Initial results of a computerized screening alert for abdominal aortic aneurysm in patients undergoing vascular assessment

Although routine ultrasound screening for abdominal aortic aneurysm (AAA) reduces mortality in subjects at risk, it is often omitted in clinical practice. Because computerized alerts may systematically identify subjects at risk of AAA, we hypothesized that such alerts would encourage physicians to perform an ultrasound screening test.

Farming environments and childhood atopy, wheeze, lung function, and exhaled nitric oxide

Previous studies have demonstrated that children raised on farms are protected from asthma and allergies. It is unknown whether the farming effect is solely mediated by atopy or also affects nonatopic wheeze phenotypes.

Regulatory mechanism of the light-activable allosteric switch LOV-TAP for the control of DNA binding: a computer simulation study

The spatio-temporal control of gene expression is fundamental to elucidate cell proliferation and deregulation phenomena in living systems. Novel approaches based on light-sensitive multiprotein complexes have recently been devised, showing promising perspectives for the noninvasive and reversible modulation of the DNA-transcriptional activity in vivo. This has lately been demonstrated in a striking way through the generation of the artificial protein construct light-oxygen-voltage (LOV)-tryptophan-activated protein (TAP), in which the LOV-2-Jα photoswitch of phototropin1 from Avena sativa (AsLOV2-Jα) has been ligated to the tryptophan-repressor (TrpR) protein from Escherichia coli. Although tremendous progress has been achieved on the generation of such protein constructs, a detailed understanding of their functioning as opto-genetical tools is still in its infancy. Here, we elucidate the early stages of the light-induced regulatory mechanism of LOV-TAP at the molecular level, using the noninvasive molecular dynamics simulation technique. More specifically, we find that Cys450-FMN-adduct formation in the AsLOV2-Jα-binding pocket after photoexcitation induces the cleavage of the peripheral Jα-helix from the LOV core, causing a change of its polarity and electrostatic attraction of the photoswitch onto the DNA surface. This goes along with the flexibilization through unfolding of a hairpin-like helix-loop-helix region interlinking the AsLOV2-Jα- and TrpR-domains, ultimately enabling the condensation of LOV-TAP onto the DNA surface. By contrast, in the dark state the AsLOV2-Jα photoswitch remains inactive and exerts a repulsive electrostatic force on the DNA surface. This leads to a distortion of the hairpin region, which finally relieves its tension by causing the disruption of LOV-TAP from the DNA.

Photodissociation dynamics of tert-butylnitrite following excitation to the S(1) and S(2) states. A study by velocity-map ion-imaging and 3D-REMPI spectroscopy

Excitation of tert-butylnitrite into the first and second UV absorption bands leads to efficient dissociation into the fragment radicals NO and tert-butoxy in their electronic ground states (2)Π and (2)E, respectively. Velocity distributions and angular anisotropies for the NO fragment in several hundred rotational and vibrational quantum states were obtained by velocity-map imaging and the recently developed 3D-REMPI method. Excitation into the well resolved vibronic progression bands (k = 0, 1, 2) of the NO stretch mode in the S(1) ← S(0) transition produces NO fragments mostly in the vibrational state with v = k, with smaller fractions in v = k - 1 and v = k - 2. It is concluded that dissociation occurs on the purely repulsive PES of S(1) without barrier. All velocity distributions from photolysis via the S(1)(nπ*) state are monomodal and show high negative anisotropy (β ≈ -1). The rotational distributions peak near j = 30.5 irrespective of the vibronic state S(1)(k) excited and the vibrational state v of the NO fragment. On average 46% of the excess energy is converted to kinetic energy, 23% and 31% remain as internal energy in the NO fragment and the t-BuO radical, respectively. Photolysis via excitation into the S(2) ← S(0) transition at 227 nm yields NO fragments with about equal populations in v = 0 and v = 1. The rotational distributions have a single maximum near j = 59.5. The velocity distributions are monomodal with positive anisotropy β ≈ 0.8. The average fractions of the excess energy distributed into translation, internal energy of NO, and internal energy of t-BuO are 39%, 23%, and 38%, respectively. In all cases ∼8500 cm(-1) of energy remain in the internal degrees of freedom of the t-BuO fragment. This is mostly assigned to rotational energy. An ab initio calculation of the dynamic reaction path shows that not only the NO fragment but also the t-BuO fragment gain large angular momentum during dissociation on the purely repulsive potential energy surface of S(2).

A novel computer simulation method for simulating the multiscale transduction dynamics of signal proteins

Signal proteins are able to adapt their response to a change in the environment, governing in this way a broad variety of important cellular processes in living systems. While conventional molecular-dynamics (MD) techniques can be used to explore the early signaling pathway of these protein systems at atomistic resolution, the high computational costs limit their usefulness for the elucidation of the multiscale transduction dynamics of most signaling processes, occurring on experimental timescales. To cope with the problem, we present in this paper a novel multiscale-modeling method, based on a combination of the kinetic Monte-Carlo- and MD-technique, and demonstrate its suitability for investigating the signaling behavior of the photoswitch light-oxygen-voltage-2-Jα domain from Avena Sativa (AsLOV2-Jα) and an AsLOV2-Jα-regulated photoactivable Rac1-GTPase (PA-Rac1), recently employed to control the motility of cancer cells through light stimulus. More specifically, we show that their signaling pathways begin with a residual re-arrangement and subsequent H-bond formation of amino acids near to the flavin-mononucleotide chromophore, causing a coupling between β-strands and subsequent detachment of a peripheral α-helix from the AsLOV2-domain. In the case of the PA-Rac1 system we find that this latter process induces the release of the AsLOV2-inhibitor from the switchII-activation site of the GTPase, enabling signal activation through effector-protein binding. These applications demonstrate that our approach reliably reproduces the signaling pathways of complex signal proteins, ranging from nanoseconds up to seconds at affordable computational costs.

Signaling pathway of a photoactivable Rac1-GTPase in the early stages

In modern life- and medical-sciences major efforts are currently concentrated on creating artificial photoenzymes, consisting of light- oxygen-voltage-sensitive (LOV) domains fused to a target enzyme. Such protein constructs possess great potential for controlling the cell metabolism as well as gene function upon light stimulus. This has recently been impressively demonstrated by designing a novel artificial fusion protein, connecting the AsLOV2-Jα-photosensor from Avena sativa with the Rac1-GTPase (AsLOV2-Jα-Rac1), and by using it, to control the motility of cancer cells from the HeLa-line. Although tremendous progress has been achieved on the generation of such protein constructs, a detailed understanding of their signaling pathway after photoexcitation is still in its infancy. Here, we show through computer simulations of the AsLOV2-Jα-Rac1-photoenzyme that the early processes after formation of the Cys450-FMN-adduct involve the breakage of a H-bond between the carbonyl oxygen FMN-C4O and the amino group of Gln513, followed by a rotational reorientation of its sidechain. This initial event is followed by successive events including β-sheet tightening and transmission of torsional stress along the Iβ-sheet, which leads to the disruption of the Jα-helix from the N-terminal end. Finally, this process triggers the detachment of the AsLOV2-Jα-photosensor from the Rac1-GTPase, ultimately enabling the activation of Rac1 via binding of the effector protein PAK1.

Change in dust variability in the Atlantic sector of Antarctica at the end of the last deglaciation

We present a Rare Earth Elements (REE) record determined on the EPICA ice core drilled at Dronning Maud Land (EDML) in the Atlantic sector of the East Antarctic Plateau. The record covers the transition from the last glacial stage (LGS) to the early Holocene (26 600–7500 yr BP) at decadal to centennial resolution. Additionally, samples from potential source areas (PSAs) for Antarctic dust were analyzed for their REE characteristics. The dust provenance is discussed by comparing the REE fingerprints in the ice core and the PSA samples. We find a shift in variability in REE composition at ~15 000 yr BP in the ice core samples. Before 15 000 yr BP, the dust composition is very uniform and its provenance was most certainly dominated by a South American source. After 15 000 yr BP, multiple sources such as Australia and New Zealand become relatively more important, although South America remains the major dust source. A similar change in the dust characteristics was observed in the EPICA Dome C ice core at around ~15 000 yr BP, accompanied by a shift in the REE composition, thus suggesting a change of atmospheric circulation in the Southern Hemisphere.

Endovascular stenting of a renal transplant vein

We describe successful endovascular stenting of a high-grade stenosis of a renal transplant vein in a 53-year old patient. Kidney transplantation had been performed due to IgA nephropathy and the patient had become symptomatic two months after uneventful recovery from operation.

Association of cardiovascular risk factors with pattern of lower limb atherosclerosis in 2659 patients undergoing angioplasty

OBJECTIVES: Aim of this study is to correlate distribution pattern of lower limb atherosclerosis with cardiovascular risk factor profile of patients with peripheral arterial occlusive disease (PAD). PATIENTS AND METHODS: Analysis is based on a consecutive series of 2659 patients (1583 men, 1076 women, 70+/-11 years) with chronic PAD of atherosclerotic origin undergoing primary endovascular treatment of lower extremity arteries. Pattern of atherosclerosis was grouped into iliac (n=1166), femoropopliteal (n=2151) and infrageniculate (n=888) disease defined according to target lesions treated. A multivariable multinomial logistic regression analysis was performed to assess relation with age, gender and classical cardiovascular risk factors (diabetes mellitus, arterial hypertension, hypercholesterolemia, cigarette smoking) using femoropopliteal disease as reference. RESULTS: Iliac disease was associated with younger age (RRR 0.95 per year of age, 95%-CI 0.94-0.96, p<0.001), male gender (RRR 1.32, 95%-CI 1.09-1.59, p=0.004) and cigarette smoking (RRR 2.02, 95%-CI 1.68-2.42, p<0.001). Infrageniculate disease was associated with higher age (RRR 1.02, 95%-CI 1.01-1.02, p<0.001), male gender (RRR 1.23, 95%-CI 1.06-1.41, p=0.005) and diabetes mellitus (RRR 1.68, 95%-CI 1.47-1.92, p<0.001). Hypercholesterolemia was less prevalent in patients with lesions below the knee (RRR 0.82, 95%-CI 0.71-0.94, p=0.006), whereas no distinct pattern was apparent related to arterial hypertension. CONCLUSION: Clinical phenotype of peripheral atherosclerosis varies with prevalence of cardiovascular risk factors suggesting differences in mechanisms involved in iliac as compared with infrageniculate lesions. Identification of molecular mechanism might have influence on future therapeutic strategies in PAD patients.

Analbuminemic Nagase rats: blood pressure response to dietary salt challenge

BACKGROUND: The role of albumin on blood pressure response to different salt challenges is not known. Therefore, we studied the blood pressure response of analbuminemic Nagase rats (NAR) to different salt challenges. 11beta-Hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the enzyme regulating the glucocorticoid access to the mineralocorticoid receptor, an enzyme that is decreased in humans with salt sensitive hypertension and other diseases with abnormal renal salt retention, was assessed during salt challenges. METHODS: Blood pressure was measured continuously by an intra-arterial catheter and a telemetry system in NAR (n = 8). NAR were set successively for 7 days on a normal (0.45% NaCl), high (8% NaCl), low (0.1% NaCl) and normal salt diet again, to assess salt related response in mean systolic (SBP) and diastolic blood pressure (DBP). 11beta-HSD2activity was assessed by measuring the urinary (THB + 5alpha-THB)/THA ratio with gas chromatography - mass spectrometry. RESULTS: Mean SBP and DBP increased with high salt intake (normal salt vs. high salt: SBP: 114 +/- 1 vs.119 +/- 3 mm Hg, p < 0.01; DBP: 84 +/- 1 vs. 88 +/- 3 mm Hg; n = 8; p < 0.01). Urinary (THB +5alpha-THB)/THA ratio increased during the high-salt period when compared to the normal-salt period (high salt vs. normal salt: 0.52 +/- 0.10 vs. 0.37 +/- 0.07; p = 0.05) indicating decreased 11beta-HSD2activity. CONCLUSION: Analbuminemic Nagase rats express increased blood pressure and reduced 11beta-HSD2 activity in response to a high-salt diet.

Fractured and embolized coronary stent mimicking significant internal carotid stenosis

We describe the case of 77-year-old woman who underwent five coronary angiographies in 9 months due to in-stent re-stenosis of Cypher-Stents, and who finally required coronary artery bypass grafting surgery. Preoperative investigations revealed a significant internal carotid stenosis, which was due to a fractured and embolized Cypher-Stent.

177Lu-AMBA: Synthesis and characterization of a selective 177Lu-labeled GRP-R agonist for systemic radiotherapy of prostate cancer

Gastrin-releasing peptide receptors (GRP-R) are upregulated in many cancers, including prostate, breast, and lung. We describe a new radiolabeled bombesin (BBN) analog for imaging and systemic radiotherapy that has improved pharmacokinetics (PK) and better retention of radioactivity in the tumor. METHODS: DO3A-CH2CO-G-4-aminobenzoyl-Q-W-A-V-G-H-L-M-NH2 (AMBA) was synthesized and radiolabeled. The human prostate cancer cell line PC-3 was used to determine the binding (Kd), retention, and efflux of 177Lu-AMBA. Receptor specificity was determined by in vitro autoradiography in human tissues. PK and radiotherapy studies were performed in PC-3 tumor-bearing male nude mice. RESULTS: 177Lu-AMBA has a high affinity for the GRP-R (Kd, 1.02 nmol/L), with a maximum binding capacity (Bmax) of 414 fmol/10(6) cells (2.5 x 10(5) GRP-R/cell). Internalization was similar for 177Lu-AMBA (76.8%), 177Lu-BBN8 (72.9%), and 125I-[Tyr4]-BBN (74.9%). Efflux was markedly lower for 177Lu-AMBA (2.9%) compared with 177Lu-BBN8 (15.9%) and 125I-[Tyr4]-BBN (46.1%). By receptor autoradiography, Lu-AMBA binds specifically to GRP-R (0.8 nmol/L) and to the neuromedin B receptor (NMB-R) (0.9 nmol/L), with no affinity for the bb3 receptor (>1,000 nmol/L). 177Lu-AMBA was renally excreted (55 %ID 1 h [percentage injected dose at 1 h]); tumor uptake at 1 and 24 h was 6.35 %ID/g and 3.39 %ID/g, respectively. One or 2 doses of 177Lu-AMBA (27.75 MBq/dose) significantly prolonged the life span of PC-3 tumor-bearing mice (P < 0.001 and P < 0.0001, respectively) and decreased PC-3 tumor growth rate over controls. When compared using World Health Organization criteria, mice receiving 2 doses versus 1 dose of 177Lu-AMBA demonstrated a shift away from stable/progressive disease toward complete/partial response; by RECIST (Response Evaluation Criteria in Solid Tumors), median survival increased by 36% and time to progression/progression-free survival increased by 65%. CONCLUSION: 177Lu-AMBA binds with nanomolar affinity to GRP-R and NMB-R, has low retention of radioactivity in kidney, demonstrates a very favorable risk-benefit profile, and is in phase I clinical trials.

Intraobserver and interobserver variability of 64-row computed tomography abdominal aortic aneurysm neck measurements

BACKGROUND: Integrity of the abdominal aortic aneurysm (AAA) neck is crucial for the long-term success of endovascular AAA repair (EVAR). However, suitable tools for reliable assessment of changes in small aortic volumes are lacking. The purpose of this study was to assess the intraobserver and interobserver variability of software-enhanced 64-row computed tomographic angiography (CTA) AAA neck volume measurements in patients after EVAR. METHODS: A total of 25 consecutive patients successfully treated by EVAR underwent 64-row follow-up CTA in 1.5-mm collimation. Manual CTA measurements were performed twice by three blinded and independent readers in random order with at least a 4-week interval between readings. Maximum and minimum transverse aortic neck diameters were measured twice on two different levels within the proximal neck. Volumetry of the proximal aortic neck was performed by using dedicated software. Variability was calculated as 1.96 SD of the mean arithmetic difference according to Bland and Altman. Two-sided and paired t tests were used to compare measurements. P values <.05 were considered to indicate statistical significance. RESULTS: Intraobserver agreement was excellent for dedicated aneurysmal neck volumetry, with mean differences of less than 1 mL (P > .05), whereas it was poor for transverse aortic neck diameter measurements (P < .05). However, interobserver variability was statistically significant for both neck volumetry (P < .005) and neck diameter measurements (P < .015). CONCLUSIONS: The reliability of dedicated AAA neck volumetry by using 64-row CTA is excellent for serial measurements by individual readers, but not between different readers. Therefore, studies should be performed with aortic neck volumetry by a single experienced reader.