Significant Functional Deterioration Research Articles

Impact of CFTR modulatory therapies on liver function and fibrosis indices in cystic fibrosis patients: a retrospective analysis from two Romanian medical centers

Background. Patients with cystic fibrosis (CF) frequently require modulatory therapies such as Lumacaftor/Ivacaftor (LI) and Elexacaftor/Tezacaftor/Ivacaftor (ETI) to manage their condition. Given the potential hepatic complications associated with CF, it is critical to understand the impact of these therapies on liver function and fibrosis indices. This study aimed to evaluate the changes in liver function markers and fibrosis indices in CF patients undergoing LI and ETI therapies, with a specific focus on the influence of underlying hepatic disease. Methods. In this retrospective analysis, liver function markers and fibrosis indices were assessed in CF patients receiving ETI (n=24), LI (n=4), or a combination of both (LI/ETI, n=8). Key liver function markers, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, platelet count, and fibrosis indices (APRI and FIB-4), were measured at baseline and at various time points up to 12 months. Results. In patients receiving LI therapy, ALT and AST levels demonstrated a slight but non-significant decrease over six months, accompanied by significant fluctuations in total bilirubin levels. Among those receiving ETI therapy, ALT and AST levels initially increased but stabilized over time, while total bilirubin levels significantly increased from baseline to 12 months. No significant differences were observed in liver function markers between patients with and without hepatic disease under ETI therapy. Trends in fibrosis indices (APRI and FIB-4) were modest and largely non-significant across both therapies. Conclusions. ETI therapy appears to be safe for CF patients, including those with pre-existing hepatic disease, with no significant deterioration in liver function over a 12-month period. However, the observed fluctuations in bilirubin levels underscore the necessity for ongoing monitoring. Further research is warranted to investigate the long-term hepatic effects of LI and ETI therapies.

Effect of Sport Activity on Uncomplicated Bicuspid Aortic Valve: Long-Term Longitudinal Echocardiographic Study.

The bicuspid aortic valve (BAV) is a congenital heart defect that can lead to certain complications (aortic stenosis, regurgitation, dilatation and endocarditis), the diagnosis and clinical monitoring of which are effectively entrusted to transthoracic echocardiography (TTE). The impact of training on the natural history of the disease remains unclear. A retrospective cohort of athletes with uncomplicated BAV aged 18-50 years, who underwent at least 2 TTEs with a minimum follow-up of 5 years, subdivided according to the level of physical activity during follow-up into ''untrained'' and ''trained'', was collected. 47 athletes (87.3% male, median 21.0, (18.0; 33.0) years) were included. Median follow-up was 11.6 (8.4; 16.3) years. No statistically significant difference in the growing rate of aorta, left ventricle, nor a significant worsening of aortic stenosis and regurgitation was found. Moreover, there was no significant correlation between weekly training minutes during follow-up and the echocardiographic parameters related to heart size and function. In BAV without major complications, high training volumes do not correspond to a more rapid and significant deterioration in valve function nor to a more rapid increase in aortic or cardiac chamber size.

Prognostic performance of Krebs von den Lungen-6, surfactant protein A, surfactant protein D levels in the serum and bronchoalveolar lavage fluid in chronic fibrosing interstitial pneumonia: a retrospective study

BackgroundThe serum markers Krebs von den Lungen-6 (KL-6), surfactant protein A (SP-A), and surfactant protein D (SP-D) have been used for the diagnosis, differential diagnosis, and prognosis prediction of interstitial pneumonia. However, the significance of measuring the serum and bronchoalveolar lavage fluid (BALF) KL-6, SP-D, and SP-A levels in predicting the prognosis of chronic fibrosing interstitial pneumonia (CFIP), idiopathic pulmonary fibrosis, and idiopathic nonspecific interstitial pneumonia remains unclear. We aimed to clarify the significance of measuring the serum and BALF KL-6, SP-A, and SP-D levels in predicting the prognosis of patients with CFIP.MethodsAmong 173 patients who were diagnosed with CFIP between September 2008 and February 2021, 39 who underwent bronchoalveolar lavage were included in this study. Among these, patients experiencing an annual decrease in forced vital capacity (FVC) of ≥10% or those facing challenges in undergoing follow-up pulmonary function tests owing to significant deterioration in pulmonary function were categorized as the rapidly progress group. Conversely, individuals with an annual decrease in the FVC of <10% were classified into the slowly progress group. The serum and BALF KL-6, SP-D, and SP-A levels, as well as BALF/serum SP-D and SP-A ratios were compared between the two groups.ResultsAmong the patients with CFIP, the BALF SP-D level (p=0.0111), BALF SP-A level (p<0.0010), BALF/serum SP-D ratio (p=0.0051), and BALF/serum SP-A ratio (p<0.0010) were significantly lower in the rapidly than in the slowly progress group (p<0.0010). The receiver operating characteristics analysis results demonstrated excellent performance for diagnosing patients with CFIP, with the BALF SP-D level (area under the curve [AUC], 0.7424), BALF SP-A level (AUC, 0.8842), BALF/serum SP-D ratio (AUC, 0.7673), and BALF/serum SP-A ratio (AUC, 0.8556). Moreover, the BALF SP-A level showed a notably superior CFIP diagnostic capability. Survival analysis using the Kaplan–Meier method revealed that patients with a BALF SP-A level of <1500 ng/mL and BALF/serum SP-A ratio of <15.0 had poor prognoses.ConclusionsOur results suggest that BALF SP-A measurement may be useful for predicting the prognosis in patients with CFIP.

Traditional Chinese Medicine Monomers Are Potential Candidate Drugs for Cancer-Induced Cardiac Cachexia.

Cardiovascular diseases are now the second leading cause of death among cancer patients. Heart injury in patients with terminal cancer can lead to significant deterioration of left ventricular morphology and function. This specific heart condition is known as cancer-induced cardiac cachexia (CICC) and is characterized by cardiac dysfunction and wasting. However, an effective pharmacological treatment for CICC remains elusive. The development and progression of CICC are closely related to pathophysiological processes, such as protein degradation, oxidative responses, and inflammation. Traditional Chinese medicine (TCM) monomers offer unique advantages in reversing heart injury, which is the end-stage manifestation of CICC except the regular treatment. This review outlines significant findings related to the impact of eleven TCM monomers, namely Astragaloside IV, Ginsenosides Rb1, Notoginsenoside R1, Salidroside, Tanshinone II A, Astragalus polysaccharides, Salvianolate, Salvianolic acids A and B, and Ginkgolide A and B, on improving heart injury. These TCM monomers are potential therapeutic agents for CICC, each with specific mechanisms that could potentially reverse the pathological processes associated with CICC. Advanced drug delivery strategies, such as nano-delivery systems and exosome-delivery systems, are discussed as targeted administration options for the therapy of CICC. This review summarizes the pathological mechanisms of CICC and explores the pharmacological treatment of TCM monomers that promote anti-inflammation, antioxidation, and pro-survival. It also considers pharmaceutical strategies for administering TCM monomers, highlighting their potential as therapies for CICC.

Determining the Time Points for the Development of Early and Advanced Stages of Diabetic Cardiomyopathy in Streptozotocin-Induced Type 1 Diabetes Mellitus Rat Model

The characteristics of early and advanced stages of diabetic cardiomyopathy (DCM) are well-understood; however, the time points by which these stages are developed in animal models vary and depend on the hyperglycaemic status and duration of diabetes. This study was aimed to determine the time points for the development of early and advanced stages of DCM from the induction of type 1 diabetes mellitus by identifying the functional and histological changes that occurred. Type 1 diabetes was induced via streptozotocin injection, and rats were divided into 4-week and 8-week diabetic groups. A group of non-diabetic rats served as the normal control. Cardiac functions and structural changes were analysed. Results showed that after four weeks, all diabetic rats displayed early DCM characteristics, including pronounced left ventricular diastolic dysfunction and cardiomyocyte hypertrophy (P &lt; 0.05) compared to the normal control. After eight weeks, there was a significant deterioration in both left ventricular systolic and diastolic function compared to the normal control, along with marked cardiomyocyte hypertrophy and myocardial fibrosis (P &lt; 0.05), signifying the development of advanced DCM. In summary, this findings revealed the development of early and advanced stages of DCM at four weeks and eight weeks of diabetes respectively in diabetes melitus type 1 rat model.

The functional and psychological impact of delayed hip and knee arthroplasty: a systematic review and meta-analysis of 89,996 patients

This systematic review and meta-analysis aimed to determine the impact of presurgical waiting times on pre-/post-operative joint specific pain and function, health-related quality of life (HRQOL) and perspectives of patients awaiting primary elective total hip (THR) and knee (TKR) replacements. MEDLINE, EMBASE, PUBMED, and CENTRAL databases were searched from inception until 30th January 2023 (CRD42022288128). Secondary literature and unpublished datasets containing paediatric, non-elective, partial, or revision replacement populations were excluded. PRISMA 2020 reporting and GRADE certainty of evidence guidelines were followed. Residual maximum likelihood meta-analysis and linear meta-regression was performed to elucidate the influence of presurgical waiting time. Twenty-six studies were eligible for systematic review and sixteen for meta-analysis, capturing 89,996 patients (60.6% female, mean age 67.4 years) between 2001 and 2022. A significant deterioration in joint function (mean difference (MD):0.0575%; 95% CI 0.0064, 0.1086; p = 0.028(4d.p.); I2 = 73.1%) and HRQOL (MD: 0.05%; 95% CI − 0.0001.0009; p = 0.011(4 d.p.); I2 = 80.6%) was identified per additional day of waiting. Despite qualitative evidence, meta-analysis could not observe a relationship with postoperative outcome data. Patient responses to delayed THR and TKR surgery were unanimously negative. Immediate action should seek to reduce the increased patient anxiety and significant reductions in pre-operative joint functionality and HRQOL associated with prolonged pre-surgical waiting time, whilst mitigating any potential deleterious post-operative effects.

Evaluating the effects of hypoxic storage on platelet function and health using a novel storage system.

Thousands of units of whole blood (WB) and blood components are transfused daily to treat trauma patients. Improved methods for blood storage are critical to support trauma-related care. The Hemanext ONE® system offers a unique method for hypoxic storage of WB, with successfully demonstrated storage of clinically viable RBCs. This work evaluated the system for the storage of WB, focusing on platelet health and function. WB was collected from healthy donors and processed through the Hemanext ONE® system. Hemoglobin oxygen saturation (HbSO2) levels of WB were depleted to 10%, 20%, or 30% of total HbSO2 and then stored in PVC bags sealed in oxygen-impermeable bags (except for normoxic control) with samples collected on days 1, 7, and 14 post-processing. Flow cytometry assessed the activation and apoptosis of platelets. Clot dynamics were assessed based on aggregometry and thromboelastography assays, as well as thrombin generation using a calibrated-automated thrombogram method. Hypoxic storage conditions were maintained throughout the storage period. Hypoxia triggered increased lactate production, but pH changes were negligible compared to normoxic control. Storage at 10% HbSO2 had a significant impact on platelet function, resulting in increased activation and reduced clot formation and aggregation. These effects were less significant at 20% and 30% HbSO2. This study indicates that platelets are sensitive to hypoxic storage and suffer significant metabolic and functional deterioration when stored at or below 10% HbSO2.

Open Reduction and Transosseous Plasty of the Dorsal Scapholunate Ligament in a Patient with Mayfield type IV Chronic Lunate Dislocation, Case Report, Literature Review and Description of Surgical Technique

Introduction Perilunate dislocations represent 3% of carpal injuries. They begin in a radial direction, destabilizing the scapholunate interval, and as the injury continues, there is a progressive sequence of instability, altering the anatomy of the carpus, causing significant functional deterioration. The acute diagnosis goes unnoticed, evolving into its chronic form. There are few reports of treatment in its chronic phase with a limited number of patients and follow-up evaluation is often limited. Objective We present a case of late diagnosis of chronic lunate dislocation that was managed surgically and review of the existing literature for diagnosis and treatment, as well as the surgical technique for its resolution. Clinical case 66-year-old male, fall from the plane of support, hyperextension mechanism of the right wrist, 2 months of evolution causing pain, progressive increase in volume, functional limitation. Treated with non-steroidal anti-inflammatory drugs for four weeks without improvement. Radiographically, loss of lunate joint congruity - capitate. Magnetic resonance images of avascular necrosis of the lunate. Diagnosing chronic semilunar dislocation of the right hand. Preoperative Quick-Dash 70.4 pts. A double dorsal and volar approach is performed to release the carpal tunnel, place a transosseous cerclage, and three 1.6 mm Kirschner pins in the scapholunate interval; semilunopyramidal and scaphocapitate. Immobilization with antebrachipalmar splint, removal of Kirschner pins at 7 weeks and referral to physical rehabilitation. 20 postoperative weeks, range of motion with flexion of 35° and extension of 30°, without visible sequelae to mobilization, and with Quick-Dash 20.4. Conclusion Early diagnosis and treatment are necessary to prevent the potential risk of avascular necrosis of the lunate and scaphoid, and secondary osteoarthritis. Reconstruction of the chronic pathology of lunate dislocation and scapholunate ligament (SL) remains a major challenge. There are unresolved issues regarding when to perform reconstruction rather than repair and therefore treatment remains controversial.

The use of muscle ultrasound to detect critical illness myopathy in patients with sepsis: an observational cohort study

BackgroundCritical illness myopathy (CIM) has negative impact on patient outcomes. We aimed to explore the diagnostic value of bedside ultrasonography for early identification of CIM in septic patients and its correlation with other diagnostic methods. This prospective observational study included 40 ICU patients diagnosed with sepsis on admission or within 48 h later according to the third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). They were evaluated using muscle ultrasound, electrodiagnostic and clinical muscle assessment (Medical Research Council, MRC) at two time points, the first was between days 2 and 5 and the second was between days 10 and 15.ResultsThere was significant deterioration of neuromuscular function between the two evaluation points demonstrated by decline in MRC, abnormal nerve conduction and electromyography (EMG) and increased muscle echogenicity on ultrasonography (P ≤ 0.001). Sepsis-Related Organ Failure Assessment (SOFA) score significantly correlated with different neuromuscular assessment tools. MRC had significant correlation with myopathic EMG (P ≤ 0.001, r = − 0.869) and increased muscle echogenicity (P ≤ 0.001, r = − 0.715). Abnormal ultrasonographic muscle architecture had sensitivity of 100%, specificity of 75% and positive likelihood ratio of 4 in detecting muscle dysfunction compared to myopathic EMG.ConclusionsBedside peripheral muscle ultrasound echogenicity grade could be used as an additional screening test in ICU septic patients for early detection of CIM.

Slovenia's national HIV PrEP programme: Evaluation of real-world implementation.

The aim of our study was to evaluate real-world implementation of Slovenia's national HIV PrEP programme, which is fully covered by our national health insurance. In retrospective cohort study we analysed the data from all men who have sex with men (MSM) who were enrolled in PrEP programme of our clinic between 1 January 2022 and 31 December 2022. A total of 190 MSM with an average age of 36.7years were included in our analysis. 151 (79.5%) decided for event-driven PrEP and 39 (20.5%) opted for daily PrEP. Self-reported adherence was 95%. Among eligibility criteria, unprotected sex was the most common one, followed by one or more STIs in the past, use of chemsex and use of HIV post-exposure prophylaxis in the past. No new cases of HIV infection and no significant deterioration of kidney or liver function were observed during the follow-up. Sixty-seven episodes of STIs were diagnosed and treated. Gonorrhea (32), chlamydia (14), and Mpox (10) were the most common ones. PrEP was successfully implemented into everyday clinical practice, proving to be both safe and effective. High number of diagnosed STIs suggests that the PrEP programme, combined with STI screening and vaccination, provides a strong public health impact among MSM in Slovenia.

Detection of Bronchiolitis Obliterans Syndrome Using Nitrogen Multiple Breath Washout in Children Posthemopoietic Stem Cell Transplant

Bronchiolitis obliterans syndrome (BOS) is a severe complication following hemopoietic stem cell transplantation (HSCT) and is often undetected until there is significant deterioration in pulmonary function. Lung clearance index (LCI2.5) derived from the nitrogen multiple breath washout (N2MBW) test may be more feasible and sensitive than spirometry, which is currently used for surveillance and detection of BOS. We aimed to examine the feasibility of performing surveillance N2MBW in children post-HSCT, and in an exploratory analysis, determine if LCI2.5 led to earlier detection of BOS when compared to spirometric indices. Participants aged 5 to 17 years were recruited prior to receiving HSCT into a prospective, single-center, feasibility study at the Royal Children's Hospital, Melbourne. N2MBW and spirometry were performed within the month prior to transplant and repeated at 3, 6, 9, and 12 months post-transplant. Data were also collected on the presence of graft-versus-host (GVHD) disease in any organ, including the lungs. Twenty-one (12 male) children with a mean age of 13.4 (range 9.2 to 17.1) years at recruitment participated in this study. Prior to HSCT, all participants had normal LCI2.5, while 16 (76%) demonstrated normal forced expiratory volume in 1 second (FEV1). Ninety-nine percent of N2MBW tests were technically acceptable, compared with 66% of spirometry tests. Three participants developed BOS, while 2 participants died of other respiratory complications. At 6 and 12 months post-transplant, the BOS group had increases in LCI2.5 ranging from 3 to 5 units and mean reductions in FEV1 % predicted of 40% to 53% relative to pre HSCT values, respectively. In those who developed BOS, post-HSCT LCI2.5 values were significantly worse when compared with the no BOS group (P < .001). Relative changes in LCI2.5 and FEV1 were both predictive of BOS at 6 months post HSCT. This study demonstrates that N2MBW is a more feasible test compared with spirometry in children post HSCT. However, in an exploratory analysis, LCI2.5 did not lead to earlier detection of BOS, when compared to spirometry.

Psychological Health in Late Effects of Poliomyelitis: Ten-Year Follow-Up.

Individuals with late effects of poliomyelitis (LEoP) cope with various physical and psychological symptoms throughout their entire life which become more severe as they are ageing. To perform a 10-year follow-up of the functional status and levels of psychological health of individuals with LEoP and to examine the associations of hope levels, work status, health perceptions, and life satisfaction with functional and psychological changes. A within-subject 10-year follow-up study. Eighty-two individuals with LEoP who participated in a previous study 10 years ago. Outcome measures included the functional status of individuals with LEoP assessed by the activities of daily living (ADL) questionnaire, emotional distress based on the Global Health Questionnaire (GHQ), hope based on the Hope Scale, life satisfaction as measured by the Satisfaction with Life Scale (SWLS), and subjective health perception. The McNemar test, paired t-test, Spearman's correlation coefficient, and linear regression were used for statistical analysis. The mean age was 66.9 ± 8.5 years with a male-female ratio of 0.52. A significant functional deterioration was noticed during the follow-up years. Yet, the functional deterioration was not associated with changes in psychological health. Psychological health was associated with elevated levels of hope and life satisfaction. Individuals with LEoP who continued to work demonstrated higher psychological health, higher levels of hope, and greater life satisfaction. Individuals with LEoP demonstrated significant psychological health, manifested in their ability to block emotional distress and maintain life satisfaction despite the deterioration in their functional status. Hope and psychological health were associated with increased life satisfaction. Work appeared to be a significant source of psychological health in this population.

Cardiac remodeling, amyloidosis, neurotrophic signaling and innervation impairment in the Tg2576 model of Alzheimer’s disease

AbstractBackgroundIn Alzheimer’s disease (AD), the characteristic cerebral amyloid β (Aβ) accumulation and tau pathology, are accompanied by a gradual loss of the two main neuromodulators, NGF and BDNF. This AD‐mediated derangement of the brain’s neuro‐signaling pathways may extend to the periphery and, along with potential peripheral amyloid deposition, induce peripheral nervous system impairment, thus affecting other organs, including the heart. However, whether and how AD pathology affects cardiac physiology, neurotrophins, innervation, and heart amyloidosis is still undefined.MethodHere, we describe for the first‐time that cardiac remodeling and neuro‐signaling dysregulation are present in the hearts of Tg2576 mice, a widely used model of AD and cerebral amyloidosis.ResultsEchocardiographic analysis showed significant deterioration of left ventricle function, as demonstrated by a decline of both ejection fraction and fraction shortening in 12‐month‐old Tg2576 mice compared to age‐matched WT littermates. The transgenic mice hearts presented an increase in interstitial fibrosis, with an accumulation of amyloid aggregates, including Aβ, associated with severe cardiac nervous system dysfunction. Tg2576 mice exhibited a depletion in cardiac nerve fiber density, both adrenergic (stained with tyrosine hydroxylase‐ TH) and regenerating nerve terminals (labeled with GAP‐43) compared to the WT mice. This myocardial denervation was accompanied by a decline in NGF and BDNF protein expression as well as GAP‐43 expression in both the brain and heart of Tg2576 mice. Likewise, both human neuroblastoma cells (SH‐SY5Y) and human cardiomyocytes (AC16) challenged with human Aβ‐40 or Aβ‐42 oligomers showed significant downregulation of both BDNF and GAP‐43 activity.ConclusionOverall, this study highlights the deleterious impact of cerebral amyloidosis on the cardiac nervous system and heart physiology, providing potential therapeutic targets, such as neurotrophic factors, to prevent or limit the AD‐mediated degenerative mechanisms on the cardiovascular system.

Endocardial pacing compared to epicardial left ventricle pacing and right ventricle pacing: A single-center long-term experience in a pediatric population

Background and aimsPediatric pacing is usually performed as epicardial pacing in small children in need of pacemaker therapy. Epicardial pacing compared with transvenous pacing for pediatric complete atrioventricular block (CAVB) has different strengths and weaknesses. The epicardial left ventricular wall position of the lead has been considered superior, in terms of contraction pattern, compared to a transvenous right ventricular stimulation. We aimed to compare QRS duration and cardiac function before and after the switch from epicardial to transvenous pacing in a pediatric population. MethodsPediatric patients with congenital or acquired CAVB, who underwent a switch from epicardial-to transvenous pacing at our center from 2005 to 2021, were identified through the national ICD- and Pacemaker Registry. Data regarding clinical status, ECG, and echocardiography before and after the switch and at last follow-up were collected. ResultsWe included 15 children. The median age at the switch was 6.7 (4.4–11.7) years with a median weight of 21 (15–39) Kg. The median QRS duration with the transvenous systems was 136 (128–152) ms vs. a QRS duration during epicardial stimulation of 150 (144–170) ms with a median difference in QRS duration of 14 (6–20) ms. Children with a post-surgical AV block had a broader QRS duration, both with epicardial and endocardial stimulation. Before the switch, there was one patient with impaired left ventricular function (LVF) but with normal left ventricular end-diastolic diameters. After the switch, one patient developed symptomatic LV dysfunction with the recovery of LVF at the last follow-up after being implanted with a cardiac resynchronization therapy device. ConclusionsOur report of pediatric patients after switching from epicardial to transvenous pacing shows how transvenous pacing is not inferior to epicardial pacing in terms of QRS duration and no significant deterioration of cardiac function was detectable.

Echocardiographic function evaluation in adolescents following BNT162b2 Pfizer-BioNTech mRNA vaccination: A preliminary prospective study.

Vaccination against coronavirus disease 2019 (COVID-19) is crucial for preventing and minimizing illness. Myocarditis and pericarditis after messenger RNA (mRNA) COVID-19 vaccination in adolescents and young adult males have been reported. Most of the studies in this area rely on retrospective symptom reporting, especially for adolescents experiencing myocarditis as a potential side effect. However, prospective postvaccination echocardiographic evaluation is rare. The study enrolled adolescents aged 12 to 15 years who received the second dose of the BNT162b2 Pfizer-BioNTech mRNA (BNT) vaccine. Serial echocardiographic examinations were conducted at baseline before vaccination, followed by subsequent assessments on days 2, 7, 14, and 28 to identify any notable differences or abnormal changes in cardiac function. Clinical symptom assessments were also recorded during each follow-up. The study included 25 adolescents, comprising 14 males and 11 females, who completed the four follow-ups. Their mean age was 14 ± 1 years. The average interval between the first and second BNT vaccine doses was 90 ± 7 days. Ejection fraction values were 73.8% ± 5.2% at baseline, followed by 75.7% ± 5.3%, 75.5% ± 4.6%, 75.7% ± 4.5%, and 77.8% ± 5.8% at day 2, 7, 14, and 28, respectively. The cardiac function remained stable across all time points, with no significant differences observed between male and female participants. Within postvaccination 48 hours, 18 (72%) of the enrolled adolescents experienced temporary discomfort symptoms, which completely resolved by the final follow-up on the 28th day after vaccination. Although adolescents vaccinated with the second dose of BNT vaccine commonly experienced transient postvaccination discomfort, the serial echocardiographic examinations did not reveal any significant deterioration of cardiac function within 28 days. Further studies are required to investigate the incidence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA vaccination-associated myocarditis in adolescents and the related mechanisms.

Identification of key lipid metabolism-related genes in Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) represents profound degenerative conditions of the brain that cause significant deterioration in memory and cognitive function. Despite extensive research on the significant contribution of lipid metabolism to AD progression, the precise mechanisms remain incompletely understood. Hence, this study aimed to identify key differentially expressed lipid metabolism-related genes (DELMRGs) in AD progression.MethodsComprehensive analyses were performed to determine key DELMRGs in AD compared to controls in GSE122063 dataset from Gene Expression Omnibus. Additionally, the ssGSEA algorithm was utilized for estimating immune cell levels. Subsequently, correlations between key DELMRGs and each immune cell were calculated specifically in AD samples. The key DELMRGs expression levels were validated via two external datasets. Furthermore, gene set enrichment analysis (GSEA) was utilized for deriving associated pathways of key DELMRGs. Additionally, miRNA-TF regulatory networks of the key DELMRGs were constructed using the miRDB, NetworkAnalyst 3.0, and Cytoscape software. Finally, based on key DELMRGs, AD samples were further segmented into two subclusters via consensus clustering, and immune cell patterns and pathway differences between the two subclusters were examined.ResultsSeventy up-regulated and 100 down-regulated DELMRGs were identified. Subsequently, three key DELMRGs (DLD, PLPP2, and PLAAT4) were determined utilizing three algorithms [(i) LASSO, (ii) SVM-RFE, and (iii) random forest]. Specifically, PLPP2 and PLAAT4 were up-regulated, while DLD exhibited downregulation in AD cerebral cortex tissue. This was validated in two separate external datasets (GSE132903 and GSE33000). The AD group exhibited significantly altered immune cell composition compared to controls. In addition, GSEA identified various pathways commonly associated with three key DELMRGs. Moreover, the regulatory network of miRNA-TF for key DELMRGs was established. Finally, significant differences in immune cell levels and several pathways were identified between the two subclusters.ConclusionThis study identified DLD, PLPP2, and PLAAT4 as key DELMRGs in AD progression, providing novel insights for AD prevention/treatment.

Comparing the Incidence of Propranolol and Esmolol-Related Cardiac Arrest in Patients With Thyroid Storm: A Systematic Literature Review.

A precarious complication of thyrotoxicosis, or thyroid storm, is the increased risk of cardiomyopathy, which leads to circulatory collapse and cardiopulmonary arrest. It is crucial to promptly identify this condition to prevent significant deterioration of the left ventricular function and cardiogenic shock. This article seeks to examine published research that emphasizes the connection between thyroid storm and beta-blocker usage in relation to cardiogenic collapse and provides management recommendations. The search was performed on September 9, 2022, using PubMed, Science Direct, and Google Scholar libraries. A systematic exploration was carried out using the keywords Thyroid Storm AND cardiogenic Shock AND cardiac arrest AND beta blocker. The use of beta blockers as part of thyroid storm management was linked to the development of cardiogenic collapse and cardiac arrest. Ultra-short-acting beta-blockers like esmolol were a safer option than propranolol in treating patients with a thyrotoxic storm.

Kidney urinary biomarkers in patients with branched-chain amino acid and cobalamin metabolism defects.

There is a clinical need for early detection of chronic kidney disease (CKD) in patients with organic acidurias. We measured kidney markers in a longitudinal study over 5 years in 40 patients with methylmalonic aciduria (Mut0 ), propionic aciduria (PA), cobalamin A (CblA), and cobalamin C (CblC) deficiencies. Neutrophil gelatinase-associated lipocalin (NGAL), calprotectin (CLP), kidney injury molecule-1 (KIM-1), dickkopf-3 (DKK-3), albumin and beta-2-microglobulin (B2MG) in urine, as well as cystatin C (CysC) in serum were quantified. In Mut0 patients, mean concentrations of B2MG, KIM-1, and DKK-3 were elevated compared with healthy controls, all markers indicative of proximal tubule damage. In PA patients, mean B2MG, albumin, and CLP were elevated, indicating signs of proximal tubule and glomerulus damage and inflammation. In CblC patients, mean B2MG, NGAL, and CLP were increased, and considered as markers for proximal and distal tubule damage and inflammation. B2MG, was elevated in all three diseases, and correlated with DKK-3 in Mut0 /CblA and with eGFR(CysC) and KIM-1 in PA patients, respectively. None of the markers were elevated in CblA patients. Significant deterioration of kidney function, as determined by steady increase in CysC concentrations was noted in seven patients within the observation period. None of the investigated biomarker profiles showed a clear increase or added value for early detection. In conclusion, we identified disease-specific biomarker profiles for inflammation, tubular, and proximal damage in the urine of Mut0 , PA, and CblC patients. Whether these biomarkers can be used for early detection of CKD requires further investigation, as significant kidney function deterioration was observed in only a few patients.

Abstract P2013: Cardiac Remodeling, Amyloidosis, Neurotrophic Signaling, And Innervation Impairment In The Tg2576 Model Of Alzheimer's Disease

Background: In Alzheimer's disease (AD), the characteristic cerebral amyloid β (Aβ) deposition and tau pathology are accompanied by a progressive loss of the two main neuromodulators, NGF and BDNF. This AD-mediated derangement of the brain's neuro-signaling pathway may extend to the periphery and, along with potential peripheral amyloid deposition, induce peripheral nervous system impairment, thus affecting other organs, including the heart. However, whether and how AD pathology affects cardiac physiology, neurotrophins, innervation, and heart amyloidosis is still unclear. Method: Here, we describe for the first time that cardiac remodeling and neuro-signaling dysregulation are present in the hearts of Tg2576 mice, a widely used model of AD and cerebral amyloidosis. Results: Echocardiographic analysis showed significant deterioration of left ventricle function, as demonstrated by a decline of both ejection fraction and fraction shortening in 12-month-old Tg2576 mice compared to age-matched WT littermates. The transgenic mice hearts displayed an increase in interstitial fibrosis, with an accumulation of amyloid aggregates, including Aβ, associated with severe cardiac nervous system dysfunction. Tg2576 mice exhibited a depletion in cardiac nerve fiber density, both adrenergic (stained with tyrosine hydroxylase- TH) and regenerating nerve terminals (labeled with GAP-43), compared to the WT mice. This myocardial denervation was accompanied by a decline in NGF and BDNF protein expression as well as GAP-43 expression in both the brain and heart of Tg2576 mice. Likewise, human neuroblastoma cells (SH-SY5Y) and human cardiomyocytes (AC16) challenged with human Aβ-40 or, Aβ-42 oligomers showed significant downregulation of both BDNF and GAP-43 activity. Conclusion: Overall, this study highlights the harmful impact of cerebral amyloidosis on the cardiac nervous system and heart physiology, providing potential therapeutic targets, such as neurotrophic factors, to prevent or limit AD-mediated degenerative mechanisms in the cardiovascular system.

Kisspeptin regulates airway hyperresponsiveness and remodeling in a mouse model of asthma.

Asthma is a multifactorial disease of origin characterized by airway hyperresponsiveness (AHR) and airway remodeling. Several pieces of evidence from other pathologies suggest that Kisspeptins (Kp) regulate cell proliferation, migration, and invasion, mechanisms that are highly relevant to asthma. Our recent in vitro studies show Kp-10 (active peptide of Kp), via its receptor, KISS1R, inhibits human airway smooth muscle cell proliferation. Here, we hypothesize a crucial role for Kp-10 in regulating AHR and airway remodeling in vivo. Utilizing C57BL/6J mice, we assessed the effect of chronic intranasal Kp-10 exposure on mixed allergen (MA)-induced mouse model of asthma. MA-challenged mice showed significant deterioration of lung function compared to those exposed to vehicle (DPBS); Kp-10 treatment significantly improved the MA-altered lung functions. Mice treated with Kp-10 alone did not show any notable changes in lung functions. MA-exposed mice showed a significant reduction in KISS1R expression as compared to vehicle alone. MA-challenged mice showed significant alterations in immune cell infiltration in the airways and remodeling changes. Proinflammatory cytokines were significantly increased upon MA exposure, an effect abrogated by Kp-10 treatment. Furthermore, biochemical and histological studies showed Kp-10 exposure significantly reduced MA-induced smooth muscle mass and soluble collagen in the lung. Overall, our findings highlight the effect of chronic Kp-10 exposure in regulating MA-induced AHR and remodeling. © 2023 The Pathological Society of Great Britain and Ireland.