The Ataxia Telangiectasia Mutated Kinase Pathway Regulates IL-23 Expression by Human Dendritic Cells.

The Ataxia Telangiectasia Mutated Kinase Pathway Regulates IL-23 Expression by Human Dendritic Cells.

J Immunol. 2013 Mar 4;
Wang Q, Franks HA, Lax SJ, El Refaee M, Malecka A, Shah S, Spendlove I, Gough MJ, Seedhouse C, Madhusudan S, Patel PM, Jackson AM

Little is known of the regulation of IL-23 secretion in dendritic cells (DC) despite its importance for human Th17 responses. In this study, we show for first time, to our knowledge, that the ataxia telangiectasia mutated (ATM) pathway, involved in DNA damage sensing, acts as an IL-23 repressor. Inhibition of ATM with the highly selective antagonist KU55933 markedly increased IL-23 secretion in human monocyte-derived DC and freshly isolated myeloid DC. In contrast, inhibiting the closely related mammalian target of rapamycin had no effect on IL-23. Priming naive CD4+ T cells with ATM-inhibited DC increased Th17 responses over and above those obtained with mature DC. Although ATM blockade increased the abundance of p19, p35, and p40 mRNA, IL-12p70 secretion was unaffected. To further examine a role for ATM in IL-23 regulation, we exposed DC to low doses of ionizing radiation. Exposure of DC to x-rays resulted in ATM phosphorylation and a corresponding depression of IL-23. Importantly, ATM inhibition with KU55933 prevented radiation-induced ATM phosphorylation and abrogated the capacity of x-rays to suppress IL-23. To explore how ATM repressed IL-23, we examined a role for endoplasmic reticulum stress responses by measuring generation of the spliced form of X-box protein-1, a key endoplasmic reticulum stress transcription factor. Inhibition of ATM increased the abundance of X-box protein-1 mRNA, and this was followed 3 h later by increased peak p19 transcription and IL-23 release. In summary, ATM activation or inhibition, respectively, inhibited or augmented IL-23 release. This novel role of the ATM pathway represents a new therapeutic target in autoimmunity and vaccine development. HubMed – depression


Thresholds and Perception of Cold Pain, Heat Pain, and the Thermal Grill Illusion in Patients With Major Depressive Disorder.

Psychosom Med. 2013 Mar 4;
Boettger MK, Grossmann D, Bär KJ

ObjectiveThe thermal grill illusion (TGI) in which interlacing cold and warm bars create the illusion of a painful sensation has been suggested as an experimental model for central pain states and pain processing. The aim of this study was to use this technique to gain further insights into the altered pain perception in major depressive disorder (MDD).MethodsIn 18 unmedicated patients with MDD, cold and heat pain thresholds (CPT/HPT) as well as the perception of the TGI were examined and compared with 18 matched controls.ResultsCPT and HPT were significantly increased in patients (7.9°C and 47.5°C) compared with controls (15.9°C and 45.2°C, respectively; p < .05). In the range of TGI stimuli that were perceived painful by controls, the patients did not indicate painful sensations, thereby indicating a shift of the stimulus-response curve of TGI pain perception toward higher stimulus intensities, that is, greater temperature differentials between cold and warm bars (11.5°C for controls, 16.7°C for patients). The patients rated the pain intensity perceived at the respective pain thresholds (CPT and HPT) in tendency higher than did the controls, whereas they perceived the TGI less painful despite increased stimulus intensities. Unpleasantness ratings were similar between groups.ConclusionsCPT, HPT and temperature differentials for the perception of the TGI, were increased in patients with MDD as compared with controls. Pain intensity, however, was rated differently for CPT and HPT, where patients indicated higher ratings in tendency, and for the TGI stimulation, where pain was perceived less intense. HubMed – depression


Geriatric Factors Predict Chemotherapy Feasibility: Ancillary Results of FFCD 2001-02 Phase III Study in First-Line Chemotherapy for Metastatic Colorectal Cancer in Elderly Patients.

J Clin Oncol. 2013 Mar 4;
Aparicio T, Jouve JL, Teillet L, Gargot D, Subtil F, Le Brun-Ly V, Cretin J, Locher C, Bouché O, Breysacher G, Charneau J, Seitz JF, Gasmi M, Stefani L, Ramdani M, Lecomte T, Mitry E

PURPOSEElderly patients form a heterogeneous population. Evaluation of geriatric factors may help evaluate a patient’s health status to better adapt treatment. PATIENTS AND METHODSElderly patients with previously untreated metastatic colorectal cancer (mCRC) were randomly assigned to receive fluorouracil (FU) -based chemotherapy either alone or in combination with irinotecan (IRI) in the Fédération Francophone de Cancérologie Digestive (FFCD) 2001-02 study. Sites participating in the geriatric substudy completed geriatric screening tools to perform prognostic factor analyses for treatment safety during the first 4 months after treatment initiation.ResultsThe geriatric score was calculated in 123 patients (44%). Median age was 80 years (range, 75 to 91 years). The Charlson comorbidity index was ? 1 in 75%, Mini-Mental State Examination (MMSE) score was ? 27/30 in 31%, and Instrumental Activities of Daily Living (IADL) showed impairment in 34% of the patients. Seventy-one patients (58%) had grade 3 to 4 toxicity, 41 (33%) had a dose-intensity reduction of more than 33%, and 54 (44%) had at least one unexpected hospitalization during the first 4 months after starting treatment. In multivariate analysis, significant predictive factors for grade 3-4 toxicity were IRI arm (odds ratio [OR], 5.03), MMSE ? 27/30 (OR, 3.84), and impaired IADL (OR, 4.67); for dose-intensity reduction of > 33%, the significant predictive factors were alkaline phosphates > 2 × upper limit of normal (OR, 4.16) and IRI arm (OR, 6.85); and for unexpected hospitalization, significant predictive factors were MMSE ? 27/30 (OR, 4.56) and Geriatric Depression Scale ? 2 (OR, 5.52). CONCLUSIONGeriatric factors (MMSE and IADL) are predictive of severe toxicity or unexpected hospitalization (MMSE) in a randomized prospective phase III study in mCRC. These results suggest that cognitive function and autonomy impairment should be taken into account when choosing a regimen for chemotherapy. HubMed – depression


Postpartum Anxiety and Maternal-Infant Health Outcomes.

Pediatrics. 2013 Mar 4;
Paul IM, Downs DS, Schaefer EW, Beiler JS, Weisman CS

OBJECTIVE:Postpartum anxiety screening does not typically occur, despite changes in life roles and responsibility after childbirth. We sought to determine the prevalence of postpartum anxiety during the maternity hospitalization and its associations with maternal and child outcomes. We further aimed to compare correlates of anxiety with correlates of depression.METHODS:For a randomized controlled trial of mothers with “well” newborns ?34 weeks’ gestation comparing 2 post-hospital discharge care models, mothers completed baseline in-person interviews during the postpartum stay and telephone surveys at 2 weeks, 2 months, and 6 months to assess health care use, breastfeeding duration, anxiety, and depression. All participants intended to breastfeed. State anxiety scores ?40 on the State Trait Anxiety Inventory (STAI) and depression scores ?12 on the Edinburgh Postnatal Depression Survey (EPDS) were considered positive.RESULTS:A total of 192 (17%) of 1123 participating mothers had a positive baseline STAI; 62 (6%) had a positive EPDS. Primiparity was associated with a positive STAI (20% vs 15%, P = .02), but not a positive EPDS (4% vs 7%, P = .05). Positive STAI scores were associated with cesarean delivery (22% vs 15%, P = .001), reduced duration of breastfeeding (P = .003), and increased maternal, but not infant total unplanned health care utilization within 2 weeks of delivery (P = .001). Positive STAI scores occurred more frequently than positive EPDS scores at each assessment through 6 months postpartum.CONCLUSIONS:Postpartum state anxiety is a common, acute phenomenon during the maternity hospitalization that is associated with increased maternal health care utilization after discharge and reduced breastfeeding duration. State anxiety screening during the postpartum stay could improve these outcomes. HubMed – depression