The transition from acute to chronic pain is critically important but not well understood. Here, we investigated the pathophysiological mechanisms underlying the transition from acute to chronic low ...back pain (LBP) and performed transcriptome-wide analysis in peripheral immune cells of 98 participants with acute LBP, followed for 3 months. Transcriptomic changes were compared between patients whose LBP was resolved at 3 months with those whose LBP persisted. We found thousands of dynamic transcriptional changes over 3 months in LBP participants with resolved pain but none in those with persistent pain. Transient neutrophil-driven up-regulation of inflammatory responses was protective against the transition to chronic pain. In mouse pain assays, early treatment with a steroid or nonsteroidal anti-inflammatory drug (NSAID) also led to prolonged pain despite being analgesic in the short term; such a prolongation was not observed with other analgesics. Depletion of neutrophils delayed resolution of pain in mice, whereas peripheral injection of neutrophils themselves, or S100A8/A9 proteins normally released by neutrophils, prevented the development of long-lasting pain induced by an anti-inflammatory drug. Analysis of pain trajectories of human subjects reporting acute back pain in the UK Biobank identified elevated risk of pain persistence for subjects taking NSAIDs. Thus, despite analgesic efficacy at early time points, the management of acute inflammation may be counterproductive for long-term outcomes of LBP sufferers.
Background Atopic dermatitis (AD) is a chronic inflammatory skin disease that is characterized by a defective skin barrier function. Recent studies have reported mutations of the skin barrier gene ...encoding filaggrin in a subset of patients with AD. Objective We investigated whether reduced filaggrin expression was found in patients with AD who were not carriers of known filaggrin mutations and whether filaggrin expression was modulated by the atopic inflammatory response. Methods Filaggrin expression was measured in skin biopsies and cultured keratinocytes using real-time RT-PCR and immunohistochemistry. Filaggrin loss-of-function mutations were screened in a total of 69 subjects. Results Compared with normal skin, filaggrin expression was significantly reduced ( P < .05) in acute AD skin, with further reduction seen in acute lesions from 3 European American subjects with AD who were heterozygous for the 2282del4 mutation. This was confirmed by using immunohistochemistry. AD skin is characterized by the overexpression of IL-4 and IL-13. Keratinocytes differentiated in the presence of IL-4 and IL-13 exhibited significantly reduced filaggrin gene expression (0.04 ± 0.01 ng filaggrin/ng glyceraldehyde 3-phosphate dehydrogenase; P < .05) compared with media alone (0.16 ± 0.03). Conclusion Patients with AD have an acquired defect in filaggrin expression that can be modulated by the atopic inflammatory response. Clinical implications The atopic immune response contributes to the skin barrier defect in AD; therefore, neutralization of IL-4 and IL-13 could improve skin barrier integrity.
Efforts to build representative studies are defeated when scientists discard data from certain groups. Instead, researchers should work to balance statistical needs with fairness.
Background Atopic dermatitis (AD) is a chronic inflammatory skin disease that is characterized by a defective skin barrier function. Recent studies have reported mutations of the skin barrier gene ...encoding filaggrin in a subset of patients with AD. Objective We investigated whether reduced filaggrin expression was found in patients with AD who were not carriers of known filaggrin mutations and whether filaggrin expression was modulated by the atopic inflammatory response. Methods Filaggrin expression was measured in skin biopsies and cultured keratinocytes using real-time RT-PCR and immunohistochemistry. Filaggrin loss-of-function mutations were screened in a total of 69 subjects. Results Compared with normal skin, filaggrin expression was significantly reduced ( P < .05) in acute AD skin, with further reduction seen in acute lesions from 3 European American subjects with AD who were heterozygous for the 2282del4 mutation. This was confirmed by using immunohistochemistry. AD skin is characterized by the overexpression of IL-4 and IL-13. Keratinocytes differentiated in the presence of IL-4 and IL-13 exhibited significantly reduced filaggrin gene expression (0.04 ± 0.01 ng filaggrin/ng glyceraldehyde 3-phosphate dehydrogenase; P < .05) compared with media alone (0.16 ± 0.03). Conclusion Patients with AD have an acquired defect in filaggrin expression that can be modulated by the atopic inflammatory response. Clinical implications The atopic immune response contributes to the skin barrier defect in AD; therefore, neutralization of IL-4 and IL-13 could improve skin barrier integrity.
In a Letter to the Editor regarding our recently published paper (1), Macfarlane and colleagues (2) argue that our method of analysis of data from the UK Biobank (UKB) project was inappropriate and ...that we came to an incorrect conclusion regarding a potential sex-dependent effect of pain on mortality. The regression results indicated that each additional chronic pain site increased risk for death (with a HR = 1.7) and that BMI and alcohol consumption were additional risk factors (HR > 1), as already substantiated in the literature. Persons with chronic widespread pain experience excess mortality: longitudinal results from UK Biobank and meta-analysis.
Chronic pain is a prevalent disease with increasing clinical challenges. Genome-wide association studies in chronic pain patients have identified hundreds of common pathogenic variants, yet they only ...explained a portion of individual variance of chronic pain. With the advances in next-generation sequencing technologies, it is now feasible to conduct rarer variants studies in large-scale databases. Here, we performed gene-based rare variant analyses in 200,000 human subjects in the UK biobank whole-exome sequencing database for investigating 9 different chronic pain states and validated our findings in 3 other large-scale databases. Our analyses identified the SLC13A1 gene coding for sodium/sulfate symporter associated with chronic back pain and multisite pain at the genome-wide level and with chronic headache, knee, and neck and shoulder pain at the nominal level. Seven loss-of-function rare variants were identified within the gene locus potentially contributing to the development of chronic pain, with 2 of them individually associated with back pain and multisite pain. These 2 rare variants were then tested for replication in 3 other biobanks, and the strongest evidence was found for rs28364172 as an individual contributor. Transcriptional analyses of Slc13a1 in rodents showed substantial regulation of its expression in the dorsal root ganglia and the sciatic nerve in neuropathic pain assays. Our results stress the importance of the SLC13A1 gene in sulfate homeostasis in the nervous system and its critical role in preventing pain states, thus suggesting new therapeutic approaches for treating chronic pain in a personalized manner, especially in people with mutations in the SLC13A1 gene.
ISG15 is an Interferon (IFN)-α/β—inducible, ubiquitin-like intracellular protein. Its conjugation to various proteins (ISGylation) contributes to antiviral immunity in mice. Here, we describe human ...patients with inherited ISG15 deficiency and mycobacterial, but not viral, diseases. The lack of intracellular ISG15 production and protein ISGylation was not associated with cellular susceptibility to any viruses that we tested, consistent with the lack of viral diseases in these patients. By contrast, the lack of mycobacterium-induced ISG15 secretion by leukocytes—granulocyte, in particular—reduced the production of IFN-γ by lymphocytes, including natural killer cells, probably accounting for the enhanced susceptibility to mycobacterial disease. This experiment of nature shows that human ISGylation is largely redundant for antiviral immunity, but that ISG15 plays an essential role as an IFN-γ-inducing secreted molecule for optimal antimycobacterial immunity.
We describe a Turkish patient with tyrosine kinase 2 deficiency who suffered from disseminated Bacille Calmette-Guerin infection, neurobrucellosis, and cutaneous herpes zoster infection. Tyrosine ...kinase 2 deficiency should be considered in patients susceptible to herpes viruses and intramacrophage pathogens even in the absence of atopy, high serum IgE, and staphylococcal disease.
To address the need for systematic investigation of the phenome enabled by ever-growing genotype and phenotype data, we describe our step-by-step software implementation of a graph-embedded topic ...model, including data preprocessing, graph learning, topic inference, and phenotype prediction. As a demonstration, we use simulated data that mimic the UK Biobank data as in our original study. We will demonstrate topic analysis to discover disease comorbidities and computational phenotyping via the inferred topic mixture for each subject.
For complete details on the use and execution of this protocol, please refer to Wang et al. (2022).1
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•Preprocess the patient health record and graph taxonomy data•Apply graph learning scripts to obtain phenotype embedding•Infer distributions over medical codes to identify disease comorbidity•Infer phenotypic mixture membership to phenotype patients
Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
To address the need for systematic investigation of the phenome enabled by ever-growing genotype and phenotype data, we describe our step-by-step software implementation of a graph-embedded topic model, including data preprocessing, graph learning, topic inference, and phenotype prediction. As a demonstration, we use simulated data that mimic the UK Biobank data as in our original study. We will demonstrate topic analysis to discover disease comorbidities and computational phenotyping via the inferred topic mixture for each subject.
After sustained exposure to Mycobacterium leprae, only a subset of exposed individuals develops clinical leprosy. Moreover, leprosy patients show a wide spectrum of clinical manifestations that ...extend from the paucibacillary (PB) to the multibacillary (MB) form of the disease. This "polarization" of leprosy has long been a major focus of investigation for immunologists because of the different immune response in these two forms. But while leprosy per se has been shown to be under tight human genetic control, few epidemiological or genetic studies have focused on leprosy subtypes. Using PubMed, we collected available data in English on the epidemiology of leprosy polarization and the possible role of human genetics in its pathophysiology until September 2015. At the genetic level, we assembled a list of 28 genes from the literature that are associated with leprosy subtypes or implicated in the polarization process. Our bibliographical search revealed that improved study designs are needed to identify genes associated with leprosy polarization. Future investigations should not be restricted to a subanalysis of leprosy per se studies but should instead contrast MB to PB individuals. We show the latter approach to be the most powerful design for the identification of genetic polarization determinants. Finally, we bring to light the important resource represented by the nine-banded armadillo model, a unique animal model for leprosy.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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