P = 0.01), higher admission pain score (8 ± 1 vs 5 ± 3, P = 0.02), longer intervals from admission to antibiotic administration (16 ± 20 vs 6 ± 12 hours, P = 0.02), and fewer surgical debridements (2.6 ± 1.1 vs 3.6 ± 1.7, P = 0.04). No independent risk factors of mortality or ICU admission were identified. We concluded that severe local pain and a significantly elevated white blood cell count on admission should alert the physician to the presence of severe infection and prompt the initiation of expeditious aggressive treatment.

Esophageal anastomotic leak is associated with high morbidity and mortality and potentially lethal if not recognized promptly and treated aggressively. While many studies have attempted to delineate the surgical techniques associated with lower rates of anastomotic leak, few have attempted to determine its long term effects on adjuvant therapy and patient quality of life.We reviewed our prospective 350 patient esophageal-gastric database and found 194 esophageal anastomoses performed from 1994 to 2013. Leaks were classified based on timing, severity, and location. We then compared their postoperative courses of adjuvant treatment, morbidity/mortality, and quality of life measured by Karnofsky performance status and EORTC score. Statistical correlations were calculated with χ(2) , T-test, Kaplain-Meier, ANOVA, and Cox Regression analyses as appropriate.Of 194 patients receiving esophageal anastomoses for cancer, 35 (18%) developed clinically diagnosed anastomotic leak 27 from esophagogastric and 8 from esophagojejunal. These groups were similar in preoperative history, preoperative staging, and type of tumor. Type of operation and variations in operative technique did not significantly affect leak rate. Patients with a leak were more likely to require intraoperative transfusion (47.1% vs. 24.1%, P = 0.013). As expected, they had a greater prevalence of perioperative complications to include pneumonia (38.6% vs. 16.3%, P = 0.001), pulmonary embolus (11.3% vs. 4.3%, P = 0.043), ileus (11.4% vs. 1.6%, P = 0.006%), empyema (11.4% vs. 0%, P 0.001), and catheter related blood stream infections (8.6% vs. 0%, P = 0.001). Despite this increase in perioperative morbidity, there was no statistically significant difference in 90 day peri-operative mortality (2.8% vs. 2.3%) with similar ability to receive adjuvant therapy (38.6% vs. 48.0%, P = 0.303), quality of life scores (93.2 vs. 93.1, P = 0.9), and survival at 12 months (93% vs. 94%, P = 0.3).Anastomotic leak after oncologic resection does not preclude adjuvant therapy and, when managed appropriately, does not affect long term performance status or survival.

A case report, focused on vasopressor use and presented in this article, is likely to resonate with many critical care nurses. In this article the authors describe opportunities to enhance safety with vasopressor therapy. Specifically, the goal of improving communication among physicians, nurses, and pharmacists around desired endpoints for vasopressor therapy, triggers for reassessment of the therapeutic strategy and cause of the patient's shock was identified as an area for improvement. A form piloted within an organization for use during multidisciplinary rounds and key findings is shared. Vasopressors constitute the mainstay of therapy for nearly every hemodynamically unstable patient in critical care. It is hoped that the lessons and information shared help empower critical care nurses to facilitate vasopressor stewardship within their facilities and, ultimately, enhance patient safety.

Patients with chronic low back pain exhibit characteristics such as clinical pain, psychological symptoms and neuromuscular adaptations. The purpose of this study was to determine the independent contribution of clinical pain, psychological factors and neuromuscular adaptations to disability in patients with chronic low back pain. Clinical pain intensity, pain catastrophizing, fear-avoidance beliefs, anxiety, neuromuscular adaptations to chronic pain and neuromuscular responses to experimental pain were assessed in 52 patients with chronic low back pain. Lumbar muscle electromyographic activity was assessed during a flexion-extension task (flexion relaxation phenomenon) to assess both chronic neuromuscular adaptations and neuromuscular responses to experimental pain during the task. Multiple regressions showed that independent predictors of disability included neuromuscular adaptations to chronic pain (β=0.25, p=0.006, sr(2)=0.06), neuromuscular responses to experimental pain (β=-0.24, p=0.011, sr(2)=0.05), clinical pain intensity (β=0.28, p=0.002, sr(2)=0.08) and psychological factors (β=0.58, p0.001, sr(2)=0.32). Together, these predictors accounted for 65% of variance in disability (R(2)=0.65 p0.001). The current investigation revealed that neuromuscular adaptations are independent from clinical pain intensity and psychological factors, and contribute to inter-individual differences in patients' disability. This suggests that disability, in chronic low back pain patients, is determined by a combination of factors, including clinical pain, psychological factors and neuromuscular adaptations.

Esophageal dilation is a rare complication of scleroderma and CREST syndrome. A case of atelectasis secondary to right inferior bronchus compression by a massively dilated esophagus is described. The authors are unaware of any previous cases of atelectasis secondary to esophageal dilation in scleroderma.

A study of the pupillary responses to light comparing the suppressed and nonsuppressed eyes in normals during retinal rivalry, in alternate suppression in exotropia, and the normal and amblyopic eye in strabismic amblyopia is reported. Measuring pupillomotor responses with the infrared pupillograph, it is shown that the fixing or normal eye, when stimulated by light, will cause a greater pupillary contraction than the suppressed or amblyopic eye. This effect is small in normals during rivalry, and increases in magnitude as suppression and amblyopia deepens. This suggests there may be a common anatomic pathway for visual and pupillomotor suppression.

Although the importance of the macrophage complement receptor immunoglobulin (CRIg) in the phagocytosis of complement opsonized bacteria and in inflammation has been established, the regulation of CRIg expression remains undefined. Because cellular activation during inflammation leads to the release of arachidonate, a stimulator of leukocyte function, we sought to determine whether arachidonate regulates CRIg expression. Adding arachidonate to maturing human macrophages and to prematured CRIg(+) macrophages caused a significant decrease in the expression of cell-surface CRIg and CRIg mRNA. This effect was independent of the metabolism of arachidonate via the cyclooxygenase and lipoxygenase pathways, because it was not inhibited by the nonsteroidal anti-inflammatory drugs indomethacin and nordihydroguaiaretic acid. Studies with specific pharmacological inhibitors of arachidonate-mediated signaling pathways showed that protein kinase C was involved. Administration of dexamethasone to macrophages caused an increase in CRIg expression. Studies with proinflammatory and immunosuppressive cytokines showed that IL-10 increased, but interferon-gamma, IL-4, and transforming growth factor-beta 1 decreased CRIg expression on macrophages. This down- and up-regulation of CRIg expression was reflected in a decrease and increase, respectively, in the phagocytosis of complement opsonized Candida albicans. These data suggest that a unique inflammatory mediator network regulates CRIg expression and point to a mechanism by which arachidonate and dexamethasone have reciprocal effects on inflammation. Refereed/Peer-reviewed

From birth, the vault of the skull grows at a prodigious rate, driven by the activity of osteoblastic cells at the fibrous joints (sutures) that separate the bony calvarial plates. One in 2500 children is born with a medical condition known as craniosynostosis because of premature bony fusion of the calvarial plates and a cessation of bone growth at the sutures. Bone morphogenetic proteins (BMPs) are potent growth factors that promote bone formation. Previously, we found that Glypican-1 (GPC1) and Glypican-3 (GPC3) are expressed in cranial sutures and are decreased during premature suture fusion in children. Although glypicans are known to regulate BMP signalling, a mechanistic link between GPC1, GPC3 and BMPs and osteogenesis has not yet been investigated. We now report that human primary suture mesenchymal cells coexpress GPC1 and GPC3 on the cell surface and release them into the media. We show that they inhibit BMP2, BMP4 and BMP7 activities,which both physically interact with BMP2 and that immunoblockade of endogenous GPC1 and GPC3 potentiates BMP2 activity. In contrast, increased levels of GPC1 and GPC3 as a result of over expression or the addition of recombinant protein, inhibit BMP2 signalling and BMP2-mediated osteogenesis. We demonstrate that BMP signalling in suture mesenchymal cells is mediated by both SMAD-dependent and SMAD-independent pathways and that GPC1 and GPC3 inhibit both pathways. GPC3 inhibition of BMP2 activity is independent of attachment of the glypican on the cell surface and post-translational glycanation, and thus appears to be mediated by the core glypican protein. The discovery that GPC1 and GPC3 regulate BMP2-mediated osteogenesis,and that inhibition of endogenous GPC1 and GPC3 potentiates BMP2 responsiveness of human suture mesenchymal cells, indicates how down regulation of glypican expression could lead to the bony suture fusion that characterizes craniosynostosis.