-
Channels (Austin, Tex.) Dec 2024Alterations in ion channel expression and function known as "electrical remodeling" contribute to the development of hypertrophy and to the emergence of arrhythmias and...
Alterations in ion channel expression and function known as "electrical remodeling" contribute to the development of hypertrophy and to the emergence of arrhythmias and sudden cardiac death. However, comparing current density values - an electrophysiological parameter commonly utilized to assess ion channel function - between normal and hypertrophied cells may be flawed when current amplitude does not scale with cell size. Even more, common routines to study equally sized cells or to discard measurements when large currents do not allow proper voltage-clamp control may introduce a selection bias and thereby confound direct comparison. To test a possible dependence of current density on cell size and shape, we employed whole-cell patch-clamp recording of voltage-gated sodium and calcium currents in Langendorff-isolated ventricular cardiomyocytes and Purkinje myocytes, as well as in cardiomyocytes derived from trans-aortic constriction operated mice. Here, we describe a distinct inverse relationship between voltage-gated sodium and calcium current densities and cell capacitance both in normal and hypertrophied cells. This inverse relationship was well fit by an exponential function and may be due to physiological adaptations that do not scale proportionally with cell size or may be explained by a selection bias. Our study emphasizes the need to consider cell size bias when comparing current densities in cardiomyocytes of different sizes, particularly in hypertrophic cells. Conventional comparisons based solely on mean current density may be inadequate for groups with unequal cell size or non-proportional current amplitude and cell size scaling.
Topics: Myocytes, Cardiac; Animals; Cell Size; Cardiomegaly; Mice; Male; Patch-Clamp Techniques
PubMed: 38836323
DOI: 10.1080/19336950.2024.2361416 -
Allergologie Select 2024Development, production, and marketing authorization of allergen products is generally challenging due to several specific characteristics, including the natural source... (Review)
Review
Development, production, and marketing authorization of allergen products is generally challenging due to several specific characteristics, including the natural source as well as the multitude of allergenic materials. Also, depending on the frequency of sensitization in the population, the number of patients available for inclusion in clinical trials can be a limiting factor for product development. In the development of allergen products for diagnosis of type I and type IV allergies these challenges are particularly demanding because, in contrast to certain products for allergen-specific immunotherapy, no exemptions from marketing authorization are foreseen for this product group in Directive 2001/83/EC. Thus, the regulatory framework is constantly adapted within the legal scope in order to balance necessary regulatory requirements ensuring quality, safety, and efficacy with the clinical need for a comprehensive range of diagnostic allergen products. In this article, we give an overview on the current regulatory framework for development and marketing authorization of allergen products for diagnosis of rare type I and type IV allergies.
PubMed: 38835748
DOI: 10.5414/ALX02505E -
Skin Appendage Disorders Jun 2024Rosacea is a common chronic inflammatory dermatosis characterized by erythema, telangiectasia, papules, and pustules on the central face. The frequency of contact...
INTRODUCTION
Rosacea is a common chronic inflammatory dermatosis characterized by erythema, telangiectasia, papules, and pustules on the central face. The frequency of contact sensitization complicating rosacea and its therapy is unknown, with only few studies published in the literature. In the present study, we aimed to evaluate contact sensitivity in patients with rosacea.
METHODS
A total of 50 rosacea patients and 50 age- and sex-matched healthy controls were enrolled. Both groups were patch tested with the European Baseline Series.
RESULTS
A positive reaction to at least one allergen of the European Baseline Series was observed in 15 (30%) of rosacea patients and 10 (20%) of the healthy controls. Although the rate of positive reaction in the rosacea group was higher than in the controls, no statistically significant difference was documented. In addition, the total number of positive reactions to allergens in the rosacea group was higher than the control group, namely, 26 versus 17.
CONCLUSION
Contact hypersensitivity may coexist with rosacea. Its identification holds significant clinical relevance, influencing the long-term management and justifying the application of patch testing in rosacea patients.
PubMed: 38835717
DOI: 10.1159/000536246 -
Frontiers in Neuroscience 2024Glioblastoma (GBM) is a highly aggressive malignant tumor of the central nervous system that displays varying molecular and morphological profiles, leading to...
INTRODUCTION
Glioblastoma (GBM) is a highly aggressive malignant tumor of the central nervous system that displays varying molecular and morphological profiles, leading to challenging prognostic assessments. Stratifying GBM patients according to overall survival (OS) from H&E-stained whole slide images (WSI) using advanced computational methods is challenging, but with direct clinical implications.
METHODS
This work is focusing on GBM (IDH-wildtype, CNS WHO Gr.4) cases, identified from the TCGA-GBM and TCGA-LGG collections after considering the 2021 WHO classification criteria. The proposed approach starts with patch extraction in each WSI, followed by comprehensive patch-level curation to discard artifactual content, i.e., glass reflections, pen markings, dust on the slide, and tissue tearing. Each patch is then computationally described as a feature vector defined by a pre-trained VGG16 convolutional neural network. Principal component analysis provides a feature representation of reduced dimensionality, further facilitating identification of distinct groups of morphology patterns, via unsupervised k-means clustering.
RESULTS
The optimal number of clusters, according to cluster reproducibility and separability, is automatically determined based on the rand index and silhouette coefficient, respectively. Our proposed approach achieved prognostic stratification accuracy of 83.33% on a multi-institutional independent unseen hold-out test set with sensitivity and specificity of 83.33%.
DISCUSSION
We hypothesize that the quantification of these clusters of morphology patterns, reflect the tumor's spatial heterogeneity and yield prognostic relevant information to distinguish between short and long survivors using a decision tree classifier. The interpretability analysis of the obtained results can contribute to furthering and quantifying our understanding of GBM and potentially improving our diagnostic and prognostic predictions.
PubMed: 38831756
DOI: 10.3389/fnins.2024.1304191 -
Journal of AOAC International Jun 2024Federal legislation still prohibits the cultivation, sale and consumption of cultivars of delta 9-tetrahydrocannabinol cannabis (>0.3%), however, as of November 2022, 39...
BACKGROUND
Federal legislation still prohibits the cultivation, sale and consumption of cultivars of delta 9-tetrahydrocannabinol cannabis (>0.3%), however, as of November 2022, 39 states have legalized these products for medicinal consumption and 21 states have legalized for adult-use consumption. This state-by-state approach has produced a patch work of regulations that multi-state operators (MSO) must learn to navigate. Furthermore cannabis laboratories often lack the space and skill needed to perform method validations adding another layer of complexity. While these barriers exist, it is paramount for MSOs to demonstrate the fitness of purpose of their methods.
OBJECTIVE
This review presents the complexity that a MSOs navigated in developing microbiology method validation study designs for two proprietary Real-Time PCR (RT-PCR) assays to meet four state (California, Florida, Michigan and Oklahoma) testing requirements. The testing in each state was conducted in addition to certification of the assays through the AOAC Performance Tested Method SM (PTM) program.
METHODS
Matrix studies were conducted targeting three analytes (Aspergillus spp., Salmonella spp., and Shiga toxin-producing Escherichia coli) as directed by the state regulatory authorities. For California, inclusivity and exclusivity studies were performed. The number of contamination levels, test portion replicates, and total target organisms evaluated varied by state. Culture confirmation was not performed outside of the AOAC PTM studies.
RESULTS
Data from each study was collected, summarized, and provided to the state regulatory agencies. Review of the data consisted of identifying discrepant results and verification of controls. After review, each assay was certified for use in the respective state.
CONCLUSION
Requirements from each of the states demonstrate the complexities MSO face and emphasize the need for a more standardized approach to streamline acceptance of alternative methods.
HIGHLIGHTS
While varying state regulations can be complex, validation studies performed for the candidate methods have led to adoption across 31 states.
PubMed: 38831615
DOI: 10.1093/jaoacint/qsae046 -
Contact Dermatitis Jun 2024Machine learning (ML) offers an opportunity in contact dermatitis (CD) research, where with full clinical picture, may support diagnosis and patch test accuracy.
BACKGROUND
Machine learning (ML) offers an opportunity in contact dermatitis (CD) research, where with full clinical picture, may support diagnosis and patch test accuracy.
OBJECTIVE
This review aims to summarise the existing literature on how ML can be applied to CD in its entirety.
METHODS
Embase, Medline, IEEE Xplore, and ACM Digital Library were searched from inception to February 7, 2024, for primary literature reporting on ML models in CD.
RESULTS
7834 articles were identified in the search, with 110 moving to full-text review, and six articles included. Two used ML to identify key biomarkers to help distinguish between allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD), three used image data to distinguish between ACD and ICD, and one used clinical and demographical data to predict the risk of positive patch tests. All studies used supervision in their ML model training with a total of 49 704 patients across all data sets. There was sparse reporting of the accuracy of these models.
CONCLUSIONS
Although the available research is still limited, there is evidence to suggest that ML has potential to support diagnostic outcomes in a clinical setting. Further research on the use of ML in clinical practice is recommended.
PubMed: 38831517
DOI: 10.1111/cod.14595 -
Cell Communication and Signaling : CCS Jun 2024Interleukin 24 (IL-24) has been implicated in the nociceptive signaling. However, direct evidence and the precise molecular mechanism underlying IL-24's role in...
BACKGROUND
Interleukin 24 (IL-24) has been implicated in the nociceptive signaling. However, direct evidence and the precise molecular mechanism underlying IL-24's role in peripheral nociception remain unclear.
METHODS
Using patch clamp recording, molecular biological analysis, immunofluorescence labeling, siRNA-mediated knockdown approach and behavior tests, we elucidated the effects of IL-24 on sensory neuronal excitability and peripheral pain sensitivity mediated by T-type Ca channels (T-type channels).
RESULTS
IL-24 enhances T-type channel currents (T-currents) in trigeminal ganglion (TG) neurons in a reversible and dose-dependent manner, primarily by activating the interleukin-22 receptor 1 (IL-22R1). Furthermore, we found that the IL-24-induced T-type channel response is mediated through tyrosine-protein kinase Lyn, but not its common downstream target JAK1. IL-24 application significantly activated protein kinase A; this effect was independent of cAMP and prevented by Lyn antagonism. Inhibition of PKA prevented the IL-24-induced T-current response, whereas inhibition of protein kinase C or MAPK kinases had no effect. Functionally, IL-24 increased TG neuronal excitability and enhanced pain sensitivity to mechanical stimuli in mice, both of which were suppressed by blocking T-type channels. In a trigeminal neuropathic pain model induced by chronic constriction injury of the infraorbital nerve, inhibiting IL-22R1 signaling alleviated mechanical allodynia, which was reversed by blocking T-type channels or knocking down Cav3.2.
CONCLUSION
Our findings reveal that IL-24 enhances T-currents by stimulating IL-22R1 coupled to Lyn-dependent PKA signaling, leading to TG neuronal hyperexcitability and pain hypersensitivity. Understanding the mechanism of IL-24/IL-22R1 signaling in sensory neurons may pave the way for innovative therapeutic strategies in pain management.
Topics: Animals; Calcium Channels, T-Type; src-Family Kinases; Cyclic AMP-Dependent Protein Kinases; Trigeminal Ganglion; Male; Sensory Receptor Cells; Receptors, Interleukin; Mice; Signal Transduction; Mice, Inbred C57BL; Interleukins
PubMed: 38831315
DOI: 10.1186/s12964-024-01688-6 -
Asia Pacific Allergy Jun 2024Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome belong to a family of severe cutaneous adverse reactions that can be life-threatening and carry a risk of...
Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome belong to a family of severe cutaneous adverse reactions that can be life-threatening and carry a risk of significant morbidity and potential mortality in the event of re-exposure. Lifelong avoidance of the culprit agent is mandated, which can lead to the exclusion of multiple medications if the trigger is unclear. This can result in adverse health outcomes analogous to that of a penicillin allergy label. We present a case in which the patient would progress to fatal myeloma in the absence of treatment, however, multiple medications were administered prior to the occurrence of TEN following previous chemotherapy. Available risk stratification tools including human leucocyte antigen assessment and the algorithm of drug causality for epidermal necrolysis scoring system were utilized followed by patch testing which identified a lesser-suspected agent as possibly causative. Further evidence-based in vivo testing and subsequent challenges allowed for the reintroduction of life-saving chemotherapy.
PubMed: 38827259
DOI: 10.5415/apallergy.0000000000000125 -
Cognition Aug 2024Perceptual decision-making often lacks explicit feedback, making confidence in our choices pivotal for guiding subsequent actions. Recent studies have highlighted the...
Perceptual decision-making often lacks explicit feedback, making confidence in our choices pivotal for guiding subsequent actions. Recent studies have highlighted the role of motor responses in modulating decision confidence. Two competing mechanisms have been proposed to elucidate this phenomenon. The "fluency hypothesis" posits that the ease and smoothness of executing a motor response can serve as a cue to enhance retrospective confidence. Conversely, the "monitoring hypothesis" suggests that the extent of action monitoring during response selection may boost retrospective confidence, with heightened monitoring potentially offsetting response fluency. We conducted a pre-registered experiment to directly test these hypotheses. Participants engaged in a perceptual task involving the discrimination of Gabor patch orientation. Perceptual responses required high or low motor precision, manipulated by the size of target circles that participants had to reach with the computer mouse to provide a response. Contrary to the "fluency hypothesis", our results showed that, in trials requiring higher precision (utilizing small circles), participants reported higher confidence levels compared to trials with less demanding responses (involving larger circles). Importantly, this increase in confidence did not coincide with any change in perceptual accuracy. These findings align with the "monitoring hypothesis," suggesting that the degree of action monitoring during response execution can indeed influence retrospective decision confidence.
Topics: Humans; Decision Making; Adult; Young Adult; Psychomotor Performance; Female; Male; Motor Activity; Metacognition
PubMed: 38824695
DOI: 10.1016/j.cognition.2024.105832 -
Actas Dermo-sifiliograficas 2024After the meeting held by the Spanish Contact Dermatitis and Skin Allergy Research Group (GEIDAC) back in October 2021, changes were suggested to the Spanish Standard...
After the meeting held by the Spanish Contact Dermatitis and Skin Allergy Research Group (GEIDAC) back in October 2021, changes were suggested to the Spanish Standard Series patch testing. Hydroxyethyl methacrylate (2% pet.), textile dye mixt (6.6% pet.), linalool hydroperoxide (1% pet.), and limonene hydroperoxide (0.3% pet.) were, then, added to the series that agreed upon in 2016. Ethyldiamine and phenoxyethanol were excluded. Methyldibromoglutaronitrile, the mixture of sesquiterpene lactones, and hydroxyisohexyl 3-cyclohexene (Lyral) were also added to the extended Spanish series of 2022.
Topics: Patch Tests; Humans; Spain; Dermatitis, Allergic Contact; Allergens
PubMed: 38823769
DOI: 10.1016/j.ad.2024.05.018