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Biomolecules & Therapeutics Jun 2024Colorectal cancer (CRC) continues to demonstrate high incidence and mortality rates, emphasizing that implementing strategic measures for prevention and treatment is...
Colorectal cancer (CRC) continues to demonstrate high incidence and mortality rates, emphasizing that implementing strategic measures for prevention and treatment is crucial. Recently, the dopamine receptor D2 (DRD2), a G protein-coupled receptor, has been reported to play multiple roles in growth of tumor cells. This study investigated the anticancer potential of domperidone, a dopamine receptor D2 antagonist, in HCT116 human CRC cells. Domperidone demonstrated concentration- and time-dependent reductions in cell viability, thereby inducing apoptosis. The molecular mechanism revealed that domperidone modulated the mitochondrial pathway, decreasing mitochondrial Bcl-2 levels, elevating cytosolic cytochrome C expression, and triggering caspase- 3, -7, and -9 cleavage. Domperidone decreased in formation of β-arrestin2/MEK complex, which contributing to inhibition of ERK activation. Additionally, treatment with domperidone diminished JAK2 and STAT3 activation. Treatment of U0126, the MEK inhibitor, resulted in reduced phosphorylation of MEK, ERK, and STAT3 without alteration of JAK2 activation, indicating that domperidone targeted both MEK-ERK-STAT3 and JAK2-STAT3 signaling pathways, respectively. Immunoblot analysis revealed that domperidone also downregulated DRD2 expression. Domperidone-induced reactive oxygen species (ROS) generation and -acetylcysteine treatment mitigated ROS levels and restored cell viability. An xenograft study verified the significant antitumor effects of domperidone. These results emphasize the multifaceted anticancer effects of domperidone, highlighting its potential as a promising therapeutic agent for human CRC.
PubMed: 38914471
DOI: 10.4062/biomolther.2024.048 -
Pharmacological Reviews Jun 2024Voltage-gated sodium (Na) channels are intimately involved in the generation and transmission of action potentials, and dysfunction of these channels may contribute to...
Voltage-gated sodium (Na) channels are intimately involved in the generation and transmission of action potentials, and dysfunction of these channels may contribute to nervous system diseases such as epilepsy, neuropathic pain, psychosis, autism and cardiac arrhythmia. Many venom peptides selectively act on Na channels. These include conotoxins, which are neurotoxins secreted by cone snails for prey capture or self-defense, but which are also valuable pharmacological tools for the identification and/or treatment of human diseases. Typically, conotoxins contain two or three disulfide bonds and these internal cross-braces contribute to conotoxins having compact, well-defined structures and high stability. Of the conotoxins containing three disulfide bonds some selectively target mammalian Na channels and can block, stimulate, or modulate these channels. Such conotoxins have great potential to serve as pharmacological tools for studying the functions and characteristics of Na channels or as drug leads for neurological diseases related to Na channels. Accordingly, discovering or designing conotoxins targeting Na channels with high potency and selectivity is important. The amino acid sequences, disulfide bond connectivity, and three-dimensional structures are key factors that affect the biological activity of conotoxins, and targeted synthetic modifications of conotoxins can greatly improve their activity and selectivity. This review examines Na channel-targeted conotoxins, focusing on their structures, activities and designed modifications, with a view towards expanding their applications. Na channels are crucial in various neurological diseases. Some conotoxins selectively target Na channels, causing either blockade or activation, thus enabling their use as pharmacological tools for studying the channels' characteristics and functions. Conotoxins also have promising potential to be developed as drug leads. The disulfide bonds in these peptides are important for stabilizing their structures, thus leading to enhanced specificity and potency. Together, conotoxins targeting Na channels have both immediate research value and promising future application prospects.
PubMed: 38914468
DOI: 10.1124/pharmrev.123.000923 -
ENeuro Jun 2024Epilepsy is often comorbid with psychiatric illnesses, including anxiety and depression. Despite the high incidence of psychiatric comorbidities in people with epilepsy,...
Epilepsy is often comorbid with psychiatric illnesses, including anxiety and depression. Despite the high incidence of psychiatric comorbidities in people with epilepsy, few studies address the underlying mechanisms. Stress can trigger epilepsy and depression. Evidence from human and animal studies support that hypothalamic-pituitary-adrenal (HPA) axis dysfunction may contribute to both disorders as well as their comorbidity (Kanner, 2003). Here, we investigate if HPA axis dysfunction may influence epilepsy outcomes and psychiatric comorbidities. We generated a novel mouse model (/ KO mice) lacking the K/Cl co-transporter, KCC2, in corticotropin-releasing hormone (CRH) neurons, which exhibit stress- and seizure-induced HPA axis hyperactivation (Melon et al., 2018). We used the / KO mice to examine the impact on epilepsy outcomes, including seizure frequency/burden, comorbid behavioral deficits, and SUDEP risk. We found sex differences in HPA axis dysfunction's effect on chronically epileptic KCC2/Crh KO mice seizure burden, vulnerability to comorbid behavioral deficits, and SUDEP. Suppressing HPA axis hyperexcitability in this model using pharmacological or chemogenetic approaches decreased SUDEP incidence, suggesting that HPA axis dysfunction may contribute to SUDEP. Altered neuroendocrine markers were present in SUDEP cases compared to people with epilepsy or individuals without epilepsy. Together, these findings implicate HPA axis dysfunction in the pathophysiological mechanisms contributing to psychiatric comorbidities in epilepsy and SUDEP. Our work provides new insight into a potential novel pathophysiological mechanism contributing to psychiatric illnesses and SUDEP in epilepsy patients, implicating HPA axis dysfunction in negative outcomes associated with epilepsy. This study is the first to link HPA axis dysfunction to SUDEP risk. Chronically epileptic male mice with exaggerated HPA axis dysfunction had increased SUDEP incidence. The translational relevance of these findings is supported by neuroendocrine abnormalities observed in postmortem samples from individuals that died of SUDEP. These data suggest that neuroendocrine mechanisms should be further explored in psychiatric comorbidities in epilepsy and SUDEP risk. Further, neuroendocrine markers may be a biomarker for SUDEP risk.
PubMed: 38914464
DOI: 10.1523/ENEURO.0162-24.2024 -
Annals of Family Medicine Jun 2024Relationship continuity of care has declined across English primary health care, with cross-sectional and longitudinal variations between general practices predicted by...
PURPOSE
Relationship continuity of care has declined across English primary health care, with cross-sectional and longitudinal variations between general practices predicted by population and service factors. We aimed to describe cross-sectional and longitudinal variations across the COVID-19 pandemic and determine whether practice factors predicted the variations.
METHODS
We conducted a longitudinal, ecological study of English general practices during 2018-2022 with continuity data, excluding practices with fewer than 750 patients or National Health Service (NHS) payments exceeding £500 per patient. Variables were derived from published data. The continuity measure was the product of weighted responses to 2 General Practice Patient Survey questions. In a multilevel mixed-effects model, the fixed effects were 11 variables' interactions with time: baseline continuity, NHS region, deprivation, location, percentage White ethnicity, list size, general practitioner and nurse numbers, contract type, NHS payments per patient, and percentage of patients seen on the same day as booking. The random effects were practices.
RESULTS
Main analyses were based on 6,010 practices (out of 7,190 active practices). During 2018-2022, mean continuity in these practices declined (from 29.3% to 19.0%) and the coefficient of variation across practices increased (from 48.1% to 63.6%). Both slopes were steepest between 2021 and 2022. Practices having more general practitioners and higher percentages of patients seen the same day had slower declines. Practices having higher baseline continuity, located in certain non-London regions, and having higher percentages of White patients had faster declines. The remaining variables were not predictors.
CONCLUSIONS
Variables potentially associated with greater appointment availability predicted slower declines in continuity, with worsening declines and relative variability immediately after the COVID-19 lockdown, possibly reflecting surges in demand. To achieve better levels of continuity for those seeking it, practices can increase appointment availability within appointment systems that prioritize continuity.
PubMed: 38914438
DOI: 10.1370/afm.3128 -
Annals of Family Medicine Jun 2024We undertook a study to investigate the relationship between duration of medication use and prevalence of impaired awareness of hypoglycemia (IAH) among patients with...
PURPOSE
We undertook a study to investigate the relationship between duration of medication use and prevalence of impaired awareness of hypoglycemia (IAH) among patients with insulin-treated or sulfonylurea-treated type 2 diabetes in Taiwan.
METHODS
A total of 898 patients (41.0% insulin users, 65.1% sulfonylurea users; mean [SD] age = 59.9 [12.3] years, 50.7% female) were enrolled in pharmacies, clinics, and health bureaus of Tainan City, Taiwan. Presence of IAH was determined with Chinese versions of the Gold questionnaire (Gold-TW) and Clarke questionnaire (Clarke-TW). Sociodemographics, disease and treatment histories, diabetes-related medical care, and health status were collected. We used multiple logistic regression models to assess the relationship between duration of medication use and IAH.
RESULTS
Overall IAH prevalence was 41.0% (Gold-TW) and 28.2% (Clarke-TW) among insulin users, and 65.3% (Gold-TW) and 51.3% (Clarke-TW) among sulfonylurea users. Prevalence increased with the duration of sulfonylurea use, whereas it decreased with the duration of insulin use. After controlling for potential confounders, 5 or more years of sulfonylurea use was significantly associated with 3.50-fold (95% CI, 2.39-5.13) and 3.06-fold (95% CI, 2.11-4.44) increases in the odds of IAH based on the Gold-TW and Clarke-TW criteria, respectively. On the other hand, regular blood glucose testing and retinal examinations were associated with reduced odds in both insulin users and sulfonylurea users.
CONCLUSIONS
The prevalence of IAH was high among patients using sulfonylureas long term, but the odds of this complication were attenuated for those who received regular diabetes-related medical care. Our study suggests that long-term sulfonylurea use and irregular follow-up increase risk for IAH. Further prospective studies are needed to confirm the observed associations.
PubMed: 38914437
DOI: 10.1370/afm.3129 -
Virologica Sinica Jun 2024Next-generation sequencing (NGS) has significantly improved the accuracy and efficiency of pathogen diagnosis for a wide range of diseases. In this study, viral...
Next-generation sequencing (NGS) has significantly improved the accuracy and efficiency of pathogen diagnosis for a wide range of diseases. In this study, viral metagenomics analysis was conducted on fecal and tissue samples from a 13-year-old recipient of hematopoietic stem cell transplantation (HSCT) afflicted with severe lingual papillomatosis. The analysis revealed a high abundance of adeno-associated virus 2 (AAV2), alongside potential helper viruses, herpesvirus type 1 (HSV-1), and the uncommon adenovirus serotype 18 (AdV18). Although a direct causal relationship was not definitively established, the concurrence of these viruses indicated a plausible link to the development of severe lingual papillomatosis in immunocompromised individuals. Notably, the study generated a complete genome sequence of AdV18, offering insights into adenovirus genetic variability, origin, and pathogenicity. Noteworthy findings include three amino acid substitutions in the polymerase and one in the hexon, distinguishing them from previously published strains of AdV18. Phylogenetic analysis unveiled a close relationship between both the polymerase and hexon regions of AdV18 in our study and previously reported AdV18 sequences. This study underscores the pivotal role of comprehensive viral scrutiny in elucidating infections among HSCT patients with lingual papillomatosis.
PubMed: 38914259
DOI: 10.1016/j.virs.2024.06.006 -
Poultry Science May 2024The H4 subtype of avian influenza virus (AIV) exhibits a wide host range and is commonly found in migratory waterfowl. Recent studies have revealed that the H4N6 AIV can... (Review)
Review
The H4 subtype of avian influenza virus (AIV) exhibits a wide host range and is commonly found in migratory waterfowl. Recent studies have revealed that the H4N6 AIV can infect guinea pigs via aerosol transmission without prior adaptation. Additionally, the Q226L/G228S substitutions in the receptor-binding site have led to structural changes in globular head of H4 AIV, resulting in a configuration similar to that of pandemic H2N2 and H3N2 human influenza viruses. This article provides an updated review of the historical evolution, global distribution, adaptive mutations, receptor-binding preferences, and host range of H4 AIV. The insights presented herein will help in assessing the potential risk of future H4 AIV epidemics.
PubMed: 38914042
DOI: 10.1016/j.psj.2024.103913 -
Global Spine Journal Jun 2024Meta-analysis. (Review)
Review
STUDY DESIGN
Meta-analysis.
OBJECTIVE
To compare the effectiveness of postoperative pain control between erector spinae plane block (ESPB) and thoracolumbar interfascial plane (TLIP) block in lumbar spine surgery.
METHODS
PubMed, Embase, and MEDLINE electronic databases were searched for articles containing randomized controlled trials (RCTs) published between January 1900 and January 2024. We extracted the postoperative mean pain score, the first 24-h postoperative morphine consumption, and their standard deviation from the included studies. Meta-analysis was performed using the functions available in the metafor package in R software. We pooled continuous variables using an inverse variance method with a random-effects model and summarized them as standardized mean differences.
RESULTS
Five RCTs that directly compared the ESPB and TLIP block in lumbar spine surgery were included, enrolling 432 participants randomly into the two groups with 216 participants in each group. The pooled analyses showed that there was no significant difference between the ESPB and TLIP groups in terms of lower pain scores during the early (1 h) (standardized mean difference [SMD] -1.49, 95% confidence interval [CI], -3.10; 0.11), middle (12 h) (SMD -3.12, 95% CI, -6.86; 0.61), and late (24 h) (SMD -1.38, 95% CI, -3.01; 0.24) postoperative periods. There was also no significant difference in the first 24-h postoperative morphine equivalent consumption between the ESPB and TLIP groups (SMD -0.46 mg, 95% CI -1.23; 0.31).
CONCLUSION
No significant difference was observed between the ESPB and TLIP block in terms of postoperative pain control and 24-h morphine equivalent consumption for lumbar spine surgery.
PubMed: 38914010
DOI: 10.1177/21925682241266518 -
JMIR AI Jun 2024Breastfeeding benefits both the mother and infant and is a topic of attention in public health. After childbirth, untreated medical conditions or lack of support lead...
BACKGROUND
Breastfeeding benefits both the mother and infant and is a topic of attention in public health. After childbirth, untreated medical conditions or lack of support lead many mothers to discontinue breastfeeding. For instance, nipple damage and mastitis affect 80% and 20% of US mothers, respectively. Lactation consultants (LCs) help mothers with breastfeeding, providing in-person, remote, and hybrid lactation support. LCs guide, encourage, and find ways for mothers to have a better experience breastfeeding. Current telehealth services help mothers seek LCs for breastfeeding support, where images help them identify and address many issues. Due to the disproportional ratio of LCs and mothers in need, these professionals are often overloaded and burned out.
OBJECTIVE
This study aims to investigate the effectiveness of 5 distinct convolutional neural networks in detecting healthy lactating breasts and 6 breastfeeding-related issues by only using red, green, and blue images. Our goal was to assess the applicability of this algorithm as an auxiliary resource for LCs to identify painful breast conditions quickly, better manage their patients through triage, respond promptly to patient needs, and enhance the overall experience and care for breastfeeding mothers.
METHODS
We evaluated the potential for 5 classification models to detect breastfeeding-related conditions using 1078 breast and nipple images gathered from web-based and physical educational resources. We used the convolutional neural networks Resnet50, Visual Geometry Group model with 16 layers (VGG16), InceptionV3, EfficientNetV2, and DenseNet169 to classify the images across 7 classes: healthy, abscess, mastitis, nipple blebs, dermatosis, engorgement, and nipple damage by improper feeding or misuse of breast pumps. We also evaluated the models' ability to distinguish between healthy and unhealthy images. We present an analysis of the classification challenges, identifying image traits that may confound the detection model.
RESULTS
The best model achieves an average area under the receiver operating characteristic curve of 0.93 for all conditions after data augmentation for multiclass classification. For binary classification, we achieved, with the best model, an average area under the curve of 0.96 for all conditions after data augmentation. Several factors contributed to the misclassification of images, including similar visual features in the conditions that precede other conditions (such as the mastitis spectrum disorder), partially covered breasts or nipples, and images depicting multiple conditions in the same breast.
CONCLUSIONS
This vision-based automated detection technique offers an opportunity to enhance postpartum care for mothers and can potentially help alleviate the workload of LCs by expediting decision-making processes.
PubMed: 38913995
DOI: 10.2196/54798 -
Journal of Medical Internet Research Jun 2024Comprehensive management of multimorbidity can significantly benefit from advanced health risk assessment tools that facilitate value-based interventions, allowing for...
BACKGROUND
Comprehensive management of multimorbidity can significantly benefit from advanced health risk assessment tools that facilitate value-based interventions, allowing for the assessment and prediction of disease progression. Our study proposes a novel methodology, the Multimorbidity-Adjusted Disability Score (MADS), which integrates disease trajectory methodologies with advanced techniques for assessing interdependencies among concurrent diseases. This approach is designed to better assess the clinical burden of clusters of interrelated diseases and enhance our ability to anticipate disease progression, thereby potentially informing targeted preventive care interventions.
OBJECTIVE
This study aims to evaluate the effectiveness of the MADS in stratifying patients into clinically relevant risk groups based on their multimorbidity profiles, which accurately reflect their clinical complexity and the probabilities of developing new associated disease conditions.
METHODS
In a retrospective multicentric cohort study, we developed the MADS by analyzing disease trajectories and applying Bayesian statistics to determine disease-disease probabilities combined with well-established disability weights. We used major depressive disorder (MDD) as a primary case study for this evaluation. We stratified patients into different risk levels corresponding to different percentiles of MADS distribution. We statistically assessed the association of MADS risk strata with mortality, health care resource use, and disease progression across 1 million individuals from Spain, the United Kingdom, and Finland.
RESULTS
The results revealed significantly different distributions of the assessed outcomes across the MADS risk tiers, including mortality rates; primary care visits; specialized care outpatient consultations; visits in mental health specialized centers; emergency room visits; hospitalizations; pharmacological and nonpharmacological expenditures; and dispensation of antipsychotics, anxiolytics, sedatives, and antidepressants (P<.001 in all cases). Moreover, the results of the pairwise comparisons between adjacent risk tiers illustrate a substantial and gradual pattern of increased mortality rate, heightened health care use, increased health care expenditures, and a raised pharmacological burden as individuals progress from lower MADS risk tiers to higher-risk tiers. The analysis also revealed an augmented risk of multimorbidity progression within the high-risk groups, aligned with a higher incidence of new onsets of MDD-related diseases.
CONCLUSIONS
The MADS seems to be a promising approach for predicting health risks associated with multimorbidity. It might complement current risk assessment state-of-the-art tools by providing valuable insights for tailored epidemiological impact analyses of clusters of interrelated diseases and by accurately assessing multimorbidity progression risks. This study paves the way for innovative digital developments to support advanced health risk assessment strategies. Further validation is required to generalize its use beyond the initial case study of MDD.
Topics: Humans; Retrospective Studies; Multimorbidity; Female; Male; Middle Aged; Risk Assessment; Adult; Aged; Spain; Depressive Disorder, Major; Bayes Theorem; Disease Progression; United Kingdom; Depression; Finland
PubMed: 38913991
DOI: 10.2196/53162