Monomethylfumarate affects polarization of monocyte-derived dendritic cells resulting in down-regulated Th1 lymphocyte responses

Psoriasis vulgaris, a type-1 cytokine-mediated chronic skin disease, can be treated successfully with fumaric acid esters (FAE). Beneficial effects of this medication coincided with decreased production of IFN-gamma. Since dendritic cells (DC) regulate the differentiation of T helper (Th) cells, this study focussed on effects of monomethylfumarate (MMF, bioactive metabolite of FAE) on polarization of monocyte-derived DC. MMF-incubated, lipo-polysaccharide-stimulated DC (MMF-DC) produced dramatically (p<0.05) reduced levels of IL-12p70 and IL-10 (8+/-4% and 20+/-4%, respectively) compared to control DC. MMF-DC were mature. MMF affected polarization of DC irrespective of polarization factor(s) and ligands for the various Toll-like receptors used. Coculture of MMF-DC with naive and primed allogenous Th cells resulted in lymphocytes producing less IFN-gamma, i.e. 59% and 54% of that by the respective Th cells cocultured with control DC. IL-4 production by primed, but not naive Th cells cocultured with MMF-DC was decreased as compared to cocultures with control DC. IL-10 production by naive and primed Th cells cocultured with MMF-DC and control DC did not differ. In addition, MMF inhibited LPS-induced NF-kappaB activation in DC. Together, beneficial effects of FAE in psoriasis involve modulation of DC polarization by MMF such that these cells down-regulate IFN-gamma production by Th cells.     

Interconnections between substantia Nigra reticulata and medullary reticular formation

Injections of wheat germ agglutinin-HRP into the medullary reticular formation (MRf) or the substantia nigra reticulata (SNr) revealed the presence of reciprocating fiber connections between the two areas. Large injections in the MRf demonstrated the existence of labeled neurons in the lateral portions of the SNr. Isolated injections into the parvocellular nuclei of the MRf resulted in the presence of terminal fields in the SNr particularly its lateral portions. Injections in the SNr resulted in the presence of labeled cells in the parvocellular nuclei. The significance of these findings is discussed in terms of oro-facial dyskinesias.     

Activation of E-prostanoid4 and E-prostanoid2 receptors inhibits TNF-alpha release from human alveolar macrophages.

Prostaglandin (PG)E(2) has been shown to inhibit mediator release from human alveolar macrophages (AMs), but the prostanoid receptor(s) mediating this response have not yet been documented. To investigate this, the present authors conducted a range of pharmacological and expression-based studies in monocyte-derived macrophages (MDMs) and AMs. MDMs were obtained by in vitro differentiation of monocytes from the peripheral blood of healthy human volunteers. Human AMs were obtained by perfusion of lung tissue from carcinoma resection patients. In MDMs, PGE(2) potently inhibited lipopolysaccharide-induced tumour necrosis factor (TNF)-alpha release (p[A](50) 8.51+/-0.11, maximum inhibition 95.9+/-4.8%). In human AMs, PGE(2) also inhibited TNF-alpha release but the observed concentration-effect curve was very flat and inhibition was incomplete. The shape of the PGE(2) curve in AMs suggested that its effects were mediated by activation of a heterogeneous receptor population. Expression studies combined with the use of various E-prostanoid (EP) receptor agonists and a selective EP(4)-receptor antagonist (Ono-AE2-227) confirmed that the inhibitory effects of PGE(2) in both AMs and MDMs were mediated by activation of EP(4) and EP(2) receptors. These data indicate that both E-prostanoid(4) and E-prostanoid(2) selective agonists may have anti-inflammatory properties in lung diseases where macrophages play a role.     

Energy metabolism, nitrogen balance, and substrate utilization in critically ill children.

BACKGROUND: Critically ill patients are characterized by a hypermetabolic state, a catabolic response, higher nutritional needs, and a decreased capacity for utilization of parenteral substrate. OBJECTIVE: We sought to analyze the relation between a patient's metabolic state and their nutritional intake, substrate utilization, and nitrogen balance (NB) in mechanically ventilated, critically ill children receiving parenteral nutrition. DESIGN: This was a cross-sectional study in which resting energy expenditure (REE) and NB were measured and substrate utilization and the metabolic index (MI) ratio (REE/expected energy requirements) were calculated. RESULTS: Thirty-three children (mean age: 5 y) participated. Their average REE was 0.23 +/- 0.10 MJ x kg(-1) x d(-1) and their average MI was 1.2 +/- 0.5. Mean energy intake, protein intake, and NB were 0.25 +/- 0.14 MJ x kg(-1) x d(-1), 2.1 +/- 1 g x kg(-1) x d(-1), and -89 +/- 166 mg x kg(-1) x d(-1), respectively. Patients with an MI >1.1 (n = 19) had a higher fat oxidation than did patients with an MI <1.1 (n = 14; P < 0.05). Patients with lipogenesis (n = 13) had a higher carbohydrate intake than did patients without lipogenesis (n = 20; P < 0.05). Patients with a positive NB (n = 12) had a higher protein intake than did patients with a negative NB (n = 21; P < 0.001) and lower protein oxidation (P < 0.01). CONCLUSIONS: Critically ill children are hypermetabolic and in negative NB. In this population, fat is used preferentially for oxidation and carbohydrate is utilized poorly. A high carbohydrate intake was associated with lipogenesis and less fat oxidation, a negative NB was associated with high oxidation rates for protein, and a high protein intake was associated with a positive NB.     

Pain, anxiety and powerlessness

This paper explores the subject of postoperative pain, touching on the theories of the physiological mechanisms by which pain is perceived and exploring in some detail the literature on those factors which affect the pain experience. The need for a detailed assessment of the pain which an individual experiences is suggested by this study of the literature. This concept is explored in some detail. The author explores the relationship between pain and anxiety, commenting on that which affects patients undergoing surgery. The relationship between anxiety and perceived helplessness or powerlessness is also discussed. The paper concludes by drawing together the information from the literature reviewed and the author suggests a hypothesis that pain, anxiety and perceived powerlessness have an effect on each other. There is a suggestion that decreasing perception of powerlessness may decrease the intensity of the pain experience for the individual. It is suggested that this is an area for future research into postoperative pain management.     

Time to deterioration of patient-reported outcomes in non-small cell lung cancer: exploring different definitions

Purpose

The clinical relevance of different time-to-deterioration (TTD) definitions for patient-reported outcomes were explored.

Methods

TTD definitions differing by reference score and deterioration event were used to analyse data from the phase 3 FLAURA trial of first-line osimertinib versus erlotinib or gefitinib in patients with EGFR-mutated advanced non-small cell lung cancer. Pre-specified key symptoms were fatigue, appetite loss, cough, chest pain and dyspnoea, scored using the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-LC13 questionnaires (≥?10-point difference?=?clinically relevant).

Results

No significant treatment differences in TTD (distributions) were observed using definitions based on transient or definitive deterioration alone. TTD definitions based on definitive, sustained deterioration, with death not included as an event, yielded a significant treatment difference for dyspnoea (hazard ratio [HR] 0.71; P?=?0.034) when baseline was the reference, and for cough (HR 0.70; P?=?0.009) and dyspnoea (HR 0.71; P?=?0.004) when best previous score was the reference. With death included as an event, treatment differences were significant for dyspnoea (HR 0.70; P?=?0.025) when baseline was the reference, and for cough (HR 0.70; P?=?0.011), dyspnoea (HR 0.71; P?=?0.003) and chest pain (HR 0.71; P?=?0.038) when best previous score was the reference. Irrespective of definition, TTD for appetite loss and fatigue did not differ significantly between arms.

Conclusion

This exploratory work showed that different TTD definitions yield different magnitudes of treatment difference, highlighting the importance of pre-specifying TTD definitions upfront in clinical trials.

Clinical trial registration

ClinicalTrials.gov NCT02296125.

     

Correction to: Time to deterioration of patient-reported outcomes in non-small cell lung cancer: exploring different definitions

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