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Nature Communications Jun 2024IncX3 plasmids carrying the New Delhi metallo-β-lactamase-encoding gene, bla, are rapidly spreading globally in both humans and animals. Given that carbapenems are...
IncX3 plasmids carrying the New Delhi metallo-β-lactamase-encoding gene, bla, are rapidly spreading globally in both humans and animals. Given that carbapenems are listed on the WHO AWaRe watch group and are prohibited for use in animals, the drivers for the successful dissemination of Carbapenem-Resistant Enterobacterales (CRE) carrying bla-IncX3 plasmids still remain unknown. We observe that E. coli carrying bla-IncX3 can persist in chicken intestines either under the administration of amoxicillin, one of the largest veterinary β-lactams used in livestock, or without any antibiotic pressure. We therefore characterise the bla-IncX3 plasmid and identify a transcription regulator, VirBR, that binds to the promoter of the regulator gene actX enhancing the transcription of Type IV secretion systems (T4SS); thereby, promoting conjugation of IncX3 plasmids, increasing pili adhesion capacity and enhancing the colonisation of bla-IncX3 transconjugants in animal digestive tracts. Our mechanistic and in-vivo studies identify VirBR as a major factor in the successful spread of bla-IncX3 across one-health AMR sectors. Furthermore, VirBR enhances the plasmid conjugation and T4SS expression by the presence of copper and zinc ions, thereby having profound ramifications on the use of universal animal feeds.
Topics: Animals; Plasmids; beta-Lactamases; Chickens; Humans; Escherichia coli; Anti-Bacterial Agents; Conjugation, Genetic; Escherichia coli Proteins; Type IV Secretion Systems; Transcription Factors; Amoxicillin; Promoter Regions, Genetic; Escherichia coli Infections; Gene Expression Regulation, Bacterial; Intestines
PubMed: 38944647
DOI: 10.1038/s41467-024-49800-1 -
NPJ Biofilms and Microbiomes Jun 2024Gut metaproteomics can provide direct evidence of microbial functions actively expressed in the colonic environments, contributing to clarify the role of the gut... (Meta-Analysis)
Meta-Analysis
Gut metaproteomics can provide direct evidence of microbial functions actively expressed in the colonic environments, contributing to clarify the role of the gut microbiota in human physiology. In this study, we re-analyzed 10 fecal metaproteomics datasets of healthy individuals from different continents and countries, with the aim of identifying stable and variable gut microbial functions and defining the contribution of specific bacterial taxa to the main metabolic pathways. The "core" metaproteome included 182 microbial functions and 83 pathways that were identified in all individuals analyzed. Several enzymes involved in glucose and pyruvate metabolism, along with glutamate dehydrogenase, acetate kinase, elongation factors G and Tu and DnaK, were the proteins with the lowest abundance variability in the cohorts under study. On the contrary, proteins involved in chemotaxis, response to stress and cell adhesion were among the most variable functions. Random-effect meta-analysis of correlation trends between taxa, functions and pathways revealed key ecological and molecular associations within the gut microbiota. The contribution of specific bacterial taxa to the main biological processes was also investigated, finding that Faecalibacterium is the most stable genus and the top contributor to anti-inflammatory butyrate production in the healthy gut microbiota. Active production of other mucosal immunomodulators facilitating host tolerance was observed, including Roseburia flagellin and lipopolysaccharide biosynthetic enzymes expressed by members of Bacteroidota. Our study provides a detailed picture of the healthy human gut microbiota, contributing to unveil its functional mechanisms and its relationship with nutrition, immunity, and environmental stressors.
Topics: Humans; Gastrointestinal Microbiome; Proteomics; Bacteria; Feces; Bacterial Proteins; Healthy Volunteers; Proteome; Metabolic Networks and Pathways
PubMed: 38944645
DOI: 10.1038/s41522-024-00526-4 -
International Journal of Cardiology Jun 2024Guidelines recommend insertable cardiac monitor (ICM) in the early phases of the evaluation of unexplained syncope (US) syncope, when an arrhythmic etiology is...
AIMS
Guidelines recommend insertable cardiac monitor (ICM) in the early phases of the evaluation of unexplained syncope (US) syncope, when an arrhythmic etiology is suspected. We examined the diagnostic yield of the last generation ICM (LG-ICM) to establish the causes of US, by assessing in the clinical practice the incidence of: relevant arrhythmia diagnosis, syncope recurrences and CM-guided cardiac electronic device (CIED) implantation. We investigated also baseline patient characteristics associated to an increased risk of relevant arrhythmias and of syncope recurrence.
METHODS
Data prospectively collected from consecutive patients receiving LG-ICM for investigation of US or presyncope in our institution between November 2020 and January 2023 were analyzed.
RESULTS
A total of 109 patients (mean age 64.4 ± 16.1 years, 40.4% women) with US or pre-syncope episodes underwent implantation of the LG-ICM. During a mean follow-up of 11.7 ± 8.1 months, LG-ICM diagnostic yield was 42% . In particular, LG-ICM detected cardiac arrhythmias in 29 (27%) patients (in 6 out of them during a syncope recurrence) and to exclude the arrhythmic origin of the syncope in additional 19 (17%) patients. LG-ICM guided the implantation of a CIED in 16 (15%) US patients, due to the diagnosis of asystole or severe bradycardia. Age ≥ 65 years (p = 0.012) and atrial arrhythmia history (p = 0.004) are significant independent predictors of arrhythmic diagnoses performed by LG-ICM, while CAD is predictor of syncope recurrence (bordering on statistical significance, p = 0.056).
CONCLUSIONS
The diagnostic yield of LG-ICM in US syncope is comparable to those of ILR and previous generation ICM. The advantages of LG-ICM should be sought in lower hospital workload necessary to manage ICM data. Age ≥ 65 years and atrial arrhythmia history are independent predictors of significant ICM-detected arrhythmias.
PubMed: 38944347
DOI: 10.1016/j.ijcard.2024.132301 -
Pharmacological Research Jun 2024The global incidence of cardiac diseases is increasing, imposing a substantial socioeconomic burden on healthcare systems. The pathogenesis of cardiovascular disease is... (Review)
Review
The global incidence of cardiac diseases is increasing, imposing a substantial socioeconomic burden on healthcare systems. The pathogenesis of cardiovascular disease is complex and not fully understood, and the physiological function of the heart is inextricably linked to well-regulated cardiac muscle movement. Myosin light chain kinase (MLCK) is essential for myocardial contraction and diastole, cardiac electrophysiological homeostasis, vasoconstriction of vascular nerves and blood pressure regulation. In this sense, MLCK appears to be an attractive therapeutic target for cardiac diseases. MLCK participates in myocardial cell movement and migration through diverse pathways, including regulation of calcium homeostasis, activation of myosin light chain phosphorylation, and stimulation of vascular smooth muscle cell contraction or relaxation. Recently, phosphorylation of myosin light chains has been shown to be closely associated with the activation of myocardial exercise signaling, and MLCK mediates systolic and diastolic functions of the heart through the interaction of myosin thick filaments and actin thin filaments. It works by upholding the integrity of the cytoskeleton, modifying the conformation of the myosin head, and modulating innervation. MLCK governs vasoconstriction and diastolic function and is associated with the activation of adrenergic and sympathetic nervous systems, extracellular transport, endothelial permeability, and the regulation of nitric oxide and angiotensin II. Additionally, MLCK plays a crucial role in the process of cardiac aging. Multiple natural products/phytochemicals and chemical compounds, such as quercetin, cyclosporin, and ML-7 hydrochloride, have been shown to regulate cardiomyocyte MLCK. The MLCK-modifying capacity of these compounds should be considered in designing novel therapeutic agents. This review summarizes the mechanism of action of MLCK in the cardiovascular system and the therapeutic potential of reported chemical compounds in cardiac diseases by modifying MLCK processes.
PubMed: 38944220
DOI: 10.1016/j.phrs.2024.107276 -
Gene Jun 2024Vascular calcification is prevalent in chronic kidney disease (CKD). Genetic causes of CKD account for 10-20% of adult-onset disease. Vascular calcification is thought...
Vascular calcification is prevalent in chronic kidney disease (CKD). Genetic causes of CKD account for 10-20% of adult-onset disease. Vascular calcification is thought to be one of the most important risk factors for increased cardiovascular morbidity and mortality in CKD patients and is detectable in 80% of patients with end stage kidney disease (ESKD). Despite the high prevalence of vascular calcification in CKD, no single gene cause has been described. We hypothesized that variants in vascular calcification genes may contribute to disease pathogenesis in CKD, particularly in families who exhibit a predominant vascular calcification phenotype. We developed a list of eight genes that are hypothesized to play a role in vascular calcification due to their involvement in the ectopic calcification pathway: ABCC6, ALPL, ANK1, ENPP1, NT5E, SLC29A1, SLC20A2, and S100A12. With this, we assessed exome data from 77 CKD patients, who remained unsolved following evaluation for all known monogenic causes of CKD. We also analyzed an independent cohort (Ontario Neurodegenerative Disease Research Initiative (ONDRI), n = 520) who were screened for variants in ABCC6 and compared this to a control cohort of healthy adults (n = 52). We identified two CKD families with heterozygous pathogenic variants (R1141X and A667fs) in ABCC6. We identified 10 participants from the ONDRI cohort with heterozygous pathogenic or likely pathogenic variant in ABCC6. Replication in a healthy control cohort did not reveal any variants. Our study provides preliminary data supporting the hypothesis that ABCC6 may play a role in vascular calcification in CKD. By screening CKD patients for genetic causes early in the diagnostic pathway, patients with genetic causes associated with vascular calcification can be preventatively treated with new therapeutics with aims to decrease mortality.
PubMed: 38944164
DOI: 10.1016/j.gene.2024.148731 -
Biomedicine & Pharmacotherapy =... Jun 2024Idiopathic pulmonary fibrosis is an aging-related, chronic lung disease, with unclear pathogenesis and no effective treatment. One of the triggering factors in cell...
Idiopathic pulmonary fibrosis is an aging-related, chronic lung disease, with unclear pathogenesis and no effective treatment. One of the triggering factors in cell aging is oxidative stress and it is known to have a role in idiopathic pulmonary fibrosis. In this paper, the protective effect of the E-CG-01 (3,4-lacto-cycloastragenol) molecule in terms of its antioxidant properties was evaluated in the bleomycin induced mice lung fibrosis model. Bleomycin sulfate was administered as a single dose (2.5 U/kg body weight) intratracheally to induce lung fibrosis. E-CG-01 was administered intraperitoneally in three different doses (2 mg/kg/day, 6 mg/kg/day, and 10 mg/kg/day) for 14 days, starting three days before the bleomycin administration. Fibrosis was examined by Hematoxylin-Eosin, Masson Trichrome, and immunohistochemical staining for TGF-beta1, Type I collagen Ki-67, and gama-H2AX markers. Activity analysis of catalase and Superoxide dismutase enzymes, measurement of total oxidant, total glutathione, and Malondialdehyde levels. In histological analysis, it was determined that all three different doses of the molecule provided a prophylactic effect against the progression of fibrosis compared to the bleomycin control group. However, it was observed that only the molecule applied in the high dose decreased the total oxidant stress level. Lung weight ratio increased in the BLM group but significantly reduced with high-dose E-CG-01. E-CG-01 at all doses reduced collagen deposition, TGF-β expression, and Ki-67 expression compared to the BLM group. Intermediate and high doses of E-CG-01 also significantly reduced alveolar wall thickness and edema formation. These findings suggest that E-CG-01 has potential therapeutic effects in mitigating lung fibrosis through its antioxidant properties.
PubMed: 38943992
DOI: 10.1016/j.biopha.2024.117016 -
International Journal of Surgery Case... Jun 2024Transverse testicular ectopia (TTE) is a rare congenital condition characterized by migration of both testes through the same inguinal canal and often presents with an...
INTRODUCTION
Transverse testicular ectopia (TTE) is a rare congenital condition characterized by migration of both testes through the same inguinal canal and often presents with an inguinal hernia. TTE is associated with various genitourinary anomalies.
CASE PRESENTATION
A three-year-old boy presented with a non-palpable right testis and a palpable undescended left testis in the left inguinal area. Ultrasound (US) indicated the presence of both testes in the left inguinal canal. In surgery, the two testes were found with separated cord and one hernia sac which was dissected and ligated thus the two cords freed. Next, subdartos pouches were created on both scrotum sides, so that testes placed into the left side first, and then a window created in the scrotal septum which allowed the right testis to be translocated and secured in the right subdartos pouch without tension.
DISCUSSION
TTE is a rare condition and the etiology is not definitively known. TTE usually presents with an inguinal hernia and contralateral cryptorchidism. The diagnosis is made during surgery, but some radiological methods can help in diagnosis. Management is usually surgical and involves interventions such as hernia repair, reduction of the testis and orchiopexy. Continuous monitoring is essential for ensuring postoperative testes health and evaluating the risk of malignancy.
CONCLUSION
TTE should be suspected in cases with unilateral empty scrotum and family history of genital disorders. US is critical for accurately localizing the testes, along with surgical exploration, to proceed with the appropriate surgical intervention.
PubMed: 38943934
DOI: 10.1016/j.ijscr.2024.109949 -
Schizophrenia Research Jun 2024Deficits in N-methyl-d-aspartate receptor (NMDAR) signaling are implicated in the pathogenesis of schizophrenia. Luvadaxistat (TAK-831/NBI-1065844) is an investigational...
Deficits in N-methyl-d-aspartate receptor (NMDAR) signaling are implicated in the pathogenesis of schizophrenia. Luvadaxistat (TAK-831/NBI-1065844) is an investigational d-amino acid oxidase (DAAO) inhibitor that increases d-serine levels at NMDAR coagonist sites. INTERACT is a phase 2 randomized, placebo-controlled study that evaluated the efficacy and safety of three doses of luvadaxistat, covering a range of DAAO occupancy and d-serine levels, in patients with schizophrenia with persistent negative symptoms. The study included a 14-day, single-blinded placebo run-in period and a 12-week, double-blinded treatment period. The primary efficacy endpoint was the 12-week change from baseline in Positive and Negative Syndrome Scale-Negative Symptom Factor Score (PANSS NSFS). Secondary efficacy endpoints included the 12-week changes from baseline in Brief Assessment of Cognition in Schizophrenia (BACS) score and Schizophrenia Cognition Rating Scale (SCoRS) score. Safety endpoints included adverse event assessments. The full analysis set included all randomized patients (N = 256 [placebo, n = 87; luvadaxistat 50 mg, n = 58; 125 mg, n = 56; 500 mg, n = 55]); 228 patients completed the study. No significant improvements in PANSS NSFS were observed at any dose versus placebo at week 12. Improvements were observed with luvadaxistat 50 mg versus placebo in cognitive endpoints: BACS composite score (nominal one-sided p = 0.031) and SCoRS interviewer total score (nominal one-sided p = 0.011). Luvadaxistat did not significantly improve negative symptoms of schizophrenia. However, luvadaxistat 50 mg met the prespecified secondary endpoints for cognitive performance (BACS) and function (SCoRS), warranting further investigation in patients with cognitive impairment associated with schizophrenia. Luvadaxistat was well-tolerated in INTERACT, with no new safety signals observed. ClinicalTrials.gov: NCT03382639.
PubMed: 38943928
DOI: 10.1016/j.schres.2024.06.017 -
Nutrition Research (New York, N.Y.) Jun 2024Colorectal cancer (CRC) is one of the leading causes of cancer-related death. Currently, dietary factors are being emphasized in the pathogenesis of CRC. There is strong... (Review)
Review
Colorectal cancer (CRC) is one of the leading causes of cancer-related death. Currently, dietary factors are being emphasized in the pathogenesis of CRC. There is strong evidence that fatty acids (FAs) and free FA receptors (FFARs) are involved in CRC. This comprehensive review discusses the role of FAs and their receptors in CRC pathophysiology, development, and treatment. In particular, butyrate and n-3 polyunsaturated fatty acids have been found to exert anticancer properties by, among others, inhibiting proliferation and metastasis and inducing apoptosis in tumor cells. Consequently, they are used in conjunction with conventional therapies. Furthermore, FFAR gene expression is down-regulated in CRC, suggesting their suppressive character. Recent studies showed that the FFAR4 agonist, GW9508, can inhibit tumor growth. In conclusion, natural as well as synthetic FFAR ligands are considered promising candidates for CRC therapy.
PubMed: 38943731
DOI: 10.1016/j.nutres.2024.05.007 -
Journal of Obstetrics and Gynaecology :... Dec 2024This study examined the improvement of dysmenorrhoea and menorrhagia after uterine artery embolisation (UAE) in women with symptomatic adenomyosis and identified factors...
BACKGROUND
This study examined the improvement of dysmenorrhoea and menorrhagia after uterine artery embolisation (UAE) in women with symptomatic adenomyosis and identified factors that could predict the improvement of dysmenorrhoea and menorrhagia.
METHODS
This retrospective study included women with adenomyosis who underwent bilateral UAE between December 2014 and December 2016. The percentage of the volume of the absence of contrast enhancement on T1-weighted images was evaluated 5-7 days after UAE. A receiver operating characteristic (ROC) analysis was used to determine a cut-off point and predict the improvement of dysmenorrhoea and menorrhagia.
RESULTS
Forty-eight patients were included. At 24 and 36 months after UAE, the improvement rates for dysmenorrhoea and menorrhagia were 60.4% (29/48) and 85.7% (30/35), and the recurrence rates were 19.4% (7/36) and 9.1% (3/33), respectively. Only the percentage of the volume of the absence of contrast enhancement on T1-weighted images was associated with the improvement of dysmenorrhoea (=0.001, OR = 1.051; 95% CI: 1.02-1.08) and menorrhagia (=0.006, OR = 1.077; 95% CI: 1.021-1.136). When the cut-off value of the ROC analysis was 73.1%, sensitivity, specificity, positive predictive value, and negative predictive value for the improvement of dysmenorrhoea were 58.6%, 94.7%, 94.4%, and 60%, while they were 58.9%, 80%, 100%, 100%, and 45.5% for the improvement of dysmenorrhoea.
CONCLUSION
Bilateral UAE for symptomatic adenomyosis led to good improvement of dysmenorrhoea and menorrhagia. The percentage of the volume of the absence of contrast enhancement on T1-weighted images of the uterus in postoperative magnetic resonance imaging might be associated with the improvement of dysmenorrhoea and menorrhagia.
Topics: Humans; Female; Menorrhagia; Adenomyosis; Dysmenorrhea; Retrospective Studies; Uterine Artery Embolization; Adult; Treatment Outcome; Middle Aged; Magnetic Resonance Imaging; ROC Curve
PubMed: 38943550
DOI: 10.1080/01443615.2024.2372645