1. 在此片中(也出於《科•化》封面上)，常的滑膜充著度生的，包括血管(洋色)。滑膜薄且光滑。
In this image (also on the cover of Science Translational Medicine), abnormal synovial tissue is shot through with excessive tissue growth, including blood vessels (in magenta). Synovium should be thin and smooth.
Treatment for rheumatoid arthritis (RA) has come a long way in recent years. In many cases, a battery of medications can now successfully stymy the inflammatory cells that cause swelling and pain when they infiltrate tissues around the joints.
近年，性炎(RA)的治，已取得足的展。目前一系列物，在多病例中能成功阻，入周，引起及疼痛的炎胞。
Yet for some reason, about 20% of patients with painful, visibly swollen joints consistently get no relief from multiple rounds of even the strongest of these anti-inflammatory drugs.
然而，由於某原因，大20%具有疼痛、明之的患者，即使多次服用最效的抗炎物，一直有得解。
Surgical interventions intended to remove inflamed tissue have revealed why: “In some cases, their joints aren’t actually inflamed,” says co-senior author Dana Orange, an associate professor of clinical investigation in Rockefeller’s Laboratory of Molecular Neuro-oncology.
共同深撰文人，美洛克菲勒大分子神瘤室床查研究副教授，Dana Orange表示，旨在移除炎的手干，已揭露原因：「在某些病例中，上他的有炎。」
“With these patients, if you press on the joint, it feels mushy and thick to the touch, but it’s not caused by the infiltrating immune cells. They have excessive tissue growth, but without inflammation. So why are they experiencing pain?”
此些患者而言，倘若按，摸感且厚。不，非由浸的免疫胞所引起。它有度的生，不有炎。那，他何感受疼痛？
In a new paper in Science Translational Medicine, she and her colleagues suggest an explanation. These patients have a suite of 815 genes that activate abnormal growth of sensory neurons in tissues that cushion the affected joints.
在表於《科•化》期刊的一篇新文中，她及其同僚提出了一解。此些患者具有一，激活中，受影之感神元常生的815基因。
“These 815 genes are rewiring the sensory nerves, which explains why anti-inflammatory drugs don’t work to alleviate pain for these patients,” says Orange. The findings may lead to new treatments for these outliers.
Orange宣：「815基因，正在重新接感神。解了，何抗炎物，不起些患者疼痛的作用。」此些研究，可能些常者，引出新的治方法。
Rheumatoid arthritis is a tricky chronic disease. Its symptoms—stiffness, tenderness, swelling, limited motion, and pain—slowly emerge in the hands, wrists, feet, and other joints. It occurs symmetrically (not just in one hand but in both, for instance) and sporadically, with irregular flare-ups. Extreme fatigue and depression are also common.
性炎是一棘手的慢性疾病。其僵硬、痛、、活受限及疼痛等症，慢慢出於手、手腕、及其他中。(譬如，不在一手，而是在手)且零星地生，以不的突然作。度疲也很常。
Most cases of RA are caused by products of immune cells such as cytokines, bradykinins, or prostanoids invading the synovium—a soft tissue lining the joints—where they bind to damage-sensing pain receptors. Drugs that target immune mediators have made RA a far more tolerable condition for most, but those suffering from the disconnection between inflammation and ache haven’t benefitted.
大多RA病例是由，如胞激素、激肽或前列腺素等，免疫胞的物侵入滑膜(的)所引起。於滑膜中，它感知的疼痛受合。定免疫介的物，已使得性炎大多人，得更容易忍受的疾病。不，那些罹患炎疼痛之的人，有受益。
Doctors often prescribe these patients drug after anti-inflammatory drug in an ultimately fruitless attempt to give relief. As a result, “we are subjecting some patients to a lot of medications that cause immunosuppression and yet have little chance of making their symptoms better,” Orange says.
在予解，最後效。生常此些患者，立一又一抗炎的物方。果，Orange宣：「我一些患者接受大量，致免疫抑制的物治。不，乎改善他的症。」
She and her colleagues sought answers in the genes expressed in the joint tissue samples of these patients.
她及其同僚，在此些患者本的基因表中，找答案。
The researchers looked at tissue samples and self-reported pain reports from 39 patients with RA who had pain but little inflammation. They also developed a machine-learning analysis that they coined graph-based gene expression module identification (GbGMI).
此些研究人探究了，自39名具有疼痛，不少有炎之RA患者的本，及自行述的疼痛告。些患者有疼痛但很少有炎。他也了一他所造，以表基之基因表模辨(GbGMI)的器分析法。
GbGMI tests every possible combination of genes in a dataset to determine the optimal set of genes that together associate with a targeted clinical feature—in this case, pain.
GbGMI分析於一料集中，所有可能的基因合，定一起定之床特徵(在本例中，是疼痛)相的最佳基因。
Using RNA sequencing, the researchers found that of the 15,000 genes expressed in the tissue samples, about 2,200 had increased expression in the 39 patients. Using GbGMI, they identified 815 genes that together associated with patient reports of pain.
使用RNA排序，此些研究人，在此些本中，表的15000基因中，2200基因，在39名患者中，已增表。
“This is a challenging problem, because we have a large number of genes but a limited number of patients,” co-senior author Fei Wang, professor of population health sciences and founding director of the Institute of Artificial Intelligence for Digital Health at Weill Cornell Medicine. “The graph-based approach we used effectively explored the collective associations between a gene set and patient-reported pain.”
共同深撰文人，康乃大威康奈院，人口健康科教授、位健康人工智慧研究所始主任，Fei Wang宣：「是一挑性的，因我有大量的基因，不有限的患者量。我使用之以表基的方法，有效探索了，一基因患者述之疼痛的共同性。」
Single cell sequencing analysis found that of the four types of fibroblasts in synovial tissue, CD55+ fibroblasts exhibited the highest expression of pain-associated genes. Located in the outer synovial lining, CD55+ cells secrete synovial fluid, allowing for frictionless joint movement.
胞排序分析，於分泌滑液之的四成胞(母胞)中，CD55+成胞展了，疼痛相基因的最高表。位於滑膜外，CD55+胞分泌容摩擦之活的滑液。
They also expressed the NTN4 gene, which codes for a protein called Netrin-4. Proteins in the netrin family guide axon growth paths and promote new vascular growth.
他也使，一被Netrin-4之蛋白指定的 NTN4基因，作出了表。於netrin群中的多蛋白，引神突生途，促新血管生。
These genes, it turned out, were enriched in pathways that are important for neuron axon growth, the researchers discovered. The keys to sensation, sensory neurons receive and transmit information to the central nervous system. Axons are the tendrils that branch out from them into tissues.
此些研究人，些基因富含於，神元突生重要的途中。感能的多，感神元接收及送信息到中神系。神突是感神元，分支入中的物。
“That led us to hypothesize that perhaps the fibroblasts are producing things that alter the growth of sensory nerves,” Orange says. But what role was the protein playing in the sensation of pain?
Orange宣：「那引了我假，些成胞正在生，改感神生的物。」不，在疼痛的感能中，蛋白是什角色？
To find out, they grew neurons in vitro and then doused them with Netrin-4, which sparked the sprouting and branching of CGRP+ (gene-related peptide) pain receptors. It’s the first time that Netrin-4 has been shown to alter the growth of pain-sensitive neurons, she notes.
了找到答案，他在活外培了神元，然後以Netrin-4浸泡它。引了CGRP+(相基因的肽)疼痛受的生及分支。她特指出，是Netrin-4首次已被，改疼痛敏感之神元的生。
Imaging of RA synovial tissue also revealed an overabundance of blood vessels, which feed and nurture new cells. These vessels were encased by CGRP+ sensory nerve fibers and were growing towards the lining fibroblasts in areas of excessive tissue growth, or hyperplasia. This process likely leads to the squishy swelling that many rheumatologists and surgeons have mistaken for inflammtion.
RA滑膜的造影也揭露了，供及新胞物的血管多。此些被CGRP+感神包裹的血管，在度生或增生域中，朝向成胞生。此程可能致，多病家及外科生，一直炎的。
In the future, the researchers aim to home in on other products that fibroblasts may be producing that can affect the growth of pain-sensitive neurons. They’ll also delve into the other types of sensory nerves that might be affected.
於未，此些研究人著重於，成胞可能生，影疼痛敏感之神元生的其他物。他也深入研究，可能受影之其他型的感神。
“We studied one type, but there are about a dozen. We don’t know if all nerves are affected equally. And we don’t want to block all sensation. Sensory nerves are important for knowing that you should avoid certain movements and the position of your joint in space, for instance,” Orange says.
Orange宣：「我研究了一型，不大有十。我不知道，是否所有神皆同受到影。因此，我不想阻所有感能。譬如，感神於解，避免某些，及在空中的位置是重要的。
“We want to drill down on those details so that hopefully we can come up with other treatments for patients who don’t have a lot of inflammation. Right now, they’re taking medications that can cost $70,000 a year but have no chance of working. We must do a better job of getting the right drug to the right patient.”
我想深入探究那些，以便如果利的，能有重炎的患者，提出其他治方法。目前，他正在服用，一年花7美元的物。不，有起作用的。我必行一，得患者之正物的更好工作。」
址：https://www.rockefeller.edu/news/35668-why-some-people-with-rheumatoid-arthritis-have-pain-without-inflammation/
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