-
Cell Reports. Medicine Jun 2024Progressive multifocal leukoencephalopathy (PML) has been associated with different forms of immune compromise. This study analyzes the chemokine signals and attracted...
Progressive multifocal leukoencephalopathy (PML) has been associated with different forms of immune compromise. This study analyzes the chemokine signals and attracted immune cells in cerebrospinal fluid (CSF) during PML to define immune cell subpopulations relevant for the PML immune response. In addition to chemokines that indicate a general state of inflammation, like CCL5 and CXCL10, the CSF of PML patients specifically contains CCL2 and CCL4. Single-cell transcriptomics of CSF cells suggests an enrichment of distinct CD4 and CD8 T cells expressing chemokine receptors CCR2, CCR5, and CXCR3, in addition to ITGA4 and the genetic PML risk genes STXBP2 and LY9. This suggests that specific immune cell subpopulations migrate into the central nervous system to mitigate PML, and their absence might coincide with PML development. Monitoring them might hold clues for PML risk, and boosting their recruitment or function before therapeutic immune reconstitution might improve its risk-benefit ratio.
PubMed: 38917802
DOI: 10.1016/j.xcrm.2024.101622 -
BioRxiv : the Preprint Server For... Jun 2024While cancer survivorship has increased due to advances in treatments, chemotherapy often carries long-lived neurotoxic side effects which reduce quality of life....
While cancer survivorship has increased due to advances in treatments, chemotherapy often carries long-lived neurotoxic side effects which reduce quality of life. Commonly affected domains include memory, executive function, attention, processing speed and sensorimotor function, colloquially known as chemotherapy-induced cognitive impairment (CICI) or "chemobrain". Oxidative stress and neuroimmune signaling in the brain have been mechanistically linked to the deleterious effects of chemotherapy on cognition and sensorimotor function. With this in mind, we tested if activation of the master regulator of antioxidant response nuclear factor E2-related factor 2 (Nrf2) alleviates cognitive and sensorimotor impairments induced by doxorubicin. The FDA-approved systemic Nrf2 activator, diroximel fumarate (DRF) was used, along with our recently developed prodrug which has the advantage of specifically releasing monomethyl fumarate at sites of oxidative stress. DRF and both reversed doxorubicin-induced deficits in executive function, spatial and working memory, as well as decrements in fine motor coordination and grip strength, across both male and female mice. Both treatments reversed doxorubicin-induced loss of synaptic proteins and microglia phenotypic transition in the hippocampus. Doxorubicin-induced myelin damage in the corpus callosum was reversed by both Nrf2 activators. These results demonstrate the therapeutic potential of Nrf2 activators to reverse doxorubicin-induced cognitive impairments, motor incoordination, and associated structural and phenotypic changes in the brain. The localized release of monomethyl fumarate by has the potential to diminish unwanted effects of fumarates while retaining efficacy.
PubMed: 38915544
DOI: 10.1101/2024.06.10.598291 -
BioRxiv : the Preprint Server For... Jun 2024Akt1 and Akt2, isoforms of the serine threonine kinase Akt, are essential for T cell development. However, their role in peripheral T cell differentiation remains...
Akt1 and Akt2, isoforms of the serine threonine kinase Akt, are essential for T cell development. However, their role in peripheral T cell differentiation remains undefined. Using mice with germline deletions of either Akt1 or Akt2, we found that both isoforms are important for Th17 differentiation, although Akt2 loss had a greater impact than loss of Akt1. In contrast to defective IL-17 production, Akt2 T cells exhibited enhanced IL-4 production under Th2 polarizing conditions. , Akt2 mice displayed significantly diminished IL-17A and GM-CSF production following immunization with myelin oligodendrocyte glycoprotein (MOG). This dampened response was associated with further alterations in Th cell differentiation including decreased IFNγ production but preserved IL-4 production, and preferential expansion of regulatory T cells compared to non-regulatory CD4 T cells. Taken together, we identify Akt2 as an important signaling molecule in regulating peripheral CD4 T cell responses.
PubMed: 38915532
DOI: 10.1101/2024.06.07.598023 -
Cureus Jun 2024Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal plasma cell disorder characterized by monoclonal immunoglobulins and/or an abnormal...
Uncommon Presentation of IgM Monoclonal Gammopathy of Undetermined Significance (MGUS) and Anti-Myelin-Associated Glycoprotein (MAG)-Associated Demyelinating Peripheral Neuropathy as Respiratory Failure: A Case Report.
Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal plasma cell disorder characterized by monoclonal immunoglobulins and/or an abnormal free immunoglobulin light chain ratio. MGUS can be associated with immune-mediated neuropathies, including chronic inflammatory demyelinating neuropathy and its variants. Here, we report the case of a 76-year-old male who presented with progressive weakness, initially in the lower extremities and later including the upper extremities. Serum protein electrophoresis and immunofixation identified an IgM kappa monoclonal protein and further testing confirmed high titers of anti-myelin-associated glycoprotein (MAG) antibodies, leading to a diagnosis of anti-MAG-associated demyelinating peripheral neuropathy. The coexistence of MGUS and anti-MAG antibodies requires meticulous diagnosis and management, especially in patients who present with atypical symptoms of the disease.
PubMed: 38912071
DOI: 10.7759/cureus.62865 -
Biomedicine & Pharmacotherapy =... Jun 2024Cyclic adenosine monophosphate (cAMP) is a key second messenger that regulates signal transduction pathways pivotal for numerous biological functions. Intracellular cAMP... (Review)
Review
Cyclic adenosine monophosphate (cAMP) is a key second messenger that regulates signal transduction pathways pivotal for numerous biological functions. Intracellular cAMP levels are spatiotemporally regulated by their hydrolyzing enzymes called phosphodiesterases (PDEs). It has been shown that increased cAMP levels in the central nervous system (CNS) promote neuroplasticity, neurotransmission, neuronal survival, and myelination while suppressing neuroinflammation. Thus, elevating cAMP levels through PDE inhibition provides a therapeutic approach for multiple CNS disorders, including multiple sclerosis, stroke, spinal cord injury, amyotrophic lateral sclerosis, traumatic brain injury, and Alzheimer's disease. In particular, inhibition of the cAMP-specific PDE4 subfamily is widely studied because of its high expression in the CNS. So far, the clinical translation of full PDE4 inhibitors has been hampered because of dose-limiting side effects. Hence, focusing on signaling cascades downstream activated upon PDE4 inhibition presents a promising strategy, offering novel and pharmacologically safe targets for treating CNS disorders. Yet, the underlying downstream signaling pathways activated upon PDE(4) inhibition remain partially elusive. This review provides a comprehensive overview of the existing knowledge regarding downstream mediators of cAMP signaling induced by PDE4 inhibition or cAMP stimulators. Furthermore, we highlight existing gaps and future perspectives that may incentivize additional downstream research concerning PDE(4) inhibition, thereby providing novel therapeutic approaches for CNS disorders.
PubMed: 38908196
DOI: 10.1016/j.biopha.2024.117009 -
PloS One 2024To understand the neurocognitive mechanisms that underlie heterogeneity in cognitive ageing, recent scientific efforts have led to a growing public availability of...
To understand the neurocognitive mechanisms that underlie heterogeneity in cognitive ageing, recent scientific efforts have led to a growing public availability of imaging cohort data. The Advanced BRain Imaging on ageing and Memory (ABRIM) project aims to add to these existing datasets by taking an adult lifespan approach to provide a cross-sectional, normative database with a particular focus on connectivity, myelinization and iron content of the brain in concurrence with cognitive functioning, mechanisms of reserve, and sleep-wake rhythms. ABRIM freely shares MRI and behavioural data from 295 participants between 18-80 years, stratified by age decade and sex (median age 52, IQR 36-66, 53.20% females). The ABRIM MRI collection consists of both the raw and pre-processed structural and functional MRI data to facilitate data usage among both expert and non-expert users. The ABRIM behavioural collection includes measures of cognitive functioning (i.e., global cognition, processing speed, executive functions, and memory), proxy measures of cognitive reserve (e.g., educational attainment, verbal intelligence, and occupational complexity), and various self-reported questionnaires (e.g., on depressive symptoms, pain, and the use of memory strategies in daily life and during a memory task). In a sub-sample (n = 120), we recorded sleep-wake rhythms using an actigraphy device (Actiwatch 2, Philips Respironics) for a period of 7 consecutive days. Here, we provide an in-depth description of our study protocol, pre-processing pipelines, and data availability. ABRIM provides a cross-sectional database on healthy participants throughout the adult lifespan, including numerous parameters relevant to improve our understanding of cognitive ageing. Therefore, ABRIM enables researchers to model the advanced imaging parameters and cognitive topologies as a function of age, identify the normal range of values of such parameters, and to further investigate the diverse mechanisms of reserve and resilience.
Topics: Humans; Male; Female; Aged; Middle Aged; Adult; Magnetic Resonance Imaging; Brain; Aged, 80 and over; Adolescent; Aging; Young Adult; Memory; Cognition; Cross-Sectional Studies; Neuroimaging; Research Design; Data Collection
PubMed: 38905233
DOI: 10.1371/journal.pone.0306006 -
BMJ Open Jun 2024WHO recommends human papillomavirus (HPV) testing for cervical screening, with triage of high-risk HPV (hrHPV) positive women. However, there are limitations to... (Observational Study)
Observational Study
Performance of and methylation as triage markers for early detection of cervical cancer in self-collected and clinician-collected samples: an exploratory observational study in Papua New Guinea.
OBJECTIVE
WHO recommends human papillomavirus (HPV) testing for cervical screening, with triage of high-risk HPV (hrHPV) positive women. However, there are limitations to effective triage for low-resource, high-burden settings, such as Papua New Guinea. In this exploratory study, we assessed the performance of host methylation as triage tools for predicting high-grade squamous intraepithelial lesions (HSIL) in self-collected and clinician-collected samples.
DESIGN
Exploratory observational study.
SETTING
Provincial hospital, same-day cervical screen-and-treat trial, Papua New Guinea.
PARTICIPANTS
44 hrHPV+women, with paired self/clinician-collected samples (4 squamous cell carcinomas (SCC), 19 HSIL, 4 low-grade squamous intraepithelial lesions, 17 normal).
PRIMARY AND SECONDARY OUTCOME MEASURES
Methylation levels of and analysed by methylation-specific PCRs against the clinical endpoint of HSIL or SCC (HSIL+) measured using liquid-based-cytology/p16-Ki67 stain.
RESULTS
In clinician-collected samples, and methylation levels were significantly higher with increasing grade of disease (p=0.0046 and p<0.0015, respectively). was the best predictor of HSIL (area under the curve, AUC 0.819) while of SCC (AUC 0.856). In self-collected samples, best predicted HSIL (AUC 0.595) while SCC (AUC 0.812). Combined methylation yielded sensitivity and specificity for HSIL+ of 90.5% (95% CI 69.6% to 98.8%) and 70% (95% CI 45.7% to 88.1%), respectively, in clinician-collected samples, and 81.8% (95% CI 59.7% to 94.8%) and 47.6% (95% CI 25.7% to 70.2%), respectively, in self-collected samples. plus HPV16/HPV18 improved sensitivity for HSIL+ (95.2%, 95% CI 76.2% to 99.9%) but decreased specificity (55.0%, 95% CI 31.5% to 76.9%).
CONCLUSION
methylation is a potential triage strategy for the detection of HSIL/SCC in low-income and middle-income country.
Topics: Humans; Female; MicroRNAs; Uterine Cervical Neoplasms; Papua New Guinea; Early Detection of Cancer; Cell Adhesion Molecule-1; Adult; Triage; DNA Methylation; Middle Aged; Myelin and Lymphocyte-Associated Proteolipid Proteins; Papillomavirus Infections; Biomarkers, Tumor; Carcinoma, Squamous Cell; Specimen Handling; Young Adult; Sensitivity and Specificity; Vaginal Smears
PubMed: 38904134
DOI: 10.1136/bmjopen-2023-081282 -
Cureus May 2024We discuss a perplexing case of a 51-year-old female with a history of asthma and morbid obesity, presenting with acute bilateral vision loss of unknown etiology. The...
We discuss a perplexing case of a 51-year-old female with a history of asthma and morbid obesity, presenting with acute bilateral vision loss of unknown etiology. The patient's clinical course was marked by a constellation of symptoms, including blurry vision, eyeball pain, photophobia, headache, nausea, and dizziness, prompting a multidisciplinary approach for diagnostic evaluation. Despite a comprehensive workup and a temporal artery biopsy ruling out large vessel arteritis, the etiology of vision loss remained elusive until myelin oligodendrocyte glycoprotein (MOG) antibody testing returned positive, implicating myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). High-dose corticosteroid therapy was initiated. However, the patient had worsening visual symptoms and was started on plasmapheresis and subsequent administration of Rituximab to prevent relapses, along with a long-term steroid taper regimen. This case underscores the diagnostic challenge of optic neuritis, particularly in MOGAD. It emphasizes the importance of a thorough evaluation and multidisciplinary collaboration.
PubMed: 38903369
DOI: 10.7759/cureus.60612 -
Annals of Palliative Medicine Jun 2024Radiofrequency ablation (RFA), a minimally invasive procedure for pain reduction, is increasingly used for managing chronic neck pain and headaches. This article offers...
Radiofrequency ablation (RFA), a minimally invasive procedure for pain reduction, is increasingly used for managing chronic neck pain and headaches. This article offers a concise overview of cervical spine RFA. In the context of RFA, heat is applied to specific nerve tissues to interrupt pain signals. Wallarian degeneration occurs as a result of the thermal injury to the nerve. The heat generated by the RFA procedure can damage the nerve fibers, initiating the degenerative process. Wallarian degeneration is a process that occurs in a nerve axon due to the thermal injury, leading to the breakdown and eventual degradation of the axon and its myelin sheath. However, nerves have regeneration capacity, especially the peripheral nerves, which are often the target of RFA for pain management. After Wallarian degeneration takes place, the nerve sheath, or the connective tissue surrounding the nerve, can serve as a scaffold for the growth of new nerve fibers. Over time, these new fibers can regenerate and re-establish connections, potentially restoring nerve function. Three common types are traditional thermal, water-cooled, and pulsed radio frequency ablation. Given the regenerative potential of nerves, these procedures are typically effective for 1 to 2 years, with some variability. Despite a 112% increase in Medicare claims for RFA from 2009 to 2018, it's recommended for patients who respond positively to diagnostic medial branch blocks, with recent guidelines suggesting a single block may be sufficient. Although generally effective, the procedure carries risks, including nerve and tissue injury. Notably, the procedure's increased utilization notably surpasses the most commonly reported prevalence rates of conditions it aims to treat. Moreover, diagnostic blocks performed before cervical RFA also have their risks, such as inadvertent vascular injections leading to seizures or paralysis. In summary, the risks and benefits of cervical RFA must be considered with regards to the patient's comorbidities and specific pain issues. The skill and experience of the practitioner plays a significant role in minimizing these risks. Detailed discussions with healthcare providers about the risks, benefits, and alternatives can help in making an informed decision about the procedure.
PubMed: 38902987
DOI: 10.21037/apm-23-520 -
Translational Psychiatry Jun 2024Whereas meta-analytical data highlight abnormal frontocortical macrostructure (thickness/surface area/volume) in Major Depressive Disorder (MDD), the underlying...
Whereas meta-analytical data highlight abnormal frontocortical macrostructure (thickness/surface area/volume) in Major Depressive Disorder (MDD), the underlying microstructural processes remain uncharted, due to the use of conventional MRI scanners and acquisition techniques. We uniquely combined Ultra-High Field MRI at 7.0 Tesla with Quantitative Imaging to map intracortical myelin (proxied by longitudinal relaxation time T) and iron concentration (proxied by transverse relaxation time T*), microstructural processes deemed particularly germane to cortical macrostructure. Informed by meta-analytical evidence, we focused specifically on orbitofrontal and rostral anterior cingulate cortices among adult MDD patients (N = 48) and matched healthy controls (HC; N = 10). Analyses probed the association of MDD diagnosis and clinical profile (severity, medication use, comorbid anxiety disorders, childhood trauma) with aforementioned microstructural properties. MDD diagnosis (p's < 0.05, Cohen's D = 0.55-0.66) and symptom severity (p's < 0.01, r = 0.271-0.267) both related to decreased intracortical myelination (higher T values) within the lateral orbitofrontal cortex, a region tightly coupled to processing negative affect and feelings of sadness in MDD. No relations were found with local iron concentrations. These findings allow uniquely fine-grained insights on frontocortical microstructure in MDD, and cautiously point to intracortical demyelination as a possible driver of macroscale cortical disintegrity in MDD.
Topics: Humans; Depressive Disorder, Major; Magnetic Resonance Imaging; Female; Male; Adult; Prefrontal Cortex; Gyrus Cinguli; Myelin Sheath; Middle Aged; Iron; Case-Control Studies
PubMed: 38902245
DOI: 10.1038/s41398-024-02976-y