[Analysis of a pedigree with inherited factor V deficiency caused by compound heterozygous mutation].

Objective: To explore the molecular pathogenesis of a family with hereditary factor Ⅴ (FⅤ) deficiency. Methods: All the exons, flanking sequences, 5' and 3' untranslated regions of the F5 of the proband, and the corresponding mutation sites of the family members were analyzed via direct DNA sequencing. The CAT measurement was used to detect the amount of thrombin produced. The ClustalX software was used to analyze the conservation of mutation sites. The online bioinformatics software, Mutation Taster, PolyPhen-2, PROVEAN, LRT, and SIFT were applied to predict the effects of mutation sites on protein function. The Swiss-PdbViewer software was used to analyze the changes in the protein model and intermolecular force before and after amino acid variation. Results: The proband had a heterozygous missense mutation c.1258G>T (p.Gly392Cys) in exon 8 of the F5, and a heterozygous deletion mutation c.4797delG (p.Glu1572Lys fsX19) in exon 14, which results in a frameshift and produces a truncated protein. Her grandfather and father had p.Gly392Cys heterozygous variation, whereas her maternal grandmother, mother, little aunt, and cousin all had p.Glu1572LysfsX19 heterozygous variation. The ratio of proband's thrombin generation delay to peak time was significantly increased. Conservation analysis results showed that p.Gly392 was located in a conserved region among the 10 homologous species. Five online bioinformatics software predicted that p.Gly392Cys was pathogenic, and Mutation Taster also predicted p.Glu1572Lys fsX19 as a pathogenic variant. Protein model analysis showed that the replacement of Gly392 by Cys392 can lead to the extension of the original hydrogen bond and the formation of a new steric hindrance, which affected the stability of the protein structure. Conclusion: The c.1258G>T heterozygous missense mutation in exon 8 and the c.4797delG heterozygous deletion mutation in exon 14 of the F5 may be responsible for the decrease of FⅤ levels in this family.

Prediction of biomechanical parameters in the lumbar spine during static sagittal plane lifting.

A combined approach involving optimization and the finite element technique was used to predict biomechanical parameters in the lumbar spine during static lifting in the sagittal plane. Forces in muscle fascicles of the lumbar region were first predicted using an optimization-based force model including the entire lumbar spine. These muscle forces as well as the distributed upper body weight and the lifted load were then applied to a three-dimensional finite element model of the thoracolumbar spine and rib cage to predict deformation, the intradiskal pressure, strains, stresses, and load transfer paths in the spine. The predicted intradiskal pressures in the L3-4 disk at the most deviated from the in vivo measurements by 8.2 percent for the four lifting cases analyzed. The lumbosacral joint flexed, while the other lumbar joints extended for all of the four lifting cases studied (rotation of a joint is the relative rotation between its two vertebral bodies). High stresses were predicted in the posterolateral regions of the endplates and at the junctions of the pedicles and vertebral bodies. High interlaminar shear stresses were found in the posterolateral regions of the lumbar disks. While the facet joints of the upper two lumbar segments did not transmit any load, the facet joints of the lower two lumbar segments experienced significant loads. The ligaments of all lumbar motion segments except the lumbosacral junction provided only marginal moments. The limitations of the current model and possible improvements are discussed.

Effects of muscle dysfunction on lumbar spine mechanics. A finite element study based on a two motion segments model.

STUDY DESIGN: A combined finite element and optimization approach was developed to investigate the clinically relevant biomechanical parameters of the muscular lumbar spine under five quasistatic back-lifting conditions. OBJECTIVES: To quantify the effects of muscle "dysfunction" on the mechanical behavior of the lumbar spine. SUMMARY OF BACKGROUND DATA: Trunk muscles have been proven to play an important role in the normal functioning of the spine. Although passive structures of the spine are believed to be subjected increasingly to mechanical stresses when muscular support is inadequate, supportive quantitative data have been lacking. METHODS: External loads at L3-L4 for various lifting tasks were estimated experimentally and partitioned to the disc and muscles across the L3-L4 segment using an optimization scheme. These forces were incorporated into a finite element model of the ligamentous L3-L5 lumbar spine. Muscle "dysfunction" was simulated by decreasing the computed muscle forces. RESULTS: The range of motion intradiscal pressure forces in ligaments, and load across facets increased nonlinearly with the increases in trunk flexion and the load held in hands. At higher loads or at larger flexed postures, muscles were found to play a more crucial role in stabilizing the spine compared with the passive structures. Muscle "dysfunction" destabilized the spine, reduced the role of facet joints in transmitting load, and shifted loads to the discs and ligaments. CONCLUSIONS: Muscle dysfunction disturbs the normal functioning of other spinal components and may cause spinal disorders.

Finite element methods in spine biomechanics research.

The finite element method has been used in spine biomechanics research for nearly a quarter of a century. Recent developments have made it possible to simulate a variety of clinically relevant situations in an increasingly realistic manner, elevating the finite element method into a fully complementary partnership with experimental approaches for the investigation of clinical problems in the spine. These new developments are presented in a historical context to evaluate their potential impact on future spine biomechanics research.