Impaired Function Research Articles

The additional impact of metabolic syndrome on left ventricular deformation and myocardial energetic efficiency impairment in ischemia with nonobstructive coronary arteries patients

BackgroundIschemia with nonobstructive coronary arteries (INOCA) has high morbidity, mortality, and poor quality of life. Metabolic syndrome (MetS) is a complex of multiple cardiac metabolic risk factors, significantly increasing the risk of major adverse cardiovascular events in INOCA patients. The study aimed to investigate the aggravating effect of MetS on left ventricular (LV) deformation and function impairment in INOCA patients.Materials and methods This study collected 104 INOCA patients (INOCA [MetS−]: n = 56; INOCA [MetS+]: n = 48) and 41 sex- and age-matched controls. LV function, indexed myocardial energetic efficiency (MEEI), and LV global peak strains (including radial, circumferential, and longitudinal directions) were measured among the three groups. The independent factors of reduced MEEI and impaired LV function and strain parameters for all INOCA patients were assessed using multivariable linear regression analyses.ResultsIn contrast to the INOCA (MetS-) group, the indexed LV stroke volume (LVSVI) (49.57 ± 11.58 mL/m2 vs. 42.58 ± 12.23 mL/m2, p = 0.007), MEEI [0.85(0.70–1.03) ml/s/g vs. 0.75(0.54–0.91) ml/s/g, p = 0.045] and LV global longitudinal peak strain (GLPS) (− 13.26 ± 2.86% vs. -10.95 ± 3.93%, p = 0.001) reduced in the INOCA (MetS+) group. Compared with the controls, LV GLPS decreased in the INOCA (MetS-) group (− 15.14 ± 2.83% vs. −13.26 ± 2.86%, p = 0.017). MetS was negatively associated with LVSVI, MEEI, and LV GLPS (all p < 0.05). After multivariable adjustment, MetS was found to be an independent factor of decreased LVSVI (β = −0.231, p = 0.012), MEEI (β = −0.262, p = 0.009), and LV GLPS (β = −0.266, p = 0.002) in INOCA patients. Using calcium channel blockers medication (β = 0.320, p = 0.001) and hypertension (β = −0.298, p = 0.002) were also independently associated with impaired MEEI.ConclusionsMetS aggravated LV deformation and function impairment in patients with INOCA. MetS was found to be an independent factor of impaired MEEI and LV GLPS, the further decrease of MEEI and LV GLPS in INOCA patients caused by MetS might involve the synergistic injury mechanism. Early diagnosis and treatment of MetS in patients with INOCA are important.

Early developmental trajectories of the impaired hand in infants with unilateral cerebral palsy.

To identify developmental trajectories of impaired hand function in infants aged 3 to 15 months with unilateral cerebral palsy (CP). Sixty-three infants (37 male; median gestational age 37 weeks [interquartile range 30-39.1 weeks]) recruited as part of a randomized trial with a confirmed diagnosis of unilateral CP were included. All infants received early upper limb therapy. The Hand Assessment for Infants (HAI) was completed at baseline and until 12 to 15 months corrected age. Group-based trajectory modelling identified groups with similar trajectories of development of impaired hand function. Multinomial logistic regression determined associations between demographic variables and trajectory membership. The three-group trajectory model comprised 'low' 29%, 'moderate' 35%, and 'high' 36% functioning groups. The relative risk ratio of being in the low or moderate relative to high group increased by 16% (95% confidence interval [CI] 1.02-1.32) and 14% (95% CI 1.01-1.29) respectively for each 1 week increase in gestational age. Males were more likely to be in the low relative to high group (relative risk ratio 7.22; 95% CI 1.6-32.5). Three distinct trajectories of development of the impaired hand were identified. Males and infants born closer to term age were at higher risk of being in a low group with little improvement over time, despite receiving early intervention.

Molecular mechanism of osteoclast differentiation of PBMC in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune condition that causes severe joint deformities and impaired functionality, affecting the well-being and daily life of individuals. Consequently, there is a pressing demand for identifying viable therapeutic targets for treating RA. This study aimed to explore the molecular mechanisms of osteoclast differentiation in PBMC from patients with RA through transcriptome sequencing and bioinformatics analysis. Blood samples were collected from 20 patients with RA, including 15 females and 5 males. Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation. Osteoclast differentiation was induced using a medium containing RANKL and M-CSF for 14 days, with medium changes every 2 days. After 14 days, osteoclasts were identified by TRAP staining, and multinucleated TRAP-positive cells were counted as osteoclasts. Subsequently, transcriptome sequencing was performed using the Illumina Novaseq 6000 platform, and differential expression analysis was conducted using the DESeq2 package in R. Differentially expressed genes were selected with a significance threshold of p < 0.05 and a fold change ≥ 2 (|Log2FC|≥ 1). Bioinformatics analysis was performed using R, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. TRAP staining showed successful induction of PBMCs into osteoclasts. Transcriptome sequencing revealed a significant number of differentially expressed genes (DEGs) in the induced groups compared with the control group. GO analysis showed that these DEGs were predominantly associated with biological processes related to the transmission of chemokine signals, reactions to living organisms, and bolstering neutrophil-driven defense mechanisms. KEGG analysis showed that these DEGs were enriched by primary signaling pathways, including interactions between cytokines and their receptors, chemokine signaling pathway, cell cycle regulation, neutrophil extracellular trap formation, and TNF signaling pathway. Osteoclast differentiation of PBMC from patients with RA involves various gene alterations, multiple biological processes, and signaling pathways, providing insight into the potential mechanism of PBMC osteoclast differentiation in RA. Key Points • A total of 1841 DEGs were obtained between the induced group and the normal group. • These DEGs were involved in multiple biological processes and signaling pathways.

Altered immune surveillance of B and T cells in patients with persistent residual lung abnormalities 12 months after severe COVID-19

BackgroundPost-COVID-19 respiratory sequelae often involve lung damage, which is called residual lung abnormalities, and potentially lead to chronic respiratory issues. The adaptive immune response, involving T-cells and B-cells, plays a critical role in pathogen control, inflammation, and tissue repair. However, the link between immune dysregulation and the development of residual lung abnormalities remains unclear.Methods109 patients discharged with residual lung abnormalities after a critical COVID-19 were followed for 12 months and divided as full recovery patients (FRG, n = 88) and persistent lung abnormalities (PLAG, n = 21). Cell profiling analysis was done using flow cytometry at 24 h of not antigen-specific in vitro stimulation. Plasma or supernatant levels of IFN-g, IL-4, IL-10, IgM, and IgG were assessed, and 10 patients (5 FRG, 5 PLAG) were randomly selected for detailed immune cell phenotyping and functional analysis of peripheral blood mononuclear cells using flow cytometry.ResultsCompared to the FRG group, PLAG exhibited an increase of unswitched (p = 0.0159) and decreased double-negative activated B-cells (p = 0.0317), systemic IL-10 levels were lower, displayed reduced frequency of total B-cells, and impaired spontaneous IgM (p = 0.0357) and IgG (p = 0.0079) release in culture. Regarding T-cells, PLAG patients showed a reduction in effector memory CD4 + cells (p = 0.0159) and an increase in CD4 + TEMRA cells (p = 0.0079) following in vitro stimulation. Notably, the PLAG group also exhibited higher frequencies of central memory CD4 + Th2 (GATA3+) T-cells in response to activation than the FRG group (p = 0.0079).ConclusionsPatients with residual lung abnormalities 12 months post-critical COVID-19 exhibit impaired B-cell function, increased unswitched B-cells, and higher frequencies of CD4 + TEMRA T-cells following in vitro activation. These immune imbalances may contribute to ongoing lung dysfunction and warrant further investigation as a potential mechanism in residual lung abnormalities. Larger studies are necessary to confirm these findings.

Validation of the role of apolipoproteins in coronary artery disease patients with impaired kidney function for prognosis: a prospective cohort study in China

ObjectiveThis study aims to evaluate the relationship between apolipoproteins (ApoA1, ApoB, and the ApoB/A1 ratio) and the incidence of major adverse cardiovascular events (MACE) in patients with coronary artery disease (CAD) and impaired kidney function, assessing their potential role in secondary prevention.MethodA prospective cohort of 1,640 patients with impaired kidney function who underwent percutaneous coronary intervention in China was analyzed. Patients were categorized based on the measurements of ApoA1, ApoB, and ApoB/A1 ratio. MACE, defined as a composite of all-cause mortality, cardiovascular death, nonfatal myocardial infarctions, strokes, and unplanned revascularizations, was tracked post-procedure, with statistical analyses including Kaplan–Meier survival curves and Cox regression models to identify associations with apolipoproteins. Subgroup analyses according to kidney function were conducted.ResultDuring a median follow-up of 3.1 years, 324 MACE events were observed. Multivariable Cox regression analyses illustrated higher levels of ApoB and the ApoB/A1 ratio were significantly associated with increased MACE incidence (adjusted HR [95%CI] 1.668[1.044–2.666]; adjusted HR [95%CI] 2.231[1.409–3.533], respectively), while lower ApoA1 levels correlated with a higher risk (adjusted HR [95%CI] 0.505[0.326–0.782]). ROC curve analyses indicated comparable predictive performances to traditional risk factors like LDL cholesterol. Subgroup analysis revealed that the above association was not statistically significant in the moderate-to-severe renal impairment CAD patients (eGFR < 45 mL/min/1.73 m2).ConclusionOur findings illustrate that apolipoproteins, specifically ApoA1 and ApoB, along with their ratio, are significant predictors of major adverse cardiovascular events in CAD patients with impaired kidney function. These results emphasize the need for incorporating apolipoprotein measurements in secondary prevention strategies for this high-risk population.

The safety and feasibility of transcranial direct current stimulation and exercise therapy for the treatment of cervicogenic headaches: A randomized pilot trial.

Our primary objective was to evaluate the safety and feasibility of transcranial direct current stimulation combined with exercise therapy for the treatment of cervicogenic headache. Our exploratory objectives compared symptoms of headache, mood, pain, and quality of life between active and sham transcranial direct stimulation combined with exercise therapy. Cervicogenic headache arises from injury to the cervical spine or degenerative diseases impacting cervical spine structure resulting in pain, reduced quality of life, and impaired function. Current standard-of-care treatments such as radiofrequency ablation, pharmacotherapy, manual therapy, and exercise therapy lack efficacy for some patients. Transcranial direct current stimulation is a neuromodulation technique that has shown promise in treating chronic pain conditions by positively altering neuronal activity but has not been evaluated as treatment for cervicogenic headache. This double-blind, sham-controlled, randomized, feasibility trial recruited 32 participants between the ages of 18 and 65 years that met the International Classification of Headache Disorders third edition criteria for cervicogenic headache. Participants were randomized to receive either active or sham transcranial direct current stimulation both combined with daily exercise therapy over 6 weeks. Transcranial direct current stimulation was applied over the primary motor cortex ipsilateral to worse pain for 20 min at 2 mA with a 30 s ramp up/down period. Recruitment, retention, and adherence were evaluated for feasibility. Safety was assessed through serious and minor adverse events and an adverse effect questionnaire. Clinical outcome measures assessed headache, pain, quality of life, and mood symptoms at pre-treatment, post-treatment, and 6- and 12-weeks post-treatment. A total of 97 participants were contacted to participate with 32 recruited, 16 randomized into each group, and 14 completing the treatment protocol in both groups. Within each group 12 (active) and nine (sham) completed treatment within the proposed 6 weeks (three sessions per week), others received 18 sessions but took longer. Exercise therapy was completed on an average of 87% of days for both groups. Transcranial direct current stimulation was safe, with no serious adverse events and one minor adverse event in the active group. Itching was a more common post-intervention complaint in the active group (64% active vs. 43% sham). Exploratory analysis revealed significant group × time interactions for average headache pain from pre- to post-treatment (β = -1.012, 95% confidence interval [CI] -1.751 to -0.273; p = 0.008), 6-weeks (β = -1.370, 95% CI -2.109 to -0.631; p < 0.001), and 12-weeks (β = -1.842, 95% CI -2.600 to -1.085; p < 0.001) post-treatment, and for neck pain from pre- to post-treatment (β = -1.184, 95% CI -2.076 to -0.292; p = 0.010) and 12-weeks (β = -1.029, 95% CI -1.944 to -0.114; p = 0.028) post-treatment favoring active vs. sham. There were no significant group × time interactions for quality of life or mood. The combination of transcranial direct stimulation and exercise therapy is safe and feasible for treating cervicogenic headache. While some promise has been shown for reducing headache and neck pain, larger scale trials with adequate power are needed to confirm these findings.

Cannabis vaping elicits transcriptomic and metabolomic changes in inflammatory, oxidative stress and cancer pathways in human bronchial epithelial cells.

The increasing shift from cannabis smoking to cannabis vaping is largely driven by the perception that vaping to form an aerosol represents a safer alternative to smoking and is a form of consumption appealing to youth. Herein, we compared the chemical composition and receptor-mediated activity of cannabis smoke extract (CaSE) to cannabis vaping extract (CaVE) along with the biological response in human bronchial epithelial cells. Chemical analysis using HPLC and GC/MS revealed that cannabis vaping aerosol contained fewer toxicants than smoke; CaSE and CaVE contained teratogens, carcinogens, and respiratory toxicants. A bioluminescence resonance energy transfer (BRET)-based biosensor detected the receptor-mediated activity of the extracts, primarily driven by Δ9-THC concentration. RNA- sequencing showed both CaSE and CaVE induced similar transcriptional responses, significantly upregulating genes within pathways related to inflammation, cancer, and cellular stress. This was paralleled by downregulation of pathways related to lipid synthesis and metabolism similarly from both CaSE and CaVE. Targeted metabolomics revealed significant changes in metabolites involved in lipid and membrane metabolism, energy production, nucleotide/DNA/RNA pathways, and oxidative stress response, suggesting potential impairment of lung epithelial cell repair and function. Additionally, the upregulation of 5-hydroxymethylcytosine (5hmC) indicates epigenetic changes potentially contributing to inflammation, oxidative stress, and an increased risk of cancer. These findings challenge the notion that cannabis vaping is risk-free, highlighting an urgent need for comprehensive research into its respiratory health effects. This comparison of cannabis consumption methods offers insights that could inform public health policies and raise consumer awareness regarding the potential risks of inhaling cannabis aerosol.

Longitudinal assessment of retinal and visual pathway electrophysiology and structure after high altitude exposure.

High altitude (HA) exposure induces impairments in visual function. This study was designed to dynamically observe visual function after returning to lowland and elucidate the underlying mechanism by examining the structure and function of retina and visual pathway. Twenty-three subjects were recruited before (Test 1), and one week (Test 2) and three months (Test 3) after their return from HA (4300m) where they resided for 30 days. The clock task was used to assess visual cognition; and pattern-reversal visual evoked potential (p-VEP) and full-field electroretinogram (ff-ERG) were employed to record electrophysiological responses of retinal cells; optical coherence tomography (OCT), color doppler imaging (CDI) and magnetic resonance imaging(MRI) were used to measure structures of retina and visual pathway. In Test 2 vs. Test 1, there was increased reaction time during angle task; the amplitudes of scotopic 3.0cd·s/m2 and scotopic 10.0cd·s/m2 ERG a-wave and scotopic 3.0cd·s/m2 oscillatory potential in the right eye were significantly decreased, all of which were negatively correlated with the increased reaction time during the angle task. In Test 3 vs. Test 1, there were decreased amplitude of scotopic 10.0cd·s/m2 a-wave in the right eye and increased velocity of ophthalmic artery and ocular perfusion pressure in bilateral eyes. The VEP and visual pathway structures remained normal throughout the entire test. HA exposure caused damage to rod and cone responses in both outer and inner retina. After returning to sea level, the damaged visual cell functions gradually recovered over time, coinciding with an increase in the ocular perfusion.

Fucoidan Oligosaccharide Supplementation Relieved Kidney Injury and Modulated Intestinal Homeostasis in D-Galactose-Exposed Rats

Background/Objectives: A fucoidan oligosaccharide (FOS), a potent compound derived from algae, is known for its diverse biological activities, including prebiotic activity, anticancer activity, and antioxidative properties, and has demonstrated supportive therapeutic effects in treating kidney ailments. This study was conducted to explore the protective influence of FOS on kidney damage due to aging induced by D-galactose in Sprague Dawley (SD) rats. Methods: The low-dose FOS group was administered FOS (100 mg/kg) by gavage, and the high-FOS group received FOS (200 mg/kg) by gavage. Results: The findings showed that FOS could effectively mitigate kidney damage and improve the pathological condition of kidney tissues caused by D-gal and enhance kidney function. Intervention with FOS significantly reduced serum creatinine, serum uric acid, and serum urea nitrogen levels, compared to the model group. The protective mechanism of FOS on D-gal-induced kidney injury may be to inhibit oxidative stress and improve impaired mitochondrial function by downregulating the AMPK/ULK1 signaling pathway. FOS could also modulate the expression of mitochondrial autophagy-related proteins (Beclin-1, P62, and LC3II/LC3I), thereby mitigate D-gal-induced excessive mitophagy in the kidney. Furthermore, FOS may protect against kidney injury by preserving intestinal homeostasis. FOS decreased serum lipopolysaccharide levels and enhanced intestinal mucosal barrier function. FOS upregulated the abundances of Bacteroidota, Muribaculaceae, and Lactobacillus, while it decreased the abundances of Firmicutes, NK4A136_group, and Lachnospiraceae_NK4A136_group. FOS supplementation modulated gut microbiota composition, increasing beneficial bacteria and reducing detrimental ones, potentially contributing to improved kidney function. Conclusions: FOS may safeguard against renal injury in D-gal-exposed rats by inhibiting kidney excessive mitophagy, preserving mitochondrial function, and regulating intestinal homeostasis.

High Serum S100B Protein Levels as a Risk Factor for Impaired Cognitive Function in Acute Non- Hemorrhagic Stroke: A Literature Review

The incidence of acute non-hemorrhagic stroke disease has a high disability rate and mortality rate and is a serious threat to people’s health and life and can burden families and society. The development of stroke after the onset of acute stroke, especially acute non-hemorrhagic stroke is not uncommon and has become a popular research topic in recent years. Various mechanism can occur, one of which is neuroinflammation. Stroke often leads to lifelong disability, including motor impairment, cognitive impairment, language impairment, and psychological impairment. Serum S100B is a calcium-binding protein that can determine disease severity and predict clinical outcomes to monitor disease progression and response to treatment. It was reported that serum S100B protein levels were detected to be higher in patients with cognitive impairment compared to normal ones. Keywords: Serum S100B protein, cognitive impairment, non-hemorrhagic stroke

Cognitive dysfunction, psychiatric distress, and functional decline after liver transplantation

Impaired cognition in liver recipients has been studied in the immediate post-transplant period but is poorly understood long-term, despite its importance to quality of life. In a single-center cohort of liver recipients transplanted 2010-2022 and &gt;1 years post-transplant, we assessed cognitive performance using a telephone-based battery. We compared depression, anxiety, and self-reported function by cognitive performance using descriptive statistics. Among 120 participants (median age 65, median 7.3 y post-transplant), 25% had below-expectation cognition, 53% at-expectation cognition, and 22% above-expectation. Baseline characteristics were similar between groups. Below-expectation performance was most commonly observed in verbal learning (28%) and verbal memory (22%). Overall, 46% had symptoms of depression (38%) and/or anxiety (28%); anxiety was less common among those with above-expectation cognition (0%) versus below-expectation (34%) or at-expectation cognition (38%, P=0.01). Impaired global daily function was reported by 36% of recipients but was not associated with objective cognitive performance. Below-expectation cognition was prevalent among 25% of liver recipients at least 1 year post-transplant and was associated with higher likelihood of reporting psychiatric distress. These findings underscore the need for longitudinal assessment of cognitive and mental health outcomes among liver transplant recipients.

Kemampuan Bahasa Tulis pada Individu dengan Alzheimer: Kajian Neurolinguistik

Impaired brain function in individual with Alzheimer’s progressively affects to the cognitive and motor functions required to perform written language skills. This study aims to identify and describe the written skill in individual with Alzheimer’s through a case study approach. Data was obtained from a 56 years old elderly whose initials is KA and lives in PPSLU Potroyudan Jepara. Data collection techniques were carried out through documentation, observation, and interviews. Then, KA’s handwriting analysed using writing disorders theory through Neurolinguistic studies. The results showed that there are four forms of disturbance in KA’s written language, those are irregular writing, word omission in long sentences, letter omission, and letter replacement. The findings showed that Allzheimer which causes dysfunction in several parts of the brain also resulted in agraphia and a decrease in the syntactic complexity of writing.

Amauroderma rugosum Extract Improves Brain Function in d‐Galactose‐Induced Aging Mouse Models via the Regulatory Effects of Its Polysaccharides on Oxidation, the mTOR‐Dependent Pathway, and Gut Microbiota

ABSTRACTThe pharmacological effects of Amauroderma rugosum (AR), an edible mushroom found mainly in Southeast Asia, are not well studied, particularly its neuroprotective properties. This study investigated the neuroprotective effects of AR aqueous extract (ARW) in a d‐galactose‐induced accelerated aging mouse model and senescent SH‐SY5Y neuronal cells. Behavioral tests (open field, Morris water maze, Y‐maze, and rotarod) demonstrated that d‐galactose‐induced aging mice exhibited impaired cognitive function, memory loss, anxiety, and reduced locomotor ability, all of which were alleviated by ARW treatment. Histological analysis showed that ARW reduced neuropathological lesions in the hippocampus. In SH‐SY5Y neuronal cells, ARW and AR polysaccharide extract (ARP) enhanced cell viability and decreased intracellular reactive oxygen species (ROS) levels in a concentration‐dependent manner. ARW and ARP also reduced cellular senescence and apoptosis in d‐galactose‐treated cells. Western blot analysis indicated that ARW and ARP upregulated the phosphorylation of mTOR and increased the expression of antioxidant enzymes, including superoxide dismutase 1 and heme‐oxygenase‐1. Additionally, ARW altered the gut microbiota, increasing the relative abundance of beneficial bacteria such as Lactobacillus reuteri and decreasing harmful bacteria like Clostridium scindens. These findings suggest that AR exerts neuroprotective effects primarily through its polysaccharides by modulating oxidative stress, activating the mTOR‐dependent pathway, and influencing the gut microbiota. Consequently, AR could serve as a potential dietary supplement for the prevention and treatment of neurodegenerative diseases.

Effect of the maternal sleep disturbances and obstructive sleep apnea on feto-placental Doppler: A systematic review.

Literature evidenced an association of maternal sleep disturbances and maternal obstructive sleep apnea with significant obstetric complications. Moreover, the maternal sleep disturbances effect on feto-placental circulation had not been extensively examined. Our objective is to explore the possible maternal sleep disturbances impact on the feto-placental indices evaluated through the Doppler study. A systematic review of the following databases was performed: PubMed, EMBASE, Cochrane Library and Google Scholar from the beginning to June 2024. Only studies that enrolled pregnant women with signs and symptoms of maternal sleep disturbances or obstructive sleep apnea diagnosis, which analysed the feto-placental Doppler parameters, were considered eligible (PROSPERO ID: CRD42024553926). We included a total of four studies with 1715 cases of pregnant women. Various instrumental and non-instrumental diagnostic methods were adopted for detection of maternal sleep disturbances. The ultrasound exam was performed mainly in the third trimester of pregnancies, and all the studies explored the uterine Doppler parameters. Only two studies explore the foetal Doppler parameters. Only one study disclosed that maternal sleep disturbances are related to altered uterine Doppler indices with probable placental dysfunction. This review did not evidence a significant influence of maternal sleep disturbances and obstructive sleep apnea on foetal Doppler indices. Moreover, one large prospective study showed a possible impact of maternal sleep disturbances on uterine Doppler with a potential impairment of the placentation function. Additional studies with detailed data and larger samples are needed to throw light on this relationship and its impact on the foetal outcomes.

α-Actinin-1 deficiency in megakaryocytes causes low platelet count, platelet dysfunction, and mitochondrial impairment.

Cytoskeletal remodeling and mitochondrial bioenergetics play important roles in thrombocytopoiesis and platelet function. Recently, α-actinin-1 mutations have been reported in patients with congenital macrothrombocytopenia. However, the role and underlying mechanism of α-actinin-1 in thrombocytopoiesis and platelet function remain elusive. Using MK-specific α-actinin-1 knockout (PF4-Actn1-/-) mice, we demonstrated that PF4-Actn1-/- mice exhibited reduced platelet counts. The decreased platelet number in PF4-Actn1-/- mice was due to defects in thrombocytopoiesis. H&E staining and flow cytometry revealed a decrease in the number of MKs in the bone marrow of PF4-Actn1-/- mice. The absence of α-actinin-1 increased the proportion of 2 N-4 N MKs and decreased the proportion of 8 N-32 N MKs. CFU-MK colony formation, the ratio of proplatelet formation-bearing MKs, and MK migration in response to SDF-1 signaling were inhibited in PF4-Actn1-/- mice. Platelet spreading, clot retraction, aggregation, integrin αIIbβ3 activation, and P-selectin exposure in response to various agonists were decreased in PF4-Actn1-/- platelets. Notably, PF4-Actn1-/- platelets inhibited calcium mobilization, ROS generation, and actin polymerization in response to collagen and thrombin. Furthermore, the PF4-Actn1-/- mice exhibited impaired hemostasis and thrombosis. Mechanistically, proteomic analysis of low-ploidy (2-4 N) and high-ploidy (≥8 N) PF4-Actn1-/- MKs revealed that α-actinin-1 deletion reduced platelet activation and mitochondrial function. PF4-Actn1-/- platelets and Actn1 KO 293T cells exhibited reduced mitochondrial membrane potential, mitoROS generation, mitochondrial calcium mobilization, and mitochondrial bioenergetics. Overall, in this study, we report that mice with α-actinin-1 deficiency in MKs exhibit low platelet count and impaired platelet function, thrombosis, and mitochondrial bioenergetics.

Motor cortical neuronal hyperexcitability associated with α-synuclein aggregation

ΑbstractIn Parkinson’s disease (PD), Lewy pathology deposits in the cerebral cortex, but how the pathology disrupts cortical circuit integrity and function remains poorly understood. To begin to address this question, we injected α-synuclein (αSyn) preformed fibrils (PFFs) into the dorsolateral striatum of mice to seed αSyn pathology in the cortical cortex and induce degeneration of midbrain dopaminergic neurons. We reported that αSyn aggregates accumulate in the motor cortex in a layer- and cell-subtype-specific pattern. Specifically, αSyn aggregates-bearing intratelencephalic neurons (ITNs) showed hyperexcitability, increased input resistance, and decreased cell capacitance, which were associated with impaired HCN channel function. Morphologically, the αSyn aggregates-bearing ITNs showed shrinkage of cell bodies and loss of dendritic spines. Last, we showed that partial dopamine depletion is not sufficient to alter thalamocortical transmission to cortical pyramidal neurons. Our results provide a novel mechanistic understanding of cortical circuit dysfunction in PD.

Su’al-Qinya: Unani Perspective on Iron Deficiency Anemia, its Pathogenesis, and Therapeutic Interventions

Anemia, a pervasive global health concern, affects millions worldwide. This study aims to provide an in-depth examination of anemia from the perspective of Unani medicine, exploring its etiology, pathogenesis, and treatment modalities. A comprehensive review of classical Unani texts and contemporary research reveals that anemia is attributed to alterations in blood composition, impaired liver function, and nutrient deficiencies. Unani practitioners employ a holistic approach, incorporating regimenal therapy, herbal remedies, and lifestyle modifications to address the underlying causes of anemia. This study highlights the significance of integrating Unani principles into modern healthcare practices, providing a complementary approach to addressing anemia and promoting overall well-being. This study aims to explore the Unani perspective on anemia, examining its etiology, pathogenesis, and treatment modalities, and highlighting the potential benefits of integrating Unani principles into modern healthcare practices. This study demonstrates the relevance of Unani medicine in understanding and addressing anemia, emphasizing the importance of a holistic approach to healthcare. By integrating Unani principles into modern healthcare practices, healthcare providers can offer a more comprehensive and patient-centred approach to managing anemia and promoting overall well-being. Keywords: Su’al-Qinya, Faqru-dam, Qillatu-dam, Anemia, Unani medicine, Iron deficiency anemia.

Efficacy and safety of cardiac myosin inhibitors for symptomatic hypertrophic cardiomyopathy: a meta-analysis of randomized controlled trials

IntroductionHypertrophic cardiomyopathy (HCM) is a common genetic heart disorder. It is characterized by left ventricular hypertrophy and impaired cardiac function, with forms categorized into obstructive (oHCM) and nonobstructive (nHCM). Traditional treatments address symptoms but not the underlying disease mechanism, highlighting the need for novel therapies. Cardiac myosin inhibitors such as mavacamten and aficamten present potential new treatment options.MethodsA meta-analysis of randomized controlled trials (RCTs) was conducted following PRISMA guidelines. Studies comparing cardiac myosin inhibitors with placebo were reviewed, and outcomes related to NYHA functional class, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), LVOT gradients, and left ventricular ejection fraction (LVEF) were analyzed.ResultsSix RCTs involving 826 participants demonstrated that mavacamten and aficamten significantly improved NYHA functional class and KCCQ-CSS scores. The incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) was similar between the treatment and control groups, indicating a comparable safety profile.ConclusionCardiac myosin inhibitors are effective in improving cardiac function and reducing LVOT obstruction in HCM patients. They offer a promising alternative to current treatments, with a safety profile comparable to placebo. Further research is needed to confirm long-term benefits.

Difference between estimated glomerular filtration rate based on cystatin C versus creatinine and cardiovascular–kidney–metabolic health

BackgroundThe difference between the estimated glomerular filtration rate (eGFR) calculated from cystatin C and creatinine (eGFRdiff) serves as a biomarker of kidney function impairment. However, the role of eGFRdiff in cardiovascular–kidney–metabolic (CKM) health and its impact on mortality in CKM syndrome patients has not yet been studied.MethodsThis study included 3,622 participants from the National Health and Nutrition Examination Survey (NHANES) conducted between 1999 and 2004. Weighted ordinal logistic regression was used to explore the link between eGFRdiff and CKM health, while weighted Cox regression was used to examine the relationship between eGFRdiff and mortality in CKM syndrome patients. Restricted cubic splines (RCSs) were used to analyze the dose–response relationship.ResultsThe common odds ratio (cOR) per 10 mL/min/1.73m2 increase in eGFRdiff was 0.86 [95% confidence interval (CI), 0.81 to 0.91]. Compared to the midrange eGFRdiff, the cOR values for the negative and positive eGFRdiff were 1.88 [95% CI, 1.23 to 2.88] and 0.69 [95% CI, 0.58 to 0.83], respectively. During a median follow-up of 201 months, 853 participants died from all causes, while 265 died due to cardiovascular causes. The hazard ratios (HRs) per 10 mL/min/1.73m2 increase in eGFRdiff were 0.88 [95% CI, 0.83 to 0.93] for all-cause mortality and 0.90 [95% CI, 0.81 to 1.00] for cardiovascular mortality cases. Compared to the participants with a midrange eGFRdiff, those with negative eGFRdiff had a 48% higher risk of all-cause mortality, while those with positive eGFRdiff had a 30% lower risk. No significant non-linear associations were found in these regression analyses.ConclusionOur study found that eGFRdiff is associated with CKM health and stratified mortality risk in CKM syndrome patients.

Modulating Ferroptosis: A Novel Approach to Promote Neural Repair in Brain Injury.

The increasing prevalence of brain injuries resulting in cognitive and motor function impairments poses a substantial global medical challenge. Nerve repair therapies offer promise for addressing brain injury-related disorders. Ferroptosis, as a cell death mechanism associated with oxidative stress and inflammation. Certain ferroptosis inhibitors, such as iron chelators and antioxidants, exhibit therapeutic potential for brain injury-related conditions. This review explores the fundamental processes and associated mechanisms that regulate neural repair by inhibiting ferroptosis, thereby alleviating brain injury and promoting neuroregeneration. Furthermore, it examines the action mechanisms and potential therapeutic applications of ferroptosis inhibitors in neural repair, aiming to provide novel insights for treating brain injuries.