Full Spectrum of Postnatal Tooth Phenotypes in a Novel Irf6 Cleft Lip Model.

Clefting of the lip, with or without palatal involvement (CLP), is associated with a higher incidence of developmental tooth abnormalities, including hypodontia and supernumerary teeth, aberrant crown and root morphologies, and enamel defects, although the underlying mechanistic link is poorly understood. As most CLP genes are expressed throughout the oral epithelium, the authors hypothesized that the expression of CLP genes may persist in the dental epithelium and thus, in addition to their earlier role in labiopalatine development, may play an important functional role in subsequent tooth patterning and amelogenesis. To address this, the authors generated a unique conditional knockout model involving the major CLP gene, Irf6, that overcomes the previously reported perinatal lethality to enable assessment of any posteruption dental phenotypes. A dental epithelium-specific Irf6 conditional knockout (Irf6-cKO) mouse was generated via a Pitx2-Cre driver line. Dental development was analyzed by microcomputed tomography, scanning electron microscopy, histology, immunohistochemistry, and quantitative polymerase chain reaction. Irf6-cKO mice displayed variable hypodontia, occasional supernumerary incisors and molars, as well as crown and root patterning anomalies, including peg-shaped first molars and taurodontic and C-shaped mandibular second molars. Enamel density was reduced in preeruption Irf6-cKO mice, and some shearing of enamel rods was noted in posteruption incisors. There was also rapid attrition of Irf6-cKO molars following eruption. Histologically, Irf6-cKO ameloblasts exhibited disturbances in adhesion and polarity, and delayed enamel formation was confirmed immunohistochemically. Altered structure of Hertwig's epithelial root sheath was also observed. These data support a role for IRF6 in tooth number, crown and root morphology and amelogenesis that is likely due to a functional role of Irf6 in organization and polarity of epithelial cell types. This data reinforce the notion that various isolated tooth defects could be considered part of the CLP spectrum in relatives of an affected individual.

Mutant Cu/Zn-superoxide dismutase proteins have altered solubility and interact with heat shock/stress proteins in models of amyotrophic lateral sclerosis.

Mutations in the Cu/Zn-superoxide dismutase (SOD-1) gene are responsible for a familial form of amyotrophic lateral sclerosis. In humans and experimental models, death of motor neurons is preceded by formation of cytoplasmic aggregates containing mutant SOD-1 protein. In our previous studies, heat shock protein 70 (HSP70) prolonged viability of cultured motor neurons expressing mutant human SOD-1 and reduced formation of aggregates. In this paper, we report that mutant SOD-1 proteins have altered solubility in cells relative to wild-type SOD-1 and can form a direct association with HSP70 and other stress proteins. Whereas wild-type human and endogenous mouse SOD-1 were detergent-soluble, a portion of mutant SOD-1 was detergent-insoluble in protein extracts of NIH3T3 transfected with SOD-1 gene constructs, spinal cord cultures established from G93A SOD-1 transgenic mouse embryos, and lumbar spinal cord from adult G93A transgenic mice. A direct association of HSP70, HSP40, and alphaB-crystallin with mutant SOD-1 (G93A or G41S), but not wild-type or endogenous mouse SOD-1, was demonstrated by coimmunoprecipitation. Mutant SOD-1.HSP70 complexes were predominantly in the detergent-insoluble fraction. However, only a small percentage of total cellular mutant SOD-1 was detergent-insoluble, suggesting that mutation-induced alteration of protein conformation may not in itself be sufficient for direct interaction with heat shock proteins.

Event-related potentials as a function of movement parameter variations during motor imagery and isometric action.

Neuroimaging and electrophysiological studies have shown that executed action and motor imagery activate common neuronal substrates, leading to the hypothesis that movement preparation and motor imagery are functionally equivalent processes. This study further tested the functional equivalence hypothesis by determining whether electrocortical patterns associated with variations in motor control parameters are similar during imagined and executed actions. Event-related potentials (ERPs) were recorded from the supplementary motor/premotor area (SMA/PMA; FCz site) and primary motor area (M1; C3, C4 sites) during an executed and an imagined, cued, discrete isometric contraction task while target force (TF; low, moderate) and rate of force development (RFD; slow, rapid) were varied. For M1, the correlation of ERPs between moderate- and low force-executions was near zero and N2 amplitude was greater for moderate than low force executions, indicating that M1 activity is related to TF. Rapid executions were greater in amplitude and longer in latency than slow executions and the ERPs for rapid- and slow-executions were negatively correlated, indicating that M1 activity is also related to RFD. There were no differences in N2 amplitude and a zero correlation between execution and imagined actions of similar TF and RFD, indicating that neither TF or RFD are represented in M1 activity during imagery. For SMA/PMA, there was a moderate correlation between moderate- and low force-executions and larger N2 amplitude for moderate- than for low force-executions, indicating that TF may be related to SMA/PMA electrocortical activity. ERP patterns were uncorrelated between rapid- and slow-execution at FCz, but N2 amplitude was the same, making it unclear whether the RFD parameter is represented in FCz activity. The correlational and N2 amplitude analyses demonstrate that patterns of electrocortical activity at SMA/PMA are nearly isomorphic during executed and imagined actions as TF and RFD are varied. These results provide evidence that patterns of electrocortical activity associated with variations in the parameters of executed action are similar during motor imagery at SMA/PMA but not at M1.

Cortical potentials during imagined movements in individuals with chronic spinal cord injuries.

A closed-loop model of motor control predicts that central deafferentation should disrupt cortical motor processes when imagining movements of paralyzed limbs. To test this prediction, event-related potentials (ERP) were recorded from the supplementary motor area and the primary sensorimotor area in individuals with paraplegia or quadriplegia as well as able-bodied controls during executed/attempted and imagined movements of the hand and foot. The cross-correlation of ERPs generated during hand movement and imagery was slightly negative for controls, moderate and positive for paraplegics, and high and positive for quadriplegics. The cross-correlation between foot movement and imagery was moderate for controls, moderate to high for paraplegic and high for quadriplegic groups. For hand tasks, ERPs were uncorrelated between controls and quadriplegics; for the foot tasks, the correlations were low between controls and both paraplegics and quadriplegics. Amplitudes and latencies of the ERP were also compared between movement and imagery and between the three injury groups. A biphasic waveform appears prior to and during movements in controls that is absent during imagery and when attempting/imagining movements of paralyzed limbs. Two hypotheses are proposed to explain the differences in cortical processing between movement and imagery and between injury groups. First, cortical motor processes are altered by the absence of kinesthetic feedback during attempted movement of a deafferented limb as well as during imagery. Second, inhibitory processes, present during imagined movements of an intact limb, may be weakened by a spinal cord injury (SCI) so that movement and imagery processes appear isomorphic. While the absence of kinesthetic feedback from deafferented limbs likely contributes to some variability in motor processing, the influence of an SCI on movement inhibition requires further testing.

Physical performance measures that predict faller status in community-dwelling older adults.

Falls are a leading cause of fatal and nonfatal injuries among the elderly. Accurate determination of risk factors associated with falls in older adults is necessary, not only for individual patient management, but also for the development of fall prevention programs. The purpose of this study was to evaluate the effectiveness of clinical measures, such as the one-legged stance test (OLST), sit-to-stand test (STST), manual muscle tests (MMT), and response speed in predicting faller status in community-dwelling older adults (N = 94, age 60-89 years). The variables assessed were single-leg standing (as measured by OLST), STST, and MMT of 12 different muscle groups (hip flexors, hip abductors, hip adductors, knee flexors, knee extensors, ankle dorsiflexors, ankle plantarflexors, shoulder flexors, shoulder abductors, elbow flexors, elbow extensors, and finger flexors), and speed of response (as measured by a visual hand reaction and movement time task). Of the 94 older adults assessed, 28 (29.7%) reported at least one fall within the previous year. The discriminant analysis revealed that there were six variables that significantly discriminated between fallers and nonfallers. These variables included MMT of the ankle dorsiflexors, knee flexors, hip abductors, and knee extensors, as well as time on the OLST and the STST. The results indicate that simple clinical measures of musculoskeletal function can discriminate fallers from nonfallers in community-dwelling older adults. J Orthop Sports Phys Ther 1992;16(3):123-128.