Damage accrual related to pregnancies before and after diagnosis of systemic lupus erythematosus: a cross-sectional and nested case-control analysis from a lupus registry.

OBJECTIVE: The objective of this study was to evaluate the chronic damage associated with pregnancies before and after the diagnosis of systemic lupus erythematosus (SLE). METHODS: Using childbearing-aged female SLE patient data registered at the Okayama and Showa University Hospitals, a nested case-control analysis was performed to investigate the relationship between pregnancy and chronic damage using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). RESULTS: Pregnancy occurred in 22 patients before and 13 patients after the diagnosis of SLE in 104 eligible patients. Live births occurred in 82% (33/40) and 50% (9/18) of the pregnancies before and after the diagnosis of SLE, respectively. After matching age and disease duration, 33 case patients with chronic damage (SDI ≥ 1) and 33 control patients without chronic damage (SDI = 0) were selected. Hypertension was more frequent in cases than in controls (48% vs. 24%, p = 0.041). Pregnancies before and after the diagnosis of SLE were comparable between cases and controls (before the diagnosis: nine case patients and eight control patients; after the diagnosis: three case patients and five control patients; p = 1.00). Even after adjusting for hypertension using multivariate analysis, the pregnancies before and after the diagnosis were not significant predictors for chronic damage (odds ratio = 1.48 (95% confidence interval 0.33-6.65)), p = 0.60 of the pregnancy before the diagnosis; odds ratio = 0.78 (95% confidence interval 0.13-4.74), p = 0.78 of the pregnancy after the diagnosis). CONCLUSION: Pregnancies, either before or after the diagnosis of SLE, did not show any differences in chronic damage. Our results help alleviate fears regarding childbearing in female patients with SLE and their families.

Progressive reduction of serum complement levels: a risk factor for relapse in patients with hypocomplementemia in systemic lupus erythematosus.

OBJECTIVE: Serologically active clinically quiescent (SACQ)-SLE is a subtype of systemic lupus erythematosus (SLE); most SACQ-SLE patients relapse. Although complement and/or anti-dsDNA level fluctuations during SACQ status are reportedly not useful for predicting relapse, they might be useful in specific clinical settings. We aimed to assess the correlation between future relapse and progressive reductions in serum complement levels following remission in patients with hypocomplementemia . METHODS: We retrospectively reviewed patients aged ≥15 years who were treated with ≥20 mg/day of prednisolone for remission induction. After achieving remission, the patients treated with prednisolone tapered to ≤15 mg/day without relapse and followed by hypocomplementemia (first hypocomplementemia point) were analyzed. The primary outcome was the relapse during the first 24 months. RESULTS: Seventy-six patients were enrolled; 31 (40.8%) relapsed. A ≥10% reduction after the first hypocomplementemia point in serum C3, C4, and CH50 levels was found in 10, 21, and 16 patients, respectively. Hazard ratios (95% confidence intervals) for relapse were 2.32 (0.92-5.12) for serum C3 levels and 2.46 (1.18-5.01) for serum C4 levels. Progressive reductions in serum C3 and C4 levels had relatively high specificity (93.3% and 82.2%) but limited sensitivity (22.6% and 41.9%) for predicting relapse. However, simultaneous progressive reduction in C3 levels and increase in anti-dsDNA antibody levels had the highest specificity (97.8%), and simultaneous progressive reduction in C4 levels or increase in anti-dsDNA antibody levels had the highest sensitivity (71.0%). CONCLUSION: Simultaneous progressive reductions in complement levels and increases in anti-dsDNA antibody levels may indicate future relapse SACQ-SLE patients.

Salvage chemoradiotherapy for locally advanced esophageal carcinomas.

'Salvage chemoradiotherapy (CRT)' was introduced in 2005 to treat thoracic esophageal carcinomas deemed unresectable based on the intraoperative findings. The therapeutic concept is as follows: the surgical plan is changed to an operation that aims to achieve curability by the subsequent definitive CRT. For this purpose, the invading tumor is resected as much as possible, and systematic lymph node dissection is performed except for in the area around the bilateral recurrent nerves. The definitive CRT should be started as soon as possible and should be performed as planned. We hypothesized that this treatment would be feasible and provide good clinical effects. We herein verified this hypothesis. Twenty-seven patients who received salvage CRT were enrolled in the study, and their clinical course, therapeutic response, and prognosis were evaluated. The patients who had poor oral intake because of esophageal stenosis were able to eat solid food soon after the operation. The radiation field could be narrowed after surgery, and this might have contributed to the high rate of finishing the definitive CRT as planned. As a result, the overall response rate was 74.1%, and 48.1% of the patients had a complete response. No patient experienced fistula formation. The 1-, 3-, and 5-year overall survival rates were 66.5%, 35.2%, and 35.2%, respectively. Salvage CRT had clinical benefits, such as the fact that patients became able to have oral intake, that fistula formation could be prevented, that the adverse events associated with the definitive CRT could be reduced, and that prognosis of the patients was satisfactory. Although the rate of recurrent nerve paralysis was relatively high even after the suspension of aggressive bilateral recurrent nerve lymph node dissection, and the rate of the progressive disease after the definitive CRT was high, salvage CRT appears to provide some advantages for the patients who would otherwise not have other treatment options following a non-curative and residual operation.

Neural decoding of visual imagery during sleep.

Visual imagery during sleep has long been a topic of persistent speculation, but its private nature has hampered objective analysis. Here we present a neural decoding approach in which machine-learning models predict the contents of visual imagery during the sleep-onset period, given measured brain activity, by discovering links between human functional magnetic resonance imaging patterns and verbal reports with the assistance of lexical and image databases. Decoding models trained on stimulus-induced brain activity in visual cortical areas showed accurate classification, detection, and identification of contents. Our findings demonstrate that specific visual experience during sleep is represented by brain activity patterns shared by stimulus perception, providing a means to uncover subjective contents of dreaming using objective neural measurement.

A new method for determining the optimal CT threshold for extracting the upper airway.

OBJECTIVES: The purpose of this study was to evaluate the optimal upper threshold levels of a number of individuals and determine the most suitable upper threshold. METHODS: A phantom model and ten patients were used in this study. The phantom was made of acrylic resin and urethane resin and had nine pillar-shaped air spaces. The subjects were ten female patients with jaw deformities who were not affected by respiratory disease. The optimal threshold levels were determined using the "calculation of CT value disparities" (CCTD) technique, which we devised. In other words, the mean CT values along two lines (air space and soft tissue) were calculated and the optimal threshold level was determined as the level that produced the maximum difference between the CT values measured inside and outside of the air-space border. RESULTS: The optimal upper threshold levels of the nine phantom holes calculated using the CCTD technique in the front-on standing position and side-on standing position were -434 HU and -456 HU, respectively. The optimal upper threshold level of the ten patients calculated using the CCTD technique was -472 HU. The true threshold level of each patient was defined as the optimal threshold level calculated using the CCTD technique. The mean threshold level was defined as -472 HU. The absolute differences between the volume measurements obtained with these two measures were considered. Therefore, the no error values were -460 HU and -470 HU. CONCLUSIONS: We consider that the most suitable upper threshold level for extracting the airway is from -460 HU to -470 HU.

A possible mechanism for Inv22-related F8 large deletions in severe hemophilia A patients with high responding factor VIII inhibitors.

BACKGROUND: Intron 22 inversion (Inv22) of the coagulation factor (F)VIII gene (F8) is a frequent cause of severe hemophilia A. In addition to Inv22, a variety of F8 mutations (1492 unique mutations) causing hemophilia A have been reported, of which 171 involve deletions of over 50 bp (HAMSTeRs database; http://hadb.org.uk/). However, only 10% of these large deletions have been fully characterized at the nucleotide level. PATIENTS AND METHODS: We investigated gene abnormalities in three unrelated severe hemophilia A patients with high titer FVIII inhibitors. They had previously been shown to carry large deletions of the F8, but the precise gene abnormalities remain to be elucidated. RESULTS: Inverse shifting-PCR (IS-PCR) Inv22 diagnostic tests revealed that these patients carried either type I or II Inv22. However, they showed a wild-type (WT) pattern in the IS-PCR Inv22 complementary tests. We further analyzed their X chromosomes to account for the puzzling results, and found that they had different centromeric breakpoints in the Inv22 X chromosomes, adjacent to the palindromic regions containing int22h-2 or -3, and their spacer region, respectively. The connections appeared to be shifted towards the telomere of the WT F8 Xq28, resulting in a new telomere with an additional intact int22h copy. CONCLUSIONS: These gene rearrangements might result from double-strand breaks in the most distal regions of the long arms of the Inv22 X chromosomes, followed by DNA restorations using the WT F8 Xq28 by non-homologous end joining or break-induced replication; thus leading to large F8 deletions in severe hemophilia A patients.

Life-threatening hemorrhage and prolonged wound healing are remarkable phenotypes manifested by complete plasminogen activator inhibitor-1 deficiency in humans.

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological regulator of urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA) activity. A number of studies have shown that elevated levels of PAI-1 are related to pathological states such as an increased risk of arterial thrombotic events and a poor prognosis for cancer patients; however, there are few reports about PAI-1 deficiency in humans because the disorder is very rare. OBJECTIVE: To understand the in vivo impact of a complete PAI-1 deficiency, Serpine1(-/-) mice were generated; a number of in vivo studies have been conducted to elucidate the function of PAI-1 using Serpine1(-/-) mice. The phenotypes demonstrated in Serpine1(-/-) mice, however, were quite different from those in humans. Therefore, it is necessary to find out and analyze SERPINE1 deficiency in humans. PATIENT AND METHODS: The patient is a 47-year-old woman who has had multiple episodes of major bleeding. Although most of the patient's blood coagulation factors were functionally normal, her PAI-1 antigen levels were undetectable. Therefore, DNA sequencing of the SERPINE1 gene were analyzed. RESULTS: The proband had a homozygous 1-bp duplication (C) at exon 3 (c.356dupC; p.Ile120AspfsX42). Both wild-type PAI-1 (42.7 kDa) and mutated (Mut) PAI-1 (14.7kDa) were expressed in COS-1 cells, although the level of Mut PAI-1 expressed in the cell lysates was much lower. Wild-type PAI-1 was observed in the culture supernatant, whereas no Mut PAI-1 was detected in the supernatant. CONCLUSIONS: Considering the results of the present study, the translation of mouse studies to humans must be performed with great care.

Shortening of distal motor latency in anode distal stimulation.

OBJECTIVE: Distal motor latency (DML) is shortened when the anode is held distally instead of the cathode by increasing the stimulus intensity. The objective of this study was to clarify the mechanism responsible for this shortening. METHODS: In seven healthy subjects, compound muscle action potential (CMAP) was obtained from the thenar muscle by bipolar stimulation of the median nerve at the wrist, and the intensity at which the first motor units were stimulated was defined as the threshold. Bipolar stimulation with extended interpole distance was employed to identify the generating site of the CMAP and F-wave. RESULTS: The shortening of DML was dependent on the stimulus intensity and threshold. For the low threshold condition, the CMAP generating site was replaced from the proximal cathodal pole to the distal anodal pole by increasing the stimulus intensity. The generating site of the F-wave remained at the proximal cathodal pole irrespective of stimulus intensity. CONCLUSIONS: Replacement of the generating site results in the shortening of DML. When the F-wave is recorded after being induced by anode distal stimulation, CMAP should not be simultaneously evaluated. SIGNIFICANCE: This study clarified the generation sites of CMAP and the F-wave when induced by anode distal stimulation.

The Japan Home-health Apparatus Industrial Association: investigation of home-use electronic sphygmomanometers.

The Japanese Home-health Apparatus Industrial Association is an official independent organization comprising ten departments. That concerned with home electronic sphygmomanometers, which has seven participants from different Japanese manufacturers, has already undertaken and is currently involved in various activities related to voluntary standards for performance validation and quality assurance. Because Japanese companies form a large proportion of manufacturers, these activities are important in terms of autonomic regulation. Although many improvements have been made to home electronic sphygmomanometers, some problems still remain unresolved, especially in terms of measurement reliability and easy operation by lay people. Another aspect of the department's work relates to making proposals on major validation standards, such as those of the Association for the Advancement of Medical Instrumentation, the British Hypertension Society and Comité Européen de Normalisation (CEN). Clinical validation should be discussed in order to define a more accurate standard method of measurement using auscultation and more appropriate criteria that are unaffected by primary blood pressure variation.

Effects of tensile forces on the expression of type III collagen in rat interparietal suture.

The aim was to investigate the direct contribution of mechanically induced stress to synthesized type III collagen in the interparietal suture. Twenty 4-week-old male rats were used as experimental animals. An activated expansion spring was placed across the interparietal suture. After expansion, the parietal bones including the suture were dissected and immunostained for type I and III collagens. Also, a three-dimensional model of the interparietal suture was developed to analyze stress during expansion. The localization of type III collagen in the suture was dependent upon the duration of expansion. Although the control suture exhibited no or little reactivity for type III collagen, it was observed as early as 15 h of expansion in the cambial layers, and was distributed throughout the suture at 50 h of expansion. The time-dependent distribution of type III collagen was fully consistent with that of tensile stresses calculated by the use of a three-dimensional finite-element model. It was concluded that the increases in tensile stress are associated with the synthesis of type III collagen in the suture.

Changes in the biomechanical properties of the rat interparietal suture incident to continuous tensile force application.

This study was designed to investigate the relation between the biomechanical behaviour of rat interparietal sutures and expansion forces placed on them. Thirty-five 4-week-old rats were divided into four groups, a control group and three experimental groups subjected to mechanical expansion of the interparietal sutures with a tensile force for 15, 30 and 50 h. After expansion, the parietal bones, including the interparietal suture, were dissected as specimens for tensile tests. Under tension, the relaxed stress-strain plots in the control group could be better fitted by a power of 2.00, and the relaxed moduli were 0.64 and 4.51 MPa at the lower and the higher applied strains, respectively. An initial fall in the relaxed moduli at 15 h of expansion was followed by an increase over time. It is therefore suggested that the biomechanical behaviour of the interparietal sutures is influenced by the duration of an external force.

Stress distribution in the temporomandibular joint affected by anterior disc displacement: a three-dimensional analytic approach with the finite-element method.

The purpose of this study was to investigate the influences of anterior disc displacement on TMJ loading during maximum clenching by use of finite-element analysis. Based on a young human dry skull, an analytic model of the mandible including the TMJ was developed. In addition to the standard model with normal disc-condyle relation, two models were designed to simulate various degrees of anterior disc displacement. In the standard model, compressive stresses were induced in the anterior, middle and lateral areas on the condyle and glenoid fossa, whereas tensile stresses were observed in the posterior and medial regions. In the models with anterior disc displacement, compressive stresses were recognized in all the areas of TMJ components excluding the bilaminar zone. Shear stresses in the articular disc and bilaminar zone significantly increased in most areas. In conclusion, stress distributions in the TMJ with a normal disc position was substantially different from those with anterior disc displacement, suggesting that the progress in disc displacement may have some association with the nature of stress distributions in the TMJ, in the articular disc in particular.

Viscoelastic properties of canine temporomandibular joint disc in compressive load-relaxation.

The present study was designed to investigate the mechanical properties and load-relaxation of these discs in compression. Eight discs were used for the experiments. Compression was applied to specimens up to the specified strain, and a series of load-relaxation tests was conducted on each specimen from 0.25% strain to 2.0% strain with 0.25% intervals. The load-relaxation was monitored over a period of 2 min. The elastic moduli of the canine articular discs were 30.9 and 15.8 MPa at t = 0 and 120 sec, respectively, and the discs exhibited near-linear elastic characteristics at each time within a 2-min period. At all strains, the time-dependent load-relaxation curves showed that the load decreased markedly for the initial 30 sec, after which it levelled off after 120 sec with a steady nonzero level. This relaxation feature can be well represented by Kelvin's model. It is concluded that the canine temporomandibular joint disc can be represented as a linear viscoelastic material, and that it plays an important part as a stress absorber under compression.

Immunohistochemical observation of growth-associated protein 43 (GAP-43) in the developing circumvallate papilla of the rat.

The distribution and development of growth-associated protein 43 (GAP-43)-like immunoreactivity (-LI) in the rat circumvallate papilla (CVP) were compared to those of protein gene product 9.5 (PGP 9.5)-LI. In the adult, thick GAP-43-like immunoreactive (-IR) structures gathered densely in the subgemmal region. Some of these further penetrated the apical epithelium and trench wall epithelium. At least two types of GAP-43-IR structures were recognized; taste bud-related and non-gustatory GAP-43-IR neural elements. Immunoelectron microscopy revealed that GAP-43-LI was localized predominantly in the Schwann cells, and a few axons displayed GAP-43-LI in the lamina propria. In the trench epithelium, GAP-43-LI was detected in the cytoplasmic side of the axonal membrane. Some intragemmal GAP-43-IR axons made synaptic-like contacts with taste bud cells. At least four developmental stages were defined on the basis of the changes in distribution of GAP-43-LI. In stage I [embryonic day (E) 16-17] GAP-43-IR structures accumulated at the lamina propria just beneath the newly-formed circumvallate papilla. In stage II (E18-19) GAP-43-IR nerve fibers began to penetrate the apical epithelium. In stage III [E20-postnatal day (P) 0] GAP-43-IR nerve fibers first appeared in the trench wall epithelium. Penetration of GAP-IR nerve fibers occurred in the inner trench wall epithelium first, and then in the outer trench wall epithelium. In stage IV (P1-) the distribution of GAP-43-LI was similar to that observed in the adult; but the density of GAP-43-LI was much higher than in adults. PGP 9.5-LI showed a similar distribution pattern to that of GAP-43-LI, except for round-shaped cells in the apical epithelium at the late embryonic stages, and in taste bud cells and intralingual ganglionic cells which lacked GAP-43-LI. The similarities in distribution patterns of GAP-43-LI and PGP 9.5-LI during the development and mature circumvallate papilla suggest that GAP-43 may be a key neuronal molecule for induction and maintenance of the taste buds.

Calbindin D28k-like immunoreactivity in the developing and regenerating circumvallate papilla of the rat.

The distribution of calbindin D28k (CB)-like immunoreactivity (-LI) in the circumvallate papilla (CVP) was examined during development and regeneration following bilateral crush injury to the glossopharyngeal nerve in the rat. In the adult CVP, CB-like immunoreactive (-IR) nerve fibers were observed in the subgemmal region and some penetrated into the taste buds. CB-LI was also detected in the cytoplasm of the spindle-shaped gustatory cells in the lower half of the trench epithelium, which contained numerous synaptic vesicles and bundles of intermediate filaments. These CB-IR gustatory cells made synapse-like contacts with CB-IR nerve terminals. Some CB-IR nerve terminals made contacts with the gustatory cells negative for CB-LI. At least three developmental stages were defined with regard to the developmental changes in the distribution of CB-LI: (1) Stage I (embryonic day (E) 18-postnatal day (P)5): CB-IR nerve fibers appeared in the lamina propria just beneath the newly-formed CVP at E18, but the gustatory epithelium of the CVP contained no CB-IR structures. Taste buds with taste pores appeared at P1. (2) Stage II (P5-10): thin CB-IR nerve fibers began entering the trench epithelium, but no CB-IR cells were observed. (3) Stage III (P10-adult): in addition to the intragemmal and perigemmal CB-IR nerve fibers, very few CB-IR cells appeared in the taste buds around P10, and their numbers increased progressively. The changes in the distribution of taste buds and CB-LI following glossopharyngeal nerve injury were similar to those observed during development. On post-operative day (PO) 4, the taste buds and CB-IR cells decreased markedly in number. These CB-IR cells became round in shape, and the number of CB-IR nerve fibers decreased markedly. On PO8, both taste buds and CB-IR cells disappeared completely. The regenerated taste buds were first observed on PO12, increased rapidly in number by PO20, and increased slowly thereafter. CB-IR nerve fibers accumulated at the subgemmal region and began penetrating into the trench wall epithelium around PO16. CB-IR cells appeared between PO20 and PO24, and their numbers increased progressively and reached the normal level on PO40. The topographical localizations of the taste buds and CB-IR cells during development and regeneration were comparable to those of normal animals. The delay of the time courses for appearance of CB-IR nerve fibers and CB-IR cells compared to the appearance of taste buds during development and regeneration suggests that CB in the gustatory epithelium may participate in the survival of the taste bud cells rather than in the induction of the taste buds.

Positive correlation between blood cyclosporin A level and severity of gingival overgrowth in rats.

Cyclosporin a is a drug used to control rejection of organ transplantation and autoimmune diseases; however, it has also been implicated in gingival overgrowth. The present study investigates the relationship between severity of gingival overgrowth and blood cyclosporin A (CsA) levels in Fischer rats treated orally with CsA. Thirty-six 15-day-old male rats were divided into six experimental groups and given powdered rat chow containing 0, 50, 100, 200, 300, and 400 micrograms CsA/g diet ad libitum for 40 days. At the end of the 40-day treatment period, whole blood samples were collected from each rat for assessment of CsA levels. The rats were then sacrificed and the gingival sulcus depth (pseudopocket) around mandibular molars measured to estimate gingival overgrowth. The blood levels of CsA in rats increased with increasing amounts of CsA provided in their food. A 100% incidence in gingival overgrowth was induced in all the rats treated orally with CsA. The overgrowth was more severe in buccal than in lingual gingiva. A significantly positive correlation was found between gingival sulcus depth and the blood CsA level (rs = 0.914, P < 0.0001; Spearman's correlation coefficient by rank). On histological examination, the overgrown gingiva consisted of a thickened epithelial layer and an accumulation of subepithelial fibrous connective tissue components without marked distortion of their proportion.

Calbindin D28K-like immunoreactive nerve fibres in the predentine of rat molar teeth.

Immunoelectron-microscopy was applied to reveal the existence of nerve fibres and terminals showing calbindin D28k (CB)-like immunoreactivity (IR) in the rat molar tooth pulp. In the root pulp, thick, smooth-surfaced CB-IR nerve fibres were in bundles accompanying the blood vessels. In the coronal pulp, the fibres arborized repeatedly and extensively. CB-IR nerve fibres had a predominantly thick, smooth-surfaced appearance, though parts appeared thin and beaded. Occasionally some thin, varicose CB-IR nerve fibres ran along the odontoblasts, penetrating into the predentine alongside the dentinal tubules. They could be traced for approx. 10-20 microns into the predentine from the pulp-predentine border. Immunoelectron-microscopy revealed that only some of the nerve terminals in the predentine showed CB-IR, and that predentinal CB-IR nerve terminals were located close to the odontoblast processes. No synaptic structures were observed between them. The presence of CB-IR nerve terminals in the predentine suggests that many, if not all, CB-IR nerve fibres could be nociceptors. The CB could be involved in Ca2+ homeostasis during the activation of nociceptors.

Protein gene-product 9.5 in developing mouse circumvallate papilla: comparison with neuron-specific enolase and calcitonin gene-related peptide.

The present study was made to investigate the ontogeny of protein gene-product 9.5 (PGP 9.5)-like immunoreactivity (-LI) in the developing mouse circumvallate papilla (CVP), and its distribution was compared to that of neuron-specific enolase (NSE) and calcitonin gene-related peptide (CGRP). In adult CVP, PGP 9.5-LI was observed in the subgemmal nerve plexus; some thin PGP 9.5-like immunoreactive (-IR) nerve fibers penetrated taste buds and apical epithelium. PGP 9.5-LI was also observed in the spindle-shaped cells in taste buds, and a small number of round- or oval-shaped ganglionic cells in the lamina propria. The distribution of NSE-LI was comparable to that of PGP 9.5-LI. CGRP-LI was observed in the nerve fibers only; distribution of CGRP-IR nerve fibers was similar to that of PGP 9.5-IR nerve fibers, although the number of CGRP-IR nerve fibers was smaller than that of PGP 9.5-IR nerve fibers. At least six developmental stages were defined with regard to the developmental changes in the distribution of PGP 9.5-LI from embryonic day (E) 12 to adulthood: Stage I (E12-13)-a dense nerve plexus of PGP 9.5-IR nerve fibers was detected in the lamina propria beneath the core of newly-formed papilla. Stage II (E14-16) - thin PGP 9.5-IR nerve fibers penetrated the apical epithelium, and a few round-shaped cells in the apical epithelium also displayed PGP 9.5-LI. Stage III (E17-18) - thin PGP 9.5-IR nerve fibers penetrated the inner lateral epithelium of the trench. Stage IV [Postnatal day (P) 0-3] - many PGP 9.5-IR nerve fibers penetrated the outer lateral epithelium of the trench; later in this stage, taste buds appeared. Stage V (P5-10) - a small number of PGP 9.5-IR cells in the taste buds appeared, and their number increased gradually. Stage VI (P14-adult) - the number of PGP 9.5-IR taste cells increased and reached the adult level, while the number of PGP 9.5-IR nerve fibers decreased. The development of NSE-LI was similar to that of PGP 9.5-LI. CGRP-IR nerve fibers were detected at E12 in the lamina propria, and the development of the intraepithelial CGRP-IR nerve fibers was similar to that of PGP 9.5-IR nerve fibers. The present results indicate that invasion by nerve fibers of the epithelium of lingual papillae occurs in a complex manner, and that these nerve fibers may participate in the formation of the taste buds.