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Many epigenetic regulators are involved in pain-associated spinal plasticity. Coactivator-associated arginine methyltransferase 1 (CARM1), an epigenetic regulator of histone arginine methylation, is a highly interesting target in neuroplasticity. However, its potential contribution to spinal plasticity–associated neuropathic pain development remains poorly explored. Here, we report that nerve injury decreased the expression of spinal CARM1 and induced allodynia. Moreover, decreasing spinal CARM1 expression by Fbxo3-mediated CARM1 ubiquitination promoted H3R17me2 decrement at the K+ channel promoter, thereby causing K+ channel epigenetic silencing and the development of neuropathic pain. Remarkably, in naïve rats, decreasing spinal CARM1 using CARM1 siRNA or a CARM1 inhibitor resulted in similar epigenetic signaling and allodynia. Furthermore, intrathecal administration of BC-1215 (a novel Fbxo3 inhibitor) prevented CARM1 ubiquitination to block K+ channel gene silencing and ameliorate allodynia after nerve injury. Collectively, the results reveal that this newly identified spinal Fbxo3-CARM1-K+ channel gene functional axis promotes neuropathic pain. These findings provide essential insights that will aid in the development of more efficient and specific therapies against neuropathic pain. [ABSTRACT FROM AUTHOR]

Background/Purpose Mesh-augmented vaginal surgery for treatment of pelvic organ prolapse (POP) does not meet patients' needs. This study aims to test the hypothesis that fascia tissue engineering using adipose-derived stem cells (ADSCs) might be a potential therapeutic strategy for reconstructing the pelvic floor. Methods Human ADSCs were isolated, differentiated, and characterized in vitro . Both ADSCs and fibroblastic-differentiated ADSCs were used to fabricate tissue-engineered fascia equivalents, which were then transplanted under the back skin of experimental nude mice. Results ADSCs prepared in our laboratory were characterized as a group of mesenchymal stem cells. In vitro fibroblastic differentiation of ADSCs showed significantly increased gene expression of cellular collagen type I and elastin ( p < 0.05) concomitantly with morphological changes. By contrast, ADSCs cultured in control medium did not demonstrate these changes. Both of the engrafted fascia equivalents could be traced up to 12 weeks after transplantation in the subsequent animal study. Furthermore, the histological outcomes differed with a thin (111.0 ± 19.8 μm) lamellar connective tissue or a thick (414.3 ± 114.9 μm) adhesive fibrous tissue formation between the transplantation of ADSCs and fibroblastic-differentiated ADSCs, respectively. Nonetheless, the implantation of a scaffold without cell seeding (the control group) resulted in a thin (102.0 ± 17.1 μm) fibrotic band and tissue contracture. Conclusion Our results suggest the ADSC-seeded implant is better than the implant alone in enhancing tissue regeneration after transplantation. ADSCs with or without fibroblastic differentiation might have a potential but different role in fascia tissue engineering to repair POP in the future. [ABSTRACT FROM AUTHOR]

Abstract: Huang Y-H, Bih L-I, Chen G-D, Lin C-C, Chen S-L, Chen W-W. Autonomic dysreflexia during urodynamic examinations in patients with suprasacral spinal cord injury. Objective: To investigate blood pressure (BP) and pulse rate (PR) changes during urodynamic (UD) examinations in patients with suprasacral spinal cord injury (SCI). Design: A case control study. Setting: Tertiary hospital affiliated with a medical university. Patients: Control subjects (n=22) and patients with suprasacral SCI (n=120). Interventions: Not applicable. Main Outcome Measures: Systolic (SBP) and diastolic BP (DBP) and PR before and during UD studies. Result: Healthy subjects had an average SBP change of 9.7±10.6mm Hg and a maximal SBP increase of 21mm Hg. Autonomic dysreflexia (AD) was defined as an SBP increase of 20mm Hg or more, and incidence rates were 36.7% overall, 42.6% in patients with injury level at or above T6, and 15.4% in patients with lesions below T6. Both SBP and DBP changes in patients with SCI showed significant negative correlations with injury levels (r=−.383 and −.315; P<.05). The BP increase was more significant in patients with SCI who had detrusor sphincter dyssynergia (DSD), especially the continuous type, or severely impaired bladder compliance than in those who did not. Most patients (75%) had no significant PR changes (within 10beats/min) during AD responses and only 22.7% had a decrease of 10beats/min or more. Patients younger than 50 years had a greater PR decrease than those 50 years or older (−7.1±9.0 vs 0.7±11.4 beats/min; P<.05). Conclusions: AD occurred not only in patients with lesions above T6, but also in those with lower lesion levels. Patients with higher injury level, continuous DSD, or a poorly compliant bladder had greater SBP changes during UD studies. During AD reactions, younger patients tended to have a greater PR decrease than older patients. [Copyright &y& Elsevier]

Abstract: Chen S-L, Bih L-I, Chen G-D, Huang Y-H, You Y-H, Lew HL. Transrectal ultrasound–guided transperineal botulinum toxin A injection to the external urethral sphincter for treatment of detrusor external sphincter dyssynergia in patients with spinal cord injury. Objective: To evaluate the effects of a single transrectal ultrasound (TRUS)–guided transperineal injection of botulinum toxin A (BTX-A) to the external urethral sphincter (EUS) for treating detrusor external sphincter dyssynergia (DESD). Design: Descriptive study. Setting: Rehabilitation hospital affiliated with a medical university. Participants: Patients (N=18) with suprasacral spinal cord injury who had DESD confirmed on video-urodynamic study. Interventions: A single dose of 100U BTX-A was applied into the EUS via TRUS-guided transperineal route injection. Main Outcome Measures: Maximal detrusor pressure, detrusor leak-point pressure, integrated electromyography (iEMG), maximal pressure on static urethral pressure profilometry, and postvoiding residuals. Results: There were significant reductions in iEMG (P=.008) and static (P=.012) and dynamic urethral pressure (P=.023), but not in detrusor pressure and detrusor leak-point pressure after treatment. Postvoiding residuals also significantly decreased in the first and second month after treatment (P<.012). Conclusions: TRUS-guided transperineal injection of BTX-A has beneficial effects in treating DESD. [Copyright &y& Elsevier]

It has been widely reported that ketamine rescues chronic stress-induced depression-like behavior, but the underlying cellular mechanisms of the rapid antidepressant actions of ketamine remain largely unclear. Both male and female Sprague-Dawley rats were used and received modified learned helplessness paradigm to induce depression-like behavior. Depression-like behavior was assayed and manipulated using forced swim tests, sucrose preference tests and pharmacological microinjection. We conducted whole-cell patch-clamp electrophysiological recordings in the midbrain ventrolateral periaqueductal gray (vlPAG) neurons. Surface and cytosolic glutamate receptor 1 (GluR1) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression were analyzed using Western blotting. Phosphorylated GluR1 expression was quantified using Western blotting analysis. The results showed that a single systemic administration of a ketamine metabolite (2R,6R)-hydroxynorketamine (2R,6R-HNK) rapidly rescued chronic stress-induced depression-like behavior and persisted for up to 21 days. Consistently, the chronic stress-induced diminished glutamatergic transmission and surface GluR1 expression in the vlPAG were also reversed by a single systemic injection of (2R,6R)-HNK. Furthermore, bath application of (2R,6R)-HNK increased the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) in the vlPAG. Further evidence for the antidepressant action of (2R,6R)-HNK is provided by the finding that microinjection of (2R,6R)-HNK into the vlPAG exhibited a rapid-acting and long-lasting antidepressant effect. This antidepressant effect of (2R,6R)-HNK was prevented by the intra-vlPAG microinjection of AMPA receptor antagonist CNQX. Together, the current results provide evidence that (2R,6R)-HNK rescues chronic stress-induced depression-like behavior with rapid-acting and long-lasting antidepressant effects through enhancement of AMPA receptor-mediated transmission in the vlPAG. [ABSTRACT FROM AUTHOR]

Histone deacetylase 4 (HDAC4), which actively shuttles between the nucleus and cytoplasm, is an attractive candidate for a repressor mechanism in epigenetic modification. However, the potential role of HDAC4-dependent epigenetics in the neural plasticity underlying the development of inflammatory pain has not been well established. By injecting complete Freund's adjuvant (CFA) into the hind-paw of Sprague-Dawley rats (200–250 g), we found animals displayed behavioral hyperalgesia was accompanied with HDAC4 phosphorylation and cytoplasmic redistribution in the dorsal horn neurons. Cytoplasmic HDAC4 retention led to its uncoupling with the COX2 promoter, hence prompting spinal COX2 transcription and expression in the dorsal horn. Moreover, the GluN2B-bearing N-methyl- d -aspartate receptor (GluN2B-NMDAR)/calmodulin-dependent protein kinase II (CaMKII) acted as an upstream cascade to facilitate HDAC4 phosphorylation/redistribution-associated spinal COX2 expression after inflammatory insults. The results of this pilot study demonstrated that the development and/or maintenance of inflammatory pain involved the spinal HDAC4-dependent epigenetic mechanisms. Our findings open up a new avenue for the development of a novel medical strategy for the relief of inflammatory pain. [ABSTRACT FROM AUTHOR]

Abstract: The extracellular signal-regulated kinase (ERK) cascades are suggested to contribute to excitatory plasticity in the CNS, including the spinal cord. This study investigated whether the ERK involves in the repetitive stimulation-induced spinal reflex potentiation (SRP) in the pelvic nerve-to-external urethra sphincter reflex activities. External urethra sphincter electromyogram in response to pelvic afferent nerve test stimulation (TS, 1/30Hz) or repetitive stimulation (RS, 1Hz) was recorded in anesthetized rats. TS evoked a baseline reflex activity, whereas RS produced SRP in associated with significant ERK 1/2 phosphorylation. RS-induced SRP and ERK 1/2 phosphorylation were both abolished by pretreatment of U0126 (MEK inhibitor). Intrathecal CNQX (AMPA receptor antagonist) attenuated, while AP5 (NMDA receptor antagonist) abolished the RS-induced SRP and ERK 1/2 phosphorylation. Pretreated U0126 abolished the SRP elicited by glutamatergic agonists including glutamate, NMDA and AMPA. Intrathecal H89 and BIS7 (PKA and PKC inhibitors, respectively) both abolished the RS- and glutamate agonist-induced SRP as well as ERK 1/2 phosphorylation. In addition, forskolin and PMA (PKA and PKC activator, respectively) induced SRP, which were both abolished by pretreated U0126. Saline distension, mimicking the storage phase of the urinary bladder, induced SRP and ERK 1/2 phosphorylation. In conclusion, activated ERK 1/2 may produce SRP in the pelvic nerve-to-external urethra sphincter reflex activity, which is essential for urine continence. In addition, blockage of spinal ERK 1/2 activation decreases the physiological function of the urethra, indicating that phosphorylation of the ERK 1/2 cascade may represent a novel target for the treatment of patients with neurological incontinence of spinal origin. [Copyright &y& Elsevier]

Objectives: Prevalence studies show that nocturia is a very common condition, affecting older age groups in particular. In this study, we evaluate (1) the community-based prevalence of nocturia and its associated overactive bladder according to the patient’s perception and disturbance to sleep and (2) whether age or menopausal (MP) transition has a greater effect on the occurrence of nocturia. Methods: The questions regarding nocturia were part of the Bristol female lower urinary tract symptoms questionnaire (translated into Mandarin, the correlation coefficient r=0.91). A total of 1253 (79.1% response rate) women were randomly sampled from a community-based female population, aged 20 years or older. Samples were subdivided into reproductive age, perimenopausal stage and elderly. If the participants reported having nocturia, they were further questioned with, “Does it interfere with your sleep or bother your daily life?” The chi-square test and the Cochran–Armitage trend test were used to analyze the data. Results: Nocturia in older age groups was significantly higher than that of the younger age groups. The occurrence of nocturia was significantly associated with the elderly (compared with the reproductive age, P<0.05). There were no significant differences in the prevalence of nocturia between the perimenopausal stage and the reproductive age (P>0.05). Conclusions: Our data implies that the increasing occurrence of nocturia is age-related and is not affected by the transition from pre- to postmenopause. Large-scale prospective longitudinal studies need to be conducted to clarify the effects of the aging process and estrogen deficiency. [Copyright &y& Elsevier]