The development of asymmetry: the sidedness of drug-induced limb abnormalities is reversed in situs inversus mice

We are studying the development of handedness, in particular the relationships between handed structures with bilateral symmetry, for example the limbs, and those with lateral asymmetry, such as the heart, lungs and gut. Asymmetric (unilateral) developmental limb abnormalities can be induced by chemical treatment of mouse embryos, either in utero by acetazolamide, or in culture by misonidazole. We have examined these effects in mice homozygous for the iv gene. The development of bilateral symmetry in iv/iv mice is normal, but the control of asymmetry appears to be random, that is 50% develop normally (situs solitus), 50% with laterally inverted viscera (situs inversus). We find that the handedness of induced asymmetric limb defects is highly correlated with embryonic visceral situs. Right limb defects are induced in situs solitus embryos, left-sided defects in situs inversus. This suggests that the mechanism of induction of asymmetric defects is not related to any intrinsic difference between the development of left and right limbs, but is connected to visceral asymmetry. In addition, the high correlation of limb defects with situs was observed in culture as well as in utero suggesting that the maternal environment plays no role in the development of asymmetry.     

Right-left symmetry preservation by flowers of malvaceae family

The flowers of malvaceae family preserves the symmetry between right and left in a peculiar manner. Plots belonging to this family bear two kinds of flowers, right-handed flowers with anticlockwise twisted petals and left-handed flowers with clockwise twisted petals. The branches of the plant prefers production of one type of flowers in excess of the other. There are two distinct types of branches, dextral branches and sinistral branches. Dextral (sinistral) branches produce more right-handed (left-handed) flowers than left-handed (right-handed) flowers. The average percentage of right-handed flowers in a dextral branch is same as that of left-handed flowers in a sinistral branch.     

Handedness in comparison with the asymmetry of the upper extremities]

In 1990 221 males (88 children, age 3.5-7.25 years and 133 adults, age 20-44 years) were investigated. The sample was divided into two groups based on handedness; 140 individuals were right-handed and 81 left-handed. 10 measurements were taken at the upper limbs. In addition, marked handedness, handclasping and armfolding were determined. The last three traits showed no statistically significant connection. It was determined that measurements of length, breadth and circumference are more often significantly asymmetric in favor of the right side in right-handers than in left-handers. Further, skinfolds of right-handed individuals are larger on the left side. Partially reverse results were found for left-handers as a whole, however, the results are more irregular. A difference in the degree of asymmetry exists between children and adults. Asymmetries of breadth and circumference measurements as well as forearm skinfold are larger in adults. Taking into account the error of measurement, frequencies of R > L, R = L and L > R for right- and left-handed individuals were evaluated using the chi 2-test for significance. Preponderance of measurements on the dominant side could often be secured statistically.     

Limb bone bilateral asymmetry: variability and commonality among modern humans

Humans demonstrate species-wide bilateral asymmetry in long bone dimensions. Previous studies have documented greater right-biases in upper limb bone dimensions--especially in length and diaphyseal breadth--as well as more asymmetry in the upper limb when compared with the lower limb. Some studies have reported left-bias in lower limb bone dimensions, which, combined with the contralateral asymmetry in upper limbs, has been termed "crossed symmetry." The examination of sexual dimorphism and population variation in asymmetry has been limited. This study re-examines these topics in a large, geographically and temporally diverse sample of 780 Holocene adult humans. Fourteen bilateral measures were taken, including maximum lengths, articular and peri-articular breadths, and diaphyseal breadths of the femur, tibia, humerus, and radius. Dimensions were converted into percentage directional (%DA) and absolute (%AA) asymmetries. Results reveal that average diaphyseal breadths in both the upper and lower limbs have the greatest absolute and directional asymmetry among all populations, with lower asymmetry evident in maximum lengths or articular dimensions. Upper limb bones demonstrate a systematic right-bias in all dimensions, while lower limb elements have biases closer to zero %DA, but with slight left-bias in diaphyseal breadths and femoral length. Crossed symmetry exists within individuals between similar dimensions of the upper and lower limbs. Females have more asymmetric and right-biased upper limb maximum lengths, while males have greater humeral diaphyseal and head breadth %DAs. The lower limb demonstrates little sexual dimorphism in asymmetry. Industrial groups exhibit relatively less asymmetry than pre-industrial humans and less dimorphism in asymmetry. A mixture of influences from both genetic and behavioral factors is implicated as the source of these patterns.     

Dependence of the organization of human brain electrical activity on hemispheric dominance

In healthy subjects, in a state of relative rest, with different individual profiles of asymmetry (20 right-handed and 10 left-handed subjects), a greater conjunction of electrical brain processes (estimated by mean EEG coherence levels) has been found in the dominant hemisphere as compared to the subdominant one, more distinctly expressed in the right-handed subjects. The maximum degree of interhemispheric asymmetry of the EEG coherence is observed in the posterior associative cortical areas. Specific interhemispheric theta-range differences are revealed as compared with other EEG frequency bands. Greater values are obtained of the correlation of the EEG symmetrical hemispheres points in the whole frequency band and in alpha- and beta-ranges in the right-handed subjects than in the left-handed ones.     

The effects of total ankle arthroplasty on postural stability and loading symmetry in quiet stance

Ankle osteoarthritis is a debilitating condition affecting about 1% of the population with approximately 50,000 new instances annually. One treatment is total ankle arthroplasty (TAA), however, its effects on balance are not well understood. This study analyzed balance over a two-year period following TAA. 408 subjects (177 left, 231 right ankles) diagnosed with end-stage ankle osteoarthritis performed quiet standing trials while center of pressure (COP) data were collected. Data were compared across three time points (pre-op, 1-year, and 2-years post-op) and between surgical and non-surgical limbs using a linear mixed model with significance set at P = 0.05. COP excursions in the feet-together condition were not significantly different between limbs after 2 years in anteroposterior or mediolateral directions (P = 0.06, 0.08) after being significantly different between limbs in the anteroposterior (P = 0.014) and mediolateral direction (P < 0.001) pre-op. The vertical ground reaction force significantly decreased across time in the non-surgical limb, while reciprocally increasing in the surgical limb (P < 0.001). After 2 years, no significant difference in vertical ground reaction force between limbs existed (P = 0.20). Limb asymmetry indices decreased at each time point in both conditions (all P < 0.001) and were not significantly different from zero after 2 years in the feet-together condition (P = 0.290). In conclusion, surgical limb balance improved compared to pre-op, resulting in increased symmetry between limbs after 2 years. Vertical ground reaction forces on both limbs converge and limb asymmetry indices approach zero two years post-op. Differences in the COP excursion-loading symmetry relationship between limbs could be useful for identifying instability in other pathologies.     

Bilateral organization of physiological tremor in the upper limb

The bilateral patterns of physiological tremor in the upper limb of adults were examined under conditions where eight combinations of the elbow, wrist and index-finger joints of the right arm were braced using individually molded splints. The hypotheses tested were that: (a) coordination of upper-limb tremor involves (compensatory) coupling of intra- but not inter-limb segments, (b) splinting the respective joints of the right arm changes the organization of this synergy in both limbs, and (c) reducing the involvement of joint-space degrees of freedom through restricting their motion (by splinting) results in increased tremor in the distal segments. Under no-splinting conditions, significant relationships were only observed between adjacent (intra-limb) effector units, with the strength of the correlation increasing from proximal to distal. Splinting the right limb resulted in an increase in the strength and number of significant intra-limb relationships in both limbs. No inter-limb tremor relationships were found between any segment during this task, irrespective of the splinting condition. The frequency profile for the tremor in each limb segment showed two prominent frequency peaks (at 2-4 Hz and 8-12 Hz). A third, higher frequency peak (18-22 Hz) was observed in the index fingers only. Splinting the right limb produced a general increase in the amplitude and variability of tremor in the fingertip of both arms. This effect was particularly strong under conditions where the more proximal joints were splinted. The lack of any between-limb relationships, coupled with the fact that splinting one limb influenced both limbs, suggests that some form of linkage does exist between the limbs. It is unlikely that mechanical linkages can explain fully these relationships. It is proposed that the tremor observed in either limb represents the output of a central oscillatory mechanism(s), but that this output is subsequently independently filtered in a parallel fashion on its way to each respective limb. A common bilateral (compensatory) strategy is employed to minimize the tremor in either limb during this multiple-degrees-of-freedom task.     

Heritabilities of Directional Asymmetry in the Fore- and Hindlimbs of Rabbit Fetuses

Directional asymmetry (DA), where at the population level symmetry differs from zero, has been reported in a wide range of traits and taxa, even for traits in which symmetry is expected to be the target of selection such as limbs or wings. In invertebrates, DA has been suggested to be non-adaptive. In vertebrates, there has been a wealth of research linking morphological asymmetry to behavioural lateralisation. On the other hand, the prenatal expression of DA and evidences for quantitative genetic variation for asymmetry may suggest it is not solely induced by differences in mechanic loading between sides. We estimate quantitative genetic variation of fetal limb asymmetry in a large dataset of rabbits. Our results showed a low but highly significant level of DA that is partially under genetic control for all traits, with forelimbs displaying higher levels of asymmetry. Genetic correlations were positive within limbs, but negative across bones of fore and hind limbs. Environmental correlations were positive for all, but smaller across fore and hind limbs. We discuss our results in light of the existence and maintenance of DA in locomotory traits.     

Paradoxical bilateral asymmetry in bone size and bone mass in the hand

Among 227 chronic renal disease patients, micrometer caliper radiogrammetric measurements of the second metacarpal at midshaft showed the right metacarpal to be larger (with greater bone area) and with a greater cortical area than the left second metacarpal, both in 208 right-handed individuals and in 19 left-handed individuals. This direction of asymmetry was individually characteristic of the majority of individuals, whether right-handed, left-handed or ambidextrous.     

Temperature Asymmetry of the Rat Cerebral Hemispheres

The field potential and temperature of the cerebral cortex were studied in right-handed, left-handed, and ambidextrous rats. Temperature asymmetry of the cerebral hemispheres was revealed, which proved to differ in rats with different types of interhemispheric asymmetry: the interhemispheric temperature gradient was maximal in left-handed rats, minimal in right-handed rats, and intermediate in ambidextrous rats. Both parameters of energy metabolism (field potential and temperature of the cerebral cortex) correlated with one another, and the structure of these statistically significant correlations was different in right-handed, left-handed, and ambidextrous rats. It is suggested that the previously known types of interhemispheric asymmetry—biochemical, neurophysiological, and organoelement—are based on differences in the intensity of energy-consuming processes in the cerebral hemispheres.     

On birds: scale effects in the neognath hindlimb and differences in the gross morphology of wings and hindlimbs

Scale effects on whole limb morphology (i.e. bones together with in situ overlying muscles) are well understood for the neognath forelimb. However, scale effects on neognath gross hindlimb morphology remain largely unexplored. To broaden our understanding of avian whole limb morphology, I investigated the scaling of hindlimb inertial properties in neognath birds, testing empirical scaling relationships against the model of geometric similarity. Inertial property data – mass, moment of inertia, centre of mass distance, and radius of gyration – were collected from 22 neognath species representing a wide range of locomotor specializations. When scaled against body mass, hindlimb inertial properties scale with positive allometry. Thus, in terms of morphology, larger bodied neognaths possess hindlimbs requiring disproportionately more energy to accelerate and decelerate relative to body mass than smaller bodied birds. When scaled against limb length, hindlimb inertial properties scale according to isometry. In the subclade Land Birds (sensu Hackett et al.), hindlimb inertial properties largely scale according to positive allometry. The contrasting results of positive allometry vs. isometry in neognaths are due to how hindlimb length scales against body mass. Negative allometry of hindlimb inertial properties, which would reduce terrestrial locomotion costs, would probably make the hindlimb susceptible to mechanical failure or too diminutive for its many ecological functions. Comparing the scaling relationships of wings and hindlimbs highlights how locomotor costs influence the scaling of limb inertial properties. © 2013 The Linnean Society of London, Biological Journal of the Linnean Society, 2013, 110 , 14–31.     

Bilateral variation and the evolutionary origin of macroscopic asymmetries

Given that characters exhibiting macroscopic asymmetry have evolved in a wide variety of taxa, heritable variation for bilateral asymmetry must have arisen at some point in their history. The recognition that heritable variation may underlie some statistical asymmetries not only raises concerns about the incautious use of statistical estimates of FA in studies of developmental stability, but it suggests some intriguing questions about the possible evolutionary origins of macroscopic asymmetries. First, we developed an additive model of bilateral variation based on some simple assumptions about the developmental control of bilateral variation. Second, using a new approach for studying statistical asymmetries, we conducted an analysis of bilateral variation in eight metrical traits of a harpacticoid copepod (Tigriopus californicus) to search for novel forms of statistical asymmetries. The model we developed revealed three independent statistical asymmetries of potential evolutionary significance:a) a previously unrecognized form of asymmetry (referred to here asnormal covariant asymmetry),b) antisymmetry, andc) directional asymmetry. Because each pattern of variation would seem to require different amounts and kinds of developmental-genetic information [a- only negative feedback between sides (bilateral inhibition),b- bothbilateral inhibition and average departure from symmetry (bilateral offset),c- bilateral inhibition, bilateral offset, and a consistent overdevelopment of one side or the other (side-bias control)], those requiring less information would seem more likely to represent earlier stages in the evolution of macroscopic asymmetries. Our analysis of bilateral variation inTigriopus revealed no evidence for any form of statistical asymmetry other than fluctuating asymmetry. However, a significant positive covariation between sides, even after correction for body size variation, suggested that factors influencing relative limb length (whether genetic or environmental) affected both sides equally rather than one side at the expense of the other. Finally, we note that certain statistical asymmetries (directional asymmetry, any form of covariant asymmetry) may render characters unreliable for estimating developmental stability because, unlike pure fluctuating asymmetry, they may signal a genetic component to asymmetry variation.     

Intraspecific variation in testis asymmetry in birds: evidence for naturally occurring compensation

In many taxa, the left and right testes often differ in size. The compensation hypothesis states that one testis of the pair serves as a ‘back-up’ for any reduced function in the other and provides a mechanism to explain intraspecific variation in degree and direction of gonad asymmetry. Although testis asymmetry is common in birds, evidence for natural testis compensation is unknown. Using a novel quantitative approach that can be applied to any bilateral organ or structure, we show that testis compensation occurs naturally in birds and can be complete when one testis fails to develop. Owing to a recurrent risk of testis impairment and an evolutionary trade-off between natural and sexual selections acting on the arrangement of internal organs in species with abdominal and/or seasonal testes, compensation adds an important, but neglected, dimension to measures of male reproductive investment.     

Interhemispheric interactions in right- and left-handed individuals based on EEG coherence data

The functions of interhemispheric EEG coherence were analyzed in 12 healthy subjects with the right individual profile of motor and sensor asymmetry and 7 subjects with the left profile in 2 experimental conditions: the state of rest and photostimulation of the central visual field. It was shown that in the rest condition the right-handed subjects have the higher values of EEG coherence in the thetal band in symmetrical frontal and central areas than the left-handed. These differences decreased for the frontal and central areas during activation caused by photostimulation but increased in the theta 2 and betal bands in symmetrical temporal areas (the coherence in the left-handed being higher). The difference in the EEG coherence between conditions was greater for the frontal and central areas in the right-handed than in the left-handed, especially, for the theta 1 and theta 2 bands. These findings suggest that the left-handed subjects have a less developed hierarchy of subcortical control of the functional state shifts than the right-handed.     

On the symmetry of limb deficiencies among children with multiple congenital anomalies

In humans, unpaired organs are placed in a highly ordered pattern along the left-right axis. As indicated by animal studies, a cascade of signaling molecules establish left-right asymmetry in the developing embryo. Some of the same genes are involved also in limb patterning. To provide a better insight into the connection between these processes in humans, we analysed the symmetry of limb deficiencies among infants with multiple congenital anomalies. The study was based on data collected by the International Clearinghouse for Birth Defects Monitoring Systems (ICBDMS). Registries of the ICBDMS provided information on infants who, in addition to a limb deficiency, also had at least one major congenital anomaly in other organ systems. We reviewed 815 such cases of which 149 cases (18.3 %) were syndromic and 666 (81.7 %) were nonsyndromic. The comparisons were made within the associated limb deficiencies, considering the information on symmetry, using a comparison group with malformations associated not involved in the index association. Among the non-syndromic cases, the left-right distribution of limb deficiencies did not differ appreciably between limb deficiency subtypes (e.g., preaxial, transverse, longitudinal). The left-right distribution of limb anomalies did not differ among most types of non-limb anomalies, though a predominance of left-sided limb deficiencies was observed in the presence of severe genital defects - odds ratio [OR], 2.6; 95 % CI, 1.1-6.4). Limb deficiencies (LDs) were more often unilateral than bilateral when accompanied by gastroschisis (OR, 0.1) or axial skeletal defects (OR, 0.5). On the contrary, LDs were more often bilateral than unilateral when associated with cleft lip with or without cleft palate (OR, 3.9) or micrognathia (OR, 2.6). Specifically, we found an association between bilateral preaxial deficiencies and cleft lip, bilateral amelia with gastroschisis and urinary tract anomalies, and bilateral transverse deficiencies and gastroschisis and axial skeleton defects. Of 149 syndromic cases, 62 (41.6 %) were diagnosed as trisomy 18. Out of the 30 cases of trisomy 18 with known laterality, 20 cases were bilateral. In the remainder the right and left sides were equally affected. Also, in most cases (74.4 %) only the upper limbs were involved. In conclusion the left-right distribution of limb deficiencies among some non-limb anomalies may suggest a relationship between the development of the limb and the left-right axis of the embryo.     

The comparison of characteristics of smooth pursuit in left-handed and right-handed persons

The estimation of the smooth pursuit efficiency in healthy young adults by method based on stroboscopic stimulation is given. The influence of manual function asymmetry on smooth pursuit was tested. Subjects were classified as left-handed or right-handed under a well known handedness questionnaire of Annett supplemented by Luria's tests. It was shown that the strong right-handed persons have a high quality of smooth pursuit of stimuli moving horizontally in rightward and leftward directions with the velocities 20 degrees/s and 25 degrees/s. Left-handed persons track similar stimuli, on the average, worse than the strong right-handed ones. It haven't been observed the influence of manual function asymmetry on the dependence of the smooth pursuit efficiency from the moving stimuli direction (left to right or right to left).     

Dynamics of Blood Serum Levels of Follicle-Stimulating Hormone, Luteinizing Hormone, Prolactin, Estradiol, and Progesterone in Right- and Left-Handed Women

The dynamics of follicle-stimulating hormone (FSH) luteinizing hormone (LH), prolactin (PRL), estradiol (E₂), and progesterone were studied in left- and right-handed women having a stable 28-day menstrual cycle. The hormones were determined by enzyme immunoassays on days 3, 8, 10, 13, 16, 22, 26, and 28 of the menstrual cycle. The data showed that bllod serum levels of FSH, LH, PRL, and E₂are higher in left-handed in comparison to right-handed women (p< 0.001). On days 10 through 28 of the cycle, the level of progesterone is also higher in left-handed women (p< 0.001). The dynamic of these hormones in left-handed and right-handed women appeared to remain within the normal limits. These findings indicate that the handedness correlates with the dynamucs of serum levels of these hormones. Higher serum levels of hormones in left-handed women suggests that they have higher levels of the functional activity of the hypophysis–ovarian axis and prolactin axis.     

Symmetry-based resistance as a novel means of lower limb rehabilitation

Robotic devices hold much promise for use as rehabilitation aids but their success depends on identifying effective strategies for controlling human-robot interaction forces. We developed a robotic device to test a novel method of controlling interaction forces with the intent of improving force symmetry in the limbs. Users perform lower limb extensions against a computer-controlled resistive load. The control software increases resistance above baseline in proportion to lower limb force asymmetry (balance between left and right limb forces). As a preliminary trial to test the device and controller, we conducted two experiments on neurologically intact subjects. In experiment 1, one group of subjects received symmetry-based resistance while performing lower limb extensions (n=10). A control group performed the same movements with constant resistance (n=10). The symmetry-based resistance group improved lower limb symmetry during training (ANOVA, p<0.05), whereas the control subjects did not. In experiment 2, subjects (n=10) successfully used symmetry-based resistance to alter their lower limb force production towards a target asymmetry (ANOVA, p<0.05). These studies suggest that symmetry-based resistance may hold rehabilitation benefits after orthopedic or neurological injury. Specifically, performing strength training therapy with this controller may allow hemiparetic individuals to focus better on increasing strength and neuromuscular recruitment in their paretic limb while experiencing symmetric limb forces.     

FFU complex: an analysis of 491 cases

A study of 491 patients with femur-fibula-ulna (FFU) complex is presented. The term FFU complex has been proposed for cases in which the femur, fibula and/or ulna show defects, which tend to be associated. These cases are usually sporadic. Some rare anomalies of the arms which are present are particularly frequent in FFU complex. These are amelia, peromelia of humerus, humeroradial synostosis and defect of ulna. In our study, 491 patients were investigated for involvement of limb malformations. Our results, showing nearly equal proportions of the most common malformations in four analysed groups (with one, two, three and four limbs affected) supports the hypothesis that even if one arm or one leg only is affected, the cases may still be classifiable as FFU complex. There is a striking asymmetry in presence and in degree. All malformations are more often unilateral than bilateral. Upper limbs are affected more often than lower limbs. The right side and the male sex are preferentially affected. The limb malformations present in the FFU complex are different from those seen in most other types of limb defects, so there is virtually no overlap between FFU and other limb malformations. Some arguments in favour of early somatic mutation as a cause are discussed.     

The AEP T-complex to synthesised musical tones: left-right asymmetry in relation to handedness and hemisphere dominance

Auditory evoked potentials were recorded to onset and offset of synthesised instrumental tones in 40 normal subjects, 20 right-handed for writing and 20 left-handed. The majority of both groups showed a T-complex which was larger at the right temporal electrode (T4) than the left (T3). In the T4-T3 difference waveforms, the mean potential between latencies of 130 and 165 ms was negative in all right-handed subjects except two for whom the waveforms were marginally positive-going. Amongst the left-handers, however, this converse asymmetry was seen in 7 subjects, 5 of them more than 2 standard deviations from the mean of the right-handed group. The degree of asymmetry was not significantly correlated with the degree of left-handedness according to the Edinburgh Handedness Inventory. Asymmetry of the T-complex to instrumental tones appears to reflect the lateralisation of auditory `musical' processing in the temporal cortex, confirming evidence from other sources including PET that this is predominantly right-sided in the majority of individuals. The proportion of left-handers showing the converse laterality is roughly in accordance with those likely to be right-hemisphere-dominant for language. If linguistic and `musical' processes are consistently located in opposite hemispheres, AEPs to complex tones may prove a useful tool in establishing functional lateralisation.