Artery of the Superior Orbital Fissure: An Undescribed Branch from the Pterygopalatine Segment of the Maxillary Artery to the Orbital Apex Connecting with the Anteromedial Branch of the Inferolateral Trunk.

BACKGROUND AND PURPOSE: Some branches of the internal maxillary artery have anastomoses with the inferolateral trunk that are important as intracranial-extracranial collateral pathways and as dangerous anastomoses for transarterial embolization of these branches. We present here an undescribed branch potentially anastomosing with the anteromedial branch of the inferolateral trunk, which is provisionally named the artery of the superior orbital fissure, defined as an arterial branch from the pterygopalatine segment of the maxillary artery to the orbital apex at the superior orbital fissure. MATERIALS AND METHODS: Two neuroradiologists reviewed 3D and MPR images of the external and/or common carotid artery with particular interest paid to the artery of the superior orbital fissure in 54 patients who underwent 3D angiography with a field of view covering the pterygopalatine fossa and the cavernous sinus. The underlying diseases in these patients were 17 parasellar hypervascular lesions (including 13 cavernous sinus dural arteriovenous fistulas and 4 meningiomas), 18 internal carotid artery stenoses/occlusions, and 19 other diseases. RESULTS: The artery of the superior orbital fissure was identified in 20 of 54 patients; it arose at the pterygopalatine segment of the maxillary artery, either singly or from a common trunk with the artery of the foramen rotundum, and ran upward to reach the superior orbital fissure. It anastomosed with the anteromedial branch of the inferolateral trunk at the superior orbital fissure with blood flow toward the cavernous sinus (n = 14) and/or the ophthalmic artery (n = 2). It was more prominent in parasellar hypervascular lesions and internal carotid artery stenoses/occlusions than in other diseases. CONCLUSIONS: The artery of the superior orbital fissure, a remnant of the anastomotic artery, was often identified, especially in patients with parasellar hypervascular lesions.

Survival of HER2-positive primary breast cancer patients treated by neoadjuvant chemotherapy plus trastuzumab: a multicenter retrospective observational study (JBCRG-C03 study).

We investigated the disease-free survival (DFS) of HER2-positive primary breast cancer patients treated with neoadjuvant chemotherapy plus trastuzumab, as well as predictive factors for DFS and pathologic response. Data from 829 female patients treated between 2001 and 2010 were collected from 38 institutions in Japan. Predictive factors were evaluated using multivariate analyses. The 3-year DFS rate was 87 % [95 % confidence interval (CI) 85-90]. The pathologic complete response (pCR: ypT0/is + ypN0) rate was 51 %. The pCR rate was higher in the ER/PgR-negative patients than in the ER/PgR-positive patients (64 vs. 36 %, P < 0.001). Patients with pCR showed a higher DFS rate than patients without pCR (93 vs. 82 %, P < 0.001). Multivariate analysis revealed three independent predictors for poorer DFS: advanced nodal stage [hazard ratio (HR) 2.63, 95 % CI 1.36-5.21, P = 0.004 for cN2-3 vs. cN0], histological/nuclear grade 3 (HR 1.81, 95 % CI 1.15-2.91, P = 0.011), and non-pCR (HR 1.98, 95 % CI 1.22-3.24, P = 0.005). In the ER/PgR-negative dataset, non-pCR (HR 2.63, 95 % CI 1.43-4.90, P = 0.002) and clinical tumor stage (HR 2.20, 95 % CI 1.16-4.20, P = 0.017 for cT3-4 vs. cT1-2) were independent predictors for DFS, and in the ER/PgR-positive dataset, histological grade of 3 (HR 3.09, 95 % CI 1.48-6.62, P = 0.003), clinical nodal stage (HR 4.26, 95 % CI 1.53-13.14, P = 0.005 for cN2-3 vs. cN0), and young age (HR 2.40, 95 % CI 1.12-4.94, P = 0.026 for ≤40 vs. >40) were negative predictors for DFS. Strict pCR (ypT0 + ypN0) was an independent predictor for DFS in both the ER/PgR-negative and -positive datasets (HR 2.66, 95 % CI 1.31-5.97, P = 0.006 and HR 3.86, 95 % CI 1.13-24.21, P = 0.029, respectively). These results may help assure a more accurate prognosis and personalized treatment for HER2-positive breast cancer patients.

Angioarchitecture of transverse-sigmoid sinus dural arteriovenous fistulas: evaluation of shunted pouches by multiplanar reformatted images of rotational angiography.

BACKGROUND AND PURPOSE: Recognition of shunted pouches dural arteriovenous fistula allows us to treat the disease effectively by selective embolization of the pouches at first. However, the shunted pouches in transverse-sigmoid sinus dural arteriovenous fistulas have not been well-documented. Our aim was to evaluate the angioarchitecture of transverse-sigmoid sinus dural arteriovenous fistulas, including the frequency and location of shunted pouches and their feeding arteries. MATERIALS AND METHODS Twenty-five consecutive cases of TSS-DAVFs that underwent rotational angiography and transvenous embolization between 2008 and 2011 were reviewed. Multiplanar reformatted images of rotational angiography and selective angiography were reviewed with a particular focus on the shunted pouches. RESULTS: All 25 cases showed SPs, with numbers ranging from 1 to 4 pouches (mean, 2.35). The SPs were located at the transverse-sigmoid junction in 16, close to the vein of Labbé in 9, at the dorsal-to-sigmoid sinus in 9, inferior to the sigmoid sinus in 6, at the sigmoid-jugular junction in 5, and inferior to the transverse sinus or the sinus confluence in 14. The SP at the sigmoid sinus was frequently fed by the jugular branch of the ascending pharyngeal artery and the stylomastoid artery. The SP at the transverse-sigmoid junction and the vein of Labbé was fed by the petrosal/petrosquamous and posterior branches of the middle meningeal artery and the transosseous branches of the occipital artery. The SP inferior to the transverse sinus and the sinus confluence was fed by the transosseous branches of the occipital artery and the posterior meningeal artery. All cases were successfully treated by transvenous embolization with sinus packing (n = 13) or selective embolization of the SP (n = 12). CONCLUSIONS: The presence of SP is a common angioarchitecture of TSS-DAVFs. Identification of the SPs would be useful for their treatment.

Whole sentinel lymph node analysis by a molecular assay predicts axillary node status in breast cancer.

BACKGROUND: The one-step nucleic acid amplification (OSNA) assay is a rapid procedure for the detection of lymph node (LN) metastases using molecular biological techniques. The aim of this study was to assess the reliability of the whole sentinel lymph node (SLN) analysis by the OSNA assay as a predictor of non-SLN metastases. METHODS: Consecutive 742 patients with breast cancer were enroled in the study. The association of non-SLN or ≥4 LN metastases with clinicopathological variables was investigated using multivariate logistic analysis. RESULTS: In total, 130 patients with a positive SLN who underwent complete axillary LN dissection were investigated. The frequency of non-SLN metastases in patients who were OSNA+ and ++ was 19.3% and 53.4%, respectively, and that in patients with ≥4 LN metastases who were OSNA+ and ++ was 7.0% and 27.4%, respectively. The cytokeratin 19 (CK19) mRNA copy number (≥5.0 × 10(3); OSNA++) in the SLN was the most significant predictors of non-SLN metastases (P=0.003). The CK19 mRNA copy number (≥1.0 × 10(5)) in the SLN was the only independent predictor of ≥4 LN metastases (P=0.014). CONCLUSION: Whole SLN analysis using the OSNA assay could become a valuable method for predicting non-SLN and ≥4 LN metastases.

Venous structures at the craniocervical junction: anatomical variations evaluated by multidetector row CT.

The aim of this study was to evaluate the anatomy of and normal variations in the craniocervical junction veins. We retrospectively reviewed 50 patients who underwent contrast-enhanced CT with a multidetector scanner. Axial and reconstructed images were evaluated by two neuroradiologists with special attention being paid to the existence and size of veins and their relationships with other venous branches around the craniocervical junction. The venous structures contributing to craniocervical junction venous drainage, including the inferior petrosal sinus (IPS), transverse-sigmoid sinus, jugular vein, condylar vein, marginal sinus and suboccipital cavernous sinus were well depicted in all cases. The occipital sinus (OS) was identified in 18 cases, including 4 cases of prominent-type OS. The IPS showed variations in drainage to the jugular vein through the jugular foramen or intraosseous course of occipital bone via the petroclival fissure. In all cases, the anterior condylar veins connected the anterior condylar confluence to the marginal sinus; however, a number of cases with asymmetry and agenesis in the posterior and lateral condylar veins were seen. The posterior condylar vein connected the suboccipital cavernous sinus to the sigmoid sinus or anterior condylar confluence. The posterior condylar canal in the occipital bone showed some differences, which were accompanied by variations in the posterior condylar veins. In conclusion, there are some anatomical variations in the venous structures of the craniocervical junction; knowledge of these differences is important for the diagnosis and treatment of skull base diseases. Contrast-enhanced CT using a multidetector scanner is useful for evaluating venous structures in the craniocervical junction.

Human papillomavirus detected in female breast carcinomas in Japan.

To investigate the aetiological role of human papillomavirus (HPV) in breast cancer, we examined the presence, genotype, viral load, and physical status of HPV in 124 Japanese female patients with breast carcinoma. Human papillomavirus presence was examined by PCR using SPF10 primers, and primer sets targeting the E6 region of HPV-16, -18, and -33. The INNO-LiPA HPV genotyping kit was used to determine genotype. Human papillomavirus DNA was detected in 26 (21%) breast carcinomas. The most frequently detected HPV genotype was HPV-16 (92%), followed by HPV-6 (46%), HPV-18 (12%), and HPV-33 (4%). In 11 normal epithelium specimens adjacent to 11 HPV-16-positive carcinomas, 7 were HPV-16-positive. However, none of the normal breast tissue specimens adjacent to HPV-negative breast carcinomas were HPV-positive. The real-time PCR analysis suggested the presence of integrated form of viral DNA in all HPV-16-positive samples, and estimated viral load was low with a geometric mean of 5.4 copies per 10(4) cells. In conclusion, although HPV DNA was detected in 26 (21%) breast carcinomas and, in all HPV-16-positive cases, the HPV genome was considered integrated into the host genome, their low viral loads suggest it is unlikely that integrated HPV is aetiologically involved in the development of Japanese breast carcinomas that we examined.

Dural arteriovenous fistula involving the posterior condylar canal.

Although dural arteriovenous fistulas (DAVFs) occur in any structure that is covered by the dura mater, DAVFs at the posterior condylar canal have not been reported. We present a DAVF that involves the posterior condylar canal and drains into the posterior condylar vein and the occipital sinus, which was treated by selective transvenous embolization. Knowledge of venous anatomy of the craniocervical junction and careful assessment of the location of the arteriovenous fistula can contribute to successful treatment.

Inferior mesenteric veno-caval shunt: imaging features and interventional treatment.

AIM: To describe the imaging features of inferior mesenteric vein (IMV)-inferior vena cava (IVC) shunts, and to describe a treatment strategy for portosystemic encephalopathy, which can be caused by them. MATERIALS AND METHODS: Between 2000 and 2004, we treated seven patients who had symptomatic IMV-IVC shunts. The results of imaging investigations, which included contrast-enhanced computed tomography (CT), angiography, and CT during arterial portography, were reviewed retrospectively. We also present our results in the four patients who were treated by retrograde transcaval obliteration (RTCO). RESULTS: The IMV-IVC shunts had a tortuous or cirsoid appearance ranging in size from 7.2-14.6 mm. The shunts were located at a level near to the first branch of the inferior mesenteric artery. The four patients were successfully treated by RTCO and their clinical symptoms improved. CONCLUSION: IMV-IVC shunts show a tortuous or cirsoid appearance, connecting at or near the first branch of the inferior mesenteric artery. For symptomatic IMV-IVC shunts, RTCO is recommended as the first choice treatment.

Selective transvenous embolization of dural arteriovenous fistulas involving the hypoglossal canal.

SUMMARY: The hypoglossal canal contains a venous plexus that connects the inferior petrous sinus, condylar vein, jugular vein and paravertebral plexus. The venous plexus is one of the venous drainage routes of the posterior skull base. Only a few cases of dural arteriovenous fistulas (AVFs) involving the hypoglossal canal have been reported. We describe three cases (a 62-year-old female, a 52-year-old male, and an 83-year-old male) of dural AVFs involving the hypoglossal canal. Symptoms were pulse-synchronous bruit in two cases and proptosis/chemosis in one. All dural AVFs were mainly fed by the ipsilateral ascending pharyngeal artery. Two of three dural AVFs involving the hypoglossal canal mainly drained through the anterior condylar confluence into the inferior petrosal sinus retrogradely with antegrade drainage through the lateral condylar vein. The other one drained through the lateral and posterior condylar veins into the suboccipital cavernous sinus. All dural AVFs were completely occluded by selective transvenous embolization without any complications, and the symptoms disappeared within one week in all cases. Dural AVFs involving the hypoglossal canal can be successfully treated by selective transvenous embolization with critical evaluation of venous anatomy in each case.

Para-cavernous sinus venous structures: anatomic variations and pathologic conditions evaluated on fat-suppressed 3D fast gradient-echo MR images.

BACKGROUND: The cavernous sinus communicates with several para-cavernous sinus venous structures, receiving blood flow from the superficial middle cerebral vein (SMCV), the sphenoparietal sinus (SPS), and the superior ophthalmic vein, and draining into the superior and inferior petrosal sinuses and pterygoid and basilar plexuses. Anatomic variations of these veins have been previously reported; however, some details, such as the relationship between the SPS and the SMCV, are incompletely characterized. The anatomic variations of para-cavernous sinus veins, especially drainage patterns of the SMCV, were evaluated on MR imaging. MATERIALS AND METHODS: Thirty-seven patients, including those without any lesions affecting the cavernous sinus or para-cavernous veins and patients with carotid cavernous fistulas, were examined by using fat-suppressed contrast-enhanced 3D fast gradient-echo MR imaging. Two neuroradiologists evaluated the images on a viewer, regarding the normal anatomy and the pathologic findings of the para-cavernous sinus veins. RESULTS: The fat-suppressed 3D fast gradient-echo MR images clearly depicted the para-cavernous sinus venous structures in all patients. SMCVs had 4 variations in the drainage patterns. The most frequent pattern was drainage into the SPS (39%), and other types were draining into cavernous sinus, pterygoid plexus, and tentorial sinus. The SPS had 3 variations. The most frequent pattern was drainage into cavernous sinus (72%), and others were the hypoplastic type or those draining into pterygoid plexus. CONCLUSION: The fat-suppressed 3D fast gradient-echo MR image is useful for evaluating the venous structures in the skull base. Knowledge of the variations is important for diagnosis and endovascular treatment of the cavernous sinus lesions.

[Primary malignant lymphoma of the rib; report of a case].

We experienced a rare case of primary malignant lymphoma of the rib. The case was a 67-year-old female. An abnormal shadow of the chest X-ray was pointed out. Preoperative diagnosis was extrapulmonary lesion on the chest computed tomography (CT) and magnetic resonance imaging (MRI). The tumor accompanied with chest wall resection was done. The tumor cell was appeared in the bone marrow diffusely. The tumor invaded the canal of bone cortex and expanded the neighbor tissue. Histologically tumor was diagnosis of the malignant lymphoma, diffuse large B-cell type, stained by negative in L 26, positive in CD 43, positive in CD 79 a, negative in UCHL-1, and negative in CD 3. EBV-encoded small RNAs (EBERs) and EBV-EBNA 2 was negative. This tumor was not able to proved to Epstein-Bar virus.

Clinical significance of Caveolin-1, Caveolin-2 and HER2/neu mRNA expression in human breast cancer.

Caveolin-1 and -2 (CAV1, CAV2) are closely linked genes localised to the fragile region of 7q31 (FRA7G), and loss of heterozygosity involving this region has been reported in breast cancer. Several studies have suggested that CAV1 is a negative regulator of HER2/neu signal transduction in vitro. However, the clinical significance of CAV1 in breast cancer has not yet been clarified. We examined quantitatively the mRNA levels of CAV1, CAV2 and HER2/neu in 162 cases of breast cancer using real-time PCR. Caveolin-1 and -2 protein expression was also examined by Western blotting and immunohistochemistry. We then evaluated for correlations between CAV1, CAV2 and HER2/neu gene expression and clinicopathologic factors in the 162 breast cancer cases. Results showed higher HER2/neu mRMA levels and lower CAV1 and CAV2 mRMA levels in breast cancer tissues than in corresponding normal tissues (P<0.001). Caveolin-1 and -2 protein expression levels were also suppressed in cancer tissues compared to normal tissues by Western blotting. Immunohistochemistry revealed that CAV1 and CAV2 proteins were abundantly expressed in mammary gland myoepithelial cells, but only weakly in ductalepithelial cells. Reduced CAV1 mRNA level was significantly associated with increasing tumour size (P=0.041), and negative oestrogen receptor status (P=0.021). There was also a significant association between low CAV2 mRNA level and negative progesterone receptor status (P=0.013), and between high HER2/neu mRNA level and negative hormonal receptor status (ER, P=0.029, PgR, P=0.019). While there was no relationship between HER2/neu and CAV1 mRNA levels, a significant association between CAV1 and CAV2 mRNA levels was observed (P<0.001). Our results indicated that CAV1 suppression correlated closely with that of CAV2 in breast cancer, that CAV1 level was inversely correlated with tumour size, and that CAV1 and CAV2 levels were correlated with hormonal receptor status. Therefore, CAV1 and CAV2 play an important role in tumour progression in breast cancer patients.

Epitope analysis of the cerebrospinal fluid IgG in HTLV-I associated myelopathy patients using phage display method.

We, for the first time, analyzed the binding motifs of immunoglobulin G (IgG) in the cerebrospinal fluid (CSF) of human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients with a phage library displaying 12-mer random peptides. As a result, the sequences highly homologous to HTLV-I gp46 192-199, 237-243 and 255-261 were the common linear epitopes of high affinity- IgG exclusively detected in both CSF and sera of the patients. These IgG responses were confirmed with corresponding HTLV-I peptides and serum antibody titers significantly correlated with disease severity or duration. Gp46 237-243 has not been detected in previous enzyme-linked immunosorbent assay (ELISA) studies using bound longer peptides, suggesting the usefulness of the phage display method.

[Technique for vascular management under thoracoscopic surgery].

Vascular injury is the most life-threatening complication under thoracoscopic surgery. To reduce the risk of vascular injury, knowledge of the anatomy of the pulmonary artery, variations in its branching, skillful techniques and careful maneuver are necessary. Pulmonary artery being adherent to bronchus is dangerous to dissect under thoracoscopy, so it is better to convert to open thoracotomy. A3 of the left upper lobe is occasionally injured during dissection. It is a safety technique for using vascular stapler under thoracoscopic surgery. Stapler leader can allow the passage of a stapler to encircle the vessel.

Transcription analysis of rpoH in Pseudomonas putida.

We previously determined the complete DNA sequence of the rpoH gene encoding the heat-shock sigma factor (sigmaH) of Pseudomonas putida. In the present study, the transcriptional start sites of rpoH were determined to be 41 nucleotides (T1), 153 nucleotides (T2) and 157 nucleotides (T3) upstream from the translational start codon (AUG) of rpoH by rapid amplification of cDNA 5'-ends. Based on the locations of T2 and T3, a sigma70-type promoter (P2) was determined to be located in the open reading frame region of upstream ftsX in addition to the sigmaE-type promoter (P1; DNA Res. 6 (1999) 241). In the in vitro transcription assay with reconstituted RNA polymerases (Esigma70, EsigmaE, EsigmaH and EsigmaS) of Pseudomonas aeruginosa, EsigmaE transcribed rpoH from T1 and Esigma(70) transcribed it from T2 and T3. In both cases, the level of transcription was higher at 42 degrees C than at 30 degrees C. No transcript was detected when EsigmaH or EsigmaS was used. These results indicate that EsigmaE and Esigma70 recognize P1 promoter and P2 promoter, respectively, and also prove that the synthesis of rpoH mRNA is inducible upon heat shock.

Effect of sarsasapogenin and its derivatives on the stimulus coupled responses of human neutrophils.

METHODS: The effects of three sapogenins (sarsasapogenin, tigogenin and hecogenin) on the stimulus-induced superoxide generation and protein tyrosyl phosphorylation in human neutrophils were investigated. RESULTS: When the cells were preincubated with sapogenin, three sapogenins dose-dependently suppressed the superoxide generations induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) and phorbol 12-myristate 13-acetate (PMA), respectively. In both cases, their effects were in the order: sarsasapogenin>tigogenin>hecogenin. While sarsasapogenin suppressed the superoxide generation induced by arachidonic acid (AA) as well, the superoxide generation was scarcely suppressed by tigogenin and significantly enhanced by hecogenin. In parallel to their effects on the superoxide generation, the three sapogenins dose-dependently suppressed the fMLP-induced and PMA-induced tyrosyl phosphorylations of 45 kDa protein in neutrophils, respectively. CONCLUSIONS: Of the sapogenins tested, sarsasapogenin may have the most clinical use as it suppresses superoxide generation.

Prognostic significance of thrombomodulin expression and vascular invasion in stage I squamous cell carcinoma of the lung.

Thrombomodulin (TM) is an important modulator of intravascular coagulation. TM exists on endothelial cells and on several types of tumor cells, especially squamous cell carcinoma cells. Tumor cell TM is thought to be associated with progression and metastasis of the tumor. To evaluate the prognostic significance of TM in lung cancer, we examined TM expression and vascular invasion in surgical specimens obtained from 90 patients with completely resected stage I non-small cell lung cancer (NSCLC). In addition, we correlate these pathologic data to other clinicopathologic data, including the outcome of the patients. Squamous cell carcinomas had a significantly higher incidence (P<0.0001) of TM expression (22/36 cases, 61%) than adenocarcinomas (9/54 cases, 17%). In 36 squamous cell carcinoma patients, both vascular invasion (P=0.0153; risk ratio 6.507) and TM non-expression (P=0.0282; risk ratio 3.584) were significant for a poor prognosis. Univariate analysis of patient survival rates also revealed that vascular invasion and TM expression were significant prognostic factors (P=0.0036 and 0.012, respectively). Further, combination analysis of vascular invasion and TM expression in the squamous cell carcinoma patients showed that the 5-year survival rate was 90% in patients with TM expression and without vascular invasion, but 21% in patients with vascular invasion and without TM expression (P=0.0004). Since our results suggest that vascular invasion and TM expression are independent prognostic factors of stage I squamous cell carcinoma of the lung, and since the two factors play different roles in the metastatic process of cancers (promotion of metastasis by vascular invasion and inhibition of metastasis by TM expression), the combination evaluation of vascular invasion and TM expression may be very significant in evaluating the prognosis of patients with completely resected stage I squamous cell carcinoma.

beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease.

Alzheimer's disease and Parkinson's disease are associated with the cerebral accumulation of beta-amyloid and alpha-synuclein, respectively. Some patients have clinical and pathological features of both diseases, raising the possibility of overlapping pathogenetic pathways. We generated transgenic (tg) mice with neuronal expression of human beta-amyloid peptides, alpha-synuclein, or both. The functional and morphological alterations in doubly tg mice resembled the Lewy-body variant of Alzheimer's disease. These mice had severe deficits in learning and memory, developed motor deficits before alpha-synuclein singly tg mice, and showed prominent age-dependent degeneration of cholinergic neurons and presynaptic terminals. They also had more alpha-synuclein-immunoreactive neuronal inclusions than alpha-synuclein singly tg mice. Ultrastructurally, some of these inclusions were fibrillar in doubly tg mice, whereas all inclusions were amorphous in alpha-synuclein singly tg mice. beta-Amyloid peptides promoted aggregation of alpha-synuclein in a cell-free system and intraneuronal accumulation of alpha-synuclein in cell culture. beta-Amyloid peptides may contribute to the development of Lewy-body diseases by promoting the aggregation of alpha-synuclein and exacerbating alpha-synuclein-dependent neuronal pathologies. Therefore, treatments that block the production or accumulation of beta-amyloid peptides could benefit a broader spectrum of disorders than previously anticipated.

The activation of dopamine D4 receptors inhibits oxidative stress-induced nerve cell death.

Oxidative stress is thought to be the cause of nerve cell death in many CNS pathologies, including ischemia, trauma, and neurodegenerative disease. Glutamate kills nerve cells that lack ionotropic glutamate receptors via the inhibition of the cystine-glutamate antiporter x(c)(-), resulting in the inhibition of cystine uptake, the loss of glutathione, and the initiation of an oxidative stress cell death pathway. A number of catecholamines were found to block this pathway. Specifically, dopamine and related ligands inhibit glutamate-induced cell death in both clonal nerve cell lines and rat cortical neurons. The protective effects of dopamine, apomorphine, and apocodeine, but not epinephrine and norepinephrine, are antagonized by dopamine D4 antagonists. A dopamine D4 agonist also protects, and this protective effect is inhibited by U101958, a dopamine D4 antagonist. Although the protective effects of some of the catecholamines are correlated with their antioxidant activities, there is no correlation between the protective and antioxidant activities of several other ligands. Normally, glutamate causes an increase in reactive oxygen species (ROS) and intracellular Ca(2+). Apomorphine partially inhibits glutamate-induced ROS production and blocks the opening of cGMP-operated Ca(2+) channels that lead to Ca(2+) elevation in the late part of the cell death pathway. These data suggest that the protective effects of apomorphine on oxidative stress-induced cell death are, at least in part, mediated by dopamine D4 receptors via the regulation of cGMP-operated Ca(2+) channels.