Stimulatory effects of ghrelin on circulating somatostatin and pancreatic polypeptide levels

Ghrelin, the recently identified endogenous ligand of the GH secretagogue receptor, is a gut-brain peptide with endocrine, orexigenic, and gastrointestinal effects. In rodents it increases circulating gastrin and insulin levels, whereas in man it appears to decrease insulin secretion despite a rise in blood glucose levels. The aim of the present study was to evaluate the effects of ghrelin administration on total circulating somatostatin (SS), pancreatic polypeptide (PP), and gastrin levels compared with those elicited on insulin, glucose, and GH. Eight healthy volunteers of normal weight (four women and four men) were injected with 3.3 microg/kg ghrelin or saline after an overnight fast on 2 different days. Blood was taken every 15 min for 1 h and then every 30 min for 2 h. As expected, ghrelin injection elicited a prompt GH and glucose increase with a peak at 30 min and an insulin decrease with a nadir at 60 min. Gastrin concentrations were not modified, whereas significant rises were observed in both SS (in a biphasic pattern with peaks at 15 and 120 min) and PP (which increased promptly with a peak at 15 min). A significant negative correlation was found between SS (first peak) and insulin changes (r = -0.86; P < 0.01). In conclusion, this study clearly demonstrates that ghrelin stimulates SS and PP release in man. Although the underlying mechanisms and biological significance of these pharmacological effects remain to be elucidated, a causal relationship between the SS increase and the insulin changes may be hypothesized. Finally, these findings strongly support ghrelin's postulated role in linking the endocrine control of energy balance and growth with the regulation of gastrointestinal functions.     

Liver repopulation with xenogenic hepatocytes in B and T cell-deficient mice leads to chronic hepadnavirus infection and clonal growth of hepatocellular carcinoma

To investigate host and viral mechanisms determining hepadnaviral persistence and hepatocarcinogenesis, we developed a mouse model by transplanting woodchuck hepatocytes into the liver of mice that contain the urokinase-type plasminogen activator transgene (uPA) and lack mature B and T lymphocytes due to a recombination activation gene 2 (RAG-2) gene knockout. The woodchuck hepatocytes were transplanted via intrasplenic injection and were found to integrate into the recipient mouse liver cord structure. Normal adult woodchuck hepatocytes proliferated and reconstituted up to 90% of the uPA/RAG-2 mouse liver. uPA/RAG-2 mice containing woodchuck hepatocytes were infectable with woodchuck hepatitis virus (WHV) and showed WHV replication for at least 10 months with titers up to 1 × 10¹¹ virions per ml in the peripheral blood. WHV-infected hepatocytes from chronic carrier woodchucks also established a persistent infection in uPA/RAG-2 mice after an 8- to 12-week lag period of viremia. Although WHV envelope, core, and X proteins were produced in the uPA/RAG-2 mice, no inflammatory host immune response was observed in the liver of WHV-replicating mice. A first antiviral test demonstrated a greater than four orders of magnitude drop in WHV titer in response to interferon α treatment. WHV replication was up-regulated by dexamethasone treatment. Comparison of precancerous lesions in donor woodchucks versus recipient uPA/RAG-2 mice revealed an enrichment of dysplastic precancerous hepatocytes in transplanted mice. Clonal amplification of hepatocytes from a woodchuck with hepatocellular carcinomas was demonstrated by the detection of unique WHV DNA integration patterns in hepatocellular carcinomas that arose in uPA/RAG-2 mice. In the absence of B or T cell-mediated immune responses, WHV establishes a persistent noncytotoxic infection of woodchuck hepatocytes in uPA/RAG-2 chimeric mouse livers. Further studies of the kinetics of hepadnavirus infection and replication in quiescent and proliferating hepatocytes should increase our understanding of hepadnavirus spread and aid in the design of therapies to block or cure persistent infection.     

Prognostic value of estimated glomerular filtration rate in hospitalized elderly patients

A multicenter observational study, REPOSI (REgistro POliterapie Società Italiana di Medicina Interna), was conducted to assess the prognostic value of glomerular filtration rate (eGFR) on in-hospital mortality, hospital re-admission and death within 3 months, in a sample of elderly patients (n = 1,363) admitted to 66 internal medicine and geriatric wards. Based on eGFR, calculated by the new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, subjects at hospital admission were classified into three groups: group 1 with normal eGFR (≥60 ml/min/1.73 m², reference group), group 2 with moderately reduced eGFR (30–59 ml/min/1.73 m²) and group 3 with severely reduced eGFR (<30 ml/min/1.73 m²). Patients with the lowest eGFR (group 3) on admission were more likely to be older, to have a greater cognitive and functional impairment and a high rate of comorbidities. Multivariable logistic regression analysis showed that severely reduced eGFR at the time of admission was associated with in-hospital mortality (OR 3.00; 95 % CI 1.20–7.39, p = 0.0230), but not with re-hospitalization (OR 0.97; 95 % CI 0.54–1.76, p = 0.9156) or mortality at 3 months after discharge (OR 1.93; 95 % CI 0.92–4.04, p = 0.1582). On the contrary, an increased risk (OR 2.60; 95 % CI 1.13–5.98, p = 0.0813) to die within 3 months after discharge was associated with decreased eGFR measured at the time of discharge. Our study demonstrates that severely reduced eGFRs in elderly patients admitted to hospital are strong predictors of the risk of dying during hospitalization, and that this measurement at the time of discharge helps to predict early death after hospitalization.