In conclusion, we would regard the computational effort to be a secondary problem, and the choice of computational platform rather inconsequential, relative to the main concern arising from simple mathematical arguments that Demeler's algorithm may not give correct results. The authors do qualify their algorithm to be empirical, and that ''the results are not generally in exact correspondence with the original problem'' (Brookes et al. 2006) . They argue that ''[the results] can be made sufficiently close through careful use of the given heuristics'' (Brookes et al. 2006) . We are uncertain of the process referred to here, and how closeness to the exact solution would possibly be assessed without explicitly calculating the exact best-fit solution. So far Demeler and colleagues have not brought forward any proof that the distributions returned by the 2DSA method are at least close in the major attributes to the correct solution. We believe that the question of correctness of the algorithm is critical, especially since the authors invite the general application of this method, as implemented in the ULTRASCAN software, to address data analysis problems in novel biophysical and biochemical studies, rather than simple model problems with known solutions. Extrapulmonary tissue responses in cynomolgus macaques (Macaca fascicularis) infected with highly pathogenic avian influenza A (H5N1) virus The mechanisms responsible for virulence of influenza viruses in humans remain poorly understood. A prevailing hypothesis is that the highly pathogenic virus isolates cause a severe cytokinemia precipitating acute respiratory distress syndrome and multiple organ dysfunction syndrome. Cynomolgus macaques (Macaca fascicularis) infected with a human highly pathogenic avian influenza (HPAI) H5N1 virus isolate (A/Vietnam/1203/2004) or reassortants of human influenza virus A/Texas/36/91 (H1N1) containing genes from the 1918 pandemic influenza A (H1N1) virus developed severe pneumonia within 24 h postinfection. However, virus spread beyond the lungs was only detected in the H5N1 group, and signs of extrapulmonary tissue reactions, including microglia activation and sustained up-regulation of inflammatory markers, most notably hypoxia inducible factor-1α (HIF-1α), were largely limited to this group. Extrapulmonary pathology may thus contribute to the morbidities induced by H5N1 viruses. The Spanish influenza pandemic of 1918-1919 was the most devastating outbreak of infectious disease in recorded history, with an estimated 20-50 million human deaths following an unusually severe and rapid clinical course [1, 2] . The molecular pathogenesis of this pandemic is still poorly understood, but a prevailing hypothesis is that the severe tissue necrosis, influx of inflammatory cells and profound vascular leakage in the lower respiratory tract precipitated an acute respiratory distress syndrome (ARDS) leading to multiple organ dysfunction syndrome (MODS). Similar mechanisms have been proposed for the clinical symptomatology and the pathology induced by the currently circulating avian H5N1 influenza A virus strains [3] .