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1.
Cureus ; 16(6): e62528, 2024 Jun.
Article in English | MEDLINE | ID: mdl-39022488

ABSTRACT

Sjogren's syndrome (SS) is an autoimmune disease characterized by inflammation of exocrine glands. The disorder predominantly affects middle-aged women. Autoantibodies, including anti-SS-A/Ro and anti-SS-B/La antibodies, are present in most cases of SS. These antibodies can cross the placenta and likely play a role in pregnancy complications as well as the development of neonatal lupus, resulting in congenital heart block (CHB). It is essential to monitor the fetus for CHB during pregnancy. In particular, screening with echocardiography and monitoring heart rate at home are recommended practices. Regarding medical management, hydroxychloroquine and glucocorticoids have shown promise in reducing cardiac manifestations, but further research is needed to elucidate their longer term efficacy and safety. This scoping review analyzes literature from 2001 to 2024, focusing on pregnancy outcomes among women with SS, clinical manifestations of neonatal lupus, the role of anti-SS-A/Ro and anti-SS-B/La antibodies in the development of neonatal lupus and CHB, and emphasizes the need for future research efforts to refine treatment protocols and enhance clinical care strategies for pregnant women with SS.

2.
Pediatr Crit Care Med ; 25(7): 643-675, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38959353

ABSTRACT

OBJECTIVES: To present recommendations and consensus statements with supporting literature for the clinical management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus conference. DATA SOURCES: Systematic review was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial meetings of international, interprofessional experts in the management ECMO for critically ill children. STUDY SELECTION: The management of ECMO anticoagulation for critically ill children. DATA EXTRACTION: Within each of eight subgroup, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. DATA SYNTHESIS: A systematic review was conducted using MEDLINE, Embase, and Cochrane Library databases, from January 1988 to May 2021. Each panel developed evidence-based and, when evidence was insufficient, expert-based statements for the clinical management of anticoagulation for children supported with ECMO. These statements were reviewed and ratified by 48 PEACE experts. Consensus was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed 23 recommendations, 52 expert consensus statements, and 16 good practice statements covering the management of ECMO anticoagulation in three broad categories: general care and monitoring; perioperative care; and nonprocedural bleeding or thrombosis. Gaps in knowledge and research priorities were identified, along with three research focused good practice statements. CONCLUSIONS: The 91 statements focused on clinical care will form the basis for standardization and future clinical trials.


Subject(s)
Anticoagulants , Critical Illness , Extracorporeal Membrane Oxygenation , Extracorporeal Membrane Oxygenation/methods , Humans , Anticoagulants/therapeutic use , Anticoagulants/administration & dosage , Child , Critical Illness/therapy , Infant, Newborn , Infant , Child, Preschool
3.
Pediatr Crit Care Med ; 25(7 Suppl 1): e53-e65, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38959360

ABSTRACT

OBJECTIVES: To derive systematic review-informed, modified Delphi consensus regarding the management of children on extracorporeal membrane oxygenation (ECMO) undergoing invasive procedures or interventions developed by the Pediatric Anticoagulation on ECMO CollaborativE (PEACE) Consensus Conference. DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021. STUDY SELECTION: ECMO anticoagulation and hemostasis management in the perioperative period and during procedures. DATA EXTRACTION: Two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. Seventeen references were used for data extraction and informed recommendations. Evidence tables were constructed using a standardized data extraction form. DATA SYNTHESIS: Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation system. Forty-eight experts met over 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements for the management of bleeding and thrombotic complications in pediatric ECMO patients. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was defined as greater than 80% agreement. Four good practice statements, 7 recommendations, and 18 consensus statements are presented. CONCLUSIONS: Although agreement among experts was strong, important future research is required in this population for evidence-informed recommendations.


Subject(s)
Anticoagulants , Delphi Technique , Extracorporeal Membrane Oxygenation , Humans , Extracorporeal Membrane Oxygenation/methods , Extracorporeal Membrane Oxygenation/adverse effects , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Child , Perioperative Period , Consensus , Perioperative Care/methods , Perioperative Care/standards , Hemorrhage/chemically induced , Thrombosis/prevention & control , Thrombosis/etiology
4.
Cureus ; 16(6): e61846, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38975405

ABSTRACT

The recent rise in hand sanitizer use due to the COVID-19 pandemic has had a beneficial impact on stopping the spread of disease, but the potential negative implications of its overuse on the body and the microbiome have yet to be thoroughly reviewed. Epidermal layers absorb hand sanitizer from direct application to the skin, making them some of the most susceptible cells to the adverse effects of overuse. The increased usage of hand sanitizer can affect the variation, quantity, and diversity of the skin microflora, leading to conditions such as eczema, atopic dermatitis, and even systemic toxicity due to colonization of the skin with pathogenic bacteria. Due to the close-knit relationship between the skin and gut, the gastrointestinal system can also incur disruptions due to the negative effects on the skin as a result of excessive hand sanitizer use, leading to gut dysbiosis. Additionally, the accidental ingestion of hand sanitizer, and its abuse or misuse, can be toxic and lead to alcohol poisoning, which is an issue most commonly seen not only in the pediatric population but also in adolescents and adults due to aberrant recreational exposure. As a vulnerable body system, the eyes can also be negatively impacted by hand sanitizer misuse leading to chemical injury, visual impairment, and even blindness. In this review, we aim to highlight the variations in hand sanitizer formulation, the benefits, and how misuse or overuse may lead to adverse effects on the skin, gut, and eyes. In particular, we review the advantages and disadvantages of alcohol-based hand sanitizers (ABHSs) and non-alcohol-based hand sanitizers (NABHSs) and how the components and chemicals used in each can contribute to organ dysbiosis and systemic damage.

5.
Commun Biol ; 7(1): 818, 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38969758

ABSTRACT

Speech brain-computer interfaces aim to support communication-impaired patients by translating neural signals into speech. While impressive progress was achieved in decoding performed, perceived and attempted speech, imagined speech remains elusive, mainly due to the absence of behavioral output. Nevertheless, imagined speech is advantageous since it does not depend on any articulator movements that might become impaired or even lost throughout the stages of a neurodegenerative disease. In this study, we analyzed electrocortigraphy data recorded from 16 participants in response to 3 speech modes: performed, perceived (listening), and imagined speech. We used a linear model to detect speech events and examined the contributions of each frequency band, from delta to high gamma, given the speech mode and electrode location. For imagined speech detection, we observed a strong contribution of gamma bands in the motor cortex, whereas lower frequencies were more prominent in the temporal lobe, in particular of the left hemisphere. Based on the similarities in frequency patterns, we were able to transfer models between speech modes and participants with similar electrode locations.


Subject(s)
Brain-Computer Interfaces , Electrocorticography , Imagination , Speech , Humans , Electrocorticography/methods , Speech/physiology , Male , Female , Adult , Imagination/physiology , Young Adult , Motor Cortex/physiology
6.
Obes Surg ; 2024 Jun 19.
Article in English | MEDLINE | ID: mdl-38898310

ABSTRACT

Robotic Roux-en-Y gastric bypass (RRYGB) is an innovative alternative to traditional laparoscopic approaches. Literature has been published investigating its safety/efficacy; however, the quality of reporting is uncertain. This systematic review used the Idea, Development, Exploration, Assessment and Long-term follow-up (IDEAL) framework to assess the reporting quality of available literature. A narrative summary was formulated, assessing how comprehensively governance/ethics, patient selection, demographics, surgeon expertise/training, technique description and outcomes were reported. Forty-seven studies published between 2005 and 2024 were included. There was incomplete/inconsistent reporting of governance/ethics, patient selection, surgeon expertise/training and technique description, with heterogenous outcome reporting. RRYGB reporting was poor and did not align with IDEAL guidance. Robust prospective studies reporting findings using IDEAL/other guidance are required to facilitate safe widespread adoption of RRYGB and other surgical innovations.

7.
Cureus ; 16(5): e60821, 2024 May.
Article in English | MEDLINE | ID: mdl-38910626

ABSTRACT

Lyme disease is a tick-borne illness known for its ability to cause multi-systemic manifestations. It can affect several different systems, including neurological, musculoskeletal, and dermatological systems. However, one of the most concerning biological systems affected is the cardiac system. Lyme carditis typically presents with varying degrees of atrioventricular (AV) block. Additionally, current literature also endorses atypical manifestations, including but not limited to atrial fibrillation and bundle branch blocks. These atypical manifestations are important as they can be the first presenting symptoms in patients with Lyme disease. Therefore, educating clinicians on various signs, symptoms, and manifestations of Lyme carditis remains paramount in reducing morbidity and mortality. We conducted a literature review using PubMed, MEDLINE, and CINAHL, collecting a total of 13 articles to gather information on atypical manifestations of Lyme carditis. This literature review serves to summarize the current research and studies describing these cardiac manifestations and the cardiac pathophysiology associated with Lyme disease. These findings aim to contribute to the expanding understanding of Lyme carditis, subsequently preventing long-term effects through prompt diagnosis and treatment.

8.
Nucleic Acids Res ; 2024 Jun 22.
Article in English | MEDLINE | ID: mdl-38908029

ABSTRACT

Formamidopyrimidine (Fapy•dG) is a major lesion arising from oxidation of dG that is produced from a common chemical precursor of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OxodGuo). In human cells, replication of single-stranded shuttle vectors containing Fapy•dG is more mutagenic than 8-OxodGuo. Here, we present the first data regarding promoter dependent RNA polymerase II bypass of Fapy•dG. 8-OxodGuo bypass was examined side-by-side. Experiments were carried out using double-stranded shuttle vectors in HeLa cell nuclear lysates and in HEK 293T cells. The lesions do not significantly block transcriptional bypass efficiency. Less than 2% adenosine incorporation occurred in cells when the lesions were base paired with dC. Inhibiting base excision repair in HEK 293T cells significantly increased adenosine incorporation, particularly from Fapy•dG:dC bypass which yielded ∼25% adenosine incorporation. No effect was detected upon transcriptional bypass of either lesion in nucleotide excision repair deficient cells. Transcriptional mutagenesis was significantly higher when shuttle vectors containing dA opposite one of the lesions were employed. For Fapy•dG:dA bypass, adenosine incorporation was greater than 85%; whereas 8-OxodGuo:dA yielded >20% point mutations. The combination of more frequent replication mistakes and greater error-prone Pol II bypass suggest that Fapy•dG is more mutagenic than 8-OxodGuo.

9.
Lung ; 2024 Jun 10.
Article in English | MEDLINE | ID: mdl-38856932

ABSTRACT

PURPOSE: Skin pigmentation influences peripheral oxygen saturation (SpO2) compared to arterial saturation of oxygen (SaO2). Occult hypoxemia (SaO2 ≤ 88% with SpO2 ≥ 92%) is associated with increased in-hospital mortality in venovenous-extracorporeal membrane oxygenation (VV-ECMO) patients. We hypothesized VV-ECMO cannulation, in addition to race/ethnicity, accentuates the SpO2-SaO2 discrepancy due to significant hemolysis. METHODS: Adults (≥ 18 years) supported with VV-ECMO with concurrently measured SpO2 and SaO2 measurements from over 500 centers in the Extracorporeal Life Support Organization Registry (1/2018-5/2023) were included. Multivariable logistic regressions were performed to examine whether race/ethnicity was associated with occult hypoxemia in pre-ECMO and on-ECMO SpO2-SaO2 calculations. RESULTS: Of 13,171 VV-ECMO patients, there were 7772 (59%) White, 2114 (16%) Hispanic, 1777 (14%) Black, and 1508 (11%) Asian patients. The frequency of on-ECMO occult hypoxemia was 2.0% (N = 233). Occult hypoxemia was more common in Black and Hispanic patients versus White patients (3.1% versus 1.7%, P < 0.001 and 2.5% versus 1.7%, P = 0.025, respectively). In multivariable logistic regression, Black patients were at higher risk of pre-ECMO occult hypoxemia versus White patients (adjusted odds ratio [aOR] = 1.55, 95% confidence interval [CI] = 1.18-2.02, P = 0.001). For on-ECMO occult hypoxemia, Black patients (aOR = 1.79, 95% CI = 1.16-2.75, P = 0.008) and Hispanic patients (aOR = 1.71, 95% CI = 1.15-2.55, P = 0.008) had higher risk versus White patients. Higher pump flow rates (aOR = 1.29, 95% CI = 1.08-1.55, P = 0.005) and on-ECMO 24-h lactate (aOR = 1.06, 95% CI = 1.03-1.10, P < 0.001) significantly increased the risk of on-ECMO occult hypoxemia. CONCLUSION: SaO2 should be carefully monitored if using SpO2 during ECMO support for Black and Hispanic patients especially for those with high pump flow and lactate values at risk for occult hypoxemia.

10.
Cureus ; 16(5): e60224, 2024 May.
Article in English | MEDLINE | ID: mdl-38868293

ABSTRACT

Introduction Malaria is a major public health concern, especially in developing countries. Malaria often presents with recurrent fever, malaise, and other nonspecific symptoms mistaken for influenza. Light microscopy of peripheral blood smears is considered the gold standard diagnostic test for malaria. Delays in malaria diagnosis can increase morbidity and mortality. Microscopy can be time-consuming and limited by skilled labor, infrastructure, and interobserver variability. Artificial intelligence (AI)-based tools for diagnostic screening can automate blood smear analysis without relying on a trained technician. Convolutional neural networks (CNN), deep learning neural networks that can identify visual patterns, are being explored for use in abnormality detection in medical images. A parameter that can be optimized in CNN models is the batch size or the number of images used during model training at once in one forward and backward pass. The choice of batch size in developing CNN-based malaria screening tools can affect model accuracy, training speed, and, ultimately, clinical usability. This study explores the impact of batch size on CNN model accuracy for malaria detection from thin blood smear images. Methods We used the publicly available "NIH-NLM-ThinBloodSmearsPf" dataset from the United States National Library of Medicine, consisting of blood smear images for Plasmodium falciparum. The collection consists of 13,779 "parasitized" and 13,779 "uninfected" single-cell images. We created four datasets containing all images, each with unique randomized subsets of images for model testing. Using Python, four identical 10-layer CNN models were developed and trained with varying batch sizes for 10 epochs against all datasets, resulting in 16 sets of outputs. Model prediction accuracy, training time, and F1-score, an accuracy metric used to quantify model performance, were collected. Results All models produced F1-scores of 94%-96%, with 10 of 16 instances producing F1-scores of 95%. After averaging all four dataset outputs by batch size, we observed that, as batch size increased from 16 to 128, the average combined false positives plus false negatives increased by 15.4% (130-150), and the average model F1-score accuracy decreased by 1% (95.3%-94.3%). The average training time also decreased by 28.11% (1,556-1,119 seconds). Conclusion In each dataset, we observe an approximately 1% decrease in F1-score as the batch size was increased. Clinically, a 1% deviation at the population level can create a relatively significant impact on outcomes. Results from this study suggest that smaller batch sizes could improve accuracy in models with similar layer complexity and datasets, potentially resulting in better clinical outcomes. Reduced memory requirement for training also means that model training can be achieved with more economical hardware. Our findings suggest that smaller batch sizes could be evaluated for improvements in accuracy to help develop an AI model that could screen thin blood smears for malaria.

11.
Microb Pathog ; 193: 106752, 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38880315

ABSTRACT

Arcobacter butzleri is a foodborne pathogen that mainly causes enteritis in humans, but the number of cases of bacteraemia has increased in recent years. However, there is still limited knowledge on the pathogenic mechanisms of this bacterium. To investigate how A. butzleri causes disease, single knockout mutants were constructed in the cadF, ABU_RS00335, ciaB, and flaAB genes, which might be involved in adhesion and invasion properties. These mutants and the isogenic wild-type (WT) were then tested for their ability to adhere and invade human Caco-2 and HT29-MTX cells. The adhesion and invasion of A. butzleri RM4018 strain was also visualized by a Leica CTR 6500 confocal microscope. The adhesion and invasion abilities of mutants lacking the invasion antigen CiaB or a functional flagellum were lower than those of the WTs. However, the extent of the decrease varied depending on the strain and/or cell line. Mutants lacking the fibronectin (FN)-binding protein CadF consistently exhibited reduced abilities, while the inactivation of the other studied FN-binding protein, ABU_RS00335, led to a reduction in only one of the two strains tested. Therefore, the ciaB and flaAB genes appear to be important for A. butzleri adhesion and invasion properties, while cadF appears to be indispensable.

12.
Sci Rep ; 14(1): 11573, 2024 05 21.
Article in English | MEDLINE | ID: mdl-38773172

ABSTRACT

GSK2838232 (GSK8232) is a second-generation maturation inhibitor (MI) developed for the treatment of HIV with excellent broad-spectrum virological profiles. The compound has demonstrated promising clinical results as an orally administered agent. Additionally, the compound's physical and pharmacological properties present opportunities for exploitation as long-acting parenteral formulations. Despite unique design constraints including solubility and dose of GSK8232, we report on three effective tunable drug delivery strategies: active pharmaceutical ingredient (API) suspensions, ionic liquids, and subdermal implants. Promising sustained drug release profiles were achieved in rats with each approach. Additionally, we were able to tune drug release rates through a combination of passive and active strategies, broadening applicability of these formulation approaches beyond GSK8232. Taken together, this report is an important first step to advance long-acting formulation development for critical HIV medicines that do not fit the traditional profile of suitable long-acting candidates.


Subject(s)
Drug Liberation , Animals , Rats , Hydrophobic and Hydrophilic Interactions , Delayed-Action Preparations , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Anti-HIV Agents/pharmacokinetics , Drug Delivery Systems/methods , Ionic Liquids/chemistry , Rats, Sprague-Dawley , Male , Solubility , HIV Infections/drug therapy , Anti-Retroviral Agents/administration & dosage , Anti-Retroviral Agents/chemistry
13.
Cureus ; 16(4): e57512, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38707123

ABSTRACT

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple systems of the body. Recent research on the gut microbiota dysbiosis associated with SLE patients has gained traction and warranted further exploration. It has not been determined whether the change in the gut microbiota is a cause of SLE or a symptom of SLE. However, based on the physiological and pathophysiological role of the bacteria in the gut microbiome, as levels of the bacteria rise or fall, symptomatology in SLE patients could be affected. This review analyzes the recent studies that examined the changes in the gut microbiota of SLE patients and highlights the correlations between gut dysbiosis and the clinical manifestations of SLE. A systematic search strategy was developed by combining the terms "SLE," "systemic lupus erythematosus," and "gut microbiome." Biomedical Reference Collection, CINAHL, Medline ProQuest, and PubMed Central databases were searched by combining the appropriate keywords with "AND." Only full-text, English-language articles were searched. The articles were restricted from 2013 to 2023. Only peer-reviewed controlled studies with both human and animal trials were included in this scoping review. Review articles, non-English articles, editorials, case studies, and duplicate articles from the four databases were excluded. Various species of bacteria were found to be positively or negatively associated with SLE gut microbiomes. Among the bacterial species increased were Clostridium, Lactobacilli, Streptococcus, Enterobacter, and Klebsiella. The bacterial species that decreased were Bifidobacteria, Prevotella, and the Firmicutes/Bacteroidetes ratio. Literature shows that Clostridium is one of several bacteria found in abundance, from pre-disease to the diseased state of SLE. Lachnospiraceae and Ruminococcaceae are both part of the family of butyrate-producing anaerobes that are known for their role in strengthening the skin barrier function and, therefore, may explain the cutaneous manifestations of SLE patients. Studies have also shown that the Firmicutes/Bacteroidetes ratio is significantly depressed, which may lead to appetite changes and weight loss seen in SLE patients. Based on the established role of these bacteria within the gut microbiome, the disruption in the gut ecosystem could explain the symptomatology common in SLE patients. By addressing these changes, our scoping review encourages further research to establish a true causal relationship between the bacterial changes in SLE patients as well as furthering the scope of microbiota changes in other systems and autoimmune diseases.

14.
Anesthesiology ; 141(2): 365-374, 2024 Aug 01.
Article in English | MEDLINE | ID: mdl-38728093

ABSTRACT

BACKGROUND: The number of trials investigating the effects of deep neuromuscular blockade (NMB) on surgical conditions and patient outcomes is steadily increasing. Consensus on which surgical procedures benefit from deep NMB (a posttetanic count [PTC] of 1 to 2) and how to implement it has not been reached. The European Society of Anaesthesiology and Intensive Care does not advise routine application but recommends use of deep NMB to improve surgical conditions on indication. This study investigates the optimal dosing strategy to reach and maintain adequate deep NMB during total intravenous anesthesia. METHODS: Data from three trials investigating deep NMB during laparoscopic surgery with total intravenous anesthesia (n = 424) were pooled to analyze the required rocuronium dose, when to start continuous infusion, and how to adjust. The resulting algorithm was validated (n = 32) and compared to the success rate in ongoing studies in which the algorithm was not used (n = 180). RESULTS: The mean rocuronium dose based on actual bodyweight for PTC 1 to 2 was (mean ± SD) 1.0 ± 0.27 mg · kg-1 ·h-1 in the trials, in which mean duration of surgery was 116 min. An induction dose of 0.6 mg ·kg-1 led to a PTC of 1 to 5 in a quarter of patients after a mean of 11 min. The remaining patients were equally divided over too shallow (additional bolus and direct start of continuous infusion) or too deep; a 15-min wait after PTC of 0 for return of PTC to 1 or higher. Using the proposed algorithm, a mean 76% of all 5-min measurements throughout surgery were on target PTC 1 to 2 in the validation cohort. The algorithm performed significantly better than anesthesiology residents without the algorithm, even after a learning curve from 0 to 20 patients (42% on target, P ≤ 0.001, Cohen's d = 1.4 [95% CI, 0.9 to 1.8]) to 81 to 100 patients (61% on target, P ≤ 0.05, Cohen's d = 0.7 [95% CI, 0.1 to 1.2]). CONCLUSIONS: This study proposes a dosing algorithm for deep NMB with rocuronium in patients receiving total intravenous anesthesia.


Subject(s)
Algorithms , Anesthesia, Intravenous , Neuromuscular Blockade , Neuromuscular Nondepolarizing Agents , Rocuronium , Humans , Rocuronium/administration & dosage , Neuromuscular Blockade/methods , Male , Middle Aged , Neuromuscular Nondepolarizing Agents/administration & dosage , Female , Anesthesia, Intravenous/methods , Adult , Dose-Response Relationship, Drug , Aged , Laparoscopy/methods , Androstanols/administration & dosage
16.
Chem Res Toxicol ; 37(5): 814-823, 2024 May 20.
Article in English | MEDLINE | ID: mdl-38652696

ABSTRACT

The major product of DNA-methylating agents, N7-methyl-2'-deoxyguanosine (MdG), is a persistent lesion in vivo, but it is not believed to have a large direct physiological impact. However, MdG reacts with histone proteins to form reversible DNA-protein cross-links (DPCMdG), a family of DNA lesions that can significantly threaten cell survival. In this paper, we developed a tandem mass spectrometry method for quantifying the amounts of MdG and DPCMdG in nuclear DNA by taking advantage of their chemical lability and the concurrent release of N7-methylguanine. Using this method, we determined that DPCMdG is formed in less than 1% yield based upon the levels of MdG in methyl methanesulfonate (MMS)-treated HeLa cells. Despite its low chemical yield, DPCMdG contributes to MMS cytotoxicity. Consequently, cells that lack efficient DPC repair by the DPC protease SPRTN are hypersensitive to MMS. This investigation shows that the downstream chemical and biochemical effects of initially formed DNA damage can have significant biological consequences. With respect to MdG formation, the initial DNA lesion is only the beginning.


Subject(s)
DNA , Deoxyguanosine , Methyl Methanesulfonate , Humans , HeLa Cells , DNA/metabolism , DNA/chemistry , DNA/drug effects , Deoxyguanosine/analogs & derivatives , Deoxyguanosine/metabolism , Deoxyguanosine/chemistry , Methyl Methanesulfonate/chemistry , Methyl Methanesulfonate/pharmacology , Tandem Mass Spectrometry , Cell Survival/drug effects , DNA Damage/drug effects , Cross-Linking Reagents/chemistry , DNA-Binding Proteins
17.
Nucleic Acids Res ; 52(9): 5392-5405, 2024 May 22.
Article in English | MEDLINE | ID: mdl-38634780

ABSTRACT

N6-(2-deoxy-α,ß-d-erythro-pentofuranosyl)-2,6-diamino-4-hydroxy-5-formamido-pyrimidine (Fapy•dG) is formed from a common intermediate and in comparable amounts to the well-studied mutagenic DNA lesion 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OxodGuo). Fapy•dG preferentially gives rise to G → T transversions and G → A transitions. However, the molecular basis by which Fapy•dG is processed by DNA polymerases during this mutagenic process remains poorly understood. To address this we investigated how DNA polymerase ß (Pol ß), a model mammalian polymerase, bypasses a templating Fapy•dG, inserts Fapy•dGTP, and extends from Fapy•dG at the primer terminus. When Fapy•dG is present in the template, Pol ß incorporates TMP less efficiently than either dCMP or dAMP. Kinetic analysis revealed that Fapy•dGTP is a poor substrate but is incorporated ∼3-times more efficiently opposite dA than dC. Extension from Fapy•dG at the 3'-terminus of a nascent primer is inefficient due to the primer terminus being poorly positioned for catalysis. Together these data indicate that mutagenic bypass of Fapy•dG is likely to be the source of the mutagenic effects of the lesion and not Fapy•dGTP. These experiments increase our understanding of the promutagenic effects of Fapy•dG.


Subject(s)
DNA Polymerase beta , DNA Replication , Formamides , Furans , Pyrimidines , Humans , Crystallography, X-Ray , DNA/chemistry , DNA/metabolism , DNA Polymerase beta/metabolism , DNA Polymerase beta/chemistry , Kinetics , Models, Molecular , Pyrimidines/chemistry , Pyrimidines/metabolism , Furans/chemistry , Furans/metabolism , Formamides/metabolism , Mutagenesis
18.
J Clin Med ; 13(8)2024 Apr 18.
Article in English | MEDLINE | ID: mdl-38673629

ABSTRACT

Peritoneal carcinomatosis (PC) is rarely discovered early due to low sensitivity of screening imaging and tumor markers, however, earlier identification may improve outcomes. This study assesses risk factors and time to recurrence of PC and implementation of a surveillance system. Patients with stage II-III colon adenocarcinoma undergoing curative colectomy between 2005-2022 were retrospectively reviewed at a single tertiary care institution. Patients were divided into three cohorts: no recurrence (NR), PC, and other types of recurrence (OTR). Baseline characteristics between cohorts were compared with univariate analysis. Overall survival and PC risk were assessed using multivariate analysis with Cox's proportional-hazard modelling. 412 patients were included; 78.4% had NR, 7.8% had PC, and 13.8% had OTR. Patient demographics, comorbidities, tumor side, and histologic features were similar between cohorts. Patients with PC were more likely to have microscopic tumor perforation (25% vs. 8.8% vs. 6.8%, p = 0.002), margin involvement (25% vs. 8.8% vs. 4.6%, p < 0.001), lymphovascular invasion (56.2% vs. 33.3%, vs. 24.5%, p < 0.001), perineural invasion (28.1% vs. 15.8% vs. 11.5%, p = 0.026) compared to OTR or NR. Median time to PC after colectomy was 11 months. Tumor characteristics of stage II-III colon cancer define a high-risk profile for PC. An early surveillance program sensitive for peritoneal disease should be adopted for these patients.

19.
Cureus ; 16(3): e57185, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38681346

ABSTRACT

Spondyloarthropathy (SpA) is one of the most common causes of low back pain. It is caused by inflammatory arthritis in the spine, manifesting in various forms such as psoriatic arthritis (PsA), ankylosing spondylitis (AS), and sacroiliitis. A comprehensive systematic literature search was done to evaluate and compare MRI, CT, single-photon emission CT, PET, ultrasound (US) imaging, low-dose CT, and diffusion-weighted imaging (DWI) techniques in assessing SpAs. The search strategy was constructed by an analysis of key terms from relevant articles in MEDLINE ProQuest, Embase, and PubMed. The key terms used to search for these articles were "SpA," "sacroiliitis," "spondylitis," "psoriatic arthritis," "MRI," "CT scan," "x-ray," "magnetic resonance imaging," "computed tomography," "bone density," and "ultrasound." A total of 1,131 articles published in English between January 1, 2003, and October 15, 2023 were identified and screened for eligibility by members of the research team, which resulted in 69 total articles selected for the final review. US has played an important role in visualizing joint inflammation and enthesitis (inflammation of the enthesis), which are common features of PsA. Although MRI and CT are considered more reliable modalities for diagnosing active sacroiliitis, US imaging with Doppler flow can also be useful in conjunction with CT images to visualize abnormal blood flow in the sacroiliac joints, as well as other joints affected by inflammatory arthritis. MRI provides increased diagnostic confidence in the diagnosis of sacroiliitis in active AS patients when compared to CT. CT is more sensitive than plain radiographs. The PET activity score showed a good correlation in diagnosing inflammatory sacroiliitis but lacked in identifying structural lesions. CT has high diagnostic accuracy, but it exposes patients to a high radiation dose. MRI visualizes joint and tissue inflammation, bone, and bone marrow change and can identify peripheral inflammation in soft tissue and joints in patients diagnosed with PsA. MRI can also visualize bone marrow changes and subchondral edema, which can aid in the early diagnosis of ankylosing SpA and gauge disease severity. DWI and short-tau inversion recovery imaging are both MRI techniques used in detecting sacroiliitis. MRI and CT are shown to be reliable imaging modalities for the diagnosis of sacroiliitis; however, it was found that Doppler US played an accurate role in the diagnosis as well. MRI visualizes joints and tissue with the most precision, making it useful in evaluating patients with PsA, while PET CT is useful in the diagnosis of inflammatory sacroiliitis patients. There is limited literature available comparing the multiple modalities of imaging available for each SpA. The review's objective is to analyze imaging findings in patients diagnosed with sacroiliitis and SpAs. The findings in this literature review are valuable for properly assessing and diagnosing patients suffering from SpAs.

20.
Article in English | MEDLINE | ID: mdl-38619942

ABSTRACT

Abdominal aortic aneurysms (AAAs) are rupture-prone dilatations of the aorta. In current clinical practice, the maximal diameter of AAAs is monitored with 2D ultrasound to estimate their rupture risk. Recent studies have shown that 3-dimensional and mechanical AAA parameters might be better predictors for aneurysm growth and rupture than the diameter. These parameters can be obtained with time-resolved 3D ultrasound (3D+t US), which requires robust and automatic segmentation of AAAs from 3D+t US. This study proposes and validates a deep learning (DL) approach for automatic segmentation of AAAs. 500 AAA patients were included for follow-up 3D+t US imaging, resulting in 2495 3D+t US images. Segmentation masks for model training were obtained using a conventional automatic segmentation algorithm ('nonDL'). Four different DL models were trained and validated by (1) comparison to CT and (2) reader scoring. Performance of the nonDL and different DL segmentation strategies were evaluated by comparing Hausdorff distance, Dice scores, accuracy, sensitivity, and specificity with a sign test. All DL models had higher median Dice scores, accuracy, and sensitivity (all p < 0.003) compared to nonDL segmentation. The full image-resolution model without data augmentation showed the highest median Dice score and sensitivity (p < 0.001). Applying the DL model on an independent test group produced fewer poor segmentation scores of 1 to 2 on a five-point scale (8% for DL, 18% for nonDL). This demonstrates that a robust and automatic segmentation algorithm for segmenting abdominal aortic aneurysms from 3D+t US images was developed, showing improved performance compared to conventional segmentation.

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