The purinergic P2×7 receptor is expressed on monocytes in Behçet's disease and is modulated by TNF‐α

The P2×7 receptor (P2×7r) is expressed in innate immune cells (e.g. monocyte/macrophages), playing a key role in IL‐1β release. Since innate immune activation and IL‐1β release seem to be implicated in Behçet's disease (BD), a systemic immune‐inflammatory disorder of unknown origin, we hypothesized that P2×7r is involved in the pathogenesis of the disease. Monocytes were isolated from 18 BD patients and 17 healthy matched controls. In BD monocytes, an increased P2×7r expression and Ca²⁺ permeability induced by the selective P2×7r agonist 2′‐3′‐O‐(4‐benzoylbenzoyl)ATP (BzATP) was observed. Moreover, IL‐1β release from LPS‐primed monocytes stimulated with BzATP was markedly higher in BD patients than in controls. TNF‐α‐incubated monocytes from healthy subjects almost reproduced the findings observed in BD patients, as demonstrated by the increase in P2×7r expression and BzATP‐induced Ca²⁺ intake. Our results provide evidence that in BD monocytes both the expression and function of the P2×7r are increased compared with healthy controls, as the possible result, at least in part, of a positive modulating effect of TNF‐α on the receptor. These data indicate P2×7r as a new potential therapeutic target for the control of BD, further supporting the rationale for the use of anti‐TNF‐α drugs in the treatment of the disease.     

Outcomes after cardiac arrest in an adult burn center

Objective

Adult burn patients who experience in-hospital cardiac arrest (CA) and undergo cardiopulmonary resuscitation (CPR) represent a unique patient population. We believe that they tend to be younger and have the added burden of the burn injury compared to other populations. Our objective was to determine the incidence, causes and outcomes following cardiac arrest (CA) and cardio-pulmonary resuscitation (CPR) within this population.

Methods

We conducted a retrospective review at the US Army Institute of Surgical Research (ISR) burn intensive care unit (BICU). Charts from 1st January 2000 through 31st August 2009 were reviewed for study. Data were collected all on adult burn patients who experienced in-hospital CA and CPR either in the BICU or associated burn operating room. Patients undergoing CPR elsewhere in our burn unit were excluded because we could not validate the time of CA since they are not routinely monitored with real-time rhythm strips. The study population included civilian burn patients from the local catchment area and burn casualties from the conflicts in Iraq and Afghanistan, but patients with do-not-resuscitate (DNR) orders were excluded.

Results

We found 57 burn patients who had in-hospital CA and CPR yielding an incidence of one or more in-hospital CA of 34 per 1000 admissions (0.34%). Fourteen of these patients (25%) survived to discharge while 43 (75%) died. The most common initial cardiac rhythm was pulseless electrical activity (50.9%). The most common etiology of CA among burn patients was respiratory failure (49.1%). The most significant variable affecting survival to discharge was duration of CPR (P < 0.01) with no patient surviving more than 7 min of CPR.

Conclusions

CPR in burn patients is sometimes effective, and those patients who survive are likely to have good neurological outcomes. However, prolonged CPR times are unlikely to result in return of spontaneous circulation and may be considered futile. Further, those who experience multiple CA are unlikely to survive to discharge.     

Influence of children's oral health-related quality of life on school performance and school absenteeism

Objective: This study assessed the relation of child oral health‐related quality of life with school performance and school absenteeism. Methods: We followed a cross‐sectional design with a multistage random sample of 312 12‐year‐old schoolchildren living in Brazil. The participants completed the child perceptions questionnaire (CPQ_11–14) that provides information about psychological factors, while their parents or guardians answered questions on their socioeconomic status measured by parents' education level and household income. A dental examination of each child provided information on the prevalence of caries and dental trauma. Data on school performance, which included the results of baseline Brazilian language (Portuguese) tests, and school absenteeism (school days missed) were obtained from the school register. Multilevel linear regression was used to investigate the association among psychological and socioeconomic status and children's school performance. Results: In the multiple model, after adjusting for individual covariates, being a girl was associated with higher school performance (P < 0.05), whereas low household income (P < 0.05), higher mean of CPQ_11–14 (P < 0.05), and higher school days missed (P < 0.001) were identified as individual determinants of lower school performance. When the school‐level covariates were included in the model, the association between subjects' level characteristics and school performance still persisted. Conclusion: Children's school performance and absence were influenced by psychological and socioeconomic conditions.     

Pharmacological Stimulation of the Brain Serotonin Receptor 7 as a Novel Therapeutic Approach for Rett Syndrome

Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG-binding protein 2 gene (MECP2) cause >95% of classic cases, and currently there is no cure for this devastating disorder. The serotonin receptor 7 (5-HT7R) is linked to neuro-physiological regulation of circadian rhythm, mood, cognition, and synaptic plasticity. We presently report that 5-HT7R density is consistently reduced in cortical and hippocampal brain areas of symptomatic MeCP2–308 male mice, a RTT model. Systemic repeated treatment with LP-211 (0.25 mg/kg once/day for 7 days), a brain-penetrant selective 5-HT7R agonist, was able to rescue RTT-related defective performance: anxiety-related profiles in a Light/Dark test, motor abilities in a Dowel test, the exploratory behavior in the Marble Burying test, as well as memory in the Novelty Preference task. In the brain of RTT mice, LP-211 also reversed the abnormal activation of PAK and cofilin (key regulators of actin cytoskeleton dynamics) and of the ribosomal protein (rp) S6, whose reduced activation in MECP2 mutant neurons by mTOR is responsible for the altered protein translational control. Present findings indicate that pharmacological targeting of 5-HT7R improves specific behavioral and molecular manifestations of RTT, thus representing a first step toward the validation of an innovative systemic treatment. Beyond RTT, the latter might be extended to other disorders associated with intellectual disability.     

Plasma for burn shock resuscitation: is it time to go back to the future?

Patients with burn shock can be challenging to resuscitate. Burn shock produces a variety of physiologic derangements: Patients are hypovolemic from volume loss, have a increased systemic vascular resistance, and may have a depressed cardiac output depending on the extent of the thermal injury. Additionally, the burn wound produces a significant inflammatory cascade of events that contributes to the shock state. Fluid resuscitation is foundational for the initial treatment of burn shock. Typical resuscitation is with intravenous lactated Ringer's in accordance with well‐established formulas based on burn wound size. In the past century, as therapies to treat thermal injuries were being developed, plasma was the fluid used for burn resuscitation; in fact, plasma was used in World War II and throughout the 1950s and 1960s. Plasma was abandoned because of infectious risks and complications. Despite huge strides in transfusion medicine and the increased safety of blood products, plasma has never been readopted for burn resuscitation. Over the past 15 years, there has been a paradigm shift in trauma resuscitation: Less crystalloid and more blood products are used; this strategy has demonstrated improved outcomes. Plasma is a physiologic fluid that stabilizes the endothelium. The endotheliopathy of trauma has been described and is mitigated by transfusion strategies with a 1:1 ratio of RBCs to plasma. Thermal injury also results in endothelial dysfunction: the endotheliopathy of burns. Plasma is likely a better resuscitation fluid for patients with significant burn wounds because of its capability to restore intravascular volume status and treat the endotheliopathy of burns.