Suggestive evidence of a multi-cytokine resistin pathway in humans and its role on cardiovascular events in high-risk individuals

In cells and tissues resistin affects IL-1β, IL-6, IL-8, IL-12 and TNF-α expression, thus suggesting the existence of a multi-cytokine "resistin pathway". We investigated whether such pathway does exist in humans and, if so, if it is associated with cardiovascular risk factors and with major adverse cardiovascular events (MACE). Serum cytokines were measured in 280 healthy subjects from the Gargano Study 2 (GS2) whose BMI, waist circumference, HOMA IR, triglycerides, HDL-cholesterol, systolic and diastolic blood pressure data were available and in 353 patients with type 2 diabetes and coronary artery disease from the Gargano Heart Study (GHS)-prospective design (follow-up 5.4 ± 2.5 years; 71 MACE). In GS2, cytokines mRNA levels in white blood cells were also measured. In GS2, resistin mRNA was correlated with all cytokines expression (all p < 0.001), but IL-12B. Consistently, serum resistin was correlated with all serum cytokines (all p < 0.001), but IL-12. Expression (eRPS) and serum (sRPS) resistin pathway scores (excluding IL-12) were each other correlated (p < 0.001) and both associated with cardiovascular risk factors (all p < 0.01). In GHS, sRPS was independently associated with MACE (HR = 1.44, 95% CI = 1.10-1.90). Our data indicate the existence of a resistin pathway, which is associated with cardiovascular risk factors and which strongly and independently predicts MACE

Strategies for Psychiatric Rehabilitation and their Cognitive Outcomes in Schizophrenia: Review of Last Five-year Studies

Background: Cognitive deficits are core features of Schizophrenia, showing poor response to antipsychotic treatment, therefore non-pharmacological rehabilitative approaches to such a symptom domain need to be identified. However, since not all patients with Schizophrenia exhibit the same cognitive impairment profile, individualized rehabilitative approaches should be set up. Objectives: We explored the last five-year literature addressing the issue of cognitive dysfunction response to rehabilitative methodologies in Schizophrenia to identify possible predictors of response and individualized strategies to treat such a dysfunction. Conclusion: A total of 76 studies were reviewed. Possible predictors of cognitive rehabilitation outcome were identified among patient-specific and approachspecific variables and a general overview of rehabilitative strategies used in the last five years has been depicted. Studies suggest the existence of multifaced and multi-domain variables that could significantly predict pro-cognitive effects of cognitive rehabilitation, which could also be useful for identifying individual-specific rehabilitation trajectories over time. An individualized rehabilitative approach to cognitive impairment in Schizophrenia is possible if taking into account both patient and approach specific predictors of outcomes

An X-ray view of the INTEGRAL/IBIS blazars

Aim of this work is a broad-band study with INTEGRAL, Swift and XMM-Newton satellites of a sample of 9 blazars (7 FSRQ and 2 BL Lac) with redshift up to about 4. The spectral analysis has shown clear evidence of a flattening of the continuum towards the low energies ($E<3$ keV observer frame). This behaviour is well reproduced both with an absorbed power-law model ($N_H\sim10^{20}$-$10^{23}$ cm$^{-2}$ in the rest-frame of the sources) or a broken power-law continuum model (with an energy break below 3 keV in the observer-frame). No Compton reflection features, Fe $K\alpha$ line and hump at high energies, have been detected, with the exception of the source IGR J22517+2218 that shows the presence of a weak iron line. In this work we also investigate a possible correlation between the absorption column density $N_H$ and the red-shift. We confirm the existence of a $N_H$-z trend, with the higher absorption at z$>$2 for a larger sample compared to previous results. The distribution of the $N_H$ and the photon index $\Gamma$ is also presented. The hard X-ray data allow us to detect highly absorbed sources (with $N_H\ge10^{23}$cm$^{-2}$ in rest-frame of the source) characterized by photon index distribution peaked at harder values ($\Gamma\sim1.4$) with respect to that obtained with XMM data only ($\Gamma\sim2$).Comment: accepted for publication in MNRA

Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18–72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18–73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen’s d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions

Loss of CDKL5 Causes Synaptic GABAergic Defects That Can Be Restored with the Neuroactive Steroid Pregnenolone-Methyl-Ether

: CDKL5 deficiency disorder (CDD) is an X-linked neurodevelopmental disorder characterised by early-onset drug-resistant epilepsy and impaired cognitive and motor skills. CDD is caused by mutations in cyclin-dependent kinase-like 5 (CDKL5), which plays a well-known role in regulating excitatory neurotransmission, while its effect on neuronal inhibition has been poorly investigated. We explored the potential role of CDKL5 in the inhibitory compartment in Cdkl5-KO male mice and primary hippocampal neurons and found that CDKL5 interacts with gephyrin and collybistin, two crucial organisers of the inhibitory postsynaptic sites. Through molecular and electrophysiological approaches, we demonstrated that CDKL5 loss causes a reduced number of gephyrin puncta and surface exposed γ2 subunit-containing GABAA receptors, impacting the frequency of miniature inhibitory postsynaptic currents, which we ascribe to a postsynaptic function of CDKL5. In line with previous data showing that CDKL5 loss impacts microtubule (MT) dynamics, we showed that treatment with pregnenolone-methyl-ether (PME), which promotes MT dynamics, rescues the above defects. The impact of CDKL5 deficiency on inhibitory neurotransmission might explain the presence of drug-resistant epilepsy and cognitive defects in CDD patients. Moreover, our results may pave the way for drug-based therapies that could bypass the need for CDKL5 and provide effective therapeutic strategies for CDD patients

Short-Term Follow-Up of Radioembolization With Yttrium-90 Microspheres Before Liver Transplantation: New Perspectives in Advanced Hepatocellular Carcinoma

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Mitogen-activated kinase kinase kinase 1 inhibits hedgehog signaling and medulloblastoma growth through GLI1 phosphorylation

The aberrant activation of hedgehog (HH) signaling is a leading cause of the development of medulloblastoma, a pediatric tumor of the cerebellum. The FDA‑approved HH inhibitor, Vismodegib, which targets the transmembrane transducer SMO, has shown limited efficacy in patients with medulloblastoma, due to compensatory mechanisms that maintain an active HH‑GLI signaling status. Thus, the identification of novel actionable mechanisms, directly affecting the activity of the HH‑regulated GLI transcription factors is an important goal for these malignancies. In this study, using gene expression and reporter assays, combined with biochemical and cellular analyses, we demonstrate that mitogen‑activated kinase kinase kinase&nbsp;1&nbsp;(MEKK1), the most upstream kinase of the mitogen‑activated protein kinase&nbsp;(MAPK) phosphorylation modules, suppresses HH signaling by associating and phosphorylating GLI1, the most potent HH‑regulated transcription factor. Phosphorylation occurred at multiple residues in the C‑terminal region of GLI1 and was followed by an increased association with the cytoplasmic proteins&nbsp;14‑3‑3. Of note, the enforced expression of MEKK1 or the exposure of medulloblastoma cells to the MEKK1 activator, Nocodazole, resulted in a marked inhibitory effect on GLI1 activity and tumor cell proliferation and viability. Taken together, the results of this study shed light on a novel regulatory mechanism of HH signaling, with potentially relevant implications in cancer therapy

Deficiency of Broad Line AGNs in Compact Groups of Galaxies

Based on a new survey of AGN activity in Compact Groups of Galaxies, we report a remarkable deficiency of Broad Line AGNs as compared to Narrow Line AGNs. The cause of such deficiency could be related to the average low luminosity of AGNs in CGs: $10^{39}$ erg s$^{-1}$. This result may imply lower accretion rates in CG AGNs, making Broad Line Regions (BLR) undetectable, or may indicate a genuine absence of BLRs. Both phenomena are consistent with gas stripping through tidal interaction and dry mergers.Comment: Accepted for publication in ApJ Lette

An X-ray view of absorbed INTEGRAL AGN

Aims. We present a 0.2--200 keV broad-band study of absorbed AGN observed with INTEGRAL, XMM-Newton, Chandra and ASCA to investigate the continuum shape and the absorbing/reflecting medium properties. Methods. The sources are selected in the INTEGRAL AGN sample to have a 20--100 keV flux below 8$\times10^{-11}$ \flux (5 mCrab), and are characterized by a 2--10 keV flux in the range (0.8--10)$\times10^{-11}$ \flux. The good statistics allow us a detailed study of the intrinsic and reflected continuum components. In particular, the analysis performed on the combined broad-band spectra allow us to investigate the presence of Compton reflection features and high energy cut-off in these objects. Results. The column density of the absorbing gas establishes the Compton thin nature for three sources in which a measure of the absorption was still missing. The Compton thin nature of all the sources in this small sample is also confirmed by the diagnostic ratios F$x/F[OIII]. The Compton reflection components we measure, reflection continuum and iron line, are not immediately compatible with a scenario in which the absorbing and reflecting media are one and the same, i.e. the obscuring torus. A possible solution is that the absorption is more effective than reflection, e.g. under the hypothesis that the absorbing/reflecting medium is not uniform, like a clumpy torus, or that the source is observed through a torus with a very shallow opening angle. The high energy cut-off (a lower limit in two cases) is found in all sources of our sample and the range of values is in good agreement with that found in type 1 Seyfert galaxies. At lower energies there is clear evidence of a soft component (reproduced with a thermal and/or scattering model), in six objects.Comment: Accepted for publication in Astronomy and Astrophysic