The interrelation of the "local" and the "general" in inflammation

The relationships between the local and the general in inflammation are analysed basing on the literature and original data. Local chemoattraction is postulated to be an underlying factor initiating primary local cooperation of cells relevant to inflammation. Being essential in this cooperation, macrophage seems to warrant both the local developments and triggering of general mechanisms of regulation which are relevant to control over subsequent secondary cell cooperation. The latter is biologically aimed at localization of the inflammation focus and separation of its pathogenic factors from intact internal medium. General mechanisms of inflammation control are provided by neuroendocrine, immune, vascular, coagulative, fibrinolytic and other systems, and operate through the products of the acute phase, by immune defence factors and rearrangement of nervous regulation of homeostasis in intact organs and tissues. The result of the regulation manifests with sequential presentation of the inflammation stages in time, correlation of local and general responses intensity. Eventually, local inflammation and lesion involve stress and intoxication which are not considered direct attributes of inflammation, nevertheless can influence general regulatory systems concerned with the course of local inflammation. It is concluded that inflammation implies dialectic unity of local and systemic responses of the body outlined to resolve inflammation and restore homeostasis.     

Bone "mass" and the "mechanostat": a proposal

The observed fit of bone mass to a healthy animal's typical mechanical usage indicates some mechanism or mechanisms monitor that usage and control the three longitudinal growth, bone modeling, and BMU-based remodeling activities that directly determine bone mass. That mechanism could be named a mechanostat. Accumulated evidence suggests it includes the bone itself, plus mechanisms that transform its mechanical usage into appropriate signals, plus other mechanisms that detect those signals and then direct the above three biologic activities. In vivo studies have shown that bone strains in or above the 1500-3000 microstrain range cause bone modelling to increase cortical bone mass, while strains below the 100-300 microstrain range release BMU-based remodeling which then removes existing cortical-endosteal and trabecular bone. That arrangement provides a dual system in which bone modeling would adapt bone mass to gross overloading, while BMU-based remodeling would adapt bone mass to gross underloading, and the above strain ranges would be the approximate "setpoints" of those responses. The anatomical distribution of those mechanical usage effects are well known. If circulating agents or disease changed the effective setpoints of those responses their bone mass effects should copy the anatomical distribution of the mechanical usage effects. That seems to be the case for many agents and diseases, and several examples are discussed, including postmenopausal osteoporosis, fluoride effects, bone loss in orbit, and osteogenesis imperfecta. The mechanostat proposal is a seminal idea which fits diverse evidence but it requires critique and experimental study.     

Comparison of the "mammal machine" and the "reptile machine": energy production

Standard metabolism and body composition were measured in Amphibolurus nuchalis and Mus musculus (a reptile and mammal with the same weight and body temperature). The metabolic capacity for energy production was assessed in liver, heart, brain, and kidney in the lizard and mouse by two methods: measurement of mitochondrial enzyme activity (cytochrome oxidase) and measurement of both mitochondrial volume density and membrane surface area. Both methods gave a three- to sixfold greater capacity for energy production in the mammal compared to the lizard which is less than the eightfold difference in their standard metabolisms. The difference in energy production capacity was not due to any single parameter but was a summation of several smaller differences. The mammal had relatively larger internal organs than the reptile, their organs had a greater proportion of mitochondria, and their mitochondria had a greater relative membrane surface area. These differences, it is suggested, may be due in part to different thyroid function in reptiles and mammals.     

Autoimmunity and the immunotherapy of cancer: targeting the "self" to destroy the "other"

It is increasingly clear that immunity to "self"-antigens may result in tumor destruction in mouse and man. But which antigens should be targeted with therapeutic cancer vaccines? In the case of melanoma, recognition of melanocyte differentiation antigens (MDA) can be associated with autoimmune depigmentation (vitiligo). We propose that intersection of protein transport to melanosomes and endosomes allows for the loading of MDA-derived peptides on MHC class II molecules, resulting in the activation of MDA-specific CD4+ "helper" T cells that aid the induction of melanoma-specific CD8+ T cells. Thus, the immunogenicity of MDA may be a consequence of their unique cell biology. Studies of MDA-based vaccines can provide new insight into the development of more effective cancer vaccines.