Medical principles and practice : international journal of the Kuwait University, Health Science Centre
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Fever is one major cardinal sign of disease. It results from an intricate interplay between the immune system and the central nervous system. Bacterial or viral infections activate peripheral immune competent organs which send inflammatory signals to the brain and lead to an increase in body temperature. ⋯ The early life pathogenic encounter heightens the hypothalamic-pituitary-adrenal axis response, dampens the innate immune system, and consequently reduces the febrile response to a subsequent immune challenge during adulthood. This 'programming' effect operates only when such early life immune challenges occur during a critical window of either prenatal or postnatal development. In this review, the mechanisms underlying the long-lasting impact of perinatal immune challenge on adult fever are addressed.
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This review positions public health as an endeavour that requires a high order of professionalism in addressing the health of populations; this requires investment in an educational capacity that is designed to meet this need. In the global context, the field has evolved enormously over the past half century, supported by institutions such as the World Bank, the World Health Organization and the Institute of Medicine. Operational structures are formulated by strategic principles, with educational and career pathways guided by competency frameworks, all requiring modulation according to local, national and global realities. ⋯ The emergence of accreditation schemes is examined, focusing on their relative merits and legitimate international variations. The role of relevant research policies is recognized, along with the need to foster professional and institutional networks in all regions of the world. It is critically important for the health of populations that nations assess their public health human resource needs and develop their ability to deliver this capacity, and not depend on other countries to supply it.
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Based on aqueous redox chemistry and simple in vivo models of oxidative stress, Escherichia coli and Saccharomyces cerevisiae, the cationic Mn(III) N-substituted pyridylporphyrins (MnPs) have been identified as the most potent cellular redox modulators within the porphyrin class of drugs; their efficacy in animal models of diseases that have oxidative stress in common is based on their high ability to catalytically remove superoxide, peroxynitrite, carbonate anion radical, hypochlorite, nitric oxide, lipid peroxyl and alkoxyl radicals, thus suppressing the primary oxidative event. While doing so MnPs could couple with cellular reductants and redox-active proteins. Reactive species are widely accepted as regulators of cellular transcriptional activity: minute, nanomolar levels are essential for normal cell function, while submicromolar or micromolar levels impose oxidative stress, which is evidenced in increased inflammatory and immune responses. ⋯ Their accumulation in mitochondria and their ability to cross the blood-brain barrier contribute to their remarkable efficacy. We summarize herein the therapeutic effects of MnPs in cancer, central nervous system injuries, diabetes, their radioprotective action and potential for imaging. Few of the most potent modulators of cellular redox-based pathways, MnTE2-PyP5+, MnTDE-2-ImP5+, MnTnHex-2-PyP5+ and MnTnBuOE-2-PyP5+, are under preclinical and clinical development.
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The need for drugs with fewer side effects cannot be overemphasized. Today, most drugs modify the actions of enzymes, receptors, transporters and other molecules by directly binding to their active (orthosteric) sites. However, orthosteric site configuration is similar in several proteins performing related functions and this leads to a lower specificity of a drug for the desired protein. ⋯ Exploitation of allosteric sites has led to the discovery of drugs which can selectively modulate the activation of only 1 (M1 muscarinic) out of the 12 different types of acetylcholine receptors. These drugs are being tested for schizophrenia treatment. It is anticipated that the drug discovery exploiting allosteric sites will lead to more effective therapeutic agents with fewer side effects.