A method for standardized computed tomography angiography-based measurement of aortic valvar structures.

AIMS: Reliable assessment of the aortic valvar apparatus (AVAp) is essential as it may facilitate consistent outcomes with percutaneous aortic valvar therapies. The commonly referenced aortic annulus is problematic since this measurement does not correspond to any actual anatomic structure. We aim to describe a reliable method of measuring relevant structures of the AVAp based on widely available computed tomography analyses. METHODS AND RESULTS: Retrospective analysis of computed tomograms of 75 patients with severe aortic stenosis (45 females, age 81.2 +/- 7.8 years). Curved multiplaner reconstruction technique was used to measure average diameters of the 'Aortic Leaflets Basal Attachment Plane' (ALBAP), sinuses of Valsalva (SV), sinutubular junction (STJ), ascending aorta (AA), and distance from coronary arteries to the base of the cusps. Angulation between the AA and the left ventricle (LV) was measured in one plane that included the LV inflow long axis and the maximum visualization of the aortic root. Inter-rater reliability and absolute agreement among three raters were evaluated. Intra-class correlation coefficients for ALBAP, SV, STJ, and AA diameters were 0.90, 0.99, 0.95, and 0.94, respectively (P < 0.001) with 95% limits of agreement of the observed differences falling in the less than 1 mm range. Intra-class correlation coefficients were 0.82 for the angle and 0.61 and 0.78 for distances to the right and left coronary arteries (P < 0.001). CONCLUSION: This method showed a high degree of inter-rater reliability and absolute agreement for AVAp diameters. Agreement was lower for AA-LV angle and distance to coronary artery measurements, emphasizing the need for software improvements and standardized image acquisition protocols.

The YSNSG cyclopeptide derived from tumstatin inhibits tumor angiogenesis by down-regulating endothelial cell migration.

We previously demonstrated that the CNYYSNS peptide derived from tumstatin inhibited in vivo tumor progression. The YSNS motif formed a beta-turn crucial for biological activity. More recently, a YSNSG cyclopeptide with a constrained beta-turn on the YSNS residues was designed. Intraperitoneal administration of the YSNSG cyclopeptide inhibited in vivo melanoma progression more efficiently than the native linear peptide. In the present article, we showed that the YSNSG cyclopeptide also triggered an inhibition of in vivo tumor neovascularization and we further analyzed its in vitroantiangiogenic effect. The YSNSG cyclopeptide did not alter endothelial cell proliferation but inhibited cell migration by 83% in an in vitro wound healing model. The inhibition was mediated by a decrease in active MT1-MMP at the migration front as well as a decrease in u-PA and u-PAR expression. The cyclopeptide also altered beta1-integrin distribution in endothelial cell lamellipodia, induced a strong decrease in the phosphorylated focal adhesion kinase (p125(FAK)), disorganized F-actin stress fibers and decreased the number of lamellipodia, resulting in a non migratory phenotype. Our results confirm the YSNSG cyclopeptide as a potent antitumor agent, through both the inhibition of invasive properties of tumor cells and the antiangiogenic activity.

Carotid stenting and bivalirudin with and without vascular closure: 3-year analysis of procedural outcomes.

OBJECTIVES: The purpose of this study was to examine the outcome of carotid stenting using bivalirudin and the influence of vascular closure devices (VCD) on the incidence and severity of peri-procedural hypotension. BACKGROUND: Bivalirudin, a short-acting direct thrombin inhibitor, has been shown to be an effective anticoagulant in coronary interventions, with less risk of bleeding compared with heparin. Routine use of VCD has become the standard of care, facilitating patient ambulation after percutaneous carotid and coronary interventions. The combined use of these two therapies (bivalirudin and VCD) may improve outcomes in carotid interventions where prolonged patient immobilization may exacerbate hypotension following stenting. METHODS: A total of 514 patients underwent 536 carotid stenting procedures in the 3-year period from September 2004 to September 2007. All patients received adjunctive bivalirudin, with and without VCD. This cohort was analyzed for peri-procedural and 30-day clinical outcomes and length of hospitalization. RESULTS: Thirty-day stroke and death rate was 1.7%. A total of 83 patients (15.4%) experienced intra- or post-procedural hypotension (systolic BP < 80 mm Hg). There were four (0.7%) major bleeding complications requiring transfusion, and length of stay was delayed more than 24 hr in five patients (0.93%), all of whom were in the manual compression group. CONCLUSIONS: This was a negative study, with no significant difference on prolonged hypotensive events in patients with vascular closure device and bivalirudin, compared with those with manual compression and bivalirudin. Vascular closure devices were safe and effective with a low incidence of complications. In carotid artery stenting, bivalirudin is safe with low incidence of major bleeding and acceptable 30-day adverse event rates (stroke and death).

Neuro-Clinical Signatures of Language Impairments after Acute Stroke: A VBQ Analysis of Quantitative Native CT Scans.

OBJECTIVES: Ischemic stroke affects language production and/or comprehension and leads to devastating long-term consequences for patients and their families. Previous studies have shown that neuroimaging can increase our knowledge of the basic mechanisms of language recovery. Currently, models for predicting patients' outcomes have limited use in the clinic for the evaluation and optimization of rehabilitative strategies mostly because that are often based on high-resolution magnetic resonance imaging (MRI) data, which are not always possible to carry out in the clinical routine. Here, we investigate the use of Voxel-Based Morphometry (VBM), multivariate modelling and native Computed Tomography (nCT) scans routinely acquired in the acute stage of stroke for identifying biological signatures that explicate the relationships between brain anatomy and types of impairments. METHODS: 80 stroke patients and 30 controls were included. nCT-scans were acquired in the acute ischemia stage and bedside clinical assessment from board-certified neurologist based on the NIH stroke scale. We use a multivariate Principal Component Analyses (PCA) to identify the brain signatures group the patients according to the presence or absence of impairment and identify the association between local Grey Matter (GM) and White Matter (WM) nCT values with the presence or absence of the impairment. RESULTS: Individual patient's nCT scans were compared to a group of controls' with no radiological signs of stroke to provide an automated delineation of the lesion. Consistently across the whole group the regions that presented significant difference GM and WM values overlap with known areas that support language processing. CONCLUSION: In summary, the method applied to nCT scans performed in the acute stage of stroke provided robust and accurate information about brain lesions' location and size, as well as quantitative values. We found that nCT and VBQ analyses are effective for identifying neural signatures of concomitant language impairments at the individual level, and neuroanatomical maps of aphasia at the population level. The signatures explicate the neurophysiological mechanisms underlying aetiology of the stroke. Ultimately, similar analyses with larger cohorts could lead to a more integrated multimodal model of behaviour and brain anatomy in the early stage of ischemic stroke.

Discriminating healthy from tumor and necrosis tissue in rat brain tissue samples by Raman spectral imaging.

The purpose of this study was to investigate molecular changes associated with glioma tissues by Raman microspectroscopy in order to develop its use in clinical practice. Spectroscopic markers obtained from C6 glioma tissues were compared to conventional histological and histochemical techniques. Cholesterol and phospholipid contents were highest in corpus callosum and decreased gradually towards the cortex surface as well as in the tumor. Two different necrotic areas have been identified: a fully necrotic zone characterized by the presence of plasma proteins and a peri-necrotic area with a high lipid content. This result was confirmed by Nile Red staining. Additionally, one structure was detected in the periphery of the tumor. Invisible with histopathological hematoxylin and eosin staining, it was revealed by immunohistochemical Ki-67 and MT1-MMP staining used to visualize the proliferative and invasive activities of glioma, respectively. Hierarchical cluster analysis on the only cluster averaged spectra showed a clear distinction between normal, tumoral, necrotic and edematous tissues. Raman microspectroscopy can discriminate between healthy and tumoral brain tissue and yield spectroscopic markers associated with the proliferative and invasive properties of glioblastoma. Development of in vivo Raman spectroscopy could thus accurately define tumor margins, identify tumor remnants, and help in the development of novel therapies for glioblastoma.

Modeling and quantifying biochemical changes in C6 tumor gliomas by Fourier transform infrared imaging.

The purpose of the study was to investigate molecular changes associated with glioma tissues using FT-IR microspectroscopic imaging (FT-IRM). A multivariate statistical analysis allowed one to successfully discriminate between normal, tumoral, peri-tumoral, and necrotic tissue structures. Structural changes were mainly related to qualitative and quantitative changes in lipid content, proteins, and nucleic acids that can be used as spectroscopic markers for this pathology. We have developed a spectroscopic model of glioma to quantify these chemical changes. The model constructed includes individual FT-IR spectra of normal and glioma brain constituents such as lipids, DNA, and proteins (measured on delipidized tissue). Modeling of FT-IR spectra yielded fit coefficients reflecting the chemical changes associated with a tumor. Our results demonstrate the ability of FT-IRM to assess the importance and distribution of each individual constituent and its variation in normal brain structures as well as in the different pathological states of glioma. We demonstrated that (i) cholesterol and phosphatidylethanolamine contributions are highest in corpus callosum and anterior commissure but decrease gradually towards the cortex surface as well as in the tumor, (ii) phosphatidylcholine contribution is highest in the cortex and decreases in the tumor, (iii) galactocerebroside is localized only in white, but not in gray matter, and decreases in the vital tumor region while the necrosis area shows a higher concentration of this cerebroside, (iv) DNA and oleic acid increase in the tumor as compared to gray matter. This approach could, in the future, contribute to enhance diagnostic accuracy, improve the grading, prognosis, and play a vital role in therapeutic strategy and monitoring.

Brain tissue characterisation by infrared imaging in a rat glioma model.

Pathological changes associated with the development of brain tumor were investigated by Fourier transform infrared microspectroscopy (FT-IRM) with high spatial resolution. Using multivariate statistical analysis and imaging, all normal brain structures were discriminated from tumor and surrounding tumor tissues. These structural changes were mainly related to qualitative and quantitative changes in lipids (tumors contain little fat) and were correlated to the degree of myelination, an important factor in several neurodegenerative disorders. Lipid concentration and composition may thus be used as spectroscopic markers to discriminate between healthy and tumor tissues. Additionally, we have identified one peculiar structure all around the tumor. This structure could be attributed to infiltrative events, such as peritumoral oedema observed during tumor development. Our results highlight the ability of FT-IRM to identify the molecular origin that gave rise to the specific changes between healthy and diseased states. Comparison between pseudo-FT-IRM maps and histological examinations (Luxol fast blue, Luxol fast blue-cresyl violet staining) showed the complementarities of both techniques for early detection of tissue abnormalities.

The Number of Genomic Copies at the 16p11.2 Locus Modulates Language, Verbal Memory, and Inhibition.

BACKGROUND: Deletions and duplications of the 16p11.2 BP4-BP5 locus are prevalent copy number variations (CNVs), highly associated with autism spectrum disorder and schizophrenia. Beyond language and global cognition, neuropsychological assessments of these two CNVs have not yet been reported. METHODS: This study investigates the relationship between the number of genomic copies at the 16p11.2 locus and cognitive domains assessed in 62 deletion carriers, 44 duplication carriers, and 71 intrafamilial control subjects. RESULTS: IQ is decreased in deletion and duplication carriers, but we demonstrate contrasting cognitive profiles in these reciprocal CNVs. Deletion carriers present with severe impairments of phonology and of inhibition skills beyond what is expected for their IQ level. In contrast, for verbal memory and phonology, the data may suggest that duplication carriers outperform intrafamilial control subjects with the same IQ level. This finding is reminiscent of special isolated skills as well as contrasting language performance observed in autism spectrum disorder. Some domains, such as visuospatial and working memory, are unaffected by the 16p11.2 locus beyond the effect of decreased IQ. Neuroimaging analyses reveal that measures of inhibition covary with neuroanatomic structures previously identified as sensitive to 16p11.2 CNVs. CONCLUSIONS: The simultaneous study of reciprocal CNVs suggests that the 16p11.2 genomic locus modulates specific cognitive skills according to the number of genomic copies. Further research is warranted to replicate these findings and elucidate the molecular mechanisms modulating these cognitive performances.

Physical fitness and reverse cholesterol transport.

BACKGROUND: Physical exercise is associated with a decreased risk of cardiovascular disease, which may be partly caused by the effect of exercise on the lipoprotein profile. The most consistent effect of exercise on lipoprotein metabolism is an increase in high-density lipoprotein (HDL). METHODS AND RESULTS: Parameters of reverse cholesterol transport (RCT) in 25 endurance-trained male athletes were compared with 33 age-matched males enjoying an active lifestyle. VO2max was higher in athletes than in controls (53.4+/-1.2 versus 38.8+/-1.0 mL/min per kg; P<0.01). The following differences in parameters of RCT were found: (1) plasma HDL cholesterol and apoA-I levels were higher in athletes compared with controls (1.7+/-0.1 versus 1.4+/-0.1 mmol/L; P<0.001; and 145+/-2 versus 128+/-3 mg/dL; P<0.001, respectively). Both correlated with VO2max up to the value of 51 mL/min per kg; (2) prebeta1-HDL was higher in athletes than in controls (54+/-4 versus 37+/-3 microg/mL; P<0.001) and correlated positively with VO2max; (3) lecithin cholesterol: acyltransferase activity was higher in athletes (29.8+/-1.2 versus 24.2+/-1.4 nmol/microL per hour; P<0.005); and (4) the capacity of plasma to promote cholesterol efflux from macrophages was higher in athletes (18.8%+/-0.8% versus 16.2%+/-0.3%; P<0.03). CONCLUSIONS: The likely reason for higher HDL concentration in physically fit people is increased formation of HDL from apoA-I and cellular lipids.

Michurinist Biology in the People's Republic of China, 1948-1956.

Michurinist biology was introduced to China in 1948; granted a state supported monopoly in 1952; and reduced to parity with western genetics from 1956. The Soviets exported it through the propaganda agencies Sino Soviet Friendship Association (SSFA) and VOKS (Cultural Relations with Foreign Countries). China's Ministry of Agriculture achieved broad public awareness and acceptance of Michurinist biology through a translation, publication, and Soviet guest speakers campaign - all managed by a team of agriculturalists led by Luo Tianyu, a veteran CCP (Communist Party) cadre. The campaign grew exponentially, but did not affect university or Chinese Academy of Sciences biology. Luo Tianyu's failed attempt to force Michurinist biology on a Beijing university triggered its second stage: monopoly status and a ban on "Mendelist-Morganist" biology in teaching, research, and publication. The CCP Central Committee supported this policy believing that Michurinst biology would increase agricultural production for the forthcoming first Five Year Plan; whereas, western genetics had no practical value. Michurinist biology flourished at all levels of education, research, and science literature; Western genetics was completely shut down. This only began to change when the CCP Central Committee became wary of China's dependency on Soviet technical expertise and failure to fully utilize that of China. Change was further promoted by significant attacks on Michurinist biology by Soviet and East German biologists. Soon, these developments informed China's "genetics question," which became a test case for larger questions about the definition of science and the relationship between scientists and the state. Under the guidance of Lu Dingyi's Central Committee Propaganda Department, the CCP eventually decided that, henceforth, science controversies would only be resolved by the science community; and that monopolies or ideological orthodoxies would not be imposed on science. At the same time, the CCP rescinded Michurinist biology's monopoly and the ban on western genetics. By the mid-1960s western genetics had successfully restored itself, largely due to the leadership of C. C. Tan, a former student of Dobzhansky. Michurinist biology's presence shrank and it became marginalized.

Cardiac perforation during patent foramen ovale closure sealed with an amplatzer PFO occluder.

Percutaneous patent foramen ovale (PFO) closure is increasingly performed for a variety of different conditions and is usually relatively straightforward, with a low adverse event rate and virtually no mortality. In cases with a long PFO tunnel, the "puncture technique" -- utilizing a transseptal puncture -- is performed to achieve better apposition of the septum primum to the septum secundum, and to avoid device deformity. Even though transseptal puncture can be safely performed by experienced operators, there is still a 1-2% risk of cardiac perforation. We report a novel technique to percutaneously close a cardiac perforation that occurred while using the puncture technique for PFO closure using an Amplatzer PFO Occluder. The PFO occluder successfully sealed the perforation, prevented development of cardiac tamponade and avoided the need for surgical intervention in a frail patient. This technique can be applied to other cardiac chamber perforations, especially if iatrogenic. This case illustrates the need to be thoroughly familiar with the cardiac anatomy and to avoid "instinctively" withdrawing the equipment once perforation occurs.

Stenting the critical calyceal carotid bifurcation--a technical update.

There are several anatomical appearances of the carotid bifurcation. A calyceal type of bifurcation, superimposed with distal angulation of the internal carotid artery (ICA) and added ICA stenosis can be extremely challenging with regard to placement of embolic protection devices, prolonging manipulation of the lesion, procedure time, increasing contrast use and thus increasing the risk of complications. Certain technical maneuvers can facilitate the procedure and minimize risk. This case study describes the steps taken to safely treat these lesions.

Minimal contrast use in carotid stenting: avoiding contrast pitfalls.

BACKGROUND: The progression of endovascular approaches to vascular disease has led to an increasing volume of procedures requiring iodinated contrast media. Accordingly, the potential for contrast-induced nephropathy (CIN) also continues to increase. Hypotension, independent of contrast use, is a well-described cause of acute renal dysfunction and an important factor in endovascular procedures complicated by hypotension. CIN is the third leading cause of hospital-acquired acute renal failure, accounting for 12% of cases, and the frequency of CIN in coronary angiography ranges from 5% in patients with mild renal insufficiency to 50% in those with severe renal dysfunction and diabetes. Prior carotid trials have demonstrated that patients with dialysis-dependent renal failure had a stroke, death and myocardial infarction rate of 28.6%. CIN is an economic burden with increased morbidity, length of hospitalization, chronic renal impairment and higher mortality. Multiple pharmacological agents have been studied as prophylaxis to CIN, but none have been shown to be beneficial, including a recent meta-analysis of 13 randomized N-acetylcysteine trials showing inconclusive efficacy. The preprocedural avoidance of nephrotoxic drugs, iso- or low-osmolar contrast, reduced volume contrast and additional intravenous fluids are all recommended as strategies in reducing the risk of CIN.