Mutations in STIL, Encoding a Pericentriolar and Centrosomal Protein, Cause Primary Microcephaly

Primary microcephaly (MCPH) is an autosomal-recessive congenital disorder characterized by smaller-than-normal brain size and mental retardation. MCPH is genetically heterogeneous with six known loci: MCPH1-MCPH6. We report mapping of a novel locus, MCPH7, to chromosome 1p32.3-p33 between markers D1S2797 and D1S417, corresponding to a physical distance of 8.39 Mb. Heterogeneity analysis of 24 families previously excluded from linkage to the six known MCPH loci suggested linkage of five families (20.83%) to the MCPH7 locus. In addition, four families were excluded from linkage to the MCPH7 locus as well as all of the six previously known loci, whereas the remaining 15 families could not be conclusively excluded or included. The combined maximum two-point LOD score for the linked families was 5.96 at marker D1S386 at theta = 0.0. The combined multipoint LOD score was 6.97 between markers D1S2797 and D1S417. Previously, mutations in four genes, MCPH1, CDK5RAP2, ASPM, and CENPJ, that code for centrosomal proteins have been shown to cause this disorder. Three different homozygous mutations in STIL, which codes for a pericentriolar and centrosomal protein, were identified in patients from three of the five families linked to the MCPH7 locus; all are predicted to truncate the STIL protein. Further, another recently ascertained family was homozygous for the same mutation as one of the original families. There was no evidence for a common haplotype. These results suggest that the centrosome and its associated structures are important in the control of neurogenesis in the developing human brain.

Consolidation Behavior of Soils

Based on Terzaghi's consolidation theory, percent of consolidation, U, versus the time factor, T, relationship for constant/linear excess pore water pressure distribution, it is possible to generate theoretical log10(H2/t) versus U curves where H is the length of the drainage path of a consolidating layer, and t is the time for different known values of the coefficient of consolidation, cν. A method has been developed wherein both the theoretical and experimental behavior of soils during consolidation can be simultaneously compared and studied on the same plot. The experimental log10(H2/t) versus U curves have been compared with the theoretical curves. The deviations of the experimental behavior from the theory are explained in terms of initial compression and secondary compression. Analysis of results indicates that the secondary compression essentially starts from about 60% consolidation. A simple procedure is presented for calculating the value of cv from the δ-t data using log10(H2/t) versus U plot.

Interference of Two Closely Spaced Strip Footings on Sand Using Model Tests

By using small scale model tests, the interference effect on the ultimate bearing capacity of two closely spaced strip footings, placed on the surface of dry sand, was investigated. At any time, the footings were assumed to (1) carry exactly the same magnitude of load; and (2) settle to the same extent. No tilt of the footing was allowed. The effect of clear spacing (s) between two footings was explicitly studied. An interference of footings leads to a significant increase in their bearing capacity; the interference effect becomes even more substantial with an increase in the relative density of sand. The bearing capacity attains a peak magnitude at a certain (critical) spacing between two footings. The experimental observations presented in this technical note were similar to those given by different available theories. However, in a quantitative sense, the difference between the experiments and theories was seen to be still significant and it emphasizes the need of doing a further rigorous analysis in which the effect of stress level on the shear strength parameters of soil mass can be incorporated properly.

A Global Constraint On Relative Rotation To Avoid Lumped Compliant Mechanisms In Topology Optimization

Some of the well known formulations for topology optimization of compliant mechanisms could lead to lumped compliant mechanisms. In lumped compliance, most of the elastic deformation in a mechanism occurs at few points, while rest of the mechanism remains more or less rigid. Such points are referred to as point-flexures. It has been noted in literature that high relative rotation is associated with point-flexures. In literature we also find a formulation of local constraint on relative rotations to avoid lumped compliance. However it is well known that a global constraint is easier to handle than a local constraint, by a numerical optimization algorithm. The current work presents a way of putting global constraint on relative rotations. This constraint is also simpler to implement since it uses linearized rotation at the center of finite-elements, to compute relative rotations. I show the results obtained by using this constraint oil the following benchmark problems - displacement inverter and gripper.

Analysis of a Genomic DNA Expression Library of Mycobacterium tuberculosis Using Tuberculosis Patient Sera: Evidence for Modulation of Host Immune Response

DNA obtained from a human sputum isolate of Mycobacterium tuberculosis, NTI-64719, which showed extensive dissemination in the guinea pig model resulting in a high score for virulence was used to construct an expression library in the lambda ZAP vector. The size of DNA inserts in the library ranged from 1 to 3 kb, and recombinants represented 60% of the total plaques obtained. When probed with pooled serum from chronically infected tuberculosis patients, the library yielded 176 recombinants with a range of signal intensities. Among these, 93 recombinants were classified into 12 groups on the basis of DNA hybridization experiments, The polypeptides synthesized by the recombinants were predominantly LacZ fusion proteins, Serum obtained from patients who were clinically diagnosed to be in the early phase of M. tuberculosis infection was used to probe the 176 recombinants obtained. interestingly, some recombinants that gave very strong signals in the original screen did not react with early-phase serum; conversely, others whose signals were extremely weak in the original screen gave very intense signals with serum from recently infected patients, This indicates the differential nature of either the expression of these antigens or the immune response elicited by them as a function of disease progression.

Nutritional support in children with end-stage liver disease : a randomized crossover trial of a branched-chain amino acid supplement

Malnutrition is common in children with end-stage liver disease (ESLD) awaiting orthotopic liver transplantation (OLT), and nutritional support is assuming an important role in preoperative management. To evaluate preoperative nutritional therapy, 19 children (median age 1.25 y) with ESLD awaiting OLT were prospectively studied. Two high-energy, isoenergetic and isonitrogenous nutritional formulations delivered nasogastrically were compared: a branched-chain amino acid (BCAA)-enriched semielemental formulation and a matched standard semielemental formulation. Twelve of 19 patients completed a randomized controlled study before OLT and 10 of 19 completed a full crossover study. Improvements in weight and height occurred during the BCAA supplements, with no statistical change on the standard formulation. Significant increases in total body potassium, midupper arm circumference, and subscapular skinfold thickness occurred during the BCAA supplements, whereas no significant changes occurred during the standard formulation period. Significantly fewer albumin infusions were required during the BCAA supplement. These findings suggest that BCAA-enriched formulas have advantages over standard semielemental formulas in improving nutritional status in children with ESLD. and are deserving of wider application and study.

A Jacobian-Based Algorithm for Planning Attitude Maneuvers Using Forward and Reverse Rotations

Algorithms for planning quasistatic attitude maneuvers based on the Jacobian of the forward kinematic mapping of fully-reversed (FR) sequences of rotations are proposed in this paper. An FR sequence of rotations is a series of finite rotations that consists of initial rotations about the axes of a body-fixed coordinate frame and subsequent rotations that undo these initial rotations. Unlike the Jacobian of conventional systems such as a robot manipulator, the Jacobian of the system manipulated through FR rotations is a null matrix at the identity, which leads to a total breakdown of the traditional Jacobian formulation. Therefore, the Jacobian algorithm is reformulated and implemented so as to synthesize an FR sequence for a desired rotational displacement. The Jacobian-based algorithm presented in this paper identifies particular six-rotation FR sequences that synthesize desired orientations. We developed the single-step and the multiple-step Jacobian methods to accomplish a given task using six-rotation FR sequences. The single-step Jacobian method identifies a specific FR sequence for a given desired orientation and the multiple-step Jacobian algorithm synthesizes physically feasible FR rotations on an optimal path. A comparison with existing algorithms verifies the fast convergence ability of the Jacobian-based algorithm. Unlike closed-form solutions to the inverse kinematics problem, the Jacobian-based algorithm determines the most efficient FR sequence that yields a desired rotational displacement through a simple and inexpensive numerical calculation. The procedure presented here is useful for those motion planning problems wherein the Jacobian is singular or null.

The nature of malnutrition in children with end-stage liver disease awaiting orthotopic liver transplantation

To evaluate malnutrition in chronic liver disease, and its relationship to nutrient deficiencies and hepatic dysfunction. 27 children with end-stage liver disease were studied. Mean protein-energy intakes were 70% of recommended daily intakes. The patients were underweight and stunted with reduced mean triceps and subscapular skinfold thicknesses and midupper arm circumference. Mean total body potassium was only 63 ± 18% of that expected for age and sex. Deficiency of essential fatty acids (32%), and low concentrations of fat-soluble vitamins (A, 92%; E, 32%), iron (32%), zinc (42%), and selenium (13%) were common. Serum ammonia concentrations were raised in all patients, and increased methionine, tyrosine, and glutamic acid, and reduced glutamine concentrations were noted. There was no correlation between the degree of malnutrition and the degree of liver synthetic function, the degree of cholestasis, or the degree of liver injury. We suggest that potentially correctable factors in addition to liver failure (eg, inadequate absorbed intake) were important determinants of malnutrition in these patients.

Fatigue crack propagation analysis of plaque rupture

Rupture of atheromatous plaque is the major cause of stroke or heart attack. Considering that the cardiovascular system is a classic fatigue environment, plaque rupture was treated as a chronic fatigue crack growth process in this study. Fracture mechanics theory was introduced to describe the stress status at the crack tip and Paris' law was used to calculate the crack growth rate. The effect of anatomical variation of an idealized plaque cross-section model was investigated. The crack initiation was considered to be either at the maximum circumferential stress location or at any other possible locations around the lumen. Although the crack automatically initialized at the maximum circumferential stress location usually propagated faster than others, it was not necessarily the most critical location where the fatigue life reached its minimum. We found that the fatigue life was minimum for cracks initialized in the following three regions: the midcap zone, the shoulder zone, and the backside zone. The anatomical variation has a significant influence on the fatigue life. Either a decrease in cap thickness or an increase in lipid pool size resulted in a significant decrease in fatigue life. Comparing to the previously used stress analysis, this fatigue model provides some possible explanations of plaque rupture at a low stress level in a pulsatile cardiovascular environment, and the method proposed here may be useful for further investigation of the mechanism of plaque rupture based on in vivo patient data.

In vivo mri-based estimation of time-dependent elastic modulus in healthy arteries

The elastic properties of the arterial wall have been the subject of physiological, clinical and biomedical research for many years. There is convincing evidence that the elastic properties of the large arteries are seriously impaired in the presence of cardiovascular disease (CVD), due to alterations in the intrinsic structural and functional characteristics of vessels [1]. Early detection of changes in the elastic modulus of arteries would provide a powerful tool for both monitoring patients at high cardiovascular risk and testing the effects of pharmaceuticals aimed at stabilizing existing plaques by stiffening them or lowering the lipids.

MRI-based measurement of carotid mechanical properties in asymptomatic patients

Arterial mechanical property may be a potential variable for risk stratification. Large artery and central arterial compliance have been shown not only to correlate well with overall cardiovascular outcome in large epidemiological studies [1, 2] but also to correlate with coronary atherosclerotic burden as measured by conventional angiography [3]. Until recently, real-time B-mode ultrasound combined with simultaneous blood pressure measurements have been used to assess large artery compliance [4]. These techniques have an excellent temporal resolution but are unable to provide adequate spatial resolution to determine changes in vessel area as opposed to diameter and make the assumption that the vessel is perfectly round. Attempts to use MR imaging to measure large artery compliance have been published previously [5]. However, they have not utilised simultaneous blood pressure measurements during sequence acquisition. We report a technique using regular and simultaneous blood pressure measurement during 2 dimensional phase contrast magnetic resonance imaging 2DPC-MRI to determine local carotid compliance.

Fluid-structure interaction study on human arterial plaque with patient specific geometry and boundary conditions

Atherosclerotic plaque rupture has been extensively considered as the leading cause of death in western countries. It is believed that high stresses within plaque can be an important factor on triggering the rupture of the plaque. Stress analysis in the coronary and carotid arteries with plaque have been developed by many researchers from 2D to 3-D models, from structure analysis only to the Fluid-Structure Interaction (FSI) models[1].

Stress analysis on human arterial plaques by fluid structure interactions - Multi-case study

Atherosclerotic plaque rupture has been extensively considered as the leading cause of death in the world. It is believed that high stress within plaque can be an important factor which can trigger the rupture of the plaque. High resolution multi-spectral magnetic resonance imaging (MRI) has allowed the plaque components (arterial wall, lipids, and fibrous cap) to be visualized in vivo [1]. The patient specific finite element model can be generated from the image data to perform stress analysis and provide critical information on understanding plaque rupture mechanisms [2]. The present work is to apply the procedure to a total of 14 patients (S1 ∼ S14), to study the stress distributions on carotid artery plaque reconstructed from multi-spectral magnetic resonance images, and the possible relationships between stress and plaque burdens.

Hydrodynamic Pressure on a Dam During Earthquakes

A straightforward analysis involving Fourier cosine transforms and the theory of Fourier seies is presented for the approximate calculation of the hydrodynamic pressure exerted on the vertical upstream face of a dam due to constant earthquake ground acceleration. The analysis uses the “Parseval relation” on the Fourier coefficients of square integrable functions, and directly brings out the mathematical nature of the approximate theory involved.