Journal of investigative medicine : the official publication of the American Federation for Clinical Research
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Review
Pharmacologic therapies on the horizon for acute lung injury/acute respiratory distress syndrome.
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent a spectrum of diseases that are commonly encountered in the intensive care unit and are associated with high mortality. Although significant advances have been made with respect to the ventilatory management of patients with ALI/ARDS with proven beneficial effects on outcomes, pharmacologic therapies remain nonexistent. ⋯ These agonists all have in common the ability to directly mediate endothelial cell signaling and induce characteristic actin cytoskeletal rearrangement leading to endothelial cell barrier protection. Our in vitro findings have been extended to animal models of ALI/ARDS and suggest that effective pharmacologic therapies for patients with ALI/ARDS may soon be available.
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Acute lung injury (ALI) and its most severe form the acute respiratory distress syndrome occur in patients who have a predisposing severe inflammatory insult to the lung. Most often ALI is due to sepsis from bacterial infection, but ALI can occur with any infection and with noninfectious insults such as severe trauma, acute pancreatitis, aspiration, and near-drowning. After any of these insults, the interindividual risk of progression to ALI and the risk of death remain difficult to predict. ⋯ There is substantial evidence for heritable predispositions to severe infections and an emerging body of literature implicating genetic factors in ALI pathogenesis. A paradigm is emerging that the genetic risk for ALI can be best understood in terms of factors that control 3 overlapping stages of ALI pathogenesis: risk for the acquisition of a predisposing condition (such as a severe pneumonia), risk for progression to lung injury during systemic inflammatory states (such as severe sepsis), and risk for failure of endogenous mechanisms to resolve the lung injury. The evidence supporting this paradigm is herein reviewed, along with potential treatment strategies that could be directed by knowledge of specific genetic factors in an individual patient.
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Fragile X-associated tremor/ataxia syndrome is a late adult onset neurodegenerative disorder that affects individuals who carry a premutation CGG repeat expansion (55-200 CGG repeats) in the 5' untranslated portion of the fragile X mental retardation 1 (FMR1) gene. Affected individuals display cognitive decline, progressive intention tremor, gait ataxia, neuropathy, psychiatric symptoms, and parkinsonism; the severity of both clinical and neuropathological phenotypes is positively correlated with the extent of the CGG expansion. ⋯ This mechanism is entirely different from the mechanism giving rise to fragile X syndrome, which is due to transcriptional silencing and consequent loss of FMR1 protein. Much of the research in the field has focused on understanding the link between the pathogenic FMR1 messenger RNA and the potential proteins that interact with it.
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Long regarded as proinflammatory molecules, prostaglandins (PGs) also have anti-inflammatory effects. Both prostaglandin D2 (PGD2) and its dehydration end product 15-deoxy-Delta-prostaglandin J2 (15d-PGJ2) seem to play important roles in regulating inflammation, via both receptor-dependent (DP1 and DP2 receptors) and receptor-independent mechanisms. Intracellular effects of PGD2 and 15d-PGJ2 that may suppress inflammation include inhibition of nuclear factor-kappaB (NF-kappaB) by multiple mechanisms (IkappaB kinase inhibition and blockade of NF-kappaB nuclear binding) and activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma). ⋯ Indeed, classic inhibitors of PG synthesis such as nonselective and cyclooxygenase-2 (COX-2) selective inhibitors (nonsteroidal anti-inflammatory drugs) may actually prolong inflammation when administered during the resolution phase. These effects may regulate not only tissue inflammation but also vascular disease, possibly shedding light on the controversy surrounding nonsteroidal anti-inflammatory drug use and its relation to myocardial infarction. In this review, we summarize the current understanding of PGs as dichotomous molecules in the inflammatory process.
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Kidney disease is one of the most striking examples of health disparities in American public health. Disparities in the prevalence and progression of kidney disease are generally thought to be a function of group differences in the prevalence of kidney disease risk factors such as diabetes, hypertension, and obesity. ⋯ We believe that the social environment is an important element in the pathway from CKD risk factors to CKD and end-stage renal disease. This review of the literature draws heavily from social science and social epidemiology to present a conceptual frame specifying how social, economic, and psychosocial factors interact to affect the risks for and the progression of kidney disease.