Role of granuloma in the immunopathogenesis of Crohn's disease.

Inflammatory bowel diseases (ulcerative colitis and Crohn's disease) are chronic long-lasting inflammatory diseases with yet unknown etiology. Recent advancement revealed that both diseases are associated with genetic predisposition and environmental factors such as luminal microorganisms and antigens. Crohn's disease is associated with histopathologic features such as granuloma formation and longitudinal ulceration. In this article we describe the role of granuloma in the immunopathogenesis of Crohn's disease. Granuloma of Crohn's disease may play crucial roles as antigen-presenting cites to memory type T cells, which leads to activation and proliferation of T cells. Antigens presented at granuloma may be closely related to the disease.

Recurrence of Cushing's disease after long-term remission due to pituitary apoplexy.

We encountered a case with long-term remission of Cushing's disease due to pituitary apoplexy. The apoplexy of pituitary adenoma secreting adrenocorticotropin hormone was diagnosed by successive and timely magnetic resonance imaging when the symptoms of the patient were not yet severe and anterior pituitary dysfunction was only a transient reduction of growth hormone secretion. Seven years after the first episode of pituitary apoplexy, hypercorticism recurred, and pituitary magnetic resonance imaging showed a regrowth of the pituitary adenoma. A spontaneous remission of Cushing's disease without significant visual, neurologic or hormonal defects seems to be a much more common phenomenon than has been previously suggested. Cases with relapse after spontaneous remission of Cushing's disease are rare and the duration of remission in previous reports was within 5 years. We observed such a patient with a 7 year-remission caused by pituitary apoplexy. We consider that a careful long-term follow-up is required for patients with Cushing's disease whose remission was due to pituitary apoplexy.

Effects of dehydroepiandrosterone on mitogen-activated protein kinase in human aortic smooth muscle cells.

The objective of the present study was to determine whether dehydroepiandrosterone (DHEA) modifies growth factor-induced mitogen-activated protein kinase (MAPK) activation, based on our previous study demonstrating that DHEA attenuates fetal calf serum-induced proliferation in human male aortic smooth muscle cells (human male aortic SMCs). Human male aortic SMCs were used for this study. Platelet-derived growth factor-BB (PDGF-BB), epidermal growth factor (EGF), and basic fibroblast growth factor (bFGF), but not insulin-like growth factor-1 (IGF-1), stimulated MAPK activity. Only MAPK activation induced by PDGF-BB was reduced by pretreatment with DHEA, although DHEA did not affect the MAPK activation induced by EGF or bFGF. The basal and PDGF-stimulated MAPK activity were decreased by two types of cyclic AMP (cAMP) elevating agents and increased by cAMP-dependent protein kinase (PKA) inhibitor in human male aortic SMCs, suggesting that cAMP regulates MAPK negatively. The intracellular cAMP was increased by PDGF-BB. The increase of cAMP by PDGF-BB was augmented by pretreatment with DHEA, although DHEA alone did not affect cAMP. Neither EGF nor bFGF affected cAMP with and without DHEA pretreatment. Secretion of PGE2 induced by PDGF was augmented by pretreatment with DHEA. Stimulatory effects of DHEA on the production of PGE2 and cAMP were partially canceled by aromatase inhibitor and completely canceled by indomethacin or selective inhibitor of cyclooxygenase-2. These results suggest that DHEA inhibited MAPK activation induced by PDGF-BB via PGE2 overproduction and subsequent cAMP-dependent pathway in human male aortic SMCs.

Primary hypomagnesemia caused by isolated magnesium malabsorption: atypical case in adult.

Isolated magnesium malabsorption is a rare disorder, which bas been described in no more than 30 patients worldwide. Patients with this disorder typically present with convulsion and diarrhea in early infancy. Hypomagnesemia and hypocalcemia were found in a 35-year-old man with muscle cramps, who bad been diagnosed as primary hypoparathyroidism. Oral magnesium therapy corrected the low serum calcium, magnesium and parathyroid hormone levels. We report an atypical case of isolated magnesium malabsorption in an adult.

Central diabetes insipidus with Behçet's disease.

We encountered a case of Behçet's disease complicated with central diabetes insipidus. A hypothalamopituitary dysfunction is rare in Behçet's disease; only three cases of this association have been reported in the literature. Magnetic resonance imaging of the brain showed a dilatation of the left Sylvian vein and thickening of the pituitary stalk, which suggested intracranial vasculitic processes and lymphocytic infundibuloneurohypophysitis. The possible relationship of this disease combination is discussed as a form of autoimmune disease.

Strong synergistic anti-peroxidative effects of HDL3 and ascorbic acid against copper-catalyzed LDL peroxidation.

The aim of this study was to investigate the effects of high density lipoprotein 3 (HDL3) and ascorbic acid (AsA) in combination on copper-catalyzed low density lipoprotein (LDL) peroxidation. LDL and HDL3 were isolated from sera of healthy volunteers. LDL protein, 200 microg/ml, was incubated in phosphate-buffered saline (PBS) containing 2.5 microM CuSO4 in the absence or presence of AsA, with HDL3 protein alone, or with coincubation of HDL3, 200 microg/ml, and AsA, 20 microg/ml, at 37 degrees C for up to 24 h. As a control, the same amount of control LDL protein was added to PBS. The protective effects of the HDL3 and AsA were examined by both electrophoresis and determination of the lipid hydroperoxide (LPO) level in each sample. The concentration of AsA was also measured in samples containing AsA. The coincubation of HDL3 and AsA exerts more powerful anti-peroxidative effects against copper-catalyzed LDL peroxidation, than either of these agents alone. In addition, AsA was retained in the media by the addition of HDL3. The findings suggest that there are strong synergistic anti-peroxidative effects of HDL3 and AsA and these two may act in concert in vivo to inhibit LDL peroxidation and thus exert an anti-atherosclerotic effect.

Surgical successful treatment of Cushing's syndrome in a pregnant patient complicated with severe cardiac involvement.

We encountered a case of a pregnant woman with adrenal causes of Cushing's syndrome who exhibited congestive heart failure as an initial symptom. Since the patient was also a diabetic, we treated her with high levels of diuretics and insulin. Echocardiography revealed a remarkable thickening of the left ventricle without asymmetric hypertrophy. The diagnosis of Cushing's syndrome caused by adrenal adenoma was confirmed by the endocrinological data and magnetic resonance imaging. The right adrenal adenoma was removed in the 28th week of pregnancy. After the operation, her congestive heart failure and hyperglycemia dramatically improved. Five weeks after the operation, she delivered a normal infant by caesarean section without complications. Only 4 months after delivery, the thickening of her left ventricle was normalized. We consider that the progression of her left ventricular hypertrophy induced by the changes in hemodynamic load during pregnancy may have been augmented by the excess of plasma cortisol. Operative therapy may be recommended for pregnant Cushing's syndrome patients with severe hypercortisolism complicating congestive heart failure.

Pregnant woman with transient diabetes insipidus resistant to 1-desamino-8-D-arginine vasopressin.

We encountered a pregnant woman with transient diabetes insipidus which developed during the third trimester. A hypertonic saline infusion study did not concentrate the osmolality of urine. Her laboratory data showed hypokalemia, hyperreninemia, an increased concentration of plasma aldosterone and an increased urinary excretion rate of prostaglandin E2, which resembled hyperprostaglandin E-syndrome. T1-weighted magnetic resonance imaging of the posterior pituitary gland revealed decreased intensity. Polyuria reached 4-6 L daily, and urine osmolality remained dilute despite a lapse of four days since treatment with intranasal 1-desamino-8-D-arginine vasopressin (dDAVP: 10-25 microg every 12 h). The patient was conservatively managed without medical treatment, then delivered in the 38th week of pregnancy without complication. The osmolality of the patient's urine was higher than that of the plasma when tested 3 days postpartum. The abnormality of magnetic resonance imaging of the posterior pituitary gland disappeared at 6 months after delivery. We consider that subclinical nephrogenic diabetes insipidus in our patient was exacerbated during pregnancy.

A novel function of the C-terminal lipid moieties of Rab3A small G protein implicated in Ca2+-dependent exocytosis--inhibition of interaction with GTP and reduction of this inhibition by phospholipid.

BACKGROUND: Rab3A small G protein is implicated in Ca2+-dependent exocytosis. It undergoes posttranslational lipid-modifications at its C-terminal region. These lipid moieties are important for the actions of the regulators of Rab3A, but not for the interaction with its downstream target. RESULTS: We have found another function of the C-terminal lipid moieties of Rab3A. GTP rapidly associates with the guanine nucleotide-free form of unmodified Rab3A, but not with the same form of modified Rab3A. Moreover, GTP rapidly dissociates from the GTP-bound form of modified Rab3A, but not from the same form of unmodified Rab3A. The association of GTP with the guanine nucleotide-free form of modified Rab3A is stimulated by the Rab3 GDP/GTP exchange protein (Rab3 GEP), and the dissociation of GTP from the GTP-bound form is markedly reduced by synaptic vesicle phospholipid. CONCLUSIONS: These results suggest that the interaction of the lipid moieties of Rab3A with Rab3 GEP or synaptic vesicles is required for the interaction of modified Rab3A with GTP. Moreover, these results - together with the fact that Rabphilin-3A associated with synaptic vesicles inhibits the activity of Rab3 GTPase-activating protein - suggest that the GTP-bound form of modified Rab3A is associated with synaptic vesicles through both Rabphilin-3A and the vesicle phospholipid.

Interaction of Rabphilin3 with synaptic vesicles through multiple regions.

Rabphilin3 is a downstream target protein of Rab3A small G protein, implicated in neurotransmitter release. We have previously reported that about 4 molecules of Rabphilin3 are associated with one synaptic vesicle through a vesicle anchoring protein(s). We have shown here that Rabphilin3 interacts with rat synaptic vesicles through at least three regions: the N-terminal region (1-280 amino acids (aa)), the C-terminal region containing the two C2 domains (440-704 aa), and an unidentified region. A model for the interaction of Rabphilin3 with the vesicles is discussed.

Rabphilin-3A is associated with synaptic vesicles through a vesicle protein in a manner independent of Rab3A.

Rabphilin-3A is a putative target protein for Rab3A small GTP-binding protein, which is implicated in regulated secretion, particularly in neurotransmitter release. Rabphilin-3A is associated with synaptic vesicles, although it has no transmembrane segment. Here we have studied how rabphilin-3A is associated with synaptic vesicles. Treatment of the synaptic vesicles isolated from rat brain with 1 M NaCl completely solubilized rabphilin-3A from the vesicles. These vesicles deprived of rabphilin-3A still contained Rab3A and synaptophysin. Exogenous rabphilin-3A bound to the vesicles deprived of endogenous rabphilin-3A in dose-dependent and saturable manners. The concentration of exogenous rabphilin-3A giving a half-maximal binding was about 50 nM and maximally 5 +/- 1 molecules of exogenous rabphilin-3A bound to one vesicle. Addition of exogenous Rab3A bound to one vesicle. Addition of exogenous Rab3A or removal of endogenous Rab3A by the action of Rab GDI did not affect the binding of exogenous rabphilin-3A to the vesicles. However, treatment of the vesicles with trypsin completely abolished the binding of exogenous rabphilin-3A. These results suggest that rabphilin-3A is associated with synaptic vesicles at least through a vesicle protein in a manner independent of Rab3A.