Changes in central dopaminergic systems with the expression of Shh or GDNF in mice perinatally exposed to bisphenol-A.

In the previous study, we reported that exposure to bisphenol-A induced the potentiation of dopamine receptor functions in the mouse limbic area, resulting in supersensitivity to methamphetamine-induced pharmacological actions. The present study was undertaken to investigate whether prenatal exposure to bisphenol-A could produce morphological change in dopaminergic neuron and the pattern of expression of genes regulating the dopaminergic neuron development. Here we found that prenatal and neonatal exposures to bisphenol-A increased the tyrosine hydroxylase- and dopamine transporter-like immunoreactivities in the adult mouse limbic area. The present molecular biological study shows that chronic bisphenol-A treatment produced a significant decrease in the dopaminergic neuron development factors, sonic hedgehog and glial cell line-derived neurotrophic factor, which were also decreased by prenatal exposure to bisphenol-A. These results suggest that chronic exposure to bisphenol-A could disrupt the dopaminergic neurotransmission in the process of dopaminergic neuron development.     

Ouabain as an amplifier of mineralocorticoid-induced hypertension.

Ouabain has recently been reported to be an endogenous Na, K-ATPase inhibitor. To evaluate whether it exerts hypertensive action itself or amplifies the hypertensive action of small doses of mineralocorticoids, 5 mg deoxycorticosterone acetate (DOCA), 1 mg ouabain, or a combination of both were injected into mononephrectomized rats weekly for 6 weeks, and changes in blood pressure were evaluated. The blood pressures of control, DOCA-treated, ouabain-treated, and the combination treatment group at the sixth week were 138 +/- 3 (SE), 160 +/- 6, 144 +/- 6, and 201 +/- 14 mmHg, respectively. The blood pressure of rats given DOCA or ouabain alone was not significantly different from that of controls. In contrast, the blood pressure of rats given the combination of DOCA and ouabain was significantly higher than that of control rats and those given DOCA or ouabain separately. Cardionephromegaly and histopathological changes found in rats given the combination of DOCA and ouabain were consistent with the effects of an elevation of blood pressure. Further evaluation revealed that the amplification effect of ouabain on the hypertensive action of DOCA was dose dependent, with the minimum dose that caused the amplification effect being 0.25 mg/week. These results indicate that ouabain, although devoid of hypertensive action itself, amplifies the hypertensive action of small doses of DOCA and can cause a hypertensive state similar to that induced by larger doses of DOCA. It is inferred that the amplification effect of ouabain on mineralocorticoids is important in the genesis of hypertension.     

GABAB receptor transduction mechanisms, and cross-talk between protein kinases A and C, in GABAergic terminals synapsing onto neurons of the rat nucleus basalis of Meynert

The transduction mechanisms underlying presynaptic GABA_B receptor-mediated inhibition of transmitter release have been characterized for a variety of synapses in the central nervous system (CNS). These studies have suggested a range of transduction mechanisms, including a role for second messengers such as protein kinases A (PKA) and C (PKC). In the present study, we have examined the intracellular signalling pathways underlying baclofen-induced inhibition of GABA release from terminals synapsing onto rat basalis of Meynert neurons using patch-clamp recordings. Baclofen, a selective GABA_B receptor agonist, reversibly decreased both evoked and spontaneous, miniature, GABAergic inhibitory postsynaptic currents (eIPSCs and mIPSCs, respectively). Such baclofen actions were completely abolished by CGP55845A, a selective GABA_B receptor antagonist, and by staurosporine, a non-selective PKA and PKC inhibitor. The mIPSC frequency was still decreased by baclofen even in the presence of 4 AP, a K⁺ channel blocker, and Cd²⁺, a voltage-dependent calcium channel blocker. Pharmacological activation or inhibition of PKC activity affected basal GABA release and mildly affected the response to baclofen. Inhibition of the cAMP/PKA cascade also affected basal GABA release and, in a subset of neurons, occluded the effects of baclofen, suggesting that the GABA_B receptor-mediated inhibitory action on GABA release was mediated via decreases in PKA activity. In addition, PKA inhibition occluded the effects of PKC modulation on both basal GABA release and on the response to baclofen. Our results characterize the transduction pathway of baclofen at these nucleus basalis of Maynert (nBM) synapses and show, for the first time, some cross-talk between the cAMP/PKA and PKC pathways in mammalian presynaptic nerve terminals.     

Dysadherin overexpression in pancreatic ductal adenocarcinoma reflects tumor aggressiveness: relationship to e-cadherin expression.

PURPOSE: The E-cadherin-mediated cell adhesion system is frequently inactivated by multiple mechanisms and is involved in tumor progression in many types of cancer. Recently, we reported the cloning and characterization of dysadherin and showed that it downregulated E-cadherin and promoted metastasis. The aim of this study was to investigate the clinical significance of dysadherin expression and the relationship between dysadherin expression and E-cadherin expression in pancreatic ductal adenocarcinoma. PATIENTS AND METHODS: We examined dysadherin and E-cadherin expression in 125 surgically resected pancreatic ductal adenocarcinoma patients using immunohistochemistry. RESULTS: Dysadherin was expressed at the cell membrane of cancer cells, but not in nontumor duct and acinar cells. Its expression was stronger in infiltrative and poorly differentiated nests compared with well-differentiated nests. Although the correlation between the expression of dysadherin and E-cadherin was not significant, a group of patients showed reduced E-cadherin expression with dysadherin overexpression. Increased dysadherin expression was significantly correlated with distant metastasis (P =.047), high tumor grade (P =.006), positive tumor margins (P =.024), and infiltrative type of growth pattern (P =.014). A survival advantage was observed in patients with 0% to 20% dysadherin-positive cells compared with patients with 51% to 100% dysadherin-positive cells, independent of tumor-node-metastasis classification, and World Health Organization tumor grade (P =.019). A combination of increased dysadherin expression and reduced E-cadherin expression (< 90%) further worsened the prognosis. CONCLUSION: In pancreatic ductal adenocarcinoma, dysadherin expression seems to reflect tumor aggressiveness and to be a positive marker of poor prognosis when considered both alone and in combination with downregulation of E-cadherin.     

Expression and regulation of periostin/OSF-2 gene in rat uterus and human endometrium

Periostin/OSF2 is a ligand for alphavbeta3 and alphavbeta5 integrins and activates the Akt/PKB pathway. Recent reports of periostin/OSF2 gene disrupted mice indicate that periostin/OSF-2 plays an important role in implantation. Quantitative RT-PCR revealed that the expression of periostin/OSF-2 mRNA in rat uteri was reduced to approximately 10% at 12 h after 17beta-estradiol (E2) injection, but was not changed after progesterone (P) injection. RT-PCR revealed the expression of periostin/OSF-2 in human endometrium, cultured human endometrial stromal cells (ESCs), and cultured human endometrial epithelial cells. In ESCs, the expression of periostin/OSF-2 mRNA was reduced to approximately 50% at 6 h after E2 treatment. The amount of periostin/OSF2 mRNA in human endometrium significantly increased during mid-proliferative and early secretory phases of menstrual cycle, and decreased during late-proliferative, mid-secretory and late secretory phases. The expression of periostin/OSF2 mRNA significantly decreased in ESCs decidualized by treatment with E2 and P for 7 and 11 days. By immunohistochemistry, the expression of periostin/OSF-2 was strongly detected in endometrial stromal cells during early proliferative, mid-proliferative and early secretory phases, and was strongly detected in endometrial epithelial cells during late secretory phase. This study demonstrated that the expression of periostin/OSF-2 is regulated by ovarian steroid hormones in rat uterus and human endometrium.     

Effect of L-dopa in young patients with hypertension

The effects of L-dopa on blood pressure, heart rate, plasma renin activity, norepinephrine, epinephrine and prolactin were studied in a randomized single-blind trial in 36 patients with essential hypertension. In response to L-dopa, 250 mg administered orally, the blood pressure decreased significantly as compared with the results of placebo treatment. The heart rate and plasma norepinephrine and epinephrine were unchanged. The plasma renin activity and prolactin decreased as a result of L-dopa administration. The administration of a peripheral DA2 dopamine receptor blocker, domperidone (20 mg, orally) prevented the L-dopa-induced reduction in plasma prolactin but failed to block the fall in blood pressure and plasma renin activity. These results suggest that the blood pressure-lowering effect of L-dopa may be mediated through multiple sites involving D1 dopamine receptors, the central nervous system, and the renin-angiotensin system.     

START domain proteins and the intracellular trafficking of cholesterol in steroidogenic cells

The intracellular trafficking of cholesterol in steroidogenic cells plays an important role in the regulation of hormone synthesis. Recent evidence indicates that a family of proteins related to the steroidogenic acute regulatory protein (StAR) perform critical functions in moving the sterol substrate to the mitochondrial inner membrane where the first committed step in steroid hormone synthesis occurs. StAR, the prototype of the family, is known to promote the translocation of cholesterol from the outer to the inner mitochondrial membrane. Mutations in StAR cause congenital lipoid adrenal hyperplasia, a cholesterol storage disorder in which synthesis of all gonadal and adrenocortical steroid hormones is severely impaired, and the cholesterol that is not efficiently moved into the mitochondria accumulates in cytoplasmic lipid droplets. The StAR-related lipid transfer (START) domain consists of an approximately 210 amino acid residue sequence that forms a compact alpha/beta structure, a helix-grip fold, with a hydrophobic tunnel that can accommodate a sterol molecule. START domains can bind sterol, facilitate the transfer of cholesterol from sterol-rich unilammelar liposomes to acceptor membranes, and stimulate steroidogenesis when expressed in cells co-expressing the cholesterol side-chain cleavage system or when added to isolated steroidogenic mitochondria. Sixteen human START domain proteins have been identified to date. Of these, StAR and MLN64 consist of one subfamily and newly described proteins named StarD4, StarD5, and StarD6 represent a closely related second subfamily. MLN64 is incorporated into the late endosomal compartment and is involved in the movement of cholesterol acquired from endocytosed LDL out of these vesicles. Expression of a dominant negative form of MLN64 causes accumulation of free cholesterol in lysosomes. The roles of StarD4, StarD5, and StarD6 in sterol movement remain to be determined. These genes have tissue-specific patterns of expression that may predict specialized roles.     

D2‐40‐positive lymphatic vessel invasion is not a poor prognostic factor in stage I lung adenocarcinoma

The present study investigates whether lymphatic vessel invasion (LVI) detected by D2‐40 staining is a prognostic factor for stage I adenocarcinoma of the lung. We retrospectively reviewed 124 patients who underwent complete resection for stage I adenocarcinoma of the lung from January 1983 to June 2003. LVI was microscopically evaluated using D2‐40 immunostaining. The median follow‐up was 71 months. The LVI positive rate was 37%. The 5‐year cancer‐specific survival rates of the D2‐40 positive LVI and negative groups were 88.8% and 84.3%, respectively (P = 0.630). The stage I lung adenocarcinoma patients who were determined to be LVI positive based on D2‐40 immunostaining did not have a significantly poorer prognosis than the LVI negative cases. Thus, lymphatic microinvasion may not be a prognostic indicator in early lung cancer, although advanced LVI does appear to correlate with survival. It is therefore unnecessary to use D2‐40 immunostaining to diagnose LVI in practical settings, and Hematoxylin‐Eosin and Elastica van Gieson staining should continue to be used to predict the prognosis of patients with stage I lung adenocarcinoma.     

Risk factors for recurrence of large HCC in patients treated by combined TAE and PEI

BACKGROUND/AIMS: In this report, risk factors of intrahepatic recurrence of a large solitary hepatocellular carcinoma after combination therapy with transcatheter arterial embolization followed by percutaneous ethanol injection were studied. METHODOLOGY: The series included 61 patients with an unresectable large solitary hepatocellular carcinoma, the largest size of which was greater than 3 cm in diameter. All patients completely responded to combination therapy and recurrence rates were determined. The following parameters; age, sex, hepatitis B virus surface antigen, hepatitis C virus antibodies, Child's classification, alcohol abuse, alanine aminotransferase, aspartate aminotransferase, alpha-fetoprotein, indocyanine green retention rate, hepatocellular carcinoma size, hepatocellular carcinoma capsule, total amount of injected ethanol and the alpha-fetoprotein 1 month after treatment were evaluated. RESULTS: The 1-, 3-, and 5-year cancer-free survival rates of all patients were calculated to be 61%, 23%, and 13%, respectively. Among pretreatment parameters, the log-rank test and subsequent Cox's proportional hazards model showed that a tumor size of more than 5 cm in diameter was independently associated with recurrence. The posttreatment parameters of total amount of injected ethanol was also shown to be significantly related to recurrence by the log-rank test. CONCLUSIONS: Lesions more than 5 cm in diameter and insufficient injected ethanol were associated with intrahepatic recurrence after this combination therapy.     

Sonographic features of acute colonic diverticulitis: the "dome sign"

PURPOSE: This study was performed to clarify the sonographic features of acute colonic diverticulitis to enable its differentiation from appendicitis. METHODS: Of 119 patients who were referred to our hospitals for lower abdominal pain between June 1997 and December 1998 and underwent sonography, 12 patients had a definitive diagnosis of acute colonic diverticulitis and 4 patients a tentative diagnosis. Seventy-eight patients were diagnosed as having acute appendicitis, confirmed by appendectomy. In the 16 patients with diagnoses of diverticulitis, the sonographic and clinical features of acute colonic diverticulitis were studied. RESULTS: Among the 12 patients with definitive diagnoses of acute colonic diverticulitis, sonographic findings included localized thickening of the colonic wall (100%) and a hemispheric mass (the "dome sign") protruding at the thickened colonic wall (100%) and consisting of a hypoechoic wall (100%) and a central echogenic area (66%). The presence of diverticula was confirmed by barium-enema x-ray study in all 12 patients. The 4 patients with tentative diagnoses of acute colonic diverticulitis all had colonic wall thickening but no dome sign. Colonoscopy revealed colitis in 3 of these patients. All 16 patients recovered with conservative treatment, without laparotomy. CONCLUSIONS: Sonography was useful for differentiating acute colonic diverticulitis from appendicitis. The sonographic finding of the dome sign seems to be specific for acute colonic diverticulitis.