A morphological and immunohistochemical study of human intestinal fibrogenesis during Crohn’s disease

Background. Several enteropathies are characterized by an intestinal fibrosis that may lead to stenosis and obstruction (1). The most frequent and severe intestinal fibrosis occurs in Crohn’s disease (CD) that is related to the abnormal accumulation of extracellular matrix (ECM) proteins. In experimental model TGF-β1/Smad3 signalling plays a major role in tissue fibrogenesis as a potent stimulus of ECM accumulation (2). Aim. To evaluate the potential role of the TGF-β1/Smads pathway in the pathogenesis of intestinal fibrosis in patients affected by CD. Methods.Human samples from terminal ileum were processed for histological (H&E, Masson, Pas) morphometric and immunohistochemical (IHC) analyses. For IHC studies TGF-β1, CTGF, collagen types I-III, Smad3, Smad7, PDGF, C-kit, α-SMA, GFAP and a neuronal cocktail (S100, antineurofilament, NSE) antibodies were used. Smooth muscle cells (SMC) were cultured (3) for morphofunctional and cell cycle analysis. Results. Histological and morphometrical evaluation of stenotic fragments revealed a significantly high degree of intestinal fibrosis with an increase in mucosa, submucosa and muscle layer thickness. Transmural inflammation was also present in stenotic lesions compared to normal tracts. SMC isolated from inflamed fragments presented a 18.7% ±5.9% lenght shortening and a 44.5%±2.9% inhibition in contractile response to acetylcholine. Furthermore, under inflammatory burst a shift from the G0/G1 to the S cell cycle phase was observed. IHC analysis showed an increase in TGF-β1,CTGF, collagen I-III, Smad3, PDGF, C-kit and α-SMA staining in stenotic lesions compared to pre-post stenotic intestinal tracts, whereas Smad7 was positive only in pre-post stenotic samples. IHC evaluation of GFAP and neuronal cocktail showed a reduction of immunoreactivity in stenotic lesions. Conclusions. The data demonstrate that the TGF-β1/Smads pathway may play a central role in the development and differentiation of mesenchymal cells and in sustaining fibrosis of intestinal tissues in CD. The results confirm those obtained previously in our experimental mice model. 1) Burke JP et al. Am J Gastro, 2007 2) Latella G. et al. Eur J Clin Invest, 2008 3) Tattoli I et al. Dig Liv Dis, 2004

Role of TGFβ1/Smads pathway in the pathogenesis of intestinal fibrosis in Crohn’s disease

Inflammatory bowel diseases (IBD) are characterized by an intestinal fibrosis that may lead to stenosis and obstruction (Burke et al., 2007) and by disfuntions of gastrointestinal (GI) motility associated with altered functions of enteric nerves, interstitial cells of Cajal or smooth muscle (Vetuschi et al., 2006). In experimental model TGFβ1/ Smad3 signalling plays a major role in tissue fibrogenesis (Latella et al, 2009). Aim of this study was to evaluate the potential role of the TGFβ1/Smads pathway in intestinal fibrosis and to explore the possible mechanisms by which fibrogenesis induces alterations of GI motility in patients affected by CD. Evaluation of TGFβ1, CTGF, collagen I-III, Smad3/7, PDGF, C-Kit, α-SMA, and a neuronal cocktail expression and a morphometrical analysis were performed in human CD terminal ileum samples; human smooth muscle cells (HSMC) were cultured for morphofuncional and mRNA expression (RT-PCR). Histo-morphometrical evaluation of stenotic fragments showed a significantly increase of a) both intestinal fibrosis and inflammation; b) mucosa, submucosa and muscle layer thickness and c) expression of TGFβ1, CTGF, collagen I-III, Smad3, PDGF, C-Kit and α-SMA staining. HSMC obtained from stenotic tracts showed an increase of PDGF-β and collagen I-III types mRNA and an inhibition in contractile response to acetylcholine compared to pre-stenotic tracts. These data support the hypothesis that TGFβ1/Smads pathway play a central role in development and differentiation of intestinal mesenchymal cells in sustaining intestinal fibrosis in CD and could be responsible for alteration of GI motility

DRD2, DRD3, and HTR2A Single-Nucleotide Polymorphisms Involvement in High Treatment Resistance to Atypical Antipsychotic Drugs

Background: The objective of this study was to investigate the DRD2 rs1800497, rs1799732, rs1801028, DRD3 rs6280, and HTR2A rs6314, rs7997012, and rs6311 single-nucleotide polymorphism (SNP) correlations with resistance to second-generation antipsychotics (SGAs) in a real-world sample of patients with treatment-resistant mental disorders. Methods: We divided 129 participants into a high treatment resistance (HTR) group (current treatment with two SGAs, or clozapine, or classic neuroleptics for a failure of previous SGAs trials) and a low treatment resistance (LTR) group (current treatment with one atypical antipsychotic). We used Next-Generation Sequencing on DNA isolated from peripheral blood samples to analyze the polymorphisms. We performed logistic regression to search for predictors of HTR membership. Results: A diagnosis of schizophrenia significantly predicted the HTR membership compared to other diagnoses. Other predictors were the DRD3 rs6280 C|T (OR = 22.195) and T|T (OR = 18.47) vs. C|C, HTR2A rs7997012 A|G vs. A|A (OR = 6.859) and vs. G|G (OR = 2.879), and DRD2 rs1799732 I|I vs. D|I (OR = 12.079) genotypes. Conclusions: A diagnosis of schizophrenia and the DRD2 rs1799732, DRD3 rs6280, and HTR2A rs7997012 genotypes can predict high treatment resistance to SGAs

Medium and long-term efficacy of psychoeducational family intervention for bipolar I disorder: Results from a real-world, multicentric study

Objectives: This study aims to explore the long-term efficacy of a psychoeducational family intervention (PFI) in bipolar I disorder at one and five years post-intervention in terms of improvement of: (1) patients’ symptoms and global functioning and (2) relatives’ objective and subjective burden and coping strategies. Methods: This is a multicentre, real-world, controlled, outpatient trial. Recruited patients and key-relatives were consecutively allocated to the experimental intervention or treatment as usual. Patients were assessed at baseline, and after one and five years. Results: One hundred and thirty-seventh number families have been recruited; 70 have been allocated to the experimental intervention, and 67 have been allocated to the control group. We observed an increasing positive effect of the PFI on patients’ clinical status, global functioning and objective and subjective burden after one year. We also found a reduction in the levels of relatives’ objective and subjective burden and a significant improvement in the levels of perceived professional support and of coping strategies. The efficacy of PFI on patients’ clinical status was maintained at five years from the end of the intervention, in terms of relapses, hospitalizations and suicide attempts. Conclusions: The study showed that the provision of PFI in real-world settings is associated with a significant improvement of patients’ and relatives’ mental health and psychosocial functioning in the long term. We found that the clinical efficacy of the intervention, in terms of reduction of patients’ relapses, hospitalization and suicide attempts, persists after 5 years. It is advisable that PFI is provided to patients with BD I in routine practice

Subclinical atherosclerosis is linked to small intestinal bacterial overgrowth via vitamin K2-dependent mechanisms

Aim To assess the rate of matrix Gla-protein carboxylation in patients with small intestinal bacterial overgrowth (SIBO) and to decipher its association with subclinical atherosclerosis. METHODS Patients with suspected SIBO who presented with a low risk for cardiovascular disease and showed no evidence of atherosclerotic plaques were included in the study. A glucose breath test was performed in order to confirm the diagnosis of SIBO and vascular assessment was carried out by ultrasound examination. Plasma levels of the inactive form of MGP (dephosphorylateduncarboxylated matrix Gla-protein) were quantified by ELISA and vitamin K2 intake was estimated using a food frequency questionnaire. RESULTS Thirty-nine patients were included in the study. SIBO was confirmed in 12/39 (30.8%) patients who also presented with a higher concentration of dephosphorylated-uncarboxylated matrix Gla-protein (9.5 \u3bc g/L vs 4.2 \u3bc g/L; P = 0.004). Arterial stiffness was elevated in the SIBO group (pulse-wave velocity 10.25 m/s vs 7.68 m/s; P = 0.002) and this phenomenon was observed to correlate linearly with the levels of dephosphorylated-uncarboxylated matrix Gla-protein ( f = 0.220, R 2 = 0.366, P = 0.03). Carotid intima-media thickness and arterial calcifications were not observed to be significantly elevated as compared to controls. CONCLUSION SIBO is associated with reduced matrix Gla-protein activation as well as arterial stiffening. Both these observations are regarded as important indicators of subclinical atherosclerosis. Hence, screening for SIBO, intestinal decontamination and supplementation with vitamin K2 has the potential to be incorporated into clinical practice as additional preventive measures

The influence of autistic symptoms on social and non-social cognition and on real-life functioning in people with schizophrenia: Evidence from the Italian Network for Research on Psychoses multicenter study

BACKGROUND: Autism spectrum disorders (ASDs) and schizophrenia spectrum disorders (SSDs), although conceptualized as separate entities, may share some clinical and neurobiological features. ASD symptoms may have a relevant role in determining a more severe clinical presentation of schizophrenic disorder but their relationships with cognitive aspects and functional outcomes of the disease remain to be addressed in large samples of individuals. AIMS: To investigate the clinical, cognitive, and functional correlates of ASD symptoms in a large sample of people diagnosed with schizophrenia. METHODS: The severity of ASD symptoms was measured with the PANSS Autism Severity Scale (PAUSS) in 921 individuals recruited for the Italian Network for Research on Psychoses multicenter study. Based on the PAUSS scores, three groups of subjects were compared on a wide array of cognitive and functional measures. RESULTS: Subjects with more severe ASD symptoms showed a poorer performance in the processing speed (p\ua0=\ua00.010), attention (p\ua0=\ua00.011), verbal memory (p\ua0=\ua00.035), and social cognition (p\ua0=\ua00.001) domains, and an overall lower global cognitive composite score (p\ua0=\ua00.010). Subjects with more severe ASD symptoms also showed poorer functional capacity (p\ua0=\ua00.004), real-world interpersonal relationships (p\ua0<\ua00.001), and participation in community-living activities (p\ua0<\ua00.001). CONCLUSIONS: These findings strengthen the notion that ASD symptoms may have a relevant impact on different aspects of the disease, crucial to the life of people with schizophrenia. Prominent ASD symptoms may characterize a specific subpopulation of individuals with SSD

Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES). a multicentre, open-label, randomised trial

Background: Observational studies suggest that bariatric-metabolic surgery might greatly improve non-alcoholic steatohepatitis (NASH). However, the efficacy of surgery on NASH has not yet been compared with the effects of lifestyle interventions and medical therapy in a randomised trial. Methods: We did a multicentre, open-label, randomised trial at three major hospitals in Rome, Italy. We included participants aged 25-70 years with obesity (BMI 30-55 kg/m2), with or without type 2 diabetes, with histologically confirmed NASH. We randomly assigned (1:1:1) participants to lifestyle modification plus best medical care, Roux-en-Y gastric bypass, or sleeve gastrectomy. The primary endpoint of the study was histological resolution of NASH without worsening of fibrosis at 1-year follow-up. This study is registered at ClinicalTrials.gov, NCT03524365. Findings: Between April 15, 2019, and June 21, 2021, we biopsy screened 431 participants; of these, 103 (24%) did not have histological NASH and 40 (9%) declined to participate. We randomly assigned 288 (67%) participants with biopsy-proven NASH to lifestyle modification plus best medical care (n=96 [33%]), Roux-en-Y gastric bypass (n=96 [33%]), or sleeve gastrectomy (n=96 [33%]). In the intention-to-treat analysis, the percentage of participants who met the primary endpoint was significantly higher in the Roux-en-Y gastric bypass group (54 [56%]) and sleeve gastrectomy group (55 [57%]) compared with lifestyle modification (15 [16%]; p&lt;0·0001). The calculated probability of NASH resolution was 3·60 times greater (95% CI 2·19-5·92; p&lt;0·0001) in the Roux-en-Y gastric bypass group and 3·67 times greater (2·23-6·02; p&lt;0·0001) in the sleeve gastrectomy group compared with in the lifestyle modification group. In the per protocol analysis (236 [82%] participants who completed the trial), the primary endpoint was met in 54 (70%) of 77 participants in the Roux-en-Y gastric bypass group and 55 (70%) of 79 participants in the sleeve gastrectomy group, compared with 15 (19%) of 80 in the lifestyle modification group (p&lt;0·0001). No deaths or life-threatening complications were reported in this study. Severe adverse events occurred in ten (6%) participants who had bariatric-metabolic surgery, but these participants did not require re-operations and severe adverse events were resolved with medical or endoscopic management. Interpretation: Bariatric-metabolic surgery is more effective than lifestyle interventions and optimised medical therapy in the treatment of NASH. Funding: Fondazione Policlinico Universitario A Gemelli, Policlinico Universitario Umberto I and S Camillo Hospital, Rome, Italy

The effects of psychoeducational family intervention on coping strategies of relatives of patients with bipolar i disorder: Results from a controlled, real-world, multicentric study

Background: Psychoeducational family intervention (PFI) has been proven to be effective in improving the levels of family burden and patients\u2019 personal functioning in schizophrenia and bipolar disorders (BDs). Less is known about the impact of PFI on relatives\u2019 coping strategies in BD. Methods: A multicenter, controlled, outpatient trial funded by the Italian Ministry of Health and coordinated by the Department of Psychiatry of the University of Campania \u201cLuigi Vanvitelli\u201d has been conducted in patients with bipolar I disorder (BD-I) and their key relatives consecutively recruited in 11 randomly selected Italian community mental health centers. We aim to test the hypothesis that PFI improves problem-oriented coping strategies in relatives of BD-I patients compared to the Treatment As Usual (TAU) group. Results: The final sample was constituted of 123 patients and 139 relatives. At baseline assessment (T0), the vast majority of relatives already adopted problem-oriented coping strategies more frequently than the emotion-focused ones. At the end of the intervention, relatives receiving PFI reported a higher endorsement of adaptive coping strategies, such as \u201cmaintenance of social interests\u201d (odds ratio [OR]=0.309, CI=0.04\u20130.57; p=0.023), \u201cpositive communication with the patient\u201d (OR=0.295, CI=0.13\u20130.46; p=0.001), and \u201csearching for information\u201d (OR=0.443, CI=0.12\u20130.76; p=0.007), compared to TAU relatives, after controlling for several confounders. As regards the emotion-focused coping strategies, relatives receiving the experimental intervention less frequently reported to adopt \u201cresignation\u201d (OR=-0.380, CI=-0.68 to -0.08; p=0.014) and \u201ccoercion\u201d (OR=-0.268, CI=-0.46 to -0.08; p=0.006) strategies, compared to TAU relatives. Conclusion: PFI is effective in improving the adaptive coping strategies of relatives of BD-I patients, but further studies are needed for evaluating the long-term benefits of this intervention

Defining robustness protocols: a method to include and evaluate robustness in clinical plans.

This is the final version of the article. It first appeared from IOP Publishing via http://dx.doi.org/10.1088/0031-9155/60/7/2671We aim to define a site-specific robustness protocol to be used during the clinical plan evaluation process. Plan robustness of 16 skull base IMPT plans to systematic range and random set-up errors have been retrospectively and systematically analysed. This was determined by calculating the error-bar dose distribution (ebDD) for all the plans and by defining some metrics used to define protocols aiding the plan assessment. Additionally, an example of how to clinically use the defined robustness database is given whereby a plan with sub-optimal brainstem robustness was identified. The advantage of using different beam arrangements to improve the plan robustness was analysed. Using the ebDD it was found range errors had a smaller effect on dose distribution than the corresponding set-up error in a single fraction, and that organs at risk were most robust to the range errors, whereas the target was more robust to set-up errors. A database was created to aid planners in terms of plan robustness aims in these volumes. This resulted in the definition of site-specific robustness protocols. The use of robustness constraints allowed for the identification of a specific patient that may have benefited from a treatment of greater individuality. A new beam arrangement showed to be preferential when balancing conformality and robustness for this case. The ebDD and error-bar volume histogram proved effective in analysing plan robustness. The process of retrospective analysis could be used to establish site-specific robustness planning protocols in proton therapy. These protocols allow the planner to determine plans that, although delivering a dosimetrically adequate dose distribution, have resulted in sub-optimal robustness to these uncertainties. For these cases the use of different beam start conditions may improve the plan robustness to set-up and range uncertainties.This work was partly funded by an MRC Doctoral Training Grant

Accuracy of self-assessment of real-life functioning in schizophrenia

A consensus has not yet been reached regarding the accuracy of people with schizophrenia in self-reporting their real-life functioning. In a large (n=618) cohort of stable, community-dwelling schizophrenia patients we sought to: (1) examine the concordance of patients' reports of their real-life functioning with the reports of their key caregiver; (2) identify which patient characteristics are associated to the differences between patients and informants. Patient-caregiver concordance of the ratings in three Specific Level of Functioning Scale (SLOF) domains (interpersonal relationships, everyday life skills, work skills) was evaluated with matched-pair t tests, the Lin's concordance correlation, Somers' D, and Bland-Altman plots with limits of agreement (LOA). Predictors of the patient-caregiver differences in SLOF ratings were assessed with a linear regression with multivariable fractional polynomials. Patients' self-evaluation of functioning was higher than caregivers' in all the evaluated domains of the SLOF and 17.6% of the patients exceeded the LOA, thus providing a self-evaluation discordant from their key caregivers. The strongest predictors of patient-caregiver discrepancies were caregivers' ratings in each SLOF domain. In clinically stable outpatients with a moderate degree of functional impairment, self-evaluation with the SLOF scale can become a useful, informative and reliable clinical tool to design a tailored rehabilitation program