Combination of chronic stress and ovariectomy causes conditioned fear memory deficits and hippocampal cholinergic neuronal loss in mice.

We have recently found that the combination of ovariectomy (OVX) and chronic restraint stress (CS) causes hippocampal pyramidal cell loss and cognitive dysfunction in female rats and that estrogen replacement prevents the OVX/CS-induced morphological and behavioral changes. In this study, to clarify the mechanisms underlying the OVX/CS-mediated memory impairment further, we examined the roles of cholinergic systems in the OVX/CS-induced memory impairment in mice. Female Slc:ICR strain mice were randomly divided into two groups: OVX and sham-operated groups. Two weeks after the operation, the mice of each group were further assigned to CS (6 h/day) or non-stress group. Following the 3-week-stress period, all mice were subjected to contextual fear conditioning, and context- and tone-dependent memory tests were conducted 1 or 24 h after the conditioning. Overburden with 3 weeks of CS from 2 weeks after OVX impaired context- and tone-dependent freezing and the OVX/CS caused significant Nissl-stained neuron-like cell loss in the hippocampal CA3 region, although OVX and CS alone did not cause such behavioral and histological changes. Replacement of 17ß-estradiol for 5 weeks after OVX suppressed OVX/CS-induced memory impairment and hippocampal Nissl-positive cell loss. Furthermore, the OVX/CS mice exhibited a significant decrease in choline acetyltransferase in the hippocampus compared with other groups. The cholinesterase inhibitors donepezil and galantamine ameliorated OVX/CS-induced memory impairment. These data suggest that cholinergic dysfunction may be involved in the OVX/CS-induced conditioned fear memory impairment. Overall, our findings suggest that the OVX/CS mouse model is useful to study the mechanisms underlying estrogen loss-induced memory deficits.

Ginkgo biloba extract EGb 761 attenuates hippocampal neuronal loss and cognitive dysfunction resulting from chronic restraint stress in ovariectomized rats.

We have recently found that a combination of ovariectomy (OVX) and chronic restraint stress causes cognitive dysfunction and reduces hippocampal CA3 neurons in female rats and that estrogen replacement suppresses the OVX/stress-induced behavioral and morphological changes. In this study, we examined the effect of Ginkgo biloba extract (EGb 761), a popular herbal supplement, on the cognitive dysfunction and neuromorphological change in OVX/stress-subjected rats. Female Fisher 344 rats were randomly divided into three groups: vehicle-treated OVX, EGb 761 (50 mg/kg) -treated OVX and vehicle-treated sham-operated control groups. Two months after ovariectomy, all animals received restraint stress for 21 days (6 h/day), and were then subjected to a novel object recognition test followed by morphological examination by Nissl staining. EGb 761 was orally administered once daily until the behavioral analysis was done. Treatment with EGb 761 improved memory impairment and neuronal loss of hippocampus in the OVX/stress-subjected group in the same ways as 17beta-estradiol. On the other hand, EGb 761 did not affect the loss of bone mineral density and increase in body weight after OVX, although 17beta-estradiol attenuated them. These results have important implications for neuroprotective and cognition enhancing effects of EGb 761 in postmenopausal women and suggest that the effects are mediated by a different mechanism from estrogen.

17beta-estradiol attenuates hippocampal neuronal loss and cognitive dysfunction induced by chronic restraint stress in ovariectomized rats.

Several lines of evidence suggest that hormonal changes after menopause may play an important role in the incidence of cognitive dysfunction, and also in the development of Alzheimer's disease. In this study, we investigated the effect of estrogen on cognitive function in rats under different stress environment. Female rats were divided into four groups: two groups were ovariectomized (OVX) and two were sham-operated. One group each of OVX and sham rats was kept in a normal environment, and the other groups were assigned to a daily restraint stress (6 h/day) for 21 days from 2 months after the operation. Following the stress period, subjects were tested for performance in novel object recognition test and then used for morphological and neurochemical analyses. The OVX plus stress (OVX/stress) group showed a significant impairment of recognition of novel objects, compared with the other groups. The OVX/stress group also showed a marked decrease in the number of pyramidal cells of the CA3 region and levels of brain-derived neurotrophic factor mRNA in the hippocampus. We further examined the effect of estrogen against cognitive dysfunction and hippocampal changes of OVX/stress rats. Vehicle or 17beta-estradiol (E2) at 20 microg/day was s.c. administered to OVX/stress rats from 2 days before the stress period to the end of behavioral analysis through an implantable osmotic pump. Chronic E2 treatment decreased stress response and improved the cognitive and morphological impairments relative to vehicle group. These data have important implications for cognition enhancing effect of estrogen treatment in postmenopausal women.

Polymorphisms of the insulin gene among Japanese subjects.

We have sequenced the insulin gene in 72 unrelated Japanese subjects (52 with type 2 diabetes mellitus and 20 with normal glucose tolerance). We identified 6 mutations and all were found at a low frequency (1% to 4%). Three mutations were new. These included a C-to-G substitution in the promoter region, a G-to-A substitution in codon-2 resulting in an Ala-to-Thr replacement in amino acid -2 of the signal peptide, and a G-to-A substitution in intron 2. We have no evidence that any of the mutations that we found are the cause of diabetes. Thus, mutations in the insulin gene do not appear to be an important genetic factor contributing to the development of diabetes in this population.

Risk factors for distant recurrence of hepatocellular carcinoma in the liver after complete coagulation by microwave or radiofrequency ablation.

BACKGROUND: In patients with hepatocellular carcinoma (HCC), recurrences in the distant liver often are observed after curative treatment. Microwave coagulation therapy (MCT) and radiofrequency ablation (RFA) have been developed as less invasive alternatives than surgical resection for small HCCs. In the current study, risk factors for distant recurrence of HCC were analyzed in patients in whom complete coagulation was achieved. METHODS: Ninety-two patients with HCCs < 3 cm in greatest dimension were treated by MCT or RFA percutaneously or laparoscopically. Eighty-four patients in whom complete coagulation was achieved without recurrence in the same subsegment as the primary nodule were included in this study. Distant recurrences were observed in 22 patients. Fifteen possible risk factors for a distant recurrence were analyzed. RESULTS: When comparing the patients with a recurrence of HCC nodules in the remnant liver to those without recurrence, the authors observed a statistically significant difference only in serum alpha-fetoprotein. The distant recurrence-free survival was analyzed by the Kaplan-Meier method. A statistically significant difference was observed in hepatitis C virus (HCV) infection as an etiopathic agent of underlying liver diseases (P < 0.005) and in the number of the primary HCC nodules (P < 0.05, log-rank test). A multivariate stepwise Cox hazard model revealed that HCV infection and the number of primary HCC nodules were statistically independent risk factors. CONCLUSIONS: Patients who had more than two HCC nodules accompanied by HCV infection had a high incidence of recurrence of HCC in the remnant liver, even when coagulation by microwave or ablation by radiofrequency was complete.

Takayasu arteritis: diagnosis with breath-hold contrast-enhanced three-dimensional MR angiography.

The purpose of the study was to determine the diagnostic accuracy of breath-hold contrast-enhanced three-dimensional (3D) magnetic resonance (MR) angiography in Takayasu arteritis. Thirty patients suspected of having Takayasu arteritis were examined with MR angiography and conventional angiography. Takayasu arteritis was diagnosed in 20 of these patients. MR angiography was performed using a 1.5-T system after bolus injection of 0.1 mmol/kg of gadodiamide. MR angiography clearly depicted various vascular lesions in the aorta and its major branches in all 20 patients with Takayasu arteritis. It also depicted pulmonary artery lesions in 10 (50%) of the 20 patients. MR angiography accurately depicted 323 (98%) of 330 arteries, but 7 (2%) stenotic arteries were overestimated as occluded. The sensitivity and specificity of MR angiography for the diagnosis of Takayasu arteritis were both 100%. Breath-hold contrast-enhanced 3D MR angiography clearly depicts various vascular lesions in both the systemic and pulmonary arteries in Takayasu arteritis, thus allowing a definitive diagnosis of Takayasu arteritis.

Renal artery lesions in patients with moyamoya disease: angiographic findings.

BACKGROUND AND PURPOSE: Renal artery lesions in moyamoya disease have been described sporadically in several case reports. The purpose of this study is to evaluate the angiographic findings of renal artery lesions in moyamoya disease and to determine the prevalence of renal artery lesions in patients with moyamoya disease. METHODS: Eighty-six consecutive patients with idiopathic moyamoya disease were prospectively examined with both cerebral angiography and abdominal aortography. The findings of abdominal aortography were reviewed for the presence and appearance of renal artery lesions and compared with the clinical data and cerebral angiographic findings. RESULTS: Of 86 patients with idiopathic moyamoya disease, 7 patients (8%) were found to have renal artery lesions. Six patients (7%) had stenosis in the renal artery, and 1 patient (1%) had a small saccular aneurysm in the renal artery. Two patients (2%) with a marked renal artery stenosis presented with renovascular hypertension, which resulted in an intraventricular hemorrhage in 1 patient. Furthermore, the renal artery stenosis in the 2 patients with renovascular hypertension was successfully treated with percutaneous transluminal angioplasty. There was no significant correlation between the presence of renal artery lesions and cerebral angiographic findings. CONCLUSIONS: Seven (8%) of 86 patients with moyamoya disease showed renal artery lesions, including 6 stenoses (7%) and 1 aneurysm (1%). Renal artery lesions are a clinically relevant systemic manifestation in patients with moyamoya disease.

Moyamoya disease: evaluation with diffusion-weighted and perfusion echo-planar MR imaging.

PURPOSE: To determine the clinical efficacy of diffusion-weighted and perfusion echo-planar magnetic resonance (MR) imaging in the evaluation of moyamoya disease. MATERIALS AND METHODS: Seventeen patients with moyamoya disease were examined prospectively with diffusion-weighted and perfusion echo-planar MR imaging and conventional angiography. The change in the effective transverse relaxation rate (delta R2*) peak value, delta R2* peak time, and delta R2* integral were calculated to assess regional cerebral perfusion. The MR images were compared with angiographic images. RESULTS: Of the 34 posterior cerebral arteries (PCAs) of the 17 patients, 14 PCAs (41%) in 11 patients showed stenosis or occlusion. The delta R2* peak value ratio in the cerebral hemispheres decreased significantly, and the delta R2* peak time ratio increased significantly, with PCA stenosis and occlusion. However, no correlation was apparent between perfusion and extent of the stenotic or occlusive lesions of the internal carotid artery bifurcation. The frequency of cerebral infarctions was significantly increased in patients with stenotic or occlusive PCA lesions. For three acute infarctions, a decrease in the apparent diffusion coefficient was significantly correlated with a decrease in the delta R2* peak value, an increase in the delta R2* peak time, and a decrease in the delta R2* integral. CONCLUSION: Regional cerebral perfusion in moyamoya disease is decreased and delayed with PCA stenosis, with greater decrease and delay with PCA occlusion. Diffusion-weighted and perfusion imaging are useful for evaluating cerebral ischemia in moyamoya disease.

Diffusion coefficients in abdominal organs and hepatic lesions: evaluation with intravoxel incoherent motion echo-planar MR imaging.

PURPOSE: To determine the true diffusion coefficients of abdominal organs and hepatic lesions with intravoxel incoherent motion (IVIM) echo-planar magnetic resonance (MR) imaging. MATERIALS AND METHODS: Seventy-eight patients suspected of having hepatic lesions were examined with IVIM echo-planar MR imaging at 1.5 T. There were 77 hepatic masses (27 hepatocellular carcinomas, 10 metastatic tumors, eight hemangiomas, and 32 cysts) in the 78 patients. The true diffusion coefficient D and the perfusion fraction f were calculated and compared with the apparent diffusion coefficient (ADC). RESULTS: Specific values of D were found for abdominal organs (liver, 0.72 x 10(-3) mm2/sec; spleen, 0.80 x 10(-3) mm2/sec; kidney, 1.38 x 10(-3) mm2/sec; gallbladder, 2.82 x 10(-3) mm2/sec) and for hepatic lesions (hepatocellular carcinoma, 1.02 x 10(-3) mm2/sec; metastasis, 1.16 x 10(-3) mm2/sec; hemangioma, 1.31 x 10(-3) mm2/sec; cysts, 3.03 x 10(-3) mm2/sec). The ADCs of solid organs and solid lesions were significantly higher than their D values, indicating a high contribution of perfusion to the ADCs. CONCLUSION: Perfusion contributes to the ADCs of abdominal organs and hepatic lesions. The D and f values are useful for the characterization of hepatic lesions.

Takayasu arteritis: evaluation of the thoracic aorta with CT angiography.

PURPOSE: To determine the diagnostic accuracy of computed tomographic (CT) angiography in the evaluation of Takayasu arteritis. MATERIALS AND METHODS: Twenty-five patients with clinical symptoms suggestive of Takayasu arteritis underwent CT angiography and conventional angiography. Takayasu arteritis was diagnosed in 20 patients on the basis of conventional angiography. CT angiography was performed with a helical CT scanner after injection of a bolus of contrast material, and images were generated for three-dimensional display, multiplanar reformation, and maximum intensity projection. For vascular assessment, all images from CT angiography were used, and the results were compared with those from conventional angiography. RESULTS: CT angiography clearly depicted various luminal changes, including stenosis, occlusion, dilatation, and aneurysm, in the thoracic aorta and its major branches. CT angiography accurately depicted 190 (95%) of 200 arteries, although the extent of the steno-occlusive lesions was overestimated in five (2%) and underestimated in five (2%). Furthermore, CT angiography depicted mural changes, including wall thickening, calcification, and mural thrombi, not seen with conventional angiography. The sensitivity and specificity of CT angiography in the diagnosis of Takayasu arteritis were 95% and 100%, respectively. CONCLUSION: CT angiography clearly depicts both luminal and mural changes in the thoracic aorta and its major branches and has a high accuracy in the diagnosis of Takayasu arteritis.

Aberrant left gastric vein demonstrated by helical CT.

PURPOSE: Our goal was to describe the CT findings of aberrant left gastric vein (ALGV) and to evaluate the clinical significance of this vein. METHOD: Four patients in whom ALGVs were demonstrated by helical CT were examined. Each patient had either intrahepatic cholangiocarcinoma, cirrhosis with gastric varices, chronic hepatitis, or nonspecific abdominal pain. All patients underwent two phase helical CT, and the patient with cholangiocarcinoma underwent CT during arterial portography, and 3D images of the abdominal veins were obtained. RESULTS: In all patients, the ALGVs ran along the hepatogastric ligament and were directly connected with the left portal branch. In the patient with cholangiocarcinoma, the portal vein had severe stenosis by tumor invasion, and both the ALGV and the aberrant right gastric vein functioned as a collateral pathway of the portal flow into the liver. In the patient with cirrhosis, dilated ALGV with hepatofugal flow caused gastric varices. CONCLUSION: The ALGV is directly connected with the left portal branch and may play an important role in the collateral pathway of the portal system.

Differential diagnosis of early homogeneously enhancing hepatocellular carcinoma and hemangioma by two-phase CT.

PURPOSE: Our goal was to differentiate between early homogeneously enhancing hepatocellular carcinoma (HCC) and hemangioma by two-phase CT. METHOD: Two phase images of 51 HCCs and 28 hemangiomas showing homogeneous high attenuation in the first series (arterial dominant phase) were reviewed. Enhancement patterns of the lesions in the second series (parenchymal phase) were classified as homogeneous high, peripheral high, iso-, and low attenuation. The attenuation values of all and the enhancement values of some (21 HCCs and 18 hemangiomas) in the first series were calculated. RESULTS: Although low and peripheral high attenuation patterns were seen during the second series only in HCCs (n = 35), which could be used to correctly diagnose HCC, other nonspecific patterns were demonstrated in both HCCs (n = 16) and hemangiomas (n = 28). The attenuation values of 49 of the 51 HCCs and 5 of the 28 hemangiomas were below 130 HU on the first series. The enhancement values of all 21 HCCs and 3 of 18 hemangiomas were below 70 HU. Combining the enhancement patterns with a borderline attenuation value of 130 HU or borderline enhancement value of 70 HU yielded overall accuracies of 94 and 92%, respectively. CONCLUSION: The combined criteria (enhancement pattern plus attenuation or enhancement value) were useful for differentiating between early homogeneously enhancing HCCs and hemangiomas.

Segmental anatomy of the liver under the right diaphragmatic dome: evaluation with axial CT.

PURPOSE: To evaluate the segmental anatomy of the liver under the right side of the diaphragm with axial computed tomography (CT). MATERIALS AND METHODS: Forty-six patients underwent CT arteriography with selective catheterization of the right hepatic artery in 25 cases, the left hepatic artery in 12, the anterior branch of the right hepatic artery in six, the posterior branch of the right hepatic artery in five, the superior anterior branch of the right hepatic artery in 10, and the superior posterior branch of the right hepatic artery in eight. RESULTS: The boundary between the right and left lobes shifted by 16.2 degrees +/- 16.8 anteriorly, and the boundary between the anterior and posterior segments shifted by 43.9 degrees +/- 14.0 posteriorly to the line through the middle or right hepatic vein from the inferior vena cava. The top of the liver consisted of both lobes in 22 patients, only the right lobe in 17, and only the left lobe in two. Participation of segment 7 in the top was not demonstrated. CONCLUSION: The line that extends beyond the middle or right hepatic vein from the inferior vena cava does not coincide with the main or right longitudinal scissura on axial images of the upper portion of the liver.

Evaluation of the argyrophilic nucleolar organizer region, nuclear DNA content and mean nuclear area in transitional cell carcinoma of bladder using a quantitative image analyzer.

To search for reliable parameters that reflect the biological potential of bladder cancer, the argyrophilic nucleolar organizer region (AgNOR), nuclear DNA content and mean nuclear area (MNA) were studied in paraffin-embedded materials of 75 primary transitional cell carcinomas (TCCs) using a quantitative image analyzer, and were also compared with histological findings and prognosis. The AgNOR parameters studied were the mean AgNOR count (C-AgNOR) and the percentage of cells exhibiting more than 4 AgNOR dots within nuclei (P-AgNOR), whereas the DNA parameters were the 2c deviation index (2cDI) and 5c exceeding rate (5cER). These 5 parameters significantly correlated with the histological grade (p < 0.0001, respectively). Similarly, these 5 parameters correlated with the histological stage, but the correlation was higher in 2cDI and 5cER (p < 0.0001, respectively) in comparison with the AgNOR parameters and MNA. Using univariate analysis, the prognostic relevance was noted in all but P-AgNOR. The 5cER value could discriminate histological grade-II tumors in relation to prognosis, whereas the remaining parameters could not. In addition, the significant difference between noninvasive and invasive tumors was noted in 2cDI and 5cER (p < 0.05, respectively), but not in C-AgNOR, P-AgNOR and MNA. These results suggest that (i) 2cDI and 5cER exhibit superiority over the AgNOR parameters and MNA in predicting survival, and (ii) in histological grade-II tumors, evaluation of the 5cER value is most important when predicting survival as well as judging the necessity for further aggressive treatment in patients with TCCs of the bladder.

Preliminary results of concurrent methotrexate, cisplatin and radiation treatment for locally advanced urothelial cancers.

Ten patients with invasive bladder cancer and one with locally advanced renal pelvic cancer were treated with concurrent methotrexate, cisplatin and radiotherapy. Methotrexate 30 mg/m2 was administered intravenously on the day of the initiation of radiotherapy and cisplatin 70 mg/m2 on the second day. The number of chemotherapy cycles delivered was 1 in 7 patients and 2 in 4. The median dose of radiation was 50 Gy. Of 11 patients, 7 (64%) achieved a partial response and 4 had no change in disease. The median duration of response was 16 months for patients with a partial response. Six patients with a partial response (55%) are alive for a median of 22.5 months and 2 of 4 with no change are alive for 4 and 15 months, respectively. Leukopenia less than 3000 cell/mm3 was observed in 4 (36%) and thrombocytopenia less than 100,000 cells/mm3 in 3 (27%). Local control could be achieved safely with concurrent methotrexate, cisplatin and radiation therapy in patients with locally advanced urothelial cancer who were unsuitable for surgery.

Angiographic findings in Buerger disease.

To clarify the angiographic findings in patients with Buerger disease and to elucidate the relationship between the angiographic findings and the clinical prognosis, 144 angiographic images of the lower extremities of 119 patients with Buerger disease have been studied. The present study has included patient data in our previous report. Results of this study revealed that in lower extremities showing a femoropopliteal arterial occlusion (n = 57), the frequency of gangrene was significantly lower statistically in limbs in which the main arteries of the lower leg and foot were well visualized (2 (12%) of 17 limbs) than in limbs in which the main arteries did not visualize (25 (63%) of 40 limbs) (P < 0.001). Further, in lower extremities showing a crural arterial occlusion (n = 59), the incidence of pedal gangrene increased as the extent of pedal arterial occlusion increased, though this rise was not statistically significant. Also, the collateral vessels had a 'corkscrew' appearance in 39 (27%) of 144 limbs affected by Buerger disease, whereas this appearance was seen in only 2 (3%) of 63 limbs of patients with arteriosclerosis obliterans (P < 0.001). Another finding of this study is that corkscrew-shaped vessels that extend from the sites of the arterial occlusion to the periphery of the feet without opacification of the main pedal arteries indicate a poor prognosis. Based on the above findings, we thus believe that the appearance of corkscrew-shaped vessels is the most characteristic feature of Buerger disease and that each represents a dilated vasa vasorum of the occluded main arteries.

Posterior circulation in moyamoya disease: angiographic study.

PURPOSE: To clarify the angiographic findings of the posterior circulation in patients with moyamoya disease. MATERIALS AND METHODS: Seventy-six patients with idiopathic moyamoya disease were studied with conventional angiography. The angiographic findings were reviewed for steno-occlusive lesions, collateral vessels, and aneurysms and compared with the finding of parenchymal lesions on computed tomographic and magnetic resonance images. RESULTS: Of 152 posterior cerebral arteries (PCAs), 66 (43%) had a stenotic or occluded lesion. The frequency of PCA lesions statistically significantly increased with the extent of the internal carotid artery (ICA) bifurcation steno-occlusive lesion. As the severity of ICA stenosis increased, basal cerebral moyamoya vessels and transdural collateral vessels similarly increased in number, but leptomeningeal collateral vessels decreased owing to the progressive development of more PCA lesions. Cerebral infarctions, ventricular dilatation, and cerebral atrophy were found to increase in frequency in patients with steno-occlusive PCA lesions. CONCLUSION: Steno-occlusive lesions of the PCA increase in frequency proportionally with severity of ICA bifurcation steno-occlusive lesions, so that cerebral infarctions increase in frequency with the extent of the PCA lesions.

Hepatic hemangioma: findings with two-phase CT.

PURPOSE: To characterize the appearance of hemagiomas at two-phase dynamic incremental computed tomography (CT) and to determine the cause of contrast material enhancement of adjacent parenchyma in the first series. MATERIALS AND METHODS: Contrast-enhanced CT images of 51 hemangiomas in 20 patients were reviewed. Enhancement patterns of hemangiomas in the first series were classified as homogeneous high, peripheral high, and low attenuation; in the second series, as homogeneous high, peripheral high, iso-, and low attenuation. Correlations between arterioportal shunts and early parenchymal enhancement were evaluated in 45 hemangiomas in the 17 patients who underwent angiography. RESULTS: Thirty-two hemangiomas progressively became enhanced. Four had low and eight had homogeneous high attenuation in both series. Seven changed from homogeneous high to isoattenuation. Early parenchymal enhancement was well correlated with presence of arterioportal shunt. CONCLUSION: Low-attenuation hemangiomas and those that changed from homogeneous high to isoattenuation are atypical and difficult to differentiate from other neoplasms. Most early parenchymal enhancement is caused by associated arterioportal shunts.

Hepatic pseudolesion in the left lobe around the falciform ligament at helical CT.

PURPOSE: To determine the prevalence and possible cause of pseudolesions in the left hepatic lobe around the falciform ligament at hepatic helical computed tomography (CT). MATERIALS AND METHODS: Portal venous-dominant CT scans of 472 consecutive patients were reviewed. CT of the left hepatic lobe was performed after injection of contrast material into the portal vein in 73 patients, the hepatic artery in 32, and the internal thoracic artery in four. The scans were compared with those obtained at helical CT, and the findings were analyzed. RESULTS: Pseudolesions were seen on 64 (14%) of 472 helical CT scans and correlated well (accuracy, 96%) with portal perfusion defects. They were not more enhanced than the surrounding liver parenchyma at CT arteriography with hepatic artery injection but were enhanced in two patients at CT arteriography with internal thoracic artery injection. CONCLUSION: Pseudolesions are caused by portal perfusion defects and may receive an aberrant blood supply.