Receptor activity-modifying proteins of adrenomedullin (RAMP2/3): Roles in the pathogenesis of ARDS.

Acute respiratory distress syndrome (ARDS) is a life-threatening lung condition characterized by widespread inflammation and pulmonary edema. Adrenomedullin (AM), a bioactive peptide with various functions, is expected to be applied in treating ARDS. Its functions are regulated primarily by two receptor activity-modifying proteins, RAMP2 and RAMP3, which bind to the AM receptor calcitonin receptor-like receptor (CLR). However, the roles of RAMP2 and RAMP3 in ARDS remain unclear. We generated a mouse model of ARDS via intratracheal administration of lipopolysaccharide (LPS), and analyzed the pathophysiological significance of RAMP2 and RAMP3. RAMP2 expression declined with LPS administration, whereas RAMP3 expression increased at low doses and decreased at high doses of LPS. After LPS administration, drug-inducible vascular endothelial cell-specific RAMP2 knockout mice (DI-E-RAMP2-/-) showed reduced survival, increased lung weight, and had more apoptotic cells in the lungs. DI-E-RAMP2-/- mice exhibited reduced expression of Epac1 (which regulates vascular endothelial cell barrier function), while RAMP3 was upregulated in compensation. In contrast, after LPS administration, RAMP3-/- mice showed no significant changes in survival, lung weight, or lung pathology, although they exhibited significant downregulation of iNOS, TNF-α, and NLRP3 during the later stages of inflammation. Based on transcriptomic analysis, RAMP2 contributed more to the circulation-regulating effects of AM, whereas RAMP3 contributed more to its inflammation-regulating effects. These findings indicate that, while both RAMP2 and RAMP3 participate in ARDS pathogenesis, their functions differ distinctly. Further elucidation of the pathophysiological significance and functional differences between RAMP2 and RAMP3 is critical for the future therapeutic application of AM in ARDS.

Alkalized lidocaine in a tapered cuff suppresses endotracheal tube-induced hemodynamic changes: a randomized controlled trial.

PURPOSE: The use of an endotracheal tube (ET) cuff filled with alkalized lidocaine (AL) can suppress ET-induced emergence phenomena, such as hypertension, tachycardia and coughing, and postoperative sore throat (POST) and hoarseness (PH). The efficacy of intracuff lidocaine may vary depending on the cuff shape, but there has been no study on the effects of a tapered cuff filled with AL. We examined whether intracuff AL suppresses ET-induced emergence phenomena, POST and PH. METHODS: Sixty-two patients were enrolled in this study and the patients were randomly allocated to a group in which the tapered cuff was filled with AL (Group AL) and a group in which the tapered cuff was filled with normal saline (Group S). The primary outcomes of this study were changes in mean blood pressure (MBP) and heart rate (HR) at extubation. MBP, HR and the number of coughs were recorded before and up to 10 min after extubation. The degree of POST and the incidences of POST and PH were recorded at 15 min, 2 h and 24 h after extubation. RESULTS: Changes in MBP before extubation and HR before and after extubation were significantly lower in Group AL than in Group S (p < 0.025). The number of coughs at extubation and the incidence of PH at 2 h after extubation were significantly lower in Group AL than in Group S (p < 0.0001 and p = 0.014, respectively). CONCLUSION: AL in a tapered cuff significantly suppresses ET-induced cardiovascular changes in MBP and HR.

TRPV1 is involved in abdominal hyperalgesia in a mouse model of lipopolysaccharide-induced peritonitis and influences the immune response via peripheral noradrenergic neurons.

AIMS: The transient receptor potential vanilloid subfamily 1 (TRPV1) not only plays a role as a nociceptor but also has some regulatory effects on the immune system. We investigated the effects of TRPV1 on abdominal pain and the immune system in lipopolysaccharide (LPS)-induced peritonitis and the association between TRPV1 and peripheral noradrenergic neurons. MAIN METHODS: Experiments were performed in 8- to 14-week-old male wild-type (WT) and TRPV1 knockout (KO) mice. The mice were intraperitoneally injected with a non-lethal dose of LPS. Pain assessment and investigation of changes in the immune system were performed. Denervation of sympathetic nerves and the noradrenergic splenic nerve was induced by intraperitoneal administration of 6-hydroxydopamine. KEY FINDINGS: The levels of serum cytokines were not significantly different in WT mice and TRPV1 KO mice. Abdominal mechanical hyperalgesia was greater in WT mice than in TRPV1 KO mice from 6 h to 3 days. The numbers of macrophages, neutrophils, dendritic cells, and CD4 T cells in the spleens of TRPV1 KO mice were significantly increased compared to those in WT mice 4 days after LPS administration. By noradrenergic denervation, the numbers of those cells in WT mice increased to levels comparable to those in TRPV1 KO mice. SIGNIFICANCE: In LPS-induced peritonitis, abdominal inflammatory pain was transmitted via TRPV1. In addition, TRPV1 had an anti-inflammatory effect on the spleen in the late phase of peritonitis. This anti-inflammatory effect was thought to be mediated by activation of the sympathetic nervous system and/or noradrenergic splenic nerve induced by TRPV1 activation.

A randomized, double-blinded, placebo-controlled, crossover study of the HCN channel blocker ivabradine in a capsaicin-induced pain model in healthy volunteers.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been focused on as a potential therapeutic target for inflammatory and neuropathic pain in rodent models. However, roles of HCN channels in human pain states have been scarcely investigated. We evaluated analgesic effects of 2-day administration of ivabradine, the only clinically available HCN channel blocker, on a capsaicin pain model in a randomized, double-blinded, placebo-controlled, crossover study. Twenty healthy adult subjects (18 males, 2 females) received ivabradine (5-7.5 mg) or a placebo 3 times in 2 days. Then capsaicin (0.5%) was topically applied on the volar forearm for 30 min. The primary outcome was capsaicin-induced spontaneous pain. The secondary outcomes included heat-pain threshold (HPT), flare size, and areas of secondary punctate mechanical hyperalgesia (PMH) and secondary dynamic mechanical allodynia (DMA). There was no significant difference in spontaneous pain (p = 0.7479), HPT (p = 0.7501), area of PMH (p = 0.1052) or flare size (p = 0.5650) at 30 min after capsaicin application between the groups. In contrast, the area of DMA in the ivabradine group was significantly smaller (p < 0.001) than that in the placebo group. HCN channels may be differentially involved in the various pain signal transmission pathways in humans.

An unusual foreign body in the oral cavity: a case report from a patient safety point of view and literature review.

Accidental foreign bodies (FBs) in the oral cavity, airway, esophagus and breathing circuit associated with anesthetic procedures are rare but can cause serious and life-threatening complications. We here present a case in which an unusual FB in the oral cavity was found after emergence from general anesthesia. The FB was later identified as a melted cap of a felt-tip pen. We investigated the cleaning process for reusable materials and concluded that the FB was accidentally placed in the inner lumen of the reusable bite block during the cleaning process. We then performed a review of the literature on FBs other than those of dental origin which were entrapped in the oral cavity, pharynx, larynx, trachea, esophagus, and anesthetic breathing circuit due to anesthetic procedures. From our case and 53 cases found in the search, we concluded that 1) use of disposable medical devices is recommended, 2) FBs can easily migrate into the oral cavity and airway during anesthesia, 3) delayed FB recognition may be associated with difficult intubation situations, and 4) more attention should be paid to the possibility of any medical or non-medical device becoming an FB during anesthesia.

Subfascial infiltration of 0.5% ropivacaine, but not 0.25% ropivacaine, exacerbates damage and inflammation in surgically incised abdominal muscles of rats.

Ropivacaine-induced myotoxicity in surgically incised muscles has not been fully investigated. We evaluated the effects of infiltration anesthesia with ropivacaine on damage, inflammation and regeneration in the incised muscles of rats undergoing laparotomy. Ropivacaine or saline was infiltrated below the muscle fascia over the incised muscles. Pain-related behaviors and histological muscle damage were assessed. Macrophage infiltration at days 2 and 5 and proliferation of satellite cells at day 5 were detected by CD68 and MyoD immunostaining, respectively. Pain-related behaviors were inhibited by 0.25% and 0.5% of ropivacaine for 2 h after surgery. Single infiltration of 0.5% ropivacaine did not induce injury in intact muscles without incision, but single and repeated infiltration of 0.5% ropivacaine significantly augmented laparotomy-induced muscle injury and increased the numbers of CD68-positve macrophages and MyoD-positive cells compared to those in rats with infiltration of saline or 0.25% ropivacaine. In contrast, there were no significant differences in them between rats with saline infusion and rats with 0.25% ropivacaine infiltration. In conclusion, single or repeated subfascial infiltration of 0.25% ropivacaine can be used without exacerbating the damage and inflammation in surgically incised muscles, but the use of 0.5% ropivacaine may be a concern because of potentially increased muscle damage.

Calcitonin gene-related peptide is not involved in neuropathic pain induced by partial sciatic nerve ligation in mice.

BACKGROUND: Optimal neuropathic pain (NeP) therapy has still not been established despite great efforts to develop new strategies for NeP analgesia. One possible target might be calcitonin gene-related peptide (CGRP). This is because the expression of CGRP and its receptors in the dorsal horn of the spinal cord might be associated with the persistence of pain symptoms including symptoms of NeP. We previously developed αCGRP knockout mice, and we aimed in this study to clarify the roles of CGRP in NeP by partial sciatic nerve ligation (PSNL) using the knockout mice. METHODS: PSNL was performed in αCGRP knockout mice and wild-type (WT) mice, and spontaneous pain behavior and mechanical and thermal hyperalgesia were evaluated after PSNL. CGRP immunoreactivity (IR) was also observed in the superficial dorsal horn and deep dorsal horn of L4 to L5 segments of the spinal cord in WT mice after PSNL. RESULTS: Spontaneous pain behavior and mechanical and thermal hyperalgesia after PSNL were not different between αCGRP knockout mice and WT mice throughout the observation period. The expression of CGRP-IR was not different between the PSNL model and the sham operation model at 1 day and 7 days after surgery. CONCLUSION: The results suggest that the involvement of αCGRP may differ depending on the type and site of nerve injury, and clinical indications for anti-CGRP treatment of NeP should be carefully based on various pathophysiological conditions of NeP.

Whole Genome Analysis Detects the Emergence of a Single Salmonella enterica Serovar Chester Clone in Japan's Kanto Region.

In Japan's Kanto region, the number of Salmonella enterica serovar Chester infections increased temporarily between 2014 and 2016. Concurrently with this temporal increase in the Kanto region, S. Chester isolates belonging to one clonal group were causing repetitive outbreaks in Europe. A recent study reported that the European outbreaks were associated with travelers who had been exposed to contaminated food in Morocco, possibly seafood. Because Japan imports a large amount of seafood from Morocco, we aimed to establish whether the temporal increase in S. Chester infections in the Kanto region was associated with imported Moroccan seafood. Short sequence reads from the whole-genome sequencing of 47 S. Chester isolates from people in the Kanto region (2014-2016), and the additional genome sequences from 58 isolates from the European outbreaks, were analyzed. The reads were compared with the complete genome sequence from a S. Chester reference strain, and 347 single nucleotide polymorphisms (SNPs) were identified. These SNPs were used in this study. Cluster and Bayesian cluster analyses showed that the Japanese and European isolates fell into two different clusters. Therefore, Φ PT and I A S values were calculated to evaluate genetic differences between these clusters. The results revealed that the Japanese and European isolates were genetically distinct populations. Our root-to-tip analysis showed that the Japanese isolates originating from one clone had accumulated mutations, suggesting that an emergence of this organism occurred. A minimum spanning tree analysis demonstrated no correlation between genetic and geographical distances in the Japanese isolates, suggesting that the emergence of the serovar in the Kanto region did not involve person-to-person contact; rather, it occurred through food consumption. The d N /d S ratio indicated that the Japanese strain has evolved under positive selection pressure. Generally, a population of bacterial clones in a reservoir faces negative selection pressure. Therefore, the Japanese strain must have existed outside of any reservoir during its emergence. In conclusion, S. Chester isolates originating from one clone probably emerged in the Kanto region via the consumption of contaminated foods other than imported Moroccan seafood. The emerging strain may have not established a reservoir for survival in the food supply chain resulting in its disappearance after 2017.

Comparison of Oxygen Saturation Between Nasal High-Flow Oxygen and Conventional Nasal Cannula in Obese Patients Undergoing Dental Procedures With Deep Sedation: A Randomized Crossover Trial.

PURPOSE: In anesthetic management, it is widely accepted that obese patients are more likely to suffer airway obstructions and reductions in arterial oxygen saturation (SpO2). Therefore, it is important to take special measures to prevent oxygen desaturation during the deep sedation of obese patients. This clinical study examined whether the use of nasal high-flow systems (NHFS) keep higher SpO2 and reduced hypoxemia than conventional nasal cannula during the deep sedation of obese patients with intellectual disabilities for dental treatment. MATERIALS AND METHODS: Eighteen obese patients (body mass index: >25) with intellectual disabilities who underwent dental sedation were enrolled. In each case, sedation was induced using propofol and maintained at a bispectral index of 50 to 70. The subjects were randomly assigned to the control oxygen administration (5 L/min via a nasal cannula) or NHFS (40% O2, 40 L/min, 37 °C) arm in alternate shifts as a crossover trial. The primary endpoint was the minimum SpO2 value, and the incidence of hypoxemia during dental treatment was also evaluated. RESULTS: The mean minimum SpO2 value was significantly higher in the NHFS arm than in the control arm (95.8 ± 2.1 % vs 93.6 ± 4.1 %, P = 0.0052, 95% confidence interval: 0.608-3.947). Hypoxemic episodes (SpO2: ≤94%) occurred 3 cases (16.7%) in the NHFS arm and 11 cases (61.1%) in the control arm (P = 0.0076, odds ratio: 0.127, 95% confidence interval 0.0324 - 0.630). CONCLUSION: NHFS resulted in higher minimum SpO2 and reduced hypoxemia than nasal cannula in obese patients during deep sedation for dental treatment.

Plantar incision with severe muscle injury can be a cause of long-lasting postsurgical pain in the skin.

AIMS: Although chronic local inflammation in deeper tissues after skin wound healing might produce chronification of acute postsurgical pain, its mechanisms have not been fully elucidated. We hypothesized that muscle injury and severe inflammation would prolong acute postsurgical pain by its central nervous system mechanisms. MAIN METHODS: After approval of the Animal Care Committee, experiments were performed in Male Sprague-Dawley rats weighing 250-300 g. Plantar incision and plantar incision combined with cryoinjury of the plantar flexor digitorum brevis muscle were made in the plantar incision group and muscle injury group, respectively. Pain-related behaviors were assessed, and inflammatory cells were isolated from injured muscle and analyzed by flow cytometry. Spinal microglial activation was assessed with Iba-1 staining. KEY FINDINGS: Mechanical hyperalgesia from day 5 to day 8 and spontaneous pain-related behavior from day 3 to day 7 were significantly greater in the muscle injury group than in the plantar incision group (P < 0.05), whereas there was no significant difference between the two groups in thermal hyperalgesia. In the muscle injury group, the number of inflammatory cells on day 4 was significantly larger and spinal Iba-1 expression levels on days 4 and 7 were significantly higher than those in the plantar incision group (P < 0.05). SIGNIFICANCE: Surgical injury in deep tissues accompanying severe muscle inflammation induced prolonged postsurgical pain in the healing wound of the skin not by the persistence of muscle inflammation but by a central mechanism involving microglial activation at the level of the spinal cord.

Phospholipase Cß3 Expressed in Mouse DRGs is Involved in Inflammatory and Postoperative Pain.

BACKGROUND: Previous studies suggested that phospholipase Cß3 (PLCß3), which is a common downstream component in the signaling cascade, plays an important role in peripheral mechanisms of perception including nociception. However, detailed profiles of PLCß3-expressing dorsal root ganglion (DRG) neurons and involvement of PLCß3 in inflammatory and postoperative pain have not been fully investigated. PURPOSE: We evaluated neurochemical char0acteristics of PLCß3-expressing DRG neurons in mice and then we examined the effects of selective knockdown of PLCß3 expression in DRGs on inflammatory and postoperative pain. METHODS: Male C57BL/6-strain mice were used. For the inflammatory model, each mouse received subcutaneous injection of complete Freund's adjuvant (CFA) in the left hindpaw. For the postoperative pain model, a plantar incision was made in the left hindpaw. PLCß3 antisense oligodeoxynucleotide or PLCß3 mismatch oligodeoxynucleotide was intrathecally administered once a day for three consecutive days in each model. The time courses of thermal hyperalgesia and mechanical hyperalgesia were investigated. Changes in PLCß3 protein levels in DRGs were evaluated by Western blotting. RESULTS: Immunohistochemical analysis showed that high proportion of the PLCß3-positive profiles were biotinylated isolectin B4-positive or transient receptor potential vanilloid subfamily 1-positive. PLCß3 protein level in DRGs during CFA-induced inflammation was comparable to that at baseline. Intrathecal administration of PLCß3 antisense oligodeoxynucleotide, which significantly suppressed PLCß3 expression in DRGs, did not affect pain thresholds in normal conditions but inhibited CFA-induced thermal and mechanical hyperalgesia both at the early and late phases compared to that in mismatch oligodeoxynucleotide-treated mice. Intrathecal administration of PLCß3 antisense oligodeoxynucleotide also inhibited surgical incision-induced thermal and mechanical hyperalgesia. CONCLUSION: Our results uncover a unique role of PLCß3 in the development and maintenance of inflammatory pain induced by CFA application and in those of surgical incision-induced pain, although PLCß3 does not play a major role in thermal nociception or mechanical nociception in normal conditions.

Acute postoperative pain is correlated with the early onset of postpartum depression after cesarean section: a retrospective cohort study.

The primary purpose of this study was to evaluate the correlation between the intensity of acute postoperative pain and development of postpartum depression (PPD) after cesarean section (CS). The secondary purpose was to investigate perioperative risk factors for PPD detected in the postoperative period after CS. We retrospectively reviewed 615 women who had undergone CS between January 2017 and October 2019 in our hospital. The incidence of PPD was 22.7% on postoperative day (POD) 5 in the 247 women whose numerical rating scale (NRS) scores on POD3 were available. The severity of acute postoperative pain evaluated by NRS was higher in women with than in those without PPD on POD3 (P < 0.02). The independent risk factors for the onset of PPD on POD5 were being a primipara [adjusted odds ratio (aOR), 2.08; 95% confidence interval (CI), 1.03-4.20, P < 0.05], preoperative presence of chronic pain (OR, 4.44; 95% CI 1.82-10.81, P < 0.001), and NRS ≥ 2 on POD3 (aOR, 4.90; 95% CI 1.06-22.61, P < 0.05). Our findings suggest that assessing both acute postoperative pain and presence of PPD can inform the introduction of interventions in the early phase to prevent development of PPD after CS.

Endogenous Calcitonin Gene-Related Peptide Deficiency Exacerbates Postoperative Lymphedema by Suppressing Lymphatic Capillary Formation and M2 Macrophage Accumulation.

Lymphedema is a chronic condition caused by disruption of lymphatic vessels, which often occurs after invasive surgery. Calcitonin gene-related peptide (CGRP) is a 37-amino acid peptide produced by alternative splicing of the primary transcript of the calcitonin/CGRP gene (Calca). CGRP was initially identified as a neuropeptide released primarily from sensory nerves and involved in regulating pathophysiological nociceptive pain. However, recent studies have shown CGRP is also released from a variety of other cells and possesses multiple functions. In this study, CGRP knockout (-/-) mice were used to show the actions of endogenous CGRP in postoperative lymphedema. After generating a mouse postoperative tail lymphedema model, the edema was observed to be more severe in CGRP-/- mice than in wild-type mice. Numbers of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1)-positive lymphatic capillaries were decreased and lymphatic capillary formation-related factors were down-regulated in CGRP-/- mice. In addition, accumulation of M2 but not M1 macrophages was selectively reduced in the edematous tissue of CGRP-/- mice. Selective depletion of M2 macrophages decreased lymphatic capillary formation and worsened lymphedema in wild-type mice but not CGRP-/- mice, where numbers of M2 macrophages were already diminished. These findings suggest that endogenous CGRP acts to ameliorate postoperative lymphedema by enhancing lymphatic capillary formation and that M2 macrophages play critical roles. CGRP may be a useful therapeutic target for the treatment of postoperative lymphedema.

Prostanoid EP4 Receptor-Mediated Augmentation of I h Currents in Aß Dorsal Root Ganglion Neurons Underlies Neuropathic Pain.

An injury of the somatosensory system causes neuropathic pain, which is usually refractory to conventional analgesics, thus warranting the development of novel drugs against this kind of pain. The mechanism of neuropathic pain in rats that had undergone left L5 spinal nerve transection was analyzed. Ten days after surgery, these rats acquired neuropathic pain. The patch-clamp technique was used on the isolated bilateral L5 dorsal root ganglion neurons. The current-clamped neurons on the ipsilateral side exhibited significantly higher excitability than those on the contralateral side. However, only neurons with diameters of 40-50 µm on the ipsilateral side exhibited significantly larger voltage sags in response to hyperpolarizing current pulses than those on the contralateral side. Under the voltage clamp, only these neurons on the ipsilateral side showed a significantly larger density of an inward current at < -80 mV [hyperpolarization-activated nonselective cation (I h) current] with a rightward-shifted activation curve than that on the contralateral side. Ivabradine-an I h current inhibitor-inhibited I h currents in these neurons on both sides in a similar concentration-dependent manner, with an IC50 value of ∼3 µM. Moreover, the oral administration of ivabradine significantly alleviated the neuropathic pain on the ipsilateral side. An inhibitor of adenylyl cyclase or an antagonist of prostanoid EP4 receptors (CJ-023423) inhibited ipsilateral, but not contralateral I h, currents in these neurons. Furthermore, the intrathecal administration of CJ-023423 significantly attenuated neuropathic pain on the ipsilateral side. Thus, ivabradine and/or CJ-023423 may be a lead compound for the development of novel therapeutics against neuropathic pain.

Airway obstruction due to a laryngeal polyp following insertion of a laryngeal mask airway.

BACKGROUND: Laryngeal mask airway (LMA) insertion contributes to airway protection in patients with a laryngeal tumor around the glottis. There has been no report of LMA insertion itself exacerbating airway obstruction in such patients. CASE PRESENTATION: A 62-year-old male underwent elective surgical resection of a large laryngeal polyp. The polyp was attached to the right vocal fold and synchronously swung inward into the trachea and outward to the larynx with inspiration and expiration, respectively. Although manual positive pressure ventilation was easily achieved without any airway obstruction after anesthetic induction, the airway was completely obstructed by the polyp lodged between the vocal cords immediately after LMA insertion. Soon after removal of the LMA, patency of the airway was dramatically improved. CONCLUSION: Our experience indicates that we should pay attention to airway obstruction due to lodging of the polyp between the vocal cords after LMA insertion in patients with a laryngeal polyp.

Transversus abdominis plane block with 0.25 % levobupivacaine: a prospective, randomized, double-blinded clinical study.

PURPOSE: Because blood concentrations of local anesthetics sometimes reach toxic levels after transversus abdominis plane (TAP) block, reduction of the dose has been necessary to reduce the risk of systemic toxicity. We therefore investigated the effects of TAP block with 0.25 % levobupivacaine (100 mg) on postoperative pain and measured its plasma concentration after gynecological surgery. METHODS: Forty women undergoing elective open gynecological surgery were randomized to receive bilateral TAP block with 20 ml 0.25 % levobupivacaine on each side (TAP group) or not (non-TAP group) before surgery. Postoperative pain was treated with intravenous patient-controlled analgesia by use of morphine. Patients were evaluated 3 and 24 h after the end of surgery. Visual analog scale (VAS) for pain at rest and with movement, and morphine consumption were recorded. Plasma concentrations of levobupivacaine after TAP block were measured. RESULTS: Three hours after surgery, total morphine consumption was significantly lower in the TAP group (2.8 ± 1.6 mg) than in the non-TAP group (6.4 ± 4.8 mg, P = 0.03). There were no significant differences between VAS in the two groups. Mean plasma concentration of levobupivacaine peaked 10 min after TAP block (0.99 ± 0.43 µg/ml), and the highest concentration was 1.99 µg/ml. CONCLUSION: TAP block with 100 mg levobupivacaine is a safe and efficacious multimodal analgesic regimen for postoperative pain after open gynecological surgery.

Calcitonin gene-related peptide is involved in inflammatory pain but not in postoperative pain.

BACKGROUND: The aim of this study was to clarify the roles of calcitonin gene-related peptide (CGRP) in postoperative pain and inflammatory pain. METHODS: αCGRP knockout mice that the authors have developed and wild-type mice were used. Pain behaviors were assessed after incision and complete Freund's adjuvant (CFA) injection. Changes in CGRP and c-Fos expression in the dorsal horn were also examined. RESULTS: Guarding pain scores in αCGRP knockout mice were lower than those in wild-type mice at 24 h (3.8 ± 1.6 vs. 6.8 ± 1.5, P = 0.044) and 48 h (1.8 ± 1.7 vs. 6.0 ± 1.5, P = 0.001) after CFA injection (n = 8 to 9). Withdrawal latencies to heat stimulation in αCGRP knockout mice were higher than those in wild-type mice at 24 to 72 h after CFA injection (4.9 ± 1.0 vs. 3.4 ± 0.8 at 24 h, P = 0.04; 5.1 ± 0.3 vs. 3.2 ± 0.9 at 48 h, P = 0.047; and 5.4 ± 1.6 vs. 3.5 ± 0.5 s at 72 h, P = 0.045) (n = 11 to 13), but withdrawal thresholds to mechanical stimulation were comparable. CGRP expression was increased at 24 h after CFA injection in wild-type mice, and the c-Fos-positive profile was increased at 4 h after CFA injection (ipsilateral vs. contralateral: 12.3 ± 4.6 vs. 1.3 ± 1.9, P < 0.0001) and maintained at 24 h (10.0 ± 4.1 vs. 0.8 ± 1.3, P < 0.0001) (n = 4 to 6). CONCLUSION: These results suggest that contribution of the αCGRP system depends on the modality of pain and the stage of inflammation.

Annual incidence of persistent proteinuria in the general population from Ibaraki annual urinalysis study.

BACKGROUND: For a definitive diagnosis of chronic kidney disease, at least 2 consecutive positive results of proteinuria with an interval of >3 months are required. However, most previous reports were based on single-screening data. PATIENTS AND METHODS: The subjects in this study were participants in an annual health examination held in Ibaraki, Japan, between 1993 and 2003. The follow-up duration with serial urinalysis for 3 years of patients who were negative for proteinuria in the initial year was 330,614 person-years in males and 687,381 person-years in females among 81,854 male and 155,256 female subjects. We evaluated the incidence and risk factor for the incidence of proteinuria and persistent proteinuria. RESULT: The annual incidence of proteinuria and persistent proteinuria was 1.31 and 0.33 % in males and 0.68 and 0.14 % in females. Among the subjects without hypertension and diabetes, the annual incidence was 0.81 and 0.16 % in males and 0.37 and 0.06 % in females, respectively. Risk analysis indicated that hypertension in males [hazard ratio (HR) 2.052] and females (2.477), diabetes in males (3.532) and females (3.534) and reduced renal function in males (3.097) and females (2.827) were significant positive risks for development of persistent proteinuria. CONCLUSION: By annual urinalysis screening of the general population, 1 out of 303 male subjects and 1 out of 725 female subjects developed persistent proteinuria every year. Subjects with diabetes, hypertension and reduced renal function had a 2 or 3 times higher risk for the incidence of persistent proteinuria in both males and females.