Diseases (Basel, Switzerland)最新文献

Background: O⁶-Methylguanine-DNA methyltransferase (MGMT) is a unique antimutagenic DNA repair protein that plays a crucial role in conferring resistance to various alkylating agents in brain tumor therapy. In this study, we exploited the susceptibility of the active site Cys145 of MGMT for thiolation and nitrosylation, both of which inactivate the enzyme. Methods: We designed a redox perturbing glutathione mimetic, a platinated homoglutathione disulfide (hGTX) by adding small amounts of cisplatin (1000:10) and used a nitric oxide-donor spermine NONOate. N6022, a potent inhibitor of S-nitrosoglutathione reductase was used to extend the retention of nitrosylated MGMT in tumor cell culture and subcutaneous xenografts. Results: Both hGTX and spermine NONOate inhibited MGMT activity in HT29, SF188, T98G, and other brain tumor cells. There was a robust increase in the alkylation-induced DNA interstrand cross-linking, G2/M cell cycle arrest, cytotoxicity, and the levels of apoptotic markers when either of the agents was used with alkylating agents. In the nude mice bearing T98G and HT29-luc2 xenografts, combinations of hGTX and spermine NONOate with alkylating agents produced a marked reduction in MGMT protein and tumor growth delay and regressions. N6022 treatment increased the presence of nitrosylated MGMT for a longer time, thereby extending the DNA-repair deficient state both in cell culture and preclinical settings. Conclusions: Our findings highlight the options for redox-driven therapeutic strategies for MGMT and suggest that oxidative and/or nitrosative inactivation of DNA repair in combination with alkylating agents could be exploited.

Background/objectives: In brain physiology and disease, MMP-9 is a significant and apparently peculiar factor. Numerous studies have implicated neuroinflammatory processes involving MMP-9 in the pathophysiology of addiction. This study aims to evaluate plasma MMP-9 level as a biomarker for the stages of alcohol and opioid addiction.

Methods: The case subjects were patients with opioid and alcohol addiction. The quantitative assessment of MMP-9 plasma concentration was performed using monoclonal antibodies against human MMP-9.

Results: MMP-9 levels in the plasma of patients with alcohol and opioid dependence differ from MMP-9 concentrations in apparently healthy donors. During the intoxication stage, MMP-9 concentrations in individuals with alcohol and opioid dependence are similar and higher than in the control group. While the MMP-9 level is close to the control level after alcohol withdrawal, it stays increased during opioid withdrawal. When MMP-9 levels in plasma were measured in three distinct intoxicated states (light, moderate, and heavy) in cases of alcohol addiction, the results were all similar. Two distinct opioid intoxicated states (methadone and buprenorphine) and three withdrawals-following methadone, buprenorphine, and heroin abuse-were associated with high MMP-9 levels.

Background and objectives: Considering the link between childhood experiences with adult health and well-being, this study examined how living with a heavy drinker (HD) during childhood affected self-rated mental health (SRMH) in adulthood, while identifying risk and protective factors and assessing the prevalence within a regional context.

Materials and methods: Data (N = 11,113) were obtained from a cross-sectional DEEP SEAS survey (2021) of the general population, aged 18-64 years, in six countries (Croatia, Bosnia and Herzegovina, Slovenia, Austria, Hungary, and Italy).

Results: A statistically significant difference in SRMH was found, related to the childhood experience of living with an HD (MD = -0.221, 95% CI -0.250-0.172, N = 10,886) and being negatively affected (MD = -0.216, 95% CI -0.311-0.122, N = 2978). The correlation analysis revealed that individuals who lived with an HD during childhood perceived poorer SRMH in adulthood, consistently across all observed countries. Subsequent logistic regression identified different predictors for SRMH between those who were negatively affected and those who were not. The relationship satisfaction (RAS) was the strongest predictor, significantly contributing to better SRMH, especially in the subgroup that was not negatively affected (OR 28.724, 95% CI 3.450-239.173). A high prevalence of individuals negatively affected was found, especially in Hungary (34.4%) and Croatia (26.5%).

Conclusions: Growing up with someone who was a heavy drinker may have lasting negative consequences on SRMH, with a negative subjective evaluation of mental health in adulthood. Targeted public health and preventive measures are needed to protect those living with heavy drinkers.

Background: Current guidelines advise against platelet transfusion prior to emergent esophageal variceal band ligation (EVL) in cirrhotic patients with platelet counts below 50 × 10³/μL. However, recommendations for elective EVL remain unclear. This study evaluates the outcomes of cirrhotic patients undergoing outpatient EVL.

Methods: Adult patients aged 18 years and older diagnosed with cirrhosis, with or without significant thrombocytopenia (<50 × 10³/μL), were identified using the TriNetX database. Patients who received platelet transfusions within one week prior to or on the day of EVL were excluded. Cirrhotic patients with significant thrombocytopenia undergoing outpatient elective EVL were categorized into two cohorts: (1) those with platelet counts between 30 and 49 × 10³/μL and (2) those with platelet counts ≥50 × 10³/μL. Propensity score matching (PSM) was employed to compare rates of post-EVL esophageal variceal bleeding and 14-day mortality between the two cohorts.

Results: A total of 16,718 cirrhotic patients undergoing outpatient EVL were included in the analysis. Of these, 17.2% (n = 2874) had significant thrombocytopenia, while 82.8% (n = 13,844) had platelet counts ≥50 × 10³/μL. Two well-matched cohorts (2864 patients each) were created using 1:1 PSM. No statistically significant differences were observed between the groups regarding 14-day post-EVL esophageal variceal bleeding (13.7% vs. 15.2%; p = 0.12), 14-day mortality (5.7% vs. 5.0%; p = 0.28), and 28-day mortality (8.4% vs. 7.5%; p = 0.20).

Conclusions: Elective EVL appears to be safe in cirrhotic patients with platelet counts as low as 30 × 10³/μL, challenging the current threshold of 50 × 10³/μL for platelet transfusion.

Background: Pseudohypertriglyceridemia (pseudo-HTG) is a condition in patients with glycerol kinase deficiency or other disorders of glycerol metabolism, as well as in individuals with alcoholism, severe liver disease, or metabolic disturbances, and those receiving heparin therapy. Exogenous glycerol intake can also trigger this condition. However, the causes of pseudo-HTG are poorly understood, and a clinical algorithm for its diagnosing remains to be developed.

Case presentation: We present the case of a 46-year-old man admitted to hospital with hypertriglyceridemia-induced severe acute pancreatitis (HTG-SAP) and type 2 diabetes mellitus. Upon admission, his plasma triglyceride (TG) level was critically high at 43.78 mmol/L (3877 mg/dL). During hospitalization, he developed acute renal insufficiency and diabetic ketoacidosis (DKA). Despite conventional lipid-lowering treatments, including extracorporeal lipoprotein apheresis, his TG levels remained elevated. The unusually clear serum led to suspicion of pseudo-HTG. A glycerol-corrected TG assay confirmed normal TG values, thereby diagnosing pseudo-HTG.

Conclusions: This report presents the first confirmed case of pseudo-HTG verified through definitive glycerol kinase (GK) gene testing in a patient without glycerol kinase deficiency. We also include a review of the relevant literature and propose a clinical algorithm. The case report highlights the importance of considering pseudo-HTG in hypertriglyceridemia patients who do not respond well to the standard TG-lowering treatment. Our proposed clinical algorithm for diagnosing pseudo-HTG is potentially invaluable in clinical practice, and helps to prevent unnecessary lipid-lowering treatments for patients with pseudo-HTG.

Background: Hepatitis C virus (HCV) infection accelerates the progression of chronic kidney disease (CKD), increasing the risk of kidney failure and end-stage renal disease. Direct-acting antiviral (DAA) therapies for HCV infection inhibit viral replication by 95-97%, leading to a sustained virologic response. Our objective was to assess renal function in patients with chronic HCV infection in Taiwan after receiving DAA therapy.

Goal: Our study included 4823 patients with HCV infection who were undergoing DAA therapy. Renal function was evaluated by calculating the glomerular filtration rate (eGFR). eGFR assessed at the initiation of the treatment, during treatment, and at 3 months, 6 months, 1 year, and 3 years after completion of treatment. The baseline demographic and laboratory parameters of the study participants were evaluated, and the results were analyzed using statistical methods.

Results: The average age of the study participants was 61.35 ± 12.50 years, and 54.5% of were male. The mean of eGFR in baseline and after treatment showed a decrease. Liver fibrosis scores (FIB4, APRI, Fibroscan) and liver function tests were significantly improved after DAA treatment (p = 0.001). However, white blood count (5.41 ± 1.7 vs. 5.73 ± 1.9), platelet count (168.04 ± 74.0 vs. 182.11 ± 69.4), and creatinine levels (1.05 ± 1.3 vs. 1.12 ± 1.3) increased after treatment (p = 0.001). The number of patients with an eGFR of 60 mL/min/1.73 m² decreased both during and after treatment (p < 0.001). Among patients with CKD, eGFR improved after DAA treatment (n = 690, 35.93 ± 19.7 vs. 38.71 ± 23.8; 95% CI -3.56-1.98; p = 0.001). Logistic regression analysis revealed that renal function improved in patients with CKD who had an eGFR of less than 60 mL/min/1.73 m² before DAA treatment (OR 1.62, 95% CI 1.37-1.91, p = 0.001).

Conclusions: In individuals with CKD and a baseline eGFR < 60 mL/min per 1.73 m², eGFR level was increased during DAA treatment. This suggests that initiating DAA therapy in HCV-infected patients, even those without clinical manifestations, could be a crucial strategy to prevent further decline in renal function.

Purpose: To assess the presence and quantity of CD34+ hematopoietic stem cells in patients with Alzheimer's disease (AD) through a meta-analysis.

Methods: A systematic search of the databases identified the observational and interventional studies reporting baseline CD34+ cell counts in AD patients. The data on mean counts and the measures of variation were extracted. Standardized mean differences (SMDs) were calculated using common and random effects models to compare the CD34+ cell counts between the AD patients and controls. Heterogeneity among the studies was evaluated using tau², tau, and I² statistics. The risk of bias was assessed using the Newcastle-Ottawa Scale and the ROBINS-I tool.

Patients: Five studies were included, comprising four observational studies and one open-label trial, with a total of 271 participants (139 AD patients and 132 controls).

Results: The meta-analysis indicated an increase in CD34+ cell counts of the AD patients when compared to the controls. The common effects model showed a moderate SMD of 0.2964 (95% CI:0.0490-0.5437). However, the random effects model yielded a non-significant SMD of 0.2326 (95% CI: -0.4832-0.9484). Significant heterogeneity was observed among the studies (I² = 87.1%, p < 0.0001).

Conclusion: AD patients may exhibit higher circulating CD34+ cell counts than the controls, but substantial heterogeneity and potential biases limit definitive conclusions.

Background: Cancer remains a leading cause of morbidity and mortality worldwide. Traditional treatments like chemotherapy and radiation often result in significant side effects and varied patient outcomes. Immunotherapy has emerged as a promising alternative, harnessing the immune system to target cancer cells. However, the complexity of immune responses and tumor heterogeneity challenges its effectiveness.

Objective: This mini-narrative review explores the role of artificial intelligence [AI] in enhancing the efficacy of cancer immunotherapy, predicting patient responses, and discovering novel therapeutic targets.

Methods: A comprehensive review of the literature was conducted, focusing on studies published between 2010 and 2024 that examined the application of AI in cancer immunotherapy. Databases such as PubMed, Google Scholar, and Web of Science were utilized, and articles were selected based on relevance to the topic.

Results: AI has significantly contributed to identifying biomarkers that predict immunotherapy efficacy by analyzing genomic, transcriptomic, and proteomic data. It also optimizes combination therapies by predicting the most effective treatment protocols. AI-driven predictive models help assess patient response to immunotherapy, guiding clinical decision-making and minimizing side effects. Additionally, AI facilitates the discovery of novel therapeutic targets, such as neoantigens, enabling the development of personalized immunotherapies.

Conclusions: AI holds immense potential in transforming cancer immunotherapy. However, challenges related to data privacy, algorithm transparency, and clinical integration must be addressed. Overcoming these hurdles will likely make AI a central component of future cancer immunotherapy, offering more personalized and effective treatments.

Background: Respiratory syncytial virus (RSV) infection is a common cause of hospital admission. The association between chronic obstructive pulmonary disease (COPD) exacerbation and RSV infection is not well studied.

Objective: To analyze the hospitalizations of patients with COPD and RSV infection in Spain between 2018 and 2022.

Methods: The data used were obtained from the Spanish Hospital Discharge Database. We selected subjects aged ≥40 years diagnosed with COPD, admitted to the hospital from 1 January 2018 to 31 December 2022. The COPD population that met the selection criteria was subdivided based on the presence of an ICD-10 code for RSV infection. To obtain comparable populations, for each subject with COPD and RSV infection, a subject without an RSV code was selected, with the COPD code in the same diagnostic position (1 to 20), as well as the same year of admission, sex, and age.

Results: Among subjects aged ≥40 years, 1,429,288 were identified as having COPD, of whom 5673 also had RSV infection. The number of hospitalizations with COPD and RSV infection increased during the study period. The proportion of RSV infection among patients admitted for COPD increased significantly over time, from 0.32% in 2018 to 0.65% in 2022, p < 0.001. In-hospital mortality (IHM) increased over time, but the differences were not significant (6.23% in 2018 vs. 6.79% in 2022). Patients with COPD and RSV infection had, compared with those without RSV infection, a higher use of mechanical ventilation, both invasive (3.44% vs. 1.34%, p < 0.001) and noninvasive (8.09% vs. 4.51%, p < 0.001) and a higher proportion of intensive care unit (ICU) admission (7.21% vs. 3.9%, p < 0.001). After multivariate adjustment, a significant increase in IHM was found from 2018 to 2022 in subjects with and without RSV infection. The presence of RSV infection was associated with a higher mortality (OR 1.22; 95% CI 1.01-1.46).

Conclusions: The proportion of RSV infection among patients admitted for COPD increased significantly over time. Patients with COPD and RSV infection had, compared with those without RSV infection, a higher severity, a higher use of mechanical ventilation, and a higher proportion of ICU admission. The presence of RSV infection was associated with IHM. These results can help to identify patients at higher risk and make decisions to avoid the increased risk of hospitalization and mortality in this population.