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γδ T lymphocytes are a unique T cell population with important anti-inflammatory capabilities. Their role in acute lung injury, however, is poorly understood but may provide significant insight into lung-protective mechanisms occurring after injury. In a murine model of lung injury, wild-type C57BL/6 and TCRδ(-/-) mice were exposed to Escherichia coli LPS, followed by analysis of γδ T cell and macrophage subsets. In the absence of γδ T cells, TCRδ(-/-) mice developed increased inflammation and alveolar-capillary leak compared with wild-type C57BL/6 mice after LPS exposure that correlated with expansion of distinct macrophage populations. Classically activated M1 macrophages were increased in the lung of TCRδ(-/-) mice at d 1, 4, and 7 after LPS exposure that peaked at d 4 and persisted at d 7 compared with wild-type animals. In response to LPS, Vγ1 and Vγ7 γδ T cells were expanded in the lung and expressed IL-4. Coculture experiments showed decreased expression of TNF-α by resident alveolar macrophages in the presence of γδ T cells that was reversed in the presence of an anti-IL-4-blocking antibody. Treatment of mice with rIL4 resulted in reduced numbers of M1 macrophages, inflammation, and alveolar-capillary leak. Therefore, one mechanism by which Vγ1 and Vγ7 γδ T cells protect against LPS-induced lung injury is through IL-4 expression, which decreases TNF-α production by resident alveolar macrophages, thus reducing accumulation of M1 macrophages, inflammation, and alveolar-capillary leak., (© Society for Leukocyte Biology.)

Introduction: Sedation with dexmedetomidine may facilitate ventilator liberation and limit the occurrence of delirium. No trial has assessed patient recall or the development of psychological outcomes after dexmedetomidine sedation. This pilot study evaluated whether transitioning benzodiazepine sedation to dexmedetomidine alters patient recall and the incidence of anxiety, depression, or acute stress disorder (ASD)., Methods: This investigation was a randomized, double-blind, single-center study. Existing continuous benzodiazepine sedation was converted to dexmedetomidine or midazolam when patients qualified for daily awakenings. Sedation was titrated to achieve Riker sedation agitation scores of 3 to 4. The intensive care unit (ICU) Stressful Experiences Questionnaire, hospital anxiety and depression scale, and the impact of event scale-revised were administered before hospital discharge to assess recall, anxiety, depression, and manifestations of ASD., Results: A total of 11 patients received dexmedetomidine, and 12 patients received midazolam. Median dosing was 0.61 µg/kg/h for 3.5 days for dexmedetomidine and 3.7 mg/h for 3 days for midazolam. Attainment of goal sedation and analgesia was similar; however, more dexmedetomidine patients experienced agitation and pain. The median duration of mechanical ventilation from study drug initiation to extubation was 3.4 days in dexmedetomidine patients and 2.9 days in midazolam patients. Dexmedetomidine patients remembered 18.5 experiences compared with 8.5 in midazolam patients (P = .015). Rates of anxiety and depression were similar. In all, 5 (62.5%) dexmedetomidine patients and 1 (12.5%) midazolam patient manifested ASD (P = .063), and 1 dexmedetomidine patient and 5 midazolam patients developed new-onset delirium (P = .07). Hypotension occurred in 10 (90.9%) dexmedotomidine patients and 6 (50%) midazolam patients (P = .069)., Conclusions: Transitioning benzodiazepine sedation to dexmedetomidine when patients qualify for daily awakenings may reduce the development of delirium and facilitate remembrance of ICU experiences but may lead to manifestations of ASD. Monitoring hypotension is required for both the sedatives. Additional comparative studies focusing on the long-term impact of ICU recall and psychological outcomes are needed., (© The Author(s) 2013.)

Transfusion-related acute lung injury (TRALI) is a rare complication of transfusion, for which the true incidence remains obscure, since there are a number of factors that may lead to misdiagnosis. Despite this, it continues to be the leading cause of transfusion-associated mortality. Here we present a historical case of TRALI in an elderly female who received group AB plasma and discuss how current mitigation strategies would likely have prevented its occurrence. It is important to remember that both immune and non-immune factors play a role in TRALI pathogenesis, and although current preventative strategies may decrease TRALI's incidence, they likely will not eliminate it.

Objectives: To evaluate dexmedetomidine as adjunctive therapy to lorazepam for severe alcohol withdrawal., Design: Prospective, randomized, double-blind, placebo-controlled trial., Setting: Single center; medical ICU., Patients: Twenty-four adult patients with a Clinical Institute Withdrawal Assessment score greater than or equal to 15 despite greater than or equal to 16 mg of lorazepam over a 4-hour period., Interventions: Patients received a symptom-triggered Clinical Institute Withdrawal Assessment protocol with lorazepam and were randomized to dexmedetomidine 1.2 μg/kg/hr (high dose), 0.4 μg/kg/hr (low dose), or placebo as adjunctive therapy for up to 5 days or resolution of withdrawal symptoms., Measurement and Main Results: High-dose and low-dose groups were combined as a single dexmedetomidine group for primary analysis with secondary analysis exploring a dose-response relationship. The difference in 24-hour lorazepam requirements after versus before study drug was greater in the dexmedetomidine group compared with the placebo group (-56 mg vs -8 mg, p = 0.037). Median differences were similar for high dose and low dose. The 7-day cumulative lorazepam requirements were not statistically different between dexmedetomidine and placebo (159 mg vs 181 mg). Clinical Institute Withdrawal Assessment or Riker sedation-agitation scale scores representing severe agitation (13% vs 25%) or moderate agitation (27% vs 22%) within 24 hours of initiating study drug were similar for dexmedetomidine and placebo groups, respectively. Bradycardia occurred more frequently in the dexmedetomidine group versus placebo group (25% vs 0%, p = not significant), with the majority of bradycardia occurring in the high-dose group (37.5%). Study drug rate adjustments occurred more often in the dexmedetomidine group compared with the placebo group (50% vs 0%, p = 0.02). Neither endotracheal intubation nor seizure occurred in any group while on study drug., Conclusions: Adjunctive dexmedetomidine for severe alcohol withdrawal maintains symptom control and reduces lorazepam exposure in the short term, but not long term, when using a symptom-triggered protocol. Monitoring for bradycardia is needed with dexmedetomidine but the occurrence may be lessened with low dose. Further study is needed to evaluate the clinical impact of dexmedetomidine.

Background: Synovia of patients with long-standing rheumatoid arthritis (RA) are typically infiltrated with B lymphocytes and plasma cells that secrete large amounts of immunoglobulin. The CDR3 of an immunoglobulin heavy chain is composed of the VH-DH-JH join, with interposed N region addition, and thus defines clonal relatedness. Furthermore, the CDR3 lies at the center of the antigen binding site, so its length and composition influence antigen binding. We sought definitive evidence of an antigen-driven B cell response (i.e., clones derived from the same VH, DH, and JH gene segments with shared somatic mutations) in RA synovial mRNA transcripts, and to characterize CDR3 intervals at the target of inflammation in this autoimmune disease., Materials and Methods: We screened a cDNA library generated from unselected cells from the knee joint of a 62-year-old white female with long-standing RA. This technique does not have the potential bias of selecting for antibodies that express a particular reactivity such as rheumatoid factor. C gamma recombinants were sequenced and progenitor VH, DH, and JH gene segments were assigned and somatic mutations determined by comparison to germline sequences. Analyses of DH reading frame utilization and hydropathy characteristics of CDR3s were performed., Results: Two of 67 recombinants were derived from the same VH (V3-11) and JH gene segments, demonstrated shared mutations, and contained nearly identical VH-DH-JH joins, including N region addition. Three other recombinants contained identical sequence throughout the variable domain. We also found preferential utilization of a limited number of VH and DH gene segments and marked preference for a DH reading frame encoding predominantly hydrophilic residues., Conclusions: Analysis of expressed heavy chain variable domains strongly supports the hypothesis that the B cell response in RA synovium is at least in part antigen driven and oligoclonal.

Immunoglobulin secretion by plasma cells infiltrating synovial membranes is a prominent feature of RA. Previous analyses of a cDNA library generated from synovium of RA patient BC revealed immunoglobulin kappa light chain transcripts with extensive somatic mutation, frequent N region addition, and unexpected variation in the lengths of CDR3 regions which form the center of the antigen binding site. To determine if these characteristics are present in other individuals, we performed reverse transcription-polymerase chain reaction amplification and sequenced > or = 10 V kappa-containing amplicons from nine tissue samples: synovia of three individuals with long-standing RA (including patient BC), PBLs of two of these individuals, and PBLs or splenocytes of four normal individuals. Increased levels of somatic mutation in PBLs appeared to correlate with increased age, which may reflect accumulation of circulating memory cells and/or decreased bone marrow production of naive B lymphocytes. Two of three RA synovial samples and both RA PBL samples exhibited increased proportions of clones with unusual CDR3 lengths. Enrichment for these antibody binding sites could be due to abnormal regulation of the emerging repertoire or to selection for B lymphocytes bearing antibodies of unusual specificity, and may play a role in the pathogenesis of RA.