Compromised Function Research Articles

Protective Effect of Carbon Dots Derived from Salvia miltiorrhiza Pretreatment in Acute Myocardial Infarction in Rats

Acute myocardial infarction is an ischemic injury of the myocardium caused by an imbalance in the blood supply to myocardial tissues, which poses a serious threat to human life and health. Oxidative stress has been recognized as a significant contributor to acute myocardial infarction. Salvia miltiorrhiza Carbonisata (SMC) is among the most frequently employed herbal remedies for the treatment of acute myocardial infarction; however, the exact identity of its principal active constituents is not well defined. Research indicates that carbon dots (CDs) exhibit significant biological properties. Consequently, we initially synthesized carbon dots (CDs) from Salvia miltiorrhiza Carbonisata, with the objective of exploring how SMC-CDs mitigate isoproterenol (ISO)-induced myocardial infarction (MI) in rats. The results showed that the pretreatment with SMC-CDs markedly enhanced compromised cardiac function, mitigated myocardial fibrosis and the infiltration of inflammatory cells, decreased the size of the infarct, and suppressed cardiomyocyte apoptosis. Furthermore, the antioxidant properties of myocardial tissue were enhanced, and oxidative stress caused by free radicals was effectively mitigated by SMC-CDs, which succeeded in reducing levels of myocardial enzymes and elevating the activity of relevant ATPases. This implies that SMC-CDs could be a potential candidate for novel nanomedicine strategies designed to address cardiovascular ailments.

The LINC complex in blood vessels: from physiology to pathological implications in arterioles.

The LINC (linker of nucleoskeleton and cytoskeleton) complex is a critical component of the cellular architecture that bridges the nucleoskeleton and cytoskeleton and mediates mechanotransduction to and from the nucleus. Though it plays important roles in all blood vessels, it is in arterioles that this complex plays a pivotal role in maintaining endothelial cell integrity, regulating vascular tone, forming new microvessels and modulating responses to mechanical and biochemical stimuli. It is also important in vascular smooth muscle cells and fibroblasts, where it possibly plays a role in the contractile to secretory phenotypic transformation during atherosclerosis and vascular ageing, and in fibroblasts' migration and inflammatory responses in the adventitia. Physiologically, the LINC complex contributes to the stability of arteriolar structure, adaptations to changes in blood flow and injury repair mechanisms. Pathologically, dysregulation or mutations in LINC complex components can lead to compromised endothelial function, vascular remodelling and exacerbation of cardiovascular diseases such as atherosclerosis (arteriolosclerosis). This review summarizes our current understanding of the roles of the LINC complex in cells from arterioles, highlighting its most important physiological functions, exploring its implications for vascular pathology and emphasizing some of its functional characteristics in endothelial cells. By elucidating the LINC complex's role in health and disease, we aim to provide insights that could improve future therapeutic strategies targeting LINC complex-related vascular disorders.

Acute Kidney Injury During Sepsis and Prognostic Role of Coexistent Chronic Heart Failure

Background: The recently updated definition of sepsis considers pathophysiologic mechanisms to guide initial therapy. Clearly, generalized recommendations for sepsis therapy may be limited by pre-existing multimorbidity in addition to sepsis-related multi-organ failure. In particular, a recommendation regarding fluid rescue therapy may require adequate cardiac function and/or the absence of sepsis-induced cardiomyopathy. In all sepsis patients with compromised cardiac function or sepsis-induced cardiomyopathy, a patient-specific therapy regimen is required to prevent pulmonary edema and early death. Similarly, in sepsis, acute kidney injury with or without pre-existing chronic kidney disease requires attention to be paid to excretory renal function to avoid hypervolemia-mediated acute heart failure. In addition, hyponatremia related to intravascular hypovolemia may be explained by vasopressin stimulation. However, hypothetically, vasopressin hyporesponsiveness may contribute to sepsis-related acute kidney injury. In this review, relevant cardiorenal pathomechanisms will be assessed in the context of sepsis therapy. Conclusions: In conclusion, therapy for sepsis with acute kidney injury has to take cardiac comorbidity, if present, into account. The extent to which vasopressin hyporesponsiveness aggravates sepsis-mediated hypovolemia and renal insufficiency should remain a subject of further study.

T. pallidum achieves immune evasion by blocking autophagic flux in microglia through hexokinase 2.

Increasing evidence suggests that immune cell clearance is closely linked to cellular metabolism. Neurosyphilis, a severe neurological disorder caused by Treponema pallidum (T. pallidum) infection, significantly impacts the brain. Microglia, the innate immune cells of the central nervous system, play a critical role in neuroinflammation and immune surveillance. However, the inability of the nervous system to fully eliminate T. pallidum points to a compromised clearance function of microglia. This study investigates how T. pallidum alters the immune clearance ability of microglia and explores the underlying metabolic mechanisms. RNA sequencing (RNA seq), LC-MS metabolomics, and XFe96 Seahorse assays were employed to assess metabolic activity in microglial cells. Western blotting, qPCR, and immunofluorescence imaging were utilized to evaluate autophagy flux and extent of T. pallidum infections. Transcriptomic analysis revealed that T. pallidum alters the transcription expression of key glycolytic enzymes, including hexokinase 1 (HK1), hexokinase 2 (HK2), and lactate dehydrogenase A (LDHA), leading to significant metabolic dysregulation. Specifically, metabolomic analysis showed reduced levels of phosphoenolpyruvate and citrate, while lactate production was notably increased. Functional assays confirmed that T. pallidum impairs glycolytic activity in microglial, as evidenced by decreased glycolytic flux, glycolytic reserve capacity, and maximum glycolytic capacity. Moreover, our results indicate that HK2, a crucial glycolytic enzyme, is closely associated with the autophagy. T. pallidum infection inhibits HK2 expression, which in turn suppresses autophagic flux by reducing the formation of lysosome-associated membrane protein 2 (LAMP2) and disrupting autophagosome-lysosome fusion. These findings suggest that T. pallidum hijacks microglial metabolic pathways, specifically glycolysis, to evade immune clearance. By inhibiting the glycolytic enzyme HK2, T. pallidum modulates autophagy and enhances immune evasion, providing a novel insight into the pathogenesis of neurosyphilis. This study paves the way for further investigations into the role of metabolic reprogramming in the immune escape mechanisms of T. pallidum.

Cancer-associated mutation at glycine 400 in TIP60 disrupt its phase separation property and catalytic activity resulting in compromised DNA damage repair function of the cell

Cancer-associated mutation at glycine 400 in TIP60 disrupt its phase separation property and catalytic activity resulting in compromised DNA damage repair function of the cell

Working memory deficit in patients with focal epilepsy is associated with higher interictal theta connectivity.

Interictal cognitive disturbances are frequent in patients with focal epilepsies and the links with alteration of resting state brain oscillations are not well known. Changes in theta oscillations, may contribute to cognitive impairment. This study aimed to investigate whether changes in theta activity are related to cognitive disturbances. Retrospective data of 23 patients with temporal/frontal lobe epilepsy were included. Theta connectivity, power and interictal spikes rate from five-minute interictal resting state stereoelectroencephalography datasets were computed. Cognitive performances were assessed by Wechsler Intelligence Scale (WAIS-IV) and Weschler Memory Scale (WMS-III). Linear regression was performed to evaluate effect of interictal activity and seizure related parameters on cognitive scores. WAIS-IV working memory score in patients with epilepsy showed negative correlation with frontotemporal theta connectivity (F(1,17)=5,239, p=0,036, R2=0,200, β=-0,497). Moreover, theta connectivity was correlated with mesial temporal spike rate and theta power (F(2,17)=10,967, p=0,001, adj.R2=0,540). Patients with focal epilepsy often encounter compromised cognitive functions, particularly notable in the domain of working memory. This impairment might be attributed to physiological mechanisms involving increased theta connectivity within the frontotemporal regions and interictal spiking. Our study highlights the relation between theta connectivity and working memory impairments in patients with focal epilepsy.

Long-term effects of superselective renal artery embolization on renal function after percutaneous nephrolithotomy.

To investigate the long-term impact of superselective renal artery embolization (SRAE) on renal function in cases of severe post-percutaneous nephrolithotomy (PCNL) haemorrhage, and to identify the factors associated with the long-term outcome of renal function. Patients treated with SRAE for post-PCNL hemorrhage between September 2016 and September 2021 were included. Patients' demographic and clinical data were recorded. Multiple linear regression and logistic regression were used to identify the factors related to the percentages of estimated glomerular filtration rate (eGFR) change and the risk factors of worsening renal function (WRF), respectively. A total of 80 patients were included. There was no significant change in eGFR before and after SRAE immediately within 1.45 ± 1.66 days (66.37 ± 28.45 vs. 63.86 ± 29.26 mL/min/1.73m², p = 0.202). Patient's eGFR increased significantly from 66.37 ± 28.45 to 70.94 ± 30.48 mL/min/1.73m² (p = 0.044) with a mean follow-up of 30.4 months after SRAE, especially in patients with compromised renal function before SRAE (β = 0.297, p = 0.039). However, BMI > 24kg/m2 was significantly associated with the decrease of eGFR (β = -0.343, p = 0.016). 12 (15.0%) patients developed WRF, logistic regression analysis showed that BMI > 24.0kg/m2 (OR = 4.144, p = 0.045) and atrophic renal cortex (OR = 4.180, p = 0.040) were independent risk factors of WRF. SRAE is an effective treatment for post-PCNL severe haemorrhage, and is not deleterious to long term renal function. Notably, BMI > 24.0kg/m2 and atrophic renal cortex were significant predictors of long-term WRF in SRAE patients.

TRNA m1A modification regulates cholesterol biosynthesis to promote antitumor immunity of CD8+ T cells.

Activation of CD8+ T cells necessitates rapid metabolic reprogramming to fulfill the substantial biosynthetic demands of effector functions. However, the posttranscriptional mechanisms underpinning this process remain obscure. The transfer RNA (tRNA) N1-methyladenine (m1A) modification, essential for tRNA stability and protein translation, has an undefined physiological function in CD8+ T cells, particularly in antitumor responses. Here, we demonstrate that the tRNA m1A "writer" gene Trmt61a enhances the tumor-killing capacity of CD8+ T cells by regulating cholesterol biosynthesis. Deletion of Trmt61a in CD8+ T cells leads to a compromised tumor-killing function in both in vivo and in vitro assays. Mechanistically, tRNA m1A promotes antitumor immunity in CD8+ T cells by enhancing the translation of ATP citrate lyase, a key enzyme for cholesterol biosynthesis. Cholesterol supplementation rescues the impaired tumor-killing function and proliferation of TRMT61A-deficient CD8+ T cells. Our findings highlight tRNA m1A modification as a regulatory checkpoint in cholesterol metabolism in CD8+ T cells, suggesting potential novel strategies for cancer immunotherapy.

Low agreement and frequent invalid controls in two SARS-CoV-2 T-cell assays in people with compromised immune function.

T-cell response plays an important role in SARS-CoV-2 immunogenicity. For people living with HIV (PWH) and solid organ transplant (SOT) recipients there is limited evidence on the reliability of commercially available T-cell tests. We assessed 173 blood samples from 81 participants (62 samples from 35 PWH; 111 samples from 46 SOT recipients [lung and kidney]) with two commercial SARS-CoV-2 Interferon-γ (IFN-γ) release assays (IGRA; SARS-CoV-2 IGRA by Euroimmun, and IGRA SARS-CoV-2 by Roche). The reliability between the tests was judged as low (Cohen's kappa [κ] = 0.20; overall percent agreement [OPA] = 66%). A high proportion of tests were invalid (22% Euroimmun; 8% Roche). When excluding these invalid tests, the agreement was higher (κ = 0.43; OPA = 90%). The low reliability between the two T-cell tests indicates that results should be interpreted with caution in SOT recipients and PWH and that SARS-CoV-2 T-cell tests need to be optimized and further validated for use in vulnerable patient populations.

DOP116 Preclinical characterization of IMU-856, an orally available epigenetic modulator of gut barrier function and regeneration

Abstract Background A dysfunctional intestinal mucosal barrier is a key pathophysiological hallmark and driver of a broad range of gastrointestinal diseases, including inflammatory bowel disease (IBD). To date, there are no adequate treatment strategies to ameliorate impaired barrier function. IMU-856 is an orally available and systemically acting small molecule modulator of sirtuin 6 (SIRT6), a histone/non-histone protein deacetylase and transcriptional regulator that targets the restoration of intestinal barrier function and regeneration of bowel epithelium without having any direct effect on the immune system. A double-blind, randomized, placebo-controlled phase 1/1b clinical trial of IMU-856 has been completed [1]. IMU-856 was shown to be safe and well-tolerated with a benign adverse event profile and pharmacokinetics that allow once-daily dosing. In Part C, a ‘proof of concept study’ in patients with celiac disease, IMU-856 demonstrated positive effects in four key dimensions of clinical outcome: protecting gut architecture, improving patients' symptoms severity, biomarker response and enhancing nutrient absorption. Methods In the presented preclinical studies, the target specificity and effects of IMU-856 on intestinal barrier function and regeneration were elucidated by in-vitro sirtuin activity assays, transepithelial electrical resistance (TEER) assays, dextran sulphate sodium (DSS)-induced colitis mouse models and gene expression analysis (bulk RNA sequencing). Moreover, potential immune suppressive effects of IMU-856 were assessed in stimulated human peripheral blood mononuclear cells (PBMCs). Multiple biomarkers related to health of intestinal epithelium and of enteric function were also assessed in preclinical studies and in the phase 1 trial. Results IMU-856 is a highly selective and potent modulator of SIRT6. In TEER assays, IMU-856 treatment enhanced the epithelial barrier recovery of Caco-2 monolayers after a destructive cytokine challenge and modulated tight junction protein levels. IMU-856 demonstrated activity in acute DSS-induced colitis models by reducing the severity of colitis, improving the mucosal architecture and preserving functional enterocytes (upregulation of enterocyte marker genes and the plasma biomarker citrulline). No effects of IMU-856 on T-cell proliferation and cytokine secretion (interferon-g (IFN-g)) were observed in human PBMCs. Conclusion IMU-856 data indicate restoration of intestinal barrier function and promotion of physiological mucosal regeneration without direct immunosuppressive effects and may therefore offer potential for the treatment of IBD and other gastrointestinal diseases with compromised barrier function.

DOP012 Promising effects of IMU-856, an orally available epigenetic modulator of barrier regeneration - biomarker findings from a Phase 1 clinical study

Abstract Background A dysfunctional intestinal mucosal barrier is a key pathophysiological hallmark and driver of a broad range of gastrointestinal diseases including inflammatory bowel disease (IBD). To date, there are no adequate treatment strategies to ameliorate impaired barrier function. IMU-856 is an orally available and systemically acting small molecule modulator of sirtuin 6 (SIRT6), a histone/non-histone protein deacetylase which serves as a transcriptional regulator of intestinal barrier function and regeneration of bowel epithelium. In preclinical studies, IMU-856´s mechanism of action has been shown to avoid suppression of immune cells. This could present a new approach to treat intestinal barrier function associated diseases without the serious consequences associated with many immunosuppressive therapies. Methods This was a first-in-human, double-blind, randomized, placebo-controlled clinical trial of IMU-856 in healthy volunteers and patients with celiac disease. In the multiple ascending dose part, healthy human subjects were dosed once-daily for 14 consecutive days with IMU-856 at three different dose levels or placebo. Phase 1b was designed to assess safety and tolerability of IMU-856 at two different dose levels in patients with celiac disease during periods of gluten-free diet and a 15-day gluten challenge. Further objectives included pharmacokinetics and the assessment of histological changes. Biomarkers reflecting intestinal enterocyte function, intestinal integrity, nutrient absorption and general gut health were analyzed to assess the effect on the overall protection of gut architecture. Results IMU-856 was safe and well-tolerated with a benign adverse event profile and pharmacokinetics that allow once-daily dosing. There were no systematic clinically relevant findings relative to safety and tolerability. Treatment with IMU-856 improved the mass, metabolic function and health of intestinal enterocytes as measured by nutrient uptake as well as several biomarkers for intestinal function and integrity as well as general gut health [1]. Conclusion IMU-856 is a safe, highly selective and potent epigenetic modulator, showing signals of improving the intestinal barrier function in patients with celiac disease undergoing a gluten challenge.The positive effects of IMU-856 on various biomarkers for intestinal function, overall health and integrity in conjunction with the protection of gut architecture show that IMU-856 may offer extensive potential in other gastrointestinal diseases with compromised intestinal barrier function like IBD.

Autophagy-mediated TET2 degradation by ALV-J Env protein suppresses innate immune activation to promote viral replication.

ALV-J is a carcinogenic retrovirus that plays a critical role in avian leukosis, primarily affecting chickens. Infection with ALV-J leads to decreased production performance, compromised immune function, and the development of tumors, such as myelocytoma. Currently, there are no effective treatments for ALV-J, making the control of outbreaks a significant challenge with severe economic consequences for the poultry industry. The Env protein of ALV-J has been implicated in the virus's pathogenicity. Our study shows that ALV-J infection induces autophagy in host cells through its Env protein, leading to the autophagic degradation of TET2, a key epigenetic regulator. The loss of TET2 in macrophages results in the downregulation of innate immune-related gene expression, thereby promoting viral replication. This is the first report to elucidate the role of the ALV-J Env protein in immune suppression via TET2 autophagic degradation during ALV-J infection, providing new insights into the mechanisms of viral immune evasion.

The lipocalin saga: Insights into its role in cancer-associated cachexia.

Cancer-associated cachexia (CAC) is a debilitating condition, observed in patients with advanced stages of cancer. It is marked by ongoing weight loss, weakness, and nutritional impairment. Lower tolerance of chemotherapeutic agents and radiation therapy makes it difficult to treat CAC. Anorexia is a significant contributor to worsening CAC. Anorexia can be found in the early or advanced stages of cancer. Anorexia in cancer patients arises from a confluence of factors. Tumor-related inflammatory cytokines can directly impact the gastrointestinal tract, leading to dysphagia and compromised gut function. Additionally, increased serotonin and hormonal disruptions lead to early satiety, suppressing appetite. Due to the complexities in the pathogenesis of the disease, identifying druggable targets is a challenge. Research is ongoing to identify novel targets for the treatment of this condition. Recent research suggests a potential link between elevated levels of Lipocalin 2 (LCN2) and cachexia in cancer patients. LCN2, a glycoprotein primarily released by neutrophils, is implicated in numerous illnesses, including skin disorders, cancer, atherosclerosis, and type 2 diabetes. LCN2 suppresses hunger by binding to the melanocortin-4 receptors. Several in vitro, in vivo, and clinical studies indicate the association between LCN2 levels and appetite suppression. Further research should be explored emphasizing the significance of well-crafted clinical trials to confirm LCN2's usefulness as a therapeutic target and its ability to help cancer patients who are suffering from the fatal hallmark of cachexia. This review explores LCN2's function in the multifaceted dynamics of CAC and anorexia.

Adalimumab-induced optic neuropathy in a patient with Behçet’s syndrome

A 37-year-old woman with a diagnosis of Behçet’s syndrome, treated with colchicine and prednisolone, maintained low disease activity for a period of 10 years, after which, she developed a new episode of anterior uveitis. A cycle of high dose systemic corticosteroids was required but the patient presented with a new flare during dose tapering. A decision to initiate a corticosteroid-sparing agent was then made, with an initially satisfactory response. However, 3 months later the ocular symptoms recurred, and a new bout of oral ulceration appeared concurrently. As a result, adalimumab was then started, but the patient presented with a sudden and severe decrease of visual acuity in her right eye 4 months later. The initial bloodwork showed no elevated inflammatory markers. A lumbar puncture showed a normal cerebrospinal fluid composition. Although these findings made it less probable that the patient’s symptoms were caused by infectious or autoimmune disease, extensive investigations directed at these possible causes were performed, with negative results. Several imaging tests were also performed, which showed no alterations. However, a sensory evoked potentials test revealed a functional compromise at the pre-chiasmatic level. An iatrogenic optic neuropathy induced by adalimumab seemed the most probable cause and a decision to suspend the treatment was made. A new cycle of high dose systemic corticosteroids consisting of three pulses of methylprednisolone followed by pred-nisolone with a quick tapering over 4 weeks was also started, with gradual improvement of visual acuity.

Adalimumab-induced optic neuropathy in a patient with Behçet’s syndrome

A 37-year-old woman with a diagnosis of Behçet’s syndrome, treated with colchicine and prednisolone, maintained low disease activity for a period of 10 years, after which, she developed a new episode of anterior uveitis. A cycle of high dose systemic corticosteroids was required but the patient presented with a new flare during dose tapering. A decision to initiate a corticosteroid-sparing agent was then made, with an initially satisfactory response. However, 3 months later the ocular symptoms recurred, and a new bout of oral ulceration appeared concurrently. As a result, adalimumab was then started, but the patient presented with a sudden and severe decrease of visual acuity in her right eye 4 months later. The initial bloodwork showed no elevated inflammatory markers. A lumbar puncture showed a normal cerebrospinal fluid composition. Although these findings made it less probable that the patient’s symptoms were caused by infectious or autoimmune disease, extensive investigations directed at these possible causes were performed, with negative results. Several imaging tests were also performed, which showed no alterations. However, a sensory evoked potentials test revealed a functional compromise at the pre-chiasmatic level. An iatrogenic optic neuropathy induced by adalimumab seemed the most probable cause and a decision to suspend the treatment was made. A new cycle of high dose systemic corticosteroids consisting of three pulses of methylprednisolone followed by pred-nisolone with a quick tapering over 4 weeks was also started, with gradual improvement of visual acuity.

Omega-3 Polyunsaturated Fatty Acids in Chronic Obstructive Pulmonary Disease Patients with COVID-19: A Review.

Mounting evidence indicates that individuals with chronic obstructive pulmonary disease (COPD) face a heightened risk of severe outcomes upon contracting coronavirus disease 2019 (COVID-19). Current medications for COVID-19 often carry side effects, necessitating alternative therapies with improved tolerance. This review explores the biological mechanisms rendering COPD patients more susceptible to severe COVID-19 and investigates the potential of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in mitigating the severity of COVID-19 in COPD patients. Current evidence indicates that COPD patients are at an increased risk of severe COVID-19due to factors including compromised pulmonary function, dysregulated inflammation, weakened immune response, increased oxidative stress, elevated expression of angiotensin-converting enzyme (ACE2) receptors in the lungs, and genetic predispositions. Remarkably, n-3 PUFAs exhibit the potential in ameliorating the clinical outcomes of COPD patients with COVID-19 by modulating inflammation, reinforcing the body's antioxidant defenses, reducing viral entry and replication, and enhancing immunity. N-3 PUFAs hold potential for improving COVID-19 outcomes in patients with COPD. However, there has been limited investigation into the therapeutic effects of n-3 PUFAs in enhancing clinical outcomes for COPD patients. Rigorous clinical studies are essential to evaluate the impact of n-3 PUFAs on COPD patients with concurrent COVID-19 infection.

Associations Between Bone Mineral Density and WOMAC Scores in Healthy Individuals: Insights from the Qatar Biobank

Bone mineral density (BMD) is an indicator of bone health that predicts future bone fractures. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is used to assess the severity of symptoms related to pain, stiffness, and function in diseased hip and knee joints. Here we assessed whether BMD measured at specific sites predicts WOMAC scores in healthy individuals whilst controlling for sociodemographic variables. BMD, sociodemographic, and WOMAC data were collected from 1764 healthy adult individuals attending the Qatar Biobank (QBB). Multiple linear regression was used to examine associations between sociodemographic factors, total body BMD and BMD related to specific skeletal sites (including femoral (femoral neck and trochanter), trunk, pelvis and total spine), and the three WOMAC subscales (pain, stiffness, and physical function). After controlling for sociodemographic variables, total body and specific BMD measures did not predict pain. However, BMD measures significantly contributed to predicting stiffness after controlling for sociodemographic variables (R2 = 0.065, ΔF(7, 1724) = 3.34, p = 0.002), with a higher total body BMD associated with increased stiffness and a higher trunk BMD associated with decreased stiffness. Total body BMD measures also significantly contributed to predicting compromised physical function (R2 = 0.091, ΔF(7, 1724) = 3.762, p < 0.001) after controlling for sociodemographic variables, with a higher total body BMD associated with an increase in compromised physical function. Total body BMD seems to be a more important predictor of stiffness and physical function than specific skeletal sites BMD measures. Monitoring BMD may have important implications for osteoarthritis patients.

Non-Anatomic Reconstruction in Multiligament Knee Injuries: A Functional Approach.

Background/Objectives: Multiligament knee injuries, involving damage to multiple stabilizing structures, present a significant challenge in orthopedic surgery, often resulting in knee instability and compromised function. While anatomic ligament reconstruction has been traditionally advocated, non-anatomic techniques may provide effective alternatives, particularly for patients with moderate functional demands who do not require high-level athletic performance. Material and methods: In this study, we assessed the outcomes of a non-anatomic, hybrid surgical approach involving combined arthroscopic and open non-anatomic ligament reconstruction in 60 patients with multiligament knee injuries. Using simplified reconstruction methods for the medial collateral ligament (MCL) and lateral collateral ligament (LCL), we tailored the procedures to the needs of active, non-professional patients. Functional outcomes were evaluated using the International Knee Documentation Committee (IKDC) Questionnaire, Lysholm Knee Scoring Scale, and Knee Injury and Osteoarthritis Outcome Score (KOOS). Results: Postoperative improvements were significant, with the total IKDC score increasing from a median of 39.1 preoperatively to 75.9 postoperatively, Lysholm from 61.0 to 87.0, and KOOS from 47.6 to 85.7 (p < 0.01). The results demonstrated significant improvements across all scoring systems, with enhanced knee stability, reduced pain, and better quality of life. Conclusions: These findings support the feasibility of non-anatomic reconstructions as a practical solution for patients seeking a return to daily activities and recreational sports without the complexity of full anatomic reconstruction.

BPZ inhibits early mouse embryonic development by disrupting maternal-to-zygotic transition and mitochondrial function.

The use of Bisphenol A (BPA) has been widely restricted due to its adverse health effects. Bisphenol Z (BPZ) is used as an alternative to BPA, and humans are widely exposed to BPZ through various routes. Recent studies have shown that BPZ exposure adversely affects mouse oocyte meiotic maturation. This study investigates the impact of BPZ exposure on early mouse embryonic development alongside an exploration of the underlying mechanisms. The findings reveal that exposure to BPZ leads to a reduction in early embryo quality and hinders developmental progression. RNA sequencing analysis has identified 593 differentially expressed genes as a result of BPZ exposure, highlighting considerable changes in early embryonic gene expression. Mechanistically, BPZ exposure inhibits the activation of the zygotic genome and impedes maternal mRNA degradation, thereby interfering with maternal-to-zygotic transition (MZT). Further analysis indicates compromised mitochondrial function, as evidenced by abnormal distribution, diminished membrane potential, and lower ATP levels. Consequently, BPZ-exposed embryos exhibit elevated levels of reactive oxygen species, superoxide anions, and oxidative DNA damage. Moreover, BPZ exposure is associated with an increase in γ-H2A.X expression. Additionally, BPZ exposure alters the expression levels of histone modifications, including H3K27me2, H3K27me3, H3K9me3, and H3K27ac, in early embryos. Collectively, BPZ exposure significantly impairs early embryo quality by disrupting mitochondrial function, inducing oxidative stress and DNA damage, altering histone modifications, and inhibiting MZT, ultimately resulting in hindered blastocyst formation. These findings underscore the profound adverse effects of BPZ on early embryonic development, indicating the need for caution when considering it as a safe alternative to BPA.

Assessing the impact of e-cigarettes on human barrier systems: A systematic review.

The use of e-cigarettes has grown rapidly in recent years, raising concerns about their impact on human health, particularly on critical physiological barriers such as the blood-brain barrier (BBB), alveolar-capillary barrier, and vascular systems. This systematic review evaluates the current literature on the effects of e-cigarette exposure on these barrier systems. E-cigarettes, regardless of nicotine content, have been shown to induce oxidative stress, inflammation, and disruption of tight junction proteins, leading to impaired barrier function. Key findings include compromised pulmonary function, increased vascular stiffness, and neuroinflammation. The review highlights potential long-term health risks associated with e-cigarette use, such as cardiovascular disease, neurodevelopmental disorders, and multi-organ fibrosis, and emphasizes the need for public health interventions to regulate e-cigarette use, especially in vulnerable populations like pregnant women and adolescents.