Neuropeptide Deficient Mice Have Attenuated Nociceptive, Vascular, and Inflammatory Changes in a Tibia Fracture Model of Complex Regional Pain Syndrome

BACKGROUND: Distal limb fracture in man can induce a complex regional pain syndrome (CRPS) with pain, warmth, edema, and cutaneous inflammation. In the present study substance P (SP, Tac1(−/−)) and CGRP receptor (RAMP1(−/−)) deficient mice were used to investigate the contribution of neuropeptide signaling to CRPS-like changes in a tibia fracture mouse model. Wildtype, Tac1(−/−), and RAMP1(−/−) mice underwent tibia fracture and casting for 3 weeks, then the cast was removed and hindpaw mechanical allodynia, unweighting, warmth, and edema were tested over time. Hindpaw skin was collected at 3 weeks post-fracture for immunoassay and femurs were collected for micro-CT analysis. RESULTS: Wildtype mice developed hindpaw allodynia, unweighting, warmth, and edema at 3 weeks post-fracture, but in the Tac1(−/−) fracture mice allodynia and unweighting were attenuated and there was no warmth and edema. RAMP1(−/−) fracture mice had a similar presentation, except there was no reduction in hindpaw edema. Hindpaw skin TNFα, IL-1β, IL-6 and NGF levels were up-regulated in wildtype fracture mice at 3 weeks post-fracture, but in the Tac1(−/−) and RAMP1(−/−) fracture mice only IL-6 was increased. The epidermal keratinocytes were the cellular source for these inflammatory mediators. An IL-6 receptor antagonist partially reversed post-fracture pain behaviors in wildtype mice. CONCLUSIONS: In conclusion, both SP and CGRP are critical neuropeptide mediators for the pain behaviors, vascular abnormalities, and up-regulated innate immune responses observed in the fracture hindlimb. We postulate that the residual pain behaviors observed in the Tac1(−/−) and RAMP1(−/−) fracture mice are attributable to the increased IL-6 levels observed in the hindpaw skin after fracture

Perceived stigma among discharged patients of COVID-19 in Wuhan, China: A latent profile analysis

BackgroundPerceived stigma has greatly influenced the life quality of the COVID-19 patients who recovered and were discharged (RD hereafter). It is essential to understand COVID-19 stigma of RD and its related risk factors. The current study aims to identify the characteristics of perceived COVID-19 stigma in RD using latent profile analysis (LPA), to explore its psycho-social influencing factors, and to determine the cut-off point of the stigma scale using receiver operating characteristic (ROC) analysis.MethodsA cross-sectional study was conducted among COVID-19 RD in 13 communities in Jianghan District, Wuhan City, Hubei Province, China from June 10 to July 25, 2021, enrolling total 1,297 participants. Data were collected on demographic characteristics, COVID-19 perceived stigma, post-traumatic stress disorder (PTSD), anxiety, depression, sleep disorder, fatigue, resilience, social support, and peace of mind. LPA was performed to identify different profiles of perceived COVID-19 stigma level. Univariate analysis and multinominal logistic regression analysis were conducted to explore the influencing factors in different profiles. ROC analyses was carried out to identify the cut-off value of perceived stigma.ResultsAmong the participants, three profiles of perceived stigma were identified: “low perceived COVID-19 stigma” (12.8%), “moderate perceived COVID-19 stigma” (51.1%), and “severe perceived COVID-19 stigma” (36.1%). Multinominal logistic regression analysis revealed that older age, living with other people, anxiety, and sleep disorder were positively associated with moderate perceived COVID-19 stigma, while higher educational level was negatively associated with moderate perceived COVID-19 stigma. Female, older age, living with other people, anxiety, and sleep disorder were positively associated with severe perceived COVID-19 stigma, while higher educational level, social support, and peace of mind were negatively associated with severe perceived COVID-19 stigma. ROC curve of the Short Version of COVID-19 Stigma Scale (CSS-S) for screening perceived COVID-19 stigma showed that the optimal cut-off value was ≥ 20.ConclusionThe study focuses on the issue of perceived COVID-19 stigma and its psycho-socio influencing factors. It provides evidence for implementing relevant psychological interventions to COVID-19 RD

Family history of cancer and risk for esophageal and gastric cancer in Shanxi, China

<p>Abstract</p> <p>Background</p> <p>Family history (FH) by different relative types and risk of upper gastrointestinal (UGI) cancers has been only rarely reported; the data on UGI cancer survival are sparse.</p> <p>Methods</p> <p>600 esophageal squamous cell carcinoma (ESCC) cases, 598 gastric cardia adenocarcinoma cases, and 316 gastric non-cardia adenocarcinoma cases, and 1514 age-, gender-, and neighborhood-matched controls were asked for FH in first degree relatives and non-blood relatives. Odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regressions, and hazard ratios (HRs) from Cox proportional hazard regressions were estimated.</p> <p>Results</p> <p>Increased ESCC risk was associated with FH of any cancer (OR = 1.72, 95% CI = 1.39–2.12), FH of any UGI cancer (OR = 2.28, 95%CI = 1.77–2.95) and FH of esophageal cancer (OR = 2.84, 95%CI = 2.09–3.86), but not FH of non-UGI cancer. Individuals with two or more affected first-degree relatives had 10-fold increased ESCC risk. FH of gastric cardia cancer was associated with an increased risk of all three cancers. Cancer in non-blood relatives was not associated with risk of any UGI cancer. FH of UGI cancer was associated with a poorer survival rate among younger ESCC cases (HR = 1.82, 95%CI = 1.01–3.29).</p> <p>Conclusion</p> <p>These data provide strong evidence that shared susceptibility is involved in esophageal carcinogenesis and also suggest a role in prognosis.</p

Chronic morphine administration enhances nociceptive sensitivity and local cytokine production after incision

Abstract Background - The chronic use of opioids prior to surgery leads to lowered pain thresholds and exaggerated pain levels after these procedures. Several mechanisms have been proposed to explain this heightened sensitivity commonly termed opioid-induced hyperalgesia (OIH). Most of these proposed mechanisms involve plastic events in the central or peripheral nervous systems. Alterations in the abundance of peripheral mediators of nociception have not previously been explored. Results - In these experiments mice were treated with saline (control) or ascending daily doses of morphine to generate a state of OIH followed by hind paw incision. In other experiments morphine treatment was initiated at the time of incision. Both mechanical allodynia and peri-incisional skin cytokine levels were measured. Myeloperoxidase (MPO) assays were used to determine neutrophil activity near the wounds. The cytokine production inhibitor pentoxifylline was used to determine the functional significance of the excess cytokines in previously morphine treated animals. Mice treated chronically treated with morphine prior to incision were found to have enhanced skin levels of IL-1β, IL-6, G-CSF, KC and TNFα after incision at one or more time points compared to saline pretreated controls. The time courses of individual cytokines followed different patterns. There was no discernable effect of chronic morphine treatment on wound area neutrophil infiltration. Pentoxifylline reduced cytokine levels and reversed the excess mechanical sensitization caused by chronic morphine administration prior to incision. Morphine treatment initiated at the time of incision did not lead to a generalized enhancement of cytokine production or nociceptive sensitization in excess of the levels observed after incision alone. Conclusion - The enhanced level of nociceptive sensitization seen after incision in animals chronically exposed to morphine is associated with elevated levels of several cytokines previously reported to be relevant to this incisional pain model. The cytokines may be functional in supporting nociceptive sensitization because pentoxifylline reverses both peri-incisional skin cytokine levels and OIH. Opioid administration beginning at the time of incision does not seem to have the same cytokine enhancing effect. Approaches to postoperative pain control involving a reduction of cytokines may be an effective way to control excessive pain in patients chronically using opioids prior to surgical procedures.</p

Neuropeptide regulation of adaptive immunity in the tibia fracture model of complex regional pain syndrome

Abstract Background Both dysfunctional neuropeptide signaling and immune system activation are characteristic of complex regional pain syndrome (CRPS). Unknown is whether substance P (SP) or calcitonin gene-related peptide (CGRP) support autoantibody production and, consequently, nociceptive sensitization. Methods These experiments involved the use of a well-characterized tibia fracture model of CRPS. Mice deficient in SP expression (Tac1−/−) and CGRP signaling (RAMP1−/−) were used to probe the neuropeptide dependence of post-fracture sensitization and antibody production. The deposition of IgM in the spinal cord, sciatic nerves, and skin was followed using Western blotting, as was expression of the CRPS-related autoantigen cytokeratin 16 (Krt16). Passive serum transfer to B-cell-deficient muMT mice was used to assess the production of functional autoantibodies in CRPS model mice. The use of immunohistochemistry allowed us to assess neuropeptide-containing fiber distribution and Langerhans cell abundance in mouse and human CRPS patient skin, while Langerhans cell-deficient mice were used to assess the functional contributions of these cells. Results Functional SP and CGRP signaling were required both for the full development of nociceptive sensitization after fracture and the deposition of IgM in skin and neural tissues. Furthermore, the passive transfer of serum from wildtype but not neuropeptide-deficient mice to fractured muMT mice caused enhanced allodynia and postural unweighting. Langerhans cells were increased in number in the skin of fracture mice and CRPS patients, and those increases in mice were reduced in neuropeptide signaling-deficient animals. Unexpectedly, Langerhans cell-deficient mice showed normal nociceptive sensitization after fracture. However, the increased expression of Krt16 after tibia fracture was not seen in neuropeptide-deficient mice. Conclusions Collectively, these data support the hypothesis that neuropeptide signaling in the fracture limb of mice is required for autoantigenic IgM production and nociceptive sensitization. The mechanism may be related to neuropeptide-supported autoantigen expression

Ultrasound imaging for assessing aortic phenotypes: A preclinical tool for measuring cardiac disease model progression and therapeutic effect

Cardiac dysfunction is a common feature of numerous diseases, ranging from metabolic disorders like Mucopolysaccharidosis Type 1 (MPS I), a.k.a. Hurler syndrome to neuromuscular disorders such as Myotonic Dystrophy type 1 (DM1). The ability to quantify cardiac abnormalities in animal models of these diseases is a valuable translational tool for preclinical testing of novel therapeutic approaches. In contrast to methods that measure the left ventricle (LV) phenotype, we employed ultrasound imaging to assess the ascending aortic diameter and ascending aortic blood velocity. Methods: We imaged two disease models - MPS I Hurler mouse model and DM1 mouse model (DMSXL) - using the Vevo2100 platform. Ascending aortic diameter in the proximal thoracic aortic region and ascending aortic blood velocity just before the branching point of the brachiocephalic artery were measured as rapid imaging readouts. In addition, histopathology was performed on relevant tissue samples. Results: The two mouse models demonstrate opposing aorta phenotypes. Hurler mice had a dilated aorta and slightly increased blood velocity with disease progression, while the aorta diameter in DMSXL mice narrowed and had a blood velocity decrease as the disease progressed. In the Hurler model, we demonstrated that a single dose of adeno-associated virus (AAV) delivered gene therapy provides aortic phenotype improvement. In the DMSXL model, we established aortic phenotype criteria at baseline. Conclusion: Ultrasound imaging of aortic diameter and blood velocity can offer objective and longitudinal assessments of disease progression and treatment efficacy in real time. This method might therefore have noninvasive clinical applicability as phenotype indicator of cardiac dysfunction

Prevalence of Inconsistent Condom Use and Associated Factors Among HIV Discordant Couples in a Rural County in China

A random sample consisting of 88 sexually active people living with HIV (PLWH) and their HIV negative spouses in rural China were interviewed. Data of 68 couples (77.2 %) who gave identical responses to whether they had been using condoms consistently in the last 12 months (n = 136) were analyzed. The results showed that 27.9 % of the discordant couples used condom inconsistently in the last year. Condom non-availability was the most commonly given main reason for not using condoms. Free condoms should be made available to these low-income couples. Suicidal ideation of the PLWH and the spouse's perception on 'whether someone could contract HIV via unprotected sexual intercourse with a HIV positive person' were significantly associated with inconsistent condom use in the last year. Education program should change the cognition about the risk for HIV transmission via unprotected sex. Integrated psychological services to reduce suicidal ideation are greatly warranted

In these experiments mice were subjected to nociceptive testing of the hind paw to establish the baseline threshold

Mice were then pre-treated with either saline or morphine for 4 days prior to hind paw incisions being made. After incision, groups of mice were treated daily with daily intraperitoneal saline or pentoxifylline as described in Methods. Nociceptive testing 72 hours after hind paw incision (2 hours after the last dose of pentoxifylline). **p < 0.01, N = 8/group.<p><b>Copyright information:</b></p><p>Taken from "Chronic morphine administration enhances nociceptive sensitivity and local cytokine production after incision"</p><p>http://www.molecularpain.com/content/4/1/7</p><p>Molecular Pain 2008;4():7-7.</p><p>Published online 22 Feb 2008</p><p>PMCID:PMC2279109.</p><p></p

Panel A displays the mechanical thresholds of mice in four different treatment groups: saline pretreatment/no incision, saline pretreatment/incision, morphine pretreatment/no incision, morphine pretreatment/incision

The values labeled pre-incision represent the nociceptive thresholds measured after 4 days of saline or morphine treatment but prior to hind paw incision. In panel B data are presented representing mechanical nociceptive thresholds in mice undergoing saline or morphine treatment beginning at the time of incision. Nociceptive thresholds were measured immediately before that day's dose of morphine. The statistical analysis presented reflects the results of two-way ANOVA comparing saline/incision values to morphine/incision ones. *p < 0.05, **p < 0.01, N = 6/group.<p><b>Copyright information:</b></p><p>Taken from "Chronic morphine administration enhances nociceptive sensitivity and local cytokine production after incision"</p><p>http://www.molecularpain.com/content/4/1/7</p><p>Molecular Pain 2008;4():7-7.</p><p>Published online 22 Feb 2008</p><p>PMCID:PMC2279109.</p><p></p