IGF-I mediates regeneration of endocrine pancreas by increasing beta cell replication through cell cycle protein modulation in mice

AIMS/HYPOTHESIS: Recovery from diabetes requires restoration of beta cell mass. Igf1 expression in beta cells of transgenic mice regenerates the endocrine pancreas during type 1 diabetes. However, the IGF-I-mediated mechanism(s) restoring beta cell mass are not fully understood. Here, we examined the contribution of pre-existing beta cell proliferation and transdifferentiation of progenitor cells from bone marrow in IGF-I-induced islet regeneration. METHODS: Streptozotocin (STZ)-treated Igf1-expressing transgenic mice transplanted with green fluorescent protein (GFP)-expressing bone marrow cells were used. Bone marrow cell transdifferentiation and beta cell replication were measured by GFP/insulin and by the antigen identified by monoclonal antibody Ki67/insulin immunostaining of pancreatic sections respectively. Key cell cycle proteins were measured by western blot, quantitative RT-PCR and immunohistochemistry. RESULTS: Despite elevated IGF-I production, recruitment and differentiation of bone marrow cells to beta cells was not increased either in healthy or STZ-treated transgenic mice. In contrast, after STZ treatment, IGF-I overproduction decreased beta cell apoptosis and increased beta cell replication by modulating key cell cycle proteins. Decreased nuclear levels of cyclin-dependent kinase inhibitor 1B (p27) and increased nuclear localisation of cyclin-dependent kinase (CDK)-4 were consistent with increased beta cell proliferation. However, islet expression of cyclin D1 increased only after STZ treatment. In contrast, higher levels of cyclin-dependent kinase inhibitor 1A (p21) were detected in islets from non-STZ-treated transgenic mice. CONCLUSIONS/INTERPRETATION: These findings indicate that IGF-I modulates cell cycle proteins and increases replication of pre-existing beta cells after damage. Therefore, our study suggests that local production of IGF-I may be a safe approach to regenerate endocrine pancreas to reverse diabetes.     

Tumor size determines the efficacy of percutaneous ethanol injection for the treatment of small hepatocellular carcinoma.

This study was aimed at defining the therapeutic value of percutaneous ethanol injection in patients with solitary hepatocellular carcinoma less than 4 cm. Ultrasound-guided ethanol injection was performed in 24 cirrhotic patients (9 Child A, 10 Child B and 5 Child C), with hepatocellular carcinoma not suitable for surgical treatment. Its efficacy was assessed by repeated ultrasound, computed tomography and tumor biopsy during a follow-up ranging between 4 and 41 mo. Ethanol injection did not achieve a complete tumor necrosis in five cases after a minimum of 12 injections. Seven of the remaining 19 cases, with initial success, have shown recurrence during follow-up, thus resulting in 50% success rate, which was significantly related to baseline tumor size. The six patients with nodules less than 2 cm achieved a complete response, whereas this was recorded in 2 of the 7 with tumor size between 2 and 3 cm, and in only 1 of the 11 cases between 3 and 4 cm. The 1- and 2-yr survival of Child's A and B patients was 87% and 70%, respectively. These results indicate that percutaneous ethanol injection is a useful treatment for hepatocellular carcinoma, especially in tumors less than 3 cm. The high survival rate among patients with nonadvanced liver disease suggests that this therapeutic approach can be considered an alternative approach to surgical resection for tumors smaller than 3 cm.     

The incidence, clinical characteristics and prognostic significance of a left bundle-branch block associated with an acute myocardial infarct

To assess the current incidence and meaning of left bundle-branch block associated with acute myocardial infarction we studied 1,239 patients consecutively admitted in three hospitals. Left bundle branch block was present in 42 cases (3.3%). Compared to the patients without left bundle-branch block, those with left bundle-branch block were older (70 +/- 8.8 versus 63.9 +/- 11.4 years; p < 0.001), and had a more prevalent history of diabetes, angina, myocardial infarction and heart failure. Left bundle-branch block was associated more frequently with female gender and poor left ventricular ejection fraction. Patients with left bundle branch block were admitted with a longer interval from the onset of the symptoms (7.8 +/- 6.3 versus 5.4 +/- 6.7 hours; p < 0.01) and received in a lesser rate thrombolytics agents (21% versus 56%; p < 0.001), than those without left bundle-branch block. Complications significatively associated with left bundle-branch block were: complete AV block; heart failure and one-year mortality (40.4% versus 19.5%, p < 0.01). Female gender, age and heart failure were independent predictors of mortality whereas left bundle-branch block was not. In conclusion, current incidence of left bundle-branch block in acute myocardial infarction is lower than that referred in the pre-thrombolytic era. Left bundle-branch block is accompanied by a low rate of thrombolysis, whereas a higher mortality rate of these patients seems to depend on their clinical characteristics.     

Intermediate uveitis and alopecia areata: is there a relationship? Report of 3 pediatric cases

Three previously healthy children, aged 5, 8, and 15 years, with idiopathic intermediate uveitis (IU) and alopecia areata (AA) are described. These are the first 3 cases of which we are aware with this coexistence. The results of extensive diagnostic evaluations were negative in all 3 cases. AA preceded the diagnosis of bilateral IU in 1 child and followed within several months after IU diagnosis in 2 children. The severity of uveitis ranged from mild to sight-threatening, and hair loss ranged from local lesions in 2 cases to total alopecia in 1 case. Pathogenesis of both diseases is discussed. Theoretically, the coexistence of IU and AA might be based on the similarities in their complex pathogenesis. However, more research is needed to evaluate if the coexistence is based on an association between 2 autoimmune disorders or is a coincidence.     

Portal Hypertension may Influence the Registration of Hypointensity of Small Hepatocellular Carcinoma in the Hepatobiliary Phase in Gadoxetic Acid MR

BackgroundThe aim of the study was to analyze the association between the liver uptake of Gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) in the hepatobiliary phase (HBP) in cirrhotic patients and the presence of clinically significant portal hypertension (CSPH), and how these features impact on hepatocellular carcinoma (HCC) detection in the HBP.Patients and methodsPost-hoc analysis of a prospective cohort of 62 cirrhotic patients with newly US-detected nodule between 1–2 cm (study group). Twenty healthy subjects were used as control group. Qualitative and quantitative analysis of the liver contrast uptake in the HBP assessed by Relative Liver-Enhancement (RLE), Liver-Spleen (LSCR), Liver-Muscle (LMCR), and Liver-Kidney Contrast-Ratio (LKCR), Contrast Enhancement Index (CEI), and Hepatic Uptake (HUI), and biliary excretion, were registered. CSPH was confirmed invasively (HVPG > 10 mmHg) or by indirect parameters. The appearance of HCC at the HBP was analyzed.ResultsNineteen patients (30.6%) did not have CSPH. In 41 patients (66.1%) the final diagnosis was HCC. All indices were significantly higher in the control group, indicating a more intense HBP liver signal intensity compared to patients with cirrhosis, even if the comparison was restricted to patients with no CSPH. CSPH was associated to a lower rate of HCC hypointensity in the HBP (51.9% vs. 85.7% without CSPH, p = 0.004).ConclusionsLiver uptake of Gd-EOB-DTPA at the HBP is decreased in cirrhosis even if the liver function is minimally impaired and it falls down significantly in patients with CSPH compromising the recognition of hypointense lesions. This fact may represent a limitation for the detection of small HCC in patients with cirrhosis and CSPH.Key words: liver cirrhosis, magnetic resonance imaging, hepatocellular carcinoma     

Preservation of deep epigastric perforators during anterior component separation technique (ACST) results in equivalent wound complications compared to transversus abdominis release (TAR)

Hernia - The use of component separation results in myofascial release and increased rates of fascial closure in abdominal wall reconstruction(AWR). These complex dissections have been associated...     

Age-dependent association of clonal hematopoiesis with COVID-19 mortality in patients over 60 years

GeroScience - Clonal hematopoiesis, especially that of indeterminate potential (CHIP), has been associated with age-related diseases, such as those contributing to a more severe COVID-19. Four...