Clinical Features of 544 Patients With Ruptured Aortic Aneurysm　- A Report From the Tokyo Acute Aortic Super Network Database.

BACKGROUND: Epidemiological data on ruptured aortic aneurysms from large-scale studies are scarce. The aims of this study were to: clarify the clinical course of ruptured aortic aneurysms; identify aneurysm site-specific therapies and outcomes; and determine the clinical course of patients receiving conservative therapy.Methods and Results: Using the Tokyo Acute Aortic Super Network database, we retrospectively analyzed 544 patients (mean [±SD] age 78±10 years; 70% male) with ruptured non-dissecting aortic aneurysms (AAs) after excluding those with impending rupture. Patient characteristics, status on admission, therapeutic strategy, and outcomes were evaluated. Shock or pulselessness on admission were observed in 45% of all patients. Conservative therapy, endovascular therapy (EVT), and open surgery (OS) accounted for 32%, 23%, and 42% of cases, respectively, with corresponding mortality rates of 93%, 30%, and 29%. The overall in-hospital mortality rate was 50%. The prevalence of pulselessness was highest (48%) in the ruptured ascending AA group, and in-hospital mortality was the highest (70%) in the ruptured thoracoabdominal AA group. Multivariable logistic regression analysis indicated in-hospital mortality was positively associated with pulselessness (odds ratio [OR] 10.12; 95% confidence interval [CI] 4.09-25.07), and negatively associated with invasive therapy (EVT and OS; OR 0.11; 95% CI 0.06-0.20). CONCLUSIONS: The outcomes of ruptured AAs remain poor; emergency invasive therapy is essential to save lives, although it remains challenging to reduce the risk of death.

Estrogens influence female itch sensitivity via the spinal gastrin-releasing peptide receptor neurons.

There are sex differences in somatosensory sensitivity. Circulating estrogens appear to have a pronociceptive effect that explains why females are reported to be more sensitive to pain than males. Although itch symptoms develop during pregnancy in many women, the underlying mechanism of female-specific pruritus is unknown. Here, we demonstrate that estradiol, but not progesterone, enhances histamine-evoked scratching behavior indicative of itch in female rats. Estradiol increased the expression of the spinal itch mediator, gastrin-releasing peptide (GRP), and increased the histamine-evoked activity of itch-processing neurons that express the GRP receptor (GRPR) in the spinal dorsal horn. The enhancement of itch behavior by estradiol was suppressed by intrathecal administration of a GRPR blocker. In vivo electrophysiological analysis showed that estradiol increased the histamine-evoked firing frequency and prolonged the response of spinal GRP-sensitive neurons in female rats. On the other hand, estradiol did not affect the threshold of noxious thermal pain and decreased touch sensitivity, indicating that estradiol separately affects itch, pain, and touch modalities. Thus, estrogens selectively enhance histamine-evoked itch in females via the spinal GRP/GRPR system. This may explain why itch sensation varies with estrogen levels and provides a basis for treating itch in females by targeting GRPR.

Usefulness of hybrid veno-arterial extracorporeal membrane oxygenation for lung ischemia-reperfusion injury after biventricular assist device implantation.

We experienced a case of fulminant myocarditis complicated by severe lung ischemia-reperfusion injury after switching from veno-arterial extracorporeal membrane oxygenation to biventricular assist device. We controlled lung blood flow by hybrid veno-arterial extracorporeal membrane oxygenation, which was established by modifying the biventricular assist device circuit without resternotomy, blood delivery to the pulmonary artery and blood removal from the left ventricle in addition to central veno-arterial extracorporeal membrane oxygenation, and accelerated lung recovery. The patient's lung damage and cardiac function were restored, and she completely recovered and was discharged without any complications. Regulation of lung blood flow is important and effective for lung ischemia-reperfusion injury after biventricular assist device implantation.

Subcellular dynamics of estrogen-related receptors involved in transrepression through interactions with scaffold attachment factor B1.

Estrogen-related receptor (ERR), a member of the nuclear receptor superfamily, consists of three subtypes (α, ß, γ) and has strong homology with estrogen receptor. No endogenous ligands have been identified for ERRs, but they play key roles in metabolic, hormonal, and developmental processes as transcription factors without ligand binding. Although subnuclear dynamics are essential for nuclear events including nuclear receptor-mediated transcriptional regulation, the dynamics of ERRs are poorly understood. Here, we report that ERRs show subcellular kinetic changes in response to diethylstilbestrol (DES), a synthetic estrogen that represses the transactivity of all three ERR subtypes, using live-cell imaging with fluorescent protein labeling. Upon DES treatment, all ERR subtypes formed discrete clusters in the nucleus, with ERRγ also displaying nuclear export. Fluorescence recovery after photobleaching analyses revealed significant reductions in the intranuclear mobility of DES-bound ERRα and ERRß, and a slight reduction in the intranuclear mobility of DES-bound ERRγ. After DES treatment, colocalization of all ERR subtypes with scaffold attachment factor B1 (SAFB1), a nuclear matrix-associated protein, was observed in dot-like subnuclear clusters, suggesting interactions of the ERRs with the nuclear matrix. Consistently, co-immunoprecipitation analyses confirmed enhanced interactions between ERRs and SAFB1 in the presence of DES. SAFB1 was clarified to repress the transactivity of all ERR subtypes through the ERR-response element. These results demonstrate ligand-dependent cluster formation of ERRs in the nucleus that is closely associated with SAFB1-mediated transrepression. Taken together, the present findings provide a new understanding of the pathophysiology regulated by ERR/SAFB1 signaling pathways and their subcellular dynamics.

Scaffold attachment factor B: distribution and interaction with ERα in the rat brain.

Scaffold attachment factor (SAFB) 1 and its homologue SAFB2 are multifunctional proteins that are involved in various cellular mechanisms, including chromatin organization and transcriptional regulation, and are also corepressors of estrogen receptor alpha (ERα). Both SAFBs are expressed at high levels in the brain. However, the distributions of SAFB1 and SAFB2 have yet to be characterized in detail and it is unclear whether both proteins interact with ERα in the brain. In this study, we investigated the expression and distribution of both SAFBs and their interaction with ERα in adult male rat brain. Immunohistochemical staining showed that SAFB1 and SAFB2 have a similar distribution pattern and are widely expressed throughout the brain. Double-fluorescence immunohistochemical and immunocytochemical analyses in primary cultures showed that the two SAFB proteins are localized in nuclei of neurons, astrocytes, and oligodendrocytes. Of note, SAFB2 was also found in cytoplasmic regions in these cell lineages. Both SAFB proteins were also expressed in ERα-positive cells in the medial preoptic area (MPOA) and arcuate and ventromedial hypothalamic nuclei. Co-immunoprecipitation experiments revealed that both SAFB proteins from the MPOA reciprocally interact with endogenous ERα. These results indicate that, in addition to a role in basal cellular function in the brain, the SAFB proteins may serve as ERα corepressors in hormone-sensitive regions.

Is systolic blood pressure high in patients with acute aortic dissection on first medical contact before hospital transfer?

Acute aortic dissection (AAD) cases are thought to have high blood pressure (BP) on admission; however, little data are available on BP prior to admission. The purpose of this study was to investigate systolic blood pressure (SBP) very early after symptom onset and before hospital transfer in patients with AAD to determine whether SBPs were high, and also whether SBPs were higher or lower compared with SBPs at hospital admission. We obtained results using three-year data derived from the Tokyo Acute Aortic Super Network Database. First, we selected 830 patients with AAD for which the "duration from symptom onset to first medical contact by ambulance crews" (SO-FMC) was within 60 min. We examined the SBPs of such patients. Next, we selected 222 patients with AAD whose SBPs were measured both at FMC, within 15 min after symptom onset, and at hospital admission, and compared SBPs at FMC with those at hospital admission. Among types A (n = 190) and B (n = 117), in patients with an SO-FMC ≤ 15 min, the median SBP was 100 mmHg and 178 mmHg (p < 0.001), respectively; 9% and 50% (p < 0.001) of such patients, respectively, exhibited an SBP ≥ 180 mmHg; and 43% and 10% (p < 0.001) of such patients, respectively, had an SBP < 90 mmHg. Of patients with types A (n = 124) and B (n = 98) AAD whose SBPs were measured both at FMC, within 15 min after symptom onset, and at hospital admission, SBPs at FMC were higher than those at hospital admission for the SBP ≥ 180 mmHg subgroups of both type A (194 mmHg vs. 159 mmHg, p < 0.001) and type B (199 mmHg vs. 186 mmHg, p < 0.001). Approximately 10 min after symptom onset and before hospital transfer, the measured SBPs of many patients with type A AAD were not necessarily high. However, the SBPs of cases with type B AAD were high as previously reported for SBP on admission. In addition, for the subgroup of SBP ≥ 180 mmHg at FMC within 15 min after symptom onset, SBPs at FMC were significantly higher than those at hospital admission for both types A and B; the higher SBP at symptom onset may have been partially associated with being a trigger of AD.

A case of HeartMate II implantation in non-dilated left ventricle.

Left ventricular assist device is an established therapeutic option for the patient with end-stage heart failure. Recently, durable continuous-flow devices have replaced earlier generation of pulsatile devices and their desirable features are accelerating the utilization of these devices. However, their powerful performance could sometimes induce unfavorable complications such as sucking, especially in not so dilated left ventricle. Special maneuvers such as cannula position and lower pump speed may be reasonable for patients with non-dilated left ventricular, however, those managements have not been established yet to date. Right ventricular failure is also another concern in these devices. We experienced a patient who got a HeartMate II in spade-shaped, non-dilated left ventricle concomitant with right ventricular dysfunction, and successfully managed her.

Effect of Footprint Preparation on Tendon-to-Bone Healing: A Histologic and Biomechanical Study in a Rat Rotator Cuff Repair Model.

PURPOSE: To compare the histologic and biomechanical effects of 3 different footprint preparations for repair of tendon-to-bone insertions and to assess the behavior of bone marrow-derived cells in each method of insertion repair. METHODS: We randomized 81 male Sprague-Dawley rats and green fluorescent protein-bone marrow chimeric rats into 3 groups. In group A, we performed rotator cuff repair after separating the supraspinatus tendon from the greater tuberosity and removing the residual tendon tissue. In group B, we also drilled 3 holes into the footprint. The native fibrocartilage was preserved in groups A and B. In group C, we excavated the footprint until the cancellous bone was exposed. Histologic repair of the tendon-to-bone insertion, behavior of the bone marrow-derived cells, and ultimate force to failure were examined postoperatively. RESULTS: The areas of metachromasia in groups A, B, and C were 0.033 ± 0.019, 0.089 ± 0.022, and 0.002 ± 0.001 mm2/mm2, respectively, at 4 weeks and 0.029 ± 0.022, 0.090 ± 0.039, and 0.003 ± 0.001 mm2/mm2, respectively, at 8 weeks. At 4 and 8 weeks postoperatively, significantly higher cartilage matrix production was observed in group B than in group C (4 weeks, P = .002; 8 weeks, P < .001). In green fluorescent protein-bone marrow chimeric rats in group B, bone marrow-derived chondrogenic cells infiltrated the fibrocartilage layer. Ultimate force to failure was significantly higher in group B (19.7 ± 3.4 N) than in group C (16.7 ± 2.0 N) at 8 weeks (P = .031). CONCLUSIONS: Drilling into the footprint and preserving the fibrocartilage improved the quality of repair tissue and biomechanical strength at the tendon-to-bone insertion after rotator cuff repair in an animal model. CLINICAL RELEVANCE: Drilling into the footprint and preserving the fibrocartilage can enhance repair of tendon-to-bone insertions. This method may be clinically useful in rotator cuff repair.

Estrogen-related Receptor ß Reduces the Subnuclear Mobility of Estrogen Receptor α and Suppresses Estrogen-dependent Cellular Function.

Estrogen-related receptor (ERR) is a member of the nuclear receptor superfamily that has strong homology with estrogen receptor (ER) α. ERR has three subtypes (α, ß, and γ) expressed in estrogen-sensitive organs, including ovary, breast, and brain. No endogenous ligands of ERRs have been identified, but these receptors share a common DNA element with ERα and control estrogen-mediated gene transcription. Recent evidence suggests a role of ERRs in estrogen-related pathophysiology, but the detailed mechanisms of ERR functions in estrogen-related tissues are unclear. Using live-cell imaging with fluorescent protein labeling, we found that only ERRß among the ERRs exhibits a punctate intranuclear pattern overlapping with ERα following 17ß-estradiol (E2)-stimulation. Fluorescence recovery after photobleaching showed significant reduction of the mobility of ligand-activated ERα with co-expression of ERRß. Fluorescence resonance energy transfer revealed that ERRß directly interacts with ERα. The N-terminal domain of ERRß was identified as the region that interacts with ERα. We also found a correlation between punctate cluster formation of ERα and interaction between the receptors. Expression of ERRß significantly repressed ERα-mediated transactivity, whereas that of other ERR subtypes had no effect on the transactivity of ERα. Consistent with this finding, E2-stimulated proliferation of MCF-7 breast carcinoma cells and bcl-2 expression was significantly inhibited by expression of ERRß. These results provide strong evidence for a suppressive effect of ERRß on estrogen signaling through reduction of the intranuclear mobility of ERα. The findings further suggest a unique inhibitory role for ERRß in estrogen-dependent cellular function such as cancer cell proliferation.

A rare case of axillobifemoral bypass graft infection caused by Helicobacter cinaedi.

Helicobacter cinaedi infection is rarely encountered in nonimmunocompromised patients. We report the case of an 85-year-old man who presented with axillobifemoral bypass graft infection caused by Helicobacter cinaedi. The patient was not immunocompromised. We successfully treated him by iliac stenting of the native iliac artery, with near-total removal of the infected graft. At present, 48 months later, the patient is doing well at home, with no evidence of infection. To the best of our knowledge, this is the first report of infection of a prosthetic graft caused by Helicobacter cinaedi.

Diffusion tensor imaging assesses triceps surae dysfunction after achilles tenotomy in rats.

PURPOSE: To elucidate the relationship of diffusion tensor imaging (DTI) with structural changes and muscle function in skeletal muscle. MATERIALS AND METHODS: The subjects were 21 12-week-old male rats. Achilles tenotomy was performed on the right legs. Proton density-weighted images and DTI (7.04T) of the triceps surae at 2 and 4 weeks posttenotomy were obtained. Eigenvalues (λ) and fractional anisotropy (FA) were calculated from the muscle images. After imaging, histological specimens of the triceps surae were prepared. The long axis and cross-sectional area of the triceps surae were measured 2 and 4 weeks postoperatively. The strength of ankle plantar flexion was measured. Correlations of DTI parameters with morphological values and muscle strength were analyzed. RESULTS: λ1 declined after tenotomy (P < 0.01), and λ2 and λ3 declined at 4 weeks posttenotomy (P < 0.01). FA increased at 4 weeks posttenotomy (P < 0.01). Atrophy of the triceps surae was observed in the tissues images of the treatment group. The muscle belly significantly shortened postoperatively, and a decline in plantar flexion force was observed after tenotomy. Positive correlations were observed between λ1 and muscle strength (r = 0.89) and between λ1 and the length of the long axis of the muscle belly (r = 0.81). CONCLUSION: DTI may serve as a marker of muscle function.

Detection of early changes after growth plate injury using MRI.

BACKGROUND: To elucidate the association between growth plate injury size and the beginning of physeal growth disturbance by MRI. METHODS: Thirty-two 5-week-old male Japanese white rabbits were used. Injuries were made to the right tibial proximal growth plate central region with a 3.0-mm and a 1.2-mm drill. The left tibia was used as a control. MRI (7.04 Tesla [T], gradient echo: repetition time [TR], 71.68 ms; echo time [TE], 3.60 ms; proton-density weighted imaging: TR, 2000 ms; TE, 12 ms) of the growth plates was performed at 1, 4, 8, 10, and 12 weeks postinjury. Tibia length, histology, radiography, and microcomputed tomography (µCT) were studied. RESULTS: MRI showed that at 10 and 12 weeks postinjury in the 3.0-mm group, the medial and lateral growth plates in the noninjured regions were significantly reduced compared with the controls (P < 0.05). At 12 weeks postinjury in the 1.2-mm group, medial and lateral growth plates in the noninjured regions were significantly reduced (P < 0.05). Tibia length and histological growth plate height of injured side in both groups were significantly shorter than controls at 12 weeks postinjury (P < 0.05). Comparison with the controls showed no significant difference at any of the time periods in either the 3.0- or 1.2-mm group according to the radiographic studies (P > 0.05). Bony bridges developed in all the subjects of the 3.0-mm group and in five of eight subjects of the 1.2-mm group, as shown by µCT images. CONCLUSION: This study suggested that growth plate injury size was associated with the timing of the beginning of physeal growth disturbance.

Cortical bone water changes in ovariectomized rats during the early postoperative period: Objective evaluation using sweep imaging with Fourier transform.

PURPOSE: To evaluate the cortical bone signal-to-noise ratio (SNR) in ovariectomized (OVX) rats during the early postoperative period as a method to measure bone quality using the sweep imaging with Fourier transform (SWIFT) technique. MATERIALS AND METHODS: Twelve-week-old female Sprague-Dawley rats (n = 64) were divided into sham and OVX groups. Preoperative tetracycline was immediately administered subcutaneously to distinguish new cortical bone area, and tibial samples were collected at 2, 4, 8, and 12 weeks postoperatively. Magnetic resonance imaging (MRI) was performed using proton density-weighted imaging (PDWI) and SWIFT to obtain cross-sectional images of the tibial diaphysis. The cortical bone SNR was calculated. Bone histomorphometry was performed. RESULTS: Histomorphometry findings showed that the new bone area was significantly greater at 8 and 12 weeks postoperatively in the OVX group (P < 0.05) while the porosity area decreased gradually in both groups (P < 0.001). The difference of SNR receiving PDWI did not reach statistical significance (P = 0.057). The SWIFT technique showed that the SNR was significantly higher at 8 and 12 weeks postoperatively in the OVX group (P < 0.05) and was correlated with the new bone area (R(2) = 0.430). CONCLUSION: The SWIFT findings suggest that the SWIFT technique may depict early changes in cortical bone quality.

[Combined Open and Endovascular Repair of Multiple Aortic Aneurysms due to Syphilitic Aortitis].

The patient was a 69-year-old man who presented with low-grade fever and appetite loss. Thoracoabdominal computed tomography revealed multiple aneurysms in the distal arch and descending thoracic and infrarenal aortic regions combined with a right common iliac artery aneurysm. After endovascular stent grafting for a right iliac artery aneurysm, he underwent total arch replacement and open stent grafting for the descending thoracic aneurysms. Pathological microscopic examination revealed an inflammatory infiltrate within the adventitia and destruction of the elastic fibers in the media, which are classical features of syphilitic aortitis. Endovascular aneurysm repair is contraindicated in mycotic infected aneurysms. However, endovascular repair is useful for treating mycotic infected aneurysm, if multiple aneurysms have the possibility of rupture and a high risk of surgery.

[DeBakey type 2 Aortic Dissection Failed to Diagnose by Enhanced Computed Tomography;Report of a Case].

An 81-year-old woman presented with dyspnea and chest pain. A plain chest X-ray revealed widening of the mediastinum and a contrast-enhanced chest computed tomography showed dilatation of the ascending aorta without any specific findings of aortic dissection. Transesophageal echocardiography revealed severe aortic regurgitation (AR). We planned an aortic valve replacement on the 34th day after admission because of the severe AR. During the operation, we found an entry in the intima of the ascending aorta 5 mm above the aortic valve and she was diagnosed with DeBakey type II aortic dissection. Therefore, we decided to perform Bentall's operation and the operation was successful.

[Vacuum-assisted Closure (VAC) Treatment for Sternal Infection in a Patient after Cardiovascular Surgery; Report of a Case].

One year ago, a 42-year-old woman underwent aortic root replacement because of a pseudoaneurysm that developed at the site of an anastomosis after ascending aortic replacement for acute aortic dissection. Six months later, she complained of fever and cough. A computed tomography revealed recurrence of the peudoaneurysm at the proximal anastomosis of the aortic root replacement. After emergency re-do aortic root replacement, she was admitted to intensive care unit (ICU) without sternal closure because of mediastinitis. The mediastinitis was managed by debridement and lavage drainage, followed by vacuum-assisted closure (VAC) treatment. The VAC treatment facilitated wound healing and active rehabilitation using a portable device. Finally, the wound was closed completely using a skin graft. VAC treatment is considered very useful in a case of post-sternotomy madiastinitis.

Bisphenol A regulates the estrogen receptor alpha signaling in developing hippocampus of male rats through estrogen receptor.

Bisphenol A (BPA), one of the most common environmental endocrine disruptors, has been recognized to have wide adverse effects on the brain development and behavior. These adversities are related to its ability to bind estrogen receptor (ER) with subsequent alteration of its expression in the target areas. However, very little is known about whether BPA exposure also affects ER phosphorylation and its translocation to nucleus during postnatal development, two critical steps for its function. Here, we found that during development from postnatal day 7 (P7) to P21, the alpha subtype of ER (ERα) in the hippocampus of male rats experienced remarkable alterations in terms of its expression, phosphorylation and translocation to nucleus. Exposure to low level of BPA had bidirectional, development-dependent effects on the expression of ERα mRNA and protein, but decreased ERα phosphorylation and impaired its translocation to nucleus throughout the period investigated. Treatment with low dose of ICI 182,780 (ICI), an ER antagonist to block the binding of ER with BPA, reversed the altered ERα following BPA exposure, highlighting critical involvement of ER. Moreover, ICI treatment rescued the hippocampus-dependent behavioral deficits in the adult rats experiencing early-life BPA exposure. Overall, our results indicate that BPA interferes with the ERα signaling in the developing hippocampus in an ER-dependent manner, which may underlie its adverse behavioral and cognitive outcomes in adult animals.

Selective visualization of rabbit knee cartilage using MR imaging with a double-contrast agent.

PURPOSE: To establish a reliable method and efficient contrast agent for selective MR imaging of articular cartilage to improve the diagnosis of cartilage disorders. MATERIALS AND METHODS: A standard trace element replenisher (Mineric), which includes manganese chloride, cupric sulfate (both positive MR contrast agents), and colloidal ferric chloride (a negative contrast agent), was evaluated in comparison with gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) as a potential contrast agent. Normal saline was used as a control. The agents were injected into bilateral knee joints, and the entire joint block was dissected. Coronal images of femorotibial joints were obtained at 7.05 Tesla. Signal intensity ratios (SIRs) of cartilage to joint fluid were calculated for T1 and T2 values. The side effects of the agents were also investigated. Finally, histological evaluations were performed. RESULTS: SIRs were significantly increased in the Mineric treatment group compared with the Gd-DTPA and saline treatment groups. The T1 values of cartilage and fluid were significantly decreased in the Gd-DTPA and Mineric treatment groups. The T2 values of fluid were significantly decreased in the Mineric treatment group. No apparent side effects or degenerative changes in the joints were observed. CONCLUSION: A clinical trace element mixture was used as a novel double-contrast agent, and it exhibits selective MR contrast in articular cartilage.

Conservative therapy as a primary treatment for spontaneous isolated dissection of the superior mesenteric artery.

BACKGROUND: Spontaneous isolated dissection of the superior mesenteric artery (SIDSMA) is a rare and potentially fatal disease. Several therapeutic options are available, including conservative therapy, endovascular repair, and open surgery. Herein, we report our experiences in the treatment of SIDSMA. METHODS: Between February 2009 and June 2013, 17 patients were diagnosed as having SIDSMA. We retrospectively reviewed and analyzed their clinical characteristics, medical history, risk factors, symptoms, diagnostic imaging modality, treatment, and outcome. The lesions were categorized according to the modified Sakamoto's classification. If no evidence of bowel necrosis or arterial rupture was present in the patients with symptomatic SIDSMA, we first performed conservative therapy, even if the patients had abdominal pain. RESULTS: The subjects included 15 men and 2 women, with a median age of 62.8 years. Eight patients were symptomatic and 9 were asymptomatic. Conservative therapy included the use of antithrombotic agents in 3 patients but not in 5 patients. During the follow-up period (mean, 21.1 months), all the patients were discharged without any significant complications, and none of the patients showed the progression of the dissection on follow-up computed tomography angiography examinations. CONCLUSIONS: Conservative therapy without antithrombotic agents should be the primary treatment for SIDSMA. Endovascular repair for SIDSMA is associated with several risks, thus the procedure might occasionally be useful and necessary.

Fetal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin transactivates aryl hydrocarbon receptor-responsive element III in the tyrosine hydroxylase immunoreactive neurons of the mouse midbrain.

Fetal exposure to dioxins and related compounds is known to disrupt normal development of the midbrain dopaminergic system, which regulates behavior, cognition and emotion. The toxicity of these chemicals is mediated mainly by aryl hydrocarbon receptor (AhR) signaling. Previously, we identified a novel binding motif of AhR, the AhR-responsive element III (AHRE-III), in vitro. This motif is located upstream from the gene encoding tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine biosynthesis. To provide in vivo evidence, we investigated whether 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) could regulate AHRE-III transcriptional activity in midbrain dopaminergic neurons. We produced transgenic mice with inserted constructs of the AHRE-III enhancers, TH gene promoter and the c-myc-tagged luciferase gene. Single oral administrations of TCDD (0-2000 ng kg⁻¹ body weight) to the transgenic dams markedly enhanced TH-immunoreactive (ir) intensity in the A9, A10 and A8 areas of their offspring at 3 days and 8 weeks of age. The offspring of dams treated with 200 ng kg⁻¹ TCDD exhibited significant increases in the numbers of TH- and double (TH and c-myc)-ir neurons in area A9 compared with controls at 8 weeks. These results show that fetal exposure to TCDD upregulates TH expression and increases TH-ir neurons in the midbrain. Moreover, the results suggest that TCDD directly transactivates the TH promoter via the AhR-AHRE-III-mediated pathway in area A9. Fetal exposure to TCDD caused stable upregulation of TH via the AhR-AHRE-III signaling pathway and overgrowth of TH-ir neurons in the midbrain, implying possible involvement in the etiology of neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD).