The role of pituitary ghrelin in growth hormone (GH) secretion: GH-releasing hormone-dependent regulation of pituitary ghrelin gene expression and peptide content

Ghrelin is a GH-releasing peptide originally purified from the rat stomach. It has been demonstrated that ghrelin expression, within the gastroenteric system, is regulated by both the metabolic and GH milieu. Our laboratory and others have previously reported that ghrelin is also produced in the pituitary. Given that the receptor for ghrelin [GH secretagogue receptor (GHS-R)] is also expressed by the pituitary, the possibility exists that locally produced ghrelin plays an autocrine/paracrine role in regulating GH release. Because we have previously reported that GHRH infusion increases pituitary levels of ghrelin mRNA, we hypothesized that GHRH could be a key regulator of pituitary ghrelin expression. In this report, we demonstrate that 4-h GHRH infusion increased pituitary ghrelin peptide content. Interestingly, under experimental conditions in which hypothalamic GHRH expression is increased, e.g. GH deficiency due to GH gene mutation, glucocorticoid deficiency, and hypothyroidism, we observed that pituitary ghrelin expression (mRNA levels and peptide content) was also increased. Consistent with this positive correlation between GHRH and ghrelin, pituitary ghrelin expression (mRNA levels and peptide content) was found to be decreased in conditions in which hypothalamic GHRH expression is decreased, e.g. GH treatment, glucocorticoid excess, hyperthyroid state, and food deprivation. Collectively, these results suggest that pituitary ghrelin expression is GHRH dependent. We also conducted functional studies to examine whether the pituitary ghrelin/GHS-R system contributes to GH release after GHRH stimulation, by challenging pituitary cell cultures with GHRH in the presence of a GHS-R-specific inhibitor ([d-Lys-3]-GHRP-6). The GHS-R inhibitor did not affect GH release in the absence of GHRH, but significantly reduced GHRH-mediated GH release. This is the first report demonstrating that endogenous pituitary ghrelin can play a physiological role in GH release, by optimizing somatotroph responsiveness to GHRH.     

Monokine production by peripheral whole blood in chronic hepatitis C patients treated with interferon

Using our scoring system, we studied the production of monokines (interleukin-1, interleukin-1, tumor necrosis factor-, and interleukin-6) by lipopolysaccharide-stimulated peripheral whole blood in 35 patients with chronic hepatitis C during the interferon-/ therapy. It decreased in 25.7% (9/35, group A), fluctuated in 60.0% (21/35, group B), and increased in 14.3% (5/35, group C). The patients in group A were younger than those in group B (P<0.05). The histological grade of injury was milder in group A than in group B or C. The rate of sustained response was 66.7% (6/9) in group A, 19.0% (4/21) in group B, and 40.0% (2/5) in group C (P=0.0184, group A versus group B). In summary, monokine production by peripheral whole blood varied during interferon therapy for chronic hepatitis C patients. No significant change was noted in 60% of the patients. However, patients with decreased monokine production were younger, with a mild histological grade, and likely to respond to the interferon therapy.     

Role of p21 RAS in p210 bcr-abl transformation of murine myeloid cells

The p21 RAS product has been implicated as part of the downstream signaling of certain nonreceptor tyrosine kinase oncogenes and several growth factor receptor-ligand interactions. We have reported that the chronic myelogenous leukemia oncogene p210 bcr-abl transforms a growth- factor-dependent myeloid cell line NFS/N1.H7 to interleukin-3 (IL-3) independence. In these p210 bcr-abl-transformed cells (H7 bcr-abl.A54) and in two other murine myeloid cell lines transformed to IL-3 independence by p210 bcr-abl, endogenous p21 RAS is activated as determined by an elevated ratio of associated guanosine triphosphate (GTP)/guanosine diphosphate (GDP), assayed by thin-layer chromatography of the nucleotides eluted from p21 RAS after immunoprecipitation with the Y13-259 antibody. Treatment of p210 bcr-abl-transformed cells with a specific tyrosine kinase inhibitor herbimycin A resulted in diminished tyrosine phosphorylation of p210 bcr-abl and associated proteins, without major reduction in expression of the p210 bcr-abl protein itself. Inhibition of p210 bcr-abl-dependent tyrosine phosphorylation resulted in a reduction of active p21RAS-GTP complexes in the transformed cells, in diminished expression of the nuclear early response genes c-jun and c-fos, and in lower cellular proliferation rate. To further implicate p21 RAS in these functional events downstream of p210 bcr-abl tyrosine phosphorylation, we targeted G- protein function directly by limiting the availability of GTP with the inosine monophosphate dehydrogenase inhibitor, tiazofurin (TR). In p210 bcr-abl-transformed cells treated for 4 hours with TR, in which the levels of GTP were reduced by 50%, but GDP, guanosine monophosphate, and adenosine triphosphate (ATP) were unaffected, p210 bcr-abl tyrosine phosphorylation was at control levels. However, expression of c-fos and c-jun nuclear proto-oncogenes were strongly inhibited and p21 RAS activity was downregulated. These findings show that p210 bcr-abl transduces proliferative signals, in part, through downstream activation of p21 RAS. Furthermore, p21 RAS activity is linked to pathways that regulate c-jun and c-fos expression.     

A Case of Ruptured Mitral Valve Aneurysm Complicating Long-Standing Aortic Regurgitation

A 53-year-old man with aortic regurgitation was admitted to our hospital because of fever. A diagnosis of ruptured mitral valve aneurysm was made by Doppler echocardiography. Aortic regurgitant flow along the anterior mitral leaflet may have predisposed to mitral valve endocarditis, aneurysm formation, and its rupture.     

Rectal cancer associated with chronic lymphocytic leukemia

It has been reported that chronic lymphocytic leukemia (CLL) often occurs concomitantly with other malignant neoplasms. However, because CLL is rare in Japan, there are only a limited number of reports of the occurrence of malignant neoplasia in Japanese patients with CLL. We report here the simultaneous occurrence of rectal cancer and CLL in a 57-year-old man. Because the clinical stage of CLL was Rai system I, we decided, in accordance with the National Cancer Institute–Sponsored Working Group guidelines, to monitor him without therapy for CLL until evidence of disease progression, and we performed abdominoperineal resection of the rectum for the cancer. The small rectal tumor was associated with aggressive lymphangiosis carcinomatosa, and multiple nodal metastases were observed in the pool of CLL cells. He died of rectal cancer 7 months after the operation, and autopsy revealed extensive metastases of the cancer. Cellular and humoral immunity is often impaired in patients with CLL, and the defective immunity in this patient may have had an etiological role in the development and rapid progression of the cancer. In the follow-up of CLL patients, we must always be aware of the possible existence of a second malignant disease. Particular attention should be paid to those with defective immunity, and screening should be performed, especially for pulmonary and gastrointestinal malignancies.     

Morphological age changes in the diaphragm of rats under different protein diets

Male Donryu rats were housed in a specific pathogen free room and fed with 60% of the mean daily quantity of diet consumed by rats fed ad libitum The animals were divided into three groups of 50 and each group fed different amounts and types of dietary protein. The group P40 was fed with a diet containing 40% of total volume as vegetable protein; the agroup P10 with 10% of total volume as vegetable protein; and the group CE7 with 18% of total volume as mixed vegetable and animal proteins. Subsets of the animals were sacrificed at the ages of 6, 12, 18, 24 and 30 months. The P40 group gained body weight faster than other two groups during the first months. However, after 12 months, the body weight began to decrease, reaching the lowest mean body weight among the three groups by the end of the study. The three groups did not show any significative difference in the muscle fiber number index and in the number of capillaries per muscle fiber. The calculated diaphragm volume index increased up to a peak at 12 months in all three groups decreasing gradually thereafter, but did not show any significant difference due to dietary protein intake. The data suggest that the morphological age changes occurring in the diaphragm muscle are likely unrelated to dietary conditions and are more likely due to other factors such as changes in the neural activity during aging.     

Pseudomyxoma peritonei due to adenocarcinoma of the lung: Case report

A rare case of pseudomyxoma peritonei whose primary site was presumed to be the lung is reported. A 76-year-old woman was admitted to Hospital presenting with progressive abdominal distention. She had been admitted twice, 2 and 1 year previously for the evaluation of high plasma carcinoembryonic antigen (CEA) level, of 11.6ng/ml. Chest computed tomography (CT) scan and chest X-ray film on the third admission revealed a nodular lesion in the left lower lung field, and transbronchial lung biopsy (TBLB) revealed mucus-producing tall columnar epithelial carcinoma. Paracentesis revealed gelatinous ascitic fluid. At laparotomy, appendix and ovary were normal, and there were many small cystic tumors on the peritoneal surface and omentum. The patient died 2 years later, after repeated episodes of dynamic ileus. The lung and abdominal tumors gradually increased in size during the 2-year period, but she developed no respiratory symptoms. Based on both the clinical and pathophysiological findings, the final diagnosis made was pseudomyxoma peritonei whose origin was a lung adenocarcinoma.     

Determinants of in-hospital death and rupture in patients with a Stanford B aortic dissection.

BACKGROUND: In Stanford B acute aortic dissection (AAD), medical treatment is the choice of therapy in the acute phase, however, a portion of patients experience complications caused by serious clinical outcomes including aortic rupture and abdominal visceral ischemia. The objective of this study was to determine the predictors of in-hospital events in an Asian cohort of Stanford type B AAD. METHODS AND RESULTS: Hospital records were queried to identify patients that met following criteria: (1) AAD presenting within 14 days of symptom onset; and (2) computed tomography (CT) confirmation of a dissected descending aorta not involving the ascending aorta. An in-hospital event was defined as death, rupture/impending rupture, or organ malperfusion. Patient characteristics, inflammatory markers, and CT findings were obtained from clinical case records and retrospectively analyzed. Two hundred and twenty patients with Stanford B AAD were identified. In-hospital events occurred in 15 patients (there were 8 deaths, and 5 patients need to undergo emergent surgery because of impending rupture or rupture, and 4 patients experienced organ malperfusion). In univariate logistic regression analysis, the non-thrombosed type (odds ratio (OR) 3.88, 95% confidence interval (CI) 1.20-12.61, p=0.02) and maximum aortic diameter measured by an initial CT (each having a 5 mm increment: OR 1.61, 95% CI 1.20-2.15, p=0.001) were significant predictors of in-hospital events. In multiple logistic regression analysis, the only significant predictor was maximum aortic diameter measured by an initial CT (each having a 5 mm increment: OR 1.41, 95% CI 1.04-1.92, p=0.03). CONCLUSION: The results identified a large maximum aortic diameter as the independent predictor of in-hospital events in Stanford type B AAD. The non-thrombosed type might also help differentiate high-risk patients.     

Comparison of pharmacokinetics of saquinavir soft-gel capsule (SQV-SGC) combined with ritonavir (RTV), SQV hard-gel capsule with RTV,and SQV-SGC alone

Saquinavir (SQV) is a human immunodeficiency virus (HIV) specific protease inhibitor. When combined with ritonavir (RTV), plasma concentration of SQV is increased. In this study, we examined pharmacokinetics of SQV soft-gel capsule (SQV-SGC) 400 mg twice daily (BID) combined with RTV in HIV-1-infected patients (n = 4) and compared with those of SQV hard-gel capsule (SQV-HGC) 400 mg BID combined with RTV (n = 12). Pharmacokinetics of SQV-SGC 1,200 mg single dose in healthy subjects (n = 10) were also studied. Peak SQV concentration in plasma (Cmax) and area under the plasma concentration-time curve from 0 to 8 hour (AUC0-8 h) of SQV-SGC 400 mg BID combined with RTV group were higher than those of SQV-HGC 400 mg BID combined with RTV group; increase of 14.7% and 25.5%, respectively. Cmax and AUC0-8 h of SQV-SGC were higher than SQV-SGC 1,200 mg single dose group; increase of 3.9 fold and 8.5 fold, respectively. These results indicated that SQV-SGC combined with RTV therapy is the most potent antiviral effect among SQV-SGC with RTV, SQV-HGC with RTV, and SQV-SGC alone.     

Effects of interferon-α treatment on hepatitis B virus antigen-specific immunologic responses in patients with chronic hepatitis B

ABSTRACT— Studies were undertaken to evaluate the relationship between the immune responses and the effectiveness of interferon-α treatment in 21 patients with HBeAg-positive chronic active hepatitis. Peripheral blood mononuclear cells (PBMC), obtained on four occasions during an 8-week course of IFN-α therapy, were cultured with recombinant HBcAg, purified HBeAg or pokeweed mitogen (PWM). During follow-up for 6 months after therapy, clearance of serum HBeAg was observed in eight patients designated as responders. Immunological responses of PBMC obtained before treatment did not differ between responders and non-responders. In responders, IFN-γ and anti-HBc production was depressed during therapy, but recovered to above the pretreatment level at the end of and/or after cessation of therapy, while lymphocyte proliferation was enhanced during therapy with a subsequent decline to baseline value. In non-responders, such changes were modest throughout the study, and anti-HBc response remained decreased even after cessation of therapy. These results indicate that PBMC of responders have immunologically different responses to IFN-α therapy when compared with non-responders.