A novel stability and kinematics-driven trunk biomechanical model to estimate muscle and spinal forces

An anatomically detailed eighteen-rotational-degrees-of-freedom model of the human spine using optimization constrained to equilibrium and stability requirements is developed and used to simulate several symmetric tasks in upright and flexed standing postures. Predictions of this stability and kinematics-driven (S + KD) model for trunk muscle forces and spine compressive/shear loads are compared to those of our existing kinematics-driven (KD) model where both translational and rotational degrees-of-freedom are included but redundancy is resolved using equilibrium conditions alone. Unlike the KD model, the S + KD model predicted abdominal co-contractions that, in agreement with electromyography data, increased as lifting height increased at a constant horizontal moment arm. The S + KD model, however, could not fully explain the CNS strategy in activating antagonistic muscles for most of the remaining tasks. Despite quite distinct activities in individual muscles, both models predicted L4-L5 intradiscal pressure that matched the in vivo data, the L4-S1 compression loads, and the sum of all trunk muscle forces. For modeling applications in ergonomics, where the compressive spine loads are of interest, the two models yielded <15% difference. In the field of rehabilitation, where detailed muscle forces are required, the S + KD model explained more properly the CNS strategy in activating the antagonistic muscles for some tasks.     

Effects of predictive mechanisms on head stability during forward trunk perturbation

While much is known about reflex and mechanical contributions to the control of head stability, little is known about predictive control. The goal of this experiment was to determine the contribution of predictive mechanisms to head stability in space, in the pitch plane, during forward trunk perturbations. Eleven standing healthy subjects had their trunk pulled forward by a load-pulley apparatus. The perturbation was either self-triggered or imposed (triggered by the experimenter). Subjects were exposed to two loads: 2% and 4% of their body weight. The contributions of torques acting on the head-neck system were inferred from head and trunk kinematics, neck muscle EMG, and the torques acting on the head, which were computed using inverse dynamics. The results showed that both the head and trunk moved less during the self-triggered than imposed condition during both loads for most of the participants. There was no evidence of predictive neck countertorque or increased neck muscle co-contraction during the self-triggered condition. These findings suggest that most of the subjects improved head stability in the self-triggered condition by reducing trunk motion and the associated interactive torque that perturbed the head. Electronic Publication     

Network and intrinsic contributions to carbachol-induced oscillations in the rat subiculum

Low-frequency network oscillations occur in several areas of the limbic system where they contribute to synaptic plasticity and mnemonic functions that are in turn modulated by cholinergic mechanisms. Here we used slices of the rat subiculum (a limbic area involved in cognitive functions) to establish how network and single neuron (intrinsic) membrane mechanisms participate to the rhythmic oscillations elicited by the cholinergic agent carbachol (CCh, 50-100 microM). We have found that CCh-induced network oscillations (intraoscillatory frequency = 5-16 Hz) are abolished by an antagonist of non-N-methyl-D-aspartate (NMDA) glutamatergic receptors (n = 6 slices) but persist during blockade of GABA receptors (n = 16). In addition, during application of glutamate and GABA receptor antagonists, single subicular cells generate burst oscillations at 2.1-6.8 Hz when depolarized with steady current injection. These intrinsic burst oscillations disappear during application of a Ca(2+) channel blocker (n = 6 cells), intracellular Ca(2+) chelation (n = 6), or replacement of extracellular Na(+) (n = 4) but persist in recordings made with electrodes containing a blocker of voltage-gated Na(+) channels (n = 7). These procedures cause similar effects on CCh-induced depolarizing plateau potentials that are contributed by a Ca(2+)-activated nonselective cationic conductance (I(CAN)). Network and intrinsic oscillations along with depolarizing plateau potentials were abolished by the muscarinic receptor antagonist atropine. In conclusion, our findings demonstrate that low-frequency oscillations in the rat subiculum rely on the muscarinic receptor-dependent activation of an intrinsic oscillatory mechanism that is presumably contributed by I(CAN) and are integrated within the network via non-NMDA receptor-mediated transmission.     

Subjective well-being: genetic and environmental contributions to stability and change

BACKGROUND: Previous cross-sectional studies have found substantial genetic influences on individual variation in subjective well-being (SWB), and evidence for sex-specific genetic effects has been reported. However, the genetic and environmental influences on stability and change in SWB over time are largely unexplored. METHOD: Questionnaire data on SWB from a population-based sample of Norwegian twins born 1967 to 1979, initially surveyed in 1992 (T1) and re-surveyed in 1998 (T2), were analysed using structural equation modelling to explore the relative effects of genetic and environmental influences on phenotypic stability and change. RESULTS: The phenotypic cross-time correlations for SWB were 0.51 and 0.49 for males and females respectively. The best-fitting longitudinal model specified only additive genetic and individual environmental effects with qualitative and quantitative sex-specific genetic influences. For both males and females, the additive genetic factors influencing SWB were largely stable, although some time-specific genetic contributions were indicated. Cross-time correlations for genetic effects were 0.85 and 0.78 for males and females respectively. The individual environmental influences were primarily time-specific. Additive genetic effects explained approximately 80% of the phenotypic cross-time correlation. For females, the magnitude of the additive genetic effects decreased significantly from T1 to T2, whereas for males, the estimates generally remained unchanged. CONCLUSIONS: For both males and females, long-term stability of SWB was mainly attributable to stable additive genetic factors, whereas susceptibility to change was mostly related to individual environmental factors. However, both stable environmental contributions and emerging genetic influences were indicated.     

Deciphering complement mechanisms: the contributions of structural biology

Since the resolution of the first three-dimensional structure of a complement component in 1980, considerable efforts have been put into the investigation of this system through structural biology techniques, resulting in about a hundred structures deposited in the Protein Data Bank by the beginning of 2007. By revealing its mechanisms at the atomic level, these approaches significantly improve our understanding of complement, opening the way to the rational design of specific inhibitors. This review is co-authored by some of the researchers currently involved in the structural biology of complement and its purpose is to illustrate, through representative examples, how X-ray crystallography and NMR techniques help us decipher the many sophisticated mechanisms that underlie complement functions.     

Pronephric duct extension in amphibian embryos: migration and other mechanisms.

Initiation of excretory system development in all vertebrates requires (1) delamination of the pronephric and pronephric duct rudiments from intermediate mesoderm at the ventral border of anterior somites, and (2) extension of the pronephric duct to the cloaca. Pronephric duct extension is the central event in nephric system development; the pronephric duct differentiates into the tubule that carries nephric filtrate out of the body and induces terminal differentiation of adult kidneys. Early studies concluded that pronephric ducts formed by means of in situ segregation of pronephric duct tissue from lateral mesoderm ventral to the forming somites; more recent studies highlight caudal migration of the pronephric duct as the major morphogenetic mechanism. The purpose of this review is to provide the historical background on studies of the mechanisms of amphibian pronephric duct extension, to review evidence showing that different amphibians perform pronephric duct morphogenesis in different ways, and to suggest future studies that may help illuminate the molecular basis of the mechanisms that have evolved in amphibians to extend the pronephric duct to the cloaca.     

Task specificity in the control of intrinsic trunk muscles in man

The human trunk is a complex mechanical system comprised of large and small segments interconnected with several layers of muscles. An accurate control of this system is important during a variety of everyday tasks such as voluntary movements of the trunk, walking and running. This study was designed to investigate the interaction between muscles controlling the pelvis and the trunk during a variety of movements requiring a finely tuned coordination. Four subjects carried out seven different forms of fast oscillatory movements of the pelvis and trunk in the sagittal and transverse planes. Electromyographical activity (EMG) was recorded with surface electrodes from the abdominal muscles rectus abdominis (RA), obliquus externus (OE), obliquus internus (OI), and erector spinae (ES), from the hip flexor muscle rectus femoris (RF), the hip extensor muscle gluteus maximus (GM) and from the hip extensor/knee flexor muscles of the hamstrings group (HAM). Movements were recorded with an optoelectronic system (Selspot). The results indicate that during spontaneous flexion-extension movements of the trunk there was a basic alternating activation between a pure flexor (RF-RA-OE-OI) and an extensor synergy (ES-GM-HAM). Different mixed synergies appeared when more specific patterns of coordination of the pelvis and spine were performed. For example, during pelvic tilts in the sagittal plane, RA-OE-OI-GM formed a synergy which was activated reciprocally with ES. The neural circuitry controlling muscles of the pelvis and trunk is apparently adaptable to a variety of different tasks. Individual muscles were shown to either cause, brake or prevent a movement and to be integrated in several different task-specific motor synergies.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy

Summary: Establishing a balance between the rapid generation of effective immunity and the production of overly exuberant or excessively prolonged responses is critical to the maintenance of the equilibrium between health and disease. The preservation of homeostasis and prevention of inappropriate activation of immunity is safeguarded by systems integrating the influences of T-cell receptor signaling, pro-inflammatory danger signals, and positive costimulatory signals on the one hand with those of several layers of both cell-intrinsic and cell-extrinsic inhibitory checkpoints on the other. Evolution has thus provided an immunological system capable of clearance of pathogens and infected cells but which generally avoids the severe collateral damage that is associated with failure to control immunity. Central tolerance to self-antigens constitutes the first line of defense against self-destruction. Because central tolerance mechanisms fail to eliminate all self-reactive immune effector cells, other immune-regulating (peripheral tolerance) mechanisms are required to prevent excessive immune responses. Dysfunction of these inhibitory pathways in terms of reduced activity can result in the unmasking of self-directed responses and a variety of autoimmune morbidities. Conversely, enhanced inhibitory activity can restrict the generation of clinically useful immunity to cancers and to chronic infectious pathogens. This may manifest not only as inhibition of immunity directed towards what are largely aberrantly or overexpressed ‘self’ targets on malignant cells but also additional exaggeration of inhibitory pathway activity mediated via upregulation on tumor cells or stromal tissues of the ligands for inhibitory receptors expressed by lymphocytes. The selective pressures exerted by immuno-editing will favor the outgrowth of such immuno-evasive malignant clones. These pathways therefore represent significant hurdles to the generation of therapeutic anti-cancer responses. The most active of the T-cell intrinsic inhibitory pathways belong to the immunoglobulin superfamily, which occupies a central importance in the coordination of immune responses. The CD28/cytotoxic T-lymphocyte antigen-4 (CTLA-4):B7-1/B7-2 receptor/ligand grouping represents the archetypal example of these immune regulators. Therapies aimed at overcoming these mechanisms of peripheral tolerance, in particular by blocking the inhibitory checkpoints, offer the potential to generate anti-tumor activity, either as monotherapies or in synergism with other therapies that directly or indirectly enhance presentation of tumor epitopes to the immune system.     

Deciphering complement mechanisms: The contributions of structural biology

Since the resolution of the first three-dimensional structure of a complement component in 1980, considerable efforts have been put into the investigation of this system through structural biology techniques, resulting in about a hundred structures deposited in the Protein Data Bank by the beginning of 2007. By revealing its mechanisms at the atomic level, these approaches significantly improve our understanding of complement, opening the way to the rational design of specific inhibitors. This review is co-authored by some of the researchers currently involved in the structural biology of complement and its purpose is to illustrate, through representative examples, how X-ray crystallography and NMR techniques help us decipher the many sophisticated mechanisms that underlie complement functions.     

Vestibular contributions to gaze stability during transient forward and backward motion

The accuracy with which the vestibular system anticipates and compensates for the visual consequences of translation during forward and backward movements was investigated with transient motion profiles in rhesus monkeys trained to fixate targets on an isovergence screen. Early during motion when visuomotor reflexes remain relatively ineffective and vestibular-driven mechanisms have an important role for controlling the movement of the eyes, a large asymmetry was observed for forward and backward heading directions. During forward motion, ocular velocity gains increased steeply and reached near unity gains as early as 40-50 ms after motion onset. In addition, instantaneous directional errors also remained <10 degrees for forward headings. In contrast, backward motion was characterized by smaller vestibular gains and larger directional errors during the first 70 ms of the movement. To evaluate the accumulated retinal slip and vergence errors during the early epochs of motion when vestibular-driven mechanisms dominate gaze stability, the movement of a virtual fixation point defined by the intersection of the two gaze lines was quantitatively compared with the respective movement of the extinguished target in head coordinates. Both conjugate retinal slip and vergence errors were <0.2 degrees during the first 70 ms of the movement, with forward motion conjugate errors typically being smaller as compared with backward motion directions. Thus vestibularly driven gaze stabilization mechanisms can effectively minimize conjugate retinal slip errors as well as keep binocular disparity errors low during the open loop interval of head movement.     

Isoresistive dynamometer measurement of trunk muscle velocity at different angular phases of flexion and extension.

Isoresistive trunk muscle dynamometer is a potentially useful piece of equipment in evaluation of trunk muscle velocity, but to date, studies analysing the possibilities and limitations of such measurements are scarce. The aim of this study was to analyse the trunk muscle velocity in repetitive flexion and extension movements at three different angular phases, using an isoresistive trunk muscle dynamometer, and to assess the reliability of the measurements. The study population consisted of 120 healthy, sedentary men and women who volunteered for the study. The measurements were carried out before and after a 22-week training intervention programme. The results show that the peak velocities of the phases between 15 and 35 degrees in flexion and 20-0 degrees in extension (i.e. the second phases) correlated highly (r=0.99 in flexion and in extension) with the peak velocity of the whole movement ranging from -5 to 55 degrees in flexion and 40 to -20 degrees in extension. Correlations were high, both before and after the intervention. The LISREL model analysis showed high reliability of measurement for the second angular phases (in flexion and extension). According to the model, the correlation between the first and second measurement (with a 22-week training intervention in between) was 0.78 in flexion and 0.81 in extension. In conclusion, the angular phases from 15 to 35 degrees in flexion and from 20 to 0 degrees in extension represent the peak velocity of the whole movement. Negative residual correlations between the first and last angular phases in the LISREL model reflect the way of performing the movement: the faster the start the slower the end, and vice versa.     

Contribution of intrinsic properties and synaptic inputs to motoneuron discharge patterns: a simulation study

Motoneuron discharge patterns reflect the interaction of synaptic inputs with intrinsic conductances. Recent work has focused on the contribution of conductances mediating persistent inward currents (PICs), which amplify and prolong the effects of synaptic inputs on motoneuron discharge. Certain features of human motor unit discharge are thought to reflect a relatively stereotyped activation of PICs by excitatory synaptic inputs; these features include rate saturation and de-recruitment at a lower level of net excitation than that required for recruitment. However, PIC activation is also influenced by the pattern and spatial distribution of inhibitory inputs that are activated concurrently with excitatory inputs. To estimate the potential contributions of PIC activation and synaptic input patterns to motor unit discharge patterns, we examined the responses of a set of cable motoneuron models to different patterns of excitatory and inhibitory inputs. The models were first tuned to approximate the current- and voltage-clamp responses of low- and medium-threshold spinal motoneurons studied in decerebrate cats and then driven with different patterns of excitatory and inhibitory inputs. The responses of the models to excitatory inputs reproduced a number of features of human motor unit discharge. However, the pattern of rate modulation was strongly influenced by the temporal and spatial pattern of concurrent inhibitory inputs. Thus, even though PIC activation is likely to exert a strong influence on firing rate modulation, PIC activation in combination with different patterns of excitatory and inhibitory synaptic inputs can produce a wide variety of motor unit discharge patterns.     

Nationwide epidemic of septicemia caused by contaminated intravenous products: mechanisms of intrinsic contamination.

Between 1 July 1970 and April 1971, in many hospitals in this country, there were outbreaks of nosocomial septicemia caused by Enterobacter cloacae of E. agglomerans (formerly Erwinia, herbicola-lathyri). All of these hospitals used infusion products manufactured by one company, Abbott Laboratories, and all affected patients had onset of septicemia while receiving the company's infusion products. Septicemia was epidemiologically and microbiologically traced to intrinsic contamination of the company's screw-cap closure for infusion bottles which was sealed with a newly introduced elastomer liner. Epidemic organisms were isolated from these closures. Investigations both in the laboratory and in the manufacturing plant into the mechanism of contamination of these products revealed the following. (i) Epidemic strains were present in numerous areas throughout the manufacturing plants. (ii) Viable microorganisms gained access to the interior of screw-cap closures after the autoclave step of production. (iii) Cooling closures actively drew moisture through the thread interstices into the inner-most depths of the closure. (iv) Transfer of contaminants from closures to fluid was easily effected by simple manipulations duplicating normal in-hospital use. (v) The red-rubber liner used in the company's screw-cap closures before the introduction of elastomer contained a broad-spectrum antimicrobial inhibitor. The findings from this epidemic and the associated studies show that the screw-cap closure as it is now designed cannot be considered secure for products that must remain sterile.     

Tobacco mosaic virus replicase-mediated cross-protection: contributions of RNA and protein-derived mechanisms

Specific sequences of the tobacco mosaic virus (TMV) RNA-dependent RNA-polymerase (RdRp) gene were investigated for their ability to confer cross-protection. Nine overlapping segments ranging from 713 to 1070 nucleotides in length and covering the methyltransferase, helicase, and polymerase (POL) domains of the TMV RdRp open reading frame were systemically expressed in Nicotiana benthamiana using a potato X virus (PVX) vector [Chapman, S., Kavanagh, T., and Baulcombe, D. C. (1992). Plant J., 1, 549-557]. PVX-infected plants were subsequently challenge inoculated with 10 microg of wild-type TMV and monitored for TMV accumulation. Mock inoculated plants and plants preinfected with the unmodified PVX vector rapidly accumulated high levels of challenge virus. In contrast, plants preinfected with PVX vectors expressing segments of the TMV RdRp open reading frame displayed either high or low levels of protection. High protection levels were observed for PVX constructs expressing segments of the TMV POL domain, whereas low protection levels were observed for PVX constructs expressing segments covering the methyltransferase and helicase domains. Frameshift mutations that blocked protein expression from RdRp segments disrupted only the high levels of protection derived from POL segments and not the low levels derived from the other segments. However, all RdRp segments conferred similarly high levels of protection against a TMV construct with restricted local movement. Thus both RNA and protein sequences in conjunction with the speed of the infecting challenge virus can affect the protection derived from the TMV RdRp gene.