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Clinical and Molecular Hepatology Jun 2024In managing metabolic dysfunction-associated steatotic liver disease, which affects over 30% of the general population, effective noninvasive biomarkers for assessing... (Review)
Review
In managing metabolic dysfunction-associated steatotic liver disease, which affects over 30% of the general population, effective noninvasive biomarkers for assessing disease severity, monitoring disease progression, predicting the development of liver-related complications, and assessing treatment response are crucial. The advantage of simple fibrosis scores lies in their widespread accessibility through routinely performed blood tests and extensive validation in different clinical settings. They have shown reasonable accuracy in diagnosing advanced fibrosis and good performance in excluding the majority of patients with a low risk of liver-related complications. Among patients with elevated serum fibrosis scores, a more specific fibrosis and imaging biomarker has proved useful to accurately identify patients at risk of liver-related complications. Among specific fibrosis blood biomarkers, enhanced liver fibrosis is the most widely utilized and has been approved in the United States as a prognostic biomarker. For imaging biomarkers, the availability of vibration-controlled transient elastography has been largely improved over the past years, enabling the use of liver stiffness measurement (LSM) for accurate assessment of significant and advanced fibrosis, and cirrhosis. Combining LSM with other routinely available blood tests enhances the ability to diagnose at-risk metabolic dysfunction-associated steatohepatitis; and predict liver-related complications, some reaching an accuracy comparable to that of liver biopsy. Magnetic resonance imaging-based modalities provide the most accurate quantification of liver fibrosis, though the current utilization is limited to research settings. Expanding their future use in clinical practice depends on factors such as cost and facility availability.
PubMed: 38934108
DOI: 10.3350/cmh.2024.0246 -
Haematologica Jun 2024The treatment of blast phase chronic myeloid leukemia (bpCML) remains a challenge due at least in part to drug resistance of leukemia stem cells (LSCs). Recent clinical...
The treatment of blast phase chronic myeloid leukemia (bpCML) remains a challenge due at least in part to drug resistance of leukemia stem cells (LSCs). Recent clinical evidence suggests that the BCL-2 inhibitor venetoclax in combination with ABL-targeting tyrosine kinase inhibitors (TKIs) can eradicate bpCML LSCs. In this report, we employed preclinical models of bpCML to investigate the efficacy and underlying mechanism of LSC-targeting with venetoclax/TKI combinations. Transcriptional analysis of LSCs exposed to venetoclax and dasatinib revealed upregulation of genes involved in lysosomal biology, in particular lysosomal acid lipase A (LIPA), a regulator of free fatty acids. Metabolomic analysis confirmed increased levels of free fatty acids in response to venetoclax/dasatinib. Pre-treatment of leukemia cells with bafilomycin, a specific lysosome inhibitor, or genetic perturbation of LIPA, resulted in increased sensitivity of leukemia cells toward venetoclax/dasatinib, implicating LIPA in treatment resistance. Importantly, venetoclax/dasatinib treatment does not affect normal stem cell function, suggestive of a leukemia-specific response. These results demonstrate that venetoclax/dasatinib is an LSCselective regimen in bpCML and that disrupting LIPA and fatty acid transport enhances venetoclax/dasatinib response in targeting LSCs, providing a rationale for exploring lysosomal disruption as an adjunct therapeutic strategy to prolong disease remission.
PubMed: 38934082
DOI: 10.3324/haematol.2023.284716 -
Haematologica Jun 2024To evaluate the efficacy and safety of flumatinib in the later-line treatment of Chinese patients with Philadelphia chromosome-positive chronic-phase chronic myeloid...
To evaluate the efficacy and safety of flumatinib in the later-line treatment of Chinese patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CP-CML previously treated with tyrosine kinase inhibitors (TKIs). Patients with CML-CP were evaluated for the probabilities of responses including complete hematologic response (CHR), cytogenetic response, and molecular response (MR) and adverse events (AEs) after the later-line flumatinib therapy. Of 336 enrolled patients with median age 50 years, median duration of treatment with flumatinib was 11.04 (2-25.23) months. Patients who achieved clinical responses at baseline showed maintenance of CHR, complete cytogenetic response (CCyR)/2-log molecular response (MR2), major molecular response (MMR), and 4-log molecular response or deep molecular response (MR4/DMR) in 100%, 98.9%, 98.6%, and 92.9% patients, respectively. CHR, CCyR/MR2, MMR, and MR4/DMR responses were achieved in 86.4%, 52.7%, 49.6%, and 23.5% patients respectively, which showed the lack of respective clinical responses at baseline. The patients without response at baseline, treated with flumatinib as 2L TKI, having no resistance to prior TKI or only resistance to imatinib, with response to last TKI, and with BCR::ABL ≤10% had higher CCyR/MR2, MMR, or MR4/DMR. The AEs observed during the later-line flumatinib treatment were tolerable and consistent with those reported with the first-line therapy. Flumatinib was effective and safe in patients who are resistant or intolerant to other TKIs. In particular, 2L flumatinib treatment induced high response rates and was more beneficial to patients without previous 2G TKI resistance, thus serving as a probable treatment option for these patients.
PubMed: 38934064
DOI: 10.3324/haematol.2023.284892 -
Kidney Research and Clinical Practice May 2024Patients with end-stage kidney disease (ESKD) are more susceptible to viral epidemics and are known to have higher incidence and death rates of coronavirus disease 2019...
BACKGROUND
Patients with end-stage kidney disease (ESKD) are more susceptible to viral epidemics and are known to have higher incidence and death rates of coronavirus disease 2019 (COVID-19) compared to the general population. We determined COVID-19 incidence and mortality among chronic hemodialysis (HD), peritoneal dialysis (PD), and kidney transplantation (KT) patients in Korea.
METHODS
We conducted a retrospective cohort study and data regarding Korean ESKD adults (aged ≥18 years) were obtained from the National Health Insurance Service of Korea from October 2020 to December 2021. We examined and compared the incidence of COVID-19-related infections and deaths among the patients receiving HD, PD, and KT.
RESULTS
Of all ESKD patients, 85,018 (68.1%) were on HD, 8,399 (6.7%) on PD, and 31,343 (25.1%) on KT. The COVID-19 incidence was 1.3% for HD, 1.2% for PD, and 1.5% for KT. COVID-19 mortality was 16.3% for HD, 12.2% for PD, and 4.7% for KT. PD patients had a lower incidence of infection compared to HD patients (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.607-0.93), but KT patients had a significantly higher risk of infection (OR, 1.28; 95% CI, 1.13-1.44). Compared with HD, the risk of COVID-19-related death was not different for PD patients but was significantly lower for KT patients (hazard ratio, 0.55; 95% CI, 0.35-0.88).
CONCLUSION
COVID-19 incidence was lower in PD patients than in HD patients, but mortality was not different between them. KT was associated with a higher risk of COVID-19 infection but lower mortality compared to HD.
PubMed: 38934044
DOI: 10.23876/j.krcp.23.287 -
Heliyon Jun 2024The botulinum toxin is an extremely potent substance that impacts the nervous system. There has been a rise in cases of medical poisoning associated with it,...
BACKGROUND
The botulinum toxin is an extremely potent substance that impacts the nervous system. There has been a rise in cases of medical poisoning associated with it, particularly in the field of plastic and aesthetic procedures, in recent years.
CASE DESCRIPTION
A 51-year-old woman underwent a facial wrinkle reduction procedure with an unauthorized injection of 100 U of botulinum toxin at an unlicensed medical facility six days prior to hospitalization. Over time, her toxicity symptoms intensified, impacting her respiratory muscles, and she did not receive antitoxin treatment. She was concurrently diagnosed with a COVID-19 infection during this period. Nonetheless, she experienced a full recovery 86 days after the injection.
CONCLUSION
Currently, there is no effective antidote for botulism. Nevertheless, the timely administration of antitoxin can contribute to reducing the duration of the illness, alleviating symptoms, and preventing its recurrence. It is essential to recognize that individual responses may vary, and in this instance, the absence of antitoxin treatment did not significantly prolong the course of the disease. Accurate diagnosis of medical poisoning can be based on injection history and clinical symptoms. Early indications like fatigue and dry mouth warrant particular attention, emphasizing the importance of immediate medical intervention. To address emergencies, the Center for Disease Control (CDC) should maintain an accessible supply of antitoxin. Patients with severe poisoning should be hospitalized until their respiratory muscle strength is fully restored.
PubMed: 38933984
DOI: 10.1016/j.heliyon.2024.e32237 -
Heliyon Jun 2024() is a gram-positive coccus belonging to the Streptococcaceae family. While primarily a pathogen in fish farms causing hemorrhagic sepsis, it can act as a rare...
() is a gram-positive coccus belonging to the Streptococcaceae family. While primarily a pathogen in fish farms causing hemorrhagic sepsis, it can act as a rare opportunistic pathogen in humans. A 2021 case report by Bravo et al. documented less than 30 cases of infective endocarditis caused by worldwide at that time [1]. This case report describes the 27th documented case globally and 7th documented case in the USA of causing infective endocarditis of a prosthetic valve [1]. is found in unpasteurized dairy products, raw fish, and meat (pork, beef, and poultry), but the route of human transmission remains unclear [3]. It seems to have a predilection for individuals with prosthetic valves, immunocompromised states, prior gastrointestinal surgery, gastrointestinal disorders (colon polyps and diverticulosis), and the use of acid-reducing medications [1-3]. Infective endocarditis is the most common systemic disease caused by [1-4]. This report details the case of a 75-year-old male, with multiple comorbidities and risk factors for infection who was admitted for "symptomatic anemia". High clinical suspicion, coupled with an inadequate hemoglobin response to transfusion, a normal anemia workup, and blood cultures positive for , promoted a transesophageal echocardiogram (TEE). However, the results were negative. Consequently, an F-fluorodeoxyglucose positron emission tomography/computed tomography scan (FDG PET/CT) was performed. The scan revealed increased uptake in the aortic valve replacement consistent with prosthetic valve endocarditis in the setting of bacteremia.
PubMed: 38933970
DOI: 10.1016/j.heliyon.2024.e32383 -
Frontiers in Nutrition 2024Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by itching, epidermal barrier dysfunction, and an unbalanced inflammatory reaction. AD... (Review)
Review
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by itching, epidermal barrier dysfunction, and an unbalanced inflammatory reaction. AD pathophysiology involves a dysregulated immune response driven by T helper-2 cells. Many factors, including reactive oxygen species (ROS), are involved in AD pathogenesis by causing cellular damage and inflammation resulting in skin barrier dysfunction. This narrative review aims to provide a comprehensive overview of the role of natural molecules and antioxidant compounds, highlighting their potential therapeutic value in AD prevention and management. They include vitamin D, vitamin E, pyridoxine, Vitamin C, carotenoids, and melatonin. Some studies report a statistically significant association between antioxidant levels and improvement in AD, however, there are conflicting results in which antioxidant supplementation, especially Vitamin D, did not result in improvement in AD. Therefore, the clinical efficacy of these dietary nutritional factors in the treatment of AD needs to be further evaluated in clinical trials. Meanwhile, antioxidants can be incorporated into the management of AD patients in a personalized manner, tailored to the severity of the disease, comorbidities, and individual needs.
PubMed: 38933878
DOI: 10.3389/fnut.2024.1393673 -
Frontiers in Veterinary Science 2024Feline chronic enteropathies (FCE) are common causes of chronic gastrointestinal signs in cats and include different diseases such as food-responsive enteropathy (FRE),...
Feline chronic enteropathies (FCE) are common causes of chronic gastrointestinal signs in cats and include different diseases such as food-responsive enteropathy (FRE), inflammatory bowel diseases (IBD), and low-grade intestinal T-cell lymphoma (LGITL). Although changes in intestinal microbiota and fecal metabolites have been reported in dogs and humans with chronic enteropathy, research in cats has been limited. Therefore, this study aimed to evaluate the fecal microbiota and lipid-related fecal metabolites in cats with FCE to a clinically healthy comparison group (CG). A total of 34 cats with FCE (13 FRE, 15 IBD, and 6 LGITL) and 27 cats in the CG were enrolled in this study. The fecal microbiota was evaluated by the qPCR-based feline Dysbiosis Index (DI). The feline DI in cats with CE (median: 1.3, range: -2.4 to 3.8) was significantly higher ( < 0.0001) compared to CG (median: - 2.3, Range: -4.3 to 2.3), with no difference found among the FCE subgroups. The fecal abundances of Faecalibacterium ( < 0.0001), ( < 0.0001), ( = 0.0398), Bifidobacterium ( = 0.0004), and total bacteria ( = 0.0337) significantly decreased in cats with FCE. Twenty-seven targeted metabolites were measured by gas chromatography-mass spectrometry, including long-chain fatty acids (LCFAs), sterols, and bile acids (BAs). Fecal concentrations of 5 of 12 LCFAs were significantly increased in cats with FCE compared to CG. Fecal concentrations of zoosterol ( = 0.0109), such as cholesterol ( < 0.001) were also significantly increased in cats with FCE, but those of phytosterols were significantly decreased in this group. No differences in fecal BAs were found between the groups. Although no differences were found between the four groups, the fecal metabolomic pattern of cats with FRE was more similar to that of the CG than to those with IBD or LGITL. This could be explained by the mild changes associated with FRE compared to IBD and LGITL. The study showed changes in intestinal microbiota and alteration of fecal metabolites in FCE cats compared to the CG. Changes in fecal lipids metabolites suggest a dysmetabolism of lipids, including LCFAs, sterols, and unconjugated BAs in cats with CE.
PubMed: 38933703
DOI: 10.3389/fvets.2024.1401592 -
Frontiers in Veterinary Science 2024An increase in chronic, non-responsive bovine respiratory disease (BRD) infections in North American feedlot cattle is observed each fall, a time when cattle are... (Review)
Review
An increase in chronic, non-responsive bovine respiratory disease (BRD) infections in North American feedlot cattle is observed each fall, a time when cattle are administered multiple antimicrobial treatments for BRD. A number of factors are responsible for BRD antimicrobial treatment failure, with formation of biofilms possibly being one. It is widely accepted that biofilms play a role in chronic infections in humans and it has been hypothesized that they are the default lifestyle of most bacteria. However, research on bacterial biofilms associated with livestock is scarce and significant knowledge gaps exist in our understanding of their role in AMR of the bacterial BRD complex. The four main bacterial species of the BRD complex, , , , and are able to form biofilms and there is evidence that at least retains this ability . However, there is a need to elucidate whether their biofilm-forming ability contributes to pathogenicity and antimicrobial treatment failure of BRD. Overall, a better understanding of the possible role of BRD bacterial biofilms in clinical disease and AMR could assist in the prevention and management of respiratory infections in feedlot cattle. We review and discuss the current knowledge of BRD bacteria biofilm biology, study methodologies, and their possible relationship to AMR.
PubMed: 38933702
DOI: 10.3389/fvets.2024.1353551 -
Frontiers in Cellular and Infection... 2024This study unveils the intricate functional association between cyclic di-3',5'-adenylic acid (c-di-AMP) signaling, cellular bioenergetics, and the regulation of...
BACKGROUND
This study unveils the intricate functional association between cyclic di-3',5'-adenylic acid (c-di-AMP) signaling, cellular bioenergetics, and the regulation of lipopolysaccharide (LPS) profile in , a Gram-negative obligate anaerobe considered as a keystone pathogen involved in the pathogenesis of chronic periodontitis. Previous research has identified variations in LPS profile as a major virulence factor, yet the underlying mechanism of its modulation has remained elusive.
METHODS
We employed a comprehensive methodological approach, combining two mutants exhibiting varying levels of c-di-AMP compared to the wild type, alongside an optimized analytical methodology that combines conventional mass spectrometry techniques with a novel approach known as FLAT.
RESULTS
We demonstrate that c-di-AMP acts as a metabolic nexus, connecting bioenergetic status to nuanced shifts in fatty acid and glycosyl profiles within LPS. Notably, the predicted regulator gene , serving as a potent regulator of c-di-AMP synthesis, was found essential for producing N-acetylgalactosamine and an unidentified glycolipid class associated with the LPS profile.
CONCLUSION
The multifaceted roles of c-di-AMP in bacterial physiology are underscored, emphasizing its significance in orchestrating adaptive responses to stimuli. Furthermore, our findings illuminate the significance of LPS variations and c-di-AMP signaling in determining the biological activities and immunostimulatory potential of LPS, promoting a pathoadaptive strategy. The study expands the understanding of c-di-AMP pathways in Gram-negative species, laying a foundation for future investigations into the mechanisms governing variations in LPS structure at the molecular level and their implications for host-pathogen interactions.
Topics: Porphyromonas gingivalis; Lipopolysaccharides; Signal Transduction; Virulence Factors; Gene Expression Regulation, Bacterial; Energy Metabolism; Dinucleoside Phosphates; Fatty Acids; Humans; Bacterial Proteins
PubMed: 38933693
DOI: 10.3389/fcimb.2024.1418651