Human papillomavirus (HPV) and somatic EGFR mutations are essential, mutually exclusive oncogenic mechanisms for inverted sinonasal papillomas and associated sinonasal squamous cell carcinomas.

Background: Inverted sinonasal (Schneiderian) papilloma (ISP) is a locally aggressive neoplasm often associated with sinonasal squamous cell carcinoma (SNSCC). While the etiology of ISP is not well understood, human papillomavirus (HPV) has been detected in a subset of cases. Our group recently identified activating somatic EGFR mutations in the majority of ISP and ISP-associated SNSCC. However, the relationship between EGFR mutations and HPV infection has not been explored. Patients and methods: We evaluated 58 ISP and 22 ISP-associated SNSCC (including 13 patients with matched ISP/SNSCC samples), as well as 14 SNSCC without clinical or pathologic evidence of an associated ISP. Formalin-fixed, paraffin-embedded samples were evaluated for EGFR mutations using Sanger sequencing and for HPV infection using GP5+/GP6+ PCR. HPV subtyping based on the L1 sequence was done for HPV positive cases including temporally distinct tumors for four patients. Clinicopathologic data including progression free survival was also analyzed. Results: All ISP and ISP-associated SNSCC demonstrated either an EGFR mutation or HPV infection. HPV and EGFR mutation were mutually exclusive in all cases of ISP-associated SNSCC and all but one ISP; this case was only weakly HPV positive, and analysis of a prior temporally distinct ISP specimen from this patient failed to show HPV infection, suggesting transient infection/incidental colonization. HPV subtypes in ISP and ISP-associated SNSCC were predominantly low-risk, in contrast with SNSCC without ISP association, which showed frequent high-risk HPV. All paired ISP and associated SNSCC samples demonstrated concordant HPV status and EGFR genotypes. ISP progression to SNSCC was significantly associated with the presence of HPV infection and the absence of an EGFR mutation (log-rank = 9.620, P = 0.002). Conclusions: Collectively our data show that EGFR mutations and HPV infection represent essential, alternative oncogenic mechanisms in ISP and ISP-associated SNSCC.

The repeated bout effect can occur without mechanical and neuromuscular changes after a bout of eccentric exercise.

Changes in muscle fascicle mechanics have been postulated to underpin the repeated bout effect (RBE) observed following exercise-induced muscle damage (EIMD). However, in the medial gastrocnemius (MG), mixed evidence exists on whether fascicle stretch amplitude influences the level of EIMD, thus questioning whether changes in fascicle mechanics underpin the RBE. An alternative hypothesis is that neural adaptations contribute to the RBE in this muscle. The aim of this study was to investigate the neuromechanical adaptations during and after repeated bouts of a highly controlled muscle lengthening exercise that aimed to maximize EIMD in MG. In all, 20 subjects performed two bouts of 500 active lengthening contractions (70% of maximal activation) of the triceps surae, separated by 7 days. Ultrasound constructed fascicle length-torque (L-T) curves of MG, surface electromyography (EMG), maximum torque production, and muscle soreness were assessed before, 2 hours and 2 days after each exercise bout. The drop in maximum torque (4%) and the increase in muscle soreness (24%) following the repeated bout were significantly less than following the initial bout (8% and 59%, respectively), indicating a RBE. However, neither shift in the L-T curve nor changes in EMG parameters were present. Furthermore, muscle properties during the exercise were not related to the EIMD or RBE. Our results show that there are no global changes in gastrocnemius mechanical behavior or neural activation that could explain the observed RBE in this muscle. We suggest that adaptations in the non-contractile elements of the muscle are likely to explain the RBE in the triceps surae.

Deconstructing the power resistance relationship for squats: A joint-level analysis.

Generating high leg power outputs is important for executing rapid movements. Squats are commonly used to increase leg strength and power. Therefore, it is useful to understand factors affecting power output in squatting. We aimed to deconstruct the mechanisms behind why power is maximized at certain resistances in squatting. Ten male rowers (age = 20 ± 2.2 years; height = 1.82 ± 0.03 m; mass = 86 ± 11 kg) performed maximal power squats with resistances ranging from body weight to 80% of their one repetition maximum (1RM). Three-dimensional kinematics was combined with ground reaction force (GRF) data in an inverse dynamics analysis to calculate leg joint moments and powers. System center of mass (COM) velocity and power were computed from GRF data. COM power was maximized across a range of resistances from 40% to 60% 1RM. This range was identified because a trade-off in hip and knee joint powers existed across this range, with maximal knee joint power occurring at 40% 1RM and maximal hip joint power at 60% 1RM. A non-linear system force-velocity relationship was observed that dictated large reductions in COM power below 20% 1RM and above 60% 1RM. These reductions were due to constraints on the control of the movement.

Variations in jump height explain the between-sex difference in patellar tendon loading during landing.

Patellar tendinopathy is the most common overuse knee injury in volleyball, with men reporting more than twice the injury prevalence than women. Although high patellar tendon loading is thought to be a causative factor of patellar tendinopathy, it is unknown whether between-sex variations in landing technique account for differences in patellar tendon loading. It was hypothesized that male volleyball players would display differences in landing technique and would generate higher patellar tendon loading than their female counterparts. The landing technique and patellar tendon loading of 20 male and 20 female volleyball players performing a lateral stop-jump block movement were collected. Independent t-tests were used to identify any between-sex differences in landing technique with the data grouped to account for differences in jump height and in anthropometry. Male volleyball players were taller and heavier, landed from a higher height, displayed differences in landing kinematics, generated a significantly greater knee extensor moment, and experienced higher patellar tendon loading than female players when all 40 participants were compared. However, when participants were matched on jump height, they generated similar patellar tendon loading, irrespective of their sex. These results imply that jump height is a more important determinant of patellar tendon loading than sex.

Previously identified patellar tendinopathy risk factors differ between elite and sub-elite volleyball players.

Patellar tendinopathy is the most common knee injury incurred in volleyball, with its prevalence in elite athletes more than three times that of their sub-elite counterparts. The purpose of this study was to determine whether patellar tendinopathy risk factors differed between elite and sub-elite male volleyball players. Nine elite and nine sub-elite male volleyball players performed a lateral stop-jump block movement. Maximum vertical jump, training history, muscle extensibility and strength, three-dimensional landing kinematics (250 Hz), along with lower limb neuromuscular activation patterns (1500 Hz), and patellar tendon loading were collected during each trial. Multivariate analyses of variance (P < 0.05) assessed for between-group differences in risk factors or patellar tendon loading. Significant interaction effects were further evaluated using post-hoc univariate analysis of variance tests. Landing kinematics, neuromuscular activation patterns, patellar tendon loading, and most of the previously identified risk factors did not differ between the elite and sub-elite players. However, elite players participated in a higher training volume and had less quadriceps extensibility than sub-elite players. Therefore, high training volume is likely the primary contributor to the injury discrepancy between elite and sub-elite volleyball players. Interventions designed to reduce landing frequency and improve quadriceps extensibility are recommended to reduce patellar tendinopathy prevalence in volleyball players.

Joint-specific power-pedaling rate relationships during maximal cycling.

Previous authors have reported power-pedaling rate relationships for maximal cycling. However, the joint-specific power-pedaling rate relationships that contribute to pedal power have not been reported. We determined absolute and relative contributions of joint-specific powers to pedal power across a range of pedaling rates during maximal cycling. Ten cyclists performed maximal 3 s cycling trials at 60, 90, 120, 150, and 180 rpm. Joint-specific powers were averaged over complete pedal cycles, and extension and flexion actions. Effects of pedaling rate on relative joint-specific power, velocity, and excursion were assessed with regression analyses and repeated-measures ANOVA. Relative ankle plantar flexion power (25 to 8%; P = .01; R(2) = .90) decreased with increasing pedaling rate, whereas relative hip extension power (41 to 59%; P < .01; R(2) = .92) and knee flexion power (34 to 49%; P < .01; R(2) = .94) increased with increasing pedaling rate. Knee extension powers did not differ across pedaling rates. Ankle joint angular excursion decreased with increasing pedaling rate (48 to 20 deg) whereas hip joint excursion increased (42 to 48 deg). These results demonstrate that the often-reported quadratic power-pedaling rate relationship arises from combined effects of dissimilar joint-specific power-pedaling rate relationships. These dissimilar relationships are likely influenced by musculoskeletal constraints (ie, muscle architecture, morphology) and/or motor control strategies.

Initial ball flight characteristics of curve and instep kicks in elite women's football.

Initial ball flight characteristics of curve and instep kicks were investigated. Fifteen international female footballers performed curve and instep kicks from a distance of 20 m from goal and at a 1 m2 target. Seventeen Vicon cameras tracked three-dimensional coordinates of four reflective markers adhered to the ball. Ball flight characteristics were quantified, and the coordinates of the ball relative to the target center were recorded. The lateral launch angle and the angle of the spin axis relative to the horizontal best predicted the horizontal placement of the ball relative to the target. The vertical launch angle, antero-posterior velocity and amount of backspin best predicted the vertical coordinate. Regression models demonstrated how carefully controlled the flight characteristics must be with launch angles constrained within 3° to hit the target. Curve kicks were characterized by significantly greater lateral and vertical launch angles, increased sidespin and spin about the antero-posterior axis, and a more vertical spin axis. This information is beneficial for coaches in training players to achieve the characteristics required to score a goal and avoid a defensive wall. For example, if players consistently kick above or below the target, these findings identify the variables that will help rectify that error.

The arterial pole of the mouse heart forms from Fgf10-expressing cells in pharyngeal mesoderm.

Development of the arterial pole of the heart is a critical step in cardiogenesis, yet its embryological origin remains obscure. We have analyzed a transgenic mouse line in which beta-galactosidase activity is observed in the embryonic right ventricle and outflow tract of the heart and in contiguous splanchnic and pharyngeal mesoderm. The nlacZ transgene has integrated upstream of the fibroblast growth factor 10 (Fgf10) gene and comparison with the expression pattern of Fgf10 in pharyngeal mesoderm indicates transgene control by Fgf10 regulatory sequences. Dil labeling shows a progressive movement of cells from the pharyngeal arch region into the growing heart tube between embryonic days 8.25 and 10.5. These data suggest that arterial pole myocardium originates outside the classical heart field.

Ethanol embryotoxicity: direct effects on mammalian embryos in vitro.

Exposure to ethanol retards growth and differentiation in cultured rat embryos during organogenesis. The development of untreated embryos is indistinguishable from growth in utero. These data suggest that the hypoplastic features of children born to chronically alcoholic mothers are due, at least in part, to a direct action of ethanol, which causes reduced embryonic cellular proliferation early in gestation.

Clinicopathologic and diagnostic imaging characteristics of systemic aspergillosis in 30 dogs.

BACKGROUND: Systemic aspergillosis is a serious disease of dogs for which the clinical characteristics are poorly described. OBJECTIVE: To describe the clinical and diagnostic imaging characteristics of dogs with systemic aspergillosis. ANIMALS: Thirty dogs with systemic aspergillosis. METHODS: Retrospective case review. Medical records were reviewed for signalment, clinical features, and results of clinicopathologic testing and diagnostic imaging. Diagnosis was confirmed by culture of Aspergillus terreus (n = 13), Aspergillus deflectus (n = 11), or other Aspergillus spp. (n = 6). RESULTS: Compared with the background hospital population, German Shepherd dogs and female dogs were overrepresented (odds ratio [OR] 43, 95% confidence interval [CI] 20-91, P < .0001, and OR 2.9, 95% CI 1.2-6.7, P= .02), respectively, with 20 of the 30 dogs being German Shepherd dogs and 77% (23 of 30) of the dogs being female. The median age was 4.5 years (range 2-8 years). Anemia, leukocytosis, hyperglobulinemia, azotemia, hypercalcemia, and hypoalbuminemia were present in 8, 21, 12, 9, 8, and 6 dogs, respectively. Diskospondylitis, osteomyelitis and thoracic lymphadenomegaly were present in 16, 10, and 5 dogs, respectively. Sonographic findings were enlarged hypoechoic lymph nodes (n = 12), mottled and irregular kidneys with or without masses (n = 12), pyelectasia, and an aggregate of echogenic material in the renal pelvis (n = 9). Thirteen dogs were treated with antifungal drugs, with survival times ranging from 0 to 25 months after diagnosis. CONCLUSIONS AND CLINICAL IMPORTANCE: Systemic aspergillosis typically involves young to middle-age female German Shepherd dogs, and there are characteristic abdominal ultrasound findings with the disease process. Infection with A. deflectus was as common as A. terreus, and in rare cases, long-term survival was associated with antifungal therapy.

Tryptophan-Mediated Interactions between Tristetraprolin and the CNOT9 Subunit Are Required for CCR4-NOT Deadenylase Complex Recruitment.

The zinc-finger protein tristetraprolin (TTP) binds to AU-rich elements present in the 3' untranslated regions of transcripts that mainly encode proteins of the inflammatory response. TTP-bound mRNAs are targeted for destruction via recruitment of the eight-subunit deadenylase complex "carbon catabolite repressor protein 4 (CCR4)-negative on TATA-less (NOT)," which catalyzes the removal of mRNA poly-(A) tails, the first obligatory step in mRNA decay. Here we show that a novel interaction between TTP and the CCR4-NOT subunit, CNOT9, is required for recruitment of the deadenylase complex. In addition to CNOT1, CNOT9 is now included in the identified CCR4-NOT subunits shown to interact with TTP. We find that both the N- and C-terminal domains of TTP are involved in an interaction with CNOT9. Through a combination of SPOT peptide array, site-directed mutagenesis, and bio-layer interferometry, we identified several conserved tryptophan residues in TTP that serve as major sites of interaction with two tryptophan-binding pockets of CNOT9, previously found to interact with another modulator GW182. We further demonstrate that these interactions are also required for recruitment of the CCR4-NOT complex and TTP-directed decay of an mRNA containing an AU-rich element in its 3'-untranslated region. Together the results reveal new molecular details for the TTP-CNOT interaction that shape an emerging mechanism whereby TTP targets inflammatory mRNAs for deadenylation and decay.

Embryonic asymmetry: left TGFbeta at the right time?

Vertebrates have consistent differences between their left and right sides. In all species, nodal, a transforming growth factor beta superfamily signalling protein, is involved in a late step in the pathways that specify such asymmetry in the embryo. Earlier components seem not so well conserved.

Embryonic asymmetry: the left side gets all the best genes.

The origin of left-right developmental asymmetry is a continuing puzzle, but some recent results provide new insights into the steps leading to organ asymmetry - implicating the homeobox protein Pitz-2 in one key step - and others support a model of symmetry-breaking that involves the chirality of microtubules.

Waves of mouse Lunatic fringe expression, in four-hour cycles at two-hour intervals, precede somite boundary formation.

During somitogenesis, cells are recruited to the caudal presomitic mesoderm (PSM) from the primitive streak (and later the tail bud), while somites separate from the rostral end as epithelial cubes. This is a regular process, one somite forming every 2 hours in the mouse, that can be simulated by clock and wavefront models. The chick basic helix-loop-helix transcription factor encoded by c-hairy1 is expressed in dynamic waves in the PSM, undergoing one cycle for each somite formed. This is compatible with an underlying oscillating molecular clock. We have shown here that Lunatic fringe (L-fng) expression is indicative of it being one of the implementing outputs of this clock. Fringe genes regulate the Notch signalling pathway in boundary formation. Of the known mouse genes, only L-fng is expressed in PSM and it is required for somite segmentation and patterning. We have now shown that L-fng is expressed as dynamic, repetitive and complex waves within the mouse PSM. A wave takes 4 hours to complete one cycle and terminates immediately at, and prior to, somite boundary formation. Consecutive waves are temporally but not spatially overlapping, being initiated in the caudal PSM every 2 hours, so offset by one half-cycle. Waves of expression are not associated with cell movement and do not require cell contact for propagation, so appear to reflect a cell-autonomous clock that is synchronous in all PSM cells.

Tumor promoter actions on rat embryonic development in culture.

The many embryonic and developmental features associated with tumor promotion have prompted us to investigate the effects of a series of phorbol esters and related diterpene tumor promoters on mammalian embryogenesis. A culture system which supports the normal development of 10.4 day organogenesis-phase rat conceptuses was utilized. In this system, 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent Stage I and II promoter, disrupted the morphology and function of the embryonic visceral yolk sac (dose required to affect 50% of conceptuses, 18 nM). The effect was characterized by an abnormal, progressive separation of the two cellular layers of the yolk sac, but cellular differentiation appeared to be uninterrupted. Parallel log dose-response lines for this effect were produced by phorbol-12,13-dibenzoate (dose required to affect 50% of conceptuses, 200 nM) and phorbol-12,13-diacetate (dose required to affect 50% of conceptuses, 300 nM) which are consistent with structure-activity relationships for other promotional actions of these compounds. In addition, the weak Stage I promoter, 4-O-methyl-12-O-tetradecanoylphorbol-13-acetate, produced identical effects but was 1400 times less potent than was TPA, while mezerein, a potent Stage II promoter, was as potent as was TPA. These observations support the hypothesis that embryonic cells may be differentially sensitive to early- and late-stage promoters. Ethylphenylpropiolate, a nonpromoting hyperplastic agent in mouse skin, had no effect on yolk sac morphology or function at its maximum solubility (1.85 mM). Yolk sac disruption by TPA was potentiated by heat inactivation (56 degrees, 30 min) or 0.45-micron filtration of the culture medium. A more advanced stage of yolk sac development was less sensitive to TPA disruption since 11.4 day conceptuses, which were cultured for 30 hr, developed identical lesions, but TPA was at least 5-fold less potent. Thus, the tumor promoter-induced lesions of the rat yolk sac have some features consistent with late-stage tumor promotion and do not appear to be associated with general toxicity, hyperplasia, or alterations in cellular differentiation. We postulate that rat conceptuses maintained in vitro may provide an important model system for the study of the proposed mechanisms involved in chemical tumor promotion.

12-O-tetradecanoylphorbol-13-acetate actions on macromolecular synthesis, ornithine decarboxylase, and cellular differentiation of the rat embryonic visceral yolk sac in culture.

We have reported previously that 12-O-tetradecanoylphorbol-13-acetate (TPA) disrupts the morphology and functional development of the rat embryonic visceral yolk sac (VYS) maintained in a whole-embryo culture system. The TPA-mediated disruption of the VYS is characterized by the abnormal progressive separation of the cellular layers that comprise the VYS and appears to be related to late-stage promotion. The present study further characterizes this effect of TPA on the VYS of rat conceptuses in vitro. VYS ornithine decarboxylase levels were not induced but rather were initially depressed by TPA treatment. There was no major effect of TPA treatment on VYS hemoglobin content, as measured by absorbance at 414 nm and polyacrylamide gel electrophoresis. Changes in VYS hemoglobin synthesis during the culture period, measured by [14C]leucine incorporation with subsequent autoradiography, was likewise not a major effect of TPA treatment. VYS DNA synthesis and VYS RNA synthesis, measured by [3H]thymidine and [3H]uridine incorporation, respectively, were unchanged by TPA treatment. VYS protein synthesis, measured by [3H]leucine incorporation, was initially increased by TPA treatment but returned to control values by the end of the culture period. This increase in [3H]leucine incorporation was not due to a TPA-mediated change in the secretory function of the VYS. The data suggest that the tumor promoter-induced disruption of the VYS is not associated with cellular proliferation, ornithine decarboxylase induction, or alterations in differentiation. Effects on the cell surface, altering cell-cell interactions and/or communication might best explain these actions of TPA.

The role of the brachyury gene in heart development and left-right specification in the mouse.

The midline has a theoretical role in the development of left-right asymmetry, and this is supported by both genetic analyses and experimental manipulation of midline structures in vertebrates. The mouse brachyury (T) gene encodes a transcription factor which is expressed in the developing notochord and is required for its development. T/T mice lack a mature notochord and have a dorsalised neural tube. We have examined the hearts of T/T mice and have found consistent morphological abnormalities, resulting in ventrally displaced ventricular loops, and a 50% incidence of inverted heart situs. Three TGF-beta related genes, lefty-1, lefty-2 and nodal, are expressed asymmetrically in mouse embryos, and are implicated in the development of situs. We find that nodal, which is normally expressed around the node and in left lateral plate mesoderm in early somite embryos, is completely absent at this stage in T/T embryos. In contrast, lefty-1 and lefty-2, which are normally expressed in the left half of prospective floorplate and left lateral plate mesoderm, respectively, are both expressed in T/T embryos only in a broad patch of ventral cells in, and just rostral to, the node region. These results implicate the node as a source of instructive signals driving expression of nodal and lefty-2 in the left lateral plate mesoderm, and being required for normal looping and situs of the heart.

Establishing the anatomic hallmarks of congenitally malformed hearts.

A detailed knowledge of the precise morphology of the congenitally malformed heart has never been more important. In fields as diverse as clinical genetic counseling, epidemiology, surgery, and development biology, a proper description of morphology is essential to understand the cause and prevention of cardiac malformations. There has been a tendency in the past to categorize malformed hearts on the basis of putative developmental faults that are deduced from abnormal morphology, for example "endocardial cushion" or "looping" defects. We consider that this is potentially misleading. A better approach is exactly to determine cardiac structure so as to identify the "hallmark" (or "prototype") morphology of a given lesion. The hallmark will constitute those features, among all the changes in a malformed heart, that best define its fundamental character. As an example of the confusion produced by mechanistic extrapolation, consider the cleft in the anterior leaflet of an otherwise normal mitral valve, compared with the space between the leaflets bridging the ventricular septum in hearts with common atrioventricular junctions and deficient atrioventricular septation ("atrioventricular canal malformations"). It is probably correct to presume that both of these entities result from failure of fusion of the atrioventricular endocardial cushions. It is quite inappropriate, in contrast, to group these two lesions together morphologically, given the major anatomical differences seen in the formed hearts (Sigfússon et al. 1995). Therefore it is also important from the stance of developmental biology that the precise morphology of a genetically or chemically induced lesion be recognized if appropriate inferences are to be drawn for consideration of morphogenetic mechanisms and of comparable lesions in humans.

Cardiac morphology at late fetal stages in the mouse with trisomy 16: consequences for different formation of the atrioventricular junction when compared to humans with trisomy 21.

OBJECTIVE: The mouse with trisomy 16 (Ts16) is held to be a genetic model for humans with Down's syndrome (Ts21). Both trisomies are associated with atrioventricular septal defects, but the precise morphology in the mouse remains unclear. We have therefore characterised cardiac morphology in the mouse with Ts16. METHODS: Ts16 fetuses, from a Rb(11.16)2H/Rb(16.17)7Bnr x C57BL/6J cross, were collected on gestational days 17 or 18 (full term = 19 days) and studied using scanning electron microscopy and serial sections. RESULTS: The hearts showed a spectrum of deficient atrioventricular septation which we categorised into two types. In one, a common atrioventricular junction was separated into right and left orifices by a tongue of tissue joining two valvar leaflets that bridged the ventricular septum to varying extent. In the other, a common atrioventricular junction was connected exclusively to the left ventricle. All hearts had ostium primum atrial and ventricular septal defects, together with abnormal ventriculo-arterial connections. No heart had the typical morphology seen in the human with Down's syndrome, namely a balanced common atrioventricular junction, guarded by a common valve, with the aorta connected exclusively to the left ventricle. CONCLUSIONS: The cardiac defects seen in Ts16 mice show marked differences from the typical anatomy in human Ts21, suggesting more complex mechanisms of cardiac dysmorphogenesis in Ts16. The mouse model will prove valuable in elucidating the mechanism of normal expansion of the atrioventricular junctions, and help in charting the precise steps involved in atrial and ventricular septation.

The mouse with trisomy 16 as a model of human hearts with common atrioventricular junction.

OBJECTIVE: To establish if the mouse with trisomy 16 is a suitable animal model with which to elucidate the development of a common atrioventricular junction. METHODS: The junctional morphologies in the normal human heart and those with a common atrioventricular junction are compared and contrasted. These are then related to observations made in normal mice and those with trisomy 16. So as better to understand development, a full description is given first of the normal atrioventricular junctions. Developmental implications are discussed because failure of fusion of the endocardial cushions cannot account for all the anomalies found in RXR alpha knockout, and in iv/iv mice. RESULTS: Mice with trisomy 16 showed evidence of deficiencies of atrioventricular septation and possessed a common atrioventricular junction, but the valvar orifices were not balanced between the ventricles as is the case in humans. Whilst some mice showed affinities with human tricuspid atresia, other cardiac malformations in the mice had no counterparts in human cardiac pathology. In humans both "partial" and "complete" forms of "atrioventricular canal malformations" share a basically common muscular junctional morphology, the differences being due exclusively to the way the bridging leaflets are fused to each other and/or the septum. CONCLUSIONS: It is simplistic to use the mouse with trisomy 16 as a model for cardiac abnormalities seen in humans. A spectrum more comparable to humans is found in RXR knockout mice. Study of the iv/iv mouse may help elucidate the genetic steps involved in normal and abnormal atrioventricular septation.