A dense network of macrophages and dendritic cells (DC) expressing the chemokine receptor CX3CR1 populates most tissues. We recently reported that CX3CR1 regulates the abundance of CD11c(+) DC in the ...kidney and thereby promotes renal inflammation in glomerulonephritis. Given that chronic inflammation usually causes fibrosis, we hypothesized that CX3CR1 deficiency should attenuate renal fibrosis. However, when we tested this hypothesis using the DC-independent murine fibrosis model of unilateral ureteral obstruction, kidney fibrosis was unexpectedly more severe, despite less intrarenal inflammation. Two-photon imaging and flow cytometry revealed in kidneys of CX3CR1-deficient mice more motile Ly6C/Gr-1(+) macrophages. Flow cytometry verified that renal macrophages were more abundant in the absence of CX3CR1 and produced more of the key profibrotic mediator, TGF-β. Macrophages accumulated because of higher intrarenal proliferation, despite reduced monocyte recruitment and higher signs of apoptosis within the kidney. These findings support the theory that tissue macrophage numbers are regulated through local proliferation and identify CX3CR1 as a regulator of such proliferation. Thus, CX3CR1 inhibition should be avoided in DC-independent inflammatory diseases because it may promote fibrosis.
We calculate the spectral energy distribution (SED) of electromagnetic radiation and the spectrum of high-energy neutrinos from BL Lac objects in the context of the synchrotron proton blazar model. ...In this model, the high-energy hump of the SED is due to accelerated protons, while most of the low-energy hump is due to synchrotron radiation by co-accelerated electrons. To accelerate protons to sufficiently high energies to produce the high-energy hump, rather high magnetic fields are required. Assuming reasonable emission region volumes and Doppler factors, we then find that in low-frequency peaked BL Lacs (LBLs), which have higher luminosities than high-frequency peaked BL Lacs (HBLs), there is a significant contribution to the high-frequency hump of the SED from pion photoproduction and subsequent cascading, including synchrotron radiation by muons. In contrast, in HBLs we find that the high-frequency hump of the SED is dominated by proton synchrotron radiation. We are able to model the SED of typical LBLs and HBLs, and to model the famous 1997 flare of Markarian 501. We also calculate the expected neutrino output of typical BL Lac objects, and estimate the diffuse neutrino intensity due to all BL Lacs. Because pion photoproduction is inefficient in HBLs, as protons lose energy predominantly by synchrotron radiation, the contribution of LBLs dominates the diffuse neutrino intensity. We suggest that nearby LBLs may well be observable with future high-sensitivity TeV γ-ray telescopes.
The extracellular signal-regulated kinase (ERK) pathway mediates neuronal plasticity in the CNS. The mood stabilizers lithium and valproate activate the ERK pathway in prefrontal cortex and ...hippocampus and potentiate ERK pathway-mediated neurite growth, neuronal survival and hippocampal neurogenesis. Here, we examined the role of the ERK pathway in behavioral plasticity related to facets of bipolar disorder. Mice with ERK1 ablation acquired reduced phosphorylation of RSK1, an ERK substrate, in prefrontal cortex and striatum, but not in hippocampus or cerebellum, indicating the ablation-induced brain region-specific ERK signaling deficits. ERK1 ablation produced a behavioral excitement profile similar to that induced by psychostimulants. The profile is characterized by hyperactivity, enhanced goal-directed activity and increased pleasure-related activity with potential harmful consequence. ERK1-ablated mice were hyperactive in multiple tests and resistant to behavioral despair in the forced swim test. These mice displayed more home-cage voluntary wheel running activities, rearings in a large arena and open-arm visits in an elevated plus maze. Treatments with valproate and olanzapine, but not lithium reduced baseline activities in ERK1-ablated mice. All three treatments attenuated amphetamine-induced hyperactivity in ablated mice. These data indicate a profound involvement of ERK1 signaling in behavioral excitement and in the behavioral action of antimanic agents. The extent to which ERK pathway perturbation contributes to the susceptibility, mood switch mechanism(s) and symptom pathophysiology of bipolar disorder requires further investigation. Whether there is a shared mechanism through which mood stabilizers produce their clinical actions on mood, thought and behavioral symptoms of mania also requires further investigation.
To understand what given scores of the Brief Psychiatric Rating Scale (BPRS) and the Positive and Negative Syndrome Scale (PANSS) mean from a clinical point of view is important for the translation ...of research results into practice. We therefore (a) compared the absolute change of the BPRS/PANSS with the Clinical Global Impressions Ratings (CGI) -improvement score and the change of the CGI severity score, (b) analyzed whether the severity of illness at baseline had an impact on the latter association, and (c) attempted to replicate previous BPRS findings using a completely different data set based upon the PANSS-derived BPRS. The method used was equipercentile linking of BPRS and CGI ratings from 14 drug trials in acutely ill patients with schizophrenia (n=5970). An absolute reduction of the BPRS/PANSS by approximately 10/15 points corresponded to a CGI change of 'minimally improved' and to a change of the CGI severity score by one severity step. However, the latter associations depended on the severity of symptoms at baseline. Less severely ill patients required less BPRS/PANSS total score reduction to achieve the same CGI-improvement score than more severely ill patients. This effect of initial severity was attenuated using percentage rather than absolute BPRS/PANSS reduction scores. The linking analysis between the absolute BPRS/PANSS reduction and the CGI may have an implication for the interpretation of efficacy differences found in clinical trials, and for sample size estimations. Clinicians seem to base CGI ratings on relative change rather than on absolute change of symptoms.
Tertiary lymphoid structures (TLS) are lymph node-like immune cell clusters that emerge during chronic inflammation in non-lymphoid organs like the kidney, but their origin remains not well ...understood. Here we show, using conditional deletion strategies of the canonical Notch signaling mediator Rbpj, that loss of endothelial Notch signaling in adult mice induces the spontaneous formation of bona fide TLS in the kidney, liver and lung, based on molecular, cellular and structural criteria. These TLS form in a stereotypical manner around parenchymal arteries, while secondary lymphoid structures remained largely unchanged. This effect is mediated by endothelium of blood vessels, but not lymphatics, since a lymphatic endothelial-specific targeting strategy did not result in TLS formation, and involves loss of arterial specification and concomitant acquisition of a high endothelial cell phenotype, as shown by transcriptional analysis of kidney endothelial cells. This indicates a so far unrecognized role for vascular endothelial cells and Notch signaling in TLS initiation.
Coordination polymers, including metal-organic frameworks, are a diverse class of materials with myriad properties and potential applications. However, a number of drawbacks have hindered the scaling ...up of such materials towards commercial applications. These include health and safety risks, environmental hazards, poor cost efficiency and sustainability shortfalls. In contrast to the systematic progress of organic green chemistry, which has contributed to improvements in the sustainability of chemical processing, the development of green chemistry in the context of coordination polymers has been fragmented and sporadic. This review describes advances in the use of green components: benign sustainable ligands and non-hazardous earth abundant metals. Additionally, solvent considerations, synthesis strategies for improved sustainability and the performance of coordination polymers relative to alternative competing materials are discussed.
A perspective on the development of coordination polymers based on sustainable benign ligands and metals, and green synthesis.
The purpose of this study was to assess the pharmacological treatment strategies of inpatients with borderline personality disorder between 2008 and 2012. Additionally, we compared pharmacotherapy ...during this period to a previous one (1996 to 2004).
Charts of 87 patients with the main diagnosis of borderline personality disorder receiving inpatient treatment in the University Medical Center of Goettingen, Germany, between 2008 and 2012 were evaluated retrospectively. For each inpatient treatment, psychotropic drug therapy including admission and discharge medication was documented. We compared the prescription rates of the interval 2008-2012 with the interval 1996-2004.
94% of all inpatients of the interval 2008-2012 were treated with at least one psychotropic drug at time of discharge. All classes of psychotropic drugs were applied. We found high prescription rates of naltrexone (35.6%), quetiapine (19.5%), mirtazapine (18.4%), sertraline (12.6%), and escitalopram (11.5%). Compared to 1996-2004, rates of low-potency antipsychotics, tri-/tetracyclic antidepressants and mood stabilizers significantly decreased while usage of naltrexone significantly increased.
In inpatient settings, pharmacotherapy is still highly prevalent in the management of BPD. Prescription strategies changed between 1996 and 2012. Quetiapine was preferred, older antidepressants and low-potency antipsychotics were avoided. Opioid antagonists are increasingly used and should be considered for further investigation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective: To review and make recommendations for the definition and presentation of the terms ‘response’ and ‘remission’ in schizophrenia.
Method: Selective review of publications on definitions ...of response and remission in schizophrenia.
Results: When the Brief Psychiatric Rating Scale (BPRS) or the Positive and Negative Syndrome Scale (PANSS) are used for definitions of response, a cut‐off of at least 50% reduction of the baseline score should be used for acutely ill, non‐refractory patients and a cut‐off of at least 25% reduction for refractory patients. When percentage BPRS/PANSS reduction is calculated, the 18/30 points minimum scores meaning ‘no symptoms’ on the should be subtracted. In addition, responder rates from 0–100% could be presented in a table in steps of 25%. For large and simple practical trials, the Clinical Global Impression scale with suggested improvements could be used 1‐7 scale.
Conclusion: To show how many patients are still symptomatic at the end of study and to show the overall amount of change in both remission and responder criteria should be presented.
Transgenic mice expressing the diphtheria toxin receptor (DTR) in specific cell types are key tools for functional studies in several biological systems. B6.FVB-Tg(Itgax-DTR/EGFP)57Lan/J (CD11c.DTR) ...and B6.Cg-Tg(Itgax-DTR/OVA/EGFP)1Gjh/Crl (CD11c.DOG) mice express the DTR in CD11c(+) cells, allowing conditional depletion of dendritic cells. We report that dendritic-cell depletion in these models caused polymorphonuclear neutrophil (PMN) release from the bone marrow, which caused chemokine-dependent neutrophilia after 6-24 h and increased bacterial clearance in a mouse pyelonephritis model. We present a transgenic mouse line, B6.Cg-Tg(Itgax-EGFP-CRE-DTR-LUC)2Gjh/Crl (CD11c.LuciDTR), which is unaffected by early neutrophilia. However, CD11c.LuciDTR and CD11c.DTR mice showed late neutrophilia 72 h after dendritic cell depletion, which was independent of PMN release and possibly resulted from increased granulopoiesis. Thus, the time point of dendritic cell depletion and the choice of DTR transgenic mouse line must be considered in experimental settings where neutrophils may be involved.
The control of coercive stress in organoferroelasticity is demonstrated in single crystals of trans -1,4-cyclohexanedicarboxylic acid with bulky cyclohexane rings. Flipping difficulty, due to the ...bulkiness, increased coercive stress, which can improve mechanical damping. Crystals also undergo the spontaneous disappearance of a twinned domain upon unloading before the completion of domain formation.
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