Comparative theoretical studies of the phosphomonoester hydrolysis mechanism by purple acid phosphatases.

We present here the first ONIOM (our own n-layered integrated molecular orbital + molecular mechanics method) studies of a purple acid phosphatase enzyme. Our study focused on the structures of the red kidney bean PAP (kbPAP) complexed with phosphate and with phenyl phosphate and on the mechanism of the phenyl phosphate hydrolysis by the enzyme. Density functional theory (DFT) calculations were also performed using models of different sizes for comparison purpose. Results show that the inclusion of three histidine residues, His202, His295, and His296, with their protein surrounding, is crucial to properly describe the coordination of the substrates. They induce a conformation with the substrate closer to the nucleophilic mu-hydroxyde bridge. In the mechanistic study, a transition state is stabilized by a strong hydrogen bond between His202 and the leaving group of the substrate. Consequently, a smaller value for the activation energy barrier is obtained from DFT calculations including this histidine to the same calculations without this histidine. Using the ONIOM method, this activation energy barrier is even more reduced. So the mechanism, which considers the hydroxo group bridging the two metal ions as nucleophile, becomes really convincing, contrary to the results obtained with a small model at the DFT level.

[Pigmented villonodular synovitis in children: review of six cases]. / La synovite villonodulaire de l'enfant : une revue de six cas.

PURPOSE OF THE STUDY: Pigmented villonodular synovitis is an exceptional condition in children. The clinical, biological and imaging presentation is not specific and a histology sample is required for certain diagnosis. Because of this lack of specificity, together with the rare occurrence of the disease, late diagnosis is not uncommon, making correct management an even greater challenge in the growing child. MATERIAL AND METHOD: Between 1995 and 2001, six children were treated for pigmentary villonodular synovitis, four girls and two boys, mean age 11.5 years. The knee was involved in five cases (three diffuse forms and two localized forms). One diffuse form involved the ankle. The diagnosis was suggested by the MRI findings in all patients and confirmed at the histological examination of a biopsy sample. Surgery was used in five cases and medical treatment in one patient with a diffuse form affecting the knee. A synoviorthesis (Hexatrione) was used systematically in three diffuse forms affecting the knee joint. RESULTS: Mean follow-up was 58 months. Recurrence was noted in two diffuse forms, one involving the knee at 10 months from arthroscopic synovectomy and one involving the ankle 24 months after surgical synovectomy. Systematic use of the synoviorthesis did not prevent recurrence in one case. The synoviorthesis was also used in the two cases of recurrence as a complement to surgical treatment but with no effect. Growth was not affected in any of the children. DISCUSSION: The etiopathogenic mechanism underpinning pigmented villonodular synovitis remains unclear. Genetic factors are suspected in childhood cases. MRI is the complementary examination of choice for diagnosis and follow-up. In children, treatment of pigmented villonodular synovitis depends on marginal excision of the lesion for localized forms and total synovectomy for the diffuse forms. The efficacy of the triamcinolone hexacetonide synoviorthesis remains open to debate and would require a larger series with longer follow-up for evaluation.

[Tillaux fractures in teenagers: a review of nineteen cases]. / Fractures de Tillaux de l'adolescent: etude d'une série de 19 cas.

PURPOSE OF THE STUDY: Tillaux fractures in adolescents correspond to Salter and Harris type III fractures involving the anterolateral portion of the tibial epiphysis. These are intra-articular fractures. The objective was to determine the circumstances of these fractures, the radiological signs, and the therapeutic modalities as well as the long-term clinical and radiological outcome. MATERIAL AND METHODS: We reviewed 19 Tillaux fractures. Ten patients underwent surgical treatment and nine orthopedic treatment following importance of displacement. RESULTS: At mean follow-up of 33.8 months, results were rated good in 17 on 19 cases. DISCUSSION: This fracture is often observed in teenagers victims of trauma with external rotation of the foot. Closure of distal growth cartilage of the tibia occurs medially to laterally, the anterolateral portion remaining open longer. Forced external rotation of the anterior tibiofibular ligament pulls off an anterolateral fragment of the distal tibial epiphysis. Surgical treatment is indicated for fractures with a displacement of more than 2 mm or a vertical displacement to achieve open reduction and screw fixation. Orthopedic treatment is used for non-displaced fractures. CONCLUSION: The prognosis of Tillaux fractures is good as was observed in our series and in series reported in the literature.

[Avulsion fracture of the tibial tubercle in adolescents: 22 cases and review of the literature]. / Fracture-avulsion de la tubérosité tibiale antérieure chez l'adolescent: à propos de 22 cas et revue de la littérature.

PURPOSE OF THE STUDY: Fracture of the anterior tibial tubercle is exceptional in adolescents. The purpose of this work was to better understand the circumstances of such fractures, identify potential complications, and assess outcome of different therapeutic options. MATERIAL AND METHOD: This was a retrospective analysis of a consecutive series of 22 children with avulsion fracture of the anterior tibial tubercle. The circumstances of the fracture were noted. The Ogden classification was used to establish the radiological type. Associated lesions were also noted as were any complications. Two types of treatment were given: orthopedic or surgical (several types). The functional outcome was assessed at last follow-up. RESULTS: Mean age at fracture of the anterior tibial tubercle was 13 years (range 12-16) in 14 boys and 7 girls. It occurred after a jump or reception after a jump in 22 of the children. Five patients presented symptomatic homo- or contralateral anterior tibial apophysitis before the accident. The fracture was not displaced (type IA) in ten patients and was treated orthopedically. In twelve patients, the fracture was displaced (type IB, II, or III) and required osteosynthesis. Immobilization was maintained for four weeks on average (range 3-7). Associated lesions were observed in half of the twelve displaced fractures, with five cases of patellar ligament avulsion and three cases of meniscal injury. There were no complications with type IA fractures. For the twelve displaced fractures, complications were observed in seven children: hematoma (n = 2), infrapatellar hypoesthesia (n = 2), complete rupture of the patellar ligament 38 months after surgery (n = 1), recurvatum with leg length discrepancy (n = 1), and stiff knee (n = 1). Mean follow-up was two years (range 9 months-8 years). The functional outcome was excellent in all patients with a non-displaced fracture and in seven of the twelve patients who underwent surgical treatment. DISCUSSION: Non-displaced fracture of the anterior tibial tubercle I children (type IA) should be considered as a separate entity responding very well to orthopedic treatment. The other cases of displaced fracture generally require surgery which enables an assessment of often associated lesions. The prognosis of displaced fractures of the anterior tibial tubercle is more sever due to the associated lesions and potential complications. We describe the second case of recurvatum and leg length discrepancy following fracture of the anterior tibial tubercle. CONCLUSION: Displaced fracture of the anterior tibial tubercle in adolescents is often associated with soft tissue injury (patellar ligament, menisci). Surgery is indispensable and provides good functional results.

Brain glucocorticoid receptors are necessary for the rhythmic expression of the clock protein, PERIOD2, in the central extended amygdala in mice.

The adrenal glucocorticoid, corticosterone, induces changes in gene expression in both neural and non-neural tissues. The rhythmic release of corticosterone has been shown in rats to be necessary for the rhythmic expression of the clock protein PERIOD2 (PER2) in select regions of the limbic forebrain. The mechanisms mediating the effects of glucocorticoids on changes in gene expression have been linked to the transcriptional activity of the low affinity glucocorticoid receptor, GR. We examined the patterns of PER2 expression in the brains of mice containing an inactivation of GR gene restricted to neural tissues (GR(NesCre) mice). We found that central deletion of the GR gene blunts the daily pattern of PER2 expression in the oval nucleus of the bed nucleus of the stria terminalis (BNSTov) and central nucleus of the amygdala (CEA) both of which make up the central extended amygdala, but not in the suprachiasmatic nucleus (SCN), basolateral amygdala (BLA) or dentate gyrus of the hippocampus (DG). These results implicate brain GR receptors in the regulation of PER2 expression in the BNSTov and CEA and are consistent with our previous findings that the rhythmic expression of PER2 in these areas is selectively sensitive to fluctuations in circulating corticosterone.

[Bilateral optic atrophy in a drug addict]. / Atrophie papillaire bilatérale chez un patient héroïnomane.

Bilateral optic neuropathy in a young man is suggestive of hereditary or toxic damage. We describe the case of a 38-year-old man with bilateral optic neuropathy. His best corrected visual acuity was light perception OD and 20/125 OS. The patient's history revealed an addiction to heroin. Three drugs - heroin, quinine, and cocaine - were considered as a possible cause, which is discussed further. We suggest that the condition reported here may be attributed to the use of heroin. This underlines the importance of meticulous history taking in diagnosing a young man with bilateral loss of vision.

Glucocorticoid signalling affects pancreatic development through both direct and indirect effects.

AIMS/HYPOTHESIS: Beta cell development is sensitive to glucocorticoid levels. Although direct effects of glucocorticoids on pancreatic precursors have been shown to control beta cell mass expansion, indirect effects of these hormones on pancreatic development remain unexplored. This issue was addressed in mice lacking the glucocorticoid receptor (GR) in the whole organism. MATERIALS AND METHODS: The pancreatic phenotype of GR(null/null) mice was studied at fetal ages (embryonic day [E]) E15.5 and E18 by immunohistochemistry and beta cell fraction measurements. To distinguish between direct and indirect effects, mutant E15.5 fetal pancreata were grafted under the kidney capsule of immunodeficient mice and analysed after 1 week. RESULTS: E18 GR(null/null) fetuses had smaller digestive tracts and tiny pancreata. Massive pancreatic disorganisation and apoptosis were observed despite the presence of all cell types. E15.5 GR(null/null) mutants were indistinguishable from wild-type regarding pancreatic size, tissue structure and organisation, beta cell fraction and production of exocrine transcription factor Ptf1a, neurogenin 3 and Pdx-1. Grafting E15.5 GR(null/null) pancreata into a GR-expressing environment rescued the increased apoptosis and mature islets were observed, suggesting that GR(null/null) pancreatic cell death can be attributed to indirect effects of glucocorticoids on this tissue. Heterozygous GR(+/null) mutants with reduced GR numbers showed no apoptosis but increased beta cell fraction at E18 and the adult age, strengthening the importance of an accurate GR dosage on beta cell mass expansion. CONCLUSIONS/INTERPRETATION: Our results provide evidence for GR involvement in pancreatic tissue organisation and survival through indirect effects. GR does not appear necessary for early phases, but its accurate dosage is critical to modulate beta cell mass expansion at later fetal stages, presumably through direct effects.

Cyclizations of 4-pentenyl, 5-hexenyl, 6-heptenyl, and 7-octenyl fluorinated radicals: a density functional theory theoretical study.

The cyclization reactions of the 4-pentenyl, 5-hexenyl, 6-heptenyl, and 7-octenyl fluorinated and ether radicals have been studied by a hybrid Hartree-Fock density functional method. The reliability of this approach has been confirmed in agreement with experimental data and post-Hartree-Fock projected Møller-Plesset second-order method. The analysis of the theoretical results shows that two factors are crucial for the determination of the regiochemistry and the reactivity of these reactions. The first factor is the ability of the starting radical to have a stable conformation in position to form the transition state, and the second one is the enthalpic effect of the reaction through the stability of the resulting cyclized radical. It should be pointed out that these factors are not linked to the polarity of the radicals due to the presence of CF2 groups.

Regiochemistry in the Pauson-Khand reaction: has a trans effect been overlooked?

Alkyne-dicobalt hexacarbonyl complexes have been studied by DFT to examine whether electronic differences in the acetylenic substituents could play a role in determining the regiochemical outcome in the Pauson-Khand reaction. It appears that in some instances the regiochemistry is, in fact, governed exclusively by the electronic nature of the acetylenic substituents through the discriminant loss of a carbon monoxide ligand.