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Objective We aimed to investigate the morphological changes and potential correlation between chronic headaches and the rectus capitis posterior minor muscle (RCPmi). Methods Comparison of RCPmi between patients with chronic headaches and healthy adult volunteers were collected using magnetic resonance imaging (MRI) and Mimics software. Results Among the 235 MRI images analyzed, the data between the two groups were considered statistically significant. The number of males was larger than that of females ( p < 0.001) and the headache group showed greater hypertrophy than the control group in both males ( p < 0.001) and females ( p = 0.001). Conclusions Chronic headaches were correlated with the RCPmi. Patients with chronic headaches suffered from more obvious hypertrophy than that of the control group. Additionally, it was supposed that RCPmi hypertrophy may be one pathogenesis of the chronic headaches. [ABSTRACT FROM AUTHOR]

Background: Nowadays, many purple vegetables are available in the market. These vegetables have rich content of anthocyanins, which gives them their characteristic purple color. A high intake of anthocyanin-rich vegetables/plant parts imparts potential beneficial effects. Therefore, in this study, we investigated six purple plants (SPPs; purple cauliflower, purple potato, purple lettuce, purple carrot, purple beans, and purple tomato) for their content of functional composition and their antioxidant activity. Materials and Methods: Anthocyanins from SPPs were extracted and purified by an optimized process. Then, we determined the total anthocyanin (TA) and cyanidin-3-O-glucoside (C-3-G) content in the anthocyanin purified extracts (APEs) from the SPPs through pH difference and high-performance liquid chromatographic methods, respectively. 2,2-diphenyl-1-picrylhydrazyl and ferric reducing antioxidant power methods were used to test the antioxidant activities of the APEs. In addition, the contents of the total flavonoids, total polyphenol, Vitamin C, and dietary fiber from the SPPs were determined. Results: SPPs are rich in anthocyanins, flavonoids, phenolic acids, and other compounds that show strong antioxidant activity. According to our results, anthocyanin content was the highest in purple cauliflower, which translated into the greatest antioxidant activity of the APEs of purple cauliflower. The content of total flavonoid, polyphenol, and Vitamin C in the purple lettuce was higher than that of the other plants. The highest content of dietary fiber was found in purple potato. Conclusion: According to our results, purple cauliflower is the most potential plants to the pharmaceutical industry. Our results provide a theoretical basis for further exploration of efficacy of the purple plants and exploitation. [ABSTRACT FROM AUTHOR]

Introduction: The morphological characteristics of the endometrium in patients with choriocarcinoma have not been well described. We described the endometrial morphology patterns in 46 choriocarcinomas and analyzed their relationship with the clinicopathological characteristics of these patients. Methods: Forty-six patients diagnosed with choriocarcinoma that had sufficient endometrial tissues for histopathological diagnosis were selected. Diagnoses of choriocarcinoma and secretory status of endometrium were reviewed. LHCGR expression of endometrium was evaluated by immunostaining. Results: Endometrial morphology was classified as secretory or nonsecretory. The 15 secretory specimens included 2 highly secretory and 13 common secretory specimens. The 31 nonsecretory patterns included 1 hyperplasia without atypia, 7 disordered proliferations, 13 typical proliferations, and 10 resting endometria. Among these, 11 specimens with overall nonsecretory patterns showed focally weak secretory changes surrounding the choriocarcinoma lesion. Secretory patterns were observed in classic choriocarcinomas (8/17) and monomorphic choriocarcinomas (7/21) but not in scanty-trophoblast choriocarcinomas (0/8). Secretory changes appeared significantly less frequently in patients who received multi-agent chemotherapy (4/25) than in those who did not (7/14) or received single-agent chemotherapy (4/7) (P = 0.030). The differences in age, months since the last pregnancy, pregnancy type, recurrence, specimen type, gross diameter, human chorionic gonadotropin (hCG) levels, and expression of hCG receptors were not statistically significant. Conclusions: The endometrial morphologies in choriocarcinoma were diverse, including various proliferative and secretory changes, but rarely hypersecretory changes, compared to the prevailing hypersecretory endometrium in hydatidiform moles. The variety in endometrial morphology was the consequence of ovarian hormonal disturbances of the hypothalamic–pituitary–gonadal axis by hCG from choriocarcinoma. Therefore, the endometrium may serve as a clue for histopathological diagnosis of choriocarcinoma. Our study presents the largest cohort reported to date to describe the diverse spectrum of endometrial changes in choriocarcinoma patients. [ABSTRACT FROM AUTHOR]

Background: Severe postoperative pain remains a clinical problem that impacts patient's rehabilitation. The present work aims to investigate the role of Toll-like receptor-4 (TLR4) activation in wounded plantar tissue and dorsal root ganglion (DRG) in the genesis of postoperative pain and its underlying mechanisms. Results: Postoperative pain was induced by plantar incision in rat hind paw. Plantar incision led to increased expression of TLR4 in ipsilateral lumbar 4-5 (L4/L5) DRGs, which occurred at 2 h and was persistent to the third day after surgery. Similar to the change in TLR4 expression, there was also significant increase in phosphorylated nuclear factor-kappa B p65 (p-p65) in DRGs after surgery. Immunofluorescence staining revealed that the increased expressions of TLR4 and p-p65 not only in neuronal cells but also in satellite glial cells in DRG. Furthermore, the enhanced expressions of TLR4 and p-p65 were also detected in plantar tissues around the incision, which was observed starting at 2 h and lasting until the third day after surgery. Prior intrathecal (i.t.) injections of TAK-242 (a TLR4-specific antagonist) or 4',6-diamidino-2-phenylindole-dihydrochloride (PDTC, a nuclear factor-kappa B activation inhibitor) dose dependently alleviated plantar incision-induced mechanical allodynia and thermal hyperalgesia and inhibited the increased expressions of p-p65, tumor necrosis factor-alpha, and interleukin-1 beta in DRG. Prior subcutaneous (s.c.) plantar injection of TAK-242 or PDTC also ameliorated pain-related hypersensitivity following plantar incision. Moreover, the plantar s.c. injection of TAK-242 or PDTC inhibited the increased expressions of p-p65, tumor necrosis factor-alpha, and interleukin-1 beta not only in local wounded plantar tissue but also dramatically in ipsilateral lumbar 4-5 DRGs. Conclusion: TLR4/ nuclear factor-kappa B signaling activation in local injured tissue and DRG contribute to the development of postoperative pain via regulating pro-inflammatory cytokines release. Targeting TLR4/ nuclear factor-kappa B signaling in local tissue at early stage of surgery may be an effective strategy for the treatment of postoperative pain. [ABSTRACT FROM AUTHOR]

Metastatic bone tumor-induced changes in gene transcription and translation in pain-related regions of the nervous system may participate in the development and maintenance of bone cancer pain. Epigenetic modifications including DNA methylation regulate gene transcription. Here we report that intrathecal injection of decitabine, a DNA methyltransferase inhibitor, dosedependently attenuated the development and maintenance of bone cancer pain induced by injecting prostate cancer cells (PCC) into the tibia. The level of the de novo DNA methyltransferase DNMT3a, but not DNMT3b, time-dependently increased in the ipsilateral L4/5 dorsal horn (not L4/5 dorsal root ganglion) after PCC injection. Blocking this increase through microinjection of recombinant adeno-associated virus 5 (AAV5) expressing Dnmt3a shRNA into dorsal horn rescued PCC-induced downregulation of dorsal horn Kv1.2 expression and impaired PCC-induced pain hypersensitivity. In turn, mimicking this increase through microinjection of AAV5 expressing full-length Dnmt3a into dorsal horn reduced dorsal horn Kv1.2 expression and produced pain hypersensitivity in the absence of PCC injection. Administration of neither decitabine nor virus affected locomotor function and acute responses to mechanical, thermal, or cold stimuli. Given that Dnmt3a mRNA is co-expressed with Kcna2 mRNA (encoding Kv1.2) in individual dorsal horn neurons, our findings suggest that the increased dorsal horn DNMT3a contributes to bone cancer pain through silencing dorsal horn Kv1.2 expression. DNMT3a may represent a potential new target for cancer pain management. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury-caused hyperexcitability and abnormal ectopic discharges in the primary sensory neurons of dorsal root ganglion (DRG) play a key role in neuropathic pain development and maintenance. The two-pore domain background potassium (K2P) channels have been identified as key determinants of the resting membrane potential and neuronal excitability. However, whether K2P channels contribute to neuropathic pain is still elusive. We reported here that K2P1.1, the first identified mammalian K2P channel, was highly expressed in mouse DRG and distributed in small-, medium-, and large-sized DRG neurons. Unilateral lumbar (L) 4 spinal nerve ligation led to a significant and time-dependent reduction of K2P1.1 mRNA and protein in the ipsilateral L4 DRG, but not in the contralateral L4 or ipsilateral L3 DRG. Rescuing this reduction through microinjection of adeno-associated virus-DJ expressing full-length K2P1.1 mRNA into the ipsilateral L4 DRG blocked spinal nerve ligation-induced mechanical, thermal, and cold pain hypersensitivities during the development and maintenance periods. This DRG viral microinjection did not affect acute pain and locomotor function. Our findings suggest that K2P1.1 participates in neuropathic pain development and maintenance and may be a potential target in the management of this disorder. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury-caused hyperexcitability and abnormal ectopic discharges in the primary sensory neurons of dorsal root ganglion (DRG) play a key role in neuropathic pain development and maintenance. The two-pore domain background potassium (K2p) channels have been identified as key determinants of the resting membrane potential and neuronal excitability. However, whether K2p channels contribute to neuropathic pain is still elusive. We reported here that K2p1.1, the first identified mammalian K2P channel, was highly expressed in mouse DRG and distributed in small-, medium-, and large-sized DRG neurons. Unilateral lumbar (L) 4 spinal nerve ligation (SNL) led to a significant and time-dependent reduction of K2p1.1 mRNA and protein in the ipsilateral L4 DRG, but not in the contralateral L4 or ipsilateral L3 DRG. Rescuing this reduction through microinjection of adeno-associated virus-DJ expressing full-length K2p1.1 mRNA into the ipsilateral L4 DRG blocked SNL-induced mechanical, thermal, and cold pain hypersensitivities during the development and maintenance periods. This DRG viral microinjection did not affect acute pain and locomotor function. Our findings suggest that K2p1.1 participates in neuropathic pain development and maintenance and may be a potential target in the management of this disorder. [ABSTRACT FROM AUTHOR]

Neuropathic pain, a distressing and debilitating disorder, is still poorly managed in clinic. Opioids, like morphine, remain the mainstay of prescribed medications in the treatment of this disorder, but their analgesic effects are highly unsatisfactory in part due to nerve injury-induced reduction of opioid receptors in the first-order sensory neurons of dorsal root ganglia. G9a is a repressor of gene expression. We found that nerve injury-induced increases in G9a and its catalyzed repressive marker H3K9m2 are responsible for epigenetic silencing of Oprm1, Oprk1, and Oprd1 genes in the injured dorsal root ganglia. Blocking these increases rescued dorsal root ganglia Oprm1, Oprk1, and Oprd1 gene expression and morphine or loperamide analgesia and prevented the development of morphine or loperamide-induced analgesic tolerance under neuropathic pain conditions. Conversely, mimicking these increases reduced the expression of three opioid receptors and promoted the mu opioid receptor-gated release of primary afferent neurotransmitters. Mechanistically, nerve injury-induced increases in the binding activity of G9a and H3K9me2 to the Oprm1 gene were associated with the reduced binding of cyclic AMP response element binding protein to the Oprm1 gene. These findings suggest that G9a participates in the nerve injury-induced reduction of the Oprm1 gene likely through G9a-triggered blockage in the access of cyclic AMP response element binding protein to this gene. [ABSTRACT FROM AUTHOR]

Background: Peripheral nerve injury leads to changes in gene expression in primary sensory neurons of the injured dorsal root ganglia. These changes are believed to be involved in neuropathic pain genesis. Previously, these changes have been identified using gene microarrays or next generation RNA sequencing with poly-A tail selection, but these approaches cannot provide a more thorough analysis of gene expression alterations after nerve injury. Methods: The present study chose to eliminate mRNA poly-A tail selection and perform strand-specific next generation RNA sequencing to analyze whole transcriptomes in the injured dorsal root ganglia following spinal nerve ligation. Quantitative real-time reverse transcriptase polymerase chain reaction assay was carried out to verify the changes of some differentially expressed RNAs in the injured dorsal root ganglia after spinal nerve ligation. Results: Our results showed that more than 50 million (M) paired mapped sequences with strand information were yielded in each group (51.87 M-56.12M in sham vs. 51.08 M-57.99M in spinal nerve ligation). Six days after spinal nerve ligation, expression levels of 11,163 out of a total of 27,463 identified genes in the injured dorsal root ganglia significantly changed, of which 52.14% were upregulated and 47.86% downregulated. The largest transcriptional changes were observed in proteincoding genes (91.5%) followed by noncoding RNAs. Within 944 differentially expressed noncoding RNAs, the most significant changes were seen in long interspersed noncoding RNAs followed by antisense RNAs, processed transcripts, and pseudogenes.We observed a notable proportion of reads aligning to intronic regions in both groups (44.0% in sham vs. 49.6% in spinal nerve ligation). Using quantitative real-time polymerase chain reaction, we confirmed consistent differential expression of selected genes including Kcna2, Oprm1 as well as lncRNAs Gm21781 and 4732491K20Rik following spinal nerve ligation. Conclusion: Our findings suggest that next generation RNA sequencing can be used as a promising approach to analyze the changes of whole transcriptomes in dorsal root ganglia following nerve injury and to possibly identify new targets for prevention and treatment of neuropathic pain. [ABSTRACT FROM AUTHOR]

Background: Chronic stress has been reported to increase basal pain sensitivity and/or exacerbate existing persistent pain. However, most surgical patients have normal physiological and psychological health status such as normal pain perception before surgery although they do experience short-term stress during pre- and post-operative periods. Whether or not this short-term stress affects persistent postsurgical pain is unclear. Results: In this study, we showed that pre- or post-surgical exposure to immobilization 6 h daily for three consecutive days did not change basal responses to mechanical, thermal, or cold stimuli or peak levels of incision-induced hypersensitivity to these stimuli; however, immobilization did prolong the duration of incision-induced hypersensitivity in both male and female rats. These phenomena were also observed in post-surgical exposure to forced swimming 25 min daily for 3 consecutive days. Short-term stress induced by immobilization was demonstrated by an elevation in the level of serum corticosterone, an increase in swim immobility, and a decrease in sucrose consumption. Blocking this short-term stress via intrathecal administration of a selective glucocorticoid receptor antagonist, RU38486, or bilateral adrenalectomy significantly attenuated the prolongation of incision-induced hypersensitivity to mechanical, thermal, and cold stimuli. Conclusion: Our results indicate that short-term stress during the pre- or post-operative period delays postoperative pain recovery although it does not affect basal pain perception. Prevention of short-term stress may facilitate patients' recovery from postoperative pain. [ABSTRACT FROM AUTHOR]

Chronic pain is a major public health problem with limited treatment options. Opioids remain a routine treatment for chronic pain, but extended exposure to opioid therapy can produce opioid tolerance and hyperalgesia. Although the mechanisms underlying chronic pain, opioid-induced tolerance, and opioid-induced hyperalgesia remain to be uncovered, mammalian target of rapamycin (mTOR) is involved in these disorders. The mTOR complex 1 and its triggered protein translation are required for the initiation and maintenance of chronic pain (including cancer pain) and opioid-induced tolerance/hyperalgesia. Given that mTOR inhibitors are FDA-approved drugs and an mTOR inhibitor is approved for the treatment of several cancers, these findings suggest that mTOR inhibitors will likely have multiple clinical benefits, including anticancer, antinociception/anti-cancer pain, and antitolerance/hyperalgesia. This paper compares the role of mTOR complex 1 in chronic pain, opioid-induced tolerance, and opioid-induced hyperalgesia. [ABSTRACT FROM AUTHOR]

The complexity of chronic pain and the challenges of pharmacotherapy highlight the importance of development of new approaches to pain management. Gene therapy approaches may be complementary to pharmacotherapy for several advantages. Gene therapy strategies may target specific chronic pain mechanisms in a tissue-specific manner. The present collection of articles features distinct gene therapy approaches targeting specific mechanisms identified as important in the specific pain conditions. Dr. Fairbanks group describes commonly used gene therapeutics (herpes simplex viral vector (HSV) and adeno-associated viral vector (AAV)), and addresses biodistribution and potential neurotoxicity in pre-clinical models of vector delivery. Dr. Tao group addresses that downregulation of a voltage-gated potassium channel (Kv1.2) contributes to the maintenance of neuropathic pain. Alleviation of chronic pain through restoring Kv1.2 expression in sensory neurons is presented in this review. Drs Goins and Kinchington group describes a strategy to use the replication defective HSV vector to deliver two different gene products (enkephalin and TNF soluble receptor) for the treatment of post-herpetic neuralgia. Dr. Hao group addresses the observation that the pro-inflammatory cytokines are an important shared mechanism underlying both neuropathic pain and the development of opioid analgesic tolerance and withdrawal. The use of gene therapy strategies to enhance expression of the anti-pro-inflammatory cytokines is summarized. Development of multiple gene therapy strategies may have the benefit of targeting specific pathologies associated with distinct chronic pain conditions (by Guest Editors, Drs. C. Fairbanks and S. Hao). [ABSTRACT FROM AUTHOR]