Development Of Disease Research Articles

Impact of Surgical Technique on Gastroesophageal Reflux Disease After Laparoscopic Sleeve Gastrectomy: A Nationwide Observational Study

BackgroundLaparoscopic sleeve gastrectomy (LSG) has gained increasing popularity worldwide, yet concerns persist regarding the development of gastroesophageal reflux disease (GERD) postoperatively. ObjectiveThis study aimed to evaluate the influence of technical aspects of LSG, specifically bougie size and distance from the pylorus to resection line edge, on the risk of developing symptomatic GERD within two years following surgery. SettingData from the Scandinavian Obesity Surgery Registry and the National Prescribed Drug Register were utilized for this analysis. MethodA retrospective observational study was conducted encompassing all LSG patients in Sweden between 2012 and 2020 who did not receive preoperative proton pump inhibitor (PPI) prescriptions. Patients were categorized based on bougie size and pyloric distance. Regular PPI use, defined as a dispensed prescription of more than 300 tablets per year, was employed as a proxy measure of symptomatic GERD and was compared between the groups. ResultsThe study included 7435 patients with complete data on dispensed PPI prescription both preoperatively and throughout the two-year follow-up period. Information on Bougie size and pyloric distance was available for 97.4% and 84.9%, respectively. Narrower bougie size and greater pyloric distance were associated with increased risk of regular PPI use post-surgery. Advanced age and female sex were independent risk factors for post-LSG regular PPI use, while initial BMI, total weight loss, and comorbidities showed no significant associations. ConclusionUsing a narrow bougie and initiating resection at a greater distance from the pylorus were associated with higher risk of symptomatic de novo GERD following LSG.

The Role of the AIM2 Gene in Obesity-Related Glucose and Lipid Metabolic Disorders: A Recent Update.

Absent in melanoma 2 (AIM2) is a protein encoded by the AIM2 gene located on human chromosomes, AIM2 can recognize and bind to double stranded DNA (dsDNA), leading to the assembly of the AIM2 inflammasome. The AIM2 inflammasome plays important proinflammation role in many diseases, and can induce pyroptotic cell death. It has also been closely linked to the development and progression of metabolic diseases and can be activated in obesity, diabetes, nonalcoholic fatty liver disease, and atherosclerosis. In this article, we mainly review the role of AIM2 in glucose metabolism, especially in obesity-related disorders of glucose and lipid metabolism, and provide insights to better understand the role of AIM2 in the pathogenesis, and clinical treatment of metabolic disease.

Association of depressive symptoms and incident chronic kidney disease in middle-aged and older adults

BackgroundEmerging evidence suggests that depressive symptoms may be a risk factor for the development of Chronic kidney disease (CKD). This study aimed to investigate the association between depressive symptoms and the incidence of CKD in middle-aged and older Chinese adults. MethodsWe utilized data from the 2011–2020 China Health and Retirement Longitudinal Study (CHARLS). Depressive symptoms were assessed using the 10-item Center for Epidemiologic Studies Depression Scale (CES-D). Incident CKD was defined based on the estimated glomerular filtration rate ≤ 60 mL/min/m2 or self-reported. Cox proportional hazard models were used to estimate the hazard ratio (HR) and 95 % confidence intervals (95 % CI) for incident CKD, adjusting for potential confounders. ResultsAmong the 10,996 participants without baseline CKD, 890 developed CKD during a median follow-up of 9.0 years. After adjusting for potential covariates, participants with depressive symptoms had a significantly higher risk of developing CKD compared to those without depressive symptoms (HR: 1.450; 95 % CI: 1.249–1.682). The association remained statistically significant when the CES-D was scored according to the severity of depressive symptoms, i.e., quintiles. A linear positive association between total CES-D score and risk of incident CKD was also found using restricted cubic spline regression (Pfor non-linearity = 0.114). ConclusionsDepressive symptoms are significantly associated with an increased risk of incident CKD in middle-aged and older Chinese adults. These findings underscore the importance of mental health screening and interventions in preventing CKD in this population.

Additive manufacturing of personalized scaffolds for vascular cell studies in large arteries: A case study on carotid arteries in sickle cell disease patients

Patient-specific models have increasingly gained significance in medical and research domains. In the context of hemodynamic studies, computational fluid dynamics emerges as a highly innovative and promising approach. We propose to augment these computational studies with cell-based experiments in individualized artery geometries using personalized scaffolds and vascular cell experiments. Previous research has demonstrated that the development of Sickle Cell Disease (SCD)-Related Vasculopathy is dependent on personal geometries and flow characteristics of the carotid artery. This fact leaves conventional animal experiments unsuitable for gaining patient-specific insights into cellular signaling, as they cannot replicate the personalized geometry. These personalized dynamics of cellular signaling may further impact disease progression, yet remains unclear. This paper presents a six-step methodology for creating personalized large artery scaffolds, focusing on high-precision models that yield biologically interpretable patient-specific results. The methodology outlines the creation of personalized large artery models via Additive Manufacturing suitably for supporting cell culture and other cellular experiments. Additionally, it discusses how different Computer-Aided-Design (CAD) construction modes can be used to obtain high-precision personalized models, while simplifying model reconfigurations and facilitating adjustments to general designs such as system connections to bioreactors, fluidic systems and visualization tools. A proposal for quality control measures to ensure geometric congruence for biological relevance of the results is added. This innovative, interdisciplinary approach appears promising for gaining patient-specific insights into pathophysiology, highlighting the importance of personalized medicine for understanding complex diseases.

Clinical glycoproteomics: methods and diseases.

Glycoproteins, representing a significant proportion of posttranslational products, play pivotal roles in various biological processes, such as signal transduction and immune response. Abnormal glycosylation may lead to structural and functional changes of glycoprotein, which is closely related to the occurrence and development of various diseases. Consequently, exploring protein glycosylation can shed light on the mechanisms behind disease manifestation and pave the way for innovative diagnostic and therapeutic strategies. Nonetheless, the study of clinical glycoproteomics is fraught with challenges due to the low abundance and intricate structures of glycosylation. Recent advancements in mass spectrometry-based clinical glycoproteomics have improved our ability to identify abnormal glycoproteins in clinical samples. In this review, we aim to provide a comprehensive overview of the foundational principles and recent advancements in clinical glycoproteomic methodologies and applications. Furthermore, we discussed the typical characteristics, underlying functions, and mechanisms of glycoproteins in various diseases, such as brain diseases, cardiovascular diseases, cancers, kidney diseases, and metabolic diseases. Additionally, we highlighted potential avenues for future development in clinical glycoproteomics. These insights provided in this review will enhance the comprehension of clinical glycoproteomic methods and diseases and promote the elucidation of pathogenesis and the discovery of novel diagnostic biomarkers and therapeutic targets.

Gut microbiota plays pivotal roles in benign and malignant hematopoiesis.

Accumulated evidence emerges that dynamic changes in human gut microbiota and microbial metabolites can alter the ecological balance of symbiotic hosts. The gut microbiota plays a role in various diseases through different mechanisms. More and more attention has been paid to the effects that human microbiota extends beyond the gut. This review summarized the current understanding of the roles that gut microbiota plays in hematopoietic regulation and the occurrence and development of benign and malignant hematologic diseases. The progress of the application of microbiota in treatment was discussed in order to provide new insights into clinical diagnosis and treatment in the future.

Maternal diet in pregnancy and the risk of inflammatory bowel disease in the offspring: a prospective cohort study

BackgroundDiet has been hypothesized as a risk factor for development of inflammatory bowel disease (IBD). ObjectiveTo explore associations between maternal diet diversity and quality in pregnancy and the offspring’s risk of IBD. MethodsWe used data from a nationwide cohort study on 85,129 Norwegian children followed from birth (1999–2009) with information on maternal diet in pregnancy from validated food frequency questionnaires. Hazard ratios (aHRs) for IBD, Crohn’s disease (CD), and ulcerative colitis (UC) by maternal diet diversity, quality and intake amounts of individual food groups were adjusted for maternal body mass index, parental IBD, and socio-demographic factors. Sensitivity analyses adjusted for the child's early-life diet quality and antibiotic treatment. Dietary exposures were classified into tertiles, comparing low (reference) to medium, and high levels. ResultsDuring a mean follow-up time of 16.1 years (1,367,837 person-years of follow-up), 268 children developed IBD (CD, n=119; UC, n=76; IBD-unclassified, n=73). High compared with low diet diversity in pregnancy was associated with a lower risk of UC in the offspring (aHR 0.46, 95% confidence interval 0.25-0.87), with consistent findings after further adjustment for the child's early-life diet quality and antibiotic treatment. High compared with low diet diversity in pregnancy yielded aHRs of 0.81 for CD (0.51-1.28) and 0.75 for any IBD (0.55-1.02) in the offspring. A high compared with low diet quality in pregnancy or intakes of specific food groups were not associated with the offspring’s risk of IBD or its subtypes. ConclusionsOur findings suggest that a higher maternal diet diversity in pregnancy may be associated with a lower risk of UC in the offspring.

Comparison of the Effects of Inappropriate Meal Timing-Induced and Genetic Models of Circadian Clock Disruption on Uterine mRNA Expression Profiles

BackgroundAccumulating evidence reveals that inappropriate meal timing contributes to the development of lifestyle-related diseases. An underlying mechanism is thought to be the disruption of the intracellular circadian clock in various tissues based on observations in both systemic and tissue-specific clock gene-deficient mice. However, whether the effects of conditional clock gene knockout are comparable to those of inappropriate meal timing remains unclear. ObjectivesThis study aimed to compare the effects of a recently developed 28-h feeding cycle model with those of a core clock gene Bmal1 uterine conditional knockout (Bmal1 cKO) model on uterine mRNA expression profiles. MethodsThe models were generated by subjecting C57BL/6J mice to an 8-h/20-h feeding/fasting cycle for 2 wk and crossing Bmal1-floxed mice with PR-Cre mice. Microarray analyses were conducted using uterine samples obtained at the beginning of the dark and light periods. ResultsThe analyses identified 516 and 346, significantly 4-fold and 2-fold, up- or downregulated genes in the 28-h feeding cycle and Bmal1 cKO groups, respectively, compared with each control group. Among these genes, only 7 (1.4%) and 63 (18.2%) were significantly up- or downregulated in the other model. Moreover, most (n = 44, 62.9%) of these genes were oppositely regulated. These findings were confirmed by gene set enrichment analyses. ConclusionsThis study reveals that a 28-h feeding cycle and Bmal1 cKO differently affect gene expression profiles and highlights the need for considering this difference to assess the pathophysiology of diseases associated with inappropriate meal timing.

Cell State Transition Associated with Cyst Development in Autosomal Dominant Polycystic Kidney Disease

Cell State Transition Associated with Cyst Development in Autosomal Dominant Polycystic Kidney Disease

Taxonomic intestinal microbiota differences in Lewy body spectrum disease and cohabitant controls

Microbial dysbiosis has been reported to contribute to development of neurodegenerative diseases, however, there is a need to identify causative/prognostic indicators. To comparatively analyze gut microbiome composition in symptomatic LBD (dementia/mild cognitive impairment), iRBD, and cohabiting controls without LBD or iRBD. 16S rRNA amplicon sequencing was performed in 38 cases (27 LBD, 11 iRBD) and 39 cohabitant controls. 19 non-cohabitant healthy controls (HCs) were also included to contrast differences between cohabitant cases and controls. Microbiome composition of cohabitant controls and LBD and iRBD cases were strikingly similar. No differences were observed between LBD, and iRBD only showed reduced Bacteroides, compared with cohabitant controls. There were several taxonomic differences in gut microbiome composition between non-cohabitant HCs and cases. Minimal microbiome differences were observed between iRBD or LBD cases and cohabitant controls. These findings underscore the importance of using cohabiting controls in future gut microbiome studies.

Transcriptomic and metabolomic changes might predict frailty in SAMP8 mice.

Frailty is a geriatric, multi-dimensional syndrome that reflects multisystem physiological change and is a transversal measure of reduced resilience to negative events. It is characterized by weakness, frequent falls, cognitive decline, increased hospitalization and dead and represents a risk factor for the development of Alzheimer's disease (AD). The fact that frailty is recognized as a reversible condition encourages the identification of earlier biomarkers to timely predict and prevent its occurrence. SAMP8 (Senescence-Accelerated Mouse Prone-8) mice represent the most appropriate preclinical model to this aim and were used in this study to carry transcriptional and metabolic analyses in the brain and plasma, respectively, upon a characterization at cognitive, motor, structural, and neuropathological level at 2.5, 6, and 9 months of age. At 2.5 months, SAMP8 mice started displaying memory deficits, muscle weakness, and motor impairment. Functional alterations were associated with a neurodevelopmental deficiency associated with reduced neuronal density and glial cell loss. Through transcriptomics, we identified specific genetic signatures well distinguishing SAMP8 mice at 6 months, whereas plasma metabolomics allowed to segregate SAMP8 mice from SAMR1 already at 2.5 months of age by detecting constitutively lower levels of acylcarnitines and lipids in SAMP8 at all ages investigated correlating with functional deficits and neuropathological signs. Our findings suggest that specific genetic alterations at central level, as well as metabolomic changes in plasma, might allow to early assess a frail condition leading to dementia development, which paves the foundation for future investigation in a clinical setting.

S1883 Evaluating Differences in Screening Between Pediatric and Adult Patients for Development of Metabolic Dysfunction-Associated Steatotic Liver Disease at an Academic Primary Care Clinic

S1883 Evaluating Differences in Screening Between Pediatric and Adult Patients for Development of Metabolic Dysfunction-Associated Steatotic Liver Disease at an Academic Primary Care Clinic

Association between ankylosing spondylitis and neurodegenerative diseases: Systematic review and meta-analysis

BackgroundIncreasing evidence indicates the mechanism of overlapping immune dysfunction and inflammation disorder shared by ankylosing spondylitis (AS) and neurodegenerative diseases (NDs). However, the exact correlation between the two is still unclear. Different studies have reported inconsistent results about how AS and NDs are related. ObjectiveThis study aimed to investigate the association between AS and risk of NDs. MethodsWe searched electronic databases including PubMed, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials to identify studies reporting relationship between NDs risk and AS published before April 10th, 2024. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were estimated. All analyses were conducted using Stata V.12.0 software. ResultsA total of 15 comparisons out of 10 studies involving 851,936 participants were included. The results showed that the risk of NDs was higher among AS patients than those who were not (OR: 1.36, 95% CI: 1.15–1.60, P<0.001). In addition, subgroup analysis showed that AS was associated with an increased risk of Parkinson's disease (PD) development (OR: 1.55, 95% CI: 1.31–1.83, P<0.001), whereas there is no observed association with Alzheimer's disease (AD) and dementia (OR: 1.22, 95% CI: 0.96–1.55, P=0.098; OR: 1.34, 95% CI: 0.96–1.87, P=0.089, respectively). ConclusionThe current meta-analysis identified AS as a risk factor for the development of NDs. Clinicians should be aware of the potential association between these diseases. Further research is necessary to confirm the causal relationship and underlying mechanisms between AS and NDs.

Thalidomide mitigates Crohn's disease colitis by modulating gut microbiota, metabolites, and regulatory T cell immunity

Thalidomide (THA) is renowned for its potent anti-inflammatory properties. This study aimed to elucidate its underlying mechanisms in the context of Crohn’s disease (CD) development. Mouse colitis models were established by dextran sulfate sodium (DSS) treatment. Fecal microbiota and metabolites were analyzed by metagenomic sequencing and mass spectrometry, respectively. Antibiotic-treated mice served as models for microbiota depletion and transplantation. The expression of Forkhead box P3+ (FOXP3+) Regulatory T cells (Tregs) was measured by flow cytometry and immunohistochemical assay in colitis model and patient cohort. THA inhibited colitis in DSS–treated mice by altering the gut microbiota profile, with an increased abundance of probiotics Bacteroides fragilis (Bf), while pathogenic bacteria were depleted. In addition, THA increased beneficial metabolites bile acids and significantly restored gut barrier function. Transcriptomic profiling revealed that THA inhibited interleukin-17 (IL17), IL1β and cell cycle signaling. Fecal microbiota transplantation from THA-treated mice to microbiota-depleted mice partly recapitulated the effects of THA. Specifically, increased level of gut commensal Bf was observed, correlated with elevated levels of the microbial metabolite 7-Ketolithocholic acid (7-KA) following THA treatment. This microbial metabolite may stable FOXP3 expression by targeting the bile acid receptor farnesol X receptor 1(FXR1) to inhibit autophagy. An interaction between FOXP3 and FXR1 was identified, with binding regions localized to the FOXP3 domain (aa 238-335) and the FXR1 domain (aa 82-222), respectively. Conclusively, THA modulates the gut microbiota and metabolite profiles towards a more beneficial composition, enhances gut barrier function, promotes the differentiation of FOXP3+ Tregs and curbs pro-inflammatory pathways.

Ovariectomy and High Fat-Sugar-Salt Diet Induced Alzheimer's Disease/Vascular Dementia Features in Mice.

While the vast majority of Alzheimer's disease (AD) is non-familial, the animal models of AD that are commonly used for studying disease pathogenesis and development of therapy are mostly of a familial form. We aimed to generate a model reminiscent of the etiologies related to the common late-onset Alzheimer's disease (LOAD) sporadic disease that will recapitulate AD/dementia features. Naïve female mice underwent ovariectomy (OVX) to accelerate aging/menopause and were fed a high fat-sugar-salt diet to expose them to factors associated with increased risk of development of dementia/AD. The OVX mice fed a high fat-sugar-salt diet responded by dysregulation of glucose/insulin, lipid, and liver function homeostasis and increased body weight with slightly increased blood pressure. These mice developed AD-brain pathology (amyloid and tangle pathologies), gliosis (increased burden of astrocytes and activated microglia), impaied blood vessel density and neoangiogenesis, with cognitive impairment. Thus, OVX mice fed on a high fat-sugar-salt diet imitate a non-familial sporadic/environmental form of AD/dementia with vascular damage. This model is reminiscent of the etiologies related to the LOAD sporadic disease that represents a high portion of AD patients, with an added value of presenting concomitantly AD and vascular pathology, which is a common condition in dementia. Our model can, thereby, provide a valuable tool for studying disease pathogenesis and for the development of therapeutic approaches.

Nicotine is an Immunosuppressant: Implications for Women's Health and Disease

A plethora of evidence supports that nicotine, the primary alkaloid in tobacco products that is generally accepted for maintaining use, is immunoregulatory and may function as an immunosuppressant. Women have unique experiences with use of nicotine-containing products and also undergo significant reproductive transitions throughout their lifespan which may be impacted by nicotine use. Within the extant literature, there is conflicting evidence that nicotine may confer beneficial health effects in specific disease states (e.g., in ulcerative colitis). Use prevalence of nicotine-containing products is exceptionally high in individuals presenting with some comorbid disease states that impact immune system health and can be a risk factor for the development of diseases which disproportionately impact women; however, the mechanisms underlying these relationships are largely unclear. Further, little is known regarding the impacts of nicotine's immunosuppressive effects on women's health during the menopausal transition, which is arguably an inflammatory event characterized by a pro-inflammatory peri-menopause period. Given that post-menopausal women are at a higher risk than men for the development of neurodegenerative diseases such as Alzheimer's disease and are also more vulnerable to negative health effects associated with diseases such as HIV-1 infection, it is important to understand how use of nicotine-containing products may impact the immune milieu in women. In this review, we define instances in which nicotine use confers immunosuppressive, anti-inflammatory, or pro-inflammatory effects in the context of comorbid disease states, and focus on how nicotine impacts neuroimmune signaling to maintain use. We posit that regardless of potential health benefits, nicotine use cessation should be a priority in the clinical care of women. The synthesis of this review demonstrates the importance of systematically defining the relationships between volitional nicotine use, immune system function, and comorbid disease states in women to better understand how nicotine impacts women's health and disease.

Endogenous enzyme-activated AND-gate DNA nanomachines for intracellular miRNA detection and cell-selective imaging

The occurrence and development of tumors are accompanied by the abnormal expression of specific microRNAs (miRNAs). Therefore, miRNAs are considered as an important biomarker. The establishment of efficient, simple and sensitive miRNA imaging methods in living cells will contribute to the early diagnosis, treatment and drug development of diseases. In this study, we developed an endogenous enzyme-initiated AND logic circuit using gold nanocubes (AuNCs) as carriers for simultaneous detection of miRNA-21 and miRNA-210 in cells. Apurinic/apyrimidinic endonuclease 1 (APE1) and telomerase (TE), which are overexpressed in cancer cells, act as control switches in a logic circuit that enables sensitive in situ analysis of intracellular miRNAs without additional external intervention. At the same time, due to the lack of necessary enzymes as activation switches, the DNA circuit in normal cells remains in an inactive state. This strategy effectively reduces the risk of false positive signal generation. Our research results show that the logic circuit can not only distinguish between cancer cells and normal cells, and able to distinguish between different types of cancer cells. This finding provides a promising approach to accurately identify cell types.

Determination of limit of detection (LOD) for loop-mediated isothermal amplification (LAMP) of human cytomegalovirus (hCMV) DNA

The importance of cytomegalovirus in clinical practice remains and samples are monitored for CMV DNA titers to predict the development of disease. LAMP assays have gained increasing interest in the diagnosis of many pathogens since they do not require thermocycling, reduce the complexity of the required instrumentation as well as providing sensitivity and rapidity. So far, very few studies on CMV detection by LAMP have been reported in the literature and therefore the performance of LAMP CMV assays needs to be further characterized. In a set-up for biometrological evaluation of the suitability of the LAMP assay for CMV diagnosis, a LAMP assay was performed on a total of 192 samples with 24 replicates of 8 different hCMV DNA concentrations. The LOD was calculated as 39.09 copy/reaction (25.33 copy/reaction to 65.84 copy/reaction) with 95% confidence, representing a range that is suitable for qualitative detection. Furthermore, the lower limit of quantification was estimated at approximately 100 copy/reaction. The LOD and LLOQ values obtained in this first study to assess the biometrological relevance of LAMP CMV tests are consistent when compared to studies published before. However further study under different conditions is needed for the use of LAMP tests in clinical applications.

THE EFFECT OF POLYPHENOL COMPOUNDS ON Ca2+-INDUCED MITOCHONDRIAL POTORAGE (mPTP) IN TOXIC HEPATITIS

As a result of the development of industrial technologies and changes in the ecological environment, various xenobiotics released into the environment are increasing. Increasing exposure to xenobiotics may lead to the development of diseases associated with toxic hepatitis (TG) in the population. The following exogenous factors can cause TG: industrial and household toxic substances, chlorinated hydrocarbons, naphthalene and biphenyls, benzene, metals and other inorganic elements, monomers used for the production of polymer materials, plastics, hydrazine and its derivatives, as well as dioxins and radionuclides. All of these exogenous toxins have a cumulative damaging effect on the liver, so they must be converted into non-toxic compounds for the body and eliminated. The main mechanisms of toxic damage to the liver are lipid peroxidation, protein denaturation, reduction of ATF, mitochondrial dysfunction, inhibition of membrane receptors.

Comprehensive Evaluation of the Genetic Basis of Keratoconus: New Perspectives for Clinical Translation.

Keratoconus (KC) is a corneal disorder with complex etiology, apparently involving both genetic and environmental factors, characterized by progressive thinning and protrusion of the cornea. We aimed to identify novel genetic regions associated with KC susceptibility, elucidate relevant genes for disease development, and explore the translational implications for therapeutic intervention and risk assessment. We conducted a genome-wide association study (GWAS) that integrated previously published data with newly generated genotyping data from an independent European cohort. To evaluate the clinical translation of our results, we performed functional annotation, gene prioritization, polygenic risk score (PRS), and drug repositioning analyses. We identified two novel genetic loci associated with KC, with rs2806689 and rs807037 emerging as lead variants (P = 1.71E-08, odds ratio [OR] = 0.88; P = 1.93E-08, OR = 1.16, respectively). Most importantly, we identified 315 candidate genes influenced by confirmed KC-associated variants. Among these, MINK1 was found to play a pivotal role in KC pathogenesis through the WNT signaling pathway. Moreover, we developed a PRS model that successfully differentiated KC patients from controls (P = 7.61E-16; area under the curve = 0.713). This model has the potential to identify individuals at high risk for developing KC, which could be instrumental in early diagnosis and management. Additionally, our drug repositioning analysis identified acetylcysteine as a potential treatment option for KC, opening up new avenues for therapeutic intervention. Our study provides valuable insights into the genetic and molecular basis of KC, offering new targets for therapy and highlighting the clinical utility of PRS models in predicting disease risk.