Long-term Adverse Effects Research Articles

Mitochondria and Acute Leukemia: A Clinician's Perspective.

Acute leukemia is a group of aggressive hematological malignancies, with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) being the most common types. The biology of acute leukemia involves complex genetic and epigenetic alterations that lead to uncontrolled cell proliferation and resistance to apoptosis. Mitochondrial dysfunction is a feature of acute leukemia that results in altered energy production, unregulated cell death pathways, and increased cancer cell survival. Apoptosis, particularly via the mitochondrial pathway, is crucial for cellular homeostasis and cancer prevention. In acute leukemia, disruption of apoptosis is pivotal in disease development and progression, with elevated levels of anti-apoptotic proteins conferring a survival advantage to leukemia cells and promoting resistance to conventional therapies. Targeting mitochondrial apoptosis using BH3 mimetics and anti-apoptotic protein inhibitors is a viable therapeutic strategy. Alterations in the mitochondrial membrane potential, metabolism, and dynamics also contribute to the pathogenesis of acute leukemia. Continued research is vital for developing novel therapies and enhancing survival outcomes in patients with acute leukemia while minimizing the long-term adverse effects of treatment. In this narrative review, we provide a birds-eye view of the available scientific literature on the importance of mitochondria in acute leukemia, and discuss the role of BH3 mimetics in targeting the mitochondrial internal apoptotic machinery.

Toxicity profiles associated with EGFR-TKIs combined with angiogenesis inhibitors in non-small cell lung cancer: an epidemiological surveillance analysis of the FDA adverse event reporting system

ABSTRACT Background Ongoing studies are evaluating the efficacy and toxicity profiles of combining epidermal growth factor receptor inhibitors (EGFR-TKIs) with antiangiogenic agents in non-small cell lung cancer (NSCLC). However, the complete toxicity profiles remain elusive. Research design and methods This study conducted an extensive pharmacovigilance analysis utilizing the FDA Adverse Event Reporting System database. The analysis focused on identifying and characterizing adverse events (AEs) associated with the concurrent use of EGFR-TKIs and antiangiogenic inhibitors in patients with NSCLC. Results The study identified significant occurrences of AEs linked to the combination therapy, particularly impacting general disorders, skin and subcutaneous tissue conditions, and vascular disorders. Frequently reported AEs included rash, diarrhea, fatigue, nausea, decreased appetite, and anemia. Notably, the combination of EGFR-TKIs with antiangiogenic inhibitors resulted in an increased incidence of AEs across multiple organ systems compared to EGFR-TKIs alone, with some adverse effects, such as anemia, arrhythmia, and ulcerative keratitis, persisting beyond one year in a subset of patients. Conclusions The combination of EGFR-TKIs and antiangiogenic inhibitors in NSCLC treatment presents a distinct and substantial AE profile, often with delayed onset. This finding underscores the necessity for rigorous and ongoing monitoring protocols to mitigate potential long-term adverse effects.

Targeting mitochondrial homeostasis in the treatment of non-alcoholic fatty liver disease: a review.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and its prevalence is rapidly increasing. Antioxidants, lipid-lowering medications, and lifestyle interventions are the most commonly used treatment options for NAFLD, but their efficacy in inhibiting steatosis progression is limited and their long-term ineffectiveness and adverse effects have been widely reported. Therefore, it is important to gain a deeper understanding of the pathogenesis of NAFLD and to identify more effective therapeutic approaches. Mitochondrial homeostasis governs cellular redox biology, lipid metabolism, and cell death, all of which are crucial to control hepatic function. Recent findings have indicated that disruption of mitochondrial homeostasis occurs in the early stage of NAFLD and mitochondrial dysfunction reinforces disease progression. In this review, we summarize the physical roles of the mitochondria and describe their response and dysfunction in the context of NAFLD. We also discuss the drug targets associated with the mitochondria that are currently in the clinical trial phase of exploration. From our findings, we hope that the mitochondria may be a promising therapeutic target for the treatment of NAFLD.

STUDY OF COPPER COMPLEXES [Cu(LCF3)2] AND [Cu(Lcur)2]H2O AS RADIOPROTECTIVE COMPOUNDS

One of the first and direct signs of the impact of ionizing radiation (IR) on a cell is the destabilization of chromosomes. Radiation-induced damage to the karyotype is an important indicator both for biological indication of the severity of radiation injuries and for predicting the development of long-term adverse effects of IR. The search for new, effective radioprotective compounds is a priority task of modern radiobiology. In this area, metal-based compounds with high antioxidant activity are of particular interest. The purpose of this work is to determine the possible radioprotective properties of Cu(II) complexes, [Сu(LCF3)2] and [Cu(Lcur)2]H2O, supported by the anions of the β-diketone ligands 1,1,1,5,5,5-hexafluoro-2,4-pentanedione (HLCF3) and 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione or curcumin (HLcur). In this research work we determined survival, life expectancy and cytogenetic parameters: mitotic index, chromosome aberrations and % of polyploid cells in the bone marrow cells of the femur (count in 1000 cells in each preparation). Group I included intact animals; Group II consisted of animals exposed to the radioisotope technetium; Group III consisted of animals that were intraperitoneally injected with copper complex [Cu(LCF3)2] at a dose of 50 mg/kg in a volume of 2 mL one hour before the administration of the Tc isotope (“irradiation + copper compound [Cu(LCF3)2]); Group IV included animals that received the compound [Cu(Lcur)2]H2O before irradiation. The groups with the injection of [Cu(LCF3)2] complex had the highest survival. In terms of chromosomal aberrations and number of polyploid cells, as indicators, a significant difference was found in those irradiated compared with the “irradiation + [Cu(LCF3)2]” group (both after 15 and after 30 days), which indicates the radioprotective property of the compound. In terms of the mitotic index, a tendency towards normalization was noted after 15 days and a significant difference between Groups 2 and 3 by the end of the study (after 30 days), which also proves the beneficial effect of this compound. Analysis of survival and changes in cytogenetic parameters multiregression analysis using both complexes confirms the greatest efficiency of the [Cu(LCF3)2] complex with respect to [Cu(Lcur)2]H2O, because when using [Cu(Lcur)2]H2O in Group IV and comparing it with “pure irradiation” only a tendency toward normalization of cytogenetic parameters was observed. Multiregression analysis of cytogenetic parameters also confirmed the highest efficiency of the [Cu(LCF3)2] compound in comparison with [Cu(Lcur)2]H2O. The results of the research indicate the need to continue work in the direction of searching for agents that have a therapeutic effect in radiation injuries.

Adverse Childhood Experiences and Cognitive Change in Late-Life Depression

ObjectivesTo determine the relationship of adverse childhood experiences (ACEs) with change in cognitive performance over a 1-year period among older adults in treatment for depression. MethodsOlder depressed adults completed the ACEs questionnaire and the Consortium to Establish a Registry of Alzheimer's disease (CERAD) cognitive battery at baseline and were re-assessed with the CERAD 1 year later. ResultsChildhood physical abuse, sexual abuse, and verbal/emotional abuse, respectively, were reported by 25%, 17.5%, and 42% of participants. Total ACEs score was not associated with baseline cognitive performance or 1-year change. However, sexual abuse, physical abuse, and a measure of cumulative verbal/emotional, physical, and sexual abuse were inversely associated with 1-year change in total CERAD score. ConclusionsChildhood abuse may have long-term adverse effects, including placing depressed older adults at risk for progressive cognitive decline. ACEs should be considered in research and clinical management of depression in older adults.

Efficacyof fractional radiofrequency in the treatment of erythematous capillary rosacea: A split-face study.

To assess the effectiveness and safety of treating erythematotelangiectatic rosacea using fractional radiofrequency (FRF). Twenty patients with a confirmed diagnosis of erythema capillaris rosacea were selected, and one side of each patient's face was randomly assigned to receive FRF treatments for three to six times, with an interval of 2 weeks between each treatment. VISIA, dermoscopy, and the Clinician's Erythema Evaluation Scale (CEA) were applied to evaluate the efficacy of the treatment before and after the treatment, to record the VAS scores and adverse reactions, and to conduct a patient satisfaction survey. The characteristic counts and scores of red zone and porphyrin as assessed by VISIA test were significantly decreased, and the difference between the treated side and the pretreatment side was statistically significant (p < 0.05), and the efficacy of the treatment was statistically insignificant compared with the control side, except for the red zone and porphyrin which were statistically significant before and after the treatment (p > 0.05). By CEA score, the difference between the treated side after treatment and the control side was statistically significant (p < 0.05), and the difference between the treated side before and after treatment was statistically significant (p < 0.05); the difference between the control side before and after treatment was not statistically significant (p > 0.05). Dermatoscopic observation showed reduction in pore size, reduction of yellowish-white and black horn plugs within the pores, lightening of the red background and thinning and blurring of the capillary structure on the treated side of the skin compared to the control side, and the skin on the treated side showed the above mentioned changes before and after the treatment as well. The mean pain score of the subjects was obtained by VAS score 3.67 ± 0.90. Adverse effects included mild edema, erythema, and microscopic crusting; no long-term adverse effects were seen in all patients. The efficacy of FRF treatment was evaluated 1 month after the final treatment, and 85% of the subjects rated it as satisfactory, very satisfactory, and very satisfactory. FRF for the treatment of erythematous capillary dilatation rosacea is effective, safe, and suitable for clinical promotion.

"Effect Of Electroacupuncture On Sensory Peripheral Nerve Function In Diabetic Peripheral Neuropathy: A Randomized Controlled Trial Protocol."

Background: Diabetes, a chronic metabolic disorder, affects millions globally, with Type 2 diabetes being the most prevalent. Diabetic Peripheral Neuropathy (DPN) is a common complication, characterized by symptoms such as pain, tingling, and numbness due to peripheral nerve damage. The global burden of diabetes has been rising, particularly in low- and middle-income countries. In India, the number of diabetes cases is projected to reach over 134 million by 2045. Traditional treatments for DPN often have limited efficacy and adverse longterm effects, highlighting the need for alternative therapies. Objective: This study aims to investigate the efficacy of electroacupuncture in improving sensory nerve functions in patients with DPN. Specific acupuncture points will be targeted to assess their impact on vibration perception, hot and cold perception, touch sensitivity, and skin temperature. Methods: A randomized controlled trial will be conducted with 80 participants divided equally into an interventional group and a control group. The interventional group will receive electroacupuncture at specific points (ST44, ST36, ST43, K2, K3, BL60, SP9, and GB41) three times a week for 8 weeks. The control group will continue their usual routine and receive the treatment post-study. Primary outcomes will be measured using the NEURO TOUCH instrument to assess sensory thresholds and skin temperature. Secondary outcomes will include pain assessment using the Visual Analog Scale (VAS). Data will be analyzed using SPSS version 16. Results: The study will evaluate the degree of sensory improvement in peripheral nerves and the effectiveness of electroacupuncture in reducing neuropathic pain. This research seeks to bridge the gap in understanding the mechanisms and efficacy of electroacupuncture in DPN treatment. Conclusion: This study will provide significant insights into the potential benefits of electroacupuncture for DPN, offering an alternative approach to improve the management of this debilitating condition. The findings could inform future clinical practices and guidelines for DPN treatment

"Effect Of Electroacupuncture On Sensory Peripheral Nerve Function In Diabetic Peripheral Neuropathy: A Randomized Controlled Trial Protocol."

Background: Diabetes, a chronic metabolic disorder, affects millions globally, with Type 2 diabetes being the most prevalent. Diabetic Peripheral Neuropathy (DPN) is a common complication, characterized by symptoms such as pain, tingling, and numbness due to peripheral nerve damage. The global burden of diabetes has been rising, particularly in low- and middle-income countries. In India, the number of diabetes cases is projected to reach over 134 million by 2045. Traditional treatments for DPN often have limited efficacy and adverse longterm effects, highlighting the need for alternative therapies. Objective: This study aims to investigate the efficacy of electroacupuncture in improving sensory nerve functions in patients with DPN. Specific acupuncture points will be targeted to assess their impact on vibration perception, hot and cold perception, touch sensitivity, and skin temperature. Methods: A randomized controlled trial will be conducted with 80 participants divided equally into an interventional group and a control group. The interventional group will receive electroacupuncture at specific points (ST44, ST36, ST43, K2, K3, BL60, SP9, and GB41) three times a week for 8 weeks. The control group will continue their usual routine and receive the treatment post-study. Primary outcomes will be measured using the NEURO TOUCH instrument to assess sensory thresholds and skin temperature. Secondary outcomes will include pain assessment using the Visual Analog Scale (VAS). Data will be analyzed using SPSS version 16. Results: The study will evaluate the degree of sensory improvement in peripheral nerves and the effectiveness of electroacupuncture in reducing neuropathic pain. This research seeks to bridge the gap in understanding the mechanisms and efficacy of electroacupuncture in DPN treatment. Conclusion: This study will provide significant insights into the potential benefits of electroacupuncture for DPN, offering an alternative approach to improve the management of this debilitating condition. The findings could inform future clinical practices and guidelines for DPN treatment.

Sex-specific alterations in pulmonary metabolic, xenobiotic and lipid signalling pathways after e-cigarette aerosol exposure during adolescence in mice

BackgroundE-cigarette use is now prevalent among adolescents and young adults, raising concerns over potential adverse long-term health effects. Although it is hypothesised that e-cigarettes promote inflammation, studies have yielded conflicting...

Enhanced Recovery After Surgery (ERAS) cardiac turnkey order set for perioperative pain management in cardiac surgery: Proceedings from the American Association for Thoracic Surgery (AATS) ERAS Conclave 2023

ObjectiveOptimal perioperative pain management is an essential component of perioperative care for the cardiac surgical patient. This turnkey order set is part of a series created by the Enhanced Recovery After Surgery Cardiac Society, first presented at the Annual Meeting of The American Association for Thoracic Surgery in 2023. Several guidelines and expert consensus documents have been published to provide guidance on pain management and opioid reduction in cardiac surgery. Our objective is to consolidate that guidance into an evidence-based order set that will assist in the implementation of a comprehensive multimodal approach to pain management. MethodsSubject matter experts were consulted to translate existing guidelines and peer-reviewed literature into a sample turnkey order set for pain management. Orders derived from consistent Class I, IIA, or equivalent recommendations across referenced guidelines and consensus manuscripts appear in the order set in bold type. Selected orders that were inconsistently Class I or IIA, Class IIB, or supported by published evidence, were also included in italicized type. ResultsOpioid-based analgesia is associated with delayed recovery and opioid-related adverse events. Several multimodal medications have been shown to reduce reliance upon opioids. These include the scheduled use of acetaminophen, gabapentinoids, and nonsteroidal anti-inflammatory drugs. In addition, intravenous analgesics such as dexmedetomidine, ketamine, magnesium, and lidocaine have been shown to both complement the maintenance of anesthesia as well as optimize pain control postoperatively. Long-acting opioids remain a key component of pain management when provided to reduce the overall use of short-acting synthetic opioids or in direct response to break though pain after exhausting other alternatives. When applied in a bundled fashion, several studies have demonstrated a reduction in overall opioid administration and improved rates of postoperative recovery. ConclusionsThere has been increased awareness regarding the potential short- and long-term adverse effects of both inadequate analgesia and excessive opioid administration after cardiac surgery. This turnkey order set aims to facilitate implementation of a comprehensive approach toward provision of multimodal, opioid-sparing medications to optimize pain management in cardiac surgery.

The long-term effect of childhood left-behind experiences on entrepreneurial activities in adulthood: Empirical evidence from China

Although the issue of left-behind children has received academic attention, little is known about the potential long-term effect. This study was conducted in China, aiming to explore the impact of left-behind experiences in childhood on entrepreneurial activities in adulthood. The study design was quantitative and we used secondary data with samples from the China Labor-force Dynamic Survey. To mitigate potential endogeneity problems, we adopted the conditional mixed process approach with instrumental variable. The empirical results show that left-behind experiences decreased the likelihood of adulthood entrepreneurship, which is supported by some robustness tests. This negative impact can be partially explained by disadvantages in human capital and social networks as well as risk aversion. Moreover, we found that the exogenous shocks from hukou transfer and WTO accession weaken the negative impact of left-behind experiences and lack of entrepreneurship can further explain the income penalization effect of left-behind experiences. Our study provides new evidence for the life course theory and reveals the long-term adverse effects of left-behind experiences in childhood. Also, we shed light on safeguarding the welfare of left-behind children and young people with left-behind experiences.

Fetal exposure to toxic metals (mercury, cadmium, lead, and arsenic) via intrauterine blood transfusions.

Intrauterine blood transfusions (IUBTs) are critical for treating fetal anemia but may expose fetuses to toxic metals. This study assessed mercury (Hg), cadmium (Cd), lead (Pb), and arsenic (As) levels in red blood cell (RBC) transfusion bags used during pregnancy, examined metal exposure in maternal and cord blood, and evaluated fetal health risks. Thirty pregnant women who underwent intrauterine blood IUBTs were enrolled in this study. Metal concentrations were measured in one to nine transfusion bags for each participant. These bags contained 8-103 mL volumes and were administered between gestational weeks 18 and 35. We also tested the mothers' blood for metal levels in the final stages of pregnancy and the umbilical cord blood at birth. The assessment utilized the intravenous reference dose (IVRfD) and the hazard index (HI) to evaluate the non-carcinogenic health risks these metals might pose to the fetus. Metals were detectable in almost all transfusion bags. The IVRfD was exceeded for Hg in 16 fetuses, Cd in 8 fetuses, Pb in 30 fetuses, and As in 1 fetus. Significant correlations were found between the concentrations of Hg, Cd, and As in transfused RBCs and cord blood. No correlations were observed between these concentrations and maternal blood levels, except for Cd. The influence of multiple IUBTs was positively associated only with Cd levels in the cord (ß = 0.529, 95% confidence intervals (CI) between 0.180 and 0.879). The HI exceeded 1, indicating significant health risks, predominantly from Pb, followed by Hg and Cd. The findings of this study highlight the significant risk of fetal exposure to toxic metals, mainly Pb, through IUBTs. This underscores the critical need for prescreening blood donors for toxic metals to minimize the potential for long-term adverse effects on the fetus. The research stresses the necessity of balancing the immediate benefits of IUBTs against the risks of toxic metal exposure, underscoring the importance of safeguarding fetal health through improved screening practices. This study highlights the risk of toxic metal exposure through IUBTs, a treatment for fetal anemia. Hg, Cd, Pb, and As levels were measured in transfusion bags and linked to fetal exposure through maternal and umbilical cord blood analysis. The HI indicates significant Pb exposure risks, underscoring the need for mandatory blood donor screening. Recommendations include shifting toward safer practices in managing fetal anemia to protect fetal health.

Comparative Analysis of Nutritional Advice and a Combined Approach for Addressing Impending Stunting in Infants: A Clinical Trial.

Weight faltering (WF) has been associated with stunting and with long-term adverse consequences for health and development. Nutritional care for managing WF may consist of giving nutritional advice (NA) and/or provision of oral nutrition supplements (ONSs). In this study, we aimed to evaluate practical management options in the community for infants with WF aged 6-12 months. This nonrandomized clinical trial was conducted in the community of Makassar, South Sulawesi, from March 2022 to March 2023. A total of 1013 infants were enrolled for screening. Anthropometric measures were performed in 913 infants, of which 170 showed WF below the 15th percentile of the WHO weight increment table without stunting. Infants with a weight increment below P5th were assigned to receive NA plus ONS, while infants between P5th and below P15th were assigned to receive only NA. At the second and third months, ONSs were administered to WF infants who were below P15th. One month after the intervention, 87/105 infants in the NA-plus-ONS group (82.8%) and 52/65 infants in the NA-only group (80%) were no longer WF. After 3 months, infants in the NA-plus-ONS group achieved greater weight gain than infants in the NA group (264.1 g vs. 137.4 g, p < 0.001) as well as greater length gain (2.35 cm vs. 2.14 cm, p < 0.001). WF management should be started at below P15th to achieve a better result. Infants with greater nutritional deficits should be assigned to receive the combination of NA plus ONSs to achieve a higher rate of resolution of growth.

Impact of antenatal corticosteroids on subcortical volumes in preterm infants at term-equivalent age: A retrospective observational study

ObjectiveAntenatal corticosteroids (ACS) is a well-established treatment for women at risk of preterm birth that improves neonatal outcomes. However, several concerns have been raised regarding the potential long-term adverse effects of ACS on the offspring’s developing brain. Here we investigated the association between ACS and subcortical segmental volumes in preterm infants at term-equivalent age. Study designThis retrospective observational study was conducted using the clinical data of preterm singleton infants born between 220/7 and 336/7 gestational weeks at Nagoya University Hospital in 2014–2020. Subcortical volumes of the bilateral thalami, caudate nuclei, putamens, pallidums, hippocampi, amygdalae, and nuclei accumbens were evaluated using an automated segmentation tool, Infant FreeSurfer, and compared between neonates exposed to a single course of ACS (n = 46) and those who were not (n = 13) by multiple linear regression analysis (covariates: postmenstrual age at magnetic resonance imaging, infant sex, and gestational age at birth). We compared each subcortical volume stratified by gestational age at birth (<28 vs. ≥28 gestational weeks). ResultsMultivariate analyses revealed significantly smaller volumes in the bilateral amygdalae (left, p < 0.03; right, p < 0.03) and caudate nuclei (left, p < 0.03; right, p = 0.04) in neonates with ACS. Significantly smaller volumes in these regions were observed only in neonates born at 28 weeks of gestation or later. ConclusionsACS was associated with smaller volumes of the bilateral amygdalae and caudate nuclei at term-equivalent age. This association was observed exclusively in infants born at 28 weeks of gestation or later.

Exchange rate movements and trade balance in developing economies: Evidence of symmetry and country-specific asymmetries

The impact of exchange rate (ER) movements on the trade balance has been extensively debated in the literature, with conflicting views on the nature and magnitude of this effect. This paper investigates the relationship between ER movements and trade balance in developing economies, with a specific focus on bilateral analysis involving Pakistan. Employing the Nonlinear Autoregressive Distributed Lag (NARDL) model, our results reveal a symmetric relationship between positive and negative ER changes and the trade balance, showing significant long-term and short-term effects across the panel of developing economies. However, country-specific asymmetries are observed, especially in the cases of India and China, and are more pronounced in each bilateral analysis, whether in the short run or long run. The study findings highlight the critical importance of maintaining a stable exchange rate policy, which can provide policymakers with precise insights into the money market and the broader economy while preventing high volatility and continuous depreciation of domestic currencies. Such measures can mitigate the long-term adverse effects of ER movements on trade agreements. The study offers valuable insights for policymakers and investors in developing economies, aiding them in making informed decisions about exchange rate policies.

Exercise-Induced Cardiac Troponin I Elevation Is Associated With Regional Alterations in Left Ventricular Strain in High-Troponin Responders.

The implications of exercise-induced cardiac troponin elevation in healthy individuals are unclear. This study aimed to determine if individuals with a high exercise-induced cardiac troponin I (cTnI) response have alterations in myocardial function following high-intensity endurance exercise compared with normal-cTnI responders. Study individuals were recruited from previous participants in a 91-km mountain bike cycling race (the North Sea Race) and were classified as high- (n=34) or normal-cTnI responders (n=25) based on maximal cTnI values after the recruitment race. The present study exposed all participants to 2 prolonged high-intensity exercises: a combined lactate threshold and cardiopulmonary exercise test and repeated participation in the North Sea Race. Echocardiography was performed before, immediately after, and 24 hours following exercise. All study individuals (n=59) had normal coronary arteries, and were aged 51±10 years; 46 (74%) were men. There were no differences in baseline characteristics between the high- and normal-cTnI responders. Maximal cTnI levels 3 hours after exercise were significantly higher in the high- compared with normal-cTnI group (P<0.001-0.027). Following exercise, there were no differences in global ventricular function between the 2 groups. In contrast, high-cTnI responders had significantly lower regional strain in the anteroseptal segments following exercise, with more profound changes after the race. High-cTnI responders had lower anteroseptal segmental strain shortly after exercise than normal-cTnI responders. However, there were no permanent alterations in myocardial strain, indicating no short- or long-term adverse consequences of these exercise-induced alterations in myocardial function. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02166216.

Neonatal overfeeding promotes anxiety, impairs episodic-like memory, and disrupts transcriptional regulation of hippocampal steroidogenic enzymes

The objective of our study was to investigate the impact of neonatal overfeeding on cognitive functions and neurosteroidogenesis in male rats. Offspring were assigned to either small litters (SL; 4 pups/mother), resulting in increased milk intake and body weight gain, or normal litters (NL; 10 pups/mother). On postnatal day (PND) 21, half of the male rats were euthanized, while the remaining were kept under standard conditions (4 rats/cage) until PND70. At this stage, subjects underwent assessments for locomotor activity, anxiety levels via the elevated plus maze, and episodic-like memory (ELM) tests. By PND90, the rats were euthanized for brain dissection. Utilizing micropunch techniques, dentate gyrus (DG), CA1, and CA3 regions were extracted for analysis of mRNA expression and methylation patterns. At PND21, SL rats exhibited increased body and adipose tissue weights, alongside elevated cholesterol, glucose, and triglyceride levels compared to NL counterparts. By PND90, although metabolic disparities were no longer evident, SL rats demonstrated heightened anxiety-like behavior and diminished performance in ELM tests. Early life changes included a decreased expression of aromatase (P450arom) and 3α-HSD in CA1, with increased levels in CA3 and DG among SL rats. Additionally, PND90 rats from SL exhibited increased P450arom and decreased 5α-reductase 1 (5αR-1) expression in DG. Notably, some of these variations were correlated with changes in methylation patterns of their promoter regions. Our findings reveal that neonatal overfeeding exerts a long-term adverse effect on cognitive abilities and neurosteroidogenic pathways, underscoring the lasting impact of nutritional experiences during critical early postnatal development periods.

Clinical Effects of Glucagon-Like Peptide-1 Agonist Use for Weight Loss in Women With Polycystic Ovary Syndrome: A Scoping Review.

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal regulatory hormone that stimulates insulin release from the pancreas. While GLP-1 receptor agonists (GLP-1 RAs) have traditionally been utilized to address insulin resistance, their potential application in treating polycystic ovary syndrome (PCOS) has recently garnered attention. This study aimed to investigate the therapeutic efficacy of GLP-1 RAs use for weight loss in women diagnosed with PCOS. We conducted a scoping review following the Joanna Briggs Institute (JBI) methodology and adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our investigation delved into the clinical effects experienced by women of diverse racial and ethnic backgrounds with PCOS who were prescribed GLP-1 RAs for weight loss. Peer-reviewed articles from Ovid Medline, Web of Science, CINAHL, Cochrane CENTRAL, SCOPUS, and ClinicalTrials.gov spanning from 2012 to 2023 were scrutinized. After eliminating duplicates, 811 articles were identified, and ultimately, eight met the eligibility criteria for inclusion. All studies were published in English and exhibited wide geographic diversity. The included studies uniformly reported reductions in weight and body mass index (BMI) among patients who were prescribed GLP-1 RAs, specifically liraglutide or exenatide. Additionally, evidence pointed towards improvements in anthropometric parameters (MF1) (including total body weight, BMI, reduction in waist circumference, and total fat percentage), glucose homeostasis, cardiovascular inflammatory markers (midregional pro-atrial natriuretic peptide (MR-proANP) and mid-regional pro-adrenomedullin (MR-proADM)), rates of pregnancy, and menstrual regulation. However, findings regarding the impact of GLP-1 RAs on lipid profiles were inconsistent. Although some short-term adverse effects were noted, long-term effects of GLP-1 RAs use remain undetermined. GLP-1 RA use demonstrated promising clinical outcomes for women with PCOS, including reduced BMI, improved metabolic parameters, menstrual regularity, and increased rates of natural pregnancy. While the current evidence is encouraging, further research is warranted to elucidate both short- and long-term adverse effects of GLP-1 RAtherapy for PCOS.

Long-term experience with biohybrid cochlear implants in human neurosensory restoration

Objective The implantation of biohybrid electrodes was introduced a few years ago in our clinic. These electrodes coated with autologous mononuclear cells releasing anti-inflammatory and neuroprotective factors are thought to reduce insertion trauma and maintain the vitality of surviving spiral ganglion neurons. The clinical feasibility of this approach has already been demonstrated. In the present retrospective study, the four-year results of the two sides (classical electrode and biohybrid electrode) in the bilaterally implanted patients were compared in order to investigate possible adverse long-term effects. Methods All patients received a complete audiological diagnosis which also included a speech audiogram and impedance measurement. The measurements were carried out 1 month, 3 months, 6 months, 1 year, 2 years, 3 years and 4 years after implantation. The hearing results were assessed by pure tone audiometry. Results All patients showed satisfactory speech understanding and similar impedances on both sides although they had a long-term deafness before implantation of the side provided with a biohybrid electrode array. The results of speech understanding and impedance measurements were stable for years. Cone beam computed tomography was performed in 4 patients three years after implantation and could rule out cochlear ossification. Other complications were also not registered in any of the patients. Conclusion Due to satisfactory outcomes and lack of complications, the biohybrid electrode is considered to be a safe option in cochlear implantation. The simplicity of application of autologous cells as a source of anti-inflammatory and neuroprotective factors via a biohybrid electrode array is a key step for cell-based, regenerative therapies for deafness.

Are We Overlooking Harms of BDDE-Cross-Linked Dermal Fillers? A Scoping Review.

1,4-Butanediol ether (BDDE) is widely used as a cross-linker for hyaluronic acid in dermal fillers. The purpose of this scoping review was to determine the state of knowledge about the behaviour of cross-linked substances and safety of BDDE application. The rationale behind the review came from the clinical experience of one of the authors (KS), who noticed adverse reactions after BDDE-linked hyaluronan application. The scoping review was conducted according to PRISMA-ScR guidelines. Out of 399 articles, 52 met the inclusion criteria. Data on study design, sample/population, aims, methodology, outcomes and funding were extracted. Results were charted according to 6 subtopics: rheological properties, hydrogel stability, BDDE toxicity, immunogenicity, tissue interactions and clinical studies. In vitro, cross-linked hydrogels were characterized as effective fillers in terms of viscosity and elasticity; however, previously uncharacterized by-products of the cross-linking reaction were found. Most in vivo studies reported increased dermis regeneration, vascularization and anti-inflammatory cytokine release after implantation of BDDE-cross-linked substances. In clinical studies, BDDE was shown to sensitize subjects to 1,6-hexanediol ether and other substances found in epoxy resin systems. Occupational dermatitis and hypersensitivity reactions were documented. Our review shows that BDDE may have long-term adverse effects, which are overlooked in the safety assessment of fillers. Reviews on BDDE conducted so far have mostly been sponsored by the industry, potentially leading to incomplete reporting of adverse effects. A review of the occurrence of allergic reactions after commercial dermal filler use and analysis of possibly harmful by-products of BDDE hyaluronan degradation are needed.Level of Evidence III This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .