Developing a regional recovery framework.

A biological attack would present an unprecedented challenge for local, state, and federal agencies, the military, the private sector, and individuals on many fronts, ranging from vaccination and treatment to prioritization of cleanup actions to waste disposal. To prepare for recovery from this type of incident, the Seattle Urban Area Security Initiative (UASI) partners collaborated with military and federal agencies to develop a regional recovery framework. The goal was to identify key information that will assist policymakers and emergency managers in shortening the timeline for recovery and minimizing the economic and public health impacts of a catastrophic anthrax attack. Based on discussions in workshops, tabletop exercises, and interviews with local, state, federal, military, and private sector entities responsible for recovery, the authors identified goals, assumptions, and concepts of operation for various areas to address critical issues the region will face as recovery progresses. Although the framework is specific to a catastrophic, wide-area biological attack using anthrax, it was designed to be flexible and scalable so it could also serve as the recovery framework for an all-hazards approach in other regions and jurisdictions. Benefits from this process include enhanced coordination and collaboration across agencies, a more thorough understanding of the anthrax threat, an opportunity to proactively consider long-term recovery, and a better understanding of the specific policy questions requiring resolution.

Challenges in disposing of anthrax waste.

Disasters often create large amounts of waste that must be managed as part of both immediate response and long-term recovery. While many federal, state, and local agencies have debris management plans, these plans often do not address chemical, biological, and radiological contamination. The Interagency Biological Restoration Demonstration's (IBRD) purpose was to holistically assess all aspects of an anthrax incident and assist in the development of a plan for long-term recovery. In the case of wide-area anthrax contamination and the follow-on response and recovery activities, a significant amount of material would require decontamination and disposal. Accordingly, IBRD facilitated the development of debris management plans to address contaminated waste through a series of interviews and workshops with local, state, and federal representatives. The outcome of these discussions was the identification of 3 primary topical areas that must be addressed: planning, unresolved research questions, and resolving regulatory issues.

Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia.

Severe congenital neutropenia (SCN) is a genetically heterogeneous syndrome associated with mutations of ELANE (ELA2), HAX1, GFI1, WAS, CSF3R or G6PC3. We investigated the prevalence of mutations of ELANE in a cohort of 162 SCN patients for whom blood or bone marrow samples were submitted to the North American Severe Chronic Neutropenia Tissue Repository. Mutations of ELANE were found in 90 of 162 patients (55.6%). Subsequently, we conducted an analysis of a subset of 73 of these cases utilising a high throughput sequencing approach to determine the prevalence of other mutations associated with SCN. Among the 73 patients, mutations of ELANE were detected in 28. In the remaining 45 patients with wild type ELANE alleles, five patients had mutations: GFI1 (1), SBDS (1), WAS (1) and G6PC3 (2); no mutations of HAX1 were detected. In approximately 40% of our cases, the genetic basis of SCN remains unknown. These data suggest that for genetic diagnosis of SCN, ELANE genotyping should first be performed. In patients without ELANE mutations, other known SCN-associated gene mutations will be found rarely and genotyping can be guided by the clinical features of each patient.

Neutrophil elastase and granulocyte colony-stimulating factor receptor mutation analyses and leukemia evolution in severe congenital neutropenia patients belonging to the original Kostmann family in northern Sweden.

BACKGROUND AND OBJECTIVES: Severe congenital neutropenia (SCN) or Kostmann syndrome was originally reported to be an autosomal recessive disease of neutrophil production causing recurrent, life-threatening infections. Mutations in the neutrophil elastase gene (ELA-2) have previously been identified in patients with sporadic or autosomal dominant SCN. DESIGN AND METHODS: We studied 14 individuals (four patients with SCN and ten close relatives) belonging to the original Kostmann family in northern Sweden for mutations in the ELA-2 and the granulocyte colony-stimulating factor (G-CSF) receptor genes. RESULTS: One patient belonging to the original Kostmann family harbored a novel heterozygous ELA-2 mutation (g.2310T-->A;Leu92His) that was not inherited from her parents. The mutation was identified in DNA isolated from both whole blood and skin fibroblasts, suggesting a sporadic de novo mutation. As a young adult this patient sequentially acquired two mutations in the gene for the G-CSF receptor (G-CSFR) and therefore recently received a hematopoietic stem cell transplant, due to the risk of evolution to leukemia. Moreover, another patient developed acute leukemia and was treated with transplantation. No pathogenic ELA-2 or G-CSFR gene mutations were found in this patient or the other two patients, nor in any healthy relative. INTERPRETATION AND CONCLUSIONS: Our data are the first to document leukemia evolution and G-CSFR gene mutations in the original Kostmann kindred. In addition, our findings indicate that ELA-2 mutations are not the primary cause of SCN in the Swedish Kostmann family.

Optimized dose delivery of the peptide cyclosporine using hydrofluoroalkane-based metered dose inhalers.

The goal of this study was to illustrate the potential to deliver relatively high doses of a therapeutic peptide using hydrofluoroalkane (HFA) metered dose inhaler (MDI) drug delivery systems. For the purposes of this study, cyclosporine was used as the model compound. Cyclosporine formulations, varying in peptide concentration, ethanol cosolvent concentration, and propellant type, were evaluated and optimized for product performance. As ethanol concentration was decreased from 10 to 3% by weight, fine particle fraction (the mass of cyclosporine which passes through a 4.7-micron cut point divided by the total mass of cyclosporine delivered ex-valve) increased from 34 to 68% for 227 and 33 to 52% for 134a formulations. Because of the excellent solubility properties of cyclosporine in HFA-based systems, minimal or no ethanol was needed as a cosolvent to achieve cyclosporine concentrations of 1.5% w/w. With these formulations, it was possible to obtain a fine particle mass (mass of particles <4.7 microns) greater than 500 microg per actuation. In addition, one formulation was chosen for stability analysis: 0.09% w/w cyclosporine, 10% w/w ethanol, 134a. Three different types of container closure systems (stainless steel, aluminum, and epoxy-coated canisters) and two storage configurations (upright and inverted) were evaluated. Cyclosporine was determined to be stable in HFA 134a-based MDI systems, regardless of container closure system and configuration, over a 2-year period. Cyclosporine represents a compelling example of how significant peptide doses are attainable through the use of solution-based MDIs. It has been shown that through formulation optimization, 2-3 mg of the peptide, cyclosporine, may be delivered in five actuations to the lung for local or systemic therapy.