Peg3/Pw1 is an imprinted gene involved in the TNF-NFkappaB signal transduction pathway.

Tumor necrosis factor (TNF) mediates a variety of biological activities including cell proliferation, differentiation and programmed cell death. The specific response to TNF depends upon cell type and reflects the presence of specific regulatory proteins that participate in the TNF response pathway. TNF signal transduction is mediated by TRAF2 which binds the TNF Receptor2 (TNFR2) and activates NFkappaB. We previously identified a gene Pw1, which encodes a large zinc-finger containing protein. We have determined that Pw1 is identical to Peg3, a paternally expressed gene of unknown function (and will therefore be referred to as Peg3 throughout this text). We report here that Peg3 associates specifically with TRAF2 but not with other TRAF family members. Peg3 expression activates NFkappaB via IkappaB-NFkappaB dissociation and acts synergistically with TRAF2. Transfection of a truncated Peg3 containing the TRAF2 interaction site, abolishes NFkappaB activation by TRAF2 and/or TNF. We conclude that Peg3 is a regulator of the TNF response. These data reveal the involvement of an imprinted gene in this pathway.

CDO, a robo-related cell surface protein that mediates myogenic differentiation.

CDO, a member of the Ig/fibronectin type III repeat subfamily of transmembrane proteins that includes the axon guidance receptor Robo, was identified by virtue of its down-regulation by the ras oncogene. We report here that one prominent site of cdo mRNA expression during murine embryogenesis is the early myogenic compartment (newly formed somites, dermomyotome and myotome). CDO is expressed in proliferating and differentiating C2C12 myoblasts and in myoblast lines derived by treating 10T1/2 fibroblasts with 5-azacytidine, but not in parental 10T1/2 cells. Overexpression of CDO in C2C12 cells accelerates differentiation, while expression of secreted soluble extracellular regions of CDO inhibits this process. Oncogenic Ras is known to block differentiation of C2C12 cells via downregulation of MyoD. Reexpression of CDO in C2C12/Ras cells induces MyoD; conversely, MyoD induces CDO. Reexpression of either CDO or MyoD rescues differentiation of C2C12/Ras cells without altering anchorage-independent growth or morphological transformation. CDO and MyoD are therefore involved in a positive feedback loop that is central to the inverse relationship between cell differentiation and transformation. It is proposed that CDO mediates, at least in part, the effects of cell-cell interactions between muscle precursors that are critical in myogenesis.

The expression of myosin genes in developing skeletal muscle in the mouse embryo.

Using in situ hybridization, we have investigated the temporal sequence of myosin gene expression in the developing skeletal muscle masses of mouse embryos. The probes used were isoform-specific, 35S-labeled antisense cRNAs to the known sarcomeric myosin heavy chain and myosin alkali light chain gene transcripts. Results showed that both cardiac and skeletal myosin heavy chain and myosin light chain mRNAs were first detected between 9 and 10 d post coitum (p.c.) in the myotomes of the most rostral somites. Myosin transcripts appeared in more caudal somites at later stages in a developmental gradient. The earliest myosin heavy chain transcripts detected code for the embryonic skeletal (MHCemb) and beta-cardiac (MHC beta) isoforms. Perinatal myosin heavy chain (MHCpn) transcripts begin to accumulate at 10.5 d p.c., which is much earlier than previously reported. At this stage, MHCemb is the major MHC transcript. By 12.5 d p.c., MHCpn and MHCemb mRNAs are present to an equal extent, and by 15.5 d p.c. the MHCpn transcript is the major MHC mRNA detected. Cardiac MHC beta transcripts are always present as a minor component. In contrast, the cardiac MLC1A mRNA is initially more abundant than that encoding the skeletal MLC1F isoform. By 12.5 d p.c. the two MLC mRNAs are present at similar levels, and by 15.5 d p.c., MLC1F is the predominant MLC transcript detected. Transcripts for the ventricular/slow (MLC1V) and another fast skeletal myosin light chain (MLC3F) are not detected in skeletal muscle before 15 d p.c., which marks the beginning of the fetal stage of muscle development. This is the first stage at which we can detect differences in expression of myosin genes between developing muscle fibers. We conclude that, during the development of the myotome and body wall muscles, different myosin genes follow independent patterns of activation and accumulation. The data presented are the first detailed study of myosin gene expression at these early stages of skeletal muscle development.

Developmental regulation of myosin gene expression in mouse cardiac muscle.

Expression of the two isoforms of cardiac myosin heavy chain (MHC), MHC alpha and MHC beta, in mammals is regulated postnatally by a variety of stimuli, including serum hormone levels. Less is known about the factors that regulate myosin gene expression in rapidly growing cardiac muscle in embryos. Using isoform-specific 35S-labeled cRNA probes corresponding to the two MHC genes and the two myosin alkali light chain (MLC) genes expressed in cardiac muscle, we have investigated the temporal and spatial pattern of expression of these different genes in the developing mouse heart by in situ hybridization. Between 7.5 and 8 d post coitum (p.c.), the newly formed cardiac tube begins to express MHC alpha, MHC beta, MLC1 atrial (MLC1A), and MLC1 ventricular (MLC1V) gene transcripts at high levels throughout the myocardium. As a distinct ventricular chamber forms between 8 and 9 d p.c., MHC beta mRNAs begin to be restricted to ventricular myocytes. This process is complete by 10.5 d p.c. During this time, MHC alpha mRNA levels decrease in ventricular muscle cells but continue to be expressed at high levels in atrial muscle cells. MHC alpha transcripts continue to decrease in ventricular myocytes until 16 d p.c., when they are detectable at low levels, but then increase, and finally replace MHC beta mRNAs in ventricular muscle by 7 d after birth. Like MHC beta, MLC1V transcripts become restricted to ventricular myocytes, but at a slower rate. MLC1V mRNAs continue to be detected at low levels in atrial cells until 15.5 d p.c. MLC1A mRNA levels gradually decrease but are still detectable in ventricular cells until a few days after birth. This dynamic pattern of changes in the myosin phenotype in the prenatal mouse heart suggests that there are different regulatory mechanisms for cell-specific expression of myosin isoforms during cardiac development.

[Prevention and management of the conflict patient-doctor]. / Prévention et gestion du conflit médecin-patient.

A surgeon's daily practice evolves according to techniques, but also according to a legal and associative environment. The patient is becoming a health consumer, demanding and informed, legitimately exacting security and transparency, but also compensation in the event of accidental injury. The constraints that weigh upon this profession are growing heavier: knowledge and respect of laws, ordinances and regulations are becoming essential and law suits more and more frequent. Ever present in surgery, risk evaluation and assessing the risk-benefit ratio for the patient must be clearly stated by the practitioner and his team, despite the inherent difficulties in sharing information. A classification of surgical risk facilitates an approach to the definitions of a fault, medical accident, iatrogenic condition or undesirable event. This is a fundamental concept, since precise criteria apply to a fault in the legal sense, whereas no normative definition exists for a medical fault. Prevention of conflict requires the implementation of collective steps aimed at ensuring security in a complex system, confidence between the surgeon and his patient based on appropriate information and strict adherence to current regulations. In the event of complications, difficult after-effects, objectively unsatisfactory results or those perceived as such by the patient, post-operative follow-up must face these difficulties squarely with transparency and responsibility. Following a legal summons involving the responsibility of the practitioner, management of the conflict between the physician and the patient requires solid preparation of the medical file and his active participation in the judicial expertise so as to best inform the judge.

Differential expression patterns of Wnt genes in the murine female reproductive tract during development and the estrous cycle.

The murine female reproductive tract differentiates during postnatal development. This process of cytodifferentiation and morphogenesis is dependent upon specific mesenchymal-epithelial interactions as well as circulating steroid hormones (Cunha, G.R., 1976. Int. Rev. Cytol. 47, 137-194; Pavlova, A. et al., 1994. Development 120, 335-346). Members of the Wnt family of signaling molecules have been recently identified in this system (Pavlova, A. et al., 1994. Development 120, 335-346; Bui, T.D. et al., 1997. Br. J. Cancer 75, 1131-1136; Miller, C., Sassoon, D.A., 1998. Development, in press). We describe the expression patterns of Wnt genes in the developing and adult female reproductive tract. Additionally, we note that changes in the levels of expression occur during the estrous cycle. Wnt gene expression patterns are regulated by the presence of epithelium in tissue graft experiments, suggesting that Wnt genes may indeed play roles in the mesenchymal-epithelial interactions critical for female reproductive tract development and function.

Restricted expression of type-II TGF beta receptor in murine embryonic development suggests a central role in tissue modeling and CNS patterning.

The type-II TGF beta receptor mediates many of the biological responses to TGF beta. An examination of the expression of the type-II TGF beta receptor during mouse embryogenesis therefore provides specific information about the role of TGF beta during embryogenesis than has been available to date. We have isolated the genomic murine homologue of the human type-II TGF beta receptor corresponding to exon 2. The murine and human sequences show a high degree of homology. Using the murine probe, we found that type-II TGF beta receptor expression is regulated in both a spatial and a temporal fashion by using in situ hybridization and ribonuclease protection assays. Type-II TGF beta receptor expression is localized to the mesenchyme during critical interactions with adjacent epithelium such as developing hair follicles, whisker follicles and tooth anlage. In the central nervous system, type-II TGF beta receptor expression is highly restricted to the floor plate. Strong expression is also detected in migrating neural crest cells, meninges, and choroid plexus. Specific mesenchymal localization of type-II TGF beta receptor is also observed in lung, kidney, intestine, stomach, and bladder. The restricted expression of type-II TGF beta receptor in mesenchymal cells at sites of epithelial-mesenchymal interactions suggests that type-II TGF beta receptor plays a major role in mediating the establishment of embryonic organ systems. The highly restricted expression of type-II TGF beta receptor in the developing CNS suggests an important role for a serine/threonine kinase in patterning of the nervous system.

Wnt genes and endocrine disruption of the female reproductive tract: a genetic approach.

Reproductive tract development and function is regulated by circulating steroid hormones. In the mammalian female reproductive tract, estrogenic compounds direct many aspects of cytodifferentiation including uterine gland formation, smooth muscle morphology, and epithelial differentiation. While it is clear that these hormones act through their cognate nuclear receptors, it is less clear what signaling events follow hormonal stimulation that govern cytodifferentiation. Recent advances in molecular embryology and cancer cell biology have identified the Wnt family of secreted signaling molecules. Discussed here are recent advances that point to a definitive role during uterine development and adult function for one member of the Wnt gene family, Wnt-7a. In addition, recent data is reviewed that implicates Wnt-7a deregulation in response to pre-natal exposure to the synthetic estrogenic compound, DES. These advances point to an important role for the Wnt gene family in various reproductive tract pathologies including cancer.

The biophysical profile in labor.

To determine whether the biophysical profile would be a valuable intrapartum addition to fetal heart rate monitoring in predicting umbilical arterial acid-base status at delivery, 95 patients at term had serial studies during labor and umbilical artery blood gas analysis. There was no significant association between biophysical profile score and cord blood pH, nor was there a difference in scores between the acidemic and nonacidemic groups. Of the five components of the initial biophysical profile, only a nonreactive nonstress test (NST) was associated with both pH 7.20 or less (P = .019) and metabolic acidemia (P = .016). None of the individual variables of the final examination correlated with a pH of 7.20 or less. However, a nonreactive NST was associated with metabolic acidemia (P = .03), as was the presence of breathing (P = .03). Of the ten infants with pH 7.20 or less, eight had an initial and five had a final biophysical profile score of 8 or higher. Of the five whose pH was less than 7.15, four had an initial and three a final score of 8 or more. Finally, of the five with metabolic acidemia, four had an initial and two a final score of 8 or higher. Half of the acidemic fetuses had final biophysical profile scores of 8 or higher, suggesting that this score in labor is not reliable to rule out acidemia at delivery.(ABSTRACT TRUNCATED AT 250 WORDS)

Perinatal outcome in triplet versus twin gestations.

The present study was conducted to determine whether triplet pregnancies are associated with a significantly worse perinatal outcome than twin pregnancies. Maternal and neonatal outcome was evaluated in 15 triplet and twin pregnancies that were matched for maternal age, race, type of medical insurance, delivery mode, parity, and history of previous preterm delivery. Preterm labor occurred significantly more often in triplet than in twin gestations (80 versus 40%), as did preterm delivery (87 versus 26.7%). Triplets had a significantly lower mean birth weight (1720 versus 2475 g) and gestational age at delivery (33 versus 36.6 weeks). In addition, 53.3% of triplet pregnancies but only 6.7% of twin pregnancies had one or more neonates with intrauterine growth retardation. Discordancy also occurred more frequently in triplets than in twins (66.7 versus 13.3%). The mean averaged neonatal hospital stay was significantly higher in triplets (29 versus 8.5 days), and triplets had a fivefold increased risk of requiring neonatal intensive care as compared with twins. However, there were no significant differences between the groups in maternal morbidity or major neonatal complications such as respiratory distress syndrome or intraventricular hemorrhage. We believe that these data will be useful in counseling patients with respect to the anticipated perinatal outcome of triplet pregnancies.

Uterine leiomyomas in pregnancy: a prospective study.

Uterine leiomyomas are associated with various complications during pregnancy. During a 2-year period, pregnant women with a history of leiomyomas were referred to our antenatal testing unit for ultrasound evaluation. Eighty-five patients were found to have single or multiple leiomyomas by ultrasound examination. The size (total leiomyoma volume), number, and location of the leiomyoma(s) were ascertained. Each woman with leiomyoma(s) was matched by age, race, and parity with one without leiomyomas. Both groups were followed throughout pregnancy, and outcomes were compared. Size, number, or location of the leiomyoma had no influence on outcome. Student t test indicated a significantly (P less than .01) lower mean gestational age at the time of delivery in women with leiomyomas.

[Musculoskeletal disorders of the upper extremity associated with work: from presentation to work maintenance]. / Les troubles musculosquelettiques du membre supérieur liés au travail: de la présentation au maintien à l'emploi.

The so called Musculo-Squeletal-Disorders in the upper extremity are frequent and are responsible for a significant cost. The increase in registered work-related affections has been quite impressive in the past few years. The type of social undertaking is determinant on the evolution and final outcome of the pathology. Our proposal for a "Passport to work continuation" follows two goals: facilitate and enhance the relations between medical and social workers concerned by the patient's course reduce the time off-work, improve prevention of work related pathologies, avoid dismissal for inaptitude, start earlier a vocational training, a rehabilitation or an adaptation of the work station.

[Eight days of hand emergencies. Report of the audit carried out at the FESUM centers from June 3 to June 9, 2002]. / Huit jours d'urgences mains. Rapport de l'audit réalisé dans les centres FESUM du 3 au 9 juin 2002.

All the FESUM centers in France, Belgium and Switzerland were invited to participate in this prospective audit, during 1 week in June 2002. In these FESUM centers, the patients are operated by senior hand surgeons or trainees graduated with a microsurgical and a hand surgery University degrees. All acute hand disorders, requiring surgery or not, were to be included. For every case, a standardized form was to be filled. This form included 22 fields concerning the specificities of the patient, the circumstances of the accident, the lesions and initial treatment up to exit of the patient out of the Hand Center. Out of the 43 French centers, 38 (90%) participated in this study, but only 30% in the other French speaking countries. A total of 2360 forms were completed and analyzed, representing a mean of 8 forms per day center (6-147). The population was predominantly active men with a mean age of 31. Manual workers represented 41%, scholars 33%. Most of them came to the Hand Center with a non-specilized vehicle (86%). Emergency medical transportation was required in 130 cases (5.8%). A majority of the patients were treated on an outdoor basis. A 1-day admission concerned 29% of the patients, and 4.6% have been admitted on an indoor basis during several days. Work accident represented 28% of all the cases, while the majority was daily living (62%) or sport (15%) accidents. Closed trauma represented 50% of the cases. Amongst open trauma (974 cases), 862 were simple skin lacerations, 156 skin loss, 140 extensor tendon lacerations, 70 flexor tendon lacerations. A preliminary wound exploration had been performed in a non-specialized center in 124 cases (12%). Complete amputation of some part was observed in 33 cases. In 32%, the initial severity of the lesion led to expect some degree of definitive consequences. Some kind of anesthesia was required in 43% of the cases (local in 41%, troncular in 19%, plexical in 28% and general in 9%). A surgical procedure was performed in 45% of the patients. Microsurgery was necessary in 15%, six of which were replantations. The period between presentation to the Hand Center and treatment was less than 1 day in 95% of the cases. Time of treatment was considered to be delayed in 113 cases (5%). Following this audit, it is considered that the FESUM centers make provision for the care of 120,000 cases per year, 54,000 of which needing a surgical procedure. This may be a small part of the total load of emergency hand surgery throughout the country (generally estimated over 1.4 million), but compares quite favorably with other European studies. We believe that improvement relies essentially on a better orientation of the patients whether they need a simple skill or specialist skill treatment. An information leaflet about orientation of hand trauma has been distributed to non-specialized emergency centers. Hand surgery training must be reevaluated inside the universitary system to avoid a dramatic lack of hand surgeons within a few years. A new audit will be presented next year.

[Trigger digits]. / Les doigts à ressort.

Trigger finger is an entity seen commonly by hand surgeons. It is produced by a size mismatch between the flexor tendon and the A1 pulley, which causes pain, clicking, catching, and loss of motion of the affected finger. The diagnosis is usually easy but other pathological processes (extensor apparatus instability, locked metacarpo-phalangeal joint) must be excluded. Treatment modalities in trigger finger include splinting, corticosteroid injection and/or surgery. Indication depends on the clinical form of trigger finger.

Quantitative optical coherence tomography of arterial wall components.

Optical coherence tomography (OCT) can be used to visualize the arterial wall and atherosclerotic plaques with high resolution. In this study, we verified the application of OCT to the quantitative analysis of plaque structural dimensions and optical attenuation coefficients of the components. We assessed the effect of balloon dilation on the OCT signal from the medial layer of porcine carotid artery ex vivo. Imaging of human autopsy samples was performed from the luminal side with a high (3.5 microm axial and 7 microm lateral) resolution OCT system (approximately 800 nm) or a regular (15-20 microm axial and 20 microm lateral resolution) OCT system (approximately 1,300 nm). For each sample, dimensions were measured by histomorphometry and OCT, and the optical attenuation was measured. In a tissue culture set-up, porcine carotid arteries were dilated and the attenuation coefficients of the dilated segments were compared to a control segment for 4 h. Quantitative analysis showed a strong and significant correlation between OCT and histology cap thickness measurements for both OCT systems. For both systems, the measured attenuation coefficients for diffuse intimal thickening and lipid-rich regions differed significantly from that of calcified tissue. Balloon dilation induced a time-dependent increase in the attenuation coefficient, which may be attributed to the induction of apoptosis. In conclusion both the high and regular resolution OCT systems can image the atherosclerotic plaques precisely. Quantitative analysis of the OCT signals allowed in situ determination of the intrinsic optical attenuation coefficient for atherosclerotic tissue components within regions of interest, which can help to discriminate between plaque and arterial wall components.