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Introduction: Information on the off–label use of Long–Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on– vs off–label LAIs and predictors of off–label First– or Second–Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. Method: In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off– or on–label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off–label group. Results: SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on– and off–label use. Approximately 1 in 4 patients received an off–label prescription. In the off–label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p= 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p= 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. Conclusion: Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off–label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co–morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns.

Cell quiescence appeared early in evolution as an adaptive response to adverse conditions, i.e. nutrient depletion. In metazoans, quiescence has been enrolled in additional purposes like tissue homeostasis, which is made possible by the presence of adult stem cells (ASCs). Cell-cycle control machinery is a common hub for quiescence entrance, and evidence indicates a role for p53 in establishing the quiescent state of undamaged cells. Mechanisms responsible for waking up quiescent cells remain elusive and nutritional stimulus, as a legacy of its original role, still appears to be a player in quiescence exit. Planarians, rich in ASCs, represent a suitable system in which we characterized a quiescent population of ASCs, the dorsal midline cord (DMC) cells, exhibiting unique transcriptional features and maintained quiescent by p53 and awakened upon feeding. The function of DMC cells is puzzling and we speculate that DMC cells, despite retaining ancient properties, might represent a functional drift in which quiescence has been recruited to provide evolutionary advantages.

Background: Long acting injectable (LAI) antipsychotics have been claimed to ensure treatment adherence and possibly reduce the daily burden of oral formulations. So far, only surveys investigating the theoretical prescribing attitudes of clinicians have been employed. On this basis, we aimed to investigate reasons for prescribing LAIs in a real-world, unselected sample of patients. Methods: The STAR Network Depot Study is an observational, multicentre study consecutively enrolling adults initiating a LAI over a 12-months period. Clinical severity was assessed with the Brief Psychiatric Rating Scale, and patient’s attitude toward medications with the Drug Attitude Inventory 10 items. Psychiatrists recorded reasons for LAI prescribing for each study participant. Responses were grouped into six non-mutually exclusive categories: aggressiveness, patient engagement, ease of drug taking, side-effects, stigma, adherence. Results: Of the 451 patients included, two-thirds suffered from chronic psychoses. Improving patient engagement with the outpatient psychiatric service was the most common reason for prescribing LAIs (almost 80% of participants), followed by increasing treatment adherence (57%), decreasing aggressiveness (54%), and improving ease of drug taking (52%). After adjusting for confounders, logistic regression analyses showed that reasons for LAI use were associated with LAI choice (e.g. first-generation LAIs for reducing aggressiveness). Conclusion: Despite the wide availability of novel LAI formulation and the emphasis on their wider use, our data suggest that the main reasons for LAI use have remained substantially unchanged over the years, focusing mostly on improving patient’s engagement. Further, clinicians follow implicit prescribing patterns when choosing LAIs, and this may generate hypotheses for future experimental studies.

Background: TBX5 mutations cause Holt-Oram syndrome (HOS) characterized by upper limb and cardiac malformations, but can also contribute to early-onset of atrial fibrillation. Focusing on miRNAs involved in TBX5 regulatory circuits with a cardiac relevant role, we identified miR-182-5p, belonging to miR-183 cluster, found upregulated in Tbx5-depleted hearts of mouse and zebrafish embryos. Methods: To functionally analyse the miR-182-5p role in developing heart, miR-182-5p was dysregulated in zebrafish zygotes of Tg(Myl7:EGFP) and Tg(myl7:gCaMP) transgenic lines. To stably deregulate miR-182-5p in zebrafish heart we exploited the Gal4/UAS system to restrict the miR-182 expression into cardiac context. For physiological analyses we performed the mechanogram of cardiac contraction and electrocardiogram recording. To understand miR-182-5p downstream regulation, in silico analyses, followed by ddPCR/real-time quantifications on dissected zebrafish hearts and rescue experiments both in transient and stable miR-182-5p overexpressing zebrafish embryos were performed. Results: Depletion of Tbx5 from cardiomyocytes increased the expression of miR-182 cluster family that is controlled by Kruppel-like factor 4 (KLF4), a transcription factor repressed by Tbx5. Both transient and stable upregulation of miR-182 in zebrafish affect heart morphology, calcium handling and the onset of arrhythmia while its cardiac-specific downregulation decreases cardiac defects in zebrafish HOS hearts. Expression analyses on selected miR-182-5p putative targets revealed that several calcium channel proteins resulted downregulated in miR-182-5p overexpressing hearts. Transgenic zebrafish line stably overexpressing miR-182-5p in the heart manifested arrhythmia overtime with or without cardiac structural defects. Conclusion: We identified miR-182-5p as a potential suitable target to interfere in the circuit between upstream genetic abnormalities and downstream effectors leading to arrhythmia occurrence.

Background and Aim. Obesity is a metabolic disorder with an increasing incidence in Western countries and childhood. It is characterized by low-grade systemic inflammation and several comorbidities, including alterations of gastrointestinal (GI) functions, which impact negatively on patients’ quality of life. There is currently limited information on the morpho-functional features of the GI tract in obese subjects. Of note, the intestinal barrier function has been found to be altered in obese subjects, even before the occurrence of body weight increase [1]. In this light, the present study was carried out to assess, in a mouse model of diet-induced obesity, whether high fat diet (HFD) is associated with morphological alterations of the colonic mucosal barrier. Methods. C57BL/6 mice (n=5/group) were fed with standard diet (SD, 18% calories from fat) or HFD (60% calories from fat). After 8 weeks, body weight, and levels of blood cholesterol, triglycerides and glucose were evaluated. Malondialdehyde (MDA, colorimetric assay), IL-1β and IL-6 levels (ELISA assays) were examined in colonic tissues. Morphological features of colonic mucosal structures (lining epithelial cells, goblet cells, inflammatory infiltrates and enteric glia) were examined by histochemistry and immunohistochemistry. Results. HFD mice displayed significant differences at both molecular and histomorphological level, as compared with SD animals: increased body weight and blood metabolic indexes; increased MDA, IL-1β and IL-6 levels in colonic tissues; altered pattern of claudin-1 expression along with upregulation of transmembrane 16A protein and induced nitric oxide synthase in the enteric epithelium facing the lumen; increased proliferation rate of crypts; altered composition of goblet cell mucous; mucosal gliosis and infiltrates with mixed inflammatory cells. Conclusions. After 8 weeks, HFD intake led to significant alterations of systemic metabolic indexes, colonic tissue inflammation, and colonic mucosal barrier in obese mice, as compared with controls. Morphological studies can be useful to allow the characterization of histopathological patterns of colonic wall remodelling and inflammation underlying bowel motor dysfunctions associated with obesity., Italian Journal of Anatomy and Embryology, Vol. 122, No. 1 (Supplement) 2017

Inflammatory bowel disease (IBD) are chronic and progressive pathologies associated with invalidating abdominal symptoms and increasing incidence in Western countries. Although fibrostenosis is a rare event in ulcerative colitis [UC], it may evolve to fibrosis in the later stages (1, 2). In the present study we examined the histopathological remodeling of the colonic wall from short- and long-lasting (SL and LL) UC patients. Full-thickness left colonic surgical samples were obtained from non-stenotic SL (≤ 3 years) and LL (≥ 10 years) UC patients with a severe exacerbation of colitis and active disease, without clinical signs of fibrostenosis. Collagen and elastic fibres, vascular networks and parameters of fibrosis have been evaluated by histochemistry, immunohistochemistry, confocal immunofluorescence and/or western blot. For comparison, normal colonic control samples from subjects who underwent surgery for uncomplicated colon cancer and without IBD and diverticular disease, were considered.Both SL- and LL-UC showed a thickening in tunica muscularis and activation of transmural neovessels, with proliferating CD105-positive endothelial cells and activated nestin-positive pericytes, as compared with controls. The colonic wall of LL-UC displayed a significant increase in collagen deposition and fibrotic markers (type I and III collagen, fibronectin, vimentin, RhoA), an enhancement of proliferation (PCNA), a decrease in elastic fibres, together with a fibrotic rearrangement of the tunica muscularis smooth muscle cells. In conclusion, a significant full-thickness remodeling of the colonic wall has been documented in the colonic tissues from both SL-UC and LL-UC, as compared to controls: transmural fibrotic thickening and angiogenesis were found in both UC groups, together with a cellular fibrotic/proliferative switch in the tunica muscularis which occurs in the later stages. These histopathological remodeling may contribute to the reduced elastic properties and tissue stretch capability of the wall, thereby impairing the occurrence of a normal motor activity in these subjects., Italian Journal of Anatomy and Embryology, Vol. 121, No. 1 (Supplement) 2016

Background and Aim. Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor clinical signs, among which gastrointestinal disturbances represent relevant manifestations [1]. Nevertheless, the morphological alterations associated with intestinal dysfunctions in PD have been barely investigated [2]. The present study was aimed at investigating the remodelling of colonic wall in a rat model of PD with central dopaminergic denervation by intra-nigral injection of the neuro-toxin 6-hydroxydopamine (6-OHDA). Methods. Histopathological analysis of the whole colonic wall was performed 4 and 8 weeks after central 6-OHDA injection. Inflammatory infiltrates, collagen deposition as well as the remodelling of intestinal epithelial barrier and tunica muscularis were examined by microscopic techniques (histochemistry/immunohistochemistry/confocal immunofluorescence). Results. Colonic tissue from 8-week 6-OHDA rats were significantly altered, as compared with controls. The tunica mucosa showed: eosinophil infiltration; altered lining epithelium (reduced claudin-1 and transmembrane 16A protein expression) and goblet cells (increased mucus expression); enhanced glial fibrillar acid protein-positive cells and vimentin-positive fibroblast-like cells. Along with transmural collagen deposition, significant changes were observed also in the tunica muscularis: reduced expression of alpha-smooth muscle actin/desmin and increased proliferation index in smooth muscle cells; increased vimentin expression and proliferative phenotype in myenteric ganglia. Conclusions. A full-thickness structural remodelling occurs in the colon of PD rats 8 weeks after central dopaminergic denervation; the main changes include an alteration of the colonic epithelial barrier along with the activation of the mucosal defence and fibrotic switch of the colonic wall. Overall, these findings suggest that: a) early histological modifications occur in the colon of rats with experimental PD at both mucosal and muscular level; b) these changes and the fibrotic alterations might contribute to bowel motor dysfunctions associated with PD., Italian Journal of Anatomy and Embryology, Vol. 122, No. 1 (Supplement) 2017

Parkinson’s disease (PD) is a degenerative neurological disorder, which is often associated with gastrointestinal disturbances (e.g., constipation and defecatory dysfunctions), whose mechanisms are still unknown [1]. Recently, an inflammatory pathogenesis has been proposed to explain these colonic disorders, but low literature are available. This study aims to analyze whether the central dopaminergic denervation, induced by intranigral injection of 6-hydroxydopamine (6-OHDA), can alter the morphological arrangement of colon in rats. Animals were euthanized 4 and 8 weeks after 6-OHDA injection. Histological, histochemical and immunohistochemical analysis were carried out on formalin-fixed, paraffin-embedded colonic samples in order to evaluate: histology, inflammatory cells (eosinophils and mast cells) and collagen fibers in the whole wall; glial fibrillary acidic protein (GFAP), immunoperoxidase, alpha-smooth muscle actin (alpha-SMA) and vimentin immunofluorescence by confocal microscopy. Malondialdehyde (MDA, colorimetric assay), TNF and IL-1β (ELISA assay) levels were also examined. 6-OHDA-induced nigrostriatal denervation was associated with the following histopathological changes observed in the colonic wall: eosinophil and mast cell infiltration, collagen deposition, activation of myenteric glial cells (GFAP+), increased vimentin immunostaining associated with alpha-SMA decrease in the tunica muscularis, enhanced colonic tissue levels of MDA, TNF and IL-1β. On the basis of the present results it is possible to conclude that the induction of central nigrostriatal dopaminergic denervation is followed by inflammation and fibrotic rearrangement of the colonic wall., Italian Journal of Anatomy and Embryology, Vol. 121, No. 1 (Supplement) 2016

Background. Intestinal fibrosis is a common complication of inflammatory bowel diseases, affecting patients with both Crohn’s disease and ulcerative colitis (UC). Of note, the progression of intestinal fibrosis has been recently considered to depend on distinct processes from those involved in inflammation [1]. In this context, angiogen- esis is currently regarded as a good candidate of active gut disease, closely related to fibrogenesis [2]. Therefore, studies on the multifactorial pathways promoting these processes are needed for understanding the pathophysiology of fibrosis, and there- by identifying anti-fibrogenic therapies. Aim. The present study was performed to evaluate the distribution of fibrotic tissue, the behaviour of smooth muscle cells and the presence of neovessels in the colon of UC patients. Patients and Methods. Full- thickness left colonic samples were studied, from patients with established and phar- macologically unresponsive UC for the following parameters: collagen and elastic fib- ers by histochemistry; fibrotic and profibrotic factors [type 1 and 3 collagens, elastin, fibronectin, vimentin, alpha-smooth muscle actin (α-SMA), proliferating nuclear anti- gen (PCNA), RhoA] by immunohistochemistry and western blot; vascular networks [CD31, CD105, nestin] by confocal microscopy immunofluorescence. Results. A sig- nificant increase in collagen fibers and decrease in elastin content were detected in the colon from UC patients as compared with controls. The increment of type 1 and 3 collagens, fibronectin, vimentin, PCNA and RhoA expression was associated with alpha-SMA decrease in the tunica muscularis of UC colon. A relevant rearrangement of vascular networks was observed in the fibrotic tunica muscularis, with neovessels displaying both proliferating CD105+ endothelial cells and activated nestin+ pericytes. Conclusion. The present data show that a significant muscle and vascular remodel- ling occurs in inflamed colonic tissues from UC patients, suggesting that, under these conditions, smooth muscle cells and vascular cells may be involved in fibrogenic pro- cesses by cell transition to mesenchymal phenotype., Italian Journal of Anatomy and Embryology, Vol. 120, No. 1 (Supplement) 2015

Cx43, a predominant connexin in the heart, forms gap junctions (GJs) that facilitate electrical cell-cell coupling and hemichannels that represent a pathway for the exchange of ions and metabolites between cytoplasm and the extracellular milieu. Our recent results (1) demonstrated that an altered distribution and quantitative expression of factors involved in Cx43-made GJ regulation as Cx43, its phosphorylated form pS368-Cx43, PKC phosphorylated substrates, and adenosine 2A receptor (A2AR) are present in ventricular myocardium with left ventricular dysfunction. Moreover, dipyridamole treatment, which shows a mild protective role on left ventricular function, seems to act through re-modulating the expression and activation of these factors. The role of these factors on signal transduction cascade triggered by dipyridamole was evaluated in this study by pharmacological and immunoistochemical experiments using the rat cardiomyoblast cell line H9c2. The treatment of H9c2 cells with dipyridamole enhanced the expression of Cx43, A2AR and PKC activity while induced a decrease of pS368-Cx43. Interestingly, we found that the A2AR activation was a prerequisite for the effects of dipyridamole, in fact, the pre-treatment with CSC, a selective A2AR receptor antagonist, abolished its effects on the expression of these factors., Italian Journal of Anatomy and Embryology, Vol. 120, No. 1 (Supplement) 2015

The pathogenesis of diverticular disease (DD) seems to be a result of a complex interaction between exposure to a low-fibre diet, possible genetic influence, coexistence of other bowel disease and impact of medicine use. These conditions may lead to alterations in colonic pressure and motility [1]. To date, histopatological studies in the field of disturbances in intestinal motility have been mainly focused on the enteric nervous system and interstitial cells of Cajal, which have been found to be both variously affected in different conditions of gut dysmotility. By contrast, although smooth muscle cells (SMCs) are well recognized as the final effectors of the enteric neuromuscular units and have been extensively studied by electrophysiological experiments in colonic motility dysfunction, scarce attention has been paid to the molecular abnormalities of enteric musculature in gut dysmotility, and, in particular, data on SMCs in DD are fairly lacking. Accordingly, the aim of the present study was to evaluate the expression patterns of molecules involved in the contractile functions of SMCs within the colonic tunica muscularis from patients with DD. In particular, we examined the expression of the following molecules by immunohistochemistry and image analysis: Cx26 and Cx43, which are prominent components of gap junctions in human colonic SMCs [2], and an array of signaling molecules, which are known to regulate the functions of gap junctions and the contractile activity of SMCs [3,4,5]. The immunohistochemical analysis revealed significant abnormalities in DD samples, concerning both the expression and distribution patterns of most of the investigated molecular factors. Indeed, Cx26, Cx43, PKCps and RhoA appeared to be markedly deranged in all DD colonic samples compared to normal ones, except for α-SMA and pS368-Cx43. The present results provide the first evidence of an altered pattern of factors involved in smooth muscle contractility at level of tunica muscularis SMCs of DD patients. These abnormalities may contribute to the altered motility function, which characterize the colonic tunica muscularis of patients with DD., Italian Journal of Anatomy and Embryology, Vol 117, No 2 (Supplement) 2012

Inflammation-driven tissue remodelling may develop to fibrotic rearrangement. With regard to inflammatory bowel diseases, fibrotic remodelling has been evaluated in Crohn’s disease, while little attention to such processes has been paid to ulcerative colitis (UC) [1]. The present study evaluated the distribution of connective tissue and angiogenesis in colon of patients with UC, paying particular attention to the tonaca muscularis, which is poorly considered in histopathological studies. Full-thickness left colonic samples were obtained from 10 patients with established, severe and pharmacologically unresponsive UC, who underwent bowel resection. Routine histology, histochemistry and immunohistochemistry were conducted in paraffin cross-sections. The distribution of collagen and elastic fibers was evaluated and quantified by both histochemical (Van Gieson, orcein, Verroheff staining) and immunohistochemical (anti-collagen I and III, anti-elastin) assays. The vascular network pattern was studied by anti-CD31 and nestin immunostaining. For comparison, the same evaluations were performed in healthy colonic control samples obtained from 10 subjects, who underwent surgery for uncomplicated colon cancer. A significant increase in collagen fibers and a decrease in elastin content were detected in the UC inflamed colon, as compared with controls. In particular, enhanced collagen deposition (mainly collagen type III) were found at level of submucosa, and tonaca muscularis within the longitudinal muscle (mainly along the serosal side) and circular muscle layer, and in perivascular connective tissue. By contrast, elastic fibers were significantly reduced throughout the whole muscle compartment, with particular regard for the myenteric ridge. Microvessel density was significantly higher in both submucosa and tonaca muscularis of colonic samples from UC patients compared with those from healthy control individuals. The present findings indicate that a significant tissue remodelling occurs in the inflamed colonic wall in patients with UC, also at the level of muscle layers. This rearrangement of the connective fibers and vascular network, together with the known alterations affecting the myenteric neurons and interstitial cells of Cajal, may contribute to the development of enteric dysmotility, and, accordingly, to the serious digestive symptoms which afflict patients with UC., Italian Journal of Anatomy and Embryology, Vol 117, No 2 (Supplement) 2012

The term gastrointestinal neuromuscular disease comprises a heterogeneous group of chronic conditions associated with impaired bowel motility. Gastrointestinal motor dysfunctions, differening for etiopathogenic mechanisms, pathologic lesions, and region of gut involvement (e.g., irritable bowel syndrome, slow transit constipation, inflammatory bowel disease, diverticular disease), represent a relevant matter for public health: in fact, they are very common, can be disabling, and induce major social and economic burdens. These motor disturbances are presumed or proven to arise as a result of dysfunctional enteric neuromuscular apparatus set up by myenteric ganglionic cells, interstitial cells of Cajal and smooth muscle cells of the muscularis propria. Despite the presence of intestinal dysmotility in the clinical phenotype of these patients, scarce attention has been paid to the morphological arrangements of the enteric neuromuscular apparatus. Furthermore, standards for histopathological reports remain relatively neglected resulting in significant differences in applied methodologies which confound the reliable delineation of normality and, as a consequence, the specificity of particular pathological changes for disease. Thus, in order to overcome the lack or heterogeneity of current data, to get normative data and delineation of abnormality, careful morphological examinations and development of standardized procedures are particularly required in the field of gastrointestinal neuromuscular pathology, as recently suggested., Italian Journal of Anatomy and Embryology, Vol 116, No 1 (Supplement) 2011

Diverticular disease (DD) is one of the most common diseases related to the gastrointestinal tract in Western countries. It has been postulated that abnormal colonic motility including increased overall motility, abnormal response to a physiologic stimulus and retropropagation of mass movement, predisposes to the formation of pulsion diverticula in the segments of the bowel containing the diverticula. Intestinal motility is regulated by complex interactions among smooth muscle cells (SMCs) of muscularis propria, enteric nerve endings and interstitial cells of Cajal (ICC). ICC are emerging as potential colonic pacemaker cells which modulate neuroenteric transmission by connecting SMC with varicosities of myenteric neuron axons. In colonic SMCs, transmenbrane channels rich in connexin (Cx), in particular Cx43, contribute to intercellular gap junctions, which ensure coordinated motor responses to nerve inputs.There is evidence that SMCs motility and gap junction permeability are regulated by the GTPase RhoA, an emerging key modulator of SMCs phenotype. The aim of the present study was to evaluate the Cx43 and RhoA expression in SMCs, as well as ICC density in colonic specimens from patients affected by diverticular disease (DD). Immunohistochemistry for Cx43, RhoA and c-kit and image analysis were used to examine muscularis propria of surgical whole thickness colonic samples from DD patients. Semiquantitative analysis of DD colonic specimens displayed a marked decrease in Cx43 and RhoA expression in SMCs. There was also a reduced ICC density in myenteric ganglia (ICC-MY), circular (ICC-CM) and longitudinal (ICC-LM) muscle, as compared to controls. Overall, it is suggested that abnormalities in gap junctions and RhoA expression in SMCs, together with a reduced density of muscular ICC, account for the colonic dismotility occurring in DD., Italian Journal of Anatomy and Embryology, Vol 116, No 1 (Supplement) 2011

Italian Journal of Anatomy and Embryology, Vol 115, No 1/2 (Supplement) 2010

Objective Gut fibrosis occurs under chronic inflammation. This study examined the effects of different cyclooxygenase (COX) inhibitors on fibrosis in the inflamed colon. Methods Colitis was induced by 2,4-dinitrobenzenesulfonic acid (DNBS) in albino male Sprague–Dawley rats. After 6, 12 and 18 days, macroscopic and microscopic damage, collagen and elastic fibre content were examined. At day 6, pro-fibrotic factors (collagen I and III, hydroxyproline, fibronectin, matrix metalloproteinase-2 and -9), transforming growth factor-beta (TGF-β) signalling [TGF-β, Ras homolog gene family member A (RhoA), phosphorylated small mother against decapentaplegic (pSMAD)-2 and -6] and peristalsis were assessed, and the effects of indomethacin, SC-560 or celecoxib were tested. Key findings Six days after DNBS administration, significant histopathological signs of fibrotic remodelling were observed in rats. At day 6, pro-fibrotic factors were up-regulated and colonic peristalsis was altered. COX inhibitors reversed the histochemical, molecular and functional changes in the fibrotic colon. COX inhibition reduced TGF-β expression, SMAD2 phosphorylation and RhoA, and increased SMAD6 expression. Conclusions Colonic fibrosis is associated with altered bowel motility and induction of profibrotic factors driven by TGF-β signalling. COX-1 and COX-2 inhibition counteracts this fibrotic remodelling by the modulation of TGF-β/SMAD signalling, mainly via SMAD6 induction and reduction in SMAD2 phosphorylation.

Tau displacement from microtubules is the first step in the onset of tauopathies and is followed by toxic protein aggregation. However, other non-canonical functions of Tau might have a role in these pathologies. Here, we demonstrate that a small amount of Tau localizes in the nuclear compartment and accumulates in both the soluble and chromatin-bound fractions. We show that favoring Tau nuclear translocation and accumulation, by Tau overexpression or detachment from MTs, increases the expression of VGluT1, a disease-relevant gene directly involved in glutamatergic synaptic transmission. Remarkably, the P301L mutation, related to frontotemporal dementia FTDP-17, impairs this mechanism leading to a loss of function. Altogether, our results provide the demonstration of a direct physiological role of Tau on gene expression. Alterations of this mechanism may be at the basis of the onset of neurodegeneration.

Background For many years, long-acting intramuscular (LAI) antipsychotics have been prescribed predominantly to chronic and severe patients, as a last resort when other treatments failed. Recently, a broader and earlier use of LAIs, particularly second-generation LAIs, has been emphasized. To date, few studies attempted to frame how this change in prescribing took place in real-world practice. Therefore, this study aimed to describe the clinical features of patients prescribed with LAIs, and to explore possible prescribing differences between first- and second-generations LAIs under ordinary clinical practice in Italy. Methods The STAR Network "Depot" Study is an observational, longitudinal, multicenter study involving 35 centers in Italy. In the cross-sectional phase, patients prescribed with LAIs were consecutively recruited and assessed over a period of 12 months. Descriptive statistics and multivariable logistic regression analyses were employed. Results Of the 451 recruited patients, 61% were males. The level of social and working functioning was heterogeneous, as was the severity of disease. Seventy-two per cent of the patients had a diagnosis of the schizophrenia spectrum. Seventy per cent were prescribed with second-generation antipsychotic (SGA) LAIs (mostly paliperidone, aripiprazole and risperidone). Compared to first-generation antipsychotic (FGA) LAIs, patients prescribed with SGA LAIs were more often younger; employed; with a diagnosis of the schizophrenia spectrum or bipolar disorder; with higher levels of affective symptoms; with fewer LAI prescriptions in the past. Discussion LAIs' prescribing practices appear to be more flexible as compared to the past, although this change is mostly restricted to SGA LAIs.

Curcumin attenuates Rett syndrome symptoms Mutations in the coding sequence of the X-linked gene MeCP2 (Methyl CpG-binding protein) are present in around 80% of patients with Rett Syndrome, a common cause of intellectual disability in female and to date without any effective pharmacological treatment. A relevant, and so far unexplored feature of RTT patients, is a marked reduction in peripheral circulation. To investigate the relationship between loss of MeCP2 and this clinical aspect, we used the MeCP2 null mouse model B6.129SF1-MeCP2tm1Jae for functional and pharmacological studies. Functional experiments were performed on isolated resistance mesenteric vessels, mounted on a pressurized myograph. Vessels from female MeCP2+/- mice show a reduced endothelium-dependent relaxation, due to a reduced Nitric Oxide (NO) availability secondary to an increased Reactive Oxygen Species (ROS) generation. Such functional aspects are associated with an intravascular increase in superoxide anion production, and a decreased vascular eNOS expression. These alterations are reversed by curcumin administration (5% (w/w) dietary curcumin for 21 days), which restores endothelial NO availability, decreases intravascular ROS production and normalizes vascular eNOS gene expression. In conclusion our findings highlight alterations in the vascular/endothelial system in the absence of a correct function of MeCP2, and uncover related cellular/molecular mechanisms that are rescued by an anti-oxidant treatment. © 2013 Panighini et al.