Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro

Obesity and type 2 diabetes are associated with insulin resistance, the mechanisms of which remain poorly understood. A significant correlation between circulating IL-6 level and insulin sensitivity has recently been found in humans. Because adipose tissue could be a significant source of IL-6, we analyzed the relationship between the levels of adipose tissue IL-6 and insulin action in vivo, during a hyperinsulinemic normoglycemic clamp, and in vitro by measuring glucose transport in adipocytes from 12 obese subjects with (n = 7) or without (n = 5) diabetes. We observed an inverse correlation between adipose tissue IL-6 content and maximal insulin-responsiveness measured in vivo (P < 0.02) and in vitro (P < 0.02). Conversely, there was no significant correlation between these two later parameters and adipose tissue leptin or tumor necrosis factor-alpha protein contents. Furthermore, we showed, for the first time, the presence of immunoreactive IL-6 receptors in the plasma membrane of human abdominal sc adipocytes. This suggests that locally secreted IL-6 could act on adipocytes by an autocrine/paracrine mechanism. In conclusion, increased IL-6 production by sc adipose cells might participate to the insulin-resistant state observed in human obesity.     

Traumatic right diaphragmatic hernia in children: Diagnostic difficulties

Traumatic right diaphragmatic hernia is rare in children. Its diagnosis can be difficult in the acute phase of trauma because its signs are not specific, especially in a poly trauma context. We report two cases of traumatic right diaphragmatic hernia following a blunt thoraco-abdominal trauma, highlighting some difficulties in establishing an early diagnosis and the need for a high index of suspicion.     

Correlation of dosimetric parameters obtained with the analytical anisotropic algorithm and toxicity of chest chemoradiation in lung carcinoma

The purpose of this study was to analyze and revisit toxicity related to chest chemoradiotherapy and to correlate these side effects with dosimetric parameters obtained using analytical anisotropic algorithm (AAA) in locally unresectable advanced lung cancer. We retrospectively analyzed data from 47 lung cancer patients between 2005 and 2008. All received conformal 3D radiotherapy using high-energy linear accelerator plus concomitant chemotherapy. All treatment planning data were transferred into Eclipse 8.05 (Varian Medical Systems, Palo Alto, CA) and dosimetric calculations were performed using AAA. Thirty-three patients (70.2%) developed acute pneumopathy after radiotherapy (grades 1 and 2). One patient (2.1%) presented with grade 3 pneumopathy. Thirty-one (66%) presented with grades 1–2 lung fibrosis, and 1 patient presented with grade 3 lung fibrosis. Thirty-four patients (72.3%) developed grade 1–2 acute oesophagic toxicity. Four patients (8.5%) presented with grades 3 and 4 dysphagia, necessitating prolonged parenteral nutrition. Median prescribed dose was 64 Gy (range 50–74) with conventional fractionation (2 Gy per fraction). Dose–volume constraints were respected with a median V20 of 23.5% (maximum 34%) and a median V30 of 17% (maximum 25%). The median dose delivered to healthy contralateral lung was 13.1 Gy (maximum 18.1 Gy). At univariate analysis, larger planning target volume and V20 were significantly associated with the probability of grade ≥2 radiation-induced pneumopathy (p = 0.022 and p = 0.017, respectively). No relation between oesophagic toxicity and clinical/dosimetric parameters could be established. Using AAA, the present results confirm the predictive value of the V20 for lung toxicity as already demonstrated with the conventional pencil beam convolution approach.     

B(1) mapping with selective pulses

Knowledge of B distribution is crucial for many applications, such as quantitative MRI. A novel method has been developed to improve the accuracy of the conventionally applied double‐angle method for B mapping. It solves the remaining issues raised by the use of selective pulses for slice selection to accelerate the acquisition process. A general approach for reconstructing B maps is presented first. It takes B‐induced slice profile distortions over off‐resonance frequencies into account. It is then shown how the ratio between the prescribed flip angles can be adjusted to reach a compromise between the level of noise propagated onto B maps and the width of the range in which the field can be mapped. Lastly, several solutions are proposed for reducing the B‐dependent pollution of regions distal to the image slice which participates significantly in the inaccuracy of B mapping. These methods were experimentally tested by comparison with gold standard B maps obtained on a phantom using a non‐selective and thus much slower technique. As they are independent and lead to significant improvements, these solutions can be combined to achieve high precision and fast B mapping using spin‐echo DAM. Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.     

Suppression of cervical carcinoma cell growth by intracytoplasmic codelivery of anti-oncoprotein E6 antibody and small interfering RNA

Cervical cancer is caused by high-risk types of human papillomaviruses (HPV) that encode the E6 and E7 oncogenes. Silencing of E6 gene expression in HPV-positive cell lines by transfection of small interfering RNA (siRNA) with cationic lipids restores the dormant p53 tumor suppressor pathway. Because cationic lipids can also be used for intracytoplasmic delivery of proteins, we tested whether the delivery of monoclonal antibodies that bind to HPV16 E6 and neutralize its biological activity in vitro could restore p53 function in tumor cells. Here, we show that the 4C6 antibody is efficiently delivered into the cell cytoplasm using a lipidic reagent used for siRNA transfection. The delivery of 4C6 resulted in the nuclear accumulation of p53 protein in CaSki and SiHa cells but not in HeLa cells. Furthermore, the antibody-mediated p53 response was dramatically increased when a peptide corresponding to the 4C6 epitope and bearing a COOH-terminal cysteine residue was added to the transduction mixture. We found that a fraction of the added peptides were dimers that allowed the formation of antibody polymers adsorbed onto the lipidic matrix. With this system, the proliferation of CaSki and SiHa cells was strongly diminished, but no apoptosis was detectable. Remarkably, cell growth was almost totally suppressed by the addition of E6-specific siRNA to the transduction complex. The results indicate that the activity of E6 oncoprotein can be down-regulated in vivo by lipid-mediated antibody delivery and that antibodies and siRNA act synergistically when codelivered. This novel targeting strategy is simple to implement and may find therapeutic applications.