Intestinal Bile Acid Composition Modulates Prohormone Convertase 1/3 (PC1/3) Expression and Consequent GLP-1 Production in Male Mice.

Besides an established medication for hypercholesterolemia, bile acid binding resins (BABRs) present antidiabetic effects. Although the mechanisms underlying these effects are still enigmatic, glucagon-like peptide-1 (GLP-1) appears to be involved. In addition to a few reported mechanisms, we propose prohormone convertase 1/3 (PC1/3), an essential enzyme of GLP-1 production, as a potent molecule in the GLP-1 release induced by BABRs. In our study, the BABR colestimide leads to a bile acid-specific G protein-coupled receptor TGR5-dependent induction of PC1/3 gene expression. Here, we focused on the alteration of intestinal bile acid composition and consequent increase of total TGR5 agonistic activity to explain the TGR5 activation. Furthermore, we demonstrate that nuclear factor of activated T cells mediates the TGR5-triggered PC1/3 gene expression. Altogether, our data indicate that the TGR5-dependent intestinal PC1/3 gene expression supports the BABR-stimulated GLP-1 release. We also propose a combination of BABR and dipeptidyl peptidase-4 inhibitor in the context of GLP-1-based antidiabetic therapy.

Magnified endoscopic observation using narrow-band imaging of periampullary adenoma in a patient with familial adenomatous polyposis.

BACKGROUND: Adenoma of the major papilla carries a relatively high risk of malignant transformation to carcinoma, the leading cause of death in patients with familiar adenomatous polyposis (FAP) after colectomy. CASE REPORT: A 35-year-old man had undergone prophylactic colectomy for FAP 3 years earlier. On the forward-viewing and side-viewing endoscopy done for surveillance, the overlying mucosa of the major papilla showed even granularity. On magnifying duodenoscopy using a narrow-band system (NBI), which uses modified optical filters and yields clear images of fine surface structures on the mucosal layer, a compact formation of round pits was seen in the affected ampulla. The microvascular architecture on NBI magnification showed no abnormalities, such as dilated, tortuous or network-like vessels, suggestive of malignancy. On endoscopic retrograde pancreaticocholangiography there was no intraductal growth, and endoscopic ultrasonography showed confinement to the mucosal layer. The ampullary lesion was completely resected using endoscopic snare papillectomy. Histopathological examination of the removed specimen showed tubular adenoma without malignant foci. The patient's post-treatment course was uneventful and without complications, and no local recurrence was noted on repeat endoscopy. CONCLUSIONS: Thus, endoscopic surveillance and removal of ampullary adenomas appear to be justified.

[A randomized double-blind comparison of epidural versus intravenous tramadol infusion for postoperative analgesia].

BACKGROUND: This study compared epidural and intravenous tramadol infusions for postoperative analgesia after gastrectomy. METHODS: Twenty patients were assigned randomly to receive either tramadol epidurally and saline intravenously (group-E) or tramadol intravenously and saline, epidurally (group-I) in a double-blind fashion. At the end of the operation, each patient received a bolus of tramadol 2 mg x kg(-1) either epidurally or intravenously and 7 mg x kg(-1) x day(-1) tramadol infusion was begun via the same route. Concurrently, a saline bolus and its infusion were given via the alternate route. RESULTS: Both groups obtained adequate pain relief and there was no difference between the groups in pain score. But one patient in E-group was excluded from the study for respiratory depression 8 hours after the operation. No other side effects were detected in either group except mild nausea. CONCLUSIONS: We conclude that intravenous tramadol infusion provides effective and safe postoperative analgesia. A futher examination is required for the suitable dose of tramadol in epidural infusion.

[Cauda equina syndrome following intrathecal dibucaine].

We report three cases of cauda equina syndrome following spinal anesthesia with dibucaine. In two cases, the lumbar puncture was repeated and additional doses of dibucaine were administered to obtain adequate sensory blockade. In the last case, spinal anesthesia worked well with single injection of dibucaine. In all cases patients complained of varying degrees of bladder and bowel dysfunction, perineal sensory loss and lower extremity motor weakness on the next day, and the diagnosis of cauda equina syndrome was made. With only one case, the symptom disappeared four months later, but the rest of the patients suffered from sensory disturbance and defecation for more than four months after the surgery. One possible cause is a direct neurotoxic effect of high concentration dibucaine due to its maldistribution within the subarachnoid space. We have to consider the neurotoxicity and dose of the local anesthetic for obtaining a safer method and for preventing this complication.

NKT cell frequency in Japanese type 1 diabetes.

A numerical and functional deficit of natural killer T (NKT) cells has been reported to be associated with the pathogenesis of Caucasian patients with type 1 diabetes. However, a conflicting finding of a higher frequency of NKT cells (Valpha24+ Vbeta11+ T cells) was observed in islet-associated Ab+ and Ab- Japanese "classic" type 1 diabetes. Here, we combined the data of NKT cell frequency in Ab+ and Ab- "classic" type 1 diabetic patients and then analyzed the relationship between NKT cell frequency and disease activity.

Two cases of "fulminant" type 1 diabetes suggesting involvement of autoimmunity.

Recently, a novel subtype of type 1 diabetes, so-called fulminant type 1 diabetes, has been proposed. One of the characteristics of this subtype is the absence of detectable "islet-associated" autoantibody, so it was originally proposed as being "nonautoimmune-mediated"; however, it has not yet been concluded whether autoimmunity is involved. We have previously shown that serum interferon-inducible protein-10 and glutamic acid decarboxylase-reactive CD4(+) interferon-gamma-producing cells in the peripheral blood are good markers for T cell-mediated autoimmunity in type 1 diabetes. Here, we report two cases of fulminant type 1 diabetes in which these markers were detected and in which the involvement of islet-associated autoimmunity is suggested.

High frequency of valpha24(+) vbeta11(+) T-cells observed in type 1 diabetes.

OBJECTIVE: Natural killer T-cells (NKT cells) are believed to play an important role in the regulation of immune response, and a numerical and functional deficit of NKT cells has been reported to be associated with the pathogenesis of autoimmune diseases. Thus far, it has been shown that subjects with type 1 diabetes have a lower frequency of NKT cells than nondiabetic subjects. In this study, we measured the frequency of peripheral Valpha24(+) Vbeta11(+) T-cells, which include human NKT cells, in Japanese diabetic patients. RESEARCH DESIGN AND METHODS: Peripheral blood samples were obtained from 164 Japanese diabetic patients and 67 healthy subjects. The diabetic patients were classified into four categories as follows: islet-associated autoantibody-positive (Ab(+)) and -negative (Ab(-)) classic type 1 diabetes, latent autoimmune diabetes in adults (LADA), and type 2 diabetes. We measured the frequency of peripheral Valpha24(+) Vbeta11(+) CD3(+) triple-positive cells. RESULTS: Unexpectedly, a higher frequency of Valpha24(+) Vbeta11(+) T-cells was observed in Ab(+) and Ab(-) patients compared with LADA patients (P = 0.0294 and P = 0.0021), type 2 diabetic patients (P < 0.0001 and P < 0.0001), and healthy subjects (P = 0.0046 and P = 0.0001). Moreover, an inverse correlation between Valpha24(+) Vbeta11(+) T-cell frequency and disease duration was observed in Ab(+) (rho = -0.455; P = 0.0023) and Ab(-) (rho = -0.432; P = 0.0162) patients. CONCLUSIONS: Our findings indicate that a high frequency of Valpha24(+) Vbeta11(+) T-cells is a unique finding in recent-onset classic type 1 diabetes, and measurement of Valpha24(+) Vbeta11(+) T-cell frequency may be useful to assess the disease activity of classic type 1 diabetes.