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Targeting the nitric oxide/cGMP signaling pathway to treat chronic pain.

Nitric oxide (NO)/cyclic guanosine 3',5'-monophosphate (cGMP) signaling has been shown to act as a mediator involved in pain transmission and processing. In this review, we summarize and discuss the mechanisms of the NO/cGMP signaling pathway involved in chronic pain, including neuropathic pain, bone cancer pain, inflammatory pain, and morphine tolerance. The main process in the NO/cGMP signaling pathway in cells involves NO activating soluble guanylate cyclase, which leads to subsequent production of cGMP. cGMP then activates cGMP-dependent protein kinase (PKG), resulting in the activation of multiple targets such as the opening of ATP-sensitive K channels. The activation of NO/cGMP signaling in the spinal cord evidently induces upregulation of downstream molecules, as well as reactive astrogliosis and microglial polarization which participate in the process of chronic pain. In dorsal root ganglion neurons, natriuretic peptide binds to particulate guanylyl cyclase, generating and further activating the cGMP/PKG pathway, and it also contributes to the development of chronic pain. Upregulation of multiple receptors is involved in activation of the NO/cGMP signaling pathway in various pain models. Notably the NO/cGMP signaling pathway induces expression of downstream effectors, exerting both algesic and analgesic effects in neuropathic pain and inflammatory pain. These findings suggest that activation of NO/cGMP signaling plays a constituent role in the development of chronic pain, and this signaling pathway with dual effects is an interesting and promising target for chronic pain therapy.

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White gastric mucosa during endoscopy as a new endoscopic feature of chronic ischemic gastritis: A case report.

Chronic ischemic gastritis (CIG) requires early diagnosis and treatment as complications of thromboembolism can be fatal. Although computed tomography (CT) is useful in the diagnosis of CIG, it is difficult to diagnose from a patient's history, endoscopic findings, and tissue biopsy. Identification of the key findings that motivate computed tomography is an important issue. We report a case of CIG diagnosed by endoscopic findings of white patches of mucosa over time. A 63-year-old man presented with epigastric pain. He had a history of repeated gastric ulcers of an undetermined cause. We performed upper endoscopy and observed the appearance of multiple white patches on the gastric mucosa. Central vessel stenosis was considered, and aortic computed tomography revealed complete occlusion of the superior mesenteric artery and stenosis of the celiac artery. We carried out a surgical bypass and found no postoperative endoscopic mucosal changes or abdominal pain. White patch changes in the gastric mucosa over time during endoscopy may indicate CIG. This finding may help in the future diagnosis of CIG.

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Engineering human spinal microphysiological systems to model opioid-induced tolerance.

pioids are commonly used for treating chronic pain. However, with continued use, they may induce tolerance and/or hyperalgesia, which limits therapeutic efficacy. The human mechanisms of opioid-induced tolerance and hyperalgesia are significantly understudied, in part, because current models cannot fully recapitulate human pathology. Here, we engineered novel human spinal microphysiological systems (MPSs) integrated with plug-and-play neural activity sensing for modeling human nociception and opioid-induced tolerance. Each spinal MPS consists of a flattened human spinal cord organoid derived from human stem cells and a 3D printed organoid holder device for plug-and-play neural activity measurement. We found that the flattened organoid design of MPSs not only reduces hypoxia and necrosis in the organoids, but also promotes their neuron maturation, neural activity, and functional development. We further demonstrated that prolonged opioid exposure resulted in neurochemical correlates of opioid tolerance and hyperalgesia, as measured by altered neural activity, and downregulation of μ-opioid receptor expression of human spinal MPSs. The MPSs are scalable, cost-effective, easy-to-use, and compatible with commonly-used well-plates, thus allowing plug-and-play measurements of neural activity. We believe the MPSs hold a promising translational potential for studying human pain etiology, screening new treatments, and validating novel therapeutics for human pain medicine.

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Colonoscopy-assisted percutaneous sigmoidopexy for a complete rectal prolapse: A case report.

Colonoscopy-assisted percutaneous sigmoidopexy is a simple and swift procedure that does not require general anesthesia. While we first developed this procedure for treating sigmoid volvulus, we herein present the first case in which we used it to correct a complete rectal prolapse in an older patient. Existing treatment modalities for rectal prolapses are limited by high recurrence rates, greater invasiveness, and greater complications; thus, there is a need for minimally invasive techniques that are associated with lower recurrence rates and fewer complications. In this case, a woman in her 90s complained of persistent fecal incontinence, dysuria, anal pain, and difficulty in walking. She was diagnosed with a complete rectal prolapse of 15 cm and was treated with colonoscopy-assisted percutaneous sigmoidopexy. The sigmoid colon was tractioned colonoscopically and fixed to the abdominal wall to immobilize the prolapsed rectum. The patient developed no complications intraoperatively and postoperatively and experienced no recurrence during a 5-year postoperative period. This report documents the first case wherein colonoscopy-assisted percutaneous sigmoidopexy was used successfully to correct a complete rectal prolapse.

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Acute idiopathic blind spot enlargement syndrome (AIBSES) with retinal vasculitis.

To report the clinical and anatomical features of an unusual case of acute idiopathic blind spot enlargement syndrome (AIBSES) with retinal vasculitis.

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Microscopic corneal epithelial changes and clinical outcomes in simple limbal epithelial transplantation surgery after treatment with amniotic membrane eye drops (AMED): A case report.

To describe the microscopic epithelial changes and the clinical outcomes of a patient treated with amniotic membrane eye drops (AMED) because of a persistent epithelial defect (PED) and a partial limbal stem cell deficiency (LSCD) after simple limbal epithelial transplantation (SLET) and deep anterior lamellar keratoplasty (DALK).

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Chronic Migraine: Diagnosis and Management.

Migraine is the second leading cause of years lived with disability. Patients with chronic migraine (CM) face enormous barriers in accessing care and in receiving an accurate diagnosis and appropriate treatment. This article reviews the following: epidemiology, definition, pathophysiology, medication overuse, and acute and preventive treatment.

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Trigeminal Neuralgia: Diagnosis and Treatment.

Trigeminal neuralgia is characterized classically by recurrent, evocable, unilateral brief, electric, shocklike pains with an abrupt onset and cessation that affects one or more divisions of the trigeminal nerve. In recent years, the classification of trigeminal neuralgia has been updated based on further understanding. In this manuscript, the authors aim to explain the current understanding of the pathophysiology of trigeminal neuralgia, current diagnosis criteria, and the pharmacologic management and surgical treatments of options currently available.

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Pruritus in Chronic Liver Disease.

Pruritus can be associated with chronic liver disease, particularly cholestatic liver disease. Although the pathophysiology is uncertain, there are a few proposed mechanisms and much is still being discovered. Workup involves an assessment to rule out a dermatologic, neurologic, psychogenic, or other underlying systemic disorder. First-line therapy is cholestyramine, which is generally well tolerated and effective. In those who fail cholestyramine, alternative drugs including rifampicin and μ-opioid receptor antagonists can be considered. If medical therapy is ineffective and pruritus is significant, alternative experimental therapies such as albumin dialysis, photopheresis, plasmapheresis, and biliary diversion can be considered.

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Dataset linking free polyunsaturated fatty acid concentrations in erythrocytes with chronic pain conditions in adults.

Circulating polyunsaturated fatty acids (PUFAs) and lipid mediators were extracted from human red blood cells and quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method encompassed 13 different PUFAs and lipid mediators, however, due to instrument capability only five were confidently quantified (EPA, ALA, AA, DHA, and LA). The extraction focused on free polyunsaturated fatty acids since they have a strong correlation with health in humans. The study design was a secondary analysis of the OPPERA-2 study of chronic overlapping pain conditions in adults. The data included are: a) raw LC-MS/MS data (.raw); b) processed data (.xlsx) including chromatographic peak area for each compound and a concentration (ng/mL) based on external calibration with internal standardization using pure analytical grade standards and heavy-isotope labeled internal standards; c) study participant demographics and phenotypes (.xlsx). This dataset consisting of circulating PUFA quantities measured in 605 humans has been made publicly available for analysis and interpretation.

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