Disease Conditions Research Articles

Trans-Interacting Plasma Membrane Proteins and Binding Partner Identification.

Plasma membrane proteins (PMPs) play critical roles in a myriad of physiological and disease conditions. A unique subset of PMPs functions through interacting with each other in trans at the interface between two contacting cells. These trans-interacting PMPs (tiPMPs) include adhesion molecules and ligands/receptors that facilitate cell-cell contact and direct communication between cells. Among the tiPMPs, a significant number have apparent extracellular binding domains but remain orphans with no known binding partners. Identification of their potential binding partners is therefore important for the understanding of processes such as organismal development and immune cell activation. While a number of methods have been developed for the identification of protein binding partners in general, very few are applicable to tiPMPs, which interact in a two-dimensional fashion with low intrinsic binding affinities. In this review, we present the significance of tiPMP interactions, the challenges of identifying binding partners for tiPMPs, and the landscape of method development. We describe current avidity-based screening approaches for identifying novel tiPMP binding partners and discuss their advantages and limitations. We conclude by highlighting the importance of developing novel methods of identifying new tiPMP interactions for deciphering the complex protein interactome and developing targeted therapeutics for diseases.

Evaluation of the stress state based on fecal corticosterone metabolite concentrations in captive penguins in Japan.

Fecal corticosterone metabolite (FCM) concentrations, which can be determined noninvasively, have recently been explored as a stress indicator in birds. In our study, we measured FCM concentrations in penguins under nonmolting or molting conditions, cool or hot season, diseased condition, and incubation period. These measurements were conducted in an aquarium that housed king penguins, gentoo penguins, and African penguins. This study aimed to investigate the validity of fecal matter as a stress indicator. Our findings revealed that FCM concentrations were significantly higher in molting individuals than in nonmolting individuals. Compared with the cool season, FCM concentrations were significantly higher in penguins housed outdoors during the hot season. However, no differences were observed in penguins housed indoors. Diseased individuals and an incubating individual showed notably higher FCM concentrations than healthy individuals. Interestingly, the FCM concentration in king penguin that underwent cataract surgery was extremely high before the surgery. However, 1 month postsurgery, it decreased to a level similar to that of healthy individuals. We observed increased FCM concentrations in penguins considered to be exposed to stressors. Notably, FCM concentration decreased after removing the stress factor. The FCM concentration was found to be consistent with the stress state of penguins, suggesting its usefulness as a stress indicator.

Novel Vesicular Bilosomal Delivery Systems for Dermal/Transdermal Applications.

The application of therapeutically active molecules through the dermal/transdermal route into the skin has evolved as an attractive formulation strategy in comparison to oral delivery systems for the treatment of various disease conditions. However, the delivery of drugs across the skin is limited due to poor permeability. Dermal/transdermal delivery is associated with ease of accessibility, enhanced safety, better patient compliance, and reduced variability in plasma drug concentrations. It has the ability to bypass the first-pass metabolism, which ultimately results in steady and sustained drug levels in the systemic circulation. Vesicular drug delivery systems, including bilosomes, have gained significant interest due to their colloidal nature, improved drug solubility, absorption, and bioavailability with prolonged circulation time for a large number of new drug molecules. Bilosomes are novel lipid vesicular nanocarriers comprising bile salts, such as deoxycholic acid, sodium cholate, deoxycholate, taurocholate, glycocholate or sorbitan tristearate. These bilosomes are associated with high flexibility, deformability, and elasticity attributed to their bile acid component. These carriers are advantageous in terms of improved skin permeation, increased dermal and epidermal drug concentration, and enhanced local action with reduced systemic absorption of the drug, resulting in reduced side effects. The present article provides a comprehensive overview of the biopharmaceutical aspects of dermal/transdermal bilosome delivery systems, their composition, formulation techniques, characterization methods, and applications.

CHIP: a clonal odyssey of the bone marrow niche.

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by the selective expansion of hematopoietic stem and progenitor cells (HSPCs) carrying somatic mutations. While CHIP is typically asymptomatic, it has garnered substantial attention due to its association with the pathogenesis of multiple disease conditions, including cardiovascular disease (CVD) and hematological malignancies. In this Review, we will discuss seminal and recent studies that have advanced our understanding of mechanisms that drive selection for mutant HSPCs in the BM niche. Next, we will address recent studies evaluating potential relationships between the clonal dynamics of CHIP and hematopoietic development across the lifespan. Next, we will examine the roles of systemic factors that can influence hematopoietic stem cell (HSC) fitness, including inflammation, and exposures to cytotoxic agents in driving selection for CHIP clones. Furthermore, we will consider how - through their impact on the BM niche - lifestyle factors, including diet, exercise, and psychosocial stressors, might contribute to the process of somatic evolution in the BM that culminates in CHIP. Finally, we will review the role of old age as a major driver of selection in CHIP.

Development of a Tremor Detection Algorithm for Use in an Academic Movement Disorders Center

Tremor, defined as an “involuntary, rhythmic, oscillatory movement of a body part”, is a key feature of many neurological conditions including Parkinson’s disease and essential tremor. Clinical assessment continues to be performed by visual observation with quantification on clinical scales. Methodologies for objectively quantifying tremor are promising but remain non-standardized across centers. Our center performs full-body behavioral testing with 3D motion capture for clinical and research purposes in patients with Parkinson’s disease, essential tremor, and other conditions. The objective of this study was to assess the ability of several candidate processing pipelines to identify the presence or absence of tremor in kinematic data from patients with confirmed movement disorders and compare them to expert ratings from movement disorders specialists. We curated a database of 2272 separate kinematic data recordings from our center, each of which was contemporaneously annotated as tremor present or absent by a movement physician. We compared the ability of six separate processing pipelines to recreate clinician ratings based on F1 score, in addition to accuracy, precision, and recall. The performance across algorithms was generally comparable. The average F1 score was 0.84±0.02 (mean ± SD; range 0.81–0.87). The second highest performing algorithm (cross-validated F1=0.87) was a hybrid that used engineered features adapted from an algorithm in longstanding clinical use with a modern Support Vector Machine classifier. Taken together, our results suggest the potential to update legacy clinical decision support systems to incorporate modern machine learning classifiers to create better-performing tools.

Time series forecasting of weight for diuretic dose adjustment using bidirectional long short-term memory

Loop diuretics are prevailing drugs to manage fluid overload in heart failure. However, adjusting to loop diuretic doses is strenuous due to the lack of a diuretic guideline. Accordingly, we developed a novel clinician decision support system for adjusting loop diuretics dosage with a Long Short-Term Memory (LSTM) algorithm using time-series EMRs. Weight measurements were used as the target to estimate fluid loss during diuretic therapy. We designed the TSFD-LSTM, a bi-directional LSTM model with an attention mechanism, to forecast weight change 48 h after heart failure patients were injected with loop diuretics. The model utilized 65 variables, including disease conditions, concurrent medications, laboratory results, vital signs, and physical measurements from EMRs. The framework processed four sequences simultaneously as inputs. An ablation study on attention mechanisms and a comparison with the transformer model as a baseline were conducted. The TSFD-LSTM outperformed the other models, achieving 85% predictive accuracy with MAE and MSE values of 0.56 and 1.45, respectively. Thus, the TSFD-LSTM model can aid in personalized loop diuretic treatment and prevent adverse drug events, contributing to improved healthcare efficacy for heart failure patients.

Formulation and physicotechnical evaluation of a fixed dose combination of amlodipine, metformin and glibenclamide in the management of hypertension-diabetes mellitus comorbidity

The concept of fixed dose combination (FDC) dates as far back as the early 17th century and still finds relevance till today. Almost every disease condition has at least one approved FDC commercially available for its treatment. The prevalence of hypertension-diabetes mellitus (HTN-DM) comorbidity is high globally. However, there are no available FDC formulation approved to be used in managing patients with this comorbidity. This study was designed to fill this gap by formulating an FDC of Amlodipine (antihypertensive), Metformin (antidiabetic) and Glibenclamide (antidiabetic), which are already being used clinically as monotherapies in management of HTN-DM comorbid patients. The APIs were granulated using wet granulation method with the aid of the excipients, after which the granules properties were examined and subsequently compressed into tablets. The physicotechnical properties and in-vitro release profile were evaluated on the tablets. The results of granule properties such as angle of repose (22.8o), Hausner ratio (1.16) and Carr’s compressibility index (13) for the 8% binder batch show excellent flow properties and is indicative of forming tablets with good qualities. “8% binder” tablets batch has the following properties; hardness (kgF), friability (0.55%), disintegration time (220 secs), all within the acceptable official requirements. The release profile showed that the drugs were bioavailable from the tablets in good time. It can be concluded that the formulation of an FDC for HTN-DM comorbidity was a success and studies to confirm the compatibility of the APIs and excipients are recommended.

Using digital technology as a platform to strengthen the continuum of care at community level for maternal, child and adolescent health in Tanzania: introducing the Afya-Tek program

Inadequate care within Tanzania’s primary health system contributes to thousands of preventable maternal and child deaths, and unwanted pregnancies each year. A key contributor is lack of coordination between three primary healthcare actors: public sector Community Health Workers (CHWs) and health facilities, and private sector Accredited Drug Dispensing Outlets (ADDOs). The Afya-Tek program aims to improve the continuity of care amongst these actors in Kibaha district, through a mobile-application based digital referral system that focuses on improving maternal, child and adolescent health. The digital system called Afya-Tek was co-created with users and beneficiaries, and utilises open-source technology in-line with existing government systems. The system guides healthcare actors with individualised decision support during client visits and recommends accurate next steps (education, treatment, or referral). From July 2020 to June 2023, a total of 241,000 individuals were enrolled in the Afya-Tek program covering 7,557 pregnant women, 6,582 postpartum women, 45,900 children, and 25,700 adolescents. CHWs have conducted a total of 626,000 home visits to provide health services, including screening clients for danger signs. This has resulted in 38,100 referrals to health facilities and 24,300 linkages to ADDOs. At the ADDO level, 48,552 clients self-presented; 33% of children with pneumonia symptoms received Amoxicillin; 34% of children with diarrhoea symptoms received ORS and zinc; and 4,203 referrals were made to nearest health facilities. Adolescents preferred services at ADDOs as a result of increased perceived privacy and confidentiality. In total, 89% of all referrals were attended by health facilities. As the first digital health program in Tanzania to demonstrate the linkage among public and private sector primary healthcare actors, Afya-Tek holds promise to improve maternal, child and adolescent health as well as for scale-up and sustainability, through incorporation of other disease conditions and integration with government’s Unified Community System (UCS).

Molecular evaluation and phenotypic screening of brown and orange rust in Saccharum germplasm.

Brazil is the largest global producer of sugarcane and plays a significant role-supplier of sugar and bioethanol. However, diseases such as brown and orange rust cause substantial yield reductions and economic losses, due decrease photosynthesis and biomass in susceptible cultivars. Molecular markers associated with resistance genes, such as Bru1 (brown rust) and G1 (orange rust), could aid in predicting resistant genotypes. In this study, we sought to associate the phenotypic response of 300 sugarcane accessions with the genotypic response of Bru1 and G1 markers. The field trials were conducted in a randomized block design, and five six-month-old plants per plot were evaluated under natural disease conditions. Genotypic information about the presence or absence of Bru1 (haplotype 1) and G1 gene was obtained after extraction of genomic DNA and conventional PCR. Of the total accessions evaluated, 60.3% (181) showed resistance to brown rust in the field, and of these, 70.7% (128) had the Bru1 gene present. Considering the field-resistant accessions obtained from Brazilian breeding programs (116), the Bru1 was present in 77,6% of these accessions. While alternative resistance sources may exist, Bru1 likely confers enduring genetic resistance in current Brazilian cultivars. Regarding the phenotypic reaction to orange rust, the majority of accessions, 96.3% (288), were field resistant, and of these, 52.7% (152) carried the G1 marker. Although less efficient for predicting resistance when compared to Bru1, the G1 marker could be part of a quantitative approach when new orange rust resistance genes are described. Therefore, these findings showed the importance of Bru1 molecular markers for the early selection of resistant genotypes to brown rust by genetic breeding programs.

Nutritional ultrasound: above body mass index, two cases presentation.

Malnutrition is a prevalent condition in chronic diseases, significantly impacting morbidity and mortality. Point-of-care ultrasound (POCUS) is increasingly utilized in clinical practice as a rapid and accessible tool for evaluating muscle mass. Here, we present two cases of females with chronic diseases who presented with acute exacerbations of their conditions accompanied by fluid overload. Suspected of experiencing nutritional alterations, they underwent ultrasound evaluation to confirm muscle mass loss. These cases highlight the potential of ultrasound in guiding effective muscle mass assessment, particularly in pathologies prone to fluid overload, such as chronic kidney disease and heart failure.

Evaluating the consequences of critically ill patients with pediatric cancer at Aliasghar Children’s Hospital

ABSTRACT Background: Despite significant progress in supportive care and advancements in chemotherapy treatments, cancer remains a leading cause of mortality in children. The objective of this study was to assess the potential correlation between various risk factors and the consequences of patients with pediatric cancer who were admitted to the pediatric intensive care unit (PICU). Methods: The present investigation is a retrospective cohort study that examined children with cancer who were between the ages of 1 month and 17 years and had been admitted to the PICU. Demographic and clinical information of all patients, including such as the age, type of cancer, sex, BMI, history of specific disease, PICU admission time, disease condition on PICU admission, patient’s status at PICU admission, and number of organ failures, were extracted from each patient file Results: The number of pediatric oncology patients admitted to the PICU was 127. The highest mortality rate was observed among children with heart problems (75%), followed by CNS involvement (54.2%) and sepsis (42.9%). The study found that various factors had a significant effect on the outcomes of patients who were admitted to the PICU, including but not limited to the primary type of malignancy, disease status, indications for hospital admission, patient’s condition, inpatients’ length of stay (LOS), tumor type, and the extent of organ failure at the time of admission to the PICU. Conclusion: Despite recent advancements in healthcare, the prognosis of patients admitted to the PICU in underdeveloped areas remains suboptimal in comparison to those in developed regions. Poor outcomes were found to be significantly associated with various factors, including the primary type of malignancy, disease status, the reason for admission to the PICU, patient’s condition, LOS, tumor type, and the extent of organ failure, especially in cases involving hematological malignancies.

Evaluation of cartilage properties from NIR diffuse reflectance spectra: numerical simulation

Diseased conditions of articular cartilage such as osteoarthritis (OA) are accompanied by a change in the water concentration, together with a decrease in cartilage thickness. These parameters are important indicators of the normal joint functioning. Light scattering in a heterogeneous joint tissue is a complex process and it is important to supplement its study with understanding gained from modelling. In this work we employed Monte Carlo for analysis of the relationship between changes in cartilage parameters and calculated diffuse reflectance spectra. It has been shown that water absorption peak at 980 nm is determined by both water content and cartilage thickness, while changes in diffuse reflectance spectra at 1450 nm are mostly driven only by water content. Since independent assessment of these parameters is clinically relevant, several approaches for their determination were developed. A heuristic algorithm for cartilage thickness determination and its quality metrics (R 2 = 0.96) were obtained. Several regression models were developed using the amplitudes of diffuse reflectance spectra at different wavelengths and it was shown that the use of a wide range of wavelengths (850–1700 nm) allows to determine the cartilage water concentration and its thickness with the accuracy R 2 0.96 and 0.99 while measuring at different probe-detector distances.

Empowering patients: Harnessing mnemonics for non-communicable disease management

ABSTRACT The epidemiological transition caused a significant non-communicable disease burden in all countries, including India. It can be tackled appropriately by integrating pharmacological and non-pharmacological interventions. The outcome of the disease or control status related to the disease condition depends significantly on patient education. Mnemonics is already an accepted way of improving cognition. The newer learning theories talk about different types of mnemonics and their role in imparting knowledge. We developed three mnemonics regarding essential information related to hypertension, diabetes mellitus, and obesity. It will help achieve better control status in those diseases by improving cognition.

Mitochondrial function in oral health and disease

Monitoring mitochondrial function and mitochondrial quality control in tissues is a crucial aspect of understanding cellular health and dysfunction, which may inform about the pathogenesis of several conditions associated with aging, including chronic inflammatory conditions, neurodegenerative disorders and metabolic diseases. This process involves assessing the functionality, integrity, and abundance of mitochondria within cells. Several lines of evidence have explored techniques and methods for monitoring mitochondrial quality control in tissues. In this review, we summarize and provide our perspective considering the latest evidence in mitochondrial function and mitochondrial quality control in oral health and disease with a particular focus in periodontal inflammation. This research is significant for gaining insights into cellular health and the pathophysiology of periodontal disease, a dysbiosis-related, immune mediated and age-associated chronic condition representing a significant burden to US elderly population. Approaches for assessing mitochondrial health status reviewed here include assessing mitochondrial dynamics, mitophagy, mitochondrial biogenesis, oxidative stress, electron transport chain function and metabolomics. Such assessments help researchers comprehend the role of mitochondrial function in cellular homeostasis and its implications for oral diseases.

Effects of Air Pollution and Meteorological Conditions on DED: Associated Manifestations and Underlying Mechanisms.

This study aims to explore the associations and the underlying mechanism among dry eye disease (DED), air pollution, and meteorological conditions. DED is positively correlated with air pollutants (i.e., PM2.5, PM10, O3, NO2, CO, and SO2) and meteorological conditions (i.e., high altitude and wind speed), while negatively associated with relative humidity. Both low and high air temperatures effect DED. Atmospheric pollutants affect DED mainly through necroptosis or autophagy, inflammatory responses, and oxidative stress. Meteorological factors affect DED not only by their own affects but also by dispersing the concentration of air pollutants, and then reducing the negative exposure. In summary, this review may expand the understanding of the effects of air pollution and meteorological factors on DED and emphasize the importance of air environmental protection.

Hydrogels: a promising therapeutic platform for inflammatory skin diseases treatment.

Inflammatory skin diseases, such as psoriasis and atopic dermatitis, pose significant health challenges due to their long-lasting nature, potential for serious complications, and significant health risks, which requires treatments that are both effective and exhibit minimal side effects. Hydrogels offer an innovative solution due to their biocompatibility, tunability, controlled drug delivery capabilities, enhanced treatment adherence and minimized side effects risk. This review explores the mechanisms that guide the design of hydrogel therapeutic platforms from multiple perspectives, focusing on the components of hydrogels, their adjustable physical and chemical properties, and their interactions with cells and drugs to underscore their clinical potential. We also examine various therapeutic agents for psoriasis and atopic dermatitis that can be integrated into hydrogels, including traditional drugs, novel compounds targeting oxidative stress, small molecule drugs, biologics, and emerging therapies, offering insights into their mechanisms and advantages. Additionally, we review clinical trial data to evaluate the effectiveness and safety of hydrogel-based treatments in managing psoriasis and atopic dermatitis under complex disease conditions. Lastly, we discuss the current challenges and future opportunities for hydrogel therapeutics in treating psoriasis and atopic dermatitis, such as improving skin barrier penetration and developing multifunctional hydrogels, and highlight emerging opportunities to enhance long-term safety and stability.

Phenotypic Plasticity and Cancer: A System Biology Perspective

Epithelial-to-mesenchymal transition (EMT) is a major axis of phenotypic plasticity not only in diseased conditions such as cancer metastasis and fibrosis but also during normal development and wound healing. Yet-another important axis of plasticity with metastatic implications includes the cancer stem cell (CSCs) and non-CSC transitions. However, in both processes, epithelial (E) and mesenchymal (M) phenotypes are not merely binary states. Cancer cells acquire a spectrum of phenotypes with traits, properties, and markers of both E and M phenotypes, giving rise to intermediary hybrid (E/M) phenotypes. E/M cells play an important role in tumor initiation, metastasis, and disease progression in multiple cancers. Furthermore, the hybrid phenotypes also play a major role in causing therapeutic resistance in cancer. Here, we discuss how a systems biology perspective on the problem, which is implicit in the ‘Team Medicine’ approach outlined in the theme of this Special Issue of The Journal of Clinical Medicine and includes an interdisciplinary team of experts, is more likely to shed new light on EMT in cancer and help us to identify novel therapeutics and strategies to target phenotypic plasticity in cancer.

The effects of TGF-β-induced activation and starvation of vitamin A and palmitic acid on human stem cell-derived hepatic stellate cells

BackgroundHepatic stellate cells (HSC) have numerous critical roles in liver function and homeostasis, while they are also known for their importance during liver injury and fibrosis. There is therefore a need for relevant in vitro human HSC models to fill current knowledge gaps. In particular, the roles of vitamin A (VA), lipid droplets (LDs), and energy metabolism in human HSC activation are poorly understood.MethodsIn this study, human pluripotent stem cell-derived HSCs (scHSCs), benchmarked to human primary HSC, were exposed to 48-hour starvation of retinol (ROL) and palmitic acid (PA) in the presence or absence of the potent HSC activator TGF-β. The interventions were studied by an extensive set of phenotypic and functional analyses, including transcriptomic analysis, measurement of activation-related proteins and cytokines, VA- and LD storage, and cell energy metabolism.ResultsThe results show that though the starvation of ROL and PA alone did not induce scHSC activation, the starvation amplified the TGF-β-induced activation-related transcriptome. However, TGF-β-induced activation alone did not lead to a reduction in VA or LD stores. Additionally, reduced glycolysis and increased mitochondrial fission were observed in response to TGF-β.ConclusionsscHSCs are robust models for activation studies. The loss of VA and LDs is not sufficient for scHSC activation in vitro, but may amplify the TGF-β-induced activation response. Collectively, our work provides an extensive framework for studying human HSCs in healthy and diseased conditions.

Multi-Modal Diagnosis of Alzheimer's Disease using Interpretable Graph Convolutional Networks.

The interconnection between brain regions in neurological disease encodes vital information for the advancement of biomarkers and diagnostics. Although graph convolutional networks are widely applied for discovering brain connection patterns that point to disease conditions, the potential of connection patterns that arise from multiple imaging modalities has yet to be fully realized. In this paper, we propose a multi-modal sparse interpretable GCN framework (SGCN) for the detection of Alzheimer's disease (AD) and its prodromal stage, known as mild cognitive impairment (MCI). In our experimentation, SGCN learned the sparse regional importance probability to find signature regions of interest (ROIs), and the connective importance probability to reveal disease-specific brain network connections. We evaluated SGCN on the Alzheimer's Disease Neuroimaging Initiative database with multi-modal brain images and demonstrated that the ROI features learned by SGCN were effective for enhancing AD status identification. The identified abnormalities were significantly correlated with AD-related clinical symptoms. We further interpreted the identified brain dysfunctions at the level of large-scale neural systems and sex-related connectivity abnormalities in AD/MCI. The salient ROIs and the prominent brain connectivity abnormalities interpreted by SGCN are considerably important for developing novel biomarkers. These findings contribute to a better understanding of the network-based disorder via multi-modal diagnosis and offer the potential for precision diagnostics. The source code is available at https://github.com/Houliang-Zhou/SGCN.

Association between objective measures of oral health and salivary gland irradiation with patient-reported outcomes following head and neck radiation therapy.

To determine whether objective measures of oral health and salivary gland irradiation correlates with subjective measures of eating, drinking, and salivation in patients following head and neck radiation therapy (HNRT). This cross-sectional study included 112 patients following HNRT with a completed patient-reported outcome (PRO) scale. Objective measures at post-HNRT visit included decayed-missing-filled teeth (DMFT) scores, periodontal disease condition, oral hygiene status, dental prosthesis use, and prescribed radiation dose to salivary glands. Data were collected and statistical analysis was performed. There was no significant association between PRO scales and dental prosthesis use, periodontal disease, and oral hygiene. Although some significant findings were seen with DMFT and prescribed radiation dose to salivary glands, this explained only very small amounts of the variation in eating, drinking, and salivation measures in these patients. PRO measures should be integrated in the routine care of patients with head and neck cancer.