| 51. |
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| 52. |
- Goebel, Andreas, et al.
(författare)
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Passive transfer of fibromyalgia symptoms from patients to mice
- 2021
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Ingår i: Journal of Clinical Investigation. - : American Society For Clinical Investigation. - 0021-9738 .- 1558-8238. ; 131:13
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Tidskriftsartikel (refereegranskat)abstract
- Fibromyalgia syndrome (FMS) is characterized by widespread pain and tenderness, and patients typically experience fatigue and emotional distress. The etiology and pathophysiology of fibromyalgia are not fully explained and there are no effective drug treatments. Here we show that IgG from FMS patients produced sensory hypersensitivity by sensitizing nociceptive neurons. Mice treated with IgG from FMS patients displayed increased sensitivity to noxious mechanical and cold stimulation, and nociceptive fibers in skin-nerve preparations from mice treated with FMS IgG displayed an increased responsiveness to cold and mechanical stimulation. These mice also displayed reduced locomotor activity, reduced paw grip strength, and a loss of intraepidermal innervation. In contrast, transfer of IgG-depleted serum from FMS patients or IgG from healthy control subjects had no effect. Patient IgG did not activate naive sensory neurons directly. IgG from FMS patients labeled satellite glial cells and neurons in vivo and in vitro, as well as myelinated fiber tracts and a small number of macrophages and endothelial cells in mouse dorsal root ganglia (DRG), but no cells in the spinal cord. Furthermore, FMS IgG bound to human DRG. Our results demonstrate that IgG from FMS patients produces painful sensory hypersensitivities by sensitizing peripheral nociceptive afferents and suggest that therapies reducing patient IgG titers may be effective for fibromyalgia.
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| 53. |
- Grant, Zoe L., et al.
(författare)
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Blocking endothelial apoptosis revascularizes the retina in a model of ischemic retinopathy
- 2020
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Ingår i: Journal of Clinical Investigation. - : AMER SOC CLINICAL INVESTIGATION INC. - 0021-9738 .- 1558-8238. ; 130:8, s. 4235-4251
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Tidskriftsartikel (refereegranskat)abstract
- Aberrant, neovascular retinal blood vessel growth is a vision-threatening complication in ischemic retinal diseases. It is driven by retinal hypoxia frequently caused by capillary nonperfusion and endothelial cell (EC) loss. We investigated the role of EC apoptosis in this process using a mouse model of ischemic retinopathy, in which vessel closure and EC apoptosis cause capillary regression and retinal ischemia followed by neovascularization. Protecting ECs from apoptosis in this model did not prevent capillary closure or retinal ischemia. Nonetheless, it prevented the clearance of ECs from closed capillaries, delaying vessel regression and allowing ECs to persist in clusters throughout the ischemic zone. In response to hypoxia, these preserved ECs underwent a vessel sprouting response and rapidly reassembled into a functional vascular network. This alleviated retinal hypoxia, preventing subsequent pathogenic neovascularization. Vessel reassembly was not limited by VEGFA neutralization, suggesting it was not dependent on the excess VEGFA produced by the ischemic retina. Neutralization of ANG2 did not prevent vessel reassembly, but did impair subsequent angiogenic expansion of the reassembled vessels. Blockade of EC apoptosis may promote ischemic tissue revascularization by preserving ECs within ischemic tissue that retain the capacity to reassemble a functional network and rapidly restore blood supply.
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| 54. |
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| 55. |
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| 56. |
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| 57. |
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| 58. |
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| 59. |
- Heilig, Markus, et al.
(författare)
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Novel medications for problematic alcohol use
- 2024
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Ingår i: Journal of Clinical Investigation. - : AMER SOC CLINICAL INVESTIGATION INC. - 0021-9738 .- 1558-8238. ; 134:11
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol -related harm, a major cause of disease burden globally, affects people along a spectrum of use. When a harmful pattern of drinking is present in the absence of significant behavioral pathology, low -intensity brief interventions that provide information about health consequences of continued use provide large health benefits. At the other end of the spectrum, profound behavioral pathology, including continued use despite knowledge of potentially fatal consequences, warrants a medical diagnosis, and treatment is strongly indicated. Available behavioral and pharmacological treatments are supported by scientific evidence but are vastly underutilized. Discovery of additional medications, with a favorable balance of efficacy versus safety and tolerability can improve clinical uptake of treatment, allow personalized treatment, and improve outcomes. Here, we delineate the clinical conditions when pharmacotherapy should be considered in relation to the main diagnostic systems in use and discuss clinical endpoints that represent meaningful clinical benefits. We then review specific developments in three categories of targets that show promise for expanding the treatment toolkit. GPCRs remain the largest category of successful drug targets across contemporary medicine, and several GPCR targets are currently pursued for alcohol -related indications. Endocrine systems are another established category, and several promising targets have emerged for alcohol indications. Finally, immune modulators have revolutionized treatment of multiple medical conditions, and they may also hold potential to produce benefits in patients with alcohol problems.
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| 60. |
- Hess, Paul R, et al.
(författare)
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Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life.
- 2014
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 124:1
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Tidskriftsartikel (refereegranskat)abstract
- Mammals transport blood through a high-pressure, closed vascular network and lymph through a low-pressure, open vascular network. These vascular networks connect at the lymphovenous (LV) junction, where lymph drains into blood and an LV valve (LVV) prevents backflow of blood into lymphatic vessels. Here we describe an essential role for platelets in preventing blood from entering the lymphatic system at the LV junction. Loss of CLEC2, a receptor that activates platelets in response to lymphatic endothelial cells, resulted in backfilling of the lymphatic network with blood from the thoracic duct (TD) in both neonatal and mature mice. Fibrin-containing platelet thrombi were observed at the LVV and in the terminal TD in wild-type mice, but not Clec2-deficient mice. Analysis of mice lacking LVVs or lymphatic valves revealed that platelet-mediated thrombus formation limits LV backflow under conditions of impaired valve function. Examination of mice lacking integrin-mediated platelet aggregation indicated that platelet aggregation stabilizes thrombi that form in the lymphatic vascular environment to prevent retrograde blood flow. Collectively, these studies unveil a newly recognized form of hemostasis that functions with the LVV to safeguard the lymphatic vascular network throughout life.
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