ANGPTL3 Deficiency and Risk of Hepatic Steatosis.

BACKGROUND: ANGPTL3 (angiopoietin-like 3) is a therapeutic target for reducing plasma levels of triglycerides and low-density lipoprotein cholesterol. A recent trial with vupanorsen, an antisense oligonucleotide targeting hepatic production of ANGPTL3, reported a dose-dependent increase in hepatic fat. It is unclear whether this adverse effect is due to an on-target effect of inhibiting hepatic ANGPTL3. METHODS: We recruited participants with ANGPTL3 deficiency related to ANGPTL3 loss-of-function (LoF) mutations, along with wild-type (WT) participants from 2 previously characterized cohorts located in Campodimele, Italy, and St. Louis, MO. Magnetic resonance spectroscopy and magnetic resonance proton density fat fraction were performed to measure hepatic fat fraction and the distribution of extrahepatic fat. To estimate the causal relationship between ANGPTL3 and hepatic fat, we generated a genetic instrument of plasma ANGPTL3 levels as a surrogate for hepatic protein synthesis and performed Mendelian randomization analyses with hepatic fat in the UK Biobank study. RESULTS: We recruited participants with complete (n=6) or partial (n=32) ANGPTL3 deficiency related to ANGPTL3 LoF mutations, as well as WT participants (n=92) without LoF mutations. Participants with ANGPTL3 deficiency exhibited significantly lower total cholesterol (complete deficiency, 78.5 mg/dL; partial deficiency, 172 mg/dL; WT, 188 mg/dL; P<0.05 for both deficiency groups compared with WT), along with plasma triglycerides (complete deficiency, 26 mg/dL; partial deficiency, 79 mg/dL; WT, 88 mg/dL; P<0.05 for both deficiency groups compared with WT) without any significant difference in hepatic fat (complete deficiency, 9.8%; partial deficiency, 10.1%; WT, 9.9%; P>0.05 for both deficiency groups compared with WT) or severity of hepatic steatosis as assessed by magnetic resonance imaging. In addition, ANGPTL3 deficiency did not alter the distribution of extrahepatic fat. Results from Mendelian randomization analyses in 36 703 participants from the UK Biobank demonstrated that genetically determined ANGPTL3 plasma protein levels were causally associated with low-density lipoprotein cholesterol (P=1.7×10-17) and triglycerides (P=3.2×10-18) but not with hepatic fat (P=0.22). CONCLUSIONS: ANGPTL3 deficiency related to LoF mutations in ANGPTL3, as well as genetically determined reduction of plasma ANGPTL3 levels, is not associated with hepatic steatosis. Therapeutic approaches to inhibit ANGPTL3 production in hepatocytes are not necessarily expected to result in the increased risk for hepatic steatosis that was observed with vupanorsen.

Active optics system of the VLT Survey Telescope.

This paper describes the active optics system of the VLT Survey Telescope, the 2.6-m survey telescope designed for visible wavelengths of the European Southern Observatory at Cerro Paranal, in the Atacama desert. The telescope is characterized by a wide field of view (1.42 deg diameter), leading to tighter active optics than in conventional telescopes, in particular for the alignment requirements. We discuss the effects of typical error sources on the image quality and present the specific solutions adopted for wavefront sensing and correction of the aberrations, which are based on the shaping of a monolithic primary mirror and the positioning of the secondary in five degrees of freedom.

Active optics control of VST telescope secondary mirror.

In telescopes based on active optics, defocus and coma are usually compensated for by secondary mirror movements. They are performed at the Very Large Telescope Survey Telescope (VST) with a hexapod--a parallel robot with six degrees of freedom positioning capability. We describe the application of the two-mirror telescope theory to the VST case and the solutions adopted for the hexapod control. We present the results of performance and reliability tests performed both in the laboratory and at the telescope.

Active optics primary mirror support system for the 2.6 m VST telescope.

The Very Large Telescope Survey Telescope (VST) is equipped with an active optics system in order to correct low-order aberrations. The 2.6 m primary mirror is supported both axially and laterally and is surrounded by several safety devices for earthquake protection. We describe the mirror support system and discuss the results of the qualification test campaign.

High-intensity focused ultrasound for prostate cancer.

High-intensity focused ultrasound (HIFU) is a noninvasive procedure that has shown promising results in a wide range of malignant and nonmalignant conditions, including localized prostate cancer (PCa). This review aims to describe the application of HIFU in the management of patients with PCa, explaining its basic therapeutic principles, going through the main phases during aHIFU session, and providing an overview of the main available pieces of evidence from literature. HIFU treatment for prostate cancer is increasingly performed with high success and safety. MR guidance (MR-guided HIFU) has the advantage of real-time intraprocedural thermometric feedback that ensures that the whole region of interest has been covered by critical thermal damage (and that all surrounding healthy tissues have been spared). The absence of comparative long-term trials prevents HIFU from being considered as afirst choice for the treatment of patients with PCa.

DWI and PRECISE criteria in men on active surveillance for prostate cancer: A multicentre preliminary experience of different ADC calculations.

PURPOSE: The PRECISE score estimates the likelihood of radiological progression in patients on active surveillance (AS) for prostate cancer (PCa) with serial multiparametric magnetic resonance imaging (mpMRI). A PRECISE score of 1 or 2 denotes radiological regression, PRECISE 3 indicates stability and PRECISE 4 or 5 implies progression. We evaluated the inter-reader reproducibility of different apparent diffusion coefficient (ADC) calculations and their relationship to the PRECISE score. MATERIAL AND METHODS: Baseline and follow-up scans (on the same MR systems) of 30 patients with visible lesions from two different institutions (University College London and Sapienza University of Rome) were analysed by two radiologists (one from each site). The PRECISE score was initially assessed in consensus. At least six weeks later, to reduce the likelihood of being influenced by the consensus PRECISE reading, each radiologist independently calculated ADC for the following: lesion, non-cancerous tissue and urine in the bladder. Normalised ADC ratios were calculated with respect to normal prostatic tissue (npADC) and urine. Spearman's correlation (ρ), intraclass correlation coefficients (ICC), differences in ADC and ROC curves were computed. RESULTS: Interobserver reproducibility was very good (ρ > 0.8; ICC > 0.90). Lesion ADC (0.91 vs 0.73 × 10-3 mm2/s; p=0.025) and npADC ratio (0.68 vs 0.53; p=0.012) at follow-up mpMRI were different between patients with radiological regression or stability vs progression. Cut-offs of 0.77 × 10-3 mm2/s (lesion ADC) and 0.59 (npADC ratio) could differentiate the two groups (area under the curve: 0.74 and 0.77, respectively). CONCLUSION: The ADC, npADC ratio and the PRECISE score should be recorded for MRI-based AS.

The effects of a common stainless steel orthodontic bracket on the diagnostic quality of cranial and cervical 3T- MR images: a prospective, case-control study.

OBJECTIVES: To evaluate the effect of orthodontic stainless steel brackets and two different types of archwires on the diagnostic quality of 3-T MR images. METHODS: This prospective, case-control study was conducted following Strengthening the Reporting of Observational Studies in Epidemiology guidelines. The recruitment was conducted among orthodontic patients. 80 subjects, requiring MRI for the presence of temporomandibular disorders, were enrolled and divided into four groups: 20 patients using aligners (control group); 20 patients with stainless steel brackets without archwires; 20 patients with stainless steel brackets and nickel-titanium archwires; and 20 patients with stainless steel brackets and stainless steel archwires. Two experts in neuroradiology evaluated the images to determine the amount of distortion in 6 regions and 48 districts. A score was subjectively assigned according to a modified receiver operating characteristic method of distortion classification. Any disagreement was resolved through consensus seeking; when this was not possible, a third neuroradiologist was consulted. The following statistical methods were used: descriptive statistics, Cohen's kappa coefficient (k), Kruskal-Wallis test, pairwise comparisons using the Dunn-Bonferroni approach. The significance was set at p ≤ 0.05. RESULTS: The presence of stainless steel brackets with or without archwires negatively influenced MRI of the cervical region, paranasal sinuses, head and neck region, and cervical vertebrae but did not influence MRI of brain and temporomandibular joint regions. CONCLUSIONS: Patients with a stainless steel multibracket orthodontic appliance should remove it before cervical vertebrae, cervical region, paranasal sinuses, and head and neck MRI scans. The brain and temporomandibular joint region MRI should not require the removal of such appliances.

Role of multiparametric MRI in the diagnosis of prostate cancer: update.

Prostate cancer is the most common malignancy of the male gender. The role of magnetic resonance imaging has evolved very rapidly over the years to be currently recognized as a fundamental tool in the diagnosis, treatment and follow-up of prostate cancer.

3T multiparametric MRI of the prostate: Does intravoxel incoherent motion diffusion imaging have a role in the detection and stratification of prostate cancer in the peripheral zone?

PURPOSE: To evaluate the potential added value of the intravoxel incoherent motion model to conventional multiparametric magnetic resonance protocol in order to differentiate between healthy and neoplastic prostate tissue in the peripheral zone. MATERIAL AND METHODS: Mono-exponential and bi-exponential fits were used to calculate ADC and IVIM parameters in 53 patients with peripheral zone biopsy proved tumor. Inferential statistics analysis was performed on T2, ADC and IVIM parameters (D, D*, f) comparing healthy and neoplastic tissues. Linear discriminant analysis was performed for the conventional parameters (T2 and ADC), the IVIM parameters (molecular diffusion coefficient (D), perfusion-related diffusion coefficient (D*), and perfusion fraction (f) and the combined T2-weighted imaging/DWI and IVIM parameters (T2, ADC, D, D* and f). A correlation with Gleason scores was achieved. RESULTS: The values of T2, ADC and D were significantly lower in cancerous tissues (2749.82 ± 1324.67 ms, 0.76 ± 0.27 × 10(-3)mm(2)/s and 0.99 ± 0.38 × 10(-3)mm(2)/s respectively) compared to those found in the healthy tissues (3750.70 ± 1735.37 ms, 1.39 ± 0.48 × 10(-3)mm(2)/s and 1.77 ± 0.36 × 10(-3)mm(2)/s respectively); D* parameter was significantly increased in neoplastic compared to healthy tissue (15.56 ± 12.91 × 10(-3)mm(2)/s and 10.25 ± 10.52 × 10(-3)mm(2)/s respectively). The specificity, sensitivity and accuracy of the T2-weighted imaging/DWI and IVIM parameters were 100, 96 and 98%, respectively, compare to 88, 92 and 90% and 96, 92 and 94 for T2-weighted imaging/ADC and IVIM alone. CONCLUSIONS: IVIM parameters increase the specificity and sensitivity in the evaluation of peripheral zone prostate cancer. A statistical difference between low grade tumors and high grade tumors has been demostrated in that ADC, D and D* dataset; in particular, D has been found to have the highest significativity.