The Effects of Chronic Immunosuppressive Treatment on Morphological Changes in Cardiac Tissue and the Balance between Matrix Metalloproteinases (MMP-2 and MMP-9) and Their Inhibitors in the Rat Heart.

Using different three-drug immunosuppressive treatment regimens in a rat model, we aimed to determine the effects of long-term therapy on metalloproteinase-2 and metalloproteinase-9 activity and the expression of their inhibitors, as well as to assess the morphology of the animals' cardiac tissue. Our results suggest that chronic use of immunosuppressive drugs disrupts the balance between the activity of MMPs and TIMPs. Depending on the type of drug regimen used, this leads to abnormalities in the cardiac structure, collagen fiber accumulation, or cardiomyocyte hypertrophy. The information obtained in the present study allows us to conclude that the chronic treatment of rats with the most common clinical immunosuppressive regimens may contribute to abnormalities in the myocardial structure and function. The results presented in this study may serve as a prelude to more in-depth analyses and additional research into the optimal selection of an immunosuppressive treatment with the lowest possible risk of cardiovascular complications for patients receiving organ transplants.

The Effect of Prenatal and Neonatal Fluoride Exposure to Morphine-Induced Neuroinflammation.

Physical dependence is associated with the formation of neuroadaptive changes in the central nervous system (CNS), both at the molecular and cellular levels. Various studies have demonstrated the immunomodulatory and proinflammatory properties of morphine. The resulting neuroinflammation in drug dependence exacerbates substance abuse-related behaviors and increases morphine tolerance. Studies prove that fluoride exposure may also contribute to the development of neuroinflammation and neurodegenerative changes. Morphine addiction is a major social problem. Neuroinflammation increases tolerance to morphine, and neurodegenerative effects caused by fluoride in structures related to the development of dependence may impair the functioning of neuronal pathways, change the concentration of neurotransmitters, and cause memory and learning disorders, which implies this element influences the development of dependence. Therefore, our study aimed to evaluate the inflammatory state of selected brain structures in morphine-dependent rats pre-exposed to fluoride, including changes in cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) expression as well as microglial and astroglial activity via the evaluation of Iba1 and GFAP expression. We provide evidence that both morphine administration and fluoride exposure have an impact on the inflammatory response by altering the expression of COX-1, COX-2, ionized calcium-binding adapter molecule (Iba1), and glial fibrillary acidic protein (GFAP) in brain structures involved in dependence development, such as the prefrontal cortex, striatum, hippocampus, and cerebellum. We observed that the expression of COX-1 and COX-2 in morphine-dependent rats is influenced by prior fluoride exposure, and these changes vary depending on the specific brain region. Additionally, we observed active astrogliosis, as indicated by increased GFAP expression, in all brain structures of morphine-dependent rats, regardless of fluoride exposure. Furthermore, the effect of morphine on Iba1 expression varied across different brain regions, and fluoride pre-exposure may influence microglial activation. However, it remains unclear whether these changes are a result of the direct or indirect actions of morphine and fluoride on the factors analyzed.

Immunolocalization of Matrix Metalloproteinases 2 and 9 and Their Inhibitors in the Hearts of Rats Treated with Immunosuppressive Drugs-An Artificial Intelligence-Based Digital Analysis.

BACKGROUND: Immunosuppressive agents represent a broad group of drugs, such as calcineurin inhibitors, mTOR inhibitors, and glucocorticosteroids, among others. These drugs are widely used in a number of conditions, but lifelong therapy is crucial in the case of organ recipients to prevent rejection. To further increase the safety and efficacy of these agents, their off-target mechanisms of action, as well as processes underlying the pathogenesis of adverse effects, need to be thoroughly investigated. The aim of this study was to examine the impact of various combinations of cyclosporine/tacrolimus/mycophenolate with rapamycin and steroids (CRG, TRG, MRG), on the morphology and morphometry of rats' cardiomyocytes, together with the presence of cardiac collagen and the immunoexpression of MMPs and TIMPs. METHODS: Twenty-four rats were divided into four groups receiving different immunosuppressive regiments. After six months of treatment, the hearts were collected and analyzed. RESULTS: Cardiomyocytes from the CRG cohorts demonstrated the most pronounced morphological alterations. In addition, chronic immunosuppression reduced the width and length of cardiac cells. However, immunosuppressive therapy did not alter the presence of cardiac collagen fibers. Nevertheless, we observed significant alterations regarding MMP/TIMP homeostasis. CONCLUSIONS: Chronic immunosuppression seems to disturb the MMP/TIMP balance in aspects of immunolocalization in the hearts of rats. Further studies are required to analyze other mechanisms and pathways affected by the use of immunosuppressants.

Prevalence of life-sustaining treatment limitations in Polish very old intensive care patients (VIPs). A post-hoc analysis of two prospective observational studies.

PURPOSE: Several initiatives have recently focused on raising awareness about limitations of treatment in Poland. We aimed to assess if the propensity to limit LST among elderly patients in 2018-2019 increased compared to 2016-2017. METHODS: We analysed Polish cohorts from studies VIP1 (October 2016 - May 2017) and VIP2 (May 2018 - May 2019) that enrolled critical patients aged >80. We collected data on demographics, clinical features limitations of LST. Primary analysis assessed factors associated with prevalence of limitations of LST, A secondary analysis explored differences between patients with and without limitations of LST. RESULTS: 601 patients were enrolled. Prevalence of LST limitations was 16.1% in 2016-2017 and 20.5% in 2018-2019. No difference was found in univariate analysis (p = 0.22), multivariable model showed higher propensity towards limiting LST in the 2018-2019 cohort compared to 2016-2017 cohort (OR 1.07;95%CI, 1.01-1.14). There was higher mortality and a longer length of stay of patients with limitations of LST compared to the patients without limitations of LST. (11 vs. 6 days, p = 0.001). CONCLUSIONS: The clinicians in Poland have become more proactive in limiting LST in critically ill patients ≥80 years old over the studied period, however the prevalence of limitations of LST in Poland remains low.

Depressive and anxiety symptoms in adolescents with type 1 diabetes - a single-centre observational study.

INTRODUCTION: Type 1 diabetes mellitus (T1DM) significantly affects the everyday functioning of the child and its family. This study aimed to assess the prevalence of symptoms of depression and anxiety and estimate their potential association with various clinical parameters. MATERIAL AND METHODS: 59 adolescents with T1DM (age 15-18) and their parents answered validated questionnaires (Children's Depression Inventory 2, The State-Trait Anxiety Inventory) and a survey assessing everyday functioning. RESULTS: There were no significant differences in the occurrence of symptoms of depression in children and their parents (p = 0.975), but significant differences were found for anxiety. The distribution of the sten X1 and X2 values of adolescents and parents were different (p = 0.021 and p = 0.001, respectively). Girls were characterized by a higher level of depression both based on the overall score (p = 0.010) and the emotional problems (p = 0.022), and functional problems (p = 0.012). There was no significant correlation between diabetes duration time, glycaemic control, the occurrence of acute diabetes complications, and the parameters assessing anxiety and depression. Optimal glycaemic control, defined as HbA1c below 6.5% and TIR above 70%, was associated with sex (p = 0.001) and a high level of functional problems (p = 0.048). CONCLUSIONS: In the studied population, adolescent girls with T1DM presented depressive symptoms more often than boys, and anxiety symptoms in adolescents were described more frequently by parents than by the teenagers themselves. Higher HbA1c was correlated with a higher level of functional problems.