Mechanisms involved in an increment of multimodal excitability of medullary and upper cervical dorsal horn neurons following cutaneous capsaicin treatment

<p>Abstract</p> <p>Background</p> <p>In order to evaluate mechanisms that may underlie the sensitization of trigeminal spinal subnucleus caudalis (Vc; the medullary dorsal horn) and upper cervical spinal cord (C1-C2) nociceptive neurons to heat, cold and mechanical stimuli following topical capsaicin treatment of the facial skin, nocifensive behaviors as well as phosphorylation of extracellular regulated-kinase (pERK) in Vc and C1-C2 neurons were studied in rats.</p> <p>Results</p> <p>Compared to vehicle application, capsaicin application to the lateral facial skin produced 1 hour later a flare in the skin, and also induced significantly greater nocifensive behaviors to heat, cold or mechanical stimulus of the lateral facial skin. The intrathecal (i.t.) injection of the MEK inhibitor PD98059 markedly attenuated the nocifensive behaviors to these stimuli in capsaicin-treated rats. Moreover, the number of pERK-like immunoreactive (pERK-LI) cells in Vc and C1-C2 was significantly larger following the heat, cold and mechanical stimuli in capsaicin-treated rats compared with vehicle-treated rats. The number of pERK-LI cells gradually increased following progressive increases in the heat or mechanical stimulus intensity and following progressive decrease in the cold stimulus. The ERK phosphorylation in Vc and C1-C2 neurons was strongly inhibited after subcutaneous injection of the capsaicin antagonist capsazepine in capsaicin-treated rats.</p> <p>Conclusion</p> <p>The present findings revealed that capsaicin treatment of the lateral facial skin causes an enhancement of ERK phosphorylation in Vc and C1-C2 neurons as well as induces nocifensive behavior to heat, cold and mechanical simulation of the capsaicin-treated skin. The findings suggest that TRPV1 receptor mechanisms in rat facial skin influence nociceptive responses to noxious cutaneous thermal and mechanical stimuli by inducing neuroplastic changes in Vc and C1-C2 neurons that involve in the MAP kinase cascade.</p

Thrombocytopenia in pegylated interferon and ribavirin combination therapy for chronic hepatitis C

BACKGROUND: This study aimed to examine the therapeutic effect and prognostic indicators of pegylated interferon (PEG-IFN) and ribavirin (RBV) combination therapy in thrombocytopenic patients with chronic hepatitis C, hepatitis C virus (HCV)-related cirrhosis, and those who underwent splenectomy or partial splenic embolization (PSE). METHODS: Of 326 patients with HCV-related chronic liver disease (252 with genotype 1b and 74 with genotype 2a/2b) treated with PEG-IFN/RBV, 90 were diagnosed with cirrhosis. RESULTS: Regardless of the degree of thrombocytopenia, the administration rate was significantly higher in the splenectomy/PSE group compared to the cirrhosis group. However, in patients with genotype 1b, the sustained virological response (SVR) rate was significantly lower in the cirrhosis and the splenectomy/PSE groups compared to the chronic hepatitis group. No cirrhotic patients with platelets less than 80,000 achieved an SVR. Patients with genotype 2a/2b were more likely to achieve an SVR than genotype 1b. Prognostic factors for SVR in patients with genotype 1b included the absence of esophageal and gastric varices, high serum ALT, low AST/ALT ratio, and the major homo type of the IL28B gene. Splenectomy- or PSE-facilitated induction of IFN in patients with genotype 2a/2b was more likely to achieve an SVR by an IFN dose maintenance regimen. Patients with genotype 1b have a low SVR regardless of splenectomy/PSE. In particular, patients with a hetero/minor type of IL28B did not have an SVR. CONCLUSIONS: Splenectomy/PSE for IFN therapy should be performed in patients expected to achieve a treatment response, considering their genotype and IL28B

Potassium channels as a potential therapeutic target for trigeminal neuropathic and inflammatory pain

Previous studies in several different trigeminal nerve injury/inflammation models indicated that the hyperexcitability of primary afferent neurons contributes to the pain pathway underlying mechanical allodynia. Although multiple types of voltage-gated ion channels are associated with neuronal hyperexcitability, voltage-gated K+ channels (Kv) are one of the important physiological regulators of membrane potentials in excitable tissues, including nociceptive sensory neurons. Since the opening of K+ channels leads to hyperpolarization of cell membrane and a consequent decrease in cell excitability, several Kv channels have been proposed as potential target candidates for pain therapy. In this review, we focus on common changes measured in the Kv channels of several different trigeminal neuropathic/inflammatory pain animal models, particularly the relationship between changes in Kv channels and the excitability of trigeminal ganglion (TRG) neurons. We also discuss the potential of Kv channel openers as therapeutic agents for trigeminal neuropathic/inflammatory pain, such as mechanical allodynia

Chronic Treatment with a Water-Soluble Extract from the Culture Medium of Ganoderma lucidum

Type 2 diabetes mellitus has been known to increase systemic oxidative stress by chronic hyperglycemia and visceral obesity and aggravate cerebral ischemic injury. On the basis of our previous study regarding a water-soluble extract from the culture medium of Ganoderma lucidum mycelia (designed as MAK), which exerts antioxidative and neuroprotective effects, the present study was conducted to evaluate the preventive effects of MAK on apoptosis and necroptosis (a programmed necrosis) induced by hypoxia/ischemia (H/I) in type 2 diabetic KKAy mice. H/I was induced by a combination of unilateral common carotid artery ligation with hypoxia (8% O2 for 20 min) and subsequent reoxygenation. Pretreatment with MAK (1 g/kg, p.o.) for a week significantly reduced H/I-induced neurological deficits and brain infarction volume assessed at 24 h of reoxygenation. Histochemical analysis showed that MAK significantly suppressed superoxide production, neuronal cell death, and vacuolation in the ischemic penumbra, which was accompanied by a decrease in the numbers of TUNEL- or cleaved caspase-3-positive cells. Furthermore, MAK decreased the expression of receptor-interacting protein kinase 3 mRNA and protein, a key molecule for necroptosis. These results suggest that MAK confers resistance to apoptotic and necroptotic cell death and relieves H/I-induced cerebral ischemic injury in type 2 diabetic mice

頚椎症性脊髄症症例における頚椎アライメント評価 : 坐位頚椎レントゲンと立位全脊椎レントゲンは等しく有用か?

Study Design: Retrospective review of medical charts and radiographic data. Objectives: We aimed to clarify the differences in cervical alignment findings between sitting cervical lateral radiographs and standing whole-spine lateral radiographs with clavicle positioning in cervical spondylotic myelopathy (CSM) patients. Methods: We retrospectively evaluated the radiographs of 50 consecutive patients who underwent cervical surgery for CSM in our hospital. Cervical sagittal alignment was evaluated based on the C0-2 angles and C2-7 Gore and Cobb angles. Head position was evaluated in terms of the center of gravity of the head to C7 (CGH-C7) angle and the McGregor angle (ie, the angle between the McGregor line and a horizontal line). The T1-slope was also evaluated. Results: The mean values of the CGH-C7 angle and T1-slope were significantly lower, while the mean value of the McGregor angle was significantly higher on whole-spine lateral radiographs with clavicle positioning than on sitting cervical lateral radiographs. The mean values of the C0-2 and C2-7 angles did not differ significantly between the 2 radiographic positioning approaches. Conclusions: Using whole-spine lateral radiographs with clavicle positioning may result in a significantly lower T1-slope and a posterior tilt of the head. In the absence of a compensatory change in cervical alignment, clavicle positioning may force patients to adopt an upward gazing position of the head. These compensatory mechanisms should be considered while evaluating cervical alignment on whole-spine lateral radiographs with clavicle positioning. Surgical planning should take into account the effect of posture on the radiographic appearance of cervical alignment.博士（医学）・甲第702号・平成31年3月15日© The Author(s) 2018. Creative Commons Non Commercial No Derivs CC BY-NC-ND: This article is distributed under the terms of the Creative Commons Attribution-Non Commercial-NoDerivs 4.0 License (http://www.creativecommons.org/licenses/by-nc-nd/4.0/) which permits non-commercial use, reproduction and distribution of the work as published without adaptation or alteration, without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage)

Mechanisms involved in extraterritorial facial pain following cervical spinal nerve injury in rats

<p>Abstract</p> <p>Background</p> <p>The aim of this study is to clarify the neural mechanisms underlying orofacial pain abnormalities after cervical spinal nerve injury. Nocifensive behavior, phosphorylated extracellular signal-regulated kinase (pERK) expression and astroglial cell activation in the trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal dorsal horn (C1-C2) neurons were analyzed in rats with upper cervical spinal nerve transection (CNX).</p> <p>Results</p> <p>The head withdrawal threshold to mechanical stimulation of the lateral facial skin and head withdrawal latency to heating of the lateral facial skin were significantly lower and shorter respectively in CNX rats compared to Sham rats. These nocifensive effects were apparent within 1 day after CNX and lasted for more than 21 days. The numbers of pERK-like immunoreactive (LI) cells in superficial laminae of Vc and C1-C2 were significantly larger in CNX rats compared to Sham rats following noxious and non-noxious mechanical or thermal stimulation of the lateral facial skin at day 7 after CNX. Two peaks of pERK-LI cells were observed in Vc and C1-C2 following mechanical and heat stimulation of the lateral face. The number of pERK-LI cells in C1-C2 was intensity-dependent and increased when the mechanical and heat stimulations of the face were increased. The decrements of head withdrawal latency to heat and head withdrawal threshold to mechanical stimulation were reversed during intrathecal (i.t.) administration of MAPK/ERK kinase 1/2 inhibitor PD98059. The area of activated astroglial cells was significantly higher in CNX rats (at day 7 after CNX). The heat and mechanical nocifensive behaviors were significantly depressed and the number of pERK-LI cells in Vc and C1-C2 following noxious and non-noxious mechanical stimulation of the face was also significantly decreased following i.t. administration of the astroglial inhibitor fluoroacetate.</p> <p>Conclusions</p> <p>The present findings have demonstrated that mechanical allodynia and thermal hyperalgesia occur in the lateral facial skin after CNX and also suggest that ERK phosphorylation of Vc and C1-C2 neurons and astroglial cell activation are involved in orofacial extraterritorial pain following cervical nerve injury.</p

Alteration of primary afferent activity following inferior alveolar nerve transection in rats

<p>Abstract</p> <p>Background</p> <p>In order to evaluate the neural mechanisms underlying the abnormal facial pain that may develop following regeneration of the injured inferior alveolar nerve (IAN), the properties of the IAN innervated in the mental region were analyzed.</p> <p>Results</p> <p>Fluorogold (FG) injection into the mental region 14 days after IAN transection showed massive labeling of trigeminal ganglion (TG). The escape threshold to mechanical stimulation of the mental skin was significantly lower (i.e. mechanical allodynia) at 11-14 days after IAN transection than before surgery. The background activity, mechanically evoked responses and afterdischarges of IAN Aδ-fibers were significantly higher in IAN-transected rats than naive. The small/medium diameter TG neurons showed an increase in both tetrodotoxin (TTX)-resistant (TTX-R) and -sensitive (TTX-S) sodium currents (<it>I</it>_Na) and decrease in total potassium current, transient current (<it>I</it>_A) and sustained current (<it>I</it>_K) in IAN-transected rats. The amplitude, overshoot amplitude and number of action potentials evoked by the depolarizing pulses after 1 μM TTX administration in TG neurons were significantly higher, whereas the threshold current to elicit spikes was smaller in IAN-transected rats than naive. Resting membrane potential was significantly smaller in IAN-transected rats than that of naive.</p> <p>Conclusions</p> <p>These data suggest that the increase in both TTX-S <it>I</it>_Naand TTX-R <it>I</it>_Naand the decrease in <it>I</it>_Aand <it>I</it>_kin small/medium TG neurons in IAN-transected rats are involved in the activation of spike generation, resulting in hyperexcitability of Aδ-IAN fibers innervating the mental region after IAN transection.</p

Adaptive sampling dual terahertz comb spectroscopy using dual free-running femtosecond lasers

Terahertz (THz) dual comb spectroscopy (DCS) is a promising method for high-accuracy, high-resolution, broadband THz spectroscopy because the mode-resolved THz comb spectrum includes both broadband THz radiation and narrow-line CW-THz radiation characteristics. In addition, all frequency modes of a THz comb can be phase-locked to a microwave frequency standard, providing excellent traceability. However, the need for stabilization of dual femtosecond lasers has often hindered its wide use. To overcome this limitation, here we have demonstrated adaptive-sampling THz-DCS, allowing the use of free-running femtosecond lasers. To correct the fluctuation of the time and frequency scales caused by the laser timing jitter, an adaptive sampling clock is generated by dual THz-comb-referenced spectrum analysers and is used for a timing clock signal in a data acquisition board. The results not only indicated the successful implementation of THz-DCS with free-running lasers but also showed that this configuration outperforms standard THz-DCS with stabilized lasers due to the slight jitter remained in the stabilized lasers