-
Nephrology (Carlton, Vic.) Jul 2024IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, and almost all patients are at risk of progression to end-stage kidney disease within... (Review)
Review
IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, and almost all patients are at risk of progression to end-stage kidney disease within their lifetime. The mechanisms responsible for the presentation and development of IgAN are required for the development of highly targeted therapies for this disease. In this review, we first demonstrate the current treatment strategy of IgAN recommended by the 2021 KDIGO guideline. Then, we update the new insights into disease pathogenesis based on the well acknowledged 'multiple-hit hypothesis' and provide the potential therapeutic targets involved in the upstream production of pathogenic IgA1 and the downstream complement activation. Finally, the recent large randomized controlled trials focusing on these novel targets have been summarized, among which Nefecon and Sparsentan have received approval and Telitacicept have been used off-label for IgAN. In the future, emerging treatment approaches for IgAN is likely to evolve, which will signify a shift in the management of the IgAN from traditional immunosuppressive approaches to an era of targeted treatment based on the understanding of the pathogenic mechanisms.
PubMed: 38958055
DOI: 10.1111/nep.14340 -
Aging Cell Jul 2024Age-related chronic inflammatory lung diseases impose a threat on public health, including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease...
Age-related chronic inflammatory lung diseases impose a threat on public health, including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). However, their etiology and potential targets have not been clarified. We performed genome-wide meta-analysis for IPF with the largest sample size (2883 cases and 741,929 controls) and leveraged the summary statistics of COPD (17,547 cases and 617,598 controls). Transcriptome-wide and proteome-wide Mendelian randomization (MR) designs, together with genetic colocalization, were implemented to find robust targets. The mediation effect was assessed using leukocyte telomere length (LTL). The single-cell transcriptome analysis was performed to link targets with cell types. Individual-level data from UK Biobank (UKB) were used to validate our findings. Sixteen genetically predicted plasma proteins were causally associated with the risk of IPF and 6 proteins were causally associated with COPD. Therein, genetically-elevated plasma level of SCARF2 protein should reduce the risk of both IPF (odds ratio, OR = 0.9974 [0.9970, 0.9978]) and COPD (OR = 0.7431 [0.6253, 0.8831]) and such effects were not mediated by LTL. Genetic colocalization further corroborated these MR results of SCARF2. The transcriptome-wide MR confirmed that higher expression level of SCARF2 was associated with a reduced risk of both. However, the single-cell RNA analysis indicated that SCARF2 expression level was only relatively lower in epithelial cells of COPD lung tissue compared to normal lung tissue. UKB data implicated an inverse association of serum SCARF2 protein with COPD (hazard ratio, HR = 1.215 [1.106, 1.335]). The SCARF2 gene should be a novel target for COP.
PubMed: 38958042
DOI: 10.1111/acel.14266 -
Gut Microbes 2024The juxtaposition of well-oxygenated intestinal colonic tissue with an anerobic luminal environment supports a fundamentally important relationship that is altered in...
The juxtaposition of well-oxygenated intestinal colonic tissue with an anerobic luminal environment supports a fundamentally important relationship that is altered in the setting of intestinal injury, a process likely to be relevant to diseases such as inflammatory bowel disease. Herein, using two-color phosphorometry to non-invasively quantify both intestinal tissue and luminal oxygenation in real time, we show that intestinal injury induced by DSS colitis reduces intestinal tissue oxygenation in a spatially defined manner and increases the flux of oxygen from the tissue into the gut lumen. By characterizing the composition of the microbiome in both DSS colitis-affected gut and in a bioreactor containing a stable human fecal community exposed to microaerobic conditions, we provide evidence that the increased flux of oxygen into the gut lumen augments glycan degrading bacterial taxa rich in glycoside hydrolases which are known to inhabit gut mucosal surface. Continued disruption of the intestinal mucus barrier through such a mechanism may play a role in the perpetuation of the intestinal inflammatory process.
Topics: Gastrointestinal Microbiome; Colitis; Animals; Humans; Oxygen; Bacteria; Mice; Intestinal Mucosa; Feces; Mice, Inbred C57BL; Dextran Sulfate; Colon; Male
PubMed: 38958039
DOI: 10.1080/19490976.2024.2361493 -
Circulation Research Jul 2024Cerebral vascular malformations (CCMs) are primarily found within the brain, where they result in increased risk for stroke, seizures, and focal neurological deficits....
BACKGROUND
Cerebral vascular malformations (CCMs) are primarily found within the brain, where they result in increased risk for stroke, seizures, and focal neurological deficits. The unique feature of the brain vasculature is the blood-brain barrier formed by the brain neurovascular unit. Recent studies suggest that loss of CCM genes causes disruptions of blood-brain barrier integrity as the inciting events for CCM development. CCM lesions are proposed to be initially derived from a single clonal expansion of a subset of angiogenic venous capillary endothelial cells (ECs) and respective resident endothelial progenitor cells (EPCs). However, the critical signaling events in the subclass of brain ECs/EPCs for CCM lesion initiation and progression are unclear.
METHODS
Brain EC-specific CCM3-deficient () mice were generated by crossing mice with -CreER mice. Single-cell RNA-sequencing analyses were performed by the chromium single-cell platform (10× genomics). Cell clusters were annotated into EC subtypes based on visual inspection and GO analyses. Cerebral vessels were visualized by 2-photon in vivo imaging and tissue immunofluorescence analyses. Regulation of mTOR (mechanistic target of rapamycin) signaling by CCM3 and Cav1 (caveolin-1) was performed by cell biology and biochemical approaches.
RESULTS
Single-cell RNA-sequencing analyses from P10 0 mice harboring visible CCM lesions identified upregulated CCM lesion signature and mitotic EC clusters but decreased blood-brain barrier-associated EC clusters. However, a unique EPC cluster with high expression levels of stem cell markers enriched with mTOR signaling was identified from early stages of the P6 0 brain. Indeed, mTOR signaling was upregulated in both mouse and human CCM lesions. Genetic deficiency of Raptor (regulatory-associated protein of mTOR), but not of Rictor (rapamycin-insensitive companion of mTOR), prevented CCM lesion formation in the model. Importantly, the mTORC1 (mTOR complex 1) pharmacological inhibitor rapamycin suppressed EPC proliferation and ameliorated CCM pathogenesis in mice. Mechanistic studies suggested that Cav1/caveolae increased in CCM3-depleted EPC-mediated intracellular trafficking and complex formation of the mTORC1 signaling proteins.
CONCLUSIONS
CCM3 is critical for maintaining blood-brain barrier integrity and CCM3 loss-induced mTORC1 signaling in brain EPCs initiates and facilitates CCM pathogenesis.
PubMed: 38957991
DOI: 10.1161/CIRCRESAHA.123.324015 -
DNA and Cell Biology Jul 2024Skin homeostasis relies on a delicate balance between host proteases and protease inhibitors along with those secreted from microbial communities, as disruption to this... (Review)
Review
Skin homeostasis relies on a delicate balance between host proteases and protease inhibitors along with those secreted from microbial communities, as disruption to this harmony contributes to the pathogenesis of inflammatory skin disorders, including atopic dermatitis and Netherton's syndrome. In addition to being a prominent cause of skin and soft tissue infections, the gram-positive bacterium is a key player in inflammatory skin conditions due to its array of 10 secreted proteases. Herein we review how proteases augment the development of inflammation in skin disorders. These mechanisms include degradation of skin barrier integrity, immune dysregulation and pruritis, and impairment of host defenses. Delineating the diverse roles of proteases has the potential to reveal novel therapeutic strategies, such as inhibitors of proteases or their cognate target, as well as neutralizing vaccines to alleviate the burden of inflammatory skin disorders in patients.
PubMed: 38957987
DOI: 10.1089/dna.2024.0134 -
Journal of Burn Care & Research :... Jul 2024Burn injury contributes to significant morbidity and mortality in the United States. Despite an increased focus on racial and ethnic disparities in healthcare, there...
Burn injury contributes to significant morbidity and mortality in the United States. Despite an increased focus on racial and ethnic disparities in healthcare, there remains a critical knowledge gap in our understanding of the effect of these disparities on complications experienced by burn patients. The American Burn Association's National Burn Repository data were reviewed from 2010-2018. Information regarding demographics, burn mechanism and severity, complications, and clinical outcomes were recorded. Data analysis was performed using 1:1 propensity-score-matching and logistic regression modeling. A separate analysis of Hispanic and non-Hispanic patients was performed using Chi squared tests. Among 215,071 patients, racial distribution was 65.16% white, 19.13% black, 2.18% Asian, 0.74% American Indian/Alaskan Native, and 12.78% other. Flame injuries were the most common cause (35.2%), followed by scald burns (23.3%). All comparisons were made in reference to the white population. Black patients were more likely to die (OR: 1.28; 95%CI: 1.17-1.40), experience all (OR: 1.08; 95%CI: 1.03-1.14), cardiovascular (OR: 1.24; 95%CI: 1.08-1.43), or infectious (OR: 1.64; 95%CI: 1.40-1.91) complications, and less likely to experience airway complications (OR: 0.83; 95%CI: 0.74-0.94). American Indian/Alaskan Native patients were more likely to experience any complication (OR: 1.33; 95%CI: 1.05-1.70). All minority groups had increased length of hospital stay. Black, Asian, and other patients had longer length of ICU stay. Black patients had longer ventilator duration. Among 82,775 patients, 24,075 patients were identified as Hispanic and 58,700 as non-Hispanic. Statistically significant differences were noted between groups in age, TBSA, proportion of 2nd degree burn, and proportion of 3rd degree burn (p<0.01). These findings highlight the need for further work to determine the etiology of these disparities to improve burn care for all patients.
PubMed: 38957983
DOI: 10.1093/jbcr/irae126 -
Diabetes, Obesity & Metabolism Jul 2024Bile acids (BAs) are implicated in the pathogenesis of several metabolic syndrome-related diseases, including insulin resistance (IR) and type 2 diabetes (T2D). It has...
AIM
Bile acids (BAs) are implicated in the pathogenesis of several metabolic syndrome-related diseases, including insulin resistance (IR) and type 2 diabetes (T2D). It has been reported that IR and T2D are associated with an increased ratio of 12α/non-12α-hydroxylated BAs in the circulating BA pool. It is, however, unknown whether the improvement of insulin sensitivity inversely affects BA composition in humans. Therefore, we assessed whether lifestyle-induced weight loss induces changes in BA metabolism in people with obesity, with or without T2D, and if these changes are associated with metabolic parameters.
MATERIALS AND METHODS
Individual BAs and C4 were quantified by ultra-high-performance liquid chromatography-tandem mass spectrometry in plasma samples collected from two cohorts of people with obesity (OB) and with T2D and obesity (T2D), before and after a lifestyle intervention.
RESULTS
Lifestyle-induced weight loss improved glycaemic control in both cohorts, with plasma BA concentrations not affected by the lifestyle interventions. The ratio of 12α/non-12α-hydroxylated BAs remained unchanged in OB (p = .178) and even slightly increased upon intervention in T2D (p = .0147). Plasma C4 levels were unaffected in OB participants (p = .20) but significantly reduced in T2D after intervention (p = .0003). There were no significant correlations between the ratio of 12α/non-12α-hydroxylated BAs and glucose, insulin, or homeostatic model assessment-IR, nor in plasma triglycerides, low-density lipoprotein cholesterol, lipoprotein (a) in the T2D cohort.
CONCLUSIONS
Lifestyle-induced weight loss did improve glycaemic control but did not affect BA concentrations. Improvements in insulin sensitivity were not associated with changes in BA parameters in people with obesity, with or without T2D.
PubMed: 38957937
DOI: 10.1111/dom.15754 -
Journal of the Indian Society of... Apr 2024Dental caries results from an ecologic shift within the dental biofilm from a balanced population of microorganisms to an acidogenic, aciduric, and cariogenic... (Comparative Study)
Comparative Study Randomized Controlled Trial
INTRODUCTION
Dental caries results from an ecologic shift within the dental biofilm from a balanced population of microorganisms to an acidogenic, aciduric, and cariogenic microbiological population developed and maintained by frequent consumption of fermentable dietary carbohydrates. Total caries removal (TCR) of deep lesion may result in pulpal exposure requiring more invasive treatment. Hence, current pediatric dentistry has shifted to minimally invasive treatment that avoids more complex, time-consuming procedure, and the child's discomfort.
AIM
The aim of this study is to evaluate and compare clinical performance and radiographic changes after complete and incomplete caries removal procedures.
MATERIALS AND METHODS
The study was conducted on 60 primary molars in children aged 6-9 years. Selected 60 primary molars were randomly divided into two groups. Group 1 (PCR): infected dentin was removed, while the affected dentin was maintained on the pulpal wall. Group 2 (TCR): both infected and affected dentin were removed through low-speed carbide bur and hand excavator. Teeth were evaluated at 4 and 6 months clinically and radiographically.
RESULTS
The proportion was compared using Fisher's exact test. The Statistical Package for the Social Sciences version 21 was used for analysis. The level of significance was kept at 5%.
CONCLUSION
The clinical and radiographic success rates of ICR and CCR in primary teeth with deep carious lesions were high and did not differ significantly, indicating that the retention of carious dentin does not interfere with pulp vitality. Thus, ICR is a reliable minimally invasive approach that might replace the CCR in primary teeth when correctly indicated.
Topics: Humans; Tooth, Deciduous; Dental Caries; Child; Molar; Dental Pulp; Male; Female; Dental Cavity Preparation; Dentin
PubMed: 38957913
DOI: 10.4103/jisppd.jisppd_116_24 -
Journal of the Indian Society of... Apr 2024Mucopolysaccharidosis (MPS) is a group of lysosomal storage disorders that cause the deposition of polysaccharides in cells. This causes systemic and oral...
BACKGROUND AND OBJECTIVES
Mucopolysaccharidosis (MPS) is a group of lysosomal storage disorders that cause the deposition of polysaccharides in cells. This causes systemic and oral manifestations, which can be observed clinically and radiographically. The present study aimed to assess dental caries, the effect of salivary pH, and the change of microflora on teeth in patients diagnosed with MPS.
MATERIALS AND METHODS
The study included children affected with mucopolysaccharidosis (n = 50) and healthy children (n = 50) in the control group between 3 and 15 years of age. The pH of saliva and decayed, missing, and filled teeth/decayed extracted and filled teeth index were noted and recorded. For the microbial analysis, saliva was inoculated into blood agar, MacConkey agar, Candida CHROMagar, and Mitis Salivarius agar, then inspected for colony-forming units, which were counted and recorded based on the colony characteristics and gram staining.
STATISTICAL ANALYSIS
Intergroup comparison of the test parameters was done using the Mann-Whitney test. P < 0.05 was considered statistically significant.
RESULTS
The results showed significantly higher total microbial load (P = 0.00008), streptococcus viridans species (P = 0.00001), and Candida species (P = 0.0038) in the study group. The caries incidence was also higher in the study group for both primary (P = 0.0096) and permanent dentition (P = 0.0251), and salivary pH was more acidic (P = 0.00001) in the patients diagnosed with MPS.
INTERPRETATION AND CONCLUSION
Patients diagnosed with MPS have a higher microbial load, more acidic saliva, and subsequently, a higher caries incidence than normal healthy children. Hence, regular dental evaluation, prevention, and treatment must be integrated into their health-care regimen.
Topics: Humans; Saliva; Child; Dental Caries; Adolescent; Mucopolysaccharidoses; Child, Preschool; Female; Male; Hydrogen-Ion Concentration; DMF Index; Candida; Case-Control Studies
PubMed: 38957904
DOI: 10.4103/jisppd.jisppd_28_24 -
Ghana Medical Journal Dec 2023To determine the prevalence and severity of anaemia and assess the relationship between dietary lifestyle, hypoalbuminaemia, and anaemia of older persons.
OBJECTIVES
To determine the prevalence and severity of anaemia and assess the relationship between dietary lifestyle, hypoalbuminaemia, and anaemia of older persons.
DESIGN
A cross-sectional hospital-based study.
SETTING
This study was conducted in the General Outpatient Clinic, the primary care unit of Aminu Kano Teaching Hospital in Kano, Nigeria.
PARTICIPANTS
A total of 378 patients aged ≥ 60 years who presented to the General Out-patient Clinic.
MAIN OUTCOME MEASURES
Prevalence and severity of anaemia, relationship between anaemia and hypoalbuminaemia, and dietary lifestyle of the participants.
RESULTS
A total of 348 respondents completed the study. The mean age of respondents was 67.83 ±7.53 years, with female (60.9%) predominance. The prevalence of anaemia and hypoalbuminaemia were 42.2% and 17.8%, respectively. Hypoalbuminaemia (β=0.335, 95%CI=0.131-0.229, <0.001), long duration of comorbidities (β= -0.179, 95%CI= -0.165-0.047, <0.001), one full meal/day (β=0.130, 95%CI=0.224-1.879, =0.013), and low monthly income (β=0.122, 95%CI=0.179-1.543, =0.026) were the predictors of anaemia among the older persons in this study.
CONCLUSION
This study revealed a high prevalence of anaemia among older adults. The identified predictors, such as hypoalbuminaemia, long duration of comorbidities, reduced food intake and low monthly income, will be useful in developing guidelines and strategies for managing the condition in primary care settings and other similar sites.
FUNDING
None declared.
Topics: Humans; Female; Nigeria; Male; Aged; Hypoalbuminemia; Cross-Sectional Studies; Middle Aged; Anemia; Prevalence; Primary Health Care; Life Style; Diet; Aged, 80 and over
PubMed: 38957852
DOI: 10.4314/gmj.v57i4.7