Contiguous ∼16 Mb 1p36 deletion: Dominant features of classical distal 1p36 monosomy with haplo-lethality

Monosomy 1p36 results from heterozygous deletions of the terminal short chromosome 1 arm, the most common terminal deletion in humans. The microdeletion is split in two usually non-overlapping and clinically distinct classical distal and proximal 1p36 monosomy syndromes. Using comparative genome hybridization, MLPA and qPCR we identified the largest contiguous ∼16 Mb terminal 1p36 deletion reported to date. It covers both distal and proximal regions, causes a neonatally lethal variant with virtually exclusive features of distal 1p36 monosomy, highlighting the key importance of the gene-rich distal region for the "compound" 1p36 phenotype and a threshold deletion-size effect for haplo-lethality.

Experimental, theoretical and numerical investigation of the nonlinear micromechanical properties of bone

Aging societies suffer from an increasing incidence of bone fractures. Bone strength depends on the amount of mineral measured by clinical densitometry, but also on the micromechanical properties of the bone hierarchical organization. A good understanding has been reached for elastic properties on several length scales, but up to now there is a lack of reliable postyield data on the lower length scales. In order to be able to describe the behavior of bone at the microscale, an anisotropic elastic-viscoplastic damage model was developed using an eccentric generalized Hill criterion and nonlinear isotropic hardening. The model was implemented as a user subroutine in Abaqus and verified using single element tests. A FE simulation of microindentation in lamellar bone was finally performed show-ing that the new constitutive model can capture the main characteristics of the indentation response of bone. As the generalized Hill criterion is limited to elliptical and cylindrical yield surfaces and the correct shape for bone is not known, a new yield surface was developed that takes any convex quadratic shape. The main advantage is that in the case of material identification the shape of the yield surface does not have to be anticipated but a minimization results in the optimal shape among all convex quadrics. The generality of the formulation was demonstrated by showing its degeneration to classical yield surfaces. Also, existing yield criteria for bone at multiple length scales were converted to the quadric formulation. Then, a computational study to determine the influence of yield surface shape and damage on the in-dentation response of bone using spherical and conical tips was performed. The constitutive model was adapted to the quadric criterion and yield surface shape and critical damage were varied. They were shown to have a major impact on the indentation curves. Their influence on indentation modulus, hardness, their ratio as well as the elastic to total work ratio were found to be very well described by multilinear regressions for both tip shapes. For conical tips, indentation depth was not a significant fac-tor, while for spherical tips damage was insignificant. All inverse methods based on microindentation suffer from a lack of uniqueness of the found material properties in the case of nonlinear material behavior. Therefore, monotonic and cyclic micropillar com-pression tests in a scanning electron microscope allowing a straightforward interpretation comple-mented by microindentation and macroscopic uniaxial compression tests were performed on dry ovine bone to identify modulus, yield stress, plastic deformation, damage accumulation and failure mecha-nisms. While the elastic properties were highly consistent, the postyield deformation and failure mech-anisms differed between the two length scales. A majority of the micropillars showed a ductile behavior with strain hardening until failure by localization in a slip plane, while the macroscopic samples failed in a quasi-brittle fashion with microcracks coalescing into macroscopic failure surfaces. In agreement with a proposed rheological model, these experiments illustrate a transition from a ductile mechanical behavior of bone at the microscale to a quasi-brittle response driven by the growth of preexisting cracks along interfaces or in the vicinity of pores at the macroscale. Subsequently, a study was undertaken to quantify the topological variability of indentations in bone and examine its relationship with mechanical properties. Indentations were performed in dry human and ovine bone in axial and transverse directions and their topography measured by AFM. Statistical shape modeling of the residual imprint allowed to define a mean shape and describe the variability with 21 principal components related to imprint depth, surface curvature and roughness. The indentation profile of bone was highly consistent and free of any pile up. A few of the topological parameters, in particular depth, showed significant correlations to variations in mechanical properties, but the cor-relations were not very strong or consistent. We could thus verify that bone is rather homogeneous in its micromechanical properties and that indentation results are not strongly influenced by small de-viations from the ideal case. As the uniaxial properties measured by micropillar compression are in conflict with the current literature on bone indentation, another dissipative mechanism has to be present. The elastic-viscoplastic damage model was therefore extended to viscoelasticity. The viscoelastic properties were identified from macroscopic experiments, while the quasistatic postelastic properties were extracted from micropillar data. It was found that viscoelasticity governed by macroscale properties has very little influence on the indentation curve and results in a clear underestimation of the creep deformation. Adding viscoplasticity leads to increased creep, but hardness is still highly overestimated. It was possible to obtain a reasonable fit with experimental indentation curves for both Berkovich and spherical indenta-tion when abandoning the assumption of shear strength being governed by an isotropy condition. These results remain to be verified by independent tests probing the micromechanical strength prop-erties in tension and shear. In conclusion, in this thesis several tools were developed to describe the complex behavior of bone on the microscale and experiments were performed to identify its material properties. Micropillar com-pression highlighted a size effect in bone due to the presence of preexisting cracks and pores or inter-faces like cement lines. It was possible to get a reasonable fit between experimental indentation curves using different tips and simulations using the constitutive model and uniaxial properties measured by micropillar compression. Additional experimental work is necessary to identify the exact nature of the size effect and the mechanical role of interfaces in bone. Deciphering the micromechanical behavior of lamellar bone and its evolution with age, disease and treatment and its failure mechanisms on several length scales will help preventing fractures in the elderly in the future.

Effect of beam hardening on arterial enhancement in thoracoabdominal CT angiography with increasing patient size: an in vitro and in vivo study

To assess the effect of beam hardening on arterial enhancement in thoracoabdominal computed tomographic (CT) angiography in various body sizes in a phantom and in a clinical study.

Effect of tumor size and tumor-to-liver contrast of hypovascular liver tumors on the diagnostic performance of hepatic CT imaging

To assess the effect of tumor size and tumor-to-liver contrast of simulated hypovascular liver tumors on the diagnostic accuracy of hepatic computed tomography (CT).

Effect of patient size on radiation dose for abdominal MDCT with automatic tube current modulation: phantom study

OBJECTIVE: The purpose of this study was to evaluate in a phantom study the effect of patient size on radiation dose for abdominal MDCT with automatic tube current modulation. MATERIALS AND METHODS: One or two 4-cm-thick circumferential layers of fat-equivalent material were added to the abdomen of an anthropomorphic phantom to simulate patients of three sizes: small (cross-sectional dimensions, 18 x 22 cm), average size (26 x 30 cm), and oversize (34 x 38 cm). Imaging was performed with a 64-MDCT scanner with combined z-axis and xy-axis tube current modulation according to two protocols: protocol A had a noise index of 12.5 H, and protocol B, 15.0 H. Radiation doses to three abdominal organs and the skin were assessed. Image noise also was measured. RESULTS: Despite increasing patient size, the image noise measured was similar for protocol A (range, 11.7-12.2 H) and protocol B (range, 13.9-14.8 H) (p > 0.05). With the two protocols, in comparison with the dose of the small patient, the abdominal organ doses of the average-sized patient and the oversized patient increased 161.5-190.6%and 426.9-528.1%, respectively (p < 0.001). The skin dose increased as much as 268.6% for the average-sized patient and 816.3% for the oversized patient compared with the small patient (p < 0.001). CONCLUSION: Oversized patients undergoing abdominal MDCT with tube current modulation receive significantly higher doses than do small patients. The noise index needs to be adjusted to the body habitus to ensure dose efficiency.

Effect of X-ray tube parameters, iodine concentration, and patient size on image quality in pulmonary computed tomography angiography: a chest-phantom-study

OBJECTIVES: The aim of this phantom study was to evaluate the contrast-to-noise ratio (CNR) in pulmonary computed tomography (CT)-angiography for 300 and 400 mg iodine/mL contrast media using variable x-ray tube parameters and patient sizes. We also analyzed the possible strategies of dose reduction in patients with different sizes. MATERIALS AND METHODS: The segmental pulmonary arteries were simulated by plastic tubes filled with 1:30 diluted solutions of 300 and 400 mg iodine/mL contrast media in a chest phantom mimicking thick, intermediate, and thin patients. Volume scanning was done with a CT scanner at 80, 100, 120, and 140 kVp. Tube current-time products (mAs) varied between 50 and 120% of the optimal value given by the built-in automatic dose optimization protocol. Attenuation values and CNR for both contrast media were evaluated and compared with the volume CT dose index (CTDI(vol)). Figure of merit, calculated as CNR/CTDIvol, was used to quantify image quality improvement per exposure risk to the patient. RESULTS: Attenuation of iodinated contrast media increased both with decreasing tube voltage and patient size. A CTDIvol reduction by 44% was achieved in the thin phantom with the use of 80 instead of 140 kVp without deterioration of CNR. Figure of merit correlated with kVp in the thin phantom (r = -0.897 to -0.999; P < 0.05) but not in the intermediate and thick phantoms (P = 0.09-0.71), reflecting a decreasing benefit of tube voltage reduction on image quality as the thickness of the phantom increased. Compared with the 300 mg iodine/mL concentration, the same CNR for 400 mg iodine/mL contrast medium was achieved at a lower CTDIvol by 18 to 40%, depending on phantom size and applied tube voltage. CONCLUSIONS: Low kVp protocols for pulmonary embolism are potentially advantageous especially in thin and, to a lesser extent, in intermediate patients. Thin patients profit from low voltage protocols preserving a good CNR at a lower exposure. The use of 80 kVp in obese patients may be problematic because of the limitation of the tube current available, reduced CNR, and high skin dose. The high CNR of the 400 mg iodine/mL contrast medium together with lower tube energy and/or current can be used for exposure reduction.

Effect of discharge desynchronization on the size of motor evoked potentials: an analysis

OBJECTIVE: Motor evoked potentials (MEPs) after transcranial magnetic brain stimulation (TMS) are smaller than CMAPs after peripheral nerve stimulation, because desynchronization of the TMS-induced motor neurone discharges occurs (i.e. MEP desynchronization). This desynchronization effect can be eliminated by use of the triple stimulation technique (TST; Brain 121 (1998) 437). The objective of this paper is to study the effect of discharge desynchronization on MEPs by comparing the size of MEP and TST responses. METHODS: MEP and TST responses were obtained in 10 healthy subjects during isometric contractions of the abductor digiti minimi, during voluntary background contractions between 0% and 20% of maximal force, and using 3 different stimulus intensities. Additional data from other normals and from multiple sclerosis (MS) patients were obtained from previous studies. RESULTS: MEPs were smaller than TST responses in all subjects and under all stimulating conditions, confirming the marked influence of desynchronization on MEPs. There was a linear relation between the amplitudes of MEPs vs. TST responses, independent of the degree of voluntary contraction and stimulus intensity. The slope of the regression equation was 0.66 on average, indicating that desynchronization reduced the MEP amplitude on average by one third, with marked inter-individual variations. A similar average proportion was found in MS patients. CONCLUSIONS: The MEP size reduction induced by desynchronization is not influenced by the intensity of TMS and by the level of facilitatory voluntary background contractions. It is similar in healthy subjects and in MS patients, in whom increased desynchronization of central conduction was previously suggested to occur. Thus, the MEP size reduction observed may not parallel the actual amount of desynchronization.

Late results after percutaneous closure of patent foramen ovale for secondary prevention of paradoxical embolism using the amplatzer PFO occluder without intraprocedural echocardiography: effect of device size

OBJECTIVES: We sought to assess the safety and clinical efficacy of patent foramen ovale (PFO) closure under fluoroscopic guidance only, without intraprocedural echocardiography. BACKGROUND: Percutaneous PFO closure has been shown to be safe and feasible using several devices. It is generally performed using simultaneously fluoroscopic and transesophageal or intracardiac echocardiographic guidance. Transesophageal echocardiography requires sedation or general anesthesia and intubation to avoid aspiration. Intracardiac echocardiography is costly and has inherent risks. Both lengthen the procedure. The Amplatzer PFO Occluder (AGA Medical Corporation, Golden Valley, Minnesota) can be safely implanted without echocardiographic guidance. METHODS: A total of 620 patients (51 +/- 12 years; 66% male) underwent PFO closure using the Amplatzer PFO Occluder for secondary prevention of presumed paradoxical embolism. Based on size and mobility of the PFO and the interatrial septum, an 18-mm device was used in 50 patients, a 25-mm device in 492, and a 35-mm device in 78. RESULTS: All procedures were successful, with 5 procedural complications (0.8%): 4 arteriovenous fistulae requiring elective surgical correction, and 1 transient ischemic attack. Contrast transesophageal echocardiography at 6 months showed complete closure in 91% of patients, whereas a minimal, moderate, or large residual shunt persisted in 6%, 2%, and 1%, respectively. During a mean follow-up period of 3.0 +/- 1.9 years (median: 2.6 years; total patient-years: 1,871), 5 ischemic strokes, 8 transient ischemic attacks, and no peripheral emboli were reported. Freedom from recurrent ischemic stroke, transient ischemic attack, or peripheral embolism was 99% at 1 year, 99% at 2 years, and 97% at 5 years. CONCLUSIONS: The Amplatzer PFO Occluder affords excellent safety and long-term clinical efficacy of percutaneous PFO closure without intraprocedural echocardiography.

Endoleak detection with CT angiography in an abdominal aortic aneurysm phantom: effect of tube energy, simulated patient size, and physical properties of endoleaks

To analyze the detection of endoleaks with low-tube-voltage computed tomographic (CT) angiography.

The effect of nontemporal stimulus size on perceived duration as assessed by the method of reproduction

Perceived duration is assumed to be positively related to nontemporal stimulus magnitude. Most recently, the finding that larger stimuli are perceived to last longer has been challenged to represent a mere decisional bias induced by the use of comparative duration judgments. Therefore, in the present study, the method of temporal reproduction was applied as a psychophysical procedure to quantify perceived duration. Another major goal was to investigate the influence of attention on the effect of visual stimulus size on perceived duration. For this purpose, an additional dual-task paradigm was employed. Our results not only converged with previous findings in demonstrating a functional positive relationship between nontemporal stimulus size and perceived duration, but also showed that the effect of stimulus size on perceived duration was not confined to comparative duration judgments. Furthermore, the effect of stimulus size proved to be independent of attentional resources allocated to stimulus size; nontemporal visual stimulus information does not need to be processed intentionally to influence perceived duration. Finally, the effect of nontemporal stimulus size on perceived duration was effectively modulated by the duration of the target intervals, suggesting a hitherto largely unrecognized role of temporal context for the effect of nontemporal stimulus size to become evident.

The effect of brain size evolution on feeding propensity, digestive efficiency, and juvenile growth

One key hypothesis in the study of brain size evolution is the expensive tissue hypothesis; the idea that increased investment into the brain should be compensated by decreased investment into other costly organs, for instance the gut. Although the hypothesis is supported by both comparative and experimental evidence, little is known about the potential changes in energetic requirements or digestive traits following such evolutionary shifts in brain and gut size. Organisms may meet the greater metabolic requirements of larger brains despite smaller guts via increased food intake or better digestion. But increased investment in the brain may also hamper somatic growth. To test these hypotheses we here used guppy (Poecilia reticulata) brain size selection lines with a pronounced negative association between brain and gut size and investigated feeding propensity, digestive efficiency (DE), and juvenile growth rate. We did not find any difference in feeding propensity or DE between large- and small-brained individuals. Instead, we found that large-brained females had slower growth during the first 10 weeks after birth. Our study provides experimental support that investment into larger brains at the expense of gut tissue carries costs that are not necessarily compensated by a more efficient digestive system.