p75 neurotrophin receptor regulates glucose homeostasis and insulin sensitivity

Insulin resistance is a key factor in the etiology of type 2 diabetes. Insulin-stimulated glucose uptake is mediated by the glucose transporter 4 (GLUT4), which is expressed mainly in skeletal muscle and adipose tissue. Insulin-stimulated translocation of GLUT4 from its intracellular compartment to the plasma membrane is regulated by small guanosine triphosphate hydrolases (GTPases) and is essential for the maintenance of normal glucose homeostasis. Here we show that the p75 neurotrophin receptor (p75(NTR)) is a regulator of glucose uptake and insulin resistance. p75(NTR) knockout mice show increased insulin sensitivity on normal chow diet, independent of changes in body weight. Euglycemic-hyperinsulinemic clamp studies demonstrate that deletion of the p75(NTR) gene increases the insulin-stimulated glucose disposal rate and suppression of hepatic glucose production. Genetic depletion or shRNA knockdown of p75(NTR) in adipocytes or myoblasts increases insulin-stimulated glucose uptake and GLUT4 translocation. Conversely, overexpression of p75(NTR) in adipocytes decreases insulin-stimulated glucose transport. In adipocytes, p75(NTR) forms a complex with the Rab5 family GTPases Rab5 and Rab31 that regulate GLUT4 trafficking. Rab5 and Rab31 directly interact with p75(NTR) primarily via helix 4 of the p75(NTR) death domain. Adipocytes from p75(NTR) knockout mice show increased Rab5 and decreased Rab31 activities, and dominant negative Rab5 rescues the increase in glucose uptake seen in p75(NTR) knockout adipocytes. Our results identify p75(NTR) as a unique player in glucose metabolism and suggest that signaling from p75(NTR) to Rab5 family GTPases may represent a unique therapeutic target for insulin resistance and diabetes.     

Smoking as a risk factor for autoimmune liver disease: what we can learn from primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a cholestatic liver disease characterised by the immune-mediated destruction of biliary epithelial cells in small intrahepatic bile ducts. The disease is characterised by circulating anti-mitochondrial antibodies (AMA) as well as disease specific anti-nuclear antibodies (ANA), cholestatic liver biochemistry, and characteristic histology. The disease primarily affects middle-aged females, and its incidence is apparently increasing worldwide. Epidemiological studies have indicated several risk factors for the development of PBC, with family history of PBC, recurrent urinary tract infection, and smoking being the most widely cited. Smoking has been implicated as a risk factor in several autoimmune diseases, including the liver, by complex mechanisms involving the endocrine and immunological systems to name a few. Studies of smoking in liver disease have also shown that smoking may progress the disease towards fibrosis and subsequent cirrhosis. This review will examine the literature surrounding smoking as a risk factor for PBC, as well as a potential factor in the progression of fibrosis in PBC patients.     

FDG uptake at the bronchial stump after curative lobectomy for non-small cell lung cancer

Purpose

Focal areas of FDG uptake may occur at the bronchial stump following curative lobectomy for non-small-cell lung carcinoma (NSCLC), even in the absence of suspicious CT changes. The purpose of our study was to investigate the significance of such PET/CT findings.

Methods

FDG-PET/CT scans performed in 54 patients after lobectomy for NSCLC were reviewed. The presence of focal areas of FDG uptake at the bronchial stump, associated CT abnormalities, SUVmax, and normalized SUV (SUVnorm = SUVmax/mean liver SUV) were recorded. Final diagnosis was based on biopsy or imaging follow-up.

Results

Focal areas of FDG uptake at the bronchial stump were detected in 30 patients (56 %). Mean SUVmax was 4.0?±?1.9 (range; 2.2–12.1) and mean SUVnorm was 1.8?±?0.8 (range; 0.9–4.5). Biopsy showed recurrence in two patients. In these patients, SUVnorm was respectively 4.4 and 4.5 (with SUVmax of 8.8 and 12.1), whereas SUVnorm was lower than 4.0 in those without recurrence, with mean SUVnorm of 1.6?±?0.5 (range; 0.9–3.4) and mean SUVmax of 3.6?±?0.9 (range; 2.2–5.8). The CT component of the PET/CT revealed ill-defined peribronchial soft tissue opacity only in both patients with recurrence.

Conclusion

FDG uptake at the bronchial stump is a frequent finding after pulmonary lobectomy. Moderate levels of FDG uptake (i.e., SUVnorm?<?4.0) without corresponding abnormal CT findings might be a dual criterion for diagnosing benign post-surgical changes.

     

Diagnostic Relevance and Clinical Significance of the New Enhanced Performance M2 (MIT3) ELISA for the Detection of IgA and IgG Antimitochondrial Antibodies in Primary Biliary Cirrhosis

Background/aims: Antimitochondrial antibodies (AMAs) are the serological hallmark of primary biliary cirrhosis (PBC). We evaluated the sensitivity and specificity of a new M2 enhanced performance enzyme-linked immunosorbent assay (ELISA) (MIT3) for the detection of IgG- and IgA-specific isotypes of AMA in PBC patients including a number of PBC patients negative for AMA by indirect immunofluorescence (IIF) as well as in patients with diverse, non-PBC disorders. We also investigated the clinical significance of IgG and IgA AMA in PBC. Methods: One hundred and three Greek PBC patients including 27 with AMA IIF-negative at the time of the investigation, 29 with autoimmune hepatitis-1 (AIH-1), 12 with primary sclerosing cholangitis (PSC), 26 with hepatitis C virus (HCV), 15 with hepatitis B virus (HBV), and 29 healthy were investigated for AMA (IgG and IgA) using the MIT3-based ELISAs (INOVA Diagnostics, San Diego, CA). The samples were also tested by conventional anti-M2 ELISA (INOVA Diagnostics, Inc.). Results: The IgG MIT3-based ELISA significantly increased AMA detection in the cohort of PBC patients, over 26% of whom were AMA IIF-negative, from 63.1% by the conventional anti-M2, and 73.7% by IIF to 79.6% by MIT3-based ELISA (p<0.001). IgA AMAs were detected in 47.6% patients. Overall, IgG/IgA AMAs were detected in 84/103 (81.6%). IgG MIT3-based ELISA detected 12/27 IIF AMA-negative samples (44.4%), while IgG/IgA MIT3-based ELISAs detected 13/27 IIF AMA-negative patients (48.1%). The specificities of MIT3-based ELISAs (IgG and IgA) were 82.8% and 89.7%, respectively, in AIH-1, 100% and 93.3%, respectively, in HBV, 100% in PSC, and 96% and 93.3%, respectively, in HCV. Patients positive for IgG AMA had significantly more severe disease as shown by worse histology and elevated biochemical markers; IgG and IgA AMA titers were associated positively with the Mayo risk score but none of the isotypes were able to predict disease outcome. Conclusions: The new IgG and IgA MIT3-based ELISAs seem to have higher specificity and sensitivity for AMA detection than IIF and the conventional anti-M2. Interestingly, these assays were able to unmask AMA presence in almost half of the AMA-negative samples by IIF. These findings may suggest the use of MIT3-based ELISAs as first-line investigation for AMA detection, particularly, when the laboratories are unfamiliar with the use and interpretation of the IIF patterns of AMA. The presence of IgG AMA seems to characterize PBC patients with more severe disease, but both IgG and IgA isotypes of AMAs were not predictive markers of disease outcome.     

Periappendiceal abscess due to perforated adenocarcinoma of the caecum

Colon adenocarcinomas rank among the most common malignancies. Characteristic complications include obstruction and chronic anaemia. Perforation with consequent abscess formation is a rather atypical presentation. We present the case of a 62-year-old male patient with a periappendiceal abscess resulting from perforated caecal carcinoma. Since clinical and intraoperative findings were suggestive of associated malignancy, a right hemicolectomy with latero-lateral ileotransverse anastomosis was performed. Periappendiceal mass is a common surgical entity. The differential diagnosis includes a variety of benign conditions (infectious or inflammatory) and neoplasia. The diagnosis of associated malignancy, when radiological examination is not diagnostic, requires a high index of suspicion in order to provide the appropriate treatment.     

Treatment with bortezomib‐based regimens improves overall response and predicts for survival in patients with primary or secondary plasma cell leukemia: Analysis of the Greek myeloma study group

Plasma cell leukemia (PCL) is a rare and aggressive plasma cell disorder, with poor outcome. Bortezomib‐based regimens (BBR) are highly effective in myeloma, but there is limited information about their efficacy and safety in PCL. Thus, we retrospectively collected data from 42 consecutive PCL patients (25 with primary PCL‐pPCL and 17 with secondary PCL‐sPCL) to explore the role of BBR in this entity. BBR were administered in 29 of 42 patients, while 6 of 25 patients with pPCL underwent autologous transplantation. Objective response (≥partial response) was significantly higher in patients treated with BBR versus conventional therapies (69% vs. 30.8%, P = 0.04); 27.5% of patients treated with BBR achieved at least very good partial response (vgPR). The highest ORR was observed in pPCL patients treated with BBR (88.9%; ≥vgPR: 33.3%). In BBR‐group, grade 3 of 4 hematological, neurological and renal toxicity and neutropenic infections were observed in 41.4%, 7%, 3.4%, and 31%, respectively. With a median follow‐up of 51 months, median overall survival (OS) for patients treated with BBR versus conventional therapies was 13 versus 2 months (P < 0.007). Median OS of patients with pPCL and sPCL treated with BBR was 18 and 7 months, respectively (P < 0.001). In the multivariate analysis normal PLTs, treatment with BBR and high quality response were the only powerful predictors for survival. Our study carrying the longest reported median follow‐up, demonstrated that treatment of PCL with BBR induces high response rates and prolongs survival over conventional therapies, regardless of additional autologous transplantation rescue or established high risk features, with manageable toxicity. Am. J. Hematol. 89:145–150, 2014. © 2013 Wiley Periodicals, Inc.     

A qualitative study of early childhood educators' beliefs and practices regarding children's socioemotional development

Existing research underscores the significance of early childhood experiences in the childcare context for the development of socioemotional skills and competencies. However, the practices adopted within childcare for the enhancement of children's socioemotional development and the factors mediating these practices are less adequately researched. The present study contributes to this understanding, through studying the perceptions of 34 educators working in childcare centres in Greece with regard to children's socioemotional development and its promotion. Results showed that although they acknowledged the significance of social and emotional competencies for children's adjustment, learning and well-being, they did not report consistent use of practices having as a goal the promotion of such skills. Explanations involve on the one hand the lack of formal policy and the existence of structural barriers and on the other hand a perception that socioemotional development is mostly affected by factors beyond their influence. Results are discussed in relation to prior research and in terms of their implications for designing interventions, curricula and staff training.