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.

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.

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.

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.

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.

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.

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.

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.

Salicylidene salicylhydrazide, a selective inhibitor of beta 1-containing GABAA receptors.

1. A high-throughput assay utilizing the voltage/ion probe reader (VIPR) technology identified salicylidene salicylhydrazide (SCS) as being a potent selective inhibitor of alpha2beta1gamma1 GABA(A) receptors with a maximum inhibition of 56+/-5% and an IC(50) of 32 (23, 45) nm. 2. Evaluation of this compound using patch-clamp electrophysiological techniques demonstrated that the compound behaved in a manner selective for receptors containing the beta1 subunit (e.g. maximum inhibition of 68.1+/-2.7% and IC(50) value of 5.3 (4.4, 6.5) nm on alpha2beta1gamma1 receptors). The presence of a beta1 subunit was paramount for the inhibition with changes between alpha1 and alpha2, gamma1 and gamma2, and the presence of a subunit having little effect. 3. On all subtypes, SCS produced incomplete inhibition with the greatest level of inhibition at alpha1beta1gamma1 receptors (74.3+/-1.4%). SCS displayed no use or voltage dependence, suggesting that it does not bind within the channel region. Concentration - response curves to GABA in the presence of SCS revealed a reduction in the maximum response with no change in the EC(50) or Hill coefficient. In addition, SCS inhibited pentobarbitone-induced currents. 4. Threonine 255, located within transmembrane domain (TM) 1, and isoleucine 308, located extracellularly just prior to TM3, were required for inhibition by SCS. 5. SCS did not compete with the known allosteric modulators, picrotoxin, pregnenolone sulphate, dehydroepiandrosterone 3-sulphate, bicuculline, loreclezole or mefenamic acid. Neither was the inhibition by SCS influenced by the benzodiazepine site antagonist flumazenil. 6. In conclusion, SCS is unique in selectively inhibiting GABA(A) receptors containing the beta1 subunit via an allosteric mechanism. The importance of threonine 255 and isoleucine 308 within the beta1 subunit and the lack of interaction with a range of GABA(A) receptor modulators suggests that SCS is interacting at a previously unidentified site.

Decreasing fibrogenesis: an immunohistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B.

BACKGROUND: Activation of hepatic stellate cells is the earliest step in fibrogenesis. Alpha-smooth muscle actin (alpha-SMA), expressed by activated hepatic stellate cells, and C-terminal procollagen alpha1(III) propeptide (PIIICP) are early markers of fibrogenesis and should precede fibrosis. AIM: Determine if suppression of hepatitis B virus replication with lamivudine would decrease fibrogenesis as measured by immunohistochemical markers. METHODS: Paired liver biopsies from patients with hepatitis B before and after therapy with lamivudine (n=47) or placebo (n=33) were studied. alpha-SMA and PIIICP were detected in paraffin-embedded tissue by immunohistochemistry and quantified in a blinded manner by video imaging analysis. RESULTS: Liver biopsies from patients treated with lamivudine showed a significant decrease in alpha-SMA expression (1.06+/-0.23 vs. 0.58+/-0.11, pre vs. post, P<0.05). Placebo recipients had increased levels of alpha-SMA (0.82+/-0.14 vs. 1.32+/-0.21, P<0.05). PIIICP was similarly decreased after lamivudine. Among subjects whose Histologic Activity Index fibrosis score was unchanged or worsened, the mean change in alpha-SMA expression was significantly decreased in the lamivudine group compared with placebo. CONCLUSIONS: Lamivudine decreased markers of hepatic stellate cell activation and collagen synthesis. Immunohistochemical techniques are sensitive for assessing fibrogenesis and will be useful in trials of antiviral and antifibrotic agents.

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.

Septation and valvar formation in the outflow tract of the embryonic chick heart.

There is no agreement, in the chick, about the number of the endocardial cushions within the outflow tract or their pattern of fusion. Also, little is known of their relative contributions to the formation of the arterial valves, the subpulmonary infundibulum, and the arterial valvar sinuses. As the chick heart is an important model for studying septation of the outflow tract, our objective was to clarify these issues. Normal septation of the outflow tract was studied in a series of 60 staged chick hearts, by using stained whole-mount preparations, serial sections, and scanning electron microscopy. A further six hearts were examined subsequent to hatching. At stage 21, two pairs of endocardial cushions were seen within the developing outflow tract. One pair was positioned proximally, with the other pair located distally. By stage 25, a third distal cushion had developed. This finding was before the appearance of two further, intercalated, endocardial cushions, also distally positioned, which were first seen at stage 29. In the arterial segment, the aortic and pulmonary channels were separated by the structure known as the aortopulmonary septum. The dorsal limb of this septum penetrated the distal dorsal cushion, whereas the ventral limb grew between the remaining two distal cushions, both of which were positioned ventrally. The three distal endocardial cushions, and the two intercalated endocardial cushions, contributed to the formation of the leaflets and sinuses of the arterial roots. The two proximal cushions gave rise to a transient septum, which later became transformed into the muscular component of the subpulmonary infundibulum. Concomitant with these changes, an extracardiac tissue plane was formed which separated this newly formed structure from the sinuses of the aortic root. Our study confirms that three endocardial cushions are positioned distally, and two proximally, within the developing outflow tract of the chick. The pattern of the distal cushions, and the position of the ventral limb of the aortopulmonary septum, differs significantly from that seen in mammals.

Regulation of left-right asymmetry by thresholds of Pitx2c activity.

Although much progress has been made in understanding the molecular mechanisms regulating left-right asymmetry, the final events of asymmetric organ morphogenesis remain poorly understood. The phenotypes of human heterotaxia syndromes, in which organ morphogenesis is uncoupled, have suggested that the early and late events of left-right asymmetry are separable. The Pitx2 homeobox gene plays an important role in the final stages of asymmetry. We have used two new Pitx2 alleles that encode progressively higher levels of Pitx2c in the absence of Pitx2a and Pitx2b, to show that different organs have distinct requirements for Pitx2c dosage. The cardiac atria required low Pitx2c levels, while the duodenum and lungs used higher Pitx2c doses for normal development. As Pitx2c levels were elevated, the duodenum progressed from arrested rotation to randomization, reversal and finally normal morphogenesis. In addition, abnormal duodenal morphogenesis was correlated with bilateral expression of Pitx2c. These data reveal an organ-intrinsic mechanism, dependent upon dosage of Pitx2c, that governs asymmetric organ morphogenesis. They also provide insight into the molecular events that lead to the discordant organ morphogenesis of heterotaxia.

Misexpression of noggin leads to septal defects in the outflow tract of the chick heart.

BMP-2 and BMP-4 are known to be involved in the early events which specify the cardiac lineage. Their later patterns of expression in the developing mouse and chick heart, in the myocardium overlying the atrioventricular canal (AV) and outflow tract (OFT) cushions, also suggest that they may play a role in valvoseptal development. In this study, we have used a recombinant retrovirus expressing noggin to inhibit the function of BMP-2/4 in the developing chick heart. This procedure resulted in abnormal development of the OFT and the ventricular septum. A spectrum of abnormalities was seen ranging from common arterial trunk to double outlet right ventricle. In hearts infected with noggin virus, where the neural crest cells have been labelled, the results show that BMP-2/4 function is required for the migration of neural crest cells into the developing OFT to form the aortopulmonary septum. Prior to septation, misexpression of noggin also leads to a decrease in the number of proliferating mesenchymal cells within the proximal cushions of the outflow tract. These results suggest that BMP-2/4 function may mediate several key events during cardiac development.

MLC3F transgene expression in iv mutant mice reveals the importance of left-right signalling pathways for the acquisition of left and right atrial but not ventricular compartment identity.

Abstract Transcriptional differences between left and right cardiac chambers are revealed by an nlacZ reporter transgene controlled by regulatory sequences of the MLC3F gene, which is expressed in the left ventricle (LV), atrioventricular canal (AVC), and right atrium (RA). To examine the role of left-right signalling in the acquisition of left and right chamber identity, we have investigated MLC3F transgene expression in iv mutant mice. iv/iv mice exhibit randomised direction of heart looping and an elevated frequency of associated laterality defects, including atrial isomerism. At fetal stages, 3F-nlacZ-2E transgene expression remains confined to the morphological LV, AVC, and RA in L-loop hearts, although these appear on the opposite side of the body. In cases of morphologically distinguishable right atrial appendage isomerism, both atrial appendages show strong transgene expression. Conversely, specimens with morphological left atrial appendage isomerism show only weak expression in both atrial appendages. The earliest left-right atrial differences in the expression of the 3F-nlacZ-2E transgene are observed at E8.5. DiI labelling experiments confirmed that transcriptional regionalisation of the 3F-nlacZ-2E transgene at this stage reflects future atrial chamber identity. In some iv/iv embryos at E8.5, the asymmetry of 3F-nlacZ-2E expression was lost, suggesting atrial isomerism at the transcriptional level prior to chamber formation. These data suggest that molecular specification of left and right atrial but not ventricular chambers is dependent on left-right axial cues.

Posterior subcapsular and nuclear cataract after vitrectomy.

PURPOSE: To examine the morphological changes in the postvitrectomy lens and to monitor the development of these changes over time. SETTING: Oxford Eye Hospital, Oxford, United Kingdom. METHODS: In this prospective study, 33 consecutive phakic patients having pars plana vitrectomy were recruited. Cataract development was quantified by clinical grading and digital Scheimpflug image analysis. Slitlamp biomicroscopy and photography were used to document the morphological appearance. The main outcome measures were the incidence, morphology, and development of posterior subcapsular and nuclear cataract. RESULTS: A characteristic, transient posterior subcapsular cataract (PSC) was present in 89% (17 of 19) of tamponade patients within 24 hours of surgery. Of the patients who had vitrectomy without tamponade, 9% (1 of 11) developed similar changes. Nuclear opacity developed in 61% (11 of 18) of tamponade patients and in 50% (3 of 6) of nontamponade patients. A longer term retrospective review of the same patients' case notes revealed nuclear cataract in 67% (12 of 18) of tamponade cases and 30% (3 of 10) of nontamponade cases. Eighteen percent (2 of 11) of nontamponade cases and 67% (14 of 21) of tamponade cases had cataract surgery after a 10.7 month and a 12.4 month follow-up, respectively. CONCLUSIONS: Vitrectomy and tamponade produced a characteristic transient PSC in the immediate postoperative period. Disruption of fluid balance in the region of the posterior lens was suggested by the morphological appearance. The acute changes resolved but were followed by accelerated nuclear opacification.

Development of the human pulmonary vein and its incorporation in the morphologically left atrium.

OBJECTIVE: Using a newly acquired archive of previously prepared material, we sought to re-examine the origin of the pulmonary vein in the human heart, aiming to determine whether it originates from the systemic venous sinus ("sinus venosus"), or appears as a new structure draining to the left atrium. In addition, we examined the temporal sequence of incorporation of the initially solitary pulmonary vein to the stage at which four venous orifices opened to the left atrium. METHODS: We studied 26 normal human embryos, ranging from 3.8 mm to 112 mm crown-rump length, and representing the period from the 12th Carnegie stage to 15 weeks of gestation. RESULTS: The pulmonary vein canalised as a solitary vessel within the mediastinal tissues so as to connect the intraparenchymal pulmonary venous networks to the heart, using the regressing dorsal mesocardium as its portal of cardiac entry. The vein was always distinct from the tributaries of the embryonic systemic venous sinus. The orifice of the solitary vein became committed to the left atrium by growth of the vestibular spine. During development, a marked disparity was seen between the temporal and morphological patterns of incorporation of the left-sided and right-sided veins into the left atrium. The pattern of the primary bifurcation was asymmetrical, a much longer tributary being formed on the left than on the right. Contact between the atrial wall and the venous tributary on the left initially produced a shelf, which became effaced with incorporation of the two left-sided veins into the atrium. CONCLUSIONS: The initial process of formation of the human pulmonary vein is very similar to that seen in animal models. The walls of the initially solitary vein in humans become incorporated by a morphologically asymmetric process so that four pulmonary veins eventually drain independently into the left atrium. Failure of incorporation on the left side may provide the substrate for congenital division of the left atrium.

Spinal malformations in the fetuses of HIV infected women receiving combination antiretroviral therapy and co-trimoxazole.

HIV positive women of reproductive age are increasingly treated with a combination of antiretroviral agents, with effects on the developing human fetus that are largely unknown. We report two cases of severe spinal malformations in the fetuses of women treated with combination antiretroviral therapy and co-trimoxazole.