Temporal patterning of apical progenitors and their daughter neurons in the developing neocortex.

During corticogenesis, distinct subtypes of neurons are sequentially born from ventricular zone progenitors. How these cells are molecularly temporally patterned is poorly understood. We used single-cell RNA sequencing at high temporal resolution to trace the lineage of the molecular identities of successive generations of apical progenitors (APs) and their daughter neurons in mouse embryos. We identified a core set of evolutionarily conserved, temporally patterned genes that drive APs from internally driven to more exteroceptive states. We found that the Polycomb repressor complex 2 (PRC2) epigenetically regulates AP temporal progression. Embryonic age-dependent AP molecular states are transmitted to their progeny as successive ground states, onto which essentially conserved early postmitotic differentiation programs are applied, and are complemented by later-occurring environment-dependent signals. Thus, epigenetically regulated temporal molecular birthmarks present in progenitors act in their postmitotic progeny to seed adult neuronal diversity.

Children ankle valgus deformity treatment using a transphyseal medial malleolar screw.

INTRODUCTION: Ankle valgus deformity is rare in children. It generally leads to difficulties wearing shoes, walking instability and mechanical pain. No medical treatment is effective and the only option is surgical correction of the deformity. Two main options are available: supramalleolar osteotomy and medial malleolar epiphysiodesis. We report our experience with epiphysiodesis using a transphyseal medial malleolar screw. PATIENTS AND METHODS: This is a retrospective study of all children followed for ankle valgus and treated by transphyseal medial malleolar screw epiphysiodesis in our department. The study included 10 cases of ankle valgus deformity in seven children (four with multiple extostoses, two type 1 neurofibromatosis, one Larsen's syndrome) who completed skeletal maturity. At surgery, median bone age was 12 years (10 to 13 years and 6 months) and the median tibiotalar angle was 17.5° (10° to 30°). RESULTS: At skeletal maturity, preoperative valgus was corrected in six patients (9/10 ankles). The median tibiotalar angle was 5° (0° to 25°). Valgus was not corrected in one patient (30° to 25°). No postoperative complications occurred. DISCUSSION: Epiphysiodesis by transphyseal medial malleolar screw is a simple, efficient and safe procedure to correct a significant or symptomatic ankle valgus deformity in children before skeletal maturity. LEVEL OF EVIDENCE: Level IV, retrospective study.

[Osteochondritis dissecans of the femoral condyles: report of 892 cases]. / L'ostéochondrite disséquante des condyles fémoraux.

PURPOSE OF THE STUDY: Osteochondritis rarely involves the femoral condyles. Discovery in this localization raises several questions concerning the nature of the articular cartilage, the potential for spontaneous healing, and, in the event of a free fragment, the outcome after its loss or repair. MATERIAL AND METHODS: This multicentric study included 892 pediatric and adult cases, the cutoff between two series being defined by fusion of the inferior growth plate. We excluded medical or surgical osteochondritis, cases involving the patella, osteochondral fractures, juvenile polyosteochondrosis, adult osteonecrosis, and osteochondritis beginning after the age of 50 years. RESULTS: Mean age at diagnosis was 16.5 years. Mean age at treatment onset was 22 years. Pain was the predominant symptom. 80% of cases were unilateral and 70% involved the medial condyle. The anatomic lesions were different in adults, showing more advanced degradation. At diagnosis, Bedouelle stages Ia and IIb constituted 80% of the cases observed among children while in adults, 66% were Bedouelle stages IIb to IV. Outcome was very good for the majority of children with Hughston clinical stage 4 while half of the x-rays were Hughston stage 3 and 4. There were thus a large percentage of children with abnormal xrays whose disease history was not yet terminated. In the adult series, the percentages of Hughston 3 and 4 was about the same as clinically. The x-rays were rarely perfectly normal since half of the clinical stage 3 patients were noted in stage 4. An abnormal x-ray with a very good clinical presentation was observed in a very large proportion of patients. DISCUSSION: It is difficult to interpret the plain x-ray and identify patients with a potentially unfavorable prognosis. We defined three radiographic classes: defect, nodule and empty notch. The Bedouelle classification uses information from all available explorations, particularly MRI and arthroscopy. Numerous therapeutic methods are used. Interruption of sports activities is the first intention treatment for children. Data in the literature and the findings of this symposium do not demonstrate any beneficial effect of immobilization on healing compared with simple abstention from sports activities. Transchondral perforation is a simple operation with low morbidity. In 85% of cases, it was used for lesions with an intact joint cartilage considered stable in 96% of cases. Healing was achieved in six months for 48% if the growth plate had not fused. The fragment was fixed in 43% of the cases with a loose cartilage fragment. Outcome was fair but degraded with the state of the joint cartilage and thus the stability of the fragment. Fixation must stabilize the fragment but not prevent further consolidation via osteogenesis. This is why deep perforations are drilled beyond the ossified area and additional osteochondral grafts are used. The Wagner operation gives less satisfactory results than more complicated procedures. Removal of a sequestrum is a simple, minimally invasive procedure with an uneventful postoperative period, but in the long term it favors osteoarthritic degradation, especially when performed in adults. Mosaic grafts give good mid term results. Morbidity is low especially if the grafts are harvested above the notch. The question of chondrolysis around the grafts was beyond the scope of this study. Chondrocyte grafting is difficult to accomplish and is expensive. The mid term results are good for large lesions. Osteotomy is logical only in the event of early stage osteoarthritic degradation. DECISION ALGORITHM IN CHILDREN AND ADOLESCENTS: If the plain x-ray reveals a defect (class I), simple interruption of sports activities should be proposed. Two situations can then develop. First, in a certain number of patients, the pain disappears as the defective zone ossifies progressively. Complete cure is frequent before the age of 12 years. In the second situation, the knee remains painful and the x-ray does not change or worsens to a class II nodular formation. In this case an MRI must be obtained to determine whether the joint cartilage is normal. There are two possibilities. First, the osteochondral fragment is viable and most probably will become completely re-integrated, particularly if the lesion is far from the growth plate. Necrosis is the other possibility. Transchondral perforations are needed in this case. If on the contrary the cartilage is altered, there is little hope for spontaneous cure. Arthroscopy may be needed to complete the exploration. Fragments, especially if there is a large surface area, must be fixed. Perforations to favor revascularization are certainly useful here. In the last situation (class III), the fragment wobbles on a thin attachment or has already fallen into the joint space. This is the type of problem generally observed in adults. The decision algorithm in adults is the same as in children for the rare nodular aspects (class II). There could be a discussion between transcartilage perforation and fixation. If there are a large number of fragments, fixation may not be fully successful and the lesion might be considered class III. For class III lesions, three operations can be used: removal of the sequestrum, mosaic bone-cartilage grafts, or autologous chondrocyte grafts. At the same follow-up, mosaic grafts give better results than excision of sequestra. It may be useful to remove sequestra in a limited number of situations: if there is just a small area of osteochondritis, the lesion is old and partially healed, or the zone is non weight-bearing. For other lesions, we favor mosaic grafts. We still do not have enough follow-up to assess the long-term outcome with these mosaic grafts, but simple excision clearly favors osteoarthritic degradation. Can chondrocytes grafts be compared with mosaic grafts? Chondrocyte grafts have been used for very large lesions and have given results similar to mosaic grafts. It might also be possible to combine fixation of a loose fragment and a mosaic graft. LESSONS FROM THIS STUDY: 1) The prognosis of osteochondritis is better before than after fusion of the growth plate but the lesion does not always heal in children. 2) Presence of osteochondritis requires complementary anatomic and functional exploration to determine the stability and the vitality of the fragment. 3) Attention must be taken to perform transchondral perforations early enough, particularly in children. 4) Screw fixation is not always sufficient. The trophicity of the fragment and its blood supply must be improved. 5) Mosaic grafts are preferable to excision of the fragment. 6) Chondrocyte grafts will be more widely used in the future.

[Lameness in children: diagnostic process]. / Boiterie de l'enfant: démarche diagnostique.

A complete examination including the lower limb, the spine as well as a neurological exam must be done for every limp in children to eliminate an infectious process in particular. The complementary exams are guided by this clinical examination but standard assessment necessitate at least plain X-rays with an AP view of the pelvis and a lateral view of the hips, a blood count with the ESR and the CRP to eliminate rapidly a tumoral or an infectious process which requires quickly an appropriate treatment. In particular cases, this work-up must be repeated in association with other complementary exams to find the etiologic diagnosis. Bone pains in children are often secondary to a true pathologic process. All these examination and work-up must be done before classified them as "growing pain".

[Aneurysmal bone cyst of the spine in children: a 9-year follow-up of 7 cases and review of the literature]. / Kyste anévrysmal du rachis chez l'enfant: sept cas avec un recul moyen de 9 ans et revue de la littérature.

PURPOSE OF THE STUDY: Aneurysmal cyst is an uncommon benign primitive bone tumor generally observed in young subjects, in a spinal localization in 10% of the cases. We report the clinical, radiological, and therapeutic aspects of seven cases of aneurysmal cyst of the spine. MATERIAL AND METHODS: This series included seven children, mean age 11.7 years (range 8-14) who were followed for 9 years on the average (range 2-24 years). Findings were compared with reports in the literature. RESULTS: Four cysts were located in the cervical spine (C1, C3, C4, C7), two in the thoracic spine (T4, T7) and one in the sacrum. Biopsy-resection was performed in six patients. The sacral cyst was treated by selective arterial embolization. Two complications were observed after surgical treatment. Bony filling of the lesion, evaluated by CT scan six months after surgery, was achieved in five cases, incomplete in two without recurrence of cystic cavities. DISCUSSION AND CONCLUSION: Aneurysmal bone cysts account for 15% of all primitive tumors of the spine. They are more frequent in the cervical and thoracic spine than in a lumbar or sacral localization. One vertebra is involved in most cases, generally the vertebral body and the posterior arch with an asymmetrical extension to one pedicle in some cases. Neurological complications of variable severity are frequent and can be improved by surgical removal of the tumor. CT scan and MRI are the best exams to analyze the spinal cyst, to show bony walls and liquid-liquid levels suggestive of aneurysmal bone cyst, to evaluate the tumor extension and to search for cord compression. When the CT scan and MRI show characteristic signs of aneurysmal bone cyst of the spine, we do not perform a biopsy systematically if complete removal of the tumor appears possible. Surgical removal with biopsy is the treatment of choice. Reconstruction and stabilization of the spine must be complete using bone graft with or without instrumentation. In case of medullary involvement, decompression must be performed rapidly with the most complete tumor removal as possible. Selective arterial embolization can be used in some localizations or as preparation to surgery. Radiotherapy is contraindicated in children because of the risk of radio-induced tumors.

Synthesis and SAR of 3- and 4-substituted quinolin-2-ones: discovery of mixed 5-HT(1B)/5-HT(2A) receptor antagonists.

Quinolin-2-ones bearing a heteroaryl-piperazine linked by a two carbon chain at the 3- or 4-position were synthesised and evaluated as mixed 5-HT(1B)/5-HT(2A) receptor antagonists. Potent mixed antagonists were obtained with thieno[3,2-c]pyridine derivatives. In this series, compound 2.1 (SL 65.0472) proved to be functional antagonist at both the 5-HT(2A) receptor (rat in vivo 5-HT-induced hypertension model) and the 5-HT(1B) receptor (dog in vitro saphenous vein assay).

Cognitive impairment in motor neuron disease with bulbar onset.

METHODS: Twenty-three patients with bulbar onset motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) were clinically assessed. They subsequently underwent serial neuropsychological testing, event-related potentials (ERP) and SPECT studies. Cognitive impairment was defined by clinical evidence of dementia (DSM-IV and frontal evaluation) or by significant alteration indicated by neuropsychological testing (excluding patients with depression and major anxiety), or both. RESULTS: Eleven patients (48%) were found to be cognitively impaired. Abnormalities indicated fronto-temporal involvement, with memory impairment, alteration of judgement and reasoning, reduced speech, behavioural dyscontrol and alteration of daily living activities. This impairment correlated well with event-related potentials and SPECT studies. Event-related potentials were the most sensitive test as 100% of the impaired patients had abnormal ERP (p = 0.04). The cognitively impaired group differed from the other group mainly by gender ratio (male/female) with an important male predominance: 1.75 vs. 0.33. MND/ALS was also more severe when cognitive decline was present. CONCLUSION: This study adds further arguments for a cognitive impairment in MND/ALS. This also reinforces the hypothesis that there is continuum between MND/ALS and fronto-temporal lobe dementia.

[Anatomophysiology of the male sexual apparatus in Galen]. / L'anatomo-physiologie de l'appareil genital mâle chez Galien.

Galen builds his andrology on animals dissections which he enlarges upon human anatomy by analogy, so it's very difficult to recognize the organs he describes, especially adenoeideis parastatai. His physiology of male sexual apparatus is based on the theory that semen comes from blood perfectly cooked in gonadics vessels and testicles. As usual, he tries to demonstrate Aristotle's principle on perfection of Nature's acts by experimentation, logic, imagination and sometimes insincerity.

[Congenital pseudarthrosis of the clavicle: 25 childhood cases]. / Pseudarthrose congénitale de la clavicule.

PURPOSE OF THE STUDY: Congenital pseudarthrosis of the clavicle is rare, only 200 cases having been reported. Based on 25 personal cases and an overview of the literature, we try to explain the etiology of this condition and the different kinds of treatment. MATERIAL AND METHODS: A retrospective analysis was performed on twenty-five children (16 females, 9 males, mean age at the end of the follow up - 11.5 yrs) from three different centers. We assessed the outcome of surgical and nonsurgical procedures, based on pain, functional ability, cosmetic results, and x-ray examination. RESULTS: A family background was noted in three children. The lesion always involved the right side. Twenty patients presented a bump over the middle third of the clavicle, thirteen a foreshortened shoulder girdle, three complained of discomfort. In two cases, palpation of the clavicular area was painful. No neurovascular compressive syndrome was reported. None of the patients complained of a decrease in the range of motion or in the strength of the upper limb. X-rays showed a middle third defect. In five cases we found abnormal first ribs. Seventeen patients underwent surgery, at a mean age of 6 years and 4 months. The procedure always included excision of the pseudarthrosis at both ends and internal fixation with a wire or a plate. In only eight cases a bone graft was used. Healing was achieved in fourteen patients. Three patients needed a second surgical procedure. In these 3 cases we had not used bone grafting. All patients had a normal range of shoulder motion, except a twelve year old girl who complained of discomfort of the right upper limb. The cosmetic result was good in eleven cases, one surgical wound was noted as hypertrophic, and one developed a keloid. An asymmetry of the trunk was still noted in seven cases. The x-rays showed symmetric clavicles in ten cases. Eight patients were treated conservatively. All of them had a normal range of motion of the shoulder, six had a good cosmetic result and two cases a poor one. DISCUSSION: According to Alldred, the anomaly results from the failed coalescence of the two primary ossification centers of the clavicle. The overview of the literature and our findings (in one case) confirm that the cartilage which covers both ends of the bone is made of growth cartilage. However, the true mechanism of the nonunion is still unknown. The three familial cases of our work suggest a possible genetic transmission of the disease. The diagnosis is based on the following criteria: right side lesion, found in infancy, without previous fracture, increasing size with growth, without major functional consequences, without neurofibromatosis or cleidocranial dysostosis symptom. X-rays or histologic examination will confirm the diagnosis showing the usual findings described above. Complications of the pseudarthrosis of the clavicle are rare and late. Conservative management appears to give good results as seen with our eight patients. However surgical treatment ensures symmetrical shoulder girdles and good function with few complications. Therefore, we recommend performing an excision of the cartilaginous caps, followed by an iliac bone graft and an internal fixation with wire. Surgical management will be preferred in symptomatic patients, in the case of major or increasing deformity, or on parental request.

[Antique and medieval representations of foetus in utero]. / Les representations du foetus in utero.

Until Renaissance, human foetus had never been drawn, except in an obstetrical manuscript from Moschion. He wrote towards the VIth century A.D. a little work in Latin extracted from Soranos' Gynecia for the instruction of midwives. He reviews the different cases of foetal presentations during delivery, and gives advice on the best method to adopt for each case.

[Translation and commentary of the Hippocrates treatise 'The illness of girls']. / Traduction et commentaire du traité hippocratique 'Des maladies des jeunes filles'.

De Virginibus traditionally belongs to Cnidian gynecologic treatises. The comparison with De Mulieribus shows a great difference in the physiology of menstruation and its diseases. The author, by explaining intelligence by the participation of heart and blood, is far from De Morbo sacro and draws near to Aristole's conceptions. Moreover, its vocabulary and rhetoric style indicate that this fragment can be attributed to a physician of Aristotle's period or later.

[Myotonic seizures; the action of curare or related compounds on myotonia (author's transl)]. / Les crises myotoniques; l'action des curares sur la myotonie.

Myotonic seizures with apnea are alarming but temporary incidents occurring during curaization of a myotonic patient. Experience with regional curaization in myotonia shows that it is induced only by suxamethonium and it is only an exaggeration of the fasciculations produced by this compound. In contrast, however, competitive curare compounds have no effect on myotonia. The myotonic seizure, which is specific to myotonia, is radically different from the other respiratory accidents common to muscular dystrophies.