New-generation azaindole-adamantyl-derived synthetic cannabinoids

Purpose

This work reports the synthesis and pharmacological and analytical data for a new series of recently identified azaindole-adamantyl-derived synthetic cannabinoids (SCs).

Methods

Each SC was synthesised using an efficient and divergent synthesis, and assessed by electron ionisation mass spectrometry (EIMS). The cannabimimetic activity of each compound was conducted using a fluorometric imaging plate reader (FLIPR) assay.

Results

The described EIMS method and retention time by gas chromatography were able to effectively differentiate each of the analogues regardless of the bicyclic core. For the first time in these SC structures, the bicyclic ring system was shown to have an impact on the cannabimimetic activities in the fluorometric assay of membrane potential. Analogues ranged from moderately potent at both CB₁ and CB₂ (e.g., AP4AIC EC₅₀?=?160 nM and EC₅₀?=?64 nM, respectively) to not active at either cannabinoid receptor (AP4AICA, AP5AICA, and APIC).

Conclusions

Further investigation into receptor selectivity surrounding these bicyclic cores could prove useful for future therapeutic applications.

     

Care of the critically ill patient in a military unique environment: a program of research

The goal of the Air Force Nursing Research Program at WHMC is to conduct research on topics unique to Air Force and military nursing. The nine stressors of flight and the military environment of care have been used as a conceptual model to guide the development of research studies. The studies conducted to date describe how the environment affects practice and when the environment directly affects the patient. The studies conducted are examples of the numerous military nursing research projects supported by funding from the TSNRP. The research funded by TSNRP contributes to the body of nursing knowledge by supporting scientific research, particularly knowledge that is unique to the military. As our nation faces the threat of chemical and biologic attacks, terrorism, and increased deployment of soldiers to battlefields in remote locations throughout the world, it is more important than ever that we ensure the advancement of military nursing research. Supporting research that advances healthcare in peace and in war is critical to the care of our military members and their families. This will require that research funds continue to be available to support military nursing research, that a strong infrastructure to provide resources in support of nursing research programs continues to exist, and that the military nursing corps continues to attract, train, and retain PhD prepared nurse researchers. Given the results of the research completed to date, the following evidence-based practice can be applied to the care of the patient described at the beginning of this article: The nurse positions the patient in the center of the cargo compartment, away from the bulkhead, toward the front of the aircraft, the warmest location during flight. While enroute, the patient will need to be positioned on an aerovac mattress, repositioned frequently, and have his/her heels elevated at all times. Additional padding may be needed for areas adjacent to the litter cross members to reduce pressure on the skin in areas prone to pressure ulcer formation. Should the patient need endotracheal suctioning, the nurse knows that hyperoxygenation-hyperinflation is effective in preventing suctioning-induced hypoxemia. In addition, the suction pressure will need to be increased to account for the effects of altitude without exceeding the pressure limits on the transport ventilator and causing catastrophic ventilator failure. Because there is not enough room on the litter for the chest tube drainage tubing to lay straight, it will be coiled and should dependent loops develop, they should be drained every 15 minutes. This is Air Force nursing research in practice.     

Btk regulates multiple stages in the development and survival of B-1 cells

B-1 cells are important players in the first line of defense against pathogens. According to current models for the origin of B-1 cells, they either represent a separate lineage from conventional B-2 cells or differentiate from conventional B-2 cells via an intermediate, B-1(int), in response to positive selection by antigen. Here we show that Btk, a Tec family kinase that mediates B cell antigen receptor (BCR) signaling, is required at multiple stages of B-1 cell development. VH12 anti-phosphatidylcholine (PtC) IgH transgenic mice provide a model for the induced differentiation of B-1 cells. This transgene selects for PtC-reactive cells and induces them to adopt a B-1 phenotype. Both processes have been shown to depend on Btk. To determine whether this is secondary to a requirement for Btk in the development of mature B-2 cells, we crossed VH12 transgenic mice to mice expressing low levels of Btk. B-2 cell development occurs normally in Btk(lo) mice despite reduced responsiveness to BCR crosslinking. Analysis of VH12.Btk(lo) mice reveals that Btk regulates the B-1(int) to B-1 transition and/or the survival of splenic B-1 cells, in part via a mechanism independent of its role in BCR signaling. We also show that Btk mediates the survival of, and expression of IL-10 by, those B-1 cells that do develop and migrate to the peritoneum. Multiple roles for Btk in B-1 cell development and maintenance may explain the particular sensitivity of this population to mutations in components of Btk signaling pathways.     

Btk and phospholipase C gamma 2 can function independently during B cell development

The pre-BCR and the BCR regulate B cell development via a signalosome nucleated by the adaptor protein B cell linker protein (BLNK). Formation of this complex facilitates activation of phospholipase C (PLC) gamma2 by Bruton's tyrosine kinase (Btk). To determine whether Btk and PLCgamma2 also have separate functions, we generated Btk(-/-)PLCgamma2(-/-) mice. They demonstrated a block in development at the pre-B stage and increased pre-BCR surface expression. This phenotype was more severe than that of Btk(-/-) or PLCgamma2(-/-) mice. Although both Btk and PLCgamma2 were required for proliferation of splenic B cells in response to BCR cross-linking, they contributed differently to anti-IgM-induced phosphorylation of ERK. Btk(-/-) and PLCgamma2(-/-) mice each had a reduced frequency of Iglambda-expressing B cells and impaired migration of pre-B cells towards stromal cell-derived factor 1. However, the increase in pre-B cell malignancy that occurs in BLNK(-/-) mice in the absence of Btk was not observed in the absence of PLCgamma2. Thus, Btk and PLCgamma2 act both in concert and independently throughout B cell development.     

Complications of apheresis in children

BACKGROUND: Although the frequency of complications in adults undergoing therapeutic apheresis is low, there are little data in children. STUDY DESIGN AND METHODS: A retrospective study of 186 children who had undergone a total of 1632 apheresis procedures between 1994 and 2002 was conducted. Adverse reactions were prospectively documented. The procedures were plasma exchange (67%), hematopoietic progenitor cell collection (18%), red blood cell exchange (6.9%), leukodepletion (0.7%), and plasma exchange with immunoadsorption (6.7%). RESULTS: Adverse reactions, most minor, were reported in 55 percent of procedures in 82 percent of patients. The most frequent complications, per procedure and per patient during an entire course of therapy, were hypotension (14 and 48.4%), hypotension requiring fluid bolus (4.8 and 26.9%), symptomatic hypocalcemia (9.7 and 28.5%), allergic reactions (4.4 and 5.9%), catheter-related thrombosis (1.7 and 12.4%), catheter-related infection (2.1 and 16.1%), and severe anemia (hemoglobin [Hb] level, <7 g/dL; 2.5 and 17.2%). There were two deaths (1% of patients). Risk factors for complications by multivariate analysis were lower body weight, lower preapheresis Hb level, apheresis in a critical care unit, and number of procedures per patient. The 55 percent incidence of complications per procedure in our pediatric cohort is much higher than the 4.3 to 28 percent incidence reported in adults. The excess of adverse reactions in children are mostly related to citrate toxicity, higher relative vascular volume shifts, and the need for vascular access. CONCLUSION: Pediatric apheresis presents unique challenges and is associated with higher complication rate compared to adults. It is recommended that this procedure be performed in specialized centers.     

Impact of diagnostic and end-of-induction Curie scores with tandem high-dose chemotherapy and autologous transplants for metastatic high-risk neuroblastoma: A report from the Children's Oncology Group

Background

Diagnostic mIBG (meta-iodobenzylguanidine) scans are an integral component of response assessment in children with high-risk neuroblastoma. The role of end-of-induction (EOI) Curie scores (CS) was previously described in patients undergoing a single course of high-dose chemotherapy (HDC) and autologous hematopoietic cell transplant (AHCT) as consolidation therapy.

Objective

We now examine the prognostic significance of CS in patients randomized to tandem HDC and AHCT on the Children's Oncology Group (COG) trial ANBL0532.

Study design

A retrospective analysis of mIBG scans obtained from patients enrolled in COG ANBL0532 was performed. Evaluable patients had mIBG-avid, International Neuroblastoma Staging System (INSS) stage 4 disease, did not progress during induction therapy, consented to consolidation randomization, and received either single or tandem HDC (n = 80). Optimal CS cut points maximized the outcome difference (≤CS vs. >CS cut-off) according to the Youden index.

Results

For recipients of tandem HDC, the optimal cut point at diagnosis was CS = 12, with superior event-free survival (EFS) from study enrollment for patients with CS ≤ 12 (3-year EFS 74.2% ± 7.9%) versus CS > 12 (59.2% ± 7.1%) (p = .002). At EOI, the optimal cut point was CS = 0, with superior EOI EFS for patients with CS = 0 (72.9% ± 6.4%) versus CS > 0 (46.5% ± 9.1%) (p = .002).

Conclusion

In the setting of tandem transplantation for children with high-risk neuroblastoma, CS at diagnosis and EOI may identify a more favorable patient group. Patients treated with tandem HDC who exhibited a CS ≤ 12 at diagnosis or CS = 0 at EOI had superior EFS compared to those with CS above these cut points.