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Arthritis Research & Therapy Jun 2024Janus kinase (JAK) inhibitors, such as baricitinib, are widely used to treat rheumatoid arthritis (RA). Clinical studies show that baricitinib is more effective at...
Baricitinib ameliorates inflammatory and neuropathic pain in collagen antibody-induced arthritis mice by modulating the IL-6/JAK/STAT3 pathway and CSF-1 expression in dorsal root ganglion neurons.
BACKGROUND
Janus kinase (JAK) inhibitors, such as baricitinib, are widely used to treat rheumatoid arthritis (RA). Clinical studies show that baricitinib is more effective at reducing pain than other similar drugs. Here, we aimed to elucidate the molecular mechanisms underlying the pain relief conferred by baricitinib, using a mouse model of arthritis.
METHODS
We treated collagen antibody-induced arthritis (CAIA) model mice with baricitinib, celecoxib, or vehicle, and evaluated the severity of arthritis, histological findings of the spinal cord, and pain-related behaviours. We also conducted RNA sequencing (RNA-seq) to identify alterations in gene expression in the dorsal root ganglion (DRG) following baricitinib treatment. Finally, we conducted in vitro experiments to investigate the direct effects of baricitinib on neuronal cells.
RESULTS
Both baricitinib and celecoxib significantly decreased CAIA and improved arthritis-dependent grip-strength deficit, while only baricitinib notably suppressed residual tactile allodynia as determined by the von Frey test. CAIA induction of inflammatory cytokines in ankle synovium, including interleukin (IL)-1β and IL-6, was suppressed by treatment with either baricitinib or celecoxib. In contrast, RNA-seq analysis of the DRG revealed that baricitinib, but not celecoxib, restored gene expression alterations induced by CAIA to the control condition. Among many pathways changed by CAIA and baricitinib treatment, the interferon-alpha/gamma, JAK-signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) pathways were considerably decreased in the baricitinib group compared with the celecoxib group. Notably, only baricitinib decreased the expression of colony-stimulating factor 1 (CSF-1), a potent cytokine that causes neuropathic pain through activation of the microglia-astrocyte axis in the spinal cord. Accordingly, baricitinib prevented increases in microglia and astrocytes caused by CAIA. Baricitinib also suppressed JAK/STAT3 pathway activity and Csf1 expression in cultured neuronal cells.
CONCLUSIONS
Our findings demonstrate the effects baricitinib has on the DRG in relation to ameliorating both inflammatory and neuropathic pain.
Topics: Animals; Azetidines; Sulfonamides; Pyrazoles; STAT3 Transcription Factor; Purines; Arthritis, Experimental; Ganglia, Spinal; Neuralgia; Janus Kinases; Signal Transduction; Mice; Interleukin-6; Male; Neurons; Mice, Inbred DBA; Inflammation; Janus Kinase Inhibitors
PubMed: 38879555
DOI: 10.1186/s13075-024-03354-1 -
BMC Musculoskeletal Disorders Jun 2024Carpal tunnel syndrome (CTS), an entrapment neuropathy caused by pressure of the median nerve, is a progressive condition that can lead to a decreased quality of life....
BACKGROUND
Carpal tunnel syndrome (CTS), an entrapment neuropathy caused by pressure of the median nerve, is a progressive condition that can lead to a decreased quality of life. Studies suggest an association between CTS and arthritis; however, previous studies examining osteoarthritis (OA) and CTS are limited in number, scope and study design. This study estimated the incidence and risk of CTS among patients with OA, both overall and by specific joints, in a large population-based cohort in the United States.
METHODS
Patients from the Optum claims database aged ≥ 45 years and diagnosed with OA between January 1, 2018, and December 31, 2022, were eligible for the OA cohort. The non-OA cohort included those without a diagnosis of OA at the index date and no history of OA for 12 months pre-index. Baseline characteristics were balanced using propensity score matching. The risk of CTS in the OA and non-OA cohort were evaluated using incidence rates and adjusted hazard ratios that were estimated using Cox regression.
RESULTS
After applying the inclusion/exclusion criteria, 3,610,240 of the 6,023,384 adults with a diagnosis of OA remained in the OA cohort. After propensity-score matching, each cohort included 1,033,439 individuals. The incidence rates for CTS per 1000 person-years were 7.35 (95% confidence interval [CI] 7.21-7.49) in the OA cohort and 1.44 (95% CI 1.38-1.50) in the non-OA cohort. The risk of developing CTS in patients with OA was ~ 4 times that of patients without (hazard ratio = 3.80; 95% CI 3.54-4.07). This increased risk was found across all OA joint types, with OA of the hand/wrist having the highest risk for CTS. Additionally, multiple OA joints presented a higher risk compared with a single affected joint.
CONCLUSIONS
OA increases the risk of CTS, but this is not limited to patients with hand/wrist OA, suggesting a systemic impact of OA on CTS. While the risk appears highest for patients with hand/wrist OA, patients with more distant affected joints like knee or hip also have an increased risk of CTS.
Topics: Humans; Carpal Tunnel Syndrome; Female; Male; Middle Aged; United States; Aged; Incidence; Osteoarthritis; Risk Factors; Databases, Factual; Osteoarthritis, Knee; Risk Assessment; Retrospective Studies
PubMed: 38879540
DOI: 10.1186/s12891-024-07459-1 -
The Journal of Biological Chemistry Jun 2024Glucoselysine (GL) is a unique advanced glycation end-product derived from fructose. The main source of fructose in vivo is the polyol pathway, and an increase in its...
Glucoselysine (GL) is a unique advanced glycation end-product derived from fructose. The main source of fructose in vivo is the polyol pathway, and an increase in its activity leads to diabetic complications. Here, we aimed to demonstrate that GL can serve as an indicator of the polyol pathway activity. Additionally, we propose a novel approach for detecting GL in peripheral blood samples using LC-MS/MS and evaluate its clinical usefulness. We successfully circumvent interference from fructoselysine, which shares the same molecular weight as GL, by performing ultrafiltration and hydrolysis without reduction, successfully generating adequate peaks for quantification in serum. Furthermore, using immortalized aldose reductase knockout mouse Schwann cells, we demonstrate that GL reflects the downstream activity of the polyol pathway and that GL produced intracellularly is released into the extracellular space. Clinical studies reveal that GL levels in patients with type 2 diabetes are significantly higher than those in healthy participants, while N-(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine (MG-H1) levels are significantly lower. Both GL and MG-H1 show higher values among patients with vascular complications; however, GL varies more markedly than MG-H1 as well as hemoglobin A1c, fasting plasma glucose, and estimated glomerular filtration rate. Furthermore, GL remains consistently stable under various existing drug treatments for type 2 diabetes, whereas MG-H1 is impacted. To the best of our knowledge, we provide important insights in predicting diabetic complications caused by enhanced polyol pathway activity via assessment of GL levels in peripheral blood samples from patients.
PubMed: 38879006
DOI: 10.1016/j.jbc.2024.107479 -
Journal of Neuroimmune Pharmacology :... Jun 2024Chronic neuropathic pain precipitates a complex range of affective and behavioural disturbances that differ markedly between individuals. While the reasons for...
Chronic neuropathic pain precipitates a complex range of affective and behavioural disturbances that differ markedly between individuals. While the reasons for differences in pain-related disability are not well understood, supraspinal neuroimmune interactions are implicated. Minocycline has antidepressant effects in humans and attenuates affective disturbances in rodent models of pain, and acts by reducing neuroinflammation in both the spinal cord and brain. Previous studies, however, tend not to investigate how minocycline modulates individual affective responses to nerve injury, or rely on non-naturalistic behavioural paradigms that fail to capture the complexity of rodent behaviour. We investigated the development and resolution of pain-related affective disturbances in nerve-injured male rats by measuring multiple spontaneous ethological endpoints on a longitudinal naturalistic foraging paradigm, and the effect of chronic oral minocycline administration on these changes. Disrupted foraging behaviours appeared in 22% of nerve-injured rats - termed 'affected' rats - and were present at day 14 but partially resolved by day 21 post-injury. Minocycline completely prevented the emergence of an affected subgroup while only partly attenuating mechanical allodynia, dissociating the relationship between pain and affect. This was associated with a lasting downregulation of ΔFosB expression in ventral hippocampal neurons at day 21 post-injury. Markers of microglia-mediated neuroinflammation were not present by day 21, however proinflammatory microglial polarisation was apparent in the medial prefrontal cortex of affected rats and not in CCI minocycline rats. Individual differences in affective disturbances following nerve injury are therefore temporally related to altered microglial morphology and hippocampal neuronal activation, and are abrogated by minocycline.
Topics: Animals; Minocycline; Male; Rats; Neuroinflammatory Diseases; Rats, Sprague-Dawley; Neuralgia; Hyperalgesia; Individuality; Mood Disorders; Peripheral Nerve Injuries
PubMed: 38878098
DOI: 10.1007/s11481-024-10132-y -
Immunity & Ageing : I & A Jun 2024Alzheimer's disease (AD) is a serious brain disorder characterized by the presence of beta-amyloid plaques, tau pathology, inflammation, neurodegeneration, and... (Review)
Review
Alzheimer's disease (AD) is a serious brain disorder characterized by the presence of beta-amyloid plaques, tau pathology, inflammation, neurodegeneration, and cerebrovascular dysfunction. The presence of chronic neuroinflammation, breaches in the blood-brain barrier (BBB), and increased levels of inflammatory mediators are central to the pathogenesis of AD. These factors promote the penetration of immune cells into the brain, potentially exacerbating clinical symptoms and neuronal death in AD patients. While microglia, the resident immune cells of the central nervous system (CNS), play a crucial role in AD, recent evidence suggests the infiltration of cerebral vessels and parenchyma by peripheral immune cells, including neutrophils, T lymphocytes, B lymphocytes, NK cells, and monocytes in AD. These cells participate in the regulation of immunity and inflammation, which is expected to play a huge role in future immunotherapy. Given the crucial role of peripheral immune cells in AD, this article seeks to offer a comprehensive overview of their contributions to neuroinflammation in the disease. Understanding the role of these cells in the neuroinflammatory response is vital for developing new diagnostic markers and therapeutic targets to enhance the diagnosis and treatment of AD patients.
PubMed: 38877498
DOI: 10.1186/s12979-024-00445-0 -
Medicine Jun 2024Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated motor sensory peripheral neuropathy that is rare in clinical practice. This treatment...
RATIONALE
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated motor sensory peripheral neuropathy that is rare in clinical practice. This treatment method aims to suppress potential immunopathology. Nocardiosis is a rare, destructive, opportunistic disease. We report a case of failed treatment of CIDP combined with pulmonary nocardiosis, and for the first time, we link these 2 diseases together.
PATIENT CONCERNS
A 65-year-old man developed symmetrical limb weakness. Four months later, he was diagnosed with CIDP and started receiving glucocorticoid (GC) treatment. The disease progressed slowly and was treated with mycophenolate mofetil (MMF) in combination. He did not follow the doctor requirements for monthly follow-up visits, and the preventive medication for sulfamethoxazole/trimethoprim was not strictly implemented. Two months after the combination therapy, the patient developed fever, coughing and sputum production, as well as fatigue and poor appetite. Based on imaging and etiological results, he was diagnosed with pulmonary nocardiosis.
DIAGNOSES
Chronic inflammatory demyelinating polyneuropathy, pulmonary nocardiosis.
INTERVENTIONS
After treatment with antibiotics, the patient lung infection temporarily improved. However, the patient CIDP condition progressed, limb weakness worsened, respiratory muscle involvement occurred, and intravenous immunoglobulin (IVIG) was administered. However, there was no significant improvement in the condition, and the patient died.
OUTCOMES
In this report, we present a case of a patient with CIDP and pulmonary nocardiosis. It is worth noting that in order to avoid the progression and recurrence of CIDP, we did not stop using related therapeutic drugs during the treatment process, the patient had repeatedly refused to use IVIG. Despite this, the patient condition worsened when lung inflammation improved, leading to persistent respiratory failure and ultimately death. Treatment contradictions, medication issues, and patient compliance issues reflected in this case are worth considering.
LESSONS
For patients with CIDP receiving immunosuppressive therapy, attention should be paid to the occurrence and severity of Nocardia infection. Therefore, early detection and treatment are necessary. We need to pay attention to the compliance of patients with prophylactic use of antibiotics, strengthen the follow-up, and urge them to return to their appointments on time.
Topics: Humans; Male; Aged; Nocardia Infections; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Anti-Bacterial Agents; Immunoglobulins, Intravenous
PubMed: 38875438
DOI: 10.1097/MD.0000000000038544 -
JBJS Reviews Jun 2024» Tumors of the brachial plexus are uncommon and can present as a mass, with or without neurological symptoms. At times, asymptomatic tumors are also picked up... (Review)
Review
» Tumors of the brachial plexus are uncommon and can present as a mass, with or without neurological symptoms. At times, asymptomatic tumors are also picked up incidentally when imaging is performed for other reasons.» Magnetic resonance imaging is the main imaging modality used to evaluate tumors of the brachial plexus. Other imaging modalities can be used as required.» Benign tumors that are asymptomatic should be observed. Excision can be considered for those that are found to be growing over time.» Biopsies of tumors of the brachial plexus are associated with the risk of nerve injury. Despite this, they should be performed for tumors that are suspected to be malignant before starting definitive treatment.» For malignant tumors, treatment decisions should be discussed at multidisciplinary tumor boards, and include both the oncology and peripheral nerve surgical team, musculoskeletal radiology, neuroradiology, and general radiology.
Topics: Humans; Brachial Plexus; Peripheral Nervous System Neoplasms; Magnetic Resonance Imaging
PubMed: 38875357
DOI: 10.2106/JBJS.RVW.24.00019 -
Human Genetics Jun 2024NF1 microdeletion syndrome, accounting for 5-11% of NF1 patients, is caused by a deletion in the NF1 region and it is generally characterized by a severe phenotype....
NF1 microdeletion syndrome, accounting for 5-11% of NF1 patients, is caused by a deletion in the NF1 region and it is generally characterized by a severe phenotype. Although 70% of NF1 microdeletion patients presents the same 1.4 Mb type-I deletion, some patients may show additional clinical features. Therefore, the contribution of several pathogenic mechanisms, besides haploinsufficiency of some genes within the deletion interval, is expected and needs to be defined. We investigated an altered expression of deletion flanking genes by qPCR in patients with type-1 NF1 deletion, compared to healthy donors, possibly contributing to the clinical traits of NF1 microdeletion syndrome. In addition, the 1.4-Mb deletion leads to changes in the 3D chromatin structure in the 17q11.2 region. Specifically, this deletion alters DNA-DNA interactions in the regions flanking the breakpoints, as demonstrated by our 4C-seq analysis. This alteration likely causes position effect on the expression of deletion flanking genes.Interestingly, 4C-seq analysis revealed that in microdeletion patients, an interaction was established between the RHOT1 promoter and the SLC6A4 gene, which showed increased expression. We performed NGS on putative modifier genes, and identified two "likely pathogenic" rare variants in RAS pathway, possibly contributing to incidental phenotypic features.This study provides new insights into understanding the pathogenesis of NF1 microdeletion syndrome and suggests a novel pathomechanism that contributes to the expression phenotype in addition to haploinsufficiency of genes located within the deletion.This is a pivotal approach that can be applied to unravel microdeletion syndromes, improving precision medicine, prognosis and patients' follow-up.
Topics: Humans; Haploinsufficiency; Neurofibromatosis 1; Epigenesis, Genetic; Chromosome Deletion; Female; Male; Neurofibromin 1; Chromosomes, Human, Pair 17; Phenotype; Child; Promoter Regions, Genetic
PubMed: 38874808
DOI: 10.1007/s00439-024-02683-0 -
Predictors of developing renal dysfunction following diagnosis of transthyretin cardiac amyloidosis.Clinical Cardiology Jun 2024In patients with transthyretin cardiac amyloidosis (ATTR-CA), renal dysfunction is a poor prognostic indicator. Limited data are available on variables that portend...
BACKGROUND
In patients with transthyretin cardiac amyloidosis (ATTR-CA), renal dysfunction is a poor prognostic indicator. Limited data are available on variables that portend worsening renal function (wRF) among ATTR-CA patients.
OBJECTIVES
This study assesses which characteristics place patients at higher risk for the development of wRF (defined as a drop of ≥10% in glomerular filtration rate [GFR]) within the first year following diagnosis of ATTR-CA.
METHODS
We included patients with ATTR-CA (n = 134) evaluated between 2/2016 and 12/2022 and followed for up to 1 year at our amyloid clinic. Patients were stratified into two groups: a group with maintained renal function (mRF) and a group with wRF and compared using appropriate testing. Significant variables in the univariate analysis were included in the multivariable logistic regression model to determine characteristics associated with wRF.
RESULTS
Within a follow-up period of 326 ± 118 days, the median GFR% change measured -6% [-18%, +8]. About 41.8% (n = 56) had wRF, while the remainder had mRF. In addition, in patients with no prior history of chronic kidney disease (CKD), 25.5% developed de novo CKD. On multivariable logistic regression, only New York Heart Association (NYHA) class ≥III (odds ratio [OR]: 3.9, 95% confidence interval [CI]: [1.6-9.3]), history of ischemic heart disease (IHD) (OR: 0.3, 95% CI: [0.1-0.7]), and not receiving SGLT-2i (OR: 0.1, 95% CI: [0.02-0.5]) were significant predictors of wRF.
CONCLUSION
Our study demonstrated that the development of de novo renal dysfunction or wRF is common following the diagnosis of ATTR-CA. Additionally, we identified worse NYHA class and no prior history of IHD as significant predictors associated with developing wRF, while receiving SGLT-2i therapy appeared to be protective in this population.
Topics: Humans; Male; Female; Glomerular Filtration Rate; Amyloid Neuropathies, Familial; Aged; Cardiomyopathies; Prognosis; Retrospective Studies; Risk Factors; Middle Aged; Follow-Up Studies; Renal Insufficiency, Chronic; Disease Progression; Kidney; Time Factors; Incidence; Risk Assessment
PubMed: 38873847
DOI: 10.1002/clc.24298 -
BMC Musculoskeletal Disorders Jun 2024Double crush syndrome refers to a nerve in the proximal region being compressed, affecting its proximal segment. Instances of this syndrome involving ulnar and cubital... (Review)
Review
BACKGROUND
Double crush syndrome refers to a nerve in the proximal region being compressed, affecting its proximal segment. Instances of this syndrome involving ulnar and cubital canals during ulnar neuropathy are rare. Diagnosis solely through clinical examination is challenging. Although electromyography (EMG) and nerve conduction studies (NCS) can confirm neuropathy, they do not incorporate inching tests at the wrist, hindering diagnosis confirmation. We recently encountered eight cases of suspected double compression of ulnar nerve, reporting these cases along with a literature review.
METHODS
The study included 5 males and 2 females, averaging 45.6 years old. Among them, 4 had trauma history, and preoperative McGowan stages varied. Ulnar neuropathy was confirmed in 7 cases at both cubital and ulnar canal locations. Surgery was performed for 4 cases, while conservative treatment continued for 3 cases.
RESULTS
In 4 cases with wrist involvement, 2 showed ulnar nerve compression by a fibrous band, and 1 had nodular hyperplasia. Another case displayed ulnar nerve swelling with muscle covering. Among the 4 surgery cases, 2 improved from preoperative McGowan stage IIB to postoperative stage 0, with significant improvement in subjective satisfaction. The remaining 2 cases improved from stage IIB to IIA, respectively, with moderate improvement in subjective satisfaction. In the 3 cases receiving conservative treatment, satisfaction was significant in 1 case and moderate in 2 cases. Overall, there was improvement in hand function across all 7 cases.
CONCLUSION
Typical outpatient examinations make it difficult to clearly differentiate the two sites, and EMG tests may not confirm diagnosis. Therefore, if a surgeon lacks suspicion of this condition, diagnosis becomes even more challenging. In cases with less than expected postoperative improvement in clinical symptoms of cubital tunnel syndrome, consideration of double crush syndrome is warranted. Additional tests and detailed EMG tests, including inching tests at the wrist, may be necessary. We aim to raise awareness double crush syndrome with ulnar nerve, reporting a total of 7 cases to support this concept.
Topics: Humans; Male; Female; Middle Aged; Adult; Ulnar Nerve Compression Syndromes; Ulnar Nerve; Electromyography; Crush Syndrome; Wrist; Neural Conduction; Elbow; Treatment Outcome; Aged
PubMed: 38872094
DOI: 10.1186/s12891-024-07574-z