Medical Mitigation Model: Quantifying the Benefits of the Public Health Response to a Chemical Terrorism Attack

The Chemical Terrorism Risk Assessment (CTRA) and Chemical Infrastructure Risk Assessment (CIRA) are programs that estimate the risk of chemical terrorism attacks to help inform and improve the US defense posture against such events. One aspect of these programs is the development and advancement of a Medical Mitigation Model—a mathematical model that simulates the medical response to a chemical terrorism attack and estimates the resulting number of saved or benefited victims. At the foundation of the CTRA/CIRA Medical Mitigation Model is the concept of stock-and-flow modeling; “stocks” are states that individuals progress through during the event, while “flows” permit and govern movement from one stock to another. Using this approach, the model is able to simulate and track individual victims as they progress from exposure to an end state. Some of the considerations in the model include chemical used, type of attack, route and severity of exposure, response-related delays, detailed treatment regimens with efficacy defined as a function of time, medical system capacity, the influx of worried well individuals, and medical countermeasure availability. As will be demonstrated, the output of the CTRA/CIRA Medical Mitigation Model makes it possible to assess the effectiveness of the existing public health response system and develop and examine potential improvement strategies. Such a modeling and analysis capability can be used to inform first-responder actions/training, guide policy decisions, justify resource allocation, and direct knowledge-gap studies.     

Heptanoate as a neural fuel: energetic and neurotransmitter precursors in normal and glucose transporter I-deficient (G1D) brain

It has been postulated that triheptanoin can ameliorate seizures by supplying the tricarboxylic acid cycle with both acetyl-CoA for energy production and propionyl-CoA to replenish cycle intermediates. These potential effects may also be important in other disorders associated with impaired glucose metabolism because glucose supplies, in addition to acetyl-CoA, pyruvate, which fulfills biosynthetic demands via carboxylation. In patients with glucose transporter type I deficiency (G1D), ketogenic diet fat (a source only of acetyl-CoA) reduces seizures, but other symptoms persist, providing the motivation for studying heptanoate metabolism. In this work, metabolism of infused [5,6,7-¹³C₃]heptanoate was examined in the normal mouse brain and in G1D by ¹³C-nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry (LC-MS). In both groups, plasma glucose was enriched in ¹³C, confirming gluconeogenesis from heptanoate. Acetyl-CoA and glutamine levels became significantly higher in the brain of G1D mice relative to normal mice. In addition, brain glutamine concentration and ¹³C enrichment were also greater when compared with glutamate in both animal groups, suggesting that heptanoate and/or C5 ketones are primarily metabolized by glia. These results enlighten the mechanism of heptanoate metabolism in the normal and glucose-deficient brain and encourage further studies to elucidate its potential antiepileptic effects in disorders of energy metabolism.     

Detection of inadvertent catheter movement into a pulmonary vein during radiofrequency catheter ablation by real-time impedance monitoring

Introduction: During radiofrequency ablation to encircle or isolate the pulmonary veins (PVs), applications of radiofrequency energy within a PV may result in stenosis. The aim of this study was to determine whether monitoring of real-time impedance facilitates detection of inadvertent catheter movement into a PV.
Methods and Results: In 30 consecutive patients (mean age 53 ± 11 years) who underwent a left atrial ablation procedure, the three-dimensional geometry of the left atrium, the PVs, and their ostia were reconstructed using an electroanatomic mapping system. The PV ostia were identified based on venography, changes in electrogram morphology, and manual and fluoroscopic feedback as the catheter was withdrawn from the PV into the left atrium. Real-time impedance was measured at the ostium, inside the PV at approximately 1 and 3 cm from the ostium, in the left atrial appendage, and at the posterior left atrial wall. There was an impedance gradient from the distal PV (127 ± 30 Ω) to the proximal PV (108 ± 15 Ω) to the ostium (98 ± 11 Ω) in each PV (P < 0.01). There was no significant impedance difference between the ostial and left atrial sites. During applications of radiofrequency energy, movement of the ablation catheter into a PV was accurately detected in 80% of the cases (20) when there was an abrupt increase of ≥4 Ω in real-time impedance.
Conclusion: There is a significant impedance gradient from the distal PV to the left atrium. Continuous monitoring of the real-time impedance facilitates detection of inadvertent catheter movement into a PV during applications of radiofrequency energy. (J Cardiovasc Electrophysiol, Vol. 15, pp. 1-5, June 2004)     

Cyclosporine as prophylaxis for graft-versus-host disease: a randomized study in patients undergoing marrow transplantation for acute nonlymphoblastic leukemia

Seventy-five patients, 13 to 49 years of age, with acute nonlymphoblastic leukemia in first remission were treated with cyclophosphamide, fractionated total body irradiation, and marrow transplantation from an HLA-identical sibling and randomized to receive either cyclosporine (CSP) (n = 36) or methotrexate (MTX) (n = 39) as prophylaxis for graft-v-host disease (GVHD). All patients engrafted, and 22 who were given CSP and 21 who were given MTX, are alive at 20 to 47 (median, 35) months (P = .5). Engraftment as assessed by granulocyte recovery (P less than .0005) and platelet transfusion requirement (P = .01) was faster in patients on CSP. Twelve patients (33%) on CSP and 22 (56%) on MTX developed acute GVHD of grades II through IV (P = .07) and 15 of 30 on CSP and 14 of 32 on MTX that were at risk developed chronic GVHD. The most frequent causes of death were interstitial pneumonitis and marrow relapse of leukemia, which occurred with similar frequency in both groups. Beneficial effects observed in patients on CSP included less severe mucositis and shorter duration of hospitalization; adverse effects included renal function impairment and hypertension. These data confirm that CSP is a useful immunosuppressant in patients undergoing marrow transplantation but fail to show a significant improvement in survival as compared with the standard regimen of MTX.     

Effect of β-amyloid block of the fast-inactivating K+ channel on intracellular Ca2+ and excitability in a modeled neuron

β-Amyloid peptide (Aβ), one of the primary protein components of senile plaques found in Alzheimer disease, is believed to be toxic to neurons by a mechanism that may involve loss of intracellular calcium regulation. We have previously shown that Aβ blocks the fast-inactivating potassium (A) current. In this work, we show, through the use of a mathematical model, that the Aβ-mediated block of the A current could result in increased intracellular calcium levels and increased membrane excitability, both of which have been observed in vitro upon acute exposure to Aβ. Simulation results are compared with experimental data from the literature; the simulations quantitatively capture the observed concentration dependence of the neuronal response and the level of increase in intracellular calcium.     

Monocytoid B-cell lymphoma: its evolution and relationship to other low- grade B-cell neoplasms

Monocytoid B-cell lymphoma (MBCL) is a newly recognized B-cell neoplasm of uncertain histogenesis. The cytologic features of the neoplastic monocytoid B lymphocytes are virtually identical to those of hairy cell leukemia (HCL). As with HCL, progression of MBCL to a higher histologic grade is very unusual. However, whereas circulating leukemic cells are a characteristic feature of HCL, peripheral blood involvement has not been reported in MBCL. We recently studied a patient with MBCL of the spleen and axillary lymph nodes who developed peripheral blood involvement by MBCL cells. Unlike the cells of HCL, the circulating MBCL cells exhibited strong acid phosphatase activity that was tartrate sensitive. The leukemic cells had the antigenic phenotype IgM lambda, CD20+, CD11c+, CD5-, CD25(TAC)-, and PCA-1-. Immunogenetic studies of both lymph node and peripheral blood cells revealed identical immunoglobulin heavy-chain gene rearrangements. When compared with a series of HCL, the immunophenotype was similar except for the absence of PCA-1 and TAC. Progression of the MBCL to a large cell lymphoma, also expressing IgM lambda, was documented in an abdominal lymph node of this patient. Therefore, although rare, peripheral blood involvement by lymphoma cells may occur during the course of MBCL and should be distinguished from HCL with cytochemical and immunophenotypic studies. In addition, comparison of the clinical, pathologic, and immunologic features of MBCL with those of other low-grade B-cell neoplasms suggests that a close lineage relationship exists between MBCL and HCL.     

Pulmonary vein isolation as an end point for left atrial circumferential ablation of atrial fibrillation.

OBJECTIVES: We sought to determine whether elimination of pulmonary vein (PV) arrhythmogenicity is necessary for the efficacy of left atrial circumferential ablation (LACA) for atrial fibrillation (AF). BACKGROUND: The PVs often provide triggers or drivers of AF. It has been shown that LACA is more effective than PV isolation in eliminating paroxysmal AF. However, it is not clear whether complete PV isolation is necessary for the efficacy of LACA. METHODS: In 60 consecutive patients with paroxysmal (n = 39) or chronic (n = 21) AF (mean age 53 +/- 12 years), LACA to encircle the left- and right-sided PVs, with additional lines in the posterior left atrium and along the mitral isthmus, was performed under the guidance of an electroanatomic navigation system. The PVs were mapped with a decapolar ring catheter before and after LACA. If PV isolation was incomplete, no attempts at complete isolation were made. RESULTS: After LACA, there was incomplete electrical isolation of one or more PVs in 48 (80%) of the 60 patients. The prevalence of PV tachycardias was 82% before and 8% after LACA (p < 0.001). At 11 +/- 1 months of follow-up, 10 (83%) of the 12 patients with complete and 39 (81%) of 48 patients with incomplete PV isolation were free from recurrent AF without antiarrhythmic drug therapy (p = 1.0). A successful outcome was not related to the number of completely isolated PVs per patient (p = 0.6). CONCLUSIONS: Left atrial circumferential ablation modifies the arrhythmogenic substrate within the PVs. Complete electrical isolation of the PVs is not a requirement for a successful outcome after LACA.     

Mechanism of recurrence after radiofrequency catheter ablation of atrial fibrillation guided by complex fractionated atrial electrograms

Background A better understanding of the mechanisms of recurrent atrial fibrillation (AF) after radiofrequency ablation of complex, fractionated atrial electrograms (CFAEs) may be helpful for refining AF ablation strategies. Methods and results Electrogram-guided ablation (EGA) was repeated in 30 consecutive patients (mean age = 59 ± 8 years) for recurrent paroxysmal AF, 10 ± 4 months after the first ablation. During the first procedure, CFAEs were targeted without isolating all pulmonary veins (PVs). During repeat ablation, all PVs and the superior vena cava (SVC) were mapped with a circular catheter and the left atrium was mapped for CFAEs. EGA was performed until AF was rendered noninducible or all identified CFAEs were eliminated. During repeat ablation, ≥1 PV tachycardia was found in 83 PVs in 29 of the 30 patients (97%). Among these 83 PVs, 63 (76%) had not been completely isolated previously. During repeat ablation, drivers originating in a PV or PV antrum were identified only after infusion of isoproterenol (20 μg/min) in 12 patients (40%). At 9 ± 4 months of follow-up after the repeat ablation procedure, 21 of the 30 patients (70%) were free from recurrent AF and flutter without antiarrhythmic drugs. Conclusions Recurrence of AF after EGA is usually due to PV tachycardias. Therefore, it may be preferable to systematically map and isolate all PVs during the first procedure. High-dose isoproterenol may be helpful to identify AF drivers.     

Marrow transplantation with or without donor buffy coat cells for 65 transfused aplastic anemia patients

Sixty-five multiply transfused patients with severe aplastic anemia were given cyclophosphamide followed by grafts anemia were given cyclophosphamide followed by grafts from HLA-identical siblings. The effect of the administration of viable donor buffy coat cells following the marrow inoculum was evaluated with regard to graft rejection and survival. Results in 43 patients so treated are presented along with those in 22 concurrent patients given marrow alone. Most patients given buffy coat had positive in vitro tests of sensitization indicating a high risk for graft rejection, while all but one of the patients given marrow alone had negative tests. Thirty of the 43 (70%) patients given marrow and buffy coat are alive between 10 and 61 mo (median 36) after grafting; 4 died after graft rejection and 6 with acute or chronic graft-versus-host disease (GVHD). Eleven of the 22 (50%) patients given marrow alone are alive between 29 and 65 mo (median 52); 7 died after graft rejection and 3 with GVHD. The addition of buffy coat cell infusions to the marrow inoculum reduced the risk of rejection and increased survival in the currently reported transfused patients when compared to patients grafted before 1976. However, there was an increased risk of chronic GVHD. Recipients of marrow from female donors survived slightly better (73%) than recipients of male marrow (58%).     

X-linked chronic granulomatous disease: correction of NADPH oxidase defect by retrovirus-mediated expression of gp91-phox

Chronic granulomatous disease (CGD) is an inherited immunodeficiency resulting from the inability of an individual's phagocytes to produce superoxide anions because of defective NADPH oxidase. The disease may be treated by bone marrow transplantation and as such is a candidate for somatic gene therapy. Two thirds of patients have defects in an X- linked gene (X-CGD) encoding gp91-phox, the large subunit of the membrane cytochrome b-245 component of NADPH oxidase. Epstein-Barr virus-transformed B-cell lines from patients with CGD provide a model system for the disease. We have used retrovirus-mediated expression of gp91-phox to reconstitute functionally NADPH oxidase activity in B-cell lines from three unrelated patients with X-CGD. The protein is glycosylated and membrane associated, and the reconstituted oxidase is appropriately activated via protein kinase C. The kinetics of superoxide production by such reconstituted cells is similar to that of normal B-cell lines. These data show the potential of gene therapy for this disease.