Accurate 3D reconstruction of complex blood vessel geometries from intravascular ultrasound images: in vitro study

We present a technique that accurately reconstructs complex three dimensional blood vessel geometry from 2D intravascular ultrasound (IVUS) images. Biplane x-ray fluoroscopy is used to imagethe ultrasound catheter tip at a few key points along its path as the catheter is pulled through the blood vessel. An interpolating spline describes the continuous catheterpath. The IVUS images are located orthogonal to the path, resulting in a non-uniform structured scalar volume of echo densities. Isocontour surfaces are used to view the vessel geometry, while transparency and clipping enable interactive exploration of interior structures. The two geometries studied are a bovine artery vascular graft having U-shapeand a constriction, and a canine carotid artery having multiple branches and a constriction. Accuracy of the reconstructions is established by comparing the reconstructions to (1) silicone moulds of the vessel interior, (2) biplane x-ray images, and (3) the original echo images. Excellent shape and geometry correspondence was observed in both geometries. Quantitative measurements made at key locations of the 3D reconstructions also were in good agreement with those made in silicone moulds. The proposed technique is easily adoptable in clinical practice, since it uses x-rays with minimal exposure and existing IVUS technology.     

Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain

Caffeine, the most widely consumed psychoactive substance in the world, is used to promote wakefulness and enhance alertness. Like other wake-promoting drugs (stimulants and modafinil), caffeine enhances dopamine (DA) signaling in the brain, which it does predominantly by antagonizing adenosine A_2A receptors (A_2AR). However, it is unclear if caffeine, at the doses consumed by humans, increases DA release or whether it modulates the functions of postsynaptic DA receptors through its interaction with adenosine receptors, which modulate them. We used positron emission tomography and [¹¹C]raclopride (DA D₂/D₃ receptor radioligand sensitive to endogenous DA) to assess if caffeine increased DA release in striatum in 20 healthy controls. Caffeine (300 mg p.o.) significantly increased the availability of D₂/D₃ receptors in putamen and ventral striatum, but not in caudate, when compared with placebo. In addition, caffeine-induced increases in D₂/D₃ receptor availability in the ventral striatum were associated with caffeine-induced increases in alertness. Our findings indicate that in the human brain, caffeine, at doses typically consumed, increases the availability of DA D₂/D₃ receptors, which indicates that caffeine does not increase DA in the striatum for this would have decreased D₂/D₃ receptor availability. Instead, we interpret our findings to reflect an increase in D₂/D₃ receptor levels in striatum with caffeine (or changes in affinity). The association between increases in D₂/D₃ receptor availability in ventral striatum and alertness suggests that caffeine might enhance arousal, in part, by upregulating D₂/D₃ receptors.     

Rationale for and study design of the sulodexide trials in Type 2 diabetic, hypertensive patients with microalbuminuria or overt nephropathy.

BACKGROUND: Patients with Type 2 diabetes and albuminuria are at high risk to progress to end-stage renal disease (ESRD). Although angiotensin receptor blockers confer renoprotection, many diabetic patients still develop overt nephropathy and reach ESRD. Glycosaminoglycans belong to the same family as heparin and heparinoids. Pilot studies with sulodexide, a glycosaminoglycan, have shown that sulodexide can reduce urinary albumin excretion rates in diabetic patients. No hard renal end-point data are available. METHODS: Two multicentre, double-masked, randomized placebo controlled trials were designed to study the renoprotective potential of sulodexide. The Sulodexide Microalbuminuria Trial examined the efficacy of sulodexide given over 26 weeks in 1000 patients with Type 2 diabetes, hypertension and microalbuminuria. The Sulodexide Overt Nephropathy Trial examined the efficacy of sulodexide in 2240 patients with Type 2 diabetes, hypertension and proteinuria > or = 900 mg/24 h. RESULTS: The primary outcome of The Sulodexide Microalbuminuria Trial was (i) conversion to normoalbuminuria and at least a 25% decrease in the urinary albumin creatinine ratio (UACR), or (ii) at least a 50% reduction in UACR. The primary outcome of The Sulodexide Overt Nephropathy Trial was time to a composite end point of doubling of serum creatinine or ESRD. CONCLUSIONS: The sulodexide nephropathy programme will document whether therapy with sulodexide confers renal protection in Type 2 diabetes and nephropathy.     

Colorectal liver metastases: disappearing lesions in the era of Eovist hepatobiliary magnetic resonance imaging

Background

Hepatobiliary contrast enhanced MRI is known to be the most sensitive imaging modality for detection of colorectal hepatic metastasis. To date no study has investigated the rate of disappearing lesions with gadoxetic acid MR (Eovist/Primovist), or characterized the pathologic response of lesions which disappear on gadoxetic acid MR.

Methods

Retrospective review of hepatic resections for colorectal metastases between 01/2008 and 01/2014 was performed to evaluated the rate of disappearance of lesions on gadoxetic acid MR and the rate of complete pathologic response in the lesions that disappear. “Disappearing lesions” were lesions on baseline imaging that were not identifiable on pre-operative Eovist MRI. Complete pathologic response was defined as no viable tumor on pathology or by lack of recurrence within 1 year.

Results

In 23 patients, 200 colorectal metastases were identified on baseline imaging. On pre-operative Eovist MR 77 of the 200 lesions (38.5%) were “disappearing” lesions. At surgical pathology or 1 year follow-up imaging, 42 of 77 lesions (55%) demonstrated viable tumor (21) or recurrence (21). Thirty of 77 lesions (39%) were nonviable at pathology (10) or without evidence of recurrence at 1 year (20). 5 lesions were indeterminate.

Discussion

Despite disappearance on Eovist MR imaging (the most sensitive available imaging modality), 38.5% of all colorectal metastases disappeared and of those, 55% were viable.     

Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias

SCN5A encodes the α subunit of the major cardiac sodium channel Na_V1.5. Mutations in SCN5A are associated with conduction disease and ventricular fibrillation (VF); however, the mechanisms that link loss of sodium channel function to arrhythmic instability remain unresolved. Here, we generated a large-animal model of a human cardiac sodium channelopathy in pigs, which have cardiac structure and function similar to humans, to better define the arrhythmic substrate. We introduced a nonsense mutation originally identified in a child with Brugada syndrome into the orthologous position (E558X) in the pig SCN5A gene. SCN5A^E558X/+ pigs exhibited conduction abnormalities in the absence of cardiac structural defects. Sudden cardiac death was not observed in young pigs; however, Langendorff-perfused SCN5A^E558X/+ hearts had an increased propensity for pacing-induced or spontaneous VF initiated by short-coupled ventricular premature beats. Optical mapping during VF showed that activity often began as an organized focal source or broad wavefront on the right ventricular (RV) free wall. Together, the results from this study demonstrate that the SCN5A^E558X/+ pig model accurately phenocopies many aspects of human cardiac sodium channelopathy, including conduction slowing and increased susceptibility to ventricular arrhythmias.     

Novel NOD2 haplotype strengthens the association between TLR4 Asp299gly and Crohn's disease in an Australian population

BACKGROUND: The first major Crohn's disease (CD) susceptibility gene, NOD2, implicates the innate intestinal immune system and other pattern recognition receptors in the pathogenesis of this chronic, debilitating disorder. These include the Toll-like receptors, specifically TLR4 and TLR5. A variant in the TLR4 gene (A299G) has demonstrated variable association with CD. We aimed to investigate the relationship between TLR4 A299G and TLR5 N392ST, and an Australian inflammatory bowel disease cohort, and to explore the strength of association between TLR4 A299G and CD using global meta-analysis. METHODS: Cases (CD = 619, ulcerative colitis = 300) and controls (n = 360) were genotyped for TLR4 A299G, TLR5 N392ST, and the 4 major NOD2 mutations. Data were interrogated for case-control analysis prior to and after stratification by NOD2 genotype. Genotype-phenotype relationships were also sought. Meta-analysis was conducted via RevMan. RESULTS: The TLR4 A299G variant allele showed a significant association with CD compared to controls (P = 0.04) and a novel NOD2 haplotype was identified which strengthened this (P = 0.003). Furthermore, we identified that TLR4 A299G was associated with CD limited to the colon (P = 0.02). In the presence of the novel NOD2 haplotype, TLR4 A299G was more strongly associated with colonic disease (P < 0.001) and nonstricturing disease (P = 0.009). A meta-analysis of 11 CD cohorts identified a 1.5-fold increase in risk for the variant TLR4 A299G allele (P < 0.00001). CONCLUSIONS: TLR 4 A299G appears to be a significant risk factor for CD, in particular colonic, nonstricturing disease. Furthermore, we identified a novel NOD2 haplotype that strengthens the relationship between TLR4 A299G and these phenotypes.