VH 032-linker 5 - CAS 2172819-74-6

Schizophrenia is characterized by visual distortions in ~60% of cases, and visual hallucinations (VH) in ~25-50% of cases, depending on the sample. These symptoms have received relatively little attention in the literature, perhaps due to the higher rate of auditory vs. visual hallucinations in psychotic disorders, which is the reverse of what is found in other neuropsychiatric conditions. Given the clinical significance of these perceptual disturbances, our aim is to help address this gap by updating and expanding upon prior reviews. Specifically, we: (1) present findings on the nature and frequency of VH and distortions in schizophrenia; (2) review proposed syndromes of VH in neuro-ophthalmology and neuropsychiatry, and discuss the extent to which these characterize VH in schizophrenia; (3) review potential cortical mechanisms of VH in schizophrenia; (4) review retinal changes that could contribute to VH in schizophrenia; (5) discuss relationships between findings from laboratory measures of visual processing and VH in schizophrenia; and (6) integrate findings across biological and psychological levels to propose an updated model of VH mechanisms, including how their content is determined, and how they may reflect vulnerabilities in the maintenance of a sense of self. In particular, we emphasize the potential role of alterations at multiple points in the visual pathway, including the retina, the roles of multiple neurotransmitters, and the role of a combination of disinhibited default mode network activity and enhanced state-related apical/contextual drive in determining the onset and content of VH. In short, our goal is to cast a fresh light on the under-studied symptoms of VH and visual distortions in schizophrenia for the purposes of informing future work on mechanisms and the development of targeted therapeutic interventions.

Background and aims:Recent studies have debated the utility of beta-blockers to prevent variceal hemorrhage (V.H.) in cirrhosis patients with ascites. We aimed to evaluate the safety and efficacy of propranolol (PPL) compared to endoscopic variceal ligation (EVL) for V.H. primary prevention in patients with ascites. Methods:Cirrhosis patients with ≥ grade 2 ascites and varices needing primary prophylaxis were randomly assigned to receive either PPL (n = 80) or EVL (n = 80). Patients were followed monthly until 12 months or transplant or death. The primary endpoint was 12-month transplant-free-survival (TFS). Secondary endpoints were the incidence of V.H., acute kidney injury (AKI), and control of ascites. Results:Baseline characteristics were similar between the groups. PPL-group had a lower 12-month TFS (76.0% vs. 89.7%; p = 0.02) as compared with EVL-group. Mean arterial pressure ≤ 82 mmHg and MELD-sodium were the independent predictors of mortality. Incidence of VH was comparable between PPL and EVL-groups [6 (7.5%) vs. 2 (2.5%), p = 0.13]. In PPL vs. EVL-group, more patients had worsening of ascites (15% vs. 5%; p = 0.03), developed refractory ascites (13.7% vs.3.7%; p = 0.02), relapse of ascites (37.1% vs. 16.4%, p < 0.01), and AKI (26.2% vs. 12.5%; p = 0.02). Side effects were comparable between the two groups.Conclusions:Primary VH-prophylaxis with PPL is associated with lower survival, poor control of ascites, and increased risk of AKI in cirrhosis patients with ≥ grade 2 ascites. PPL and EVL are equally effective in preventing V.H. Serial monitoring of blood pressures and renal functions is needed in cirrhosis patients with ascites on PPL (NCT02649335).

Irritable bowel syndrome (IBS) is characterized by visceral hypersensitivity (VH) associated with abnormal serotonin/5-hydroxytryptamine (5-HT) metabolism and neurotrophin-dependent mucosal neurite outgrowth. The underlying mechanisms of VH remain poorly understood. We investigated the role of 5-HT7 receptor in mucosal innervation and intestinal hyperalgesia. A high density of mucosal nerve fibres stained for 5-HT7 was observed in colonoscopic biopsy specimens from IBS patients compared with those from healthy controls. Staining of 5-HT3 and 5-HT4 receptors was observed mainly in colonic epithelia with comparable levels between IBS and controls. Visceromotor responses to colorectal distension were evaluated in two mouse models, one postinfectious with Giardia and subjected to water avoidance stress (GW) and the other postinflammatory with trinitrobenzene sulfonic acid-induced colitis (PT). Increased VH was associated with higher mucosal density of 5-HT7-expressing nerve fibres and elevated neurotrophin and neurotrophin receptor levels in the GW and PT mice. The increased VH was inhibited by intraperitoneal injection of SB-269970 (a selective 5-HT7 antagonist). Peroral multiple doses of CYY1005 (a novel 5-HT7 ligand) decreased VH and reduced mucosal density of 5-HT7-expressing nerve fibres in mouse colon. Human neuroblastoma SH-SY5Y cells incubated with bacteria-free mouse colonic supernatant, 5-HT, nerve growth factor, or brain-derived neurotrophic factor exhibited nerve fibre elongation, which was inhibited by 5-HT7 antagonists. Gene silencing of HTR7 also reduced the nerve fibre length. Activation of 5-HT7 upregulated NGF and BDNF gene expression, while stimulation with neurotrophins increased the levels of tryptophan hydroxylase 2 and 5-HT7 in neurons. A positive-feedback loop was observed between serotonin and neurotrophin pathways via 5-HT7 activation to aggravate fibre elongation, whereby 5-HT3 and 5-HT4 had no roles. In conclusion, 5-HT7-dependent mucosal neurite outgrowth contributed to VH. A novel 5-HT7 antagonist could be used as peroral analgesics for IBS-related pain.