Clinical practice guideline for the treatment of intrinsic circadian rhythm sleep-wake disorders: advanced sleep-wake phase disorder (aswpd), delayed sleep-wake phase disorder (dswpd), non-24-hour sleep-wake rhythm disorder (n24swd), and irregular sleep-wake rhythm disorder (iswrd): an update for 2015

A systematic literature review and meta-analyses (where appropriate) were performed and the GRADE approach was used to update the previous American Academy of Sleep Medicine Practice Parameters on the treatment of intrinsic circadian rhythm sleep-wake disorders. Available data allowed for positive endorsement (at a second-tier degree of confidence) of strategically timed melatonin (for the treatment of DSWPD, blind adults with N24SWD, and children/ adolescents with ISWRD and comorbid neurological disorders), and light therapy with or without accompanying behavioral interventions (adults with ASWPD, children/adolescents with DSWPD, and elderly with dementia). Recommendations against the use of melatonin and discrete sleep-promoting medications are provided for demented elderly patients, at a second- and first-tier degree of confidence, respectively. No recommendations were provided for remaining treatments/ populations, due to either insufficient or absent data. Areas where further research is needed are discussed.

TNF-alpha increases sensitivity to LPS in chronically catheterized rats.

Patients with severe trauma injury are transiently exposed to increased serum concentrations of tumor necrosis factor-alpha (TNF-alpha). These patients are susceptible to the development of multisystem organ failure (MSOF) triggered by subsequent exposure to bacterial toxins either via infection or increased intestinal permeability. We simulated the cytokine response of trauma by infusing 0.8 or 8.0 microg/kg of TNF-alpha (priming dose) into chronically catheterized rats. After 48 h, rats were challenged with endotoxin [lipopolysaccharide (LPS); 10 or 1,000 microg/kg]. Animals primed with either dose of TNF-alpha and then challenged with 1,000 microg/kg of LPS demonstrated significantly increased mortality, mean peak serum concentrations of interferon-gamma (IFN-gamma), and blood lactate concentrations (P < 0.05) compared with nonprimed animals. Mean peak serum concentrations of IFN-gamma and blood lactate concentrations were increased after challenge with 10 microg/kg of LPS only in animals primed with 8.0 microg/kg of TNF-alpha. Priming with TNF-alpha did not increase mortality after challenge with 10 microg/kg of LPS. These data suggest that both TNF-alpha release and the subsequent exposure to bacterial toxins mediate the pathophysiological progression from trauma to subsequent MSOF.

Surface expression of lactoferrin by resting neutrophils.

We examined the surface expression of lactoferrin by human neutrophils. Western blot analysis with anti-lactoferrin antibodies demonstrated the presence of a 78- to 79-kDa band in plasma membranes isolated from resting neutrophils that corresponded to the 78- to 79-kDa protein in neutrophil secondary granules. Flow cytometry using FITC-conjugated anti-lactoferrin antibodies confirmed that lactoferrin is expressed on the neutrophil surface. Preincubating the neutrophils in acidic (pH 3.9) buffer did not alter staining of the cells by the antibodies. Surface expression of lactoferrin was also detected on neutrophils in whole blood. Neutrophil activation by C5a or the calcium ionophore A23187 did not increase the surface expression of lactoferrin. Instead, the level of lactoferrin expression detected with one of two monoclonal antibodies was diminished after neutrophil activation, suggesting a possible conformational change in the lactoferrin. The surface-expressed lactoferrin may provide a mechanism for the interaction between lactoferrin-binding microorganisms and neutrophils.

Liver plasma membrane-associated fibroblast growth: stimulatory and inhibitory activities during experimental cirrhosis.

During experimental CCl4 cirrhosis, an increase of membrane-associated factor stimulating 3T3 cell proliferation in vitro was observed. This stimulator is a 150-kD protein similar to one previously described. In situ perfusion released growth stimulatory activity, suggesting a peripheral plasma membrane protein localizing on basolateral surfaces. The activity increased with increasing number of CCl4 treatments, reaching a maximum at the 14th intoxication. It was faster than the proliferation of connective tissues determined histologically. Cessation of treatment caused a decrease in activity to that of the level of untreated liver, although the number of fibroblastlike cells remained large. This data, taken with the results of experiments with enriched hepatocyte fraction, may serve as an evidence in favor of hepatocyte origin of the factor. A factor inhibiting fibroblast proliferation was measured in detergent extracts from membranes, suggesting an integral membrane protein. The activity of the inhibitory factor increased in acute liver lesions, but at the stage of maximal fibrogenesis this factor is reduced to levels comparable to those of the intact liver. Therefore it is unlikely that this factor is involved in CCl4-induced fibrogenesis at the final stages. These factors may be common controls for various hepatic lesions causing fibrosis, both in clinical and experimental modeling.