Background-Primary pneumonic plague is rare among humans but treatment efficacy may be tested in appropriate animal models under the FDA 'Animal Rule'.

Vaccines against primary pneumonic plague, a potential bioweapon, must be tested for efficacy in well-characterized nonhuman primate models. Telemetered cynomolgus macaques (Macaca fascicularis) were challenged by the aerosol route with doses equivalent to approximately 100 50% effective doses of Yersinia pestis strain CO92 and necropsied at 24-h intervals postexposure (p.e.). Data for telemetered heart rates, respiratory rates, and increases in the temperature greater than the diurnal baseline values identified the onset of the systemic response at 55 to 60 h p.e. in all animals observed for at least 70 h p.e. Bacteremia was detected at 72 h p.e. by a Yersinia 16S rRNA-specific quantitative reverse transcription-PCR and was detected later by the culture method at the time of moribund necropsy. By 72 h p.e. multilobar pneumonia with diffuse septal inflammation consistent with early bacteremia was established, and all lung tissues had a high bacterial burden. The levels of cytokines or chemokines in serum were not significantly elevated at any time, and only the interleukin-1␤, CCL2, and CCL3 levels were elevated in lung tissue. Inhalational plague in the cynomolgus macaque inoculated by the aerosol route produces most clinical features of the human disease, and in addition the disease progression mimics the disease progression from the anti-inflammatory phase to the proinflammatory phase described for the murine model. Defined milestones of disease progression, particularly the onset of fever, tachypnea, and bacteremia, should be useful for evaluating the efficacy of candidate vaccines.Primary pneumonic plague is rarely acquired under natural conditions (5, 9, 22), but the virulence and ease of aerosolization make Yersinia pestis a potential aerosolized bioweapon (13). The FDA "animal rule" allows the use of large animal models to substitute for human testing if the disease in the model mimics human disease and is well characterized (11). Adequate characterization should include the cause of death, phases of disease progression, and definition of secondary endpoints of success in addition to the primary endpoint of a reduction in mortality.Primary pneumonic plague in the murine model following intranasal inoculation has been described well (3,14,20). The murine model mimics the human infection with respect to high mortality, focal consolidation in the lung, and high levels of bacteremia and dissemination to the liver and the spleen. The murine infection is described as a two-phase disease with an initial anti-inflammatory phase lasting 36 to 48 h after intranasal inoculation, followed by a rapidly progressing proinflammatory phase until death occurs at 4 days postinfection (3,14).Nonhuman primates (NHP) are susceptible to aerosolized Y. pestis, which produces a rapidly fatal disease similar to that seen in humans with primary pneumonic plague. Different species of NHP may display different susceptibilities and disease progressions after exposure to Y. pestis in an aerosol form (7,8,10,16), and a workshop has rec...

BackgroundPre-pandemic development of an inactivated, split-virion avian influenza vaccine is challenged by the lack of pre-existing immunity and the reduced immunogenicity of some H5 hemagglutinins compared to that of seasonal influenza vaccines. Identification of an acceptable effective adjuvant is needed to improve immunogenicity of a split-virion avian influenza vaccine.Methods and FindingsFerrets (N = 118) were vaccinated twice with a split-virion vaccine preparation of A/Vietnam/1203/2004 or saline either 21 days apart (unadjuvanted: 1.9 µg, 7.5 µg, 30 µg, or saline), or 28 days apart (unadjuvanted: 22.5 µg, or alum-adjuvanted: 22.5 or 7.5 µg). Vaccinated animals were challenged intranasally 21 or 28 days later with 106 EID50 of the homologous strain. Immunogenicity was measured by hemagglutination inhibition and neutralization assays. Morbidity was assessed by observed behavior, weight loss, temperature, cytopenias, histopathology, and viral load.No serum antibodies were detected after vaccination with unadjuvanted vaccine, whereas alum-adjuvanted vaccination induced a robust antibody response. Survival after unadjuvanted dose regimens of 30 µg, 7.5 µg and 1.9 µg (21-day intervals) was 64%, 43%, and 43%, respectively, yet survivors experienced weight loss, fever and thrombocytopenia. Survival after unadjuvanted dose regimen of 22.5 µg (28-day intervals) was 0%, suggesting important differences in intervals in this model. In contrast to unadjuvanted survivors, either dose of alum-adjuvanted vaccine resulted in 93% survival with minimal morbidity and without fever or weight loss. The rarity of brain inflammation in alum-adjuvanted survivors, compared to high levels in unadjuvanted vaccine survivors, suggested that improved protection associated with the alum adjuvant was due to markedly reduced early viral invasion of the ferret brain.ConclusionAlum adjuvant significantly improves efficacy of an H5N1 split-virion vaccine in the ferret model as measured by immunogenicity, mortality, morbidity, and brain invasion.

No abstract

Objective: To report a case of paroxysmal atrial fibrillation in a patient who was receiving a chemotherapy regimen including docetaxel plus cyclophosphamide (TC). Case Report: A 67-year-old woman was receiving TC therapy for stage IIB breast cancer. She developed symptomatic paroxysmal atrial fibrillation following chemotherapy administration. The patient presented with tachycardia-palpitations, a shaking sensation inside her body, shortness of breath, and tightness in her chest that did not radiate. Propafenone treatment was replaced with sotalol. Cycle 2 of chemotherapy was administered and symptoms of atrial fibrillation returned. Sotalol was switched to dronedarone monotherapy and the symptoms resolved. Discussion: Based on the Naranjo probability scale, chemotherapy was the probable cause of the patient's episodes of paroxysmal atrial fibrillation. Conclusions: As single agents, taxanes have minimal cardiac toxicity, although cardiac toxicity may be higher with precipitating factors. Clinicians caring for patients receiving taxane chemotherapy should be aware of the potential for docetaxel-induced paroxysmal atrial fibrillation.