Serum tissue inhibitor of matrix metalloproteinase-1 levels are associated with mortality in patients with malignant middle cerebral artery infarction

Background: In the last years, circulating matrix metalloproteinases (MMP)-9 levels have been associated with functional outcome in ischemic stroke patients. However the prognostic value of circulating levels of tissue inhibitor of matrix metalloproteinases (TIMP)-1 and MMP-10 in functional outcome of ischemic stroke patients has been scarcely studied. In addition, to our knowledge, serum MMP-9, MMP-10 and TIMP-1 levels in patients with malignant middle cerebral artery infarction (MMCAI) for mortality prediction have not been studied, and these were the objectives of this study. Methods: This was a multicenter, observational and prospective study carried out in six Spanish Intensive Care Units. We included patients with severe MMCAI defined as Glasgow Coma Scale (GCS) lower than 9. We measured circulating levels of MMP-9, MMP-10, TIMP-1, in 50 patients with severe MMCAI at diagnosis and in 50 healthy subjects. Endpoint was 30-day mortality. Results: Patients with severe MMCAI showed higher serum levels of MMP-9 (p = 0.001), MMP-10 (p 239 ng/mL are associated with 30-day mortality (OR = 5.82; 95 % CI = 1.37-24.73; P = 0.02) controlling for GCS and age. The area under the curve for TIMP-1 as predictor of 30-day mortality was 0.81 (95 % CI = 0.67-0.91; P < 0.001). We found an association between circulating levels of TIMP-1 and MMP-10 (rho = 0.45; P = 0.001), plasminogen activator inhibitor (PAI)-1 (rho = 0.53; P < 0.001), and tumor necrosis factor (TNF)-alpha (rho = 0.70; P < 0.001). Conclusions: The most relevant and new findings of our study, were that serum TIMP-1 levels in MMCAI patients were associated with mortality, and could be used as a prognostic biomarker of mortality in MMCAI patients

GC-Rich Sequence Elements Recruit PRC2 in Mammalian ES Cells

Polycomb proteins are epigenetic regulators that localize to developmental loci in the early embryo where they mediate lineage-specific gene repression. In Drosophila, these repressors are recruited to sequence elements by DNA binding proteins associated with Polycomb repressive complex 2 (PRC2). However, the sequences that recruit PRC2 in mammalian cells have remained obscure. To address this, we integrated a series of engineered bacterial artificial chromosomes into embryonic stem (ES) cells and examined their chromatin. We found that a 44 kb region corresponding to the Zfpm2 locus initiates de novo recruitment of PRC2. We then pinpointed a CpG island within this locus as both necessary and sufficient for PRC2 recruitment. Based on this causal demonstration and prior genomic analyses, we hypothesized that large GC-rich elements depleted of activating transcription factor motifs mediate PRC2 recruitment in mammals. We validated this model in two ways. First, we showed that a constitutively active CpG island is able to recruit PRC2 after excision of a cluster of activating motifs. Second, we showed that two 1 kb sequence intervals from the Escherichia coli genome with GC-contents comparable to a mammalian CpG island are both capable of recruiting PRC2 when integrated into the ES cell genome. Our findings demonstrate a causal role for GC-rich sequences in PRC2 recruitment and implicate a specific subset of CpG islands depleted of activating motifs as instrumental for the initial localization of this key regulator in mammalian genomes.Burroughs Wellcome FundCharles E. Culpeper FoundationMassachusetts General HospitalBroad Institute of MIT and Harvar

Recovery from depressive symptoms, state anxiety and post-traumatic stress disorder in women exposed to physical and psychological, but not to psychological intimate partner violence alone: A longitudinal study

<p>Abstract</p> <p>Background</p> <p>It is well established that intimate male partner violence (IPV) has a high impact on women's mental health. It is necessary to further investigate this impact longitudinally to assess the factors that contribute to its recovery or deterioration. The objective of this study was to assess the course of depressive, anxiety and post-traumatic stress disorder (PTSD) symptoms and suicidal behavior over a three-year follow-up in female victims of IPV.</p> <p>Methods</p> <p>Women (n = 91) who participated in our previous cross-sectional study, and who had been either physically/psychologically (n = 33) or psychologically abused (n = 23) by their male partners, were evaluated three years later. A nonabused control group of women (n = 35) was included for comparison. Information about mental health status and lifestyle variables was obtained through face-to-face structured interviews.</p> <p>Results</p> <p>Results of the follow-up study indicated that while women exposed to physical/psychological IPV recovered their mental health status with a significant decrease in depressive, anxiety and PTSD symptoms, no recovery occurred in women exposed to psychological IPV alone. The evolution of IPV was also different: while it continued across both time points in 65.21% of psychologically abused women, it continued in only 12.12% of physically/psychologically abused women while it was reduced to psychological IPV in 51.5%. Hierarchical multiple regression analyses indicated that cessation of physical IPV and perceived social support contributed to mental health recovery, while a high perception of lifetime events predicted the continuation of PTSD symptoms.</p> <p>Conclusion</p> <p>This study shows that the pattern of mental health recovery depends on the type of IPV that the women had been exposed to. While those experiencing physical/psychological IPV have a higher likelihood of undergoing a cessation or reduction of IPV over time and, therefore, could recover, women exposed to psychological IPV alone have a high probability of continued exposure to the same type of IPV with a low possibility of recovery. Thus, women exposed to psychological IPV alone need more help to escape from IPV and to recuperate their mental health. Longitudinal studies are needed to improve knowledge of factors promoting or impeding health recovery to guide the formulation of policy at individual, social and criminal justice levels.</p

Sleep disturbances in highly stress reactive mice: Modeling endophenotypes of major depression

<p>Abstract</p> <p>Background</p> <p>Neuronal mechanisms underlying affective disorders such as major depression (MD) are still poorly understood. By selectively breeding mice for high (HR), intermediate (IR), or low (LR) reactivity of the hypothalamic-pituitary-adrenocortical (HPA) axis, we recently established a new genetic animal model of extremes in stress reactivity (SR). Studies characterizing this SR mouse model on the behavioral, endocrine, and neurobiological levels revealed several similarities with key endophenotypes observed in MD patients. HR mice were shown to have changes in rhythmicity and sleep measures such as rapid eye movement sleep (REMS) and non-REM sleep (NREMS) as well as in slow wave activity, indicative of reduced sleep efficacy and increased REMS. In the present study we were interested in how far a detailed spectral analysis of several electroencephalogram (EEG) parameters, including relevant frequency bands, could reveal further alterations of sleep architecture in this animal model. Eight adult males of each of the three breeding lines were equipped with epidural EEG and intramuscular electromyogram (EMG) electrodes. After recovery, EEG and EMG recordings were performed for two days.</p> <p>Results</p> <p>Differences in the amount of REMS and wakefulness and in the number of transitions between vigilance states were found in HR mice, when compared with IR and LR animals. Increased frequencies of transitions from NREMS to REMS and from REMS to wakefulness in HR animals were robust across the light-dark cycle. Detailed statistical analyses of spectral EEG parameters showed that especially during NREMS the power of the theta (6-9 Hz), alpha (10-15 Hz) and eta (16-22.75 Hz) bands was significantly different between the three breeding lines. Well defined distributions of significant power differences could be assigned to different times during the light and the dark phase. Especially during NREMS, group differences were robust and could be continuously monitored across the light-dark cycle.</p> <p>Conclusions</p> <p>The HR mice, i.e. those animals that have a genetic predisposition to hyper-activating their HPA axis in response to stressors, showed disturbed patterns in sleep architecture, similar to what is known from depressed patients. Significant alterations in several frequency bands of the EEG, which also seem to at least partly mimic clinical observations, suggest the SR mouse lines as a promising animal model for basic research of mechanisms underlying sleep impairments in MD.</p

Evaluation of iron status in European adolescents through biochemical iron indicators: the HELENA Study

BACKGROUND/OBJECTIVES: To assess the iron status among European adolescents through selected biochemical parameters in a cross-sectional study performed in 10 European cities. SUBJECTS/METHODS: Iron status was defined utilising biochemical indicators. Iron depletion was defined as low serum ferritin (SF8.5 mg/l) plus iron depletion. Iron deficiency anaemia (IDA) was defined as ID with haemoglobin (Hb) below the WHO cutoff for age and sex: 12.0 g/dl for girls and for boys aged 12.5-14.99 years and 13.0 g/dl for boys aged ≥15 years. Enzyme linked immunosorbent assay was used as analytical method for SF, sTfR and C-reactive protein (CRP). Subjects with indication of inflammation (CRP >5 mg/l) were excluded from the analyses. A total of 940 adolescents aged 12.5-17.49 years (438 boys and 502 girls) were involved. RESULTS: The percentage of iron depletion was 17.6%, significantly higher in girls (21.0%) compared with boys (13.8%). The overall percentage of ID and IDA was 4.7 and 1.3%, respectively, with no significant differences between boys and girls. A correlation was observed between log (SF) and Hb (r = 0.36, P < 0.01), and between log (sTfR) and mean corpuscular haemoglobin (r = -0.30, P < 0.01). Iron body stores were estimated on the basis of log (sTfR/SF). A higher percentage of negative values of body iron was recorded in girls (16.5%) with respect to boys (8.3%), and body iron values tended to increase with age in boys, whereas the values remained stable in girls. CONCLUSIONS: To ensure adequate iron stores, specific attention should be given to girls at European level to ensure that their dietary intake of iron is adequate.status: publishe

Phase I studies of AZD1208, a proviral integration Moloney virus kinase inhibitor in solid and haematological cancers.

BACKGROUND:Proviral integration Moloney virus (PIM) kinases (PIM1, 2 and 3) are overexpressed in several tumour types and contribute to oncogenesis. AZD1208 is a potent ATP-competitive PIM kinase inhibitor investigated in patients with recurrent or refractory acute myeloid leukaemia (AML) or advanced solid tumours. METHODS:Two dose-escalation studies were performed to evaluate the safety and tolerability, and to define the maximum tolerated dose (MTD), of AZD1208 in AML and solid tumours. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics (PD) and preliminary efficacy of AZD1208. RESULTS:Sixty-seven patients received treatment: 32 in the AML study over a 120-900 mg dose range, and 25 in the solid tumour study over a 120-800 mg dose range. Nearly all patients (98.5%) in both studies experienced adverse events, mostly gastrointestinal (92.5%). Dose-limiting toxicities included rash, fatigue and vomiting. AZD1208 was not tolerated at 900 mg, and the protocol-defined MTD was not confirmed. AZD1208 increased CYP3A4 activity after multiple dosing, resulting in increased drug clearance. There were no clinical responses; PD analysis showed biological activity of AZD1208. CONCLUSIONS:Despite the lack of single-agent clinical efficacy with AZD1208, PIM kinase inhibition may hold potential as an anticancer treatment, perhaps in combination with other agents

Drug discovery in advanced prostate cancer: translating biology into therapy.

Castration-resistant prostate cancer (CRPC) is associated with a poor prognosis and poses considerable therapeutic challenges. Recent genetic and technological advances have provided insights into prostate cancer biology and have enabled the identification of novel drug targets and potent molecularly targeted therapeutics for this disease. In this article, we review recent advances in prostate cancer target identification for drug discovery and discuss their promise and associated challenges. We review the evolving therapeutic landscape of CRPC and discuss issues associated with precision medicine as well as challenges encountered with immunotherapy for this disease. Finally, we envision the future management of CRPC, highlighting the use of circulating biomarkers and modern clinical trial designs

2013 WSES guidelines for management of intra-abdominal infections

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