The dark side of drug repurposing. From clinical trial challenges to antimicrobial resistance: analysis based on three major fields.

Drug repurposing is a strategic endeavor that entails the identification of novel therapeutic applications for pharmaceuticals that are already available in the market. Despite the advantageous nature of implementing this particular strategy owing to its cost-effectiveness and efficiency in reducing the time required for the drug discovery process, it is essential to bear in mind that there are various factors that must be meticulously considered and taken into account. Up to this point, there has been a noticeable absence of comprehensive analyses that shed light on the limitations of repurposing drugs. The primary aim of this review is to conduct a thorough illustration of the various challenges that arise when contemplating drug repurposing from a clinical perspective in three major fields-cardiovascular, cancer, and diabetes-and to further underscore the potential risks associated with the emergence of antimicrobial resistance (AMR) when employing repurposed antibiotics for the treatment of noninfectious and infectious diseases. The process of developing repurposed medications necessitates the application of creativity and innovation in designing the development program, as the body of evidence may differ for each specific case. In order to effectively repurpose drugs, it is crucial to consider the clinical implications and potential drawbacks that may arise during this process. By comprehensively analyzing these challenges, we can attain a deeper comprehension of the intricacies involved in drug repurposing, which will ultimately lead to the development of more efficacious and safe therapeutic approaches.

Hepatocellular RECK as a Critical Regulator of Metabolic Dysfunction-Associated Steatohepatitis Development.

BACKGROUND AND AIMS: REversion inducing Cysteine rich protein with Kazal motifs (RECK) is an extracellular matrix regulator with anti-fibrotic effects. However, its expression and role in metabolic dysfunction-associated steatohepatitis (MASH) and hepatic fibrosis are poorly understood. METHODS: We generated a novel transgenic mouse model with RECK overexpression specifically in hepatocytes to investigate its role in Western diet (WD)-induced liver disease. Proteomic analysis and in vitro studies were performed to mechanistically link RECK to hepatic inflammation and fibrosis. RESULTS: Our results show that RECK expression is significantly decreased in liver biopsies from human patients diagnosed with MASH and correlated negatively with severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and fibrosis. Similarly, RECK expression is downregulated in WD-induced MASH in wild type mice. Hepatocyte-RECK overexpression significantly reduced hepatic pathology in WD-induced liver injury. Proteomic analysis highlighted changes in extracellular matrix and cell-signaling proteins. In vitro mechanistic studies linked RECK induction to reduced ADAM10 (A Disintegrin And Metalloproteinase domain-containing protein 10) and ADAM17 activity, amphiregulin release, epidermal growth factor receptor activation, and stellate cell activation. CONCLUSION: Our in vivo and mechanistic in vitro studies reveal that RECK is a novel upstream regulator of inflammation and fibrosis in the diseased liver, its induction is hepatoprotective, and thus highlight its potential as a novel therapeutic in MASH.

Spatial distribution and hydrogeochemical evaluations of groundwater and its suitability for drinking and irrigation purposes in kaligonj upazila of satkhira district of Bangladesh.

Groundwater is a significant water resource for drinking and irrigation in Satkhira district, Bangladesh. The depletion of groundwater resources and deterioration in its quality are the results of the confluence of factors such as industrialization, intensive irrigation, and rapid population growth. For this reason, this study focused on the evaluation of tubewell water of six unions of Kaligonj upazila in Satkhira district, which is situated in the coastal southwest part of Bangladesh. Major and trace elemental concentrations were assimilated into positive matrix factorization (PMF) to identify potential sources and their respective contributions. Principal component analysis (PCA) revealed that groundwater salinization and manmade activities were the primary causes of heavy metals in the coastal groundwater. Its average pH value was found to be 7.5, while Dissolved oxygen, Total dissolved solids, salinity, and conductivity, with values ranging from 1.18 to 7.38 mg/L, 0.5-4.88 g/L, 0.4-5%, and 0.95 to 8.56 mS/cm, respectively. The total hardness average value was 561.7 mg/L, classified into the very hard water categories, which is why 90% of the tubewell water samples were unfit for household purposes. All samples had an excessive level of arsenic present. The iron concentration of fifteen (15) samples crossed the standard limit according to WHO 2011 value. Around 63% of the samples were of the Na+-K+-Cl--SO42- type, and about 72% were sodium-potassium and alkali types. 98% of samples were covered in chloride and bicarbonate. The findings showed that 45.83% of the groundwater samples had negative Chloroalkaline index (CAIs), while 54.16% had positive. The permeability index (PI) was an average of 73%, and residual sodium carbonate (RSC) averaged 260.2 mg/L, and the findings clearly showed that 80% of the samples weren't appropriate for irrigation. According to the sodium adsorption ratio (SAR) value, 65% of the samples fell into the unsuitable category. These calculations indicated a high overall salinity hazard in the study area, which may be caused by the intrusion of sea water given that the study area is close to the coastal region. Findings compared to standards revealed that the majority of the samples were deemed unfit for drinking and irrigation purposes. Hence, additional attention must be paid to this area to ensure the availability of drinkable water and to preserve sustainable farming practices.

Novel chiral matrine derivatives as potential antitumor agents: Design, synthesis and biological evaluation.

Since the thalidomide incident, research on chiral drugs has escalated immensely. Differences in drug configuration can lead to significant variations in therapeutic efficacy. Matrine, a natural product esteemed for its low toxicity and high water solubility, has garnered significant attention in research endeavors. Nonetheless, its precise target has proven elusive. In this study, we designed and synthesized a novel chiral matrine derivative. Their cytotoxicity against three types of tumor cells was assessed. Comparing the newly synthesized derivatives to the parent matrine, most compounds exhibited significantly enhanced inhibitory effects on cancer cells. Among them, Q12 exhibited the highest activity, with IC50 values of 8.31 µM against rat glioma cells C6, 6.3 µM against human liver cancer cells HepG2 and 7.14 µM against human gastric cancer cells HGC-27, meanwhile showing low toxicity. Based on IC50 values, we constructed a preliminary structure-activity relationship (SAR). Compound Q12 significantly suppressed the cloning and migration of HepG2 cells. Further mechanistic studies indicated that Q12 inhibited Topo I in HepG2 cells, leading to DNA damage, induction of G0/G1 cell cycle arrest and ultimately causing apoptosis. The molecular docking experiments provided a rational binding mode of Q12 with the Topo I-DNA complex. In vivo, experiments demonstrated that Q12 exhibited a higher tumor growth inhibition rate (TGI) compared to the positive control drug Lenvatinib, while maintaining good safety. In summary, it suggests that Topo I might be a potential target for matrine and Q12 represents a promising candidate for cancer treatment.

Knowledge and Attitude Toward Child Safety Seat Use in Saudi Arabia: A Cross-Sectional Study.

Background Car safety seats (CSS) are a well-established strategy to reduce injuries and fatalities among children involved in road traffic accidents. However, the use of CSS is generally low globally due to limited knowledge of its benefits. This study assessed parents' knowledge and attitudes toward CSS in Saudi Arabia. Methods This cross-sectional study used an online self-administered survey distributed among residents in different regions of Saudi Arabia to assess their knowledge and attitude toward CSS. Data were analyzed using the statistical package for the social sciences (SPSS) version 23.0 (IBM Corp., Armonk, NY). Results A total of 383 Saudi residents participated in the study. The mean age was 37.14 ±9.10 years, with a female predominance (62.1%, n=238). One-third of the participants were from the western region of Saudi Arabia (30.3%, n=109). Non-use of CSS was reported by 25.8% of the participants, while 11.7% reported that they rarely used CSS. The mean total knowledge score was 2.15 (range 0 -3). A lower knowledge score was significantly associated with a lower educational level (p=0.008), not having information regarding CSS (p=0.005), none or rare use of CSS by the parent (p<0.001), and the use of media or self-education as a source of information regarding CSS (p=0.002). The mean attitude score was 12.52 (range 4 -20). The attitude score was significantly associated with gender (p=0.002), education (p=0.014), number of children (p=0.005), monthly family income (p=0.028), use of CSS by people other than the parent (p<0.001), information about CSS use in the car (p<0.002), source of information (p<0.001), and use of CSS by the parent (p<0.001). Conclusions The knowledge and attitude of the Suadi population toward CSS use are inadequate, highlighting the need to enhance awareness and understanding of the importance of CSS use.

Design, synthesis and biological evaluation of matrine contains benzimidazole derivatives as dual TOPOI and PARP inhibitors for cancer therapy.

TOPOI inhibitors have long been a focal point in the research and development of antitumor drugs. PARP-1 plays a crucial role in repairing DNA damage induced by TOPOI inhibitors. Thus, concurrent inhibition of TOPOI and PARP-1 has the potential to augment drug activity. Matrine, characterized by low toxicity and good water solubility, offers advantageous properties. In this investigation, a series of benzimidazole matrine derivatives were designed and synthesized using matrine as the lead compound with the aim of developing dual inhibitors targeting both TOPOI and PARP-1. Among these derivatives, Compound B6 exhibited potent inhibitory effects on PARP-1 and TOPOI, effectively suppressing cancer cell proliferation and migration. Mechanistic assessments revealed that B6 induced DNA damage in HGC-27 cells, leading to G0/G1 cell cycle arrest and significant apoptosis. Molecular docking experiments demonstrated that B6 can effectively enter the active pocket of target proteins, where it forms stable hydrogen bonds with amino acid residues. In vivo, experiments demonstrated that B6 exhibited antitumor activity comparable to that of the positive control drug. The tumor growth inhibition rates (TGIs) for irinotecan, B6 and matrine were 87.0%, 75.4% and 9.7%, respectively. Importantly, B6 demonstrated lower toxicity than the positive control drug. Our findings suggest that TOPOI and PARP-1 may represent potential targets for matrine and B6 emerges as a promising candidate for cancer therapy.

When Hearts and Minds Collide: A Case Report of Left Ventricle Noncompaction Syndrome as a Precursor to Acute Ischemic Stroke in a 15-Year-Old Along With a Literature Review.

Pediatric stroke, though uncommon, is often underdiagnosed due to subtle symptoms and delayed recognition. Cardiac diseases, accounting for up to 33% of pediatric ischemic strokes, play a significant role. This case report explores the rare occurrence of ischemic stroke in a 15-year-old boy with left ventricular non-compaction syndrome (LVNC). It underscores the complexity of managing pediatric ischemic stroke, particularly in the context of LVNC, emphasizing the challenges in timely diagnosis and management.

Epidemiology of healthcare-associated Pseudomonas aeruginosa in intensive care units: are sink drains to blame?

BACKGROUND: Pseudomonas aeruginosa (PA) is a common cause of healthcare-associated infection (PA-HAI) in the intensive care unit (ICU). AIM: To describe the epidemiology of PA-HAI in ICUs in Ontario, Canada, and to identify episodes of sink-to-patient PA transmission. METHODS: This was a prospective cohort study of patients in six ICUs from 2018 to 2019, with retrieval of PA clinical isolates, and PA-screening of antimicrobial-resistant organism surveillance rectal swabs, and of sink drain, air, and faucet samples. All PA isolates underwent whole-genome sequencing. PA-HAI was defined using US National Healthcare Safety Network criteria. ICU-acquired PA was defined as PA isolated from specimens obtained ≥48 h after ICU admission in those with prior negative rectal swabs. Sink-to-patient PA transmission was defined as ICU-acquired PA with close genomic relationship to isolate(s) previously recovered from sinks in a room/bedspace occupied 3-14 days prior to collection date of the relevant patient specimen. FINDINGS: Over ten months, 72 PA-HAIs occurred among 60/4263 admissions. The rate of PA-HAI was 2.40 per 1000 patient-ICU-days; higher in patients who were PA-colonized on admission. PA-HAI was associated with longer stay (median: 26 vs 3 days uninfected; P < 0.001) and contributed to death in 22/60 cases (36.7%). Fifty-eight admissions with ICU-acquired PA were identified, contributing 35/72 (48.6%) PA-HAIs. Four patients with five PA-HAIs (6.9%) had closely related isolates previously recovered from their room/bedspace sinks. CONCLUSION: Nearly half of PA causing HAI appeared to be acquired in ICUs, and 7% of PA-HAIs were associated with sink-to-patient transmission. Sinks may be an under-recognized reservoir for HAIs.

Relationship between serum ß-hydroxybutyrate and hepatic fatty acid oxidation in individuals with obesity and NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excess lipid accumulation that can progress to inflammation (nonalcoholic steatohepatitis, NASH), and fibrosis. Serum ß-hydroxybutyrate (ß-HB), a product of the ketogenic pathway, is commonly used as a surrogate marker for hepatic fatty acid oxidation (FAO). However, it remains uncertain whether this relationship holds true in the context of NAFLD in humans. We compared fasting serum ß-HB levels with direct measurement of liver mitochondrial palmitate oxidation in humans stratified based on NAFLD severity (n = 142). Patients were stratified based on NAFLD activity score (NAS): NAS = 0 (no disease), NAS = 1-2 (mild), NAS = 3-4 (moderate), and NAS ≥ 5 (advanced). Moderate and advanced NAFLD is associated with reductions in liver 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), serum ß-HB, but not 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) mRNA, relative to no disease. Worsening liver mitochondrial complete palmitate oxidation corresponded with lower HMGCS2 mRNA but not total (complete + incomplete) palmitate oxidation. Interestingly, we found that liver HMGCS2 mRNA and serum ß-HB correlated with liver mitochondrial ß-hydroxyacyl-CoA dehydrogenase (ß-HAD) activity and CPT1A mRNA. Also, lower mitochondrial mass and markers of mitochondrial turnover positively correlated with lower HMGCS2 in the liver. These data suggest that liver ketogenesis and FAO occur at comparable rates in individuals with NAFLD. Our findings support the utility of serum ß-HB to serve as a marker of liver injury and hepatic FAO in the context of NAFLD.NEW & NOTEWORTHY Serum ß-hydroxybutyrate (ß-HB) is frequently utilized as a surrogate marker for hepatic fatty acid oxidation; however, few studies have investigated this relationship during states of liver disease. We found that the progression of nonalcoholic fatty liver disease (NAFLD) is associated with reductions in circulating ß-HB and liver 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2). As well, decreased rates of hepatic fatty acid oxidation correlated with liver HMGCS2 mRNA and serum ß-HB. Our work supports serum ß-HB as a potential marker for hepatic fatty acid oxidation and liver injury during NAFLD.

Synthesis, antibacterial activity, and 3D-QASR studies of matrine-indole derivatives as potential antibiotics.

Matrine and indole have antibacterial, anticancer, and other biological activities, in order to develop new antibiotics to solve the problem of multi-drug resistant bacteria. In this paper, we synthesized a series of 29 novel matrine derivatives as potential drug candidates by combining indole analogs and matrine. The antibacterial activity of these compounds was evaluated through minimum inhibitory concentration (MIC) assays against five bacterial strains (S. aureus, C. albicans, P. acnes, P. aeruginosa, and E. coli). The obtained results demonstrated promising antibacterial efficacy, particularly for compounds A20 and A18, which exhibited MICs.au values of 0.021 and 0.031 mg/ml, respectively, against S. aureus. Moreover, compounds A20 and A27 displayed remarkable MICc.al values of 2.806 and 4.519 mg/ml, respectively, against C. albicans, surpassing the performance of the clinical antibiotic penicillin G sodium (0.0368 mg/ml) and fluconazole (4.849 mg/ml). These findings underscore the significant bacteriostatic activity of the matrine derivatives. Furthermore, to gain a deeper understanding 3D-QSAR modeling was employed, revealing the critical influence of steric structure, charge distribution, hydrophobic interactions, and hydrogen bonding within the molecular structure on the bacteriostatic activity of the compounds. Additionally, molecular docking simulations shed light on the interaction between compound A20 and bacterial proteins, highlighting the involvement of hydrogen bonding, hydrophobic interactions, and π-π conjugation in the formation of stable complexes that inhibit the normal functioning of the proteins. This comprehensive analysis provided valuable insights into the antibacterial mechanism of the novel matrine derivatives, offering theoretical support for their potential application as antibiotics.

Curcumin piperidone derivatives induce caspase-dependent apoptosis and suppress miRNA-21 expression in LN-18 human glioblastoma cells.

BACKGROUND: Previously, we have reported on the two curcuminoid analogues with piperidone derivatives, namely FLDP-5 and FLDP-8 have more potent anti-proliferative and anti-migration effects than curcumin. In this study, we further investigated the mode of cell death and the mechanism involved in the cell death process induced by these analogues on human glioblastoma LN-18 cells. RESULTS: The FLDP-5 and FLDP-8 curcuminoid analogues induced LN-18 cell death through apoptosis in a concentration-dependent manner following 24 h of treatment. These analogues induced apoptosis in LN-18 cells through significant loss of mitochondrial mass and mitochondrial membrane potential (MMP) as early as 1-hour of treatment. Interestingly, N-acetyl-l-cysteine (NAC) pretreatment did not abolish the apoptosis induced by these analogues, further confirming the cell death process is independent of ROS. However, the apoptosis induced by the analogues is caspases-dependent, whereby pan-caspase pretreatment inhibited the curcuminoid analogues-induced apoptosis. The apoptotic cell death progressed with the activation of both caspase-8 and caspase-9, which eventually led to the activation of caspase-3, as confirmed by immunoblotting. Moreover, the existing over-expression of miRNA-21 in LN-18 cells was suppressed following treatment with both analogues, which suggested the down-regulation of the miRNA-21 facilitates the cell death process. CONCLUSION: The FLDP-5 and FLDP-8 curcuminoid analogues downregulate the miRNA-21 expression and induce extrinsic and intrinsic apoptotic pathways in LN-18 cells.

Surgical Antibiotic Prophylaxis: A Proposal for a Global Evidence-Based Bundle.

In the multimodal strategy context, to implement healthcare-associated infection prevention, bundles are one of the most commonly used methods to adapt guidelines in the local context and transfer best practices into routine clinical care. One of the most important measures to prevent surgical site infections is surgical antibiotic prophylaxis (SAP). This narrative review aims to present a bundle for the correct SAP administration and evaluate the evidence supporting it. Surgical site infection (SSI) prevention guidelines published by the WHO, CDC, NICE, and SHEA/IDSA/APIC/AHA, and the clinical practice guidelines for SAP by ASHP/IDSA/SIS/SHEA, were reviewed. Subsequently, comprehensive searches were also conducted using the PubMed®/MEDLINE and Google Scholar databases, in order to identify further supporting evidence-based documentation. The bundle includes five different measures that may affect proper SAP administration. The measures included may be easily implemented in all hospitals worldwide and are based on minimal drug pharmacokinetics and pharmacodynamics knowledge, which all surgeons should know. Antibiotics for SAP should be prescribed for surgical procedures at high risk for SSIs, such as clean-contaminated and contaminated surgical procedures or for clean surgical procedures where SSIs, even if unlikely, may have devastating consequences, such as in procedures with prosthetic implants. SAP should generally be administered within 60 min before the surgical incision for most antibiotics (including cefazolin). SAP redosing is indicated for surgical procedures exceeding two antibiotic half-lives or for procedures significantly associated with blood loss. In principle, SAP should be discontinued after the surgical procedure. Hospital-based antimicrobial stewardship programmes can optimise the treatment of infections and reduce adverse events associated with antibiotics. In the context of a collaborative and interdisciplinary approach, it is essential to encourage an institutional safety culture in which surgeons are persuaded, rather than compelled, to respect antibiotic prescribing practices. In that context, the proposed bundle contains a set of evidence-based interventions for SAP administration. It is easy to apply, promotes collaboration, and includes measures that can be adequately followed and evaluated in all hospitals worldwide.

Thyroid Hormone and Mitochondrial Dysfunction: Therapeutic Implications for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed nonalcoholic fatty liver disease (NAFLD), is a widespread global health concern that affects around 25% of the global population. Its influence is expanding, and it is anticipated to overtake alcohol as the leading cause of liver failure and liver-related death worldwide. Unfortunately, there are no approved therapies for MASLD; as such, national and international regulatory health agencies undertook strategies and action plans designed to expedite the development of drugs for treatment of MASLD. A sedentary lifestyle and an unhealthy diet intake are important risk factors. Western countries have a greater estimated prevalence of MASLD partly due to lifestyle habits. Mitochondrial dysfunction is strongly linked to the development of MASLD. Further, it has been speculated that mitophagy, a type of mitochondrial quality control, may be impaired in MASLD. Thyroid hormone (TH) coordinates signals from the nuclear and mitochondrial genomes to control mitochondrial biogenesis and function in hepatocytes. Mitochondria are known TH targets, and preclinical and clinical studies suggest that TH, thyroid receptor ß (TR-ß) analogs, and synthetic analogs specific to the liver could be of therapeutic benefit in treating MASLD. In this review, we highlight how mitochondrial dysfunction contributes to development of MASLD, and how understanding the role of TH in improving mitochondrial function paved the way for innovative drug development programs of TH-based therapies targeting MASLD.

Development of a novel hypochlorite ratio probe based on coumarin and its application in living cells.

Hypochlorous acid is a reactive oxygen species that is widely present in the body and has been found to exhibit an elevated concentration in tumors. As a result, fluorescent probes for tumor detection have recently gained significant attention. In this study, we designed and synthesized a novel ratiometric fluorescent probe, LW-1, using coumarin as a scaffold, and characterized its spectral properties. LW-1 displayed indigo blue fluorescence at low concentrations of hypochlorous acid. As the concentration of hypochlorous acid increased, the probe underwent a reaction, resulting in a red shift in its fluorescence peak and exhibiting green fluorescence. The fluorescence intensity ratio (green/blue) was a susceptible detection signal for HClO. LW-1 exhibited favorable characteristics, including a low detection limit, high sensitivity, good stability, and low background interference. The detection limit has reached 2.4642 nM. Moreover, we successfully employed LW-1 to image normal human liver and colon cancer cells in vitro, demonstrating its potential as a promising tool for tumor detection. Overall, our findings suggest that LW-1 could serve as a valuable addition to the current arsenal of fluorescent probes for tumor detection, with potential applications in the diagnosis and treatment of cancer.

Fecal Calprotectin and Organic Gastrointestinal Disease: A Systematic Review.

This review aimed to assess the diagnostic utility of fecal calprotectin (FCP) for identifying organic gastrointestinal disease (OGID) in patients undergoing colonoscopy for gastrointestinal discomfort or active progression of inflammatory bowel disease (IBD). Studies published between January 2013 and December 2022 evaluating the clinical efficacy of FCP for differentiating OGID against functional gastrointestinal disease (FGID) were identified using PubMed, Cochrane, and Scopus databases. Clinical diagnostic studies involving individuals with lower gastrointestinal symptoms; using FCP as a diagnostic biomarker either in primary, secondary, or tertiary healthcare centers conducted either prospectively or retrospectively using stool samples (index test), contrasting FCP with a reference test, such as colonoscopy, or endoscopy, and assessed using enzyme-linked immunosorbent assay were reviewed. The included studies were subjected to the revised Quality Assessment of Diagnostic Accuracy Studies for assessing the methodological quality by two independent authors. An initial literature search yielded 545 articles rendering 417 records after removing the duplicate records. After reading the abstracts and titles, 89 articles were eligible for full-text screening. The qualitative synthesis resulted in 20 articles. The efficient use of FCP for differentiating IBD from irritable bowel syndrome was investigated in 15 studies.Two of the included studies assessed the diagnostic ability of FCP to distinguish OGID from FGID, two studies utilized patients with ulcerative colitis, and one study involved patients with Crohn's disease. Overall study quality was high for 65% of studies,moderate for 25% of studies, and low for 10% of studies. The review outlined the diagnostic accuracy of non-invasive FCP assessment for OGID in various clinical scenarios and in individuals of various ages. FCP is used as a tool for screening and monitoring in clinical practice for determining the need of further comprehensive investigations, thereby reducing the redundant use of invasive techniques.

Isotope Labeling and Biochemical Assessment of Liver-Triacylglycerol in Patients with Different Levels of Histologically-Graded Liver Disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) prevalence is rapidly growing, and fatty liver has been found in a quarter of the US population. Increased liver lipids, particularly those derived from the pathway of de novo lipogenesis (DNL), have been identified as a hallmark feature in individuals with high liver fat. This has led to much activity in basic science and drug development in this area. No studies to date have investigated the contribution of DNL across a spectrum of disease, although it is clear that inhibition of DNL has been shown to reduce liver fat. OBJECTIVES: The purpose of this study was to determine whether liver lipid synthesis increases across the continuum of liver injury. METHODS: Individuals (n = 49) consumed deuterated water for 10 d before their scheduled bariatric surgeries to label DNL; blood and liver tissue samples were obtained on the day of the surgery. Liver lipid concentrations were quantitated, and levels of protein and gene expression assessed. RESULTS: Increased liver DNL, measured isotopically, was significantly associated with liver fatty acid synthase protein content (R = 0.470, P = 0.003), total steatosis assessed by histology (R = 0.526, P = 0.0008), and the fraction of DNL fatty acids in plasma very low-density lipoprotein-triacylglycerol (R = 0.747, P < 0.001). Regression analysis revealed a parabolic relationship between fractional liver DNL (percent) and NAFLD activity score (R = 0.538, P = 0.0004). CONCLUSION: These data demonstrate that higher DNL is associated with early to mid stages of liver disease, and this pathway may be an effective target for the treatment of NAFLD and nonalcoholic steatohepatitis. This study was registered at clinicaltrials.gov as NCT03683589.

Quadratus lumborum block and transversus abdominis plane block in laparoscopic nephrectomy: a meta-analysis.

Aim: To study the efficacy of quadratus lumborum block (QLB) and transversus abdominis plane (TAP) in laparoscopic nephrectomy patients. Materials & methods: We conducted a meta-analysis of randomized controlled trials for QLB and/or TAP technique compared with each other or a control. Results: Direct analysis of 24 h post-op pain score at rest for each compared with control showed significant reduction, QLB (mean differences [MD] [95% CI]: -1.12 [-1.87,-0.36]; p = 0.004) and TAP (MD [95% CI]: -0.36 [-0.59, -0.12]; p = 0.003). With movement both were respectively lower than control QLB (MD [95% CI]: -1.12 [-1.51, -0.72]; p = <0.0001) and TAP (MD [95% CI]: -0.50 [-0.95, -0.05]; p = 0.03). Moreover, QLB demonstrated less risk 24 h of post-op nausea vomiting (PONV) versus control (PONV; risk ratios [RR] [95% CI]: 0.64 [0.45,0.90]; p = 0.01). Conclusion: TAP and QLB reduce pain scores compared with control, whereas only QLB reduces PONV compared with control.

Protective Effect of Daidzein against Diethylnitrosamine/Carbon Tetrachloride-Induced Hepatocellular Carcinoma in Male Rats.

Hepatocellular carcinoma (HCC) is the second-largest cause of death among all cancer types. Many drugs have been used to treat the disease for a long time but have been mostly discontinued because of their side effects or the development of resistance in the patients with HCC. The administration of DZ orally is a great focus to address the clinical crisis. Daidzein (DZ) is a prominent isoflavone polyphenolic chemical found in soybeans and other leguminous plants. It has various pharmacological effects, including anti-inflammatory, antihemolytic, and antioxidant. This present study investigates the protective effect of DZ on chemically induced HCC in rat models. The DZ was administered orally four weeks before HCC induction and continued during treatment. Our study included four treatment groups: control (group 1, without any treatment), HCC-induced rats (group II), an HCC group treated with DZ at 20 mg/kg (group III), and an HCC group treated with DZ at 40 mg/kg (group IV). HCC rats showed elevation in all the HCC markers (AFP, GPC3, and VEGF), liver function markers (ALP, ALT, and AST), inflammatory markers (IL-6, TNF-α, and CRP), and lipid markers concomitant with a decrease in antioxidant enzymes and protein. However, groups III and IV demonstrated dose-dependent alleviation in the previous parameters resulting from HCC. In addition, the high dose of DZ reduces many hepatological changes in HCC rats. All study parameters improved with DZ administration. Due to its antioxidant and anti-inflammatory characteristics, DZ is a promising HCC treatment option for clinical use.

EUS-guided versus percutaneous liver biopsy: A prospective randomized clinical trial.

Background and Objectives: Prospective studies comparing EUS-guided liver biopsy (EUS-LB) to percutaneous LB (PC-LB) are scarce. We compared the efficacy and safety of EUS-LB with those of PC-LB in a prospective randomized clinical trial. Methods: Between 2020 and 2021, patients were enrolled and randomized (1:1 ratio). The primary outcome was defined as the proportion of patients with ≥11 complete portal tracts (CPTs). The sample size (n = 80) was calculated based on the assumption that 60% of those in the EUS-LB and 90% of those in the PC-LB group will have LB with ≥11 CPTs. The secondary outcomes included proportion of patients in whom a diagnosis was established, number of CPTs, pain severity (Numeric Rating Scale-Pain Intensity), duration of hospital stay, and adverse events. Results: Eighty patients were enrolled (median age, 53 years); 67.5% were female. Sixty percent of those in the EUS-LB and 75.0% of those in the PC-LB group met the primary outcome (P = 0.232). The median number of CPTs was higher in the PC-LB (17 vs 13; P = 0.031). The proportion of patients in whom a diagnosis was established was similar between the groups (92.5% [EUS-LB] vs 95.0% [PC-LB]; P = 1.0). Patients in the EUS-LB group had less pain severity (median Numeric Rating Scale-Pain Intensity, 2.0 vs 3.0; P = 0.003) and shorter hospital stay (2.0 vs 4.0 hours; P < 0.0001) compared with the PC-LB group. No patient experienced a serious adverse event. Conclusions: EUS-guided liver biopsy was safe, effective, better tolerated, and associated with a shorter hospital stay.

A Comparison of Magnesium Levels in Obese Versus Normal-Weight Children.

Introduction One of the world's most pressing problems right now is childhood obesity. After potassium, magnesium (Mg) is the second most prevalent intracellular cation and the fourth most prevalent mineral in the human body. Numerous symptoms of magnesium insufficiency can include hypocalcemia, hypokalemia, as well as cardiac and neurological symptoms. Additionally, chronically low Mg levels have been associated with a number of chronic diseases such as diabetes, hypertension, coronary heart disease, and osteoporosis. Objectives This study aimed to compare the magnesium (Mg) level between normal-weight and obese children in a tertiary center in Saudi Arabia over the past seven years and evaluate the vitamin D and phosphorus between the two groups as a secondary objective. Methods This is a single-center, case-control study conducted on patients followed up in our center from January 2016 to December 2022. All pediatric patients were between two and 14 years of age. They were divided into two groups: one with children whose body mass index (BMI) was over the 85th percentile and the other with children whose BMI was between the 3rd and 85th percentiles. Results Mean serum Mg levels showed no significant correlation between the obese group (0.82 mg/dl) and the normal-weight group (0.83 mg/dl). However, vitamin D and phosphorus demonstrate a significant difference between the two groups. The obese group revealed a vitamin D of 1.6±0.24 and phosphorus of 4.2±0.46. On the other hand, the normal group had a vitamin D of 44.0±28.2 and phosphorus of 1.5±0.26. Conclusion There was a negative correlation between Mg levels and weight in pediatric patients. However, a positive relationship was observed between the Mg intake and Mg levels. Moreover, sodium, phosphorus, and vitamin D levels showed significant differences.