Impaired Function Research Articles

Unusual patterns of codeswitching in an unbalanced bilingual person with aphasia: effects of language and executive functions impairment

Unusual patterns of codeswitching in an unbalanced bilingual person with aphasia: effects of language and executive functions impairment

Apoptotic vesicles rescue impaired mesenchymal stem cells and their therapeutic capacity for osteoporosis by restoring miR-145a-5p deficiency

Apoptotic vesicles (apoVs) play a vital role in various physiological and pathological conditions. However, we have yet to fully understand their precise biological effects in rescuing impaired mesenchymal stem cells (MSCs). Here, we proved that systemic infusion of MSCs derived from wild-type (WT) mice rather than from ovariectomized (OVX) mice effectively improved the osteopenia phenotype and rescued the impaired recipient MSCs in osteoporotic mice. Meanwhile, apoVs derived from WT MSCs (WT apoVs) instead of OVX apoVs efficiently restored the impaired biological function of OVX MSCs and their ability to improve osteoporosis. Mechanistically, the reduced miR-145a-5p expression hindered the osteogenic differentiation and immunomodulatory capacity of OVX MSCs by affecting the TGF-β/Smad 2/3-Wnt/β-catenin signaling axis, resulting in the development of osteoporosis. WT apoVs directly transferred miR-145a-5p to OVX MSCs, which were then reused to restore their impaired biological functions. The differential expression of miR-145a-5p is responsible for the distinct efficacy between the two types of apoVs. Overall, our findings unveil the remarkable potential of apoVs, as a novel nongenetic engineering approach, in rescuing the biological function and therapeutic capability of MSCs derived from patients. This discovery offers a new avenue for exploring apoVs-based stem cell engineering and expands the application scope of stem cell therapy, contributing to the maintenance of bone homeostasis through a previously unrecognized mechanism.

Clinical characteristics and prognostic factors of pulmonary and extrapulmonary cryptococcosis

BackgroundCryptococcosis is progressively acknowledged among people, irrespective of the human with or without immunodeficiency virus (HIV). This change in epidemiology has been recorded in recent years, prompting closer examination and a broader understanding of the disease manifestations and risk factors.MethodsThe data of cryptococcal infections in China during 11 years were retrospectively analyzed. According to the position of infection, the patients were categorized into the pulmonary infection group and extrapulmonary infection group. The composition of the two groups was compared, and the potential risk factors of disseminated infection were analyzed. Logistic regression was used to analyze the prognostic risk factors of the disease.ResultsA total of 165 patients were enrolled. 113 (68.5%) were male, and the age was 47.49 (18–82) years. 101 cases (61.2%) had a normal immune function and 64 cases (38.8%) had impaired immune function. 45 patients had extrapulmonary infection, involving the central nervous system, bone and joint, skin and bloodstream, and 120 patients had simple pulmonary infection. The mortality of the extrapulmonary infection group (48.9%) was significantly higher than that of the pulmonary infection group (0.8%). According to univariate logistic regression analysis, immune status (hazard ratio [HR], 4.476; 95% confidence interval [CI], 1.725–11.618; P = 0.002), infection position ([HR], 113.826; [CI], 14.607-886.967; P < 0.001), white blood cell count, ([HR],1.209;[CI], 1.054–1.386; P = 0.007), hemoglobin ([HR], 0.970; [CI], 0.955–0.986; P < 0.001), platelet count ([HR], 0.993; [CI], 0.987–0.999; P = 0.026), neutrophil percentage ([HR], 1.115; [CI], 1.065–1.168; P < 0.001), lymphocyte percentage ([HR], 0.875; [CI], 0.827–0.927; P < 0.001), neutrophil-to-lymphocyte Ratio (NLR) ([HR], 1.144; [CI], 1.072–1.221; P < 0.001), monocyte percentage ([HR], 0.752; [CI], 0.618–0.915; P = 0.004) were related to the prognosis. Multivariate logistic regression analysis showed that the infection position was remained related to the prognosis with statistical significance ([HR], 0.018; [CI], 0.001–0.384; P = 0.001).ConclusionExtrapulmonary infection of Cryptococcosis is an important risk factor for prognosis. High levels of neutrophils and NLR, and low levels of lymphocytes and monocytes may lead to disseminated infection of Cryptococcosis. Further studies are needed to reduce the occurrence rate of extrapulmonary infection and mortality.

Multiscale and multimodal evaluation of autosomal dominant polycystic kidney disease development

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most prevalent kidney genetic disorder, producing structural abnormalities and impaired function. This research investigates its evolution on mouse models, utilizing a combination of histology imaging, Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) to evaluate its progression thoroughly. ADPKD has been induced in mice via PKD2 gene knockout, followed by image acquisition at different stages. Histology data provides two-dimensional details, like the cystic area ratio, whereas CT and MRI facilitate three-dimensional temporal monitoring. Our approach allows to quantify the affected tissue at different disease stages through multiple quantitative metrics. A pivotal point is shown at approximately ten weeks after induction, marked by a swift acceleration in disease advancement, and leading to a notable increase in cyst formation. This multimodal strategy augments our comprehension of ADPKD dynamics and suggests the possibility of employing higher-resolution imaging in the future for more accurate volumetric analyses.

Acetylsalicylic acid and dihydroartemisinin combined therapy on experimental malaria-associated acute lung injury: analysis of lung function and the inflammatory process

BackgroundSevere malaria can cause respiratory symptoms, which may lead to malaria-acute lung injury (MA-ALI) due to inflammation and damage to the blood-gas barrier. Patients with severe malaria also often present thrombocytopenia, and the use of acetylsalicylic acid (ASA), a commonly used non-steroidal anti-inflammatory drug with immunomodulatory and antiplatelet effects, may pose a risk in regions where malaria is endemic. Thus, this study aimed to investigate the systemic impact of ASA and dihydroartemisinin (DHA) on ALI induced in mice by Plasmodium berghei NK65 (PbNK65).MethodsC57BL/6 mice were randomly divided into control (C) and PbNK65 infected groups and were inoculated with uninfected or 104 infected erythrocytes, respectively. Then, the animals were treated with DHA (3 mg/kg) or vehicle (DMSO) at the 8-day post-infection (dpi) for 7 days and with ASA (100 mg/kg, single dose), and analyses were performed at 9 or 15 dpi. Lung mechanics were performed, and lungs were collected for oedema evaluation and histological analyses.ResultsPbNK65 infection led to lung oedema, as well as increased lung static elastance (Est, L), resistive (ΔP1, L) and viscoelastic (ΔP2, L) pressures, percentage of mononuclear cells, inflammatory infiltrate, hemorrhage, alveolar oedema, and alveolar thickening septum at 9 dpi. Mice that received DHA or DHA + ASA had an increase in Est, L, and CD36 expression on inflammatory monocytes and higher protein content on bronchoalveolar fluid (BALF). However, only the DHA-treated group presented a percentage of inflammatory monocytes similar to the control group and a decrease in ΔP1, L and ΔP2, L compared to Pb + DMSO. Also, combined treatment with DHA + ASA led to an impairment in diffuse alveolar damage score and lung function at 9 dpi.ConclusionsTherapy with ASA maintained lung morpho-functional impairment triggered by PbNK65 infection, leading to a large influx of inflammatory monocytes to the lung tissue. Based on its deleterious effects in experimental MA-ALI, ASA administration or its treatment maintenance might be carefully reconsidered and further investigated in human malaria cases.

Transdifferentiation of pancreatic cells: therapeutic implications for pancreatic diseases

The pancreas is a unique organ, integrating both exocrine and endocrine functions, playing critical roles in the secretion of digestive enzymes and the production of glucose-regulating hormones. An intriguing phenomenon exists where dynamic intercellular transdifferentiation occurs within the pancreas, particularly pronounced in pancreatic diseases. In diabetic patients, the transdifferentiation of pancreatic islet cells may potentially compensate for impaired pancreatic function. Conversely, abnormal transdifferentiation of exocrine cells may promote the progression of pancreatic cancer. These highlight the plasticity of pancreatic cells in adapting to changes in their microenvironment by regulating their own functions to cope with external pressures. This review summarizes recent researches into the transdifferentiation processes and mechanisms within pancreatic exocrine and endocrine cells, as well as between pancreatic and non-pancreatic cells, providing a new perspective for clinical interventions. The aim of this review is to offer novel insights and propose potential therapeutic strategies to address pancreatic-related diseases, contributing to the advancement of medical research in this field.

Comorbidities, medications, depression, and physical performance measures associated with severe cognitive impairments in community-dwelling adults

Cognitive impairment negatively impacts health, psychological, social, and economic domains. Cognitive impairment commonly affects physical functions in older adults, whereas these are deteriorated. However, the prevalence and associated factors of cognitive impairment among community-dwelling adults in Saudi Arabia have not been investigated yet. This study aimed to examine the prevalence of severe cognitive impairment and its associated factors in community-dwelling older adults in Saudi Arabia. This cross-sectional study involved adults aged ≥50 years. Demographic data and clinical data, including number of medications and body mass index (BMI), were collected. Cognitive impairment and depressive symptoms were measured using Arabic versions of the Montreal Cognitive Assessment (MoCA) and Patient Health Questionnaire-9 (PHQ-9), respectively. The participants were divided into severe cognitive impairment and mild cognitive impairment or normal cognitive function groups based on a score of &lt;20 or ≥20, respectively, using the MoCA. Physical measures included dynamic gait index (DGI) scores, timed up-and-go (TUG), 5 times sit-to-stand (5XSST), functional reach test, and 6-minute walk test. A total of 206 participants (female: n = 96) were included. The prevalence of severe cognitive impairment in the community-dwelling older adults was 12.6%. The number of chronic conditions (odds ratio [OR]: 2.31, p&lt;0.001), number of medications (OR: 1.36, p = 0.003), and depressive symptoms using PHQ-9 (OR: 1.11, p = 0.009) were significantly associated with severe cognitive impairment after adjustment for other covariates, including age, sex, and BMI. Based on the physical function measures, only the scores for DGI (OR: 0.86, p = 0.003), TUG (OR: 1.16, p = 0.035) and 5XSST (OR: 1.25, p &lt;0.001) were significantly associated with severe cognitive impairment. This study revealed a high prevalence of severe cognitive impairment among community-dwelling adults in Saudi Arabia. Its major risk factors include depressive symptoms, number of chronic conditions and medications, and physical measures, including DGI, TUG, and 5XSST.

Human cytomegalovirus infection among febrile hematological cancer patients at the Uganda Cancer Institute

ABSTRACT Hematological cancers, including Leukemias and Lymphomas, and their associated chemotherapy and disease-specific factors, are linked to impaired granulocyte function and numbers, increasing the risk of opportunistic infections, often presenting as fever. Human cytomegalovirus (HCMV) is one of the significant opportunistic infections in these patients, but limited data exists on its seroprevalence and active infection burden among febrile hematological cancer patients in Uganda. We conducted a cross-sectional study from June to August 2017 at the Uganda Cancer Institute (UCI). Blood samples from 161 febrile hematological cancer patients were collected. HCMV exposure was assessed using indirect enzyme-linked immunosorbent assay for IgG and IgM antibodies, and active infection was confirmed with PCR testing and gel electrophoresis. IgG positivity indicated previous exposure, while positive IgM or PCR results indicated active infection. Overall, HCMV seroprevalence based on IgG and/or IgM positivity was 106/161 (66%). IgG alone, IgM alone, and combined IgG/IgM positivity prevalence rates were 57/161 (35.4%), 22/161 (13.6%), and 27/161 (16.7%), respectively. HCMV DNA PCR was positive in 5 of the 161 (3%) samples. Among PCR-positive patients, one (20%) was positive for IgG alone, two (40%) for IgM alone, and two (40%) for both IgG and IgM. Active infection based on positive IgM and HCMV DNA PCR was found in 23 of the 161 (14.3%) patients. Two-thirds of febrile patients with hematological malignancies in Uganda had been exposed to HCMV infection, with 14.3% showing active infection. Routine testing for active HCMV infection among febrile hematological cancer patients at the UCI is essential for timely and appropriate antiviral treatment. IMPORTANCE In this paper, we demonstrated that over two-thirds of feverish patients with blood cancers such as leukemia at the Uganda Cancer Institute are already exposed to a type of virus infection called the human cytomegalovirus (HCMV), and 14% of the patients have active disease due to this virus. This was confirmed through finding blood samples testing positive for a type of protective antibody called IgM and also upon virus DNA detection in the blood of those patients. Routine testing for this virus is not usually done in the study settings. Our findings reveal and emphasize the importance of routinely testing blood samples for active infection with this virus among the feverish patients with blood cancers in the study settings, and prompt initiation of antiviral treatment of the actively infected patients

Current Landscape and Evolving Therapies for Primary Biliary Cholangitis

Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disorder characterized by progressive cholestatic that, if untreated, can progress to liver fibrosis, cirrhosis and liver decompensation requiring liver transplant. Although the pathogenesis of the disease is multifactorial, there is a consensus that individuals with a genetic predisposition develop the disease in the presence of specific environmental triggers. A dysbiosis of intestinal microbiota is increasingly considered among the potential pathogenic factors. Cholangiocytes, the epithelial cells lining the bile ducts, are the main target of a dysregulated immune response, and cholangiocytes senescence has been recognized as a driving mechanism, leading to impaired bile duct function, in disease progression. Bile acids are also recognized as playing an important role, both in disease development and therapy. Thus, while bile acid-based therapies, specifically ursodeoxycholic acid and obeticholic acid, have been the cornerstone of therapy in PBC, novel therapeutic approaches have been developed in recent years. In this review, we will examine published and ongoing clinical trials in PBC, including the recently approved peroxisome-proliferator-activated receptor (PPAR) agonist, elafibranor and seladelpar. These novel second-line therapies are expected to improve therapy in PBC and the development of personalized approaches.

Molecular and physiological mechanisms of aging are distinct in the cardiac right and left ventricles

AbstractAging is the primary risk factor for heart disease, the leading global cause of death. Right ventricular (RV) function predicts survival in several age‐related clinical contexts, yet no therapies directly improve RV function, in large part due to a poor mechanistic understanding of RV aging and how it is distinct from the widely studied left ventricle (LV). To address this gap, we comprehensively quantified RV functional and morphological remodeling with age. We further aimed to identify molecular mechanisms of RV aging thus we performed RNAseq on RV and LV from male and female young (4 months) and aged (19–21 months) C57BL6 mice. Contrary to the concentric hypertrophic remodeling and diastolic dysfunction that occurs in the LV, the aging RV underwent eccentric remodeling with significant dilation and impaired systolic function. Transcriptomic data were also consistent with ventricle‐specific aging, with few genes (13%) similarly shared between ventricles with aging. KEGG analysis identified shared aging genes in inflammatory and immune cell pathways that were confirmed by flow cytometry that demonstrated higher percent of GR1+ myeloid cells in both ventricles. Unique RV aging genes enriched in the biosynthesis of saturated fatty acids, PPAR signaling, and butanoate metabolism, and we identified putative novel RV‐specific aging genes. Together, we suggest that the RV and LV are unique cardiac chambers that undergo distinct remodeling with age. These robust differences may explain why therapies designed from LV‐based studies fail to improve RV function and suggest that future efforts emphasizing ventricular differences may elucidate new therapies for healthy cardiac aging.

Efficacy and safety of choline alphoscerate for amnestic mild cognitive impairment: a randomized double-blind placebo-controlled trial

BackgroundEffective interventions for overall healthy subjects with mild cognitive impairment are currently limited. Choline alphoscerate (alpha glyceryl phosphorylcholine, αGPC) is a choline-containing phospholipid used to treat cognitive function impairments in specific neurological conditions. This study aimed to investigate the efficacy and safety of αGPC in individuals diagnosed with mild cognitive impairment.MethodsIn this multicenter, randomized, placebo-controlled trial, 100 study subjects with mild cognitive impairment underwent a double-blind SHCog™ soft capsule (600 mg αGPC) or placebo treatment for 12 weeks. The primary efficacy outcome included changes from baseline on the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog). Safety assessments included regular monitoring of adverse events, and clinical laboratory tests were conducted at baseline and the end of the trial.ResultsAfter 12 weeks of αGPC treatment, the ADAS-cog score decreased by 2.34 points, which was significantly greater than the change observed in the placebo group. No serious AEs were reported, and no study subjects discontinued the intervention because of AEs. There was no significant difference in incidence rate of AEs between the αGPC group and the placebo group.ConclusionThis study suggests that αGPC is a safe and effective intervention for improving cognitive function in study subjects with mild cognitive impairment.Trial registrationClinical Research Information Service; Osong (Chungcheongbuk-do): Korea Centers for Disease Control and Prevention, Ministry of Health and Welfare (Republic of Korea); KCT0008797; A 12-week, multicenter, randomized, double-blind, placebo-controlled human application study to evaluate the efficacy and safety of SH_CAPK08 on cognitive function improvement in mild cognitive decline.

Association between Multi-Domain Lifestyle and Objective Cognitive Impairment in Elderly People with SCD and MCI in Chinese Communities

Objectives: Controlling the lifestyle associated with dementia risk can delay the process of cognitive decline. Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) are early states in the development of dementia and are also the window period for early intervention in dementia. The purpose of this study was to explore the association between multi-domain lifestyle and objective cognitive impairment in elderly people with SCD and MCI in Chinese communities and to provide reference for effective implementation of precise health management measures to reduce the risk of dementia. Methods: A total of 265 middle-aged and elderly volunteers recruited from the community were divided into SCD group (107 cases), MCI group (80 cases), and healthy control (HC) group (78 cases). All participants received clinical interview, examination, and cognitive assessments. Results: The total Dementia Risk Reduction Lifestyle Scale (DRRLS) scores in the HC, SCD, and MCI groups [110.00 (11.25) vs. 101.00 (10.00) vs. 79.50 (20.75)] exhibited statistically significant differences among them. The total score of the DRRLS showed a significant negative correlation with the Trail-Making Test (TMT), and significant positive correlations with both the Verbal Fluency Test (VFT) and Auditory Verbal Learning Test (AVLT) scores (p &lt; 0.05). After adjusting for confounding factors, such as age and years of education, multiple linear regression analysis revealed several points. In the SCD group, brain-strengthening exercise and interpersonal relationship scores were negatively correlated with TMT scores (β = −11.257, −15.077; all p &lt; 0.05), while health responsibility, smoking control behavior, and interpersonal relationship scores were positively correlated with AVLT scores (β = 0.485, 0.344, and 0.406; all p &lt; 0.05). In the MCI Group, brain-strengthening exercise, brain-healthy diet, and interpersonal relationship were negatively correlated with TMT (β = −22.011, −16.206, −11.696; all p &lt; 0.01), whereas health responsibility, mental activity, smoking control behavior, interpersonal relationship, and stress management were positively correlated with AVLT (β = 0.450, 0.435, 0.308, 0.256, 0.607; all p &lt; 0.05). Conclusions: In Chinese communities, the unhealthy lifestyle of elderly individuals with SCD and MCI is significantly associated with cognitive function impairment. The greater their unhealthy lifestyle habits, the more pronounced the scope and severity of cognitive function impairment becomes. Furthermore, different dimensions of lifestyle have varying impacts on cognitive domains.

Low-Protein Diet Inhibits the Synovial Tissue Macrophage Pro-Inflammatory Polarization Via NRF2/SIRT3/SOD2/ROS Pathway in K/BxN Rheumatoid Arthritis Mice.

Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by pain, swelling, stiffness, and impaired function. Attenuating inflammation is a crucial objective in RA management. Diet and nutrition are believed to influence RA symptomatology, with a low-protein diet being one potential nutritional strategy, although its underlying mechanisms remain to be fully elucidated. In this research, serum derived from arthritic transgenic K/BxN mice was administered to naive mice to establish a K/BxN rheumatoid arthritis model. Physiological assessments and histological staining were performed to evaluate joint pathology. (Enzyme-linked immunosorbent assay) ELISA was used to measure inflammatory cytokines. Flow cytometry and immunofluorescence were applied to characterize macrophage phenotypes. Transcriptomic analysis elucidated molecular pathways under the effect of a low-protein diet and verified by immunoblotting. Mitochondrial reactive oxygen species (ROS) was detected by Mito-SOX. Protein expression was silenced through the application of siRNA transfection. Our results indicate that a low-protein diet significantly alleviates disease symptoms and decreases pro-inflammatory cytokine levels in synovial fluid. Furthermore, this dietary intervention inhibits M1 macrophage polarization while promoting a shift towards the M2 phenotype. Transcriptomic analysis revealed that the beneficial effects of the low-protein diet in alleviating rheumatoid arthritis are closely linked to the NRF2 pathway. In vitro, low protein treatment can promote the activity of NRF2 via inhibiting the ubiquitin mediated proteolysis and activate the NRF2/SIRT3/SOD2 pathway to inhibit the production of ROS, which will further inhibit the M1 macrophage polarization. NRF2 knockdown can abolish the effects of low-protein treatment, indicating that the inhibition of M1 polarization and the anti-inflammatory response induced by low-protein treatment are dependent on NRF2. In summary, our findings propose that low-protein diet can inhibit synovial macrophage M1 polarization via activating NRF2/SIRT3/SOD2 pathway to reduce mitochondrial ROS production. This mechanism effectively decreases synovial inflammation and alleviates RA symptoms.

Nuclear expansion and chromatin structure remodeling in mouse aging neurons

Abstract Aging, particularly in the brain, involves impairments in multiple cellular functions, many regulated at the nucleus. Chromatin structure plays a critical role in regulating gene expression and the maintenance of genomic stability. During differentiation, each cell type acquire their unique topology, this should be kept for a lifetime, but may deteriorate as we age. However, the effects of aging on the chromatin 3D structure of neurons remain largely unknown and much has been inferred from senescent cells. By combining chromosome conformation capture and microscopy techniques, we investigated cortical neurons of young and aged mice and discovered signs of neuronal nuclear expansion during neuronal aging, leading to increased distances between chromosomes. This expansion alters the topology of compartments, topologically associating domains (TADs) and chromatin loops. While larger TADs tend to dissociate, smaller TADs and loops exhibit strengthened interactions of chromatin in aged neurons. These topological changes impact the borders of TADs, resulting in weakening, this is parallel to Lamin-B weakening and nuclear envelope alterations. We attribute these alterations to changes in physical forces of an expanding nucleus, driving the distancing of chromosomes filling a growing nuclear area, affecting gene expression and topology, contributing to the functional declines observed during aging.

Evaluation of Left Atrial Electromechanical Delay and Left Atrial Phasic Functions in Patients Undergoing Treatment with Cardiotoxic Chemotherapeutic Agents

Background: The aim of this study is to evaluate atrial involvement by comparing pre- and post-chemotherapy left atrial mechanical and electromechanical parameters in patients treated with cardiotoxic chemotherapeutic agents. Methods: We designed our study as a prospective cohort study. Sixty-eight female patients between the ages of 18 and 50, scheduled for treatment with cardiotoxic chemotherapeutic agents, were included in our study. Atrial mechanical functions and electromechanical parameters were examined and compared with basic echocardiographic parameters before and after chemotherapy. Results: The mean age of the patients was 41.6 ± 7.9 years. After chemotherapy, lateral PA, septal PA, and tricuspid PA durations showed a significant increase (p &lt; 0.001), but there were no statistically significant changes in the left intra-atrial electromechanical delay, the right intra-atrial electromechanical delay, or the interatrial electromechanical delay values. Following treatment, LAVmax, LAVmin, and LApreA significantly increased (p &lt; 0.001). Additionally, the left atrial passive and active emptying volumes increased (p &lt; 0.001), while the reservoir and pump (active emptying) functions decreased (with p-values of 0.03 and 0.01, respectively). The passive emptying function, however, showed no significant change (p = 0.65). Decreases in LVEF were observed, while LVEDD, LVESD, IVS, PW, and LA diameters increased (p-value of 0.02 for IVS and &lt;0.001 for the others). Conclusions: Significant impairment of atrial mechanical functions and electromechanical parameters was observed after treatment with cardiotoxic chemotherapeutic agents. This suggests an elevated likelihood of atrial arrhythmia linked to the use of cardiotoxic chemotherapeutic agents.

Novel Metabolites Associated with Decreased GFR in Finnish Men: A 12-Year Follow-Up of the METSIM Cohort

Identification of the individuals having impaired kidney function is essential in preventing the complications of this disease. We measured 1009 metabolites at the baseline study in 10,159 Finnish men of the METSIM cohort and associated the metabolites with an estimated glomerular filtration rate (eGFR). A total of 7090 men participated in the 12-year follow-up study. Non-targeted metabolomics profiling was performed at Metabolon, Inc. (Morrisville, NC, USA) on EDTA plasma samples obtained after overnight fasting. We applied liquid chromatography mass spectrometry (LC-MS/MS) to identify the metabolites (the Metabolon DiscoveryHD4 platform). We performed association analyses between the eGFR and metabolites using linear regression adjusted for confounding factors. We found 108 metabolites significantly associated with a decrease in eGFR, and 28 of them were novel, including 12 amino acids, 8 xenobiotics, 5 lipids, 1 nucleotide, 1 peptide, and 1 partially characterized molecule. The most significant associations were with five amino acids, N-acetylmethionine, N-acetylvaline, gamma-carboxyglutamate, 3-methylglutaryl-carnitine, and pro-line. We identified 28 novel metabolites associated with decreased eGFR in the 12-year follow-up study of the METSIM cohort. These findings provide novel insights into the role of metabolites and metabolic pathways involved in the decline of kidney function.

Inhalation Anesthetics Play a Janus-Faced Role in Self-Renewal and Differentiation of Stem Cells

Inhalation anesthesia stands as a pivotal modality within clinical anesthesia practices. Beyond its primary anesthetic effects, inhaled anesthetics have non-anesthetic effects, exerting bidirectional influences on the physiological state of the body and disease progression. These effects encompass impaired cognitive function, inhibition of embryonic development, influence on tumor progression, and so forth. For many years, inhaled anesthetics were viewed as inhibitors of stem cell fate regulation. However, there is now a growing appreciation that inhaled anesthetics promote stem cell biological functions and thus are now regarded as a double-edged sword affecting stem cell fate. In this review, the effects of inhaled anesthetics on self-renewal and differentiation of neural stem cells (NSCs), embryonic stem cells (ESCs), and cancer stem cells (CSCs) were summarized. The mechanisms of inhaled anesthetics involving cell cycle, metabolism, stemness, and niche of stem cells were also discussed. A comprehensive understanding of these effects will enhance our comprehension of how inhaled anesthetics impact the human body, thus promising breakthroughs in the development of novel strategies for innovative stem cell therapy approaches.

Thymidine-dependent Staphylococcus aureus and lung function in patients with cystic fibrosis: a 10-year retrospective case-control study.

Thymidine-dependent small-colony variants (TD-SCVs) of Staphylococcus aureus are being isolated with increasing frequency from patients with cystic fibrosis (CF). The aim of this study was to evaluate the relationship between TD-SCV isolation and pulmonary function in patients with CF, as well as to determine whether the emergence of TD-SCVs was associated with trimethoprim-sulfamethoxazole (TMP-SMX) use and with coinfection with other microorganisms. This was a retrospective case-control study including patients with CF who visited the Clinical Hospital Complex of the Federal University of Paraná, in Curitiba, Brazil, between 2013 and 2022. Demographic, clinical, and spirometric data, as well as information on TD-SCVs and other isolated microorganisms, were collected from the medical records of patients with CF and TD-SCVs (TD-SCV group; n = 32) and compared with those of a matched group of patients with CF without TD-SCVs (control group; n = 64). Isolation of TD-SCVs was positively associated with TMP-SMX use (p = 0.009), hospitalization (p < 0.001), and impaired pulmonary function (p = 0.04). The use of TMP-SMX seems to contribute to the emergence of TD-SCVs, the isolation of which was directly associated with worse pulmonary function in our sample.

ARGX-119 is an agonist antibody for human MuSK that reverses disease relapse in a mouse model of congenital myasthenic syndrome.

Muscle-specific kinase (MuSK) is essential for the formation, function, and preservation of neuromuscular synapses. Activation of MuSK by a MuSK agonist antibody may stabilize or improve the function of the neuromuscular junction (NMJ) in patients with disorders of the NMJ, such as congenital myasthenia (CM). Here, we generated and characterized ARGX-119, a first-in-class humanized agonist monoclonal antibody specific for MuSK, that is being developed for treatment of patients with neuromuscular diseases. We performed in vitro ligand-binding assays to show that ARGX-119 binds with high affinity to the Frizzled-like domain of human, nonhuman primate, rat, and mouse MuSK, without off-target binding, making it suitable for clinical development. Within the Fc region, ARGX-119 harbors L234A and L235A mutations to diminish potential immune-activating effector functions. Its mode of action is to activate MuSK, without interfering with its natural ligand neural Agrin, and cluster acetylcholine receptors in a dose-dependent manner, thereby stabilizing neuromuscular function. In a mouse model of DOK7 CM, ARGX-119 prevented early postnatal lethality and reversed disease relapse in adult Dok7 CM mice by restoring neuromuscular function and reducing muscle weakness and fatigability in a dose-dependent manner. Pharmacokinetic studies in nonhuman primates, rats, and mice revealed a nonlinear PK behavior of ARGX-119, indicative of target-mediated drug disposition and in vivo target engagement. On the basis of this proof-of-concept study, ARGX-119 has the potential to alleviate neuromuscular diseases hallmarked by impaired neuromuscular synaptic function, warranting further clinical development.

PDE5 inhibitor potentially improves polyuria and bladder storage and voiding dysfunctions in type 2 diabetic rats.

Bladder dysfunction associated with type 2 diabetes mellitus (T2DM) includes urine storage and voiding disorders. We examined pathological conditions of the bladder wall in a rat T2DM model and evaluated the effects of the phosphodiesterase-5 (PDE-5) inhibitor tadalafil. Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) rats were used as the T2DM and control groups, respectively. Tadalafil was orally administered for 12 weeks. Micturition behavior was monitored using metabolic cages, and bladder function was evaluated by cystometry. Bladder blood flow was evaluated by laser speckle imaging, and an organ bath bladder distention test was used to measure adenosine triphosphate (ATP) release from the bladder urothelium. The expression levels of vesicular nucleotide transporter (VNUT), hypoxia markers, pro-inflammatory cytokines and growth factors in the bladder wall were measured using real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Bladder wall contractions in response to KCl and carbachol were monitored using bladder-strip tests. With aging, OLETF rats had higher micturition frequency and greater urine volume than LETO rats. Although bladder capacity was not significantly different, non-voiding bladder contraction occurred more frequently in OLETF rats than in LETO rats. Bladder blood flow was decreased and ATP release was increased with higher VNUT expression in OLETF rats than in LETO rats. These effects were suppressed by tadalafil administration, with accompanying decreased HIF-1α, 8-OHdG, IL-6, TNF-α, IGF-1, and bFGF expression. The impaired contractile responses of bladder strips to KCl and carbachol in OLETF rats with aging were restored by tadalafil administration. The T2DM rats had polyuria, increased ATP release induced by decreased bladder blood flow and impaired contractile function. PDE5 inhibition improved these changes and may prevent T2DM-associated urinary frequency and bladder storage and voiding dysfunctions.