Activity-dependent myelination is thought to contribute to adaptive neurological function. However, the mechanisms by which activity regulates myelination and the extent to which myelin plasticity ...contributes to non-motor cognitive functions remain incompletely understood. Using a mouse model of chemotherapy-related cognitive impairment (CRCI), we recently demonstrated that methotrexate (MTX) chemotherapy induces complex glial dysfunction for which microglial activation is central. Here, we demonstrate that remote MTX exposure blocks activity-regulated myelination. MTX decreases cortical Bdnf expression, which is restored by microglial depletion. Bdnf-TrkB signaling is a required component of activity-dependent myelination. Oligodendrocyte precursor cell (OPC)-specific TrkB deletion in chemotherapy-naive mice results in impaired cognitive behavioral performance. A small-molecule TrkB agonist rescues both myelination and cognitive impairment after MTX chemotherapy. This rescue after MTX depends on intact TrkB expression in OPCs. Taken together, these findings demonstrate a molecular mechanism required for adaptive myelination that is aberrant in CRCI due to microglial activation.
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•Methotrexate (MTX) causes a microglia-dependent reduction in Bdnf expression•Activity-regulated myelination requires Bdnf-TrkB signaling and fails after MTX•Conditional, inducible TrkB loss in OPCs impairs cognitive behavioral performance•TrkB agonism rescues cognitive performance after MTX only if OPCs express TrkB
Methotrexate chemotherapy results in a microglial-dependent reduction of Bdnf expression and loss of activity-regulated myelination, which requires Bdnf to TrkB signaling. OPC-specific loss of TrkB results in cognitive impairment. Stimulating OPC TrkB signaling restores myelination and rescues cognition after MTX.
Chemotherapy results in a frequent yet poorly understood syndrome of long-term neurological deficits. Neural precursor cell dysfunction and white matter dysfunction are thought to contribute to ...this debilitating syndrome. Here, we demonstrate persistent depletion of oligodendrocyte lineage cells in humans who received chemotherapy. Developing a mouse model of methotrexate chemotherapy-induced neurological dysfunction, we find a similar depletion of white matter OPCs, increased but incomplete OPC differentiation, and a persistent deficit in myelination. OPCs from chemotherapy-naive mice similarly exhibit increased differentiation when transplanted into the microenvironment of previously methotrexate-exposed brains, indicating an underlying microenvironmental perturbation. Methotrexate results in persistent activation of microglia and subsequent astrocyte activation that is dependent on inflammatory microglia. Microglial depletion normalizes oligodendroglial lineage dynamics, myelin microstructure, and cognitive behavior after methotrexate chemotherapy. These findings indicate that methotrexate chemotherapy exposure is associated with persistent tri-glial dysregulation and identify inflammatory microglia as a therapeutic target to abrogate chemotherapy-related cognitive impairment.
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•Chemotherapy depletes oligodendrocyte lineage (OL) cells in humans•Methotrexate chemotherapy disrupts OL dynamics, myelin, and cognition in mice•Methotrexate induces chronic microglial activation and astrocyte reactivity•Microglial depletion rescues glial cell dysregulation and cognitive deficits
Microglial activation by methotrexate leads to a persistent disruption of oligodendrocyte lineage dynamics and astrocyte reactivity, resulting in the long-term cognitive impairment associated with chemotherapy.
To evaluate the benefit of single-shot erector spinae plane block (ESPB) on pain at postoperative hours 4 and 12, duration of mechanical ventilation, hospital length of stay, intensive care unit ...(ICU) length of stay, cumulative postoperative opioid usage, and incidence of postoperative nausea and vomiting (PONV) after cardiac surgery via sternotomy
A systematic review and meta-analysis of randomized controlled trials and prospective clinical trials.
Studies were identified through the search of PubMed and EMBASE on July 19, 2023.
Adults and children undergoing cardiac surgery via sternotomy.
Single-shot ESPB versus standard-of-care analgesia.
A systematic review and meta-analysis of 10 studies (N = 695 patients). The single-shot ESPB arm exhibited statistically significant reductions in pain score at postoperative hour 4 (standardized mean difference SMD −2.95, 95% CI −5.86 to -0.04, p = 0.0466), duration of mechanical ventilation (SMD −1.23, 95% CI −2.21 to −0.24, p = 0.0145), cumulative postoperative opioid usage (SMD −1.48, 95% CI −2.46 to −0.49, p = 0.0033), and PONV incidence (risk ratio 0.4358, 95% CI 0.2105-0.9021, p = 0.0252). The single-shot ESPB arm did not exhibit a statistically significant reduction in pain score at postoperative hour 12, length of hospital stay, and length of ICU stay.
Single-shot ESPB improves near-term clinical outcomes in patients undergoing cardiac surgery via sternotomy. More randomized controlled trials are needed to validate these findings.
Disability in multiple sclerosis (MS) is driven in part by the failure of remyelination and progressive neurodegeneration. Microglia, and specifically triggering receptor expressed on myeloid cells 2 ...(TREM2), a factor highly expressed in microglia, have been shown to play an important role in remyelination. Here, using a focal demyelination model in the brain, we demonstrate that demyelination is persistent in TREM2 knockout mice, lasting more than 6 weeks after lysolecithin injection and resulting in substantial neurodegeneration. We also find that TREM2 knockout mice exhibit an altered glial response following demyelination. TREM2 knockout microglia demonstrate defects in migration and phagocytosis of myelin debris. In addition, human monocyte‐derived macrophages from subjects with a TREM2 mutation prevalent in human disease also show a defect in myelin debris phagocytosis. Together, we highlight the central role of TREM2 signaling in remyelination and neuroprotection. These findings provide insights into how chronic demyelination might lead to axonal damage and could help identify novel neuroprotective therapeutic targets for MS.
Main Points
Focal demyelination in TREM2 KO mice demonstrates remyelination failure and neurodegeneration.
TREM2 KO mice exhibit altered glial response after demyelination.
Human macrophages with TREM2 mutation have defective myelin debris phagocytosis.
Human genetics and preclinical studies have identified key contributions of TREM2 to several neurodegenerative conditions, inspiring efforts to modulate TREM2 therapeutically. Here, we characterize ...the activities of three TREM2 agonist antibodies in multiple mixed-sex mouse models of Alzheimer's disease (AD) pathology and remyelination. Receptor activation and downstream signaling are explored in vitro, and active dose ranges are determined in vivo based on pharmacodynamic responses from microglia. For mice bearing amyloid-β (Aβ) pathology (PS2APP) or combined Aβ and tau pathology (TauPS2APP), chronic TREM2 agonist antibody treatment had limited impact on microglia engagement with pathology, overall pathology burden, or downstream neuronal damage. For mice with demyelinating injuries triggered acutely with lysolecithin, TREM2 agonist antibodies unexpectedly disrupted injury resolution. Likewise, TREM2 agonist antibodies limited myelin recovery for mice experiencing chronic demyelination from cuprizone. We highlight the contributions of dose timing and frequency across models. These results introduce important considerations for future TREM2-targeting approaches.
Summary
Haemophagocytic lymphohistiocytosis (HLH) is a life threatening complication of Epstein–Barr virus (EBV) infection. The anti‐CD20 antibody rituximab depletes B cells, leading to improved ...outcomes for patients with EBV‐associated B‐lymphoproliferative disorders. To gather data on the use of rituximab in EBV‐HLH, we performed a retrospective investigation involving 42 EBV‐HLH patients who had received treatment with rituximab‐containing regimens. On average, patients received 3 rituximab infusions (range 1–10) at a median dose of 375 mg/m2. In all patients, rituximab was administered with other HLH‐directed medications, including steroids, etoposide and/or ciclosporin. Rituximab‐containing regimens appeared well tolerated and improved clinical status in 43% of patients. Examination of laboratory data obtained prior to and within 2–4 weeks after the first rituximab dose revealed significant reductions in EBV load (median load pre‐rituximab: 114 200 copies/ml, median post‐rituximab: 225 copies/ml, P = 0·0001) and serum ferritin levels (median ferritin pre‐rituximab: 4260 μg/l, median post‐rituximab: 1149 μg/l, P = 0·001). Thus, when combined with conventional HLH‐directed therapies, rituximab improves symptoms, reduces viral load and diminishes inflammation. These data support the incorporation of rituximab into future prospective clinical trials for patients with EBV‐HLH.
The renin-angiotensin system plays an important role in the control of blood pressure (BP) and renal function. To illuminate the importance of renin in the context of a disease background in vivo, we ...used zinc-finger nucleases (ZFNs) designed to target the renin gene and create a renin knockout in the SS/JrHsdMcwi (SS) rat. ZFN against renin caused a 10-bp deletion in exon 5, resulting in a frameshift mutation. Plasma renin activity was undetectable in the Ren−/− rat, and renin protein was absent from the juxtaglomerular cells in the kidney. Body weight was lower in the Ren−/− rats (than in the Ren+/− or wild-type littermates), and conscious BP on low-salt diet (0.4% NaCl) was 58±2 mm Hg in the Ren−/− male rats versus 117 mm Hg in the Ren+/− littermates, a reduction of almost 50 mm Hg. Blood urea nitrogen (BUN) and plasma creatinine levels were elevated in the Ren−/− strain (BUN 112±7 versus 23±2 mg/dL and creatinine 0.53±0.02 versus 0.26±0.02 mg/dL), and kidney morphology was abnormal with a rudimentary inner renal medulla, cortical interstitial fibrosis, thickening of arterial walls, and abnormally shaped glomeruli. The development of the first rat knockout in the renin-angiotensin system demonstrates the efficacy of the ZFN technology for creating knockout rats for cardiovascular disease on any genetic background and emphasizes the role of renin in BP regulation and kidney function even in the low-renin SS rat.
A Genomic-Systems Biology Map for Cardiovascular Function Stoll, Monika; Cowley, Allen W.; Tonellato, Peter J. ...
Science (American Association for the Advancement of Science),
11/2001, Letnik:
294, Številka:
5547
Journal Article
Recenzirano
With the draft sequence of the human genome available, there is a need to better define gene function in the context of systems biology. We studied 239 cardiovascular and renal phenotypes in 113 male ...rats derived from an F2intercross and mapped 81 of these traits onto the genome. Aggregates of traits were identified on chromosomes 1, 2, 7, and 18. Systems biology was assessed by examining patterns of correlations ("physiological profiles") that can be used for gene hunting, mechanism-based physiological studies, and, with comparative genomics, translating these data to the human genome.
Consomic rats (SS.BN13), in which chromosome 13 from normotensive inbred Brown Norway rats from a colony maintained at the Medical College of Wisconsin (BN/Mcw) was introgressed into the background ...of Dahl salt-sensitive (SS/Mcw) rats, also maintained in a colony at the Medical College of Wisconsin, were bred. The present studies determined the mean arterial pressure (MAP) responses to salt and renal and peripheral vascular responses to norepinephrine and angiotensin II; 24-hour protein excretion and histological analyses were used to assess renal pathology in rats that received a high salt (4% NaCl) diet for 4 weeks. MAP of rats measured daily during the fourth week averaged 170±3.3 mm Hg in SS/Mcw rats, 119±2.1 mm Hg in SS.BN13 rats, and 103±1.3 mm Hg in BN/Mcw rats. After salt depletion, MAP fell an average of 27±4.5 mm Hg in SS/Mcw rats, 9±2.6 mm Hg in SS.BN13 rats, and 11±3.0 mm Hg in BN/Mcw rats. Protein excretion of SS/Mcw rats on a high salt diet averaged 189±30 mg/24 h, 63±18 mg/24 h in SS.BN13 rats, and 40±6.4 mg/24 h in BN/Mcw rats. Compared with SS.BN13 and BN/Mcw rats, SS/Mcw rats exhibited significantly greater increases of renal vascular resistance in response to intravenous norepinephrine and angiotensin II. Severe medullary interstitial fibrosis and tubular necrosis after a high salt diet were found consistently in SS/Mcw rat kidneys but were largely absent in the SS.BN13 and BN/Mcw rat kidneys. A similar degree of glomerular sclerosis was found in both SS/Mcw and SS.BN13 rats. In rats fed a 0.4% salt diet, the glomerular filtration rate of SS/Mcw rats was significantly less than that of BN/Mcw and SS.BN13 rats. These results reveal a powerful gene, or set of genes, within chromosome 13 of BN/Mcw rats that confers protection from the detrimental effects of high salt to the SS/Mcw rats.
ABSTRACTMucositis is a common, painful, and potentially dangerous adverse effect of many chemotherapy regimens. The mucosal barrier can be compromised from oncologic therapies resulting in high ...levels of exposure to organisms. These are often normal flora that become opportunistic pathogens, especially in these patients who already have compromised cellular immunity from neutropenia and humoral immunity from cytotoxic agents. The combination of a hampered immune system along with breakdown of the mucosa can lead to severe infections and lead to complications that undermine patient outcomes. The most common types of infections that are seen in neutropenic patients are bacterial, followed by viral, and then fungal. This case series will outline 3 vignettes of patients who developed mucositis secondary to chemotherapy-induced neutropenia and will review the most common infections seen in this delicate patient population plus empiric treatment strategies. For this review, a literature search was made using Google Scholar Database. Key words searched included bacterial, fungal, viral, mucositis, and leukemia. Articles published between 1983 and 2018 were selected.
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