Ezekiel Maloney

Vascular Inflammation, Insulin Resistance, and Reduced Nitric Oxide Production Precede the Onset of Peripheral Insulin Resistance

Objectives—Obesity causes inflammation and insulin resistance in the vasculature as well as in tissues involved in glucose metabolism such as liver, muscle, and adipose tissue. To investigate the relative susceptibility of vascular tissue to these effects, we determined the time course over which inflammation and insulin resistance develops in various tissues of mice with diet-induced obesity (DIO) and compared these tissue-based responses to changes in circulating inflammatory markers. Methods and Results—Adult male C57BL/6 mice were fed either a control low-fat diet (LF; 10% saturated fat) or a high-fat diet (HF, 60% saturated fat) for durations ranging between 1 to 14 weeks. Cellular inflammation and insulin resistance were assessed by measuring phospho-I&kgr;Bα and insulin-induced phosphorylation of Akt, respectively, in extracts of thoracic aorta, liver, skeletal muscle, and visceral fat. As expected, HF feeding induced rapid increases of body weight, fat mass, and fasting insulin levels compared to controls, each of which achieved statistical significance within 4 weeks. Whereas plasma markers of inflammation became elevated relatively late in the course of DIO (eg, serum amyloid A [SAA], by Week 14), levels of phospho-I&kgr;Bα in aortic lysates were elevated by 2-fold within the first week. The early onset of vascular inflammation was accompanied by biochemical evidence of both endothelial dysfunction (reduced nitric oxide production; induction of intracellular adhesion molecule-1 and vascular cell adhesion molecule-1) and insulin resistance (impaired insulin-induced phosphorylation of Akt and eNOS). Although inflammation and insulin resistance were also detected in skeletal muscle and liver of HF-fed animals, these responses were observed much later (between 4 and 8 weeks of HF feeding), and they were not detected in visceral adipose tissue until 14 weeks. Conclusions—During obesity induced by HF feeding, inflammation and insulin resistance develop in the vasculature well before these responses are detected in muscle, liver, or adipose tissue. This observation suggests that the vasculature is more susceptible than other tissues to the deleterious effects of nutrient overload.

Reduced NO-cGMP Signaling Contributes to Vascular Inflammation and Insulin Resistance Induced by High-Fat Feeding

Objective—Diet-induced obesity (DIO) in mice causes vascular inflammation and insulin resistance that are accompanied by decreased endothelial-derived NO production. We sought to determine whether reduced NO-cGMP signaling contributes to the deleterious effects of DIO on the vasculature and, if so, whether these effects can be blocked by increased vascular NO-cGMP signaling. Methods and Results—By using an established endothelial cell culture model of insulin resistance, exposure to palmitate, 100 &mgr;mol/L, for 3 hours induced both cellular inflammation (activation of IKK&bgr;–nuclear factor-&kgr;B) and impaired insulin signaling via the insulin receptor substrate–phosphatidylinositol 3-kinase pathway. Sensitivity to palmitate-induced endothelial inflammation and insulin resistance was increased when NO signaling was reduced using an endothelial NO synthase inhibitor, whereas endothelial responses to palmitate were blocked by pretreatment with either an NO donor or a cGMP analogue. To investigate whether endogenous NO-cGMP signaling protects against vascular responses to nutrient excess in vivo, adult male mice lacking endothelial NO synthase were studied. As predicted, both vascular inflammation (phosphorylated I&kgr;B&agr; and intercellular adhesion molecule levels) and insulin resistance (phosphorylated Akt [pAkt] and phosphorylated eNOS [peNOS] levels) were increased in endothelial NO synthase−/− (eNOS−/−) mice, reminiscent of the effect of DIO in wild-type controls. Next, we asked whether the vascular response to DIO in wild-type mice can be reversed by a pharmacological increase of cGMP signaling. C57BL6 mice were either fed a high-fat diet or remained on a low-fat diet for 8 weeks. During the final 2 weeks of the study, mice on each diet received either placebo or the phosphodiesterase-5 inhibitor sildenafil, 10 mg/kg per day orally. In high-fat diet–fed mice, vascular inflammation and insulin resistance were completely prevented by sildenafil administration at a dose that had no effect in mice fed the low-fat diet. Conclusion—Reduced signaling via the NO-cGMP pathway is a mediator of vascular inflammation and insulin resistance during overnutrition induced by high-fat feeding. Therefore, phosphodiesterase-5, soluble guanylyl cyclase, and other molecules in the NO-cGMP pathway (eg, protein kinase G) constitute potential targets for the treatment of vascular dysfunction in the setting of obesity.

The Anterolateral Ligament of the Knee: MRI Appearance, Association With the Segond Fracture, and Historical Perspective

OBJECTIVE. A recent publication has drawn attention to the anterolateral ligament, a structure of the knee with which most radiologists are unfamiliar. We evaluate this structure on MRI; clarify its origin, insertion, meniscal relationship, and morphologic appearance; and identify its relationship with the Segond fracture. MATERIALS AND METHODS. A total of 53 routine knee MRI studies interpreted as normal were reviewed to characterize the anterolateral ligament. A further 20 knee MRI studies with a Segond fracture were assessed to determine a relationship between the fracture and the anterolateral ligament. RESULTS. In all 53 cases, a structure was present along the lateral knee connecting the distal femur to the proximal tibia, with meniscofemoral and meniscotibial components. This structure was somewhat ill defined and sheetlike, inseparable from the adjacent fibular collateral ligament proximally and iliotibial band distally. Aside from one case limited by anatomic distortion, all cases with a Segond fracture exhibited attachment of this structure to the fracture fragment (19/20 cases). CONCLUSION. An ill-defined sheetlike structure along the lateral knee exists attaching the distal femur, body of lateral meniscus, and proximal tibia. This structure has been referenced in the literature dating back to Paul Segonds original description of the Segond fracture in 1879. The structure is identifiable on MRI and appears to be attached to the Segond fracture fragment. For the radiologist, it may be best to forgo an attempt to separate this structure into discrete divisions, such as the anterolateral ligament, because these individual components are inseparable on routine MRI.

Trans Fatty Acids Induce Vascular Inflammation and Reduce Vascular Nitric Oxide Production in Endothelial Cells

Intake of trans fatty acids (TFA), which are consumed by eating foods made from partially hydrogenated vegetable oils, is associated with a higher risk of cardiovascular disease. This relation can be explained by many factors including TFAs negative effect on endothelial function and reduced nitric oxide (NO) bioavailability. In this study we investigated the effects of three different TFA (2 common isomers of C18 found in partially hydrogenated vegetable oil and a C18 isomer found from ruminant-derived—dairy products and meat) on endothelial NF-κB activation and nitric oxide (NO) production. Human endothelial cells were treated with increasing concentrations of Elaidic (trans-C18:1 (9 trans)), Linoelaidic (trans-C18:2 (9 trans, 12 trans)), and Transvaccenic (trans-C18:1 (11 trans)) for 3 h. Both Elaidic and Linoelaidic acids were associated with increasing NF-κB activation as measured by IL-6 levels and phosphorylation of IκBα, and impairment of endothelial insulin signaling and NO production, whereas Transvaccenic acid was not associated with these responses. We also measured superoxide production, which has been hypothesized to be necessary in fatty acid-dependent activation of NF-κB. Both Elaidic acid and Linoelaidic acid are associated with increased superoxide production, whereas Transvaccenic acid (which did not induce inflammatory responses) did not increase superoxide production. We observed differential activation of endothelial superoxide production, NF-κB activation, and reduction in NO production by different C18 isomers suggesting that the location and number of trans double bonds effect endothelial NF-κB activation.

Emerging HIFU applications in cancer therapy

Abstract High intensity focused ultrasound (HIFU), is a promising, non-invasive modality for treatment of tumours in conjunction with magnetic resonance imaging or diagnostic ultrasound guidance. HIFU is being used increasingly for treatment of prostate cancer and uterine fibroids. Over the last 10 years a growing number of clinical trials have examined HIFU treatment of both benign and malignant tumours of the liver, breast, pancreas, bone, connective tissue, thyroid, parathyroid, kidney and brain. For some of these emerging indications, HIFU is poised to become a serious alternative or adjunct to current standard treatments – including surgery, radiation, gene therapy, immunotherapy, and chemotherapy. Current commercially available HIFU devices are marketed for their thermal ablation applications. In the future, lower energy treatments may play a significant role in mediating targeted drug and gene delivery for cancer treatment. In this article we introduce currently available HIFU systems, provide an overview of clinical trials in emerging oncological targets, and briefly discuss selected pre-clinical research that is relevant to future oncological HIFU applications.

Imaging of Adverse Reactions to Metal Debris

Hip replacements with metal-on-metal components can cause a spectrum of adverse tissue reactions-from benign localized fibrosis and chronic inflammation to delayed hypersensitivity response. In addition to history, physical examination, and relevant laboratory data, imaging plays a critical role in the evaluation of hip arthroplasties. Imaging assessment begins with radiographs and may be followed by ultrasound, computed tomography, or MRI. MRI optimized for metal artifact reduction is the most sensitive and specific imaging modality and is essential in assessing the spectrum of metal-related adverse tissue reactions. In this article, we discuss the history, pathophysiology, and imaging findings of adverse reactions to metal debris.

Endoscopic high-intensity focused US: technical aspects and studies in an in vivo porcine model (with video)

BACKGROUND High-intensity focused US (HIFU) is becoming more widely used for noninvasive and minimally invasive ablation of benign and malignant tumors. Recent studies suggest that HIFU can also enhance targeted drug delivery and stimulate an antitumor immune response in many tumors. However, targeting pancreatic and liver tumors by using an extracorporeal source is challenging due to the lack of an adequate acoustic window. The development of an EUS-guided HIFU transducer has many potential benefits including improved targeting, decreased energy requirements, and decreased potential for injury to intervening structures. OBJECTIVE To design, develop, and test an EUS-guided HIFU transducer for endoscopic applications. DESIGN A preclinical, pilot characterization and feasibility study. SETTING Academic research center. PATIENTS Studies were performed in an in vivo porcine model. INTERVENTION Thermal ablation of in vivo porcine pancreas and liver was performed with EUS-guided focused US through the gastric tract. RESULTS The transducer successfully created lesions in gel phantoms and ex vivo bovine livers. In vivo studies demonstrated that targeting and creating lesions in the porcine pancreas and liver are feasible. LIMITATIONS This was a preclinical, single-center feasibility study with a limited number of subjects. CONCLUSION An EUS-guided HIFU transducer was successfully designed and developed with dimensions that are appropriate for endoscopic use. The feasibility of performing EUS-guided HIFU ablation in vivo was demonstrated in an in vivo porcine model. Further development of this technology will allow endoscopists to perform precise therapeutic ablation of periluminal lesions without breaching the wall of the gastric tract.

Fracture of the distal radius: epidemiology and premanagement radiographic characterization.

OBJECTIVE Fractures of the distal radius are common and frequently encountered by the radiologist. We review the epidemiology, classification, as well as the concept of instability. Salient qualitative and quantitative features of the distal radius fracture identifiable on the routine radiography series are highlighted. We conclude with a synopsis of descriptors that are of greatest utility to the clinician for treatment planning and that should be addressed in the radiology report. CONCLUSION A detailed understanding of the intricacies of the distal radius fracture is necessary for the radiologist to provide a clinically relevant description.

The development of a validated checklist for ultrasound-guided thyroid nodule fine-needle aspiration biopsies preliminary results

Abstract Ultrasound-guided fine-needle aspiration (USgFNA) is the procedure of choice for biopsy of thyroid nodules (TNs) that are suspicious for malignancy. Poor technique in performing this procedure can result in nondiagnostic specimens, increased patient anxiety, repeated aspirations, and unnecessary surgery. Validated checklists are a central component of teaching and assessing procedural skills. The results of the first step of the validation of a TN USgFNA checklist are described. A comprehensive review of articles published on TN fine-needle aspiration did not yield a validated checklist. A modified Delphi technique, involving a panel of 8 interdisciplinary experts, was used to develop a TN USgFNA checklist. The internal consistency coefficient using Cronbach &agr; was 0.74. Development of the 23-item TN USgFNA checklist for teaching and assessing TN USgFNA is the first step in the validation process. Further validation can be achieved via implementation and study of the checklist in clinical settings.

Vertebral Artery Transection in Nonpenetrating Trauma: A Series of 4 Patients

Blunt cerebrovascular injury is a common and potentially devastating consequence of nonpenetrating trauma to the head and neck. The degree of injury ranges from minimal intimal disruption to complete transection with free extravasation. Although blunt carotid transection has been well characterized in clinical reports and radiologic studies, the computed tomographic angiography (CTA) features of blunt vertebral artery transection have not been well described. We report a series of 4 patients presenting to our level I trauma center with blunt vertebral artery transection, with an emphasis on their CTA imaging findings at presentation and their respective clinical courses. A brief review of the pertinent literature is provided.