The melanocortin system is involved in regulating autonomic nerve activity through central pituitary adenylate cyclase-activating polypeptide

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a peptidergic neurotransmitter that is highly expressed in the nervous system. We have previously reported that a central injection of PACAP leads to changes in the autonomic nervous system tones including sympathetic excitation and parasympathetic inhibition. An anatomical study revealed that melanocortin and PACAP are colocalized in some hypothalamic nuclei. Here, we investigated the possible role of the melanocortin system in autonomic control by PACAP using SHU9119, an antagonist of the melanocortin receptors (MC3-R/MC4-R). Pretreatment with SHU-9119 did not affect the activating neural responses of adrenal, renal, and lumbar sympathetic nerves following a PACAP injection However, SHU9119 significantly eliminated the suppressing effect of a PACAP injection on gastric vagal nerve activity and excitation effects on liver and brown adipose tissue sympathetic nerve activities. These results suggest that the brain melanocortin system might play a key role in the control of thermogenic sympathetic outflows and digestive parasympathetic outflow by PACAP, but this system does not participate in the central effects of PACAP on cardiovascular function and neural activities of renal, adrenal, and lumbar sympathetic nerves.     

Prospective randomized controlled study of gastric emptying assessed by 13C-acetate breath test after pylorus-preserving pancreaticoduodenectomy: comparison between antecolic and vertical retrocolic duodenojejunostomy

Background/Purpose  To examine whether vertical retrocolic duodenojejunostomy is superior to antecolic duodenojejunostomy with respect to gastric emptying in a prospective, randomized, controlled study of patients undergoing pylorus-preserving pancreaticoduodenectomy (PpPD). Methods  Thirty-five patients undergoing PpPD between March 2005 and July 2007 were enrolled in the study. All provided informed consent. During PpPD, the patients were randomly assigned to either the antecolic (antecolic group, n = 17) or vertical retrocolic route (vertical retrocolic group, n = 18) just before the reconstruction. Each patient ingested ¹³C-acetate in a liquid meal before surgery and on postoperative day (POD) 30. Gastric emptying variables (Tmax, T1/2) were determined and compared between groups. Results  Clinical delayed gastric emptying, defined as an inability of patients to take in an appropriate amount of solid food orally by POD 14, was found in 1 of 17 patients (6%) in the antecolic group and in 4 of 18 patients (22%) in the vertical retrocolic group, but the difference was not significant (P = 0.34). Tmax and T1/2 on POD 30 were prolonged in both groups in comparison to preoperative levels, but no significant difference was found between the two groups. Follow-up examinations revealed that gastric emptying had recovered to the preoperative level by POD 30 in approximately 80% of the patients, regardless of the reconstruction route. Conclusions  Vertical retrocolic duodenojejunostomy does not seem to offer an advantage with respect to gastric emptying.     

Surgical Strategy for Hepatocellular Carcinoma Patients with Portal Vein Tumor Thrombus Based on Prognostic Factors

Rationale  Surgical strategy for patients with hepatocellular carcinoma and portal vein tumor thrombus (PVTT) remains to be established. Methods  From 1990 to 2008, 48 hepatocellular carcinoma patients with PVTT detected by preoperative imaging underwent hepatic resection, and their clinical data were retrospectively analyzed. Possible prognostic factors for survival were analyzed with postoperative survival curves, and significant factors were determined by univariate and multivariate analysis. The frequency of postoperative severe complications was investigated for each prognostic factor. Results  Significant prognostic factors included patient age <60 years, serum total bilirubin (T-Bil) >0.8 mg/dl, serum aspartate aminotransferase >30 IU/L, serum alkaline phosphatase (ALP) >300 IU/L, tumor size >4 cm, PVTT in the main trunk (Vp4), and a surgical margin <1 mm by univariate analysis, and independent prognostic factors were serum T-Bil, ALP, and Vp4. No patient with Vp4 survived for more than 400 days after surgery, and frequency of postoperative severe complications in these Vp4 patients was significantly higher than in other Vp1–3 patients. Conclusion  Hepatic resection as a first-choice treatment should be carefully selected in patients with Vp4 unless emergent removal of the PVTT is required.     

Vertical retrocolic duodenojejunostomy decreases delayed gastric emptying after pylorus-preserving pancreatoduodenectomy

BACKGROUND/AIMS: With the aim of preventing delayed gastric emptying (DGE) after pylorus-preserving pancreatoduodenectomy (PPPD), the new reconstruction method namely vertical retrocolic duodenojejunostomy in which the stomach and duodenum are brought down through the left side of the transverse mesocolon in a straight line thereby allowing these organs apart from the excised and anastomosed field and food passage by gravity is presented. METHODOLOGY: The preoperative and intraoperative factors, and short-term outcomes with special reference to DGE were compared between the two groups, PPPD (n = 12) and standard pancreatoduodenectomy (PD, n = 9). PD was similarly carried out except for hemigastrectomy for comparison. DGE was defined as a need for nasogastric tube decompression for 10 days or more. RESULTS: Preoperative and intraoperative factors were not significantly different between the two groups. DGE was absent in both groups because nasogastric tube was removed within 7 days in all patients with a mean of postoperative day 3 in both groups. The days until liquid diet in the PPPD group were similar, but those until regular diet were significantly faster compared with the PD group. Postoperative hospital stay was similar between the two groups. CONCLUSIONS: The current reconstruction method may minimize DGE after PPPD.     

Multiple brown tumors in primary hyperparathyroidism caused by an adenoma mimicking metastatic bone disease with false positive results on computed tomography and Tc-99m sestamibi imaging: MR findings

We encountered an unusual case of hyperparathyroidism with both hemosiderin deposits on the ribs and low intensity on T2-weighted magnetic resonance imaging (MRI) caused by a parathyroid adenoma with multiple brown tumors that mimicked metastatic bone tumor due to false positive results on computed tomography (CT) and Tc-99m sestamibi (MIBI) imaging. The patient, a middle-aged woman, had very high serum levels of calcium (14.1 mg/dl), alkaline phosphatase (9,369 IU/l) and intact-PTH (12,400 pg/ml), and a large tumor (2.5 cm in diameter) in the lower portion of the left lobe of the thyroid. Plain X-ray revealed a soft tumor in the left chest wall. On CT scan, there were multiple destructive masses in the ribs, including large intramedullary masses on both 3rd ribs. On MIBI scintigraphy, there was strong late uptake in the lower portion of the left cervical region, both 3rd ribs, and the left 7th, 8th, and 10th ribs. T2-weighted image MRI scans showed that both 3rd ribs had a low intensity with hemosiderin deposits. These findings suggested that the patient had hyperparathyroidism with multiple bone metastases due to carcinoma of the parathyroid gland. However, on pathology, the resected tumor of lower portion of the left lobe of thyroid was diagnosed as a parathyroid adenoma, and the tumors of the left 3rd and 7th ribs, as well as the right 2nd rib, were shown to be brown tumors. After resection, the patient's serum levels of calcium, alkaline phosphatase, and intact-PTH normalized. At 1.5-years follow-up, CT, MIBI, and MRI scans showed no abnormal findings. It is necessary to determine whether MRI can be used to distinguish between brown tumors and metastases caused by carcinoma of the parathyroid gland.     

Human cytochrome P450 1A1 is a novel target gene of liver X receptor α

Cytochrome P450 (CYP) 1A1 is involved in the metabolic activation of polycyclic aromatic hydrocarbons (PAHs) and is induced by several compounds, including PAHs. The induction of CYP1A1 mediated by the aryl hydrocarbon receptor (AhR) has been well investigated; however, little has been reported on the mechanisms of CYP1A1 induction mediated by factors other than AhR. In this study, we investigated the involvement of liver X receptor alpha (LXRα) in the induction of CYP1A1. TO-901317, an LXRα ligand, induced CYP1A1 mRNA in a dose-dependent fashion. Luciferase reporter assays using HepG2 cells showed that TO-901317 was capable of activating the promoter of the CYP1A1 gene and that a direct repeat 4 (DR4) motif located in a region from -452 to -467 was required for the induction of CYP1A1 through LXRα. Specific binding of LXRα to this DR4 motif was confirmed by gel shift and chromatin immunoprecipitation assays. Co-treatment of HepG2 cells with TO-901317 and 2,3,7,8-tetrachlorodibenzo-p-dioxin, a typical AhR ligand, caused the synergistic induction of CYP1A1 mRNA. Thus, we propose that the expression of CYP1A1 is regulated by LXRα as well as by AhR, suggesting that exposure to both LXRα and AhR ligands can result in the alteration of individual susceptibility to environmental carcinogens metabolically activated by CYP1A1.     

PACAP is implicated in the stress axes

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved pleiotropic neuropeptide that functions as a neurotransmitter, neuromodulator and neurotrophic factor. Accumulating evidence implicates PACAP as an important regulator of both central and/or peripheral components of the stress axes, particularly exposure to prolonged or traumatic stress. Indeed, PACAP and its cognate receptors are widely expressed in the brain regions and peripheral tissues that mediate stress-related responses. In the sympathoadrenomedullary system, PACAP is required for sustained epinephrine secretion during metabolic stress. It is likely that PACAP regulates autonomic function and contributes to peripheral homeostasis by maintaining a balance between sympathetic and parasympathetic activity, favoring stimulation of the sympathetic system. Furthermore, PACAP is thought to act centrally on the paraventricular nucleus of the hypothalamus to regulate both the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Intriguingly, PACAP is also active in brain structures that mediate anxiety- and fear-related behaviors, and the expression of PACAP and its receptors are dynamically altered under pathologic conditions. Thus PACAP may influence both hard-wired (genetically determined) stress responses and gene-environment interactions in stress-related psychopathology. This article aims to overview the molecular mechanisms and psychiatric implications of PACAP-dependent stress responses.     

Assessing multidimensional cognitions of drinking among alcohol-dependent patients: development and validation of a drinking-related cognitions scale (DRCS)

The aim of this study is to develop and validate the Drinking-Related Cognitions Scale (DRCS). The DRCS is a brief measure designed to assess multidimensional cognitions of drinking, including perception of drinking problems, perception of impaired drinking control, readiness to change, decisional balancing, and self-efficacy in alcohol-dependent patients. This study was carried out in Japan, with 132 alcohol-dependent patients (mean age (SD): 49.4 (7.5) years) admitted to an inpatient treatment program. On the basis of prior studies of the rating scales of drinking-related cognitions, DRCS items were selected. Factor analysis was carried out to assess the selection of DRCS items and the factor structure. The factor analysis of the 15 DRCS items showed three factors, "expectancy and resignation," "perception of impaired control," and "perception of drinking problem." The DRCS showed good reliability (Cronbach's alpha-coefficients for the entire scale and subscales were 0.80 or higher, and the analysis of variance intraclass correlation coefficient for the test-retest method was 0.81 for the total score). The total DRCS and subscale scores predicted abstinence status at a 3-month follow-up, and the DRCS was considered to have satisfactory predictive validity. It was suggested that the DRCS would be useful for the easy measurement of multidimensional cognitions of drinking in alcohol-dependent patients.     

Correlation between adiponectin and reduction of cell adhesion molecules after pitavastatin treatment in hyperlipidemic patients with type 2 diabetes mellitus

The aim of this study was to determine whether pitavastatin may prevent the progression of atherosclerotic changes in hyperlipidemic patients. Seventy-five hyperlipidemic patients with and without type 2 diabetes were enrolled to receive pitavastatin 2 mg daily. Cell adhesion molecules (sCD40L, sP-selectin, sE-selectin, and sL-selectin), chemokines (MCP-1 and RANTES) and adiponectin were measured at baseline and after 3 and 6 months of pitavastatin treatment. Adiponectin levels prior to pitavastatin treatment in hyperlipidemic patients with and without diabetes were lower than levels in normolipidemic controls. Both total cholesterol and the LDL-cholesterol (LDL-C) decreased significantly after pitavastatin administration. Additionally, hyperlipidemic patients with type 2 diabetes exhibited a significant increase in adiponectin levels after pitavastatin treatment (before vs. 3 months, 6 months, 2.81 ± 0.95 vs. 3.84 ± 0.84 μg/ml (p < 0.01), 4.61 ± 1.15 μg/ml (p < 0.001)). Furthermore, hyperlipidemic diabetics exhibited significant decreases in sE-selectin and sL-selectin levels after 6 months of pitavastatin treatment (sE-selectin, before vs. 6 months, 74 ± 21 vs. 51 ± 10 ng/ml, p < 0.05; sL-selectin, before vs. 6 months, 896 ± 141 vs. 814 ± 129 ng/ml, p < 0.05). In addition, adiponectin showed significant correlation with sE-selectin and sL-selectin in diabetic hyperlipidemia. However, MCP-1, RANTES and sCD40L did not exhibit any differences before or after pitavastatin administration. These results suggest that pitavastatin possesses an adiponectin-dependent anti-atherosclerotic effect in hyperlipidemic patients with type 2 diabetes in addition to its lowering effects on total cholesterol and LDL-C.