Nitric oxide synthase contributes to the maintenance of LTP in the oxytocin-mRFP1 neuron of the rat hypothalamus.

Oxytocin (OXT) is a neuropeptide hormone that plays a critical role in nociception. Long-term potentiation (LTP) is a major form of synaptic plasticity in the central nervous system. Recently, LTP has been reported in the hypothalamus; however, data on LTP in hypothalamic OXT-ergic neurons are unclear. Furthermore, the signaling pathways for hypothalamic OXT-ergic neuronal LTP and its physiological significance remain unknown. Herein, we aimed to investigate the induction of hypothalamic OXT-ergic neuronal LTP and its synaptic mechanism using OXT-monomeric red fluorescent protein 1 transgenic rats to visualize and record from OXT-ergic neurons. The hypothalamic paraventricular nucleus (PVN) OXT-ergic neuronal LTP induced by the pairing protocol was dependent on N-methyl-D-aspartate receptor (NMDAR). Furthermore, nitric oxide synthase (NOS) is required to maintain the LTP regardless of the NMDARs. In addition, hypothalamic OXT-ergic neuronal LTP was not induced in the adjuvant arthritis rat model but increased excitatory postsynaptic currents were detected. LTP in hypothalamic OXT-ergic neurons in the PVN in the presence of NOS may be involved in neuronal changes during OXT synthesis in chronic inflammation.

Chemogenetic Activation of Oxytocin Neurons Improves Pain in a Reserpine-induced Fibromyalgia Rat Model.

Fibromyalgia (FM) is a syndrome characterized by chronic pain with depression as a frequent comorbidity. However, efficient management of the pain and depressive symptoms of FM is lacking. Given that endogenous oxytocin (OXT) contributes to the regulation of pain and depressive disorders, herein, we investigated the role of OXT in an experimental reserpine-induced FM model. In FM model, OXT-monomeric red fluorescent protein 1 (OXT-mRFP1) transgenic rats exhibited increased depressive behavior and sensitivity in a mechanical nociceptive test, suggesting reduced pain tolerance. Additionally, the development of the FM-like phenotype in OXT-mRFP1 FM model rats was accompanied by a significant reduction in OXT mRNA expression in the magnocellular neurons of the paraventricular nucleus. OXT-mRFP1 FM model rats also had significantly fewer tryptophan hydroxylase (TPH)- and tyrosine hydroxylase (TH)-immunoreactive (ir) neurons as well as reduced serotonin and norepinephrine levels in the dorsal raphe and locus coeruleus. To investigate the effects of stimulating the endogenous OXT pathway, rats expressing OXT-human muscarinic acetylcholine receptor (hM3Dq)-mCherry designer receptors exclusively activated by designer drugs (DREADDs) were also assessed in the FM model. Treatment of these rats with clozapine-N-oxide (CNO), an hM3Dq-activating drug, significantly improved characteristic FM model-induced pathophysiological pain, but did not alter depressive-like behavior. The chemogenetically induced effects were reversed by pre-treatment with an OXT receptor antagonist, confirming the specificity of action via the OXT pathway. These results indicate that endogenous OXT may have analgesic effects in FM, and could be a potential target for effective pain management strategies for this disorder.

Upregulation of the hypothalamo-neurohypophysial system and activation of vasopressin neurones attenuates hyperalgesia in a neuropathic pain model rat.

Arginine vasopressin (AVP) is a hypothalamic neurosecretory hormone well known as an antidiuretic, and recently reported to be involved in pain modulation. The expression kinetics of AVP and its potential involvement in the descending pain modulation system (DPMS) in neuropathic pain (NP) remains unclear. We investigated AVP expression and its effects on mechanical and thermal nociceptive thresholds using a unilateral spinal nerve ligation (SNL) model. All rats with SNL developed NP. Intensities of enhanced green fluorescent protein (eGFP) in the supraoptic and paraventricular nuclei, median eminence, and posterior pituitary were significantly increased at 7 and 14 days post-SNL in AVP-eGFP rats. In situ hybridisation histochemistry revealed significantly increased AVP mRNA expression at 14 days post-SNL compared with the sham control group. The chemogenetic activation of AVP neurones significantly attenuated mechanical and thermal hyperalgesia with elevated plasma AVP concentration. These analgesic effects were suppressed by pre-administration with V1a receptor antagonist. AVP neurones increased the neuronal activity of serotonergic dorsal raphe, noradrenergic locus coeruleus, and inhibitory interneurones in the spinal dorsal horn. These results suggest that the hypothalamo-neurohypophysial system of AVP is upregulated in NP and activated endogenous AVP exerts analgesic effects via the V1a receptors. AVP neurones may activate the DPMS.

Disturbance of osteonal bone remodeling and high tensile stresses on the lateral cortex in atypical femoral fracture after long-term treatment with Risedronate and Alfacalcidol for osteoporosis.

An 83 year-old Japanese woman complained of left lateral thigh pain following a low-energy fall 4 months prior to admission. She had been treated for osteoporosis with Risedronate and Alfacalcidol for the previous five years. She was diagnosed with an atypical femoral fracture (AFF) according to the American Society for Bone and Mineral Research (ASBMR) Task Force revised criteria. Radiographs revealed cortical thickening and a transverse radiolucent fracture line in the lateral cortex of the shaft. MRI showed a high intensity signal on the T2WI image 1 cm long in the lateral cortex. The patient had normal levels of bone resorption and formation biomarkers except for low 25(OH) Vitamin D. Double fluorescent labeling was done preoperatively. Due to significant bowing, a corrective osteotomy and intramedullary nailing were performed, and the resected bone wedge was analyzed by bone histomorphometry. Three ground sections of the lateral cortex at the fracture site showed many and large pores, with or without tetracycline labeling. Histomorphometric assessment was done on intracortical pores, classified by a novel criteria, only to assess size of the pores to know prolonged osteoclastic activity and its characteristics of inner surfaces to assess whether bone formation has been occurring or not in labeling period in remodeling cycle, and coalition of multi-pores. Increased size with widespread variation of pores suggested prolonged osteoclastic activity in the reversal/resorptive phase. Bone labeling showed lamellar bone on the endocortical surface. We hypothesize that the case had developed from a regional disturbance of osteonal remodeling in the lateral cortex, in which accumulated microcracks might have initiated a resorption process resulting in resorption cavities, i.e., pores, which became larger due to prolonged activity of secondary osteoclasts. Various sized pores could form lamellar bone, still forming at the time of biopsy, some had formed lamellar bone, but stopped to form before labeling and not to start to form at all, probably due to incomplete coupling. Endocortical lamellar bone might had started to resorbed to smooth off endocortical surface, followed by formation of lamellar bone. The endocortical bone formation was assessed and its formation period is about 2.7 years. A finite element analysis using preoperative CT data revealed high tensile stresses on the lateral aspect of the femur. Histomorphometric results suggest that there might be more pores in the tensile area than the compressive area. These findings may subsequently connect accumulation of microcracks, an increase of size and number of pores and coalition and subsequent fracture in the lateral cortex.

Heat hypersensitivity is attenuated with altered expression level of spinal astrocytes after sciatic nerve injury in TRPV1 knockout mice.

Transient receptor potential vanilloid 1 (TRPV1) modulates pain. Studies have indicated that TRPV1 is upregulated in the spinal dorsal horn in the neuropathic pain model, but its mechanism is unknown. Here, we examined the mechanism by which TRPV1 modulates neuropathic pain by employing partial sciatic nerve ligation (pSNL) in adult male C57BL/6 J (wild-type: WT) and TRPV1 knockout (Trpv1-/-) mice. We analyzed mechanical/heat sensitivities (von Frey test/hot plate test) and glial/neuronal activities (Iba-1/GFAP/FosB by immunofluorescence) in laminae I and II in the L5 ipsilateral dorsal horn of the spinal cord. Mechanical/heat sensitivities, expression levels of microglial Iba-1 and astrocytic GFAP, and the number of FosB-positive neurons were significantly increased on days 7 and 14 in the pSNL group compared with the sham-operated and non-operated groups of both WT and Trpv1-/- mice. While mechanical sensitivity was comparable between WT and Trpv1-/- mice, the threshold against heat sensitivity was markedly prolonged in Trpv1-/- than WT mice on day 14 after pSNL. Conversely, the increment of FosB positive neurons was significantly attenuated in Trpv1-/- than WT mice on days 7 and 14 after pSNL. These results suggest that TRPV1 may modulate thermal perception via increased astrocytes in the dorsal horn of the spinal cord.

Candidal Prosthetic Hip Infection in a Patient with Previous Candidal Sepsis - A Case Report.

A 60 year-old woman with hip dysplasia battled with duodenal cancer that was complicated with Candida tropicalis sepsis. Two years later, the patient underwent a total hip arthroplasty (THA). She complained of a persisting low-grade fever and local heat on the THA scar. Arthrocentesis of the hip was performed and the Candida tropicalis was detected. Debridement and polyethylene liner/modular head exchange were performed 28 days after the primary THA. Fluconazole was administrated for one year. The patient reported no symptoms five years later. It was found that periprosthetic infection could be prevented by implant preservation surgery.

The neurohypophysial oxytocin and arginine vasopressin system is activated in a knee osteoarthritis rat model.

Osteoarthritis (OA) causes chronic joint pain and significantly impacts daily activities. Hence, developing novel treatment options for OA has become an increasingly important area of research. Recently, studies have reported that exogenous, as well as endogenous, hypothalamic-neurohypophysial hormones, oxytocin (OXT) and arginine-vasopressin (AVP), significantly contribute to nociception modulation. Moreover, the parvocellular OXT neurone (parvOXT) extends its projection to the superficial spinal dorsal horn, where it controls the transmission of nociceptive signals. Meanwhile, AVP produced in the magnocellular AVP neurone (magnAVP) is released into the systemic circulation where it contributes to pain management at peripheral sites. The parvocellular AVP neurone (parvAVP), as well as corticotrophin-releasing hormone (CRH), suppresses inflammation via activation of the hypothalamic-pituitary adrenal (HPA) axis. Previously, we confirmed that the OXT/AVP system is activated in rat models of pain. However, the roles of endogenous hypothalamic-neurohypophysial hormones in OA have not yet been characterised. In the present study, we investigated whether the OXT/AVP system is activated in a knee OA rat model. Our results show that putative parvOXT is activated and the amount of OXT-monomeric red fluorescent protein 1 positive granules in the ipsilateral superficial spinal dorsal horn increases in the knee OA rat. Furthermore, both magnAVP and parvAVP are activated, concurrent with HPA axis activation, predominantly modulated by AVP, and not CRH. The OXT/AVP system in OA rats was similar to that in systemic inflammation models, including adjuvant arthritis; however, magnocellular OXT neurones (magnOXT) were not activated in OA. Hence, localised chronic pain conditions, such as knee OA, activate the OXT/AVP system without impacting magnOXT.

Presynaptic glutamatergic transmission and feedback system of oxytocinergic neurons in the hypothalamus of a rat model of adjuvant arthritis.

The neurohypophysial hormone oxytocin (OXT) is synthesized in the hypothalamic paraventricular and supraoptic nuclei. Recently, some studies have considered OXT to be important in sensory modulation and that the OXT protein is upregulated by acute and chronic nociception. However, the mechanism by which OXT is upregulated in neurons is unknown. In this study, we examined the resting membrane potentials and excitatory postsynaptic currents in OXT-ergic neurons in the paraventricular nucleus in adjuvant arthritis rat model, a model of chronic inflammation, using whole-cell patch-clamping. Transgenic rats expressing OXT and monomeric red fluorescent protein 1 (mRFP1) fusion protein to visualize the OXT-ergic neurons were used, and the OXT-mRFP1 transgenic rat model of adjuvant arthritis was developed by injection of heat-killed Mycobacterium butyricum. Furthermore, the feedback system of synthesized OXT was also examined using the OXT receptor antagonist L-368,899. We found that the resting membrane potentials and frequency of miniature excitatory postsynaptic currents and spontaneous excitatory postsynaptic currents in OXT-monomeric red fluorescent protein 1 neurons in the paraventricular nucleus were significantly increased in adjuvant arthritis rats. Furthermore, L-368,899 dose-dependently increased the frequency of miniature excitatory postsynaptic currents and spontaneous excitatory postsynaptic currents in OXT-ergic neurons. Following bath application of the GABAA receptor antagonist picrotoxin and the cannabinoid receptor 1 antagonist AM 251, L-368,899 still increased the frequency of miniature excitatory postsynaptic currents. However, following bath application of the nitric oxide synthase inhibitor Nω-Nitro-L-arginine methyl ester hydrochloride, L-368,899 did not alter the miniature excitatory postsynaptic current frequency. Thus, it is suggested that OXT-ergic neuron activity is upregulated via an increase in glutamate release, and that the upregulated OXT neurons have a feedback system with released endogenous OXT. It is possible that nitric oxide, but not GABA, may contribute to the feedback system of OXT neurons in chronic inflammation.

Transient receptor potential vanilloid 1 and 4 double knockout leads to increased bone mass in mice.

Calcium balance is important in bone homeostasis. The transient receptor potential vanilloid (TRPV) channel is a nonselective cation channel permeable to calcium and is activated by various physiological and pharmacological stimuli. TRPV1 and TRPV4, in particular, have important roles in intracellular Ca2+ signaling and extracellular calcium homeostasis in bone cells. TRPV1 and TRPV4 separately mediate osteoclast and osteoblast differentiation, and deficiency in any of these channels leads to increased bone mass. However, it remains unknown whether bone mass increases in the absence of both TRPV1 and TRPV4. In this study, we used TRPV1 and TRPV4 double knockout (DKO) mice to evaluate their bone mass in vivo, and osteoclast and osteoblast differentiation in vitro. Our results showed that DKO mice and wild type (WT) mice had no significant difference in body weight and femur length. However, the results of dual-energy X-ray absorption, microcomputed tomography, and bone histomorphometry clearly showed that DKO mice had higher bone mass than WT mice. Furthermore, DKO mice had less multinucleated osteoclasts and had lower bone resorption. In addition, the results of cell culture using flushed bone marrow from mouse femurs and tibias showed that osteoclast differentiation was suppressed, whereas osteoblast differentiation was promoted in DKO mice. In conclusion, our results suggest that the increase in bone mass in DKO mice was induced not only by the suppression of osteoclast differentiation and activity but also by the augmentation of osteoblast differentiation and activity. Our findings reveal that both the single deficiency of TRPVs and the concurrent deficiency of TRPVs result in an increase in bone mass. Furthermore, our data showed that DKO mice and single KO mice had varying approaches to osteoclast and osteoblast differentiation in vitro, and therefore, it is important to conduct further studies on TRPVs regarding the increase in bone mass to explore not only individual but also a combination of TRPVs.

Acute Mono-Arthritis Activates the Neurohypophysial System and Hypothalamo-Pituitary Adrenal Axis in Rats.

Various types of acute/chronic nociceptive stimuli cause neuroendocrine responses such as activation of the hypothalamo-neurohypophysial [oxytocin (OXT) and arginine vasopressin (AVP)] system and hypothalamo-pituitary adrenal (HPA) axis. Chronic multiple-arthritis activates the OXT/AVP system, but the effects of acute mono-arthritis on the OXT/AVP system in the same animals has not been simultaneously evaluated. Further, AVP, not corticotropin-releasing hormone (CRH), predominantly activates the HPA axis in chronic multiple-arthritis, but the participation of AVP in HPA axis activation in acute mono-arthritis remains unknown. Therefore, we aimed to simultaneously evaluate the effects of acute mono-arthritis on the activity of the OXT/AVP system and the HPA axis. In the present study, we used an acute mono-arthritic model induced by intra-articular injection of carrageenan in a single knee joint of adult male Wistar rats. Acute mono-arthritis was confirmed by a significant increase in knee diameter in the carrageenan-injected knee and a significant decrease in the mechanical nociceptive threshold in the ipsilateral hind paw. Immunohistochemical analysis revealed that the number of Fos-immunoreactive (ir) cells in the ipsilateral lamina I-II of the dorsal horn was significantly increased, and the percentage of OXT-ir and AVP-ir neurons expressing Fos-ir in both sides of the supraoptic (SON) and paraventricular nuclei (PVN) was increased in acute mono-arthritic rats. in situ hybridization histochemistry revealed that levels of OXT mRNA and AVP hnRNA in the SON and PVN, CRH mRNA in the PVN, and proopiomelanocortin mRNA in the anterior pituitary were also significantly increased in acute mono-arthritic rats. Further, plasma OXT, AVP, and corticosterone levels were significantly increased in acute mono-arthritic rats. These results suggest that acute mono-arthritis activates ipsilateral nociceptive afferent pathways at the spinal level and causes simultaneous and integrative activation of the OXT/AVP system. In addition, the HPA axis is activated by both AVP and CRH in acute mono-arthritis with a distinct pattern compared to that in chronic multiple-arthritis.

Neuropathic Pain Up-Regulates Hypothalamo-Neurohypophysial and Hypothalamo-Spinal Oxytocinergic Pathways in Oxytocin-Monomeric Red Fluorescent Protein 1 Transgenic Rat.

Despite the high incidence of neuropathic pain, its mechanism remains unclear. Oxytocin (OXT) is an established endogenous polypeptide produced in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus. OXT, which is synthesized by OXT neurons in the SON and the magnocellular part of the PVN (mPVN), is delivered into the posterior pituitary (PP), then released into the systemic blood circulation. Meanwhile, OXT-containing neurosecretory cells in the parvocellular part of the PVN (pPVN) are directly projected to the spinal cord and are associated with sensory modulation. In this study, the OXT system in the hypothalamo-neurohypophysial and hypothalamo-spinal pathway was surveyed using a rat neuropathic pain model induced by partial sciatic nerve ligation (PSL). In the present study, we used transgenic rats expressing an OXT-monomeric red fluorescent protein 1 (mRFP1) fusion gene. In a neuropathic pain model, mechanical allodynia was observed, and glial cell activation was also confirmed via immunohistochemistry. In this neuropathic pain model, a significant increase in the OXT-mRFP1 expression was observed in the PP, the SON, mPVN, and pPVN. Furthermore, OXT-mRFP1 granules with positive fluorescent reaction were remarkably increased in laminae I and II of the ipsilateral dorsal horn. Although the plasma concentrations of OXT did not significantly change, a significant increase of the mRNA levels of OXT and mRFP1 in the SON, mPVN, and pPVN were observed. These results suggest that neuropathic pain induced by PSL upregulates hypothalamic OXT synthesis and transportation to the OXTergic axon terminals in the PP and spinal cord.

Role of Trpv1 and Trpv4 in surgical incision-induced tissue swelling and Fos-like immunoreactivity in the central nervous system of mice.

Pain management remains a major concern regarding the treatment of postoperative patients. Transient receptor potential (TRP) channels are considered to be new therapeutic targets for pain control. We investigated whether the genes Trpv1 and Trpv4 are involved in hind paw swelling caused after surgical incision in mice or in incision-induced Fos-like immunoreactivity (Fos-LI) levels in the central nervous system. Mice were divided into four groups: wild-type (WT) control, WT incision, Trpv1 knockout (Trpv1-/-) incision, and Trpv4 knockout (Trpv4-/-) incision. Mice were anesthetized, and only those in the incision, and not control, groups received a surgical incision to their right plantar hind paw. Changes in paw diameter and in Fos-LI levels in the dorsal horn of the spinal cord, paraventricular nucleus of the hypothalamus (PVN), paraventricular nucleus of the thalamus, and central amygdala were evaluated 2 h after the incision. There was no significant difference in the paw diameter among groups. In contrast, in laminae I-II of the dorsal horn of the spinal cord and PVN, Fos-LI was significantly higher in all incision groups than in the WT control group. A significant increase in Fos-positive cells was also observed in the dorsal horn laminae III-IV in Trpv1-/- and Trpv4-/- incision groups compared with the WT incision group. Our results indicate that surgical incision activates the PVN and that Trpv1 and Trpv4 might be involved in neuronal activity in the dorsal horn laminae III-IV after surgical incision.

Highly Cross-Linked Polyethylene Reduces Osteolysis Incidence and Wear-Related Reoperation Rate in Cementless Total Hip Arthroplasty Compared With Conventional Polyethylene at a Mean 12-Year Follow-Up.

BACKGROUND: A number of studies on total hip arthroplasty have compared highly cross-linked polyethylene (HXLPE) with conventional polyethylene (CPE) liners beyond 10 years. However, the impact of HXLPE on the wear-related reoperation rate is unclear. The purpose of this study was to evaluate the clinical advantage of using a single manufacturer's HXLPE in terms of reducing the reoperation rate. METHODS: The study was a follow-up retrospective cohort study over a mean of 12 years that examined patients aged 45-70 years with cementless total hip arthroplasty using a 26-mm-diameter cobalt-chromium head. Sixty-seven patients (79 hips; HXLPE group = 41 hips, CPE group = 38 hips) were evaluated for a minimum 10-year follow-up. Kaplan-Meier survival analysis was performed, with wear-related reoperations and radiographic osteolysis serving as the end points. The polyethylene wear rate was also assessed. RESULTS: The mean 12-year follow-up rates of survivorship that were evaluated using wear-related reoperations as the end point were 100% and 91.4% in the HXLPE and CPE groups, respectively (P = .007), and the mean 12-year follow-up rates of survivorship with osteolysis as the end point were 100% and 36.2%, respectively (P < .001). Compared with the CPE group, the HXLPE group presented a significantly reduced wear rate (HXLPE group, 0.035 mm/y; CPE group, 0.118 mm/y). CONCLUSION: A unique strength of this study is that we assessed a single manufacturer's HXLPE while keeping most other implant parameters uniform. This study reveals the clinical advantage of using a single manufacturer's HXLPE in terms of a reduced wear-related reoperation rate at a mean 12-year follow-up.

Comparison of the induction of c-fos-eGFP and Fos protein in the rat spinal cord and hypothalamus resulting from subcutaneous capsaicin or formalin injection.

We evaluated whether a c-fos-enhanced green fluorescent protein (eGFP) transgenic rat line, which expresses the c-fos and eGFP fusion gene, can be useful for the study of nociceptive pathways and processing. Capsaicin solution (15%) or formalin (5%) was subcutaneously injected bilaterally into the hind paws (100µL per each paw) of adult male c-fos-eGFP transgenic or wild-type rats. Control rats were injected with ethanol or physiological saline respectively. Transgenic and wild-type rats were perfused at 1.5, 3 and 6h post injection, with some transgenic rats being perfused 24h post injection. A comparison of eGFP in transgenic rats and Fos-like immunoreactivity (LI) in wild-type rats was made in the dorsal spinal cord, paraventricular nucleus (PVN) and supraoptic nucleus (SON). Oxytocin-LI (OXT-LI) was carried out to examine the activation of OXT neurons in the PVN and SON. Following capsaicin or formalin treatment, eGFP was maximally expressed at 6h in the spinal cord and 3h in the PVN and SON, whereas, Fos-LI was maximally expressed at 1.5h in all the regions we analyzed. Induction of eGFP in the OXT neurons was observed after capsaicin or formalin treatment, while Fos-LI in the OXT neurons was observed only after formalin treatment. These results demonstrate that the peak induction of c-fos-eGFP following exposure to acute nociceptive stimuli was delayed by around 1.5-4.5h, but more sensitive than endogenous Fos, suggesting that the c-fos-eGFP rat line can be useful for the study of nociceptive pathways and processing.

Fifteen-Year Comparison of Wear and Osteolysis Analysis for Cross-Linked or Conventional Polyethylene in Cementless Total Hip Arthroplasty for Hip Dysplasia-A Retrospective Cohort Study.

BACKGROUND: Cross-linked polyethylene (XLPE) acetabular liners used in cementless total hip arthroplasty (THA) have demonstrated better wear resistance at 10 years compared with conventional polyethylene (CPE) liners. No clinical studies have compared XPLE to CPE liners beyond 10 years. METHODS: We performed a 15-year retrospective cohort study on cementless THA performed in patients with developmental hip dysplasia to measure the differences in polyethylene wear rates and the presence of osteolysis. Twenty-four THAs with XLPE and 17 THAs with CPE were evaluated. The mean age of patients was 55.9 years (41-68) in the XLPE group and 54.4 years (40-67) in the CPE group. The mean follow-up period was 15.1 years (13.9-16.1) in the XLPE group and 15.2 years (14.5-16.0) in the CPE group. RESULTS: The XLPE group had a significantly lower wear rate at 5 and 10 years compared with the CPE group; however, no significant difference was found at 15 years (XLPE group, 0.040 mm/y; CPE group, 0.034 mm/y). In addition, the incidence of osteolysis did not differ significantly between the groups. However, the incidence of excessive wear between 10 and 15 years after surgery in the XLPE group was significantly higher than that in the CPE group. CONCLUSION: XLPE demonstrated no advantage in the wear rate or the incidence of osteolysis at 15 years, despite having superior wear resistance up to 10 years. It is concerning that the incidence of excessive wear was higher in the XLPE group between 10 and 15 years, and this finding should alert the arthroplasty community to this possible problem with the more highly cross-linked polyethylene.

Relationship Between Oxytocin and Pain Modulation and Inflammation.

Oxytocin (OXT), which is a well-known neurohypophysial hormone that is synthesized in the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus, is secreted from the posterior pituitary (PP) into the systemic circulation, where it plays an essential role in reproduction, especially during and after childbirth. Many recent studies have shown that OXT contributes to the modulation of several functions, such as social recognition, trust building, anti-nociception, anti-inflammation, stress relief and suppression of feeding. However, little is known about the neuronal networks responsible for OXT effects. Endogenious OXT has two regulations: the 1st regulation is humoral regulation, in which OXT is delivered to target organs from PP via the bloodstream; the 2nd regulation is nerve regulations, in which OXT from parvocellular neurosecretory neurons in the PVN directly project to the central nerve system (CNS). OXT binding sites, as well as OXT receptor expression, are located in various regions of the CNS, including the dorsal horn of spinal cord in rats, where it plays an important role in nociception. We examined the response to acute and chronic nociception/-inflammation in rat models using OXT-monomeric red fluorescent protein 1 (mRFP1) transgenic rats. We used formalin test as acute nociceptive/-inflammatory rat models and adjuvant arthritis as chronic nociceptive/-inflammatory rat models. We studied the effects of acute and chronic nociception/-inflammation on OXT-mRFP1 expression in the hypothalamus, posterior pituitary and spinal cord, and examined the role that OXT plays in acute and chronic nociceptive responses in rats. This review focuses on pain modulation and anti-inflammation by OXT according to previous clinical and animal research.

Effects of central administration of oxytocin-saporin cytotoxin on chronic inflammation and feeding/drinking behaviors in adjuvant arthritic rats.

An increase in the arthritis index as a marker of chronic inflammation and suppression of food intake are observed in adjuvant arthritic (AA) rats. Our previous study demonstrated that central oxytocin (OXT)-ergic pathways were activated potently in AA rats. In the present study, OXT-saporin (SAP) cytotoxin, which chemically disrupts OXT signaling was administered centrally to determine whether central OXT may be involved in the developments of chronic inflammation and alteration of feeding/drinking behavior in AA rats. The arthritis index was significantly enhanced in AA rats pretreated with OXT-SAP administered intrathecally (i.t.) but not intracerebroventricularly (i.c.v.). Suppression of food intake was significantly attenuated transiently in AA rats pretreated with OXT-SAP administered i.c.v. but not i.t. Suppression of drinking behavior was not affected by i.t. or i.c.v. administration of OXT-SAP in AA rats. In addition, intraperitoneal administration of an OXT receptor antagonist did not change the arthritis index or feeding/drinking behavior in AA rats. These results suggest that central OXT-ergic pathways may be involved in anti-inflammation at the spinal level and suppression of feeding behavior at the forebrain-brainstem level in AA rats.

Effects of peripherally administered cholecystokinin-8 and secretin on feeding/drinking and oxytocin-mRFP1 fluorescence in transgenic rats.

Peripheral administration of cholecystokinin (CCK)-8 or secretin activates oxytocin (OXT)-secreting neurons in the hypothalamus. Although OXT is involved in the regulation of feeding behavior, detailed mechanism remains unclear. In the present study, we examined the central OXTergic pathways after intraperitoneally (i.p.) administration of CCK-8 and secretin using male OXT-monomeric red fluorescent protein 1 (mRFP1) transgenic rats and male Wistar rats. I.p. administration of CCK-8 (50µg/kg) and secretin (100µg/kg) decreased food intake in these rats. While i.p. administration of CCK-8 decreased water intake, i.p. administration of secretin increased water intake. Immunohistochemical study revealed that Fos-Like-Immunoreactive cells were observed abundantly in the brainstem and in the OXT neurons in the dorsal division of the parvocellular paraventricular nucleus (dpPVN). We could observe marked increase of mRFP1 fluorescence, as an indicator for OXT, in the dpPVN and mRFP1-positive granules in axon terminals of the dpPVN OXT neurons in the nucleus tractus solitarius (NTS) after i.p. administration of CCK-8 and secretin. These results provide us the evidence that, at least in part, i.p. administration of CCK-8 or secretin might be involved in the regulation of feeding/drinking via a OXTergic pathway from the dpPVN to the NTS.

Possible involvement of TRPV1 and TRPV4 in nociceptive stimulation- induced nocifensive behavior and neuroendocrine response in mice.

Members of the transient receptor potential (TRP) family of ion channels play important roles in inflammation and pain. Here, we showed that both TRPV1 and TRPV4 might contribute to biphasic nocifensive behavior and neuroendocrine response following a formalin test. We subcutaneously injected saline, formalin, or the TRPV4 agonist, 4α-phorbol 12,13-didecanoate (4α-PDD) into one hindpaw of wild-type (WT), TRPV1-deficient (Trpv1(-/-)), and TRPV4-deficient (Trpv4(-/-)) mice to investigate nocifensive behaviors (phase I [0-10 min] and phase II [10-60 min]) and Fos expression in the dorsal horn of the spinal cord and other brain regions related to pain, in the paraventricular nucleus (PVN), paraventricular nucleus of the thalamus, the medial habenular nucleus, the medial nucleus of the amygdala and capsular part of the central amygdala. Subcutaneous (s.c.) injection of formalin caused less nocifensive behavior in Trpv1(-/-) and Trpv4(-/-) mice than in WT mice during phase I. In phase II, however, formalin induced less nocifensive behavior only in the Trpv1(-/-) mice, but not in the Trpv4(-/-) mice, relative to WT mice. The number of Fos-like immunoreactive (LI) neurons in laminae I-II of the dorsal horn increased in all types of mice 90 min after s.c. injection of formalin; however, there was no difference in the other regions between saline- and formalin-treated mice. Furthermore, s.c. injection of 4α-PDD did not induce nociceptive behavior nor influence the number of Fos-LI neurons in the all above mentioned regions in any of the mice. These results suggest that TRPV4-mediated nociceptive information from the peripheral tissue excluding the spinal pathway might be involved the formalin behavioral response during phase I. Only TRPV1 might regulate the formalin behavioral response in peripheral neuron.

A novel non-invasive mechanical technique of cup and stem placement and leg length adjustment in total hip arthroplasty for dysplastic hips.

PURPOSE: This study assessed the accuracy of cup and stem positioning and limb length adjustment for developmental dysplasia of the hip (DDH) using our new mechanical technique compared with imageless navigation or a computed tomography (CT)-based navigation system. METHODS: One hundred thirteen primary total hip arthroplasties (THAs) for DDH were evaluated. At pre-operative positioning, patients were placed in a precise lateral decubitus position by tilting the surgical table using simple ready-made devices (two shot pipe, metal chain, level gauge and goniometer). During surgery, cups were intentionally placed at 45° inclination and 15° anteversion on radiograph by using a level gauge and goniometer. RESULTS: Cup inclination was 44.2° ± 3.4° (range, 32.0-51.2°), cup anteversion was 19.6° ± 6.1° (range, 3.0-33.1°), stem alignment was 0.04° ± 0.8° valgus (range, 2.1° varus to 1.9° valgus), and leg length discrepancy was -0.37 ± 3.7 mm (range, -12.8 to 8.8 mm) in postoperative radiographs. Outliers (outside ±10° from intentional position) occurred in 15 cases (13.3 %) in inclination or anteversion. Postoperative dislocation did not occur in any cases. CONCLUSIONS: Cup and stem positioning in THAs with our new mechanical technique yielded satisfactory results compared with previously reported imageless navigation or CT-based navigation. Our results were superior with regard to being non-invasive and low cost and involving minimum radiation exposure.