ECT non­remitters: prognosis and treatment after 12 unilateral electroconvulsive therapy sessions for major depression

Background: Depressive disorder causes significant suffering in patients and caregivers worldwide. Electroconvulsive therapy (ECT) is a highly effective antidepressant treatment, but little is known about the prognosis and treatment of patients who do not achieve remission with ECT. We investigated prognosis and treatment of patients with major depression who did not achieve remission after 12 unilateral electroconvulsive therapy sessions.  Methods: We conducted a retrospective, naturalistic follow-up study. Patients who had previously participated in a double-blind randomized controlled trial that compared brief pulse with ultra-brief pulse ECT and who had not achieved remission after 12 right unilateral (RUL) ECT sessions were selected for this study. We analysed the type of treatments received during the 6-month follow-up and studied the occurrence of remission and response. The primary outcome was remission, defined as a Montgomery-Åsberg Depression Rating Scale score <10.  Results: Eighty-one patients were randomized, of which 18 patients did not remit. Eight of these non-remitters achieved remission during follow-up (44.4%) while 7 did not achieve remission (38.9%). Remission data could not be retrieved for 3 patients (16.7%). Remission was achieved in 6 patients by a combination of continuing unilateral ECT with antidepressants or switching to bilateral ECT.  Limitations: This is a retrospective study with only a small number of patients. Treatment after RUL ECT non-remission was not standardized.  Conclusion: When patients with major depression do not achieve remission after 12 RUL ECT sessions, they have still a reasonable chance of remission within 6 months. Continuing ECT has the best chance of success

ECT non­remitters: prognosis and treatment after 12 unilateral electroconvulsive therapy sessions for major depression

Background: Depressive disorder causes significant suffering in patients and caregivers worldwide. Electroconvulsive therapy (ECT) is a highly effective antidepressant treatment, but little is known about the prognosis and treatment of patients who do not achieve remission with ECT. We investigated prognosis and treatment of patients with major depression who did not achieve remission after 12 unilateral electroconvulsive therapy sessions. Methods: We conducted a retrospective, naturalistic follow-up study. Patients who had previously participated in a double-blind randomized controlled trial that compared brief pulse with ultra-brief pulse ECT and who had not achieved remission after 12 right unilateral (RUL) ECT sessions were selected for this study. We analysed the type of treatments received during the 6-month follow-up and studied the occurrence of remission and response. The primary outcome was remission, defined as a Montgomery-Åsberg Depression Rating Scale score <10. Results: Eighty-one patients were randomized, of which 18 patients did not remit. Eight of these non-remitters achieved remission during follow-up (44.4%) while 7 did not achieve remission (38.9%). Remission data could not be retrieved for 3 patients (16.7%). Remission was achieved in 6 patients by a combination of continuing unilateral ECT with antidepressants or switching to bilateral ECT. Limitations: This is a retrospective study with only a small number of patients. Treatment after RUL ECT non-remission was not standardized. Conclusion: When patients with major depression do not achieve remission after 12 RUL ECT sessions, they have still a reasonable chance of remission within 6 months. Continuing ECT has the best chance of success

A new CARD15 mutation in Blau syndrome

The caspase recruitment domain gene CARD15/NOD2, encoding a cellular receptor involved in an NF-kappaB-mediated pathway of innate immunity, was first identified as a major susceptibility gene for Crohn's disease (CD), and more recently, as responsible for Blau syndrome (BS), a rare autosomal-dominant trait characterized by arthritis, uveitis, skin rash and granulomatous inflammation. While CARD15 variants associated with CD are located within or near the C-terminal leucine-rich repeat domain and cause decreased NF-kappaB activation, BS mutations affect the central nucleotide-binding NACHT domain and result in increased NF-kappaB activation. In an Italian family with BS, we detected a novel mutation E383K, whose pathogenicity is strongly supported by cosegregation with the disease in the family and absence in controls, and by the evolutionary conservation and structural role of the affected glutamate close to the Walker B motif of the nucleotide-binding site in the NACHT domain. Interestingly, substitutions at corresponding positions in another NACHT family member cause similar autoinflammatory phenotypes

Improving the Performance of Water Demand Forecasting Models by Using Weather Input

Literature shows that water demand forecasting models which use water demand as single input, are capable of generating a fairly accurate forecast. However, at changing weather conditions the forecasting errors are quite large. In this paper three different forecasting models are studied: an Adaptive Heuristic model, a Transfer/-noise model, and a Multiple Linear Regression model. The performance of the models was studied both with and without using weather input, in order to assess the possible performance improvement due to using weather input. Simulations with the models showed that when using weather input the largest forecasting errors can be reduced by 11%, and the average errors by 7%. This reduction is important for the application of the forecasting model for the control of water supply systems and for anomaly detection.QN/Quantum NanoscienceApplied Science

Monocyte-derived dendritic cells from Crohn patients show differential NOD2/CARD15-dependent immune responses to bacteria

BACKGROUND: Three common mutations in the NOD2/CARD15 gene are strongly associated with Crohn's disease (CD). NOD2 is an intracellular receptor of muramyl dipeptide (MDP), a component of peptidoglycan present in the cell wall of gram-positive (G+) and gram-negative (G-) bacteria. METHODS: We generated monocyte-derived dendritic cells (MoDCs) from CD patients mutated or not for CARD15 (n = 53) or from healthy donors (n = 12) and analyzed their activation in response to live Salmonella typhimurium as a model of pathogenic G- bacteria. RESULTS: MoDCs carrying the L1007fs mutation, although phenotypically activated by bacteria, produced a significantly reduced amount of tested cytokines. MoDCs carrying R702W or compound G908R/R702W NOD2 mutations displayed an increased basal level of IL-8 release. After a bacterial encounter, these cells were phenotypically activated and produced levels of cytokines similar to healthy controls. Interestingly, although L1007fs/WT mutations conferred reduced production of cytokines, including IL-12, these cells were perfectly capable of inducing T-cell polarization toward the Th1 phenotype. CONCLUSIONS: NOD2 mutations affect the basal characteristics of MoDCs and their response to G- bacteria differently. MoDCs could be involved in CD onset because they have defects in releasing inflammatory cytokines and in polarizing T-cell responses

Analysis of the CARD15 variants R702W, G908R and l1007fs in Italian IBD patients

CARD15 on chromosome 16 is the only IBD susceptibility gene identified among several mapped loci. Its recurrent variants R702W, G908R and L1007fs have shown significant association with Crohn's disease (CD), but not with ulcerative colitis (UC), in different Caucasian populations. We analysed these three variants in 184 CD and 92 UC Italian patients and in 177 healthy controls. L1007fs and G908R were independently associated with CD, while R702W showed a nonsignificant increase. After combining the three variants together, 32.6% of CD patients were positive vs 18.6% of the controls. The association was stronger for homozygotes and compound heterozygotes, OR 13.9 (1.8-108), and weaker but still significant for simple heterozygotes, OR 1.7 (1.0-2.9). An excess of homozygotes/compound heterozygotes also resulted from the comparison with Hardy-Weinberg expectations. Phenotype-genotype correlations were analysed first by univariate logistic regression and then by multivariate analysis, the effect of CARD15 positivity being adjusted according to the status of smoking, familiarity and sex, so as to focus on the predictivity of genetic and environmental risk factors on the clinical phenotype. Significant risk estimates of the CARD15 genotype were obtained for stricturing vs inflammatory behaviour, OR 2.76 (1.2-6.3), and for penetrating behaviour, 2.59 (1.0-6.6), and marginally significant for ileal vs colic location, OR 3.0 (0.9-9.8). Our findings indicate that the association of the CARD15 genotype with behaviour and location of disease holds also for the Italian population

The MET oncogene transforms human primary bone-derived cells into osteosarcomas by targeting committed osteo-progenitors

The MET oncogene is aberrantly overexpressed in human osteosarcomas. We have previously converted primary cultures of human bone-derived cells into osteosarcoma cells by overexpressing MET. To determine whether MET transforms mesenchymal stem cells or committed progenitor cells, here we characterize distinct MET overexpressing osteosarcoma (MET-OS) clones using genome-wide expression profiling, cytometric analysis, and functional assays. All the MET-OS clones consistently display mesenchymal and stemness markers, but not most of the mesenchymalstem cell-specific markers. Conversely, the MET-OS clones express genes characteristic of early osteoblastic differentiation phases, but not those of late phases. Profiling of mesenchymal stem cells induced to differentiate along osteoblast, adipocyte, and chondrocyte lineages confirms that MET-OS cells are similar to cells at an initial phase of osteoblastic differentiation. Accordingly, MET-OS cells cannot differentiate into adipocytes or chondrocytes, but can partially differentiate into osteogenic-matrix-producing cells. Moreover, in vitro MET-OS cells form self-renewing spheres enriched in cells that can initiate tumors in vivo. MET kinase inhibition abrogates the self-renewal capacity of MET-OS cells and allows them to progress toward osteoblastic differentiation. These data show that MET initiates the transformation of a cell population that has features of osteo-progenitors and suggest that MET regulates self-renewal and lineage differentiation of osteosarcoma cells. (C) 2012 American Society for Bone and Mineral Research

Activation of NOD2 in vivo induces IL-1β production in the eye via caspase-1 but results in ocular inflammation independently of IL-1 signaling

Nucleotide-binding and oligomerization domain 2 (NOD2) belongs to the emerging Nod-like receptor (NLR) family considered important in innate immunity. Mutations in NOD2 cause Blau syndrome, an inherited inflammation of eye, joints, and skin. Mutations in a homologous region of another NLR member, NALP3, cause autoinflammation, wherein IL-1β plays a critical role. Here, we tested the hypothesis that IL-1β is a downstream mediator of NOD2-dependent ocular inflammation. We used a mouse model of NOD2-dependent ocular inflammation induced by muramyl dipeptide (MDP), the minimal bacterial motif sensed by NOD2. We report that MDP-induced ocular inflammation generates IL-1β and IL-18 within the eye in a NOD2- and caspase-1-dependent manner. Surprisingly, two critical measures of ocular inflammation, leukocyte rolling and leukocyte intravascular adherence, appear to be completely independent of IL-1 signaling effects, as caspase-1 and IL-1R1-deficient mice still developed ocular inflammation in response to MDP. In contrast to the eye, a diminished neutrophil response was observed in an in vivo model of MDP-induced peritonitis in caspase-1-deficient mice, suggesting that IL-1β is not essential in NOD2-dependent ocular inflammation, but it is involved, in part, in systemic inflammation triggered by NOD2 activation. This disparity may be influenced by IL-1R antagonist (IL-1Ra), as we observed differential IL-1Ra levels in the eye versus plasma at baseline levels and in response to MDP treatment. This report reveals a new in vivo function of NOD2 within the eye yet importantly, distinguishes NOD2-dependent from NALP3-dependent inflammation, as ocular inflammation in mice occurred independently of IL-1β