Roles of prostanoids in the pathogenesis of cardiovascular diseases.

The roles of prostanoids in the pathogenesis of cardiovascular diseases and in the development of pathological conditions have been examined using mice lacking the individual, specific prostanoid receptor. Prostaglandin (PG) I2 protected the heart from ischemia-reperfusion injury in a model of acute myocardial infarction. In addition, PGI2 suppressed the development of pressure overload-induced cardiac hypertrophy. Aside from its potent vasodilatory action, PGI2 contributed critically to the development of renovascular hypertension via the activation of the renin-angiotensin-aldosterone system. Thromboxane (TX) A2 and PGF2alpha were found to be the mediators of inflammatory tachycardia under a systemic inflammatory condition induced by lipopolysaccharide. Under a septic condition leading to a vascular hypo-responsive state, TXA2 worked to maintain vascular tone by inhibiting the induction of inducible nitric oxide synthase in vascular smooth muscle cells. Mice lacking the PGE2 receptor subtype EP3 had a bleeding tendency and were resistant to thromboembolism, due to a defective activation of platelets. From these studies, the important and novel roles of prostanoids in the pathogenesis of cardiovascular diseases have been clarified.

A cardiac sodium channel mutation identified in Brugada syndrome associated with atrial standstill.

Mutations in the cardiac Na+ channel gene SCN5A are responsible for multiple lethal ventricular arrhythmias including Brugada syndrome and congenital long QT syndrome. Here we report a case of Brugada syndrome with ST elevation in the right precordial and inferior leads accompanied by atrial standstill and spontaneous ventricular fibrillation. Atrial standstill and J wave elevation were provoked by procainamide. Genetic analysis revealed a missense mutation (R367H) in SCN5A. The resultant mutant Na+ channel was nonfunctional when expressed heterologously in Xenopus oocytes. Our study suggests that genetic defects in SCN5A may be associated with atrial standstill in combination with ventricular arrhythmias.

Positron emission tomography using 2-[(18)F] fluoro-2-deoxy-D-glucose in the diagnosis of uterine leiomyosarcoma: a case report.

The preoperative diagnosis of uterine leiomyosarcoma (LMS) is very difficult. Magnetic resonance (MR) imaging is usually used for it; however, precise diagnosis by MR imaging is limited to typical LMS with coagulative tumor cell necrosis. We presented a case of LMS that was diagnosed preoperatively by positron emission tomography (PET) using 2-[(18)F] fluoro-2-deoxy-D-glucose (FDG).

Diagnostic usefulness of FDG PET for pancreatic mass lesions.

UNLABELLED: The purpose of this study was to investigate the feasibility of [18F]2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET) in patients with a pancreatic mass by comparing the results with those of X-ray computed tomography (CT) and magnetic resonance (MR) imaging. METHODS: Eighty-six patients with pancreatic lesions, included 65 malignant tumors and 21 benign masses (55 masses were proven histologically and the others were diagnosed clinically), were studied. The diagnostic factors of CT and MR imaging were evaluated, and those of FDG PET were also evaluated for malignant and benign masses by visual interpretation and quantitative interpretation with the standardized uptake value (SUV) and SUVgluc which was designed to reduce the effects of a high blood sugar level. Visual interpretations were evaluated only in FDG PET images, and quantitative interpretations were evaluated by referring to CT and/or MR imaging. The correlation between SUV and the degree of histological differentiation in pancreatic ductal adenocarcinoma was investigated. RESULTS: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy for CT imaging were 91, 62, 88, 68 and 84%, and for MR imaging 78, 70, 88, 54 and 76%, respectively. In visual interpretation of FDG PET images, the sensitivity, specificity, PPV, NPV and accuracy were 82, 81, 93, 59 and 81%, respectively. Significant differences between malignant and benign lesions existed in SUV and SUVgluc (p < 0.0001, each). With the cutoff value of SUV as 2.1 and SUVgluc as 2.2, the accuracy of diagnosis was maximal. With that cutoff value, the sensitivity, specificity, PPV, NPV and accuracy for SUV were 89, 76, 92, 70 and 86%, and for SUVgluc 91, 76, 92, 73 and 87%, respectively. The sensitivity and NPV of SUVgluc were higher than those of SUV, which suggests that SUVgluc may be more useful in reducing the number of overlooked malignant tumors. The specificity and PPV of FDG PET were superior to those of CT and MR imaging. There were no significant differences between the SUVs of moderately differentiated adenocarcinomas and those of well differentiated adenocarcinomas. CONCLUSION: To improve the diagnostic procedure for classifying masses, FDG PET with not only SUV but also SUV corrected by the blood sugar level is required in addition to morphological diagnosis by CT and/or MR imaging.

A case of tuberculous peritonitis monitored by gallium-67 scintigraphy.

An 18-year-old man was admitted to our hospital for further examination of fever of unknown origin and ascites. Ga-67 scintigraphy revealed diffuse increased uptake throughout the abdomen. He was diagnosed with tuberculous peritonitis and began the treatment for tuberculosis (rifampicin, 450 mg/day orally and isoniazid, 300 mg/day orally, and 0.75 g of streptomycin by intramuscular injection 2 times a week). One year after starting the treatment, Ga-67 scintigraphy revealed accumulation of radioactivity in the upper abdomen, but the diffuse accumulation in the abdomen decreased. A specimen obtained by tumor biopsy under ultrasonic guidance revealed a tuberculous granuloma. Percutaneous injection was performed in the tumor with 1.0 g of streptomycin. On Ga-67 scintigraphy performed 2 weeks after the injection of streptomycin, the accumulation of radioactivity in the upper abdomen had disappeared. These findings suggest that Ga-67 scintigraphy is useful for diagnosis and observation during treatment of tuberculous peritonitis.

Mesenteric desmoid with uptake on gallium-67 citrate scintigraphy.

A 72-year-old man was hospitalized for further evaluation of a space-occupying lesion in the abdomen. Magnetic resonance imaging revealed a tumor 40 mm in diameter in the abdomen. Anterior Ga-67 citrate scintigraphy revealed a region of accumulation of radioactivity in the abdomen corresponding to the tumor. Mesenteric desmoid was diagnosed on the basis of histological findings for the excised tumor. These finding suggested that mesenteric desmoid may be one of the tumors which show high uptake of Ga-67.

A case of glucagonoma with high uptake on F-18 fluorodeoxyglucose positron emission tomography.

Glucagonomas are relatively rare, and can be difficult to differentiate from other pancreatic tumors. A 62-year-old woman who had suffered from diabetes mellitus was hospitalized for further evaluation of a space-occupying lesion in the head of the pancreas and tumors in the liver. F-18 fluorodeoxyglucose positron emission tomography revealed accumulation of isotope corresponding to a tumor of the pancreas with a standardized uptake value of 4.3, and tumors in the liver with standardized uptake values of 2.4 and 2.8. The serum glucagon level was high (1,170 pg/ml) and the secretin tolerance test was negative. She was diagnosed with glucagonoma with a high serum glucagon level and clinical findings. It is suggested that glucagonoma may be one of the tumors which show high uptake of F-18 fluorodeoxyglucose.

Accessory spleen in the pelvis diagnosed by Tc-99m phytate scintigraphy.

We report a 58-year-old woman with an accessory spleen in the left side of the pelvis. She visited our outpatient clinic complaining of lower abdominal discomfort. Abdominal ultrasonography revealed a tumor 4 cm in diameter in the left side of the pelvis. Color Doppler ultrasonography demonstrated plentiful pulsating blood flow. Magnetic resonance angiography revealed that the blood supply for the tumor was from a branch of the splenic artery. Scintigraphy with Tc-99m phytate revealed accumulation of radioactivity concordant with a mass in the left side of the pelvis, and the spleen was normally visualized. These findings suggested that this tumor was an accessory spleen, and the patient underwent no further invasive procedures.

Physiological FDG uptake in the palatine tonsils.

In clinical F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) studies of the head and neck region, remarkable symmetric tonsillar FDG uptake is sometimes observed. We determined the incidence and degree of tonsillar FDG uptake and investigated the significance of tonsillar FDG uptake. Between June 1998 and August 1998, we obtained informed consent from 17 patients who were scheduled to undergo a FDG-PET study for their own disease (11 men and 6 women; aged 22 to 77 yr) and who did not have head and neck disease to perform FDG-PET scanning of the head and neck region in addition to their target organs. The incidence and degree of tonsillar FDG uptake were determined. Remarkable tonsillar FDG uptake was found in 9 patients. The SUVs of these FDG uptakes ranged from 2.48 to 6.75, with a mean of 4.29 +/- 1.20 (SD). Tonsillar FDG uptakes in the remaining 8 patients were not remarkable, and their SUVs ranged from 1.93 to 3.31, with a mean of 2.46 +/- 0.45. Head and neck disease does not appear to have been responsible for the increase in tonsillar FDG uptake. Differences among tonsillar FDG uptake in these 17 patients without head and neck disease appear to reflect differences in activity of "physiological" inflammation of the palatine tonsils.

Prognostic predictive value of 18F-fluorodeoxyglucose positron emission tomography for patients with pancreatic cancer.

18Fluorine-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) is a unique imaging diagnostic tool to evaluate glucose metabolism and hexokinase activity which may reflect the aggressiveness of a tumor. Thirty-seven patients with primary pancreatic cancer were evaluated with 18F-FDG-PET. Thirteen patients underwent resection for the pancreatic cancer and 24 patients had unresectable tumors. The standardized uptake values (SUV) of 18F-FDG in the primary tumors were calculated. No correlations were found between the SUV in the tumors and the metastatic status to the peritoneal/liver, TNM factors/stage, or resectability. The patients were divided into 2 groups with high and low SUV, with the cut-off value being 3.0 (median SUV value of 37 cases). No differences in the probability of survival were observed between the 2 groups in the patients with resectable tumors. However, in the patients with unresectable tumors, those in the high SUV group had a significantly shorter prognosis than those in the low SUV group. Moreover, a multivariate analysis of survival indicated that SUV is an independent prognostic factor for patients with unresectable pancreatic cancer.

Combined diagnostic imaging for retroperitoneal schwannoma.

Retroperitoneal tumors are occasionally encountered by gynecologists, and differential diagnosis from adnexal tumors is important, however, it is difficult in many cases. We report a case in which we preoperatively diagnosed a benign solid tumor in the retroperitoneum of the pelvic cavity on the basis of a variety of diagnostic images, including FDG-PET. Postoperative histological examination showed a benign schwannoma in the pelvis. We discuss the usefulness of FDG-PET combined with MRI and other diagnostic images as a means of differentiating between the characteristics of retroperitoneal tumors.

Changes in caveolin subtype protein expression in aging rat organs.

It is now accepted that caveolin plays a key role in signal transduction by directly binding to and regulating the function of molecules involved in transmembrane signaling, such as ras, suggesting that the amount of caveolin within cells may be an important factor in determining the cellular signaling. We investigated the ontogenic changes in the protein amount of caveolin subtypes, as well as ras protein expression in various organs (the heart, lungs, and muscles) obtained from aging rats (neonates, young and old adults). Our results demonstrated that caveolin protein expression changed ontogenically in a subtype-dependent manner. In lungs, for example, caveolin-1 expression changed in an opposite manner to caveolin-3 expression, while in the heart caveolin-1 and -3 changed in parallel. Ras expression showed an ontogenic increase in lungs and a decrease in muscles, which were both parallel to caveolin-1 expression. Our results suggest that the regulation of transmembrane signaling by caveolin may differ among developmental stages and caveolin subtypes.

Positron emission tomography with (18)F-fluorodeoxyglucose of uterine sarcoma: a comparison with magnetic resonance imaging and power Doppler imaging.

OBJECTIVE: The effectiveness of positron emission tomography with (18)F-fluorodeoxyglucose (FDG-PET) for diagnosis of uterine sarcoma was evaluated in comparison to the effectiveness of magnetic resonance (MR) imaging and power Doppler imaging. METHOD: The cases of five Osaka City University Hospital patients diagnosed with uterine sarcoma based on histopathological examination, in whom FDG-PET, MR imaging, and power Doppler imaging studies had been performed preoperatively, were reviewed. A comparative study of the usefulness of these three imaging modalities for diagnosis of sarcoma was conducted. Tumors comprised three leiomyosarcomas, one endometrial stromal sarcoma, and one carcinosarcoma. RESULTS: FDG-PET examinations were 100% positive for the five sarcomas; MR imagings were 80% positive (four of five cases), and US was 40% positive (two of five cases). The mean standardized uptake value of the sarcomas was 4.5 +/- 1.3. CONCLUSION: The sarcoma lesions were clearly imaged by FDG-PET. FDG-PET may be a most useful diagnostic method for uterine sarcoma.

Diagnosis of metastasis of ovarian clear cell carcinoma to the peritoneum of the abdominal wall by positron emission tomography with (fluorine-18)-2-deoxyglucose.

A 43-year old woman, operated on for ovarian clear cell carcinoma (stage IIc) four years previously was found to have a small mass under the abdominal wall in the right lower quadrant of the abdomen. Neither diagnostic imaging (ultrasonography and MRI) nor tumor markers showed any evidence of recurrence, but positron emission tomography revealed a hot spot area, and it was diagnosed as recurrence of the ovarian carcinoma. The postoperative histopathological diagnosis was metastasis of ovarian carcinoma to the peritoneal wall.

Glucose modifies the cross-talk between insulin and the beta-adrenergic signalling system in vascular smooth muscle cells.

BACKGROUND: Abnormalities in the vascular function of insulin are observed in insulin resistance, and hyperglycaemia is one of the important factors inducing insulin resistance. OBJECTIVE: To investigate the role of glucose in the interaction of insulin and beta-adrenergic signalling systems in vascular smooth muscle cells (VSMC). METHODS: After cells were treated with D-glucose (525 mmol/l) and insulin (100 nmol/l), adenylyl cyclase activity was measured in the presence of isoproterenol, forskolin, and cholera toxin. Assays for insulin-induced activities of insulin receptor substrate (IRS)-1, phosphoinositide 3-kinase (PI3-K) and mitogen-activated protein kinase (MAPK) were performed. RESULTS: In the presence of low glucose concentrations (5 mmol/l), insulin enhanced isoproterenol-, forskolin- and cholera toxin-stimulated adenylyl cyclase activities. This stimulatory effect was abolished by PI3-K inhibitors, wortmannin, or LY294002. In contrast, in the presence of high glucose concentrations (25 mmol/l), insulin attenuated isoproterenol-stimulated activity but not cholera toxin- or forskolin-stimulated activity. Insulin-stimulated activities of IRS-1 and PI3-K, but not MAPK activity, were also attenuated in the presence of high concentrations of glucose. The MAPK kinase inhibitor, PD98059, abolished the inhibitory effect of insulin on the beta-adrenergic signalling system. Troglitazone and pioglitazone prevented this inhibitory effect of insulin by restoring IRS-1 and PI3-K activities. CONCLUSIONS: In the presence of low glucose concentrations, insulin stimulates the beta-adrenergic signalling system through the IRS-1/PI3-K pathway. However, in the presence of high glucose concentrations, the effect of insulin is switched to an inhibitory one, through the MAPK pathway. Our finding suggests that high glucose concentrations modify the cross-talk between insulin and the beta-adrenergic signalling systems in VSMC.

The role of 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET) in the diagnosis of recurrence and lymph node metastasis of cervical cancer.

The usefulness of positron emission tomography with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG-PET) in diagnosing recurrence and lymph node metastasis of uterine cervical cancer was evaluated as a preliminary study. The FDG uptake of 13 cervical cancer patients, including 4 patients with recurrence, was evaluated. The FDG uptake of the cervices of 5 patients who underwent PET studies for non-cervical tumors were used as control. In 2 patients who had undergone radical hysterectomy, we compared the diagnosis of lymph node metastasis based on FDG-PET and magnetic resonance imaging. The FDG uptake in the 9 primary cervical cancers was greater than that in normal cervices (p=0.025). Examination of the 4 recurrent tumors revealed a higher FDG uptake than that in normal cervices (p=0.0022). Metastatic lesions in lymph nodes showed an accumulation of FDG on the PET scan. In conclusion, FDG-PET may be an effective diagnostic tool for detecting recurrence and lymph node metastasis of uterine cervical cancers.

High glucose attenuates insulin-induced mitogen-activated protein kinase phosphatase-1 (MKP-1) expression in vascular smooth muscle cells.

The mechanisms for the effect of hyperglycemia on insulin-induced mitogenesis were investigated using rat vascular smooth muscle cells (VSMC). VSMC were preincubated in serum-free medium with low (5 mM) glucose (LG condition) or high (25 mM) glucose (HG condition), and examined for DNA synthesis using bromodeoxyuridine (BrdUrd) incorporation. Mitogen-activated protein kinase (MAPK) activity and MAPK phosphatase (MKP-1) protein expression were detected by Western blot analysis. Phosphatidylinositol 3-kinase (PI-3K) activity was detected by thin layer chromatography. Insulin induced a dose-dependent increase in BrdUrd incorporation (123.3+/-2.6% over basal level with 1 microM insulin) in the LG group and this effect was significantly enhanced (161.6+/-10.4% over basal level) in the HG group. In the LG group, MAPK activity was transient with a peak activation (137.4+/-11.2% over basal level) after 10 min exposure to 100 nM insulin. In the HG group, the MAPK activity was significantly potentiated (two-fold compared to the LG group) and was sustained even after 60 min. Insulin also induced PI-3K activity and MKP-1 expression, both of which were blocked by the PI-3K inhibitor wortmannin. In the HG group, insulin-induced PI-3K and MKP-1 expression was almost abolished. In conclusion, high glucose enhances insulin-induced mitogenesis associated with the potentiation of insulin-stimulated MAPK activity in VSMC. These effects of glucose might in part be due to the attenuation of MKP-1 expression through the blockage of the insulin-PI-3K signal pathway.

Positron emission tomographic imaging of acoustic neuromas.

Positron emission tomography (PET) examination with both [11C]methyl-l-methionine (Met) and [18F]fluoro-2-deoxyglucose (FDG) was performed in the same patients with acoustic neuroma wherever possible in order to compare the usefulness of the two methods. The study included six patients who visited the Osaka City University Hospitals, between April 1994 and October 1998, for complaints associated with acoustic neuroma. All patients were examined by magnetic resonance imaging (MRI) and Met-PET. Four patients were examined by FDG-PET. The tumor's region of highest accumulation was selected as the region of interest; the tumor/normal ratio (T/N ratio) was defined as the ratio of radioisotope counts for tumor and normal gray matter. All tumors in this series were detected by MRI. In the Met-PET images, four tumors were easily identified, with a high T/N ratio. However, two tumors could not be identified using Met-PET. On FDG-PET, no cases could be identified. The T/N ratio for the four patients with positive Met-PET findings averaged 1.694 +/- 0.266. PET, especially Met-PET, is a powerful means of examination providing functional information on tumors in acoustic neuroma. Met-PET may therefore be useful for acoustic neuroma, which is known to proliferate slowly, as for malignant tumors, in evaluating the proliferating potential of a tumor, in determining patients in whom to perform radiological treatment and in monitoring post-treatment progress.

Clinical usefulness of positron emission tomography with fluorine-18-fluorodeoxyglucose in the diagnosis of liver tumors.

We studied various liver tumors by positron emission tomography with fluorine-18 fluorodeoxyglucose (FDG-PET) to examine the diagnostic usefulness of this technique. We also examined the relation between findings on FDG-PET and the characteristics of hepatocellular carcinoma. FDG-PET was performed in 78 patients with liver tumors, including 53 with primary liver cancer [48 hepatocellular carcinomas (HCC) and 5 cholangiocellular carcinomas (CCC)], 20 with metastatic liver cancer, 2 with liver hemangioma, and 3 with focal nodular hyperplasia. For quantitative evaluation, a region of interest (ROI) was placed over the entire tumor region, at the level of the maximum diameter of the tumor. A background ROI was then placed over the non-tumor region of the liver. The average activity within each ROI was subsequently corrected for radioactive decay, and the standardized uptake value (SUV) was calculated by dividing the tissue activity by the injected dose of radioactivity per unit body weight. SUV ratio was expressed as the tumor-to-non-tumor ratio of the SUV. The median SUV was significantly lower in HCC than in metastatic live cancer or CCC, and the median SUV ratio was significantly lower in HCC than in metastatic liver cancer or CCC. The median SUV was not higher in multiple HCC than in single HCC, but the median SUV ratio was significantly higher in multiple HCC than in single HCC. The median SUV and the median SUV ratio were significantly higher in the presence of portal vein thrombosis than in the absence of such thrombosis. The Cancer of the Liver Italian Program score and the alpha-fetoprotein value correlated significantly with both the SUV and SUV ratio. These results suggest that FDG-PET is clinically useful not only for the differential diagnosis of liver tumors but also for evaluation of the clinical characteristics of HCC.