Specific Disease States Research Articles

Spectrum of bowel wall thickening on ultrasound with pathological correlation in children.

Applications for bowel US in children have been well described; however, less focus has been placed on patterns of bowel wall architectural change in specific disease states. This pictorial essay reviews normal bowel wall architecture and covers a variety of inflammatory, infectious, vascular and neoplastic disorders outside the neonatal period as seen on US, with illustrative pathological correlation. A thorough understanding of normal and abnormal bowel wall architecture can enrich sonographic interpretation and provide a valuable adjunct to appropriate clinical investigation.

Melatonin Attenuates LPS-Induced Proinflammatory Cytokine Response and Lipogenesis in Human Meibomian Gland Epithelial Cells via MAPK/NF-κB Pathway.

PurposeInflammation contributes to the development of meibomian gland dysfunction (MGD) under specific disease conditions, but the underlying mechanisms remain elusive. We examined whether lipopolysaccharide (LPS) induced a proinflammatory cytokine response and lipogenesis in human meibomian gland epithelial cells (HMGECs) and whether melatonin (MLT), a powerful anti-inflammatory regent in the eyes, could protect against LPS-induced disorders.MethodsHuman meibomian gland (MG) tissues and immortalized HMGECs were stained to identify Toll-like receptor (TLR) 4 and MLT receptors (MT1 and MT2). HMGECs were pretreated with or without MLT and then stimulated with LPS. Then, TLR4 activation, cytokine levels, lipid synthesis, apoptosis, autophagy, and MAPK/NF-κB factor phosphorylation in HMGECs were analyzed.ResultsTLR4, MT1, and MT2 were expressed in human MG acini and HMGECs. Pretreatment with MLT inhibited the TLR4/MyD88 signaling and attenuated proinflammatory cytokine response and lipogenesis in LPS-stimulated HMGECs, which manifested as decreased production of cytokines (IL-1β, IL-6, IL-8, and TNF-α), reduced lipid droplet formation, and downregulated expression of meibum lipogenic proteins (ADFP, ELOVL4, and SREBP-1). Phospho-histone H2A.X foci, lysosome accumulation, and cytoplasmic cleaved caspase 3/LC3B-II staining were increased in LPS-stimulated HMGECs, indicating enhanced cell death mediated by apoptosis and autophagy during LPS-induced lipogenesis. MLT downregulated cleaved caspase 3 levels and the Bax/Bcl-2 ratio to alleviate apoptosis and ameliorated the expression of Beclin 1 and LC3B-II to inhibit autophagy. The protective mechanisms of MLT include the inhibition of MAPK and NF-κB phosphorylation.ConclusionsMLT attenuated lipogenesis, apoptosis, and autophagy in HMGECs induced by proinflammatory stimuli, indicating the protective potential of MLT in MGD.

Weibull Distribution as the Choice Model for State-Specific Failure Rates in HIV/AIDS Progression

This study considered the problem of selecting the best single model for modeling state-specific failure rates in HIV/AIDS progression for patients on antiretroviral therapy with age and gender as risk factors using exponential, twoparameter, and three-parameter Weibull distributions. CD4 count changes in any two consecutive visits, the mean waiting time (μ), and transitional rates (λ) for remaining in the same state or transiting to a better or a worse state were analyzed. Various model selection criteria, namely, Akaike Information Criteria (AIC), Bayesian Information Criteria (BIC), and Log-Likelihood (LL), were used in each specific disease state. The Maximum Likelihood Estimation (MLE) method was applied to obtain the parameters of the distributions used. Plots of State-specific transition rates (λ) depicted constant, increasing, decreasing, and unimodal trends. Three-parameter Weibull distribution was the best for male patients and patients aged (40-69) years transiting in the states 1-2, 3-4, and 4-5, and 1-2, 3-4, and 5-6, respectively, and for male, female patients, and patients aged (40-69), remaining in the same state. Two-parameter Weibull distribution was the best for female patients and patients aged (20-39) years transiting in the states 1-2, 2-3, 4-5, and 1-2, 2-3, 3-4, respectively. Exponential distribution proved inferior to the other two distributions used.

Untangling Frizzled functions

Wnt signaling is a complex network of cellular signals with multiple downstream pathways regulated by signaling complexes comprised of combinations of the 19 Wnt ligands, 10 Frizzled (FZD) receptors, various co‐receptors and Dishevelled (DVL) second messengers. Up until now, Wnt receptors have either been functionally defined as whole families or individually by how they affect specific disease states when they are dysregulated, but the specific roles each receptor plays in Wnt signaling and activating the various pathways have yet to be fully understood.CRISPR is a powerful tool that has allowed whole families of protein isomers to be knocked out. By using cellular models that have been modified by CRISPR/Cas9 and are missing key proteins in the Wnt signaling complex, we can determine their individual functions and redundancies.We have determined that a FZD is necessary but any of the individual receptors is sufficient for DVL phosphorylation. Additionally, we have found that some Wnt signals can be rescued by single receptors, or just part of a receptor, while others seem to require multiple FZDs. The expression of these receptors is crucial for not only regulation within the Wnt family of pathways, but we also discovered a new arm of crosstalk with mTOR signaling.Wnt signaling is known to play key roles in many aspects of development, but erroneous signaling can cause diseases such as cancer and osteoporosis. Current therapeutics act as a sledgehammer and target all Wnt signaling, which leads to many off‐target effects and unintended side‐effects. Since cell surface receptors are typically the easiest to therapeutically target, FZD receptors have considerable therapeutic potential. Understanding the roles of each FZD receptor will allow us to better target individual disease mechanisms.

A scoping review on the tools for assessment of Agni and its derangements including Grahani dosha

Abstract: 
 Objective: The purpose of this study was to review and analyze the tools available for the assessment of Agni and its derangements, including grahani dosha.
 Methods: A review of the published literature was conducted online using PubMed, Science Direct, and Google scholar. The keywords for the search included, "Agni,", "Agni Bala,” “Agni vaishamya," "Grahani dosha”, “Assessment tool “, and “Questionnaire”. The initial search retrieved 37 articles, of which seven were screened, classified, and coded for further analysis including their content, methodology as well as utility in clinical practice.
 Results: The review discovered four tools aimed at assessing Agni and three for diagnosing grahani roga. All were different with regards to the domains assessed, mode of administration, and methodologies in which they were developed. Only two of the tools for Agni assessment were prepared following proper methodology including the evaluation for their reliability and validity. The absence of a gold standard against which these tools can be corroborated is a major drawback, because of which these tools were neither subjected to stringent scientific validation nor evaluated for their clinical utility.
 Conclusion: None of the tools available for review could be deemed best at accurately detecting Agni and its dysfunctions. Two of the tools were developed adopting proper methodology, however, the feasibility of these in a clinical scenario has to be established with further studies. Additionally, there was no tool directed at assessing grahani dosha in specific disease states, which necessitates further research to develop and validate tools, especially in specific disorders.

CARD9 Signaling, Inflammation, and Diseases.

Caspase-recruitment domain 9 (CARD9) protein is expressed in many cells especially in immune cells, and is critically involved in the function of the innate and adaptive immune systems through extensive interactions between CARD9 and other signaling molecules including NF-κB and MAPK. CARD9-mediated signaling plays a central role in regulating inflammatory responses and oxidative stress through the productions of important cytokines and chemokines. Abnormalities of CARD9 and CARD9 signaling or CARD9 mutations or polymorphism are associated with a variety of pathological conditions including infections, inflammation, and autoimmune disorders. This review focuses on the function of CARD9 and CARD9-mediated signaling pathways, as well as interactions with other important signaling molecules in different cell types and the relations to specific disease conditions including inflammatory diseases, infections, tumorigenesis, and cardiovascular pathologies.

Phenonizer: A Fine-Grained Phenotypic Named Entity Recognizer for Chinese Clinical Texts.

Biomedical named entity recognition (BioNER) from clinical texts is a fundamental task for clinical data analysis due to the availability of large volume of electronic medical record data, which are mostly in free text format, in real-world clinical settings. Clinical text data incorporates significant phenotypic medical entities (e.g., symptoms, diseases, and laboratory indexes), which could be used for profiling the clinical characteristics of patients in specific disease conditions (e.g., Coronavirus Disease 2019 (COVID-19)). However, general BioNER approaches mostly rely on coarse-grained annotations of phenotypic entities in benchmark text dataset. Owing to the numerous negation expressions of phenotypic entities (e.g., “no fever,” “no cough,” and “no hypertension”) in clinical texts, this could not feed the subsequent data analysis process with well-prepared structured clinical data. In this paper, we developed Human-machine Cooperative Phenotypic Spectrum Annotation System (http://www.tcmai.org/login, HCPSAS) and constructed a fine-grained Chinese clinical corpus. Thereafter, we proposed a phenotypic named entity recognizer: Phenonizer, which utilized BERT to capture character-level global contextual representation, extracted local contextual features combined with bidirectional long short-term memory, and finally obtained the optimal label sequences through conditional random field. The results on COVID-19 dataset show that Phenonizer outperforms those methods based on Word2Vec with an F1-score of 0.896. By comparing character embeddings from different data, it is found that character embeddings trained by clinical corpora can improve F-score by 0.0103. In addition, we evaluated Phenonizer on two kinds of granular datasets and proved that fine-grained dataset can boost methods' F1-score slightly by about 0.005. Furthermore, the fine-grained dataset enables methods to distinguish between negated symptoms and presented symptoms. Finally, we tested the generalization performance of Phenonizer, achieving a superior F1-score of 0.8389. In summary, together with fine-grained annotated benchmark dataset, Phenonizer proposes a feasible approach to effectively extract symptom information from Chinese clinical texts with acceptable performance.

A Biomaterial Model to Assess the Effects of Age in Vascularization

As humans age, there is an increased risk for developing age-associated diseases. Many of these diseases, such as cardiovascular disease, involve dysfunction in the vasculature. Cardiovascular disease stems from endothelial cell dysfunction and reduction in vascularization. Macrophages, prominent innate immune cells involved in orchestrating inflammation and wound healing, have a significant influence on vascularization. While much recent work has investigated the crosstalk between endothelial cells and macrophages, it is still not well defined. The interactions between the cell types are even less understood in specific disease states such as advanced age. Understanding how age influences macrophage/endothelial cell interaction is essential for understanding cardiovascular disease development in the elderly. In the polyethylene glycol (PEG)-based hydrogel system, we model the effects of age on vascularization by encapsulating endothelial cells, pericytes, and human donor macrophages. We created a biomaterial model system in which macrophages, either from young (<35 years old) or old (>65 years old) donors, interact with the modeled vasculature, termed microvessels. Confocal image analysis of vessel density, vessel length, and branch points were used to quantify microvessel growth depending on the age of the macrophage donor. Alongside this, soluble factor secretion and gene expression were evaluated using ELISA and NanoString to showcase biological mechanisms based on the age of each donor. Endothelial cells cultured with macrophages from old donors have reduced microvessel density. There also is reduced soluble factor secretion by the macrophages from old donors, which likely influenced microvessel growth. Altogether, we establish our PEG-based hydrogel vascular model as a system to evaluate patient-specific cell function as well as proposed mechanisms for how age influences microvessels.

Approaches for corneal endothelium regenerative medicine

The state of the art therapy for treating corneal endothelial disease is transplantation. Advances in the reproducibility and accessibility of surgical techniques are increasing the number of corneal transplants, thereby causing a global deficit of donor corneas and leaving 12.7 million patients with addressable visual impairment. Approaches to regenerate the corneal endothelium offer a solution to the current tissue scarcity and a treatment to those in need. Methods for generating corneal endothelial cells into numbers that could address the current tissue shortage and the possible strategies used to deliver them have now become a therapeutic reality with clinical trials taking place in Japan, Singapore and Mexico. Nevertheless, there is still a long way before such therapies are approved by regulatory bodies and become clinical practice. Moreover, acellular corneal endothelial graft equivalents and certain drugs could provide a treatment option for specific disease conditions without the need of donor tissue or cells. Finally, with the emergence of gene modulation therapies to treat corneal endothelial disease, it would be possible to treat presymptomatic patients or those presenting early symptoms, drastically reducing the need for donor tissue. It is necessary to understand the most recent developments in this rapidly evolving field to know which conditions could be treated with which approach. This article provides an overview of the current and developing regenerative medicine therapies to treat corneal endothelial disease and provides the necessary guidance and understanding towards the treatment of corneal endothelial disease.

Just Like Rock and Roll, Topical Medications for Psoriasis Are Here to Stay.

Coupled with this myriad of fundamental science is the emergence of newer therapies that are more directly targeting specific disease states and dramatically changing the lives of patients. We see prominent examples of these therapeutic results every day in patients we treat, especially with psoriasis and atopic dermatitis.

Structural and functional neuroimaging of the effects of the gut microbiome.

Interactions between intestinal microbiota and the central nervous system profoundly influence brain structure and function. Over the past 15years, intense research efforts have uncovered the significant association between gut microbial dysbiosis and neurologic, neurodegenerative, and psychiatric disorders; however, our understanding of the effect of gut microbiota on quantitative neuroimaging measures of brain microstructure and function remains limited. Many current gut microbiome studies specifically focus on discovering correlations between specific microbes and neurologic disease states that, while important, leave critical mechanistic questions unanswered. To address this significant gap in knowledge, quantitative structural and functional brain imaging has emerged as a vital bridge and as the next step in understanding how the gut microbiome influences the brain. In this review, we examine the current state-of-the-art, raise awareness of this important topic, and aim to highlight immense new opportunities-in both research and clinical imaging-for the imaging community in this emerging field of study. Our review also highlights the potential for preclinical imaging of germ-free and gnotobiotic models to significantly advance our understanding of the causal mechanisms by which the gut microbiome alters neural microstructure and function. KEY POINTS: • Alterations to the gut microbiome can significantly influence brain structure and function in health and disease. • Quantitative neuroimaging can help elucidate the effect of gut microbiota on the brain and with future translational advances, neuroimaging will be critical for both diagnostic assessment and therapeutic monitoring.

Challenges and Future Directions for LncRNAs and Inflammation.

Until somewhat recently, the complexity of the human genome has not been well understood. With advancements in sequencing technology, we now know that nearly the whole genome is transcribed but a very small portion of those transcripts code for proteins. As the research of non-coding genes and transcripts has evolved rapidly in the last decade, it has become clear that many of them serve important biological functions in many previously well-studied cell processes. As the previous chapters in this book have reviewed, the field of noncoding RNA research has provided new insights into specific disease states, especially those driven by inflammation. Understanding the basic mechanisms of non-coding RNAs in the context of inflammation has led to prospective therapeutics that may overcome many of the challenges faced in diagnosing and treating inflammatory diseases. In this final chapter we discuss the current state of the field of non-coding RNA therapeutics and how it may evolve to overcome the short cummings we currently face with diagnosing and treating inflammatory diseases.

Malnutrition Among Hospitalized Adult Patients

Hospital malnutrition, although well established, has remained underrecognized in health care settings. This study aimed at determining the prevalence and factors associated with hospital malnutrition in Lahore, Pakistan. A sample of 937 hospitalized patients was screened for malnutrition using a Subjective Global Assessment (SGA). More than half (59.4%) of the sample was found to be undernourished, of which 26.4% was severely malnourished (SGA-C). Age more than 60 years (odds ratio [OR] = 0.574, P &lt; .05), comorbidities (OR = 1.388, P = .014), and specific disease conditions (cancer and renal diseases) (OR = 3.291; OR = 3.042, P &lt; .05, respectively) increased the risk of undernourishment (SGA-B&amp;C). High prevalence of disease-associated malnutrition among hospitalized patients urgently calls for preadmission screening.

Matching mouse models to specific human liver disease states by comparative functional genomics of mouse and human datasets

Omics has broadened our view of transcriptional and gene regulatory networks of multifactorial diseases, such as metabolism associated liver disease and its advanced stages including hepatocellular carcinoma. Identifying liver disease biomarkers and potential treatment targets makes use of experimental models, e.g. genetically engineered mice, which show molecular features of human pathologies but are experimentally tractable. We compared gene expression profiling data from human to our studies on transgenic mice with hepatocyte deletion of Cyp51 from cholesterol synthesis with the aim of identifying the human liver disease state best matched by the Cyp51 knockout model. Gene Expression Omnibus was used to identify relevant human datasets. We identified enriched and deregulated genes, pathways and transcription factors of mouse and human disease samples. Analysis showed a closer match of the Cyp51 knockout to the female patient samples. Importantly, CYP51 was depleted in both mouse and female human data. Among the enriched genes were the oxysterol-binding protein-related protein 3 (OSBPL3), which was enriched in all datasets, and the collagen gene COL1A2, which was enriched in both the mouse and one human dataset. KEGG and Reactome analyses revealed the most enriched pathway to be ECM-receptor interaction. Numerous transcription factors were differentially expressed in mice of both sexes and in the human female dataset, while depleted HNF4α and RXRα:PPARα-isoform1 were a hallmark in all cases. Our analysis exposed novel potential biomarkers, which may provide new avenues towards more personalized approaches and different targets in females and males. The analysis was only possible because of availability of open data resources and tools and broadly consistent annotation.

Establishment of an RI for the urine ammonia-to-creatinine ratio in dogs.

BackgroundAmmonia is produced and excreted by the kidney, contributing to systemic acid‐base homeostasis through the production of bicarbonate. Disorders of acid‐base balance can lead to many clinical problems and measuring ammonia excretion helps in determining if the kidneys are responding to acid‐base challenges appropriately. Reference intervals are integral to clinical decision‐making, and there is no current RI for the urine ammonia‐to‐creatinine ratio (UACR) in dogs.ObjectiveThis study aimed to generate an RI for the UACR in healthy adult dogs.MethodsThe study used adult, client‐owned dogs that were presented to the University of Florida Primary Care and Dentistry service (n = 60). Physical examinations were performed and serum chemistry and urinalysis samples were obtained. Urine ammonia and creatinine concentrations were determined. Dogs were excluded if there were significant abnormalities in either their urinalysis or serum chemistry results. The RI for the UACR was calculated according to the recommendation of the American Society for Veterinary Clinical Pathology. Data were evaluated for correlation with serum bicarbonate, weight, age, and sex.ResultsThe RIs for the UACR were 0.16‐23.69 with 90% confidence intervals for the lower and upper limits of (0.13‐1.17) and (20.50‐23.75), respectively. No significant impact of age, sex, or weight was found. There was no discernable relationship between serum bicarbonate and UACR.ConclusionsEstablishing an RI for UACR in healthy adult dogs will allow for further studies to determine if alterations are observed during specific disease states.

The United States 2020 Census data: implications for precision medicine and theresearch landscape.

The United States 2020 Census data: implications for precision medicine and theresearch landscape.

Precision of Medication Therapy Problem Identification and Classification amongst Primary Care Clinic Pharmacists.

This study assesses the level of agreement on medication therapy problem (MTP) identification and classification between primary care, ambulatory care pharmacists within a health-system that recently implemented system-wide pharmacist provision of comprehensive medication management (CMM) services. Twenty standardized case vignettes were created and distributed to pharmacists who reviewed each case and identified and categorized MTPs. Outcomes include the number of MTPs identified, identification (yes/no) of specific MTPs within each case (e.g., need for a statin), and Pharmacy Quality Alliance (PQA) category used when classifying MTPs. The level of agreement on MTP identification/categorization was measured using intraclass correlation coefficient (ICC) and interpreted using the Landis and Koch interpretation scale. “Moderate agreement” was observed for the number of MTPs identified by pharmacists (ICC equal to 0.45; 95% confidence interval [CI]: 0.31 to 0.65). In approximately one-half of opportunities, the pharmacists agreed perfectly on the number of MTPs; in approximately one-third of opportunities, the number of MTPs identified varied by 1; and approximately one-tenth of the time, the number of MTPs varied by 2. In regard to the MTP identification (yes/no) and categorization, percent agreement was ≥73% across all MTPs. The results support the need for further training and education and provide the information necessary to target specific disease states.

Physiological and Pathological Roles of Aldose Reductase.

Aldose reductase (AR) is an aldo-keto reductase that catalyzes the first step in the polyol pathway which converts glucose to sorbitol. Under normal glucose homeostasis the pathway represents a minor route of glucose metabolism that operates in parallel with glycolysis. However, during hyperglycemia the flux of glucose via the polyol pathway increases significantly, leading to excessive formation of sorbitol. The polyol pathway-driven accumulation of osmotically active sorbitol has been implicated in the development of secondary diabetic complications such as retinopathy, nephropathy, and neuropathy. Based on the notion that inhibition of AR could prevent these complications a range of AR inhibitors have been developed and tested; however, their clinical efficacy has been found to be marginal at best. Moreover, recent work has shown that AR participates in the detoxification of aldehydes that are derived from lipid peroxidation and their glutathione conjugates. Although in some contexts this antioxidant function of AR helps protect against tissue injury and dysfunction, the metabolic transformation of the glutathione conjugates of lipid peroxidation-derived aldehydes could also lead to the generation of reactive metabolites that can stimulate mitogenic or inflammatory signaling events. Thus, inhibition of AR could have both salutary and injurious outcomes. Nevertheless, accumulating evidence suggests that inhibition of AR could modify the effects of cardiovascular disease, asthma, neuropathy, sepsis, and cancer; therefore, additional work is required to selectively target AR inhibitors to specific disease states. Despite past challenges, we opine that a more gainful consideration of therapeutic modulation of AR activity awaits clearer identification of the specific role(s) of the AR enzyme in health and disease.

Centrosome instability: when good centrosomes go bad.

The centrosome is a tiny cytoplasmic organelle that organizes and constructs massive molecular machines to coordinate diverse cellular processes. Due to its many roles during both interphase and mitosis, maintaining centrosome homeostasis is essential to normal health and development. Centrosome instability, divergence from normal centrosome number and structure, is a common pathognomonic cellular state tightly associated with cancers and other genetic diseases. As novel connections are investigated linking the centrosome to disease, it is critical to understand the breadth of centrosome functions to inspire discovery. In this review, we provide an introduction to normal centrosome function and highlight recent discoveries that link centrosome instability to specific disease states.

A discussion on the 'dispensable' amino acids.

Recently, the concept of dietary dispensable amino acids has been increasingly challenged, as more indirect and direct (experimental) evidence has pointed to the need for them in the diet during specific life stages or disease states. Here, we discuss the classification of amino acids, methods to assess the needs for dispensable amino acids with experimental evidence from our recent studies, and highlight the role of specific dispensable amino acids in metabolism and health. There exist differences among the dispensable amino acids to act as effective nitrogen sources in humans. Glycine, a dispensable amino acid is conditionally indispensable in later stages of human pregnancy. The so-called 'dispensable' amino acids are quantitatively nearly 75% of the daily protein needs in humans. In certain life-stages and diseases, there is a dietary demand for the dispensable amino acids. Future well-designed studies are required to identify the dietary demand for these amino acids, which will certainly be useful for dietary management in specific diseases and to maintain health across all life-stages.