Alunos canhotos de odontologia da cidade de Uberlândia: perfil, ergonomia e dores osteomusculares / Left-handed dentistry students in the city of Uberlândia: profile, ergonomics and muscular pain

Os dentistas são um grupo de alto risco para o desenvolvimento de doenças de desordens musculoesqueléticas e tendo em vista que o sistema de produção industrial desenvolve produtos que atendem a maioria da população destra, os estudantes canhotos precisam se adequar a uma formação acadêmica, usando instrumentais, cadeiras odontológicas eoutros objetos projetados para destros. O presente trabalho teve como objetivo a coletade informações sobre os canhotos nos cursos de Odontologia da cidade de Uberlândia ­Minas Gerais. Foram incluídos todos os alunos canhotos matriculados no ano de 2022 e que estavam cursando ou já cursaram disciplinas com atividades laboratoriais ou clínicas. Questionários foram aplicados para identificação do perfil, das dificuldades, da ergonomia e das dores osteomusculares dos alunos canhotos em suas atividades. Os dados foram em seguida tabulados e passaram por análise estatística. Da quantidade total de alunos das três instituições (n=1.578), foram entrevistados 45 (2,8%) alunos canhotos, sendo a maioria feminina (80%), na qual identificou-se um posicionamento inadequado do operador canhoto quando comparado ao preconizado pela ISO-FDI, além da limitação de movimento na presença de auxiliar (82,2%). Os locais com maior frequência de dor/desconforto foram: pescoço (79%), costas superior esquerda (63%) e inferior esquerda (61%) e punhos/ mãos esquerda (56%). A intensidade da dor variou entre alguma, moderada e bastante. O impedimento de realizar atividades diárias foi relatado por 17% dos alunos (n=7) e destes somente 1 buscou atendimento médico. Não houve diferença estatística na comparação entre instituição pública e privada. Diante dos resultados, concluiu-se que os canhotos representam minoria dos alunos de Odontologia e apresentam várias regiões de dor/ desconforto devido às adaptações e posturas erradas durante os atendimentos. Apesar de grande parte apresentar dor, poucos tiveram impedimento de atividades rotineiras ou procuraram ajuda médica(AU)

Dentists are a high risk group for the development of musculoskeletal disorders and considering that the industrial production system develops products that serve the majority of the right-handed population, lefthanded students need to adapt to an academic training, using instruments, dental chairs and other objects designed for right-handers. This study aimed to collect information about left-handers in Dentistry courses in the city of Uberlândia - Minas Gerais. All left- handed students enrolled in the year 2022 and who were taking or had taken courses with laboratory or clinical activities were included. Questionnaires were applied to identify the profile, difficulties, ergonomics and musculoskeletal pain of left-handed students in their activities. The data were tabulated and then undergo statistical analysis. Of the total number of students from the three institutions (n=1,578), 45 (2.8%) left-handed students were interviewed, the majority being female (80%), in which an inadequate positioning of the left-handed operator was identified when compared to the recommended one by ISO-FDI, in addition to limitation of movement in the presence of an assistant (82.2%). The places with the highest frequency of pain/discomfort were: neck (79%), upper left back (63%) and lower left back (61%) and left wrists/hands (56%). The intensity of pain varied between some, moderate and a lot. The impediment to carrying out daily activities was reported by 17% of the students (n=7) and of these, only 1 sought medical attention. There was no statistical difference when comparing public and private institutions. In view of the results, it was concluded that left-handers represent a minority of dentistry students and have several regions of pain/discomfort due to adaptations and wrong postures during consultations. Although most of them had pain, few were prevented from performing routine activities or sought medical help(AU)

Survival analysis for patients with metachronous contralateral breast cancer: Insights from a retrospective study.

Continued advances in the diagnosis and treatment of breast cancer (BC) have led to an increase in the number of long-term BC survivors and an increase in the incidence of metachronous BC in the contralateral breast. Therefore, it is important to understand the factors that influence the development of metachronous BC; however, the impact of the laterality of the initial ipsilateral (I)BC as a risk factor for the development of metachronous contralateral (MC)BC has not been extensively investigated. The present study included 17,082 female patients with stage 0-3 IBC from the prospectively maintained Korean Breast Cancer Registry from 1989-2013 and divided them into two groups: Patients with MCBC (n=88) and those without MCBC (n=16,994). Risk factors that present at the initial BC diagnosis that could significantly influence the development of MCBC were screened for and risks were evaluated using the Fine-Gray subdistribution hazard model. Significant differences in baseline characteristics between MCBC and non-MCBC groups were demonstrated. Patients aged <40 years, those with histological and nuclear grade 3 tumors, and those with the triple-negative BC subtype were significantly more prevalent in the MCBC group than in the non-MCBC group. Additionally, the cumulative incidence of MCBC increased over time, with a notable increase from 0.1% in year 1 to 1.6% in year 10. Survival analysis revealed no significant differences in overall or BC-specific survival between the two groups. Key predictive factors identified for MCBC included an age of <40 years at initial diagnosis, a negative progesterone receptor status, and a Ki-67 score of >14%. Overall, the present study revealed several factors associated with MCBC and emphasized the need for long-term monitoring of BC survivors, considering these newly identified risk factors.

Footedness in merlins: Raptors perching in a cold climate.

ABSTRACTPerching or standing on one foot is commonly reported in birds but the level of consistency in using one foot over the other has been less-well documented in most species, particularly birds of prey. For birds experiencing colder temperatures, unipedal perching has been attributed to limiting heat loss through unfeathered legs and feet; individuals should spend longer periods of time perched on one foot as temperatures decrease. Using radio tracking, I collected 486 hours of observations on nine overwintering, free-living merlins (Falco columbarius) in Saskatoon, Canada. Five merlins displayed clear preferences to perch on one foot, however the direction of preference was not consistent and four birds were ambidextrous. There was a curvilinear response in the proportion of time spent in unipedal posture versus temperature, with a peak of ∼22% of the time at moderate temperatures (-10 to -19°C), but lower values at warmer and colder temperatures; the main effect of the squared term for temperature was highly influential while individual foot preference had no impact on the use of unipedal perching. Although preferential use of one foot for perching was displayed by some individuals, thermoregulation may not be the primary driver of this behaviour at colder temperatures.

Fear is more right lateralized than happiness and anger: Evidence for the motivational hypothesis of emotional face perception?

Facial emotion processing (FEP) tends to be right hemisphere lateralized. This right-hemispheric bias (RHB) for FEP varies within and between individuals. The aim of the present research was to examine evidence pertaining to the prominent theories of FEP hemispheric bias as measured by a half-emotional half-neutral (no emotion) chimeric faces task. FEP hemispheric bias was indexed using laterality quotients (LQs) calculated from a Chimeric Faces Task completed by 427 adults recruited from the general population aged 18-67 years. Participants indicated which of two identical (but mirrored) emotional-neutral chimeric faces were more emotive. While all investigated emotions (fear, anger, and happiness) were right lateralized, fear was significantly more right lateralized than anger and happiness. These results provide evidence for both the right hemisphere hypothesis and the motivational hypothesis of emotion perception.

Effect of Laterality in Microsurgery: Comparative Study of an Expert and a Novice.

Background: Hand laterality has an impact on surgical gestures. In this study, we sought to measure the multi-parameter variability of the microsurgical gesture depending on the hand used and the differences between expert microsurgeons and novices. Methods: Ten experienced microsurgeons and twenty medical students with no prior microsurgical experience performed arterial anastomosis on a chicken wing artery using dominant and non-dominant hands. We measured time and force using a homemade force-sensing microsurgical needle holder, heart rate variability with a Polar H10 chest strap, anxiety with the STAI-Y questionnaire and anastomosis quality using the MARS 10 scale. Results: In the microsurgeons' group, duration of anastomosis (p = 0.037), force applied to the needle holder (p = 0.047), anxiety (p = 0.05) and MARS10 (p = 0.291) were better with the dominant hand. For novices, there was no difference between the dominant and non-dominant hand pertaining to force, time and stress level. There were no differences between microsurgeons and novices pertaining to force and anxiety using the non-dominant hand. Conclusions: The study highlighted a marked laterality among microsurgical experts, a finding that may be explained by current learning methods. Surprisingly, no laterality is observed in students, suggesting that for a specific gesture completely different from everyday tasks, laterality is not predefined. Ambidexterity training in the residency curriculum seems relevant and may help microsurgeons improve performance and postoperative outcomes.

Novel pathogenic variants of DNAH5 associated with clinical and genetic spectra of primary ciliary dyskinesia in an Arab population.

Introduction: Primary ciliary dyskinesia (PCD) is caused by the dysfunction of motile cilia resulting in insufficient mucociliary clearance of the lungs. This study aimed to map novel PCD variants and determine their pathogenicity in PCD patients in Kuwait. Methods: Herein, we present five PCD individuals belonging to a cohort of 105 PCD individuals recruited from different hospitals in Kuwait. Genomic DNAs from the family members were analysed to screen for pathogenic PCD variants. Transmission electron microscopy (TEM) and immunofluorescence (IF) analyses were performed on the nasal biopsies to detect specific structural abnormalities within the ciliated cells. Results: Genetic screening and functional analyses confirmed that the five PCD individuals carried novel pathogenic variants of DNAH5 causing PCD in three Arabic families. Of these, one multiplex family with two affected individuals showed two novel homozygous missense variants in DNAH5 causing PCD with situs inversus; another multiplex family with two affected individuals showed two newly identified compound heterozygous variants in DNAH5 causing PCD with situs solitus. In addition, novel heterozygous variants were identified in a child with PCD and situs solitus from a singleton family with unrelated parents. TEM analysis demonstrated the lack of outer dynein arms (ODAs) in all analysed samples, and IF analysis confirmed the absence of the dynein arm component of DNAH5 from the ciliary axoneme. Conclusion: The newly identified pathogenic variants of DNAH5 are associated with PCD as well as variable pulmonary clinical manifestations in Arabic families.

Visual lateralization in the sky: Geese manifest visual lateralization when flying with pair mates.

The brain's sensory lateralization involves the processing of information from the sensory organs primarily in one hemisphere. This can improve brain efficiency by reducing interference and duplication of neural circuits. For species that rely on successful interaction among family partners, such as geese, lateralization can be advantageous. However, at the group level, one-sided biases in sensory lateralization can make individuals predictable to competitors and predators. We investigated lateral preferences in the positioning of pair mates of Greater white-fronted geese Anser albifrons albifrons. Using GPS-GSM trackers, we monitored individual geese in flight throughout the year. Our findings indicate that geese exhibit individual lateral biases when viewing their mate in flight, but the direction of these biases varies among individuals. We suggest that these patterns of visual lateralization could be an adaptive trait for the species with long-term social monogamy, high levels of interspecies communication and competition, and high levels of predator and hunting pressure.

Human Genetics of d-Transposition of Great Arteries.

Although several genes underlying occurrence of transposition of the great arteries have been found in the mouse, human genetics of the most frequent cyanotic congenital heart defect diagnosed in neonates is still largely unknown. Development of the outflow tract is a complex process which involves the major genes of cardiac development, acting on myocardial cells from the anterior second heart field, and on mesenchymal cells from endocardial cushions. These genes, coding for transcription factors, interact with each other, and their differential expression conditions the severity of the phenotype. A precise description of the anatomic phenotypes is mandatory to achieve a better comprehension of the complex mechanisms responsible for transposition of the great arteries.

Human Genetics of Tetralogy of Fallot and Double-Outlet Right Ventricle.

Tetralogy of Fallot (TOF) and double-outlet right ventricle (DORV) are conotruncal defects resulting from disturbances of the second heart field and the neural crest, which can occur as isolated malformations or as part of multiorgan syndromes. Their etiology is multifactorial and characterized by overlapping genetic causes. In this chapter, we present the different genetic alterations underlying the two diseases, which range from chromosomal abnormalities like aneuploidies and structural mutations to rare single nucleotide variations affecting distinct genes. For example, mutations in the cardiac transcription factors NKX2-5, GATA4, and HAND2 have been identified in isolated TOF cases, while mutations of TBX5 and 22q11 deletion, leading to haploinsufficiency of TBX1, cause Holt-Oram and DiGeorge syndrome, respectively. Moreover, genes involved in signaling pathways, laterality determination, and epigenetic mechanisms have also been found mutated in TOF and/or DORV patients. Finally, genome-wide association studies identified common single nucleotide polymorphisms associated with the risk for TOF.

Investigation of the genetic and clinical features of laterality disorders in prenatal diagnosis: discovery of a novel compound heterozygous mutation in the DNAH11 gene.

BACKGROUND: Left-right laterality disorders are a heterogeneous group of disorders caused by an altered position or orientation of the thoracic and intra-abdominal organs and vasculature across the left-right axis. They mainly include situs inversus and heterotaxy. Those disorders are complicated by cardiovascular abnormalities significantly more frequently than situs solitus. METHODS: In this study, 16 patients with a fetal diagnosis of laterality disorder with congenital heart defects (CHD) were evaluated with a single nucleotide polymorphism array (SNP-arry) combined with whole-exome sequencing (WES). RESULTS: Although the diagnostic rate of copy number variations was 0 and the diagnostic rate of WES was 6.3% (1/16), the likely pathogenic gene DNAH11 and the candidate gene OFD1 were ultimately identified. In addition, novel compound heterozygous mutations in the DNAH11 gene and novel hemizygous variants in the OFD1 gene were found. Among the combined CHD, a single atrium/single ventricle had the highest incidence (50%, 8/16), followed by atrioventricular septal defects (37.5%, 6/16). Notably, two rare cases of common pulmonary vein atresia (CPVA) were also found on autopsy. CONCLUSION: This study identified the types of CHD with a high incidence in patients with laterality disorders. It is clear that WES is an effective tool for diagnosing laterality disorders and can play an important role in future research.

Asymmetries in event-related potentials part 1: A systematic review of face processing studies.

The human brain shows distinct lateralized activation patterns for a range of cognitive processes. One such function, which is thought to be lateralized to the right hemisphere (RH), is human face processing. Its importance for social communication and interaction has led to a plethora of studies investigating face processing in health and disease. Temporally highly resolved methods, like event-related potentials (ERPs), allow for a detailed characterization of different processing stages and their specific lateralization patterns. This systematic review aimed at disentangling some of the contradictory findings regarding the RH specialization in face processing focusing on ERP research in healthy participants. Two databases were searched for studies that investigated left and right electrodes while participants viewed (mostly neutral) facial stimuli. The included studies used a variety of different tasks, which ranged from passive viewing to memorizing faces. The final data selection highlights, that strongest lateralization to the RH was found for the N170, especially for right-handed young male participants. Left-handed, female, and older participants showed less consistent lateralization patterns. Other ERP components like the P1, P2, N2, P3, and the N400 were overall less clearly lateralized. The current review highlights that many of the assumed lateralization patterns are less clear than previously thought and that the variety of stimuli, tasks, and EEG setups used, might contribute to the ambiguous findings.

The impact of laterality on the incidence and prognosis of epithelial ovarian cancer.

INTRODUCTION: Epithelial ovarian cancer (EOC) is the most prevalent type of ovarian cancer, yet the impact of ovarian laterality has received limited attention. MATERIALS AND METHODS: We conducted a comprehensive investigation into the impact of laterality (left-right and bilateral-unilateral) on EOC incidence and prognosis, focusing on distinct subtypes. Binomial tests and Pearson's χ2 tests were employed to compare occurrence rates among laterality groups. Cox regression analyses were used to create a proportional hazards model for tumor prognosis. Nomograms were developed and validated, including internal validation via bootstrapping. RESULTS: Our study encompassed 20,790 EOC patients, revealing disparities in incidence and prognosis between unilateral and bilateral cases. Unilateral tumor development was notably predominant in clear cell, endometrioid, brenner, and mucinous subtypes, while bilateral involvement was more frequent in serous ovarian cancer. Laterality differences, reflecting disparities between the left and right sides, were chiefly evident in the incidence rates across various stages and in the prognosis of specific subtypes. Notably, mucinous ovarian cancer exhibited significantly better prognosis on the right side compared to the left (right tumors: HR = 0.745, p = 0.015, CI: 0.587-0.945). CONCLUSION: These findings emphasize the importance of considering ovarian laterality -both left-right and bilateral-unilateral aspects -as a critical factor influencing EOC incidence and prognosis, necessitating attention in clinical practice.

Are lateralized and bold fish optimistic or pessimistic?

Cognitive bias is defined as the influence of emotions on cognitive processes. The concept of the cognitive judgement bias has its origins in human psychology but has been applied to animals over the past 2 decades. In this study we were interested in determining if laterality and personality traits, which are known to influence learning style, might also be correlated with a cognitive bias in the three-spined sticklebacks (Gasterosteus aculeatus). We used the judgement bias test with the go/no-go procedure where fish were first trained to discriminate between a black and white card and, after reaching a minimum learning criterion, tested their response to an ambiguous card (grey). Optimistic subjects were expected to have a high expectation of reward associated with an ambiguous stimulus, whereas pessimistic subjects a high expectation of non-reward. We used an emergence and a mirror test to quantify boldness and laterality, respectively. We hypothesised that male, bolder and more strongly lateralized fish would be more optimistic than female, shy and less strongly lateralised fish. We found that males and more strongly lateralized fish were more optimistic than females and less strongly lateralized fish. In addition, bold males were more optimistic than shy males as we predicted, but females showed the opposite pattern. Finally, fish trained on the black colour card learned the training task faster than those trained on a white card. Our results indicate that both laterality and personality traits are linked to animals' internal states (pessimistic or optimistic outlooks) which likely has broad implications for understanding animal behaviour particularly in a welfare context.

Mantled howler monkeys (Alouatta palliata) show no preferential hand use in two self-directed behaviors.

Hand preference is the preferential use of one hand for a single task. Its study provides insight into the neural mechanisms underlying motor skills, perception, and cognitive functions. From a comparative perspective, it also offers a window into evolutionary history, shedding light on whether manual preferences stem from genetics, environmental influences, or a combination of both. However, there is a paucity of information on preferential hand use for several primate taxa. Here we examine hand preference for the first time in mantled howler monkeys (Alouatta palliata) to determine if there is preferential hand use at the individual and population level as well as sex differences in hand use. We followed 17 wild adult individuals for 10 months and used focal animal sampling (506 focal samples) to record hand use in two types of self-directed behaviors, touching (1246 events) and scratching (1115 events). According to the binomial tests, four individuals were right-hand-preferent, two were left-hand-preferent, and 11 were ambilateral during touching, whereas for scratching seven individuals were right-hand-preferent, two were left-hand-preferent, and eight were ambilateral. At the population level, there was ambilaterality in both behaviors. At the individual level, according to the HI index, hand preference in touching and scratching were not associated and did not vary between sexes. These findings concur with previous studies with howler monkeys and other taxa suggesting that population-level hand preference is not a universal trait across primates.

Approaches to Measuring Language Lateralisation: An Exploratory Study Comparing Two fMRI Methods and Functional Transcranial Doppler Ultrasound.

In this exploratory study we compare and contrast two methods for deriving a laterality index (LI) from functional magnetic resonance imaging (fMRI) data: the weighted bootstrapped mean from the LI Toolbox (toolbox method), and a novel method that uses subtraction of activations from homologous regions in left and right hemispheres to give an array of difference scores (mirror method). Data came from 31 individuals who had been selected to include a high proportion of people with atypical laterality when tested with functional transcranial Doppler ultrasound (fTCD). On two tasks, word generation and semantic matching, the mirror method generally gave better agreement with fTCD laterality than the toolbox method, both for individual regions of interest, and for a large region corresponding to the middle cerebral artery. LI estimates from this method had much smaller confidence intervals (CIs) than those from the toolbox method; with the mirror method, most participants were reliably lateralised to left or right, whereas with the toolbox method, a higher proportion were categorised as bilateral (i.e., the CI for the LI spanned zero). Reasons for discrepancies between fMRI methods are discussed: one issue is that the toolbox method averages the LI across a wide range of thresholds. Furthermore, examination of task-related t-statistic maps from the two hemispheres showed that language lateralisation is evident in regions characterised by deactivation, and so key information may be lost by ignoring voxel activations below zero, as is done with conventional estimates of the LI.

Handedness in schizophrenia and affective disorders: a large-scale cross-disorder study.

While most people are right-handed, a minority are left-handed or mixed-handed. It has been suggested that mental and developmental disorders are associated with increased prevalence of left-handedness and mixed-handedness. However, substantial heterogeneity exists across disorders, indicating that not all disorders are associated with a considerable shift away from right-handedness. Increased frequencies in left- and mixed-handedness have also been associated with more severe clinical symptoms, indicating that symptom severity rather than diagnosis explains the high prevalence of non-right-handedness in mental disorders. To address this issue, the present study investigated the association between handedness and measures of stress reactivity, depression, mania, anxiety, and positive and negative symptoms in a large sample of 994 healthy controls and 1213 patients with DSM IV affective disorders, schizoaffective disorders, or schizophrenia. A series of complementary analyses revealed lower lateralization and a higher percentage of mixed-handedness in patients with major depression (14.9%) and schizophrenia (24.0%) compared to healthy controls (12%). For patients with schizophrenia, higher symptom severity was associated with an increasing tendency towards left-handedness. No associations were found for patients diagnosed with major depression, bipolar disorder, or schizoaffective disorder. In healthy controls, no association between hand preference and symptoms was evident. Taken together, these findings suggest that both diagnosis and symptom severity are relevant for the shift away from right-handedness in mental disorders like schizophrenia and major depression.

Enhancing Clarity and Patient Safety: Evaluating the Inclusion of Laterality in Orthopaedic Outpatient Correspondence in Galway, Ireland.

Background In medical documentation, accurate mention of laterality, whether a condition or treatment pertains to the left or the right side of the body, is critical for avoiding errors like wrong-site surgeries, which can have severe repercussions. This study aims to assess compliance regarding the mention of laterality in outpatient clinic letters at Galway University Hospital. Methods An analytical cross-sectional study was conducted at Galway University Hospital from February to August. We reviewed outpatient letters in the Orthopaedic Department. The Fisher exact and Chi-square tests were employed to observe the association between the levels of practitioners and laterality. Results A total of 278 outpatient letters from 37 practitioners in one week were analyzed. The overall laterality rate was 65.1%. It was observed that there was a male predominance in the workforce (31; 83.8%). Conclusion In conclusion, our study revealed satisfactory improvement in the prevalence of mentioning laterality among healthcare providers. It is recommended that educational sessions and re-auditing be carried out to enhance the quality of care.

Association of handgrip strength asymmetry and weakness with cognitive function: a nationally representative cohort study.

OBJECTIVE: To describe the association of handgrip strength asymmetry and weakness with cognitive function among Chinese middle-aged and older adults. STUDY DESIGN: We used data from four waves (2011, 2013, 2015, and 2018) of the China Health and Retirement Longitudinal Study. Handgrip strength was measured at baseline. Handgrip strength asymmetry was defined on the basis of the ratio of handgrip strength of the non-dominant hand to that of the dominant hand (i.e. non-dominant/dominant): a ratio of <0.9 defined as dominant handgrip strength asymmetry and >1.1 as non-dominant handgrip strength asymmetry. Weakness was defined as a handgrip strength of <28 kg for males or <18 kg for females. MAIN OUTCOME MEASURES: Cognitive function with its two core dimensions (episodic memory and mental status) at each wave was assessed and standardized. RESULTS: 9333 participants (48.3 % female, age 58.2 ± 9.0 years) were included. Non-dominant but not dominant handgrip strength asymmetry was significantly associated with poorer cognitive function at baseline (ß = -0.121, -0.092, and -0.132 for mental status, episodic memory, and global cognition, respectively). In longitudinal analyses over 2 years, dominant handgrip strength asymmetry significantly slowed cognitive decline (ß = -0.078 and -0.069 for mental status and global cognition, respectively), and non-dominant handgrip strength asymmetry accelerated cognitive decline (ß = 0.053 and 0.043 for episodic memory and global cognition, respectively). Weakness was associated with poorer cognitive function at baseline and cognitive decline over 2, 4, and 7 years (all P < 0.05). CONCLUSIONS: In middle-aged and older adults, non-dominant handgrip strength asymmetry and weakness were associated with poorer cognitive function and predicted accelerated cognitive decline. Dominant handgrip strength asymmetry may be beneficial for maintaining cognitive function.

Establishment of Cardiac Laterality.

Formation of the vertebrate heart with its complex arterial and venous connections is critically dependent on patterning of the left-right axis during early embryonic development. Abnormalities in left-right patterning can lead to a variety of complex life-threatening congenital heart defects. A highly conserved pathway responsible for left-right axis specification has been uncovered. This pathway involves initial asymmetric activation of a nodal signaling cascade at the embryonic node, followed by its propagation to the left lateral plate mesoderm and activation of left-sided expression of the Pitx2 transcription factor specifying visceral organ asymmetry. Intriguingly, recent work suggests that cardiac laterality is encoded by intrinsic cell and tissue chirality independent of Nodal signaling. Thus, Nodal signaling may be superimposed on this intrinsic chirality, providing additional instructive cues to pattern cardiac situs. The impact of intrinsic chirality and the perturbation of left-right patterning on myofiber organization and cardiac function warrants further investigation. We summarize recent insights gained from studies in animal models and also some human clinical studies in a brief overview of the complex processes regulating cardiac asymmetry and their impact on cardiac function and the pathogenesis of congenital heart defects.

Molecular Pathways and Animal Models of Defects in Situs.

Left-right patterning is among the least well understood of the three axes defining the body plan, and yet it is no less important, with left-right patterning defects causing structural birth defects with high morbidity and mortality, such as complex congenital heart disease, biliary atresia, or intestinal malrotation. The cell signaling pathways governing left-right asymmetry are highly conserved and involve multiple components of the TGF-ß superfamily of cell signaling molecules. Central to left-right patterning is the differential activation of Nodal on the left, and BMP signaling on the right. In addition, a plethora of other cell signaling pathways including Shh, FGF, and Notch also contribute to the regulation of left-right patterning. In vertebrate embryos such as the mouse, frog, or zebrafish, the specification of left-right identity requires the left-right organizer (LRO) containing cells with motile and primary cilia that mediate the left-sided propagation of Nodal signaling, followed by left-sided activation of Lefty and then Pitx2, a transcription factor that specifies visceral organ asymmetry. While this overall scheme is well conserved, there are striking species differences, including the finding that motile cilia do not play a role in left-right patterning in some vertebrates. Surprisingly, the direction of heart looping, one of the first signs of organ left-right asymmetry, was recently shown to be specified by intrinsic cell chirality, not Nodal signaling, possibly a reflection of the early origin of Nodal signaling in radially symmetric organisms. How this intrinsic chirality interacts with downstream molecular pathways regulating visceral organ asymmetry will need to be further investigated to elucidate how disturbance in left-right patterning may contribute to complex CHD.