Annals of medicine
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Several preclinical models for sepsis have been used in the last decades to successfully unravel the pathophysiologic processes during sepsis. Furthermore, these models for sepsis revealed promising immunomodulating agents for the treatment of sepsis. Nevertheless, several clinical trials evaluating the efficacy of these new anti-inflammatory agents in septic patients showed disappointing results. ⋯ Importantly, investigations studying the effects of several immunomodulating strategies have demonstrated strikingly opposite results when using models for sepsis lacking an infectious focus and when using models for sepsis with a more natural route of infection. These differences will be discussed in this article. In general, it is advised to use a combination of models to test a new therapeutic agent, before starting a clinical study evaluating this new therapy.
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Severe sepsis and septic shock are relatively common problems in intensive care. The mortality in septic shock is still high, and the main causes of death are multiple organ failure and refractory hypotension. Impaired tissue perfusion due to hypovolemia, disturbed vasoregulation and myocardial dysfunction contribute to the multiple organ dysfunction. ⋯ In septic shock, vasopressin levels are low, and therefore, vasopressin has been advocated as a vasopressor. Its effectiveness and safety have not yet been documented, and so far it is regarded as an experimental treatment Recent data support the use of corticosteroid, at least in some of the patients with septic shock. Also, activated protein C, a drug with anti-inflammatory and antithrombotic properties, decreases mortality in patients with septic shock.
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Genetic defects affecting the hypothalamic-pituitary-target organ axes can cause a variety of diseases involving restricted or broad disruptions of human development and physiology. At the level of the anterior pituitary gland, mutations in the genes encoding key transcription factors, hypothalamic releasing and inhibiting hormone receptors, and the pituitary hormones themselves, can all result in the loss of action of one or more of the specialized hormone-secreting cell types. ⋯ Mutations in the genes encoding the HESX1, PITX2, LHX3, LHX4, PROP1, PIT1, SF1, and TPIT developmental transcription factors are associated with combined pituitary hormone deficiency diseases. By contrast, deleterious alterations in the genes that encode hypothalamic releasing hormone receptors or pituitary hormones, such as the growth hormone releasing hormone receptor or growth hormone genes, usually result in phenotypes that reflect specific defects in the hormone-secreting capacities of individual anterior pituitary cell types.
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During sepsis or acute respiratory distress syndrome, the hypothalamic pituitary adrenal axis is rapidly activated through a systemic pathway, i.e. by circulating pro-inflammatory cytokines and through the vagus nerve. Subsequently, the adrenal glands release cortisol, a hormone which will likely counteract the inflammatory process and restore cardiovascular homeostasis. Both experimental models and studies in humans suggest that inadequate hypothalamic pituitary adrenal axis response to stress accounts, at least partly, for the genesis of shock and organ dysfunction in sepsis and acute respiratory distress syndrome. ⋯ These trials showed consistently that, in these patients, the use of low dose of corticosteroids alleviated inflammation, restored cardiovascular homeostasis, reduced organ dysfunction, improved survival and was safe. Further studies are ongoing to better identify the target population. In the meantime, cortisol replacement (i.e. 200 to 300 mg daily of hydrocortisone or equivalent) should be considered as standard care for these patients.
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Meta Analysis
Effects of thyroid hormone suppression therapy on adverse clinical outcomes in thyroid cancer.
Long-term thyroid hormone (TH) therapy aiming at the suppression of serum thyrotropin (TSH) has been traditionally used in the management of well differentiated thyroid cancer (ThyrCa). However, formal validation of the effects of thyroid hormone suppression therapy (THST) through randomized controlled trials is lacking. Additionally, the role - if any - of TSH effect at low ambient concentrations upon human thyroid tumorigenesis remains unclear. ⋯ THST appears justified in ThyrCa patients following initial therapy. As most primary studies were imperfect, future research will better define the effect of THST upon ThyrCa clinical outcomes.