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AimThe anticholinergic properties of medications are associated with poorer cognitive performance in schizophrenia. Numerous scales have been developed to assess anticholinergic burden and yet, there is no consensus indicating which anticholinergic burden scale is more relevant for patients with schizophrenia. We aimed to identify valid scales for estimating the risk of iatrogenic cognitive impairment in schizophrenia.MethodsWe identified 27 scales in a literature review. The responses to neuropsychological tests of 839 individuals with schizophrenia or schizoaffective disorder in the FACE-SZ database were collected between 2010 and 2021. We estimated the association between objective global cognitive performance and the 27 scales, the number of psychotropic drugs, and chlorpromazine and lorazepam equivalents in bivariable regressions in a cross-sectional design. We then adjusted the bivariable models with covariates: the predictors significantly associated with cognitive performance in multiple linear regressions were considered to have good concurrent validity to assess cognitive performance.ResultsEight scales, the number of psychotropic drugs, and drug equivalents were significantly associated with cognitive impairment. The number of psychotropic drugs, the most convenient predictor to compute, was associated with worse executive function (Standardized β = −0.12, p = .004) and reasoning (Standardized β = −0.08, p = .037).ConclusionAnticholinergic burden, the number of psychotropic drugs, and drug equivalents were weakly associated with cognition, thus suggesting that cognitive impairment in schizophrenia and schizoaffective disorder is explained by factors other than medication. The number of psychotropic drugs was the most parsimonious method to assess the risk of iatrogenic cognitive impairment.

Background: Metabolic syndrome (MetS) is a highly prevalent and harmful medical disorder often comorbid with psychosis where it can contribute to cardiovascular complications. As immune dysfunction is a key shared component of both MetS and schizophrenia (SZ), this study investigated the relationship between immune alterations and MetS in patients with SZ, whilst controlling the impact of confounding clinical characteristics including psychiatric symptoms and comorbidities, history of childhood maltreatment and psychotropic treatments. Method: A total of 310 patients meeting DSM-IV criteria for SZ or schizoaffective disorders (SZA), with or without MetS, were systematically assessed and included in the FondaMental Advanced Centers of Expertise for Schizophrenia (FACE-SZ) cohort. Detailed clinical characteristics of patients, including psychotic symptomatology, psychiatric comorbidities and history of childhood maltreatment were recorded and the serum levels of 18 cytokines were measured. A penalized regression method was performed to analyze associations between inflammation and MetS, whilst controlling for confounding factors. Results: Of the total sample, 25% of patients had MetS. Eight cytokines were above the lower limit of detection (LLOD) in more than 90% of the samples and retained in downstream analysis. Using a conservative Variable Inclusion Probability (VIP) of 75%, we found that elevated levels of interleukin (IL)-6, IL-7, IL-12/23 p40 and IL-16 and lower levels of tumor necrosis factor (TNF)-α were associated with MetS. As for clinical variables, age, sex, body mass index (BMI), diagnosis of SZ (not SZA), age at the first episode of psychosis (FEP), alcohol abuse, current tobacco smoking, and treatment with antidepressants and anxiolytics were all associated with MetS. Conclusion: We have identified five cytokines associated with MetS in SZ suggesting that patients with psychotic disorders and MetS are characterized by a specific “immuno-metabolic” profile. This may help to design tailored treatments for this subgroup of patients with both psychotic disorders and MetS, taking one more step towards precision medicine in psychiatry.

Liver tropism potentially leading to massive hepatocyte transduction and hepatotoxicity still represents a major drawback to adenovirus (Ad)-based gene therapy. We previously demonstrated that substitution of the hexon hypervariable region 5 (HVR5), the most abundant capsid protein, constituted a valuable platform for efficient Ad retargeting. The use of different mouse strains revealed that HVR5 substitution also led to dramatically less adenovirus liver transduction and associated toxicity, whereas HVR5-modified Ad were still able to transduce different cell lines efficiently, including primary hepatocytes. We showed that HVR5 modification did not significantly change Ad blood clearance or liver uptake at early times. However, we were able to link the lower liver transduction to enhanced HVR5-modified Ad liver clearance and impaired use of blood factors. Most importantly, HVR5-modified vectors continued to transduce tumors in vivo as efficiently as their wild-type counterparts. Taken together, our data provide a rationale for future design of retargeted vectors with a safer profile.

KiSS1 is a putative metastasis suppressor gene in melanoma and breast cancer-encoding kisspeptins, which are also described as neuroendocrine regulators of the gonadotropic axis. Negative as well as positive regulation of KiSS1 gene expression by estradiol (E(2)) has been reported in the hypothalamus. Estrogen receptor alpha (ERalpha level is recognized as a marker of breast cancer, raising the question of whether expression of KiSS1 and its G-protein-coupled receptor (GPR54) is down- or upregulated by estrogens in breast cancer cells. KiSS1 was found to be expressed in MDA-MB-231, MCF7, and T47D cell lines, but not in ZR75-1, L56Br, and MDA-MB-435 cells. KiSS1 mRNA levels decreased significantly in ERalpha-negative MDA-MB-231 cells expressing recombinant ERalpha. In contrast, tamoxifen (TAM) treatment of ERalpha-positive MCF7 and T47D cells increased KiSS1 and GPR54 levels. The clinical relevance of this negative regulation of KiSS1 and GPR54 by E(2) was then studied in postmenopausal breast cancers. KiSS1 mRNA increased with the grade of the breast tumors. ERalpha-positive invasive primary tumors expressed sevenfold lower KiSS1 levels than ERalpha-negative tumors. Among ERalpha-positive breast tumors from postmenopausal women treated with TAM, high KiSS1 combined with high GPR54 mRNA tumoral levels was unexpectedly associated with shorter relapse-free survival (RFS) relative to tumors expressing low tumoral mRNA levels of both genes. The contradictory observation of putative metastasis inhibitor role of kisspeptins and RFS to TAM treatment suggests that evaluation of KiSS1 and its receptor tumoral mRNA levels could be new interesting markers of the tumoral resistance to anti-estrogen treatment.

The immunogenicity of recombinant adenoviruses (Ad) constitutes a major concern for their use in gene therapy. Antibody- and cell-mediated immune responses triggered by adenoviral vectors hamper long-term transgene expression and efficient viral readministration. We previously reported that interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha play an essential role in both the acute phase and antibody response against Ad, respectively. As TNF-alpha controls the immune response and the development of the immune system, we examined here the consequence of blockade of TNF-alpha activity through Ad-mediated gene delivery of a dimeric mouse TNFR1-IgG fusion protein on transgene expression from a second Ad. Ad encoding TNFR1-IgG (AdTNFR1-Ig) was injected intravenously along with Ad encoding beta-galactosidase or alpha1-antitrypsin transgene in wild-type (IL-6(+/+)) but also in IL-6-deficient mice (IL-6(-/-)) to analyze how TNF-alpha and IL-6 diminish liver gene transfer efficacy. Blockade of TNF-alpha leads to increased transgene expression in both wild-type and IL-6(-/-) mice due to a reduced inflammatory response and to diminished recruitment of macrophages and NK cells towards the liver. Antibody responses against adenoviral particles and expressed transgenes were only delayed in AdTNFR1-Ig-treated wild-type mice, but were markedly reduced in AdTNFR1-Ig-treated IL-6(-/-) mice. Finally, treatment of mice with etanercept, a clinically approved anti-TNF-alpha drug, confirmed the importance of controlling proinflammatory cytokines during gene therapy by adenoviral vectors.

Fas and tumor necrosis factor receptor 1 (TNFR1) are death receptors involved in various diseases such as hepatitis, sepsis, or graft rejection. Neutralizing antibodies to death ligands or soluble death receptors can inhibit cell death; however, they induce side effects because of their systemic actions. To specifically block death signaling to target cells, we created death domain-deficient (DeltaDD) membrane-anchored receptors, delivered to the liver by either recombinant adenovirus or hydrodynamic pressure of nonviral recombinant plasmids. In anti-Fas antibody-induced fulminant hepatitis, mice expressing recombinant Fas-decoy receptors (FasDeltaDD) in their livers were completely protected against apoptosis and survived fulminant hepatitis. In T-cell-dependent concanavalin A-induced autoimmune hepatitis, FasDeltaDD antagonist expression prevented hepatocyte damage and mouse death. Finally, TNFR1DeltaDD effectively protected mice against LPS-induced septic shock. In conclusion, such DeltaDD-decoy receptors act as dominant-negative receptors exerting local inhibition, while avoiding systemic neutralization of apoptosis ligands, and might have therapeutic potential in hepatitis.

Background: The major concern for the use of adenoviral vectors for gene therapy is the viral-induced immune response that has been shown to be responsible for short-term transgene expression and inefficient viral readministration. In vivo studies and clinical trials with recombinant adenovirus have suggested a role for interleukin 6 (IL-6) in the inflammatory reaction that follows Ad-infection. IL-6 plays an important role in the acute-phase innate response, in the differentiation of B-cells and in the activation of the Th2 cell subsets., Methods: To clarify the role of IL-6 in the immune response to Ad-vectors, we used IL-6 knock-out mice (IL-6 -/- ). E1/E3 deleted recombinant adenoviruses encoding reporter genes were administered to wild type or IL-6-/- mice; transgene expression kinetics and immune response were analyzed., Results: Acute phase protein production was significantly diminished in IL-6 -/- mice after adenoviral injection. No significant difference between wild type and knock-out animals in the level or the nature of leucocyte recruitment in the liver was detectable. A minor decrease in the IgG response to Ad-recombinants was observed in knock-out mice. Gene transfer efficiency, both in terms of levels and duration of transgene expression, were comparable in IL-6+/+ and IL-6-/- mice. An increase in IL-1beta and tumor necrosis factor-alpha (TNF-alpha) levels was observed in the sera of IL-6 -/- mice as compared to wild type animals: this phenomenon represents a possible compensatory mechanism for the establishment of the immune phenotype observed in mutant mice., Conclusions: IL-6 plays a role in the acute phase response to adenoviral vectors. Nevertheless, possibly due to a compensatory mechanism exerted by other cytokines, the antibody and cellular responses to adenoviruses are very similar in wild type and IL-6 -/- mice.