Anaphylaxis to supplemental oral lactase enzyme.

BACKGROUND: Anaphylactic reactions involving IgE mediated hypersensitivity have been frequently reported for a number of uncommon foods. However, cases of anaphylaxis to over the counter vitamins and oral supplements have been rarely published. Lactose intolerance affects approximately 20% of Canadians and roughly 70% of the world's population of any age. Lactose intolerance develops primarily due to the absence of the enzyme lactase and treatment involves avoidance of lactose-containing foods or ingestion of commercially available lactase enzyme preparations prior to their consumption. This case report represents the first documented evidence of anaphylaxis after exposure to supplemental lactase enzyme preparation. CASE PRESENTATION: A 38 years old Caucasian female presented with a history of self-diagnosed adult-onset lactose intolerance and a suspected allergy to lactase containing tablets. She reported an episode of bilateral orbital swelling, shortness of breath, and throat constriction after oral ingestion of a supplemental lactase enzyme tablet. Her symptoms slowly resolved with the administration of inhaled salbutamol and oral diphenhydramine. She handled lactase tablets for years to her children who were lactose intolerant, but had never ingested the tablets herself prior to the reported episode. In clinic, physical examination was benign, and skin prick testing to a slurry of the lactase tablet revealed a strongly positive reaction wheal size of 10 mm and flare of 60 mm with normal controls. The patient reported throat tightness and constriction after skin prick testing and required cetirizine treatment and observation in clinic. Subsequent skin testing was performed with individual ingredients of the lactase tablet provided by the manufacturer and Aspergillus niger, a common bacteria used in lactase preparations. Only concentrated lactase enzyme elicited a positive response. The patient was diagnosed with lactase tablet induced anaphylaxis due to synthetic lactase enzyme IgE mediated allergy, and was advised to avoid all products containing lactase enzymes as an ingredient and to carry an epinephrine auto-injector. CONCLUSION: This is the first documented case report of an anaphylactic reaction to supplemental lactase enzyme. This case report reinforces the importance of thorough allergy assessment, education on avoidance of triggers, in particular with uncommon allergens.

Primary cilia expression in bone marrow in response to mechanical stimulation in explant bioreactor culture.

Bone marrow contains a multitude of mechanically sensitive cells that may participate in mechanotransduction. Primary cilia are sensory organelles expressed on mesenchymal stem cells (MSCs), osteoblasts, osteocytes, and other cell types that sense fluid flow in monolayer culture. In marrow, cilia could similarly facilitate the sensation of relative motion between adjacent cells or interstitial fluid. The goal of this study was to determine the response of cilia to mechanical stimulation of the marrow. Bioreactors were used to supply trabecular bone explants with low magnitude mechanical stimulation (LMMS) of 0.3 ×g at 30 Hz for 1 h/d, 5 d/week, inducing shear stresses in the marrow. Four groups were studied: unstimulated (UNSTIM), stimulated (LMMS), and with and without chloral hydrate (UNSTIM+CH and LMMS+CH, respectively), which was used to disrupt cilia. After 19 days of culture, immunohistochemistry for acetylated α-tubulin revealed that more cells expressed cilia in culture compared to in vivo controls. Stimulation decreased the number of cells expressing cilia in untreated explants, but not in CH-treated explants. MSCs represented a greater fraction of marrow cells in the untreated explants than CH-treated explants. MSCs harvested from the stimulated groups were more proliferative than in the unstimulated explants, but this effect was absent from CH treated explants. In contrast to the marrow, neither LMMS nor CH treatment affected bone formation as measured by mineralising surface. Computational models indicated that LMMS does not induce bone strain, and the reported effects were thus attributed to shear stress in the marrow. From a clinical perspective, genetic or pharmaceutical alterations of cilia expression may affect marrow health and function.

Osteocyte differentiation and the formation of an interconnected cellular network in vitro.

Extracellular matrix (ECM) stiffness and cell density can regulate osteoblast differentiation in two dimensional environments. However, it is not yet known how osteoblast-osteocyte differentiation is regulated within a 3D ECM environment, akin to that existing in vivo. In this study we test the hypothesis that osteocyte differentiation is regulated by a 3D cell environment, ECM stiffness and cell density. We encapsulated MC3T3-E1 pre-osteoblastic cells at varied cell densities (0.25, 1 and 2 × 106 cells/mL) within microbial transglutaminase (mtgase) gelatin hydrogels of low (0.58 kPa) and high (1.47 kPa) matrix stiffnesses. Cellular morphology was characterised from phalloidin-FITC and 4',6-diamidino-2-phenylindole (DAPI) dilactate staining. In particular, the expression of cell dendrites, which are phenotypic of osteocyte differentiation, were identified. Immunofluorescent staining for the osteocytes specific protein DMP-1 was conducted. Biochemical analyses were performed to determine cell number, alkaline phosphatase activity and mineralisation at 2.5 hours, 3, 21 and 56 days. We found that osteocyte differentiation and the formation of an interconnected network between dendritic cells was significantly increased within low stiffness 3D matrices, compared to cells within high stiffness matrices, at high cell densities. Moreover we saw that this network was interconnected, expressed DMP-1 and also connected with osteoblast-like cells at the matrix surface. This study shows for the first time the role of the 3D physical nature of the ECM and cell density for regulating osteocyte differentiation and the formation of the osteocyte network in vitro. Future studies could apply this method to develop 3D tissue engineered constructs with an osteocyte network in place.

Correlation between cardio-pulmonary exercise test variables and health-related quality of life among children with congenital heart diseases.

BACKGROUND: Health-related quality of life (HR-QoL) stands as a determinant "patient-related outcome" and correlates with cardio-pulmonary exercise test (CPET) in adults with chronic heart failure or with a congenital heart disease (CHD). No such correlation has been established in pediatric cardiology. METHODS AND RESULTS: 202 CHD children aged 8 to 18 performed a CPET (treadmill n=96, cycle-ergometer n=106). CHD severity was stratified into 4 groups. All children and parents filled out the Kidscreen HR-QoL questionnaire. Peak VO2, anaerobic threshold (AT), and oxygen pulse followed a downward significant trend with increasing CHD severity and conversely for VE/VCO2 slope. Self-reported and parent-reported physical well-being HR-QoL scores correlated with peak VO2 (respectively r=0.27, p<0.0001 and r=0.43, p<0.0001), percentage of predicted peak VO2 (r=0.28, p=0.0001 and r=0.41, p<0.0001), and percentage of predicted VO2 at AT (r=0.22, p<0.01 and r=0.31, p<0.0001). Significant correlations were also observed between several HR-QoL dimensions and dead space to tidal volume ratio (VD/VT), oxygen uptake efficiency slope (OUES), oxygen pulse but never with VE/VCO2 slope. The strongest correlations were observed in the treadmill group, especially between peak VO2 and physical well-being for parents (r=0.57, p<0.0001) and self (r=0.40, p<0.0001) reported HR-QoL. CONCLUSIONS: Peak VO2 and AT are the two CPET variables that best correlated with HR-QoL in this large pediatric cohort, parents' reports being more accurate. If HR-QoL is involved as a "PRO" in a pediatric cardiology clinical trial, we suggest using parents related physical well-being HR-QoL scores. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (number NCT01202916).

Quality of Life of Children with Congenital Heart Diseases: A Multicenter Controlled Cross-Sectional Study.

To assess the health-related quality of life (QoL) in children with congenital heart diseases (CHD) with a validated questionnaire in comparison with control children. We prospectively recruited 282 children with CHD aged from 8 to 18 years in two tertiary care centers (France and Belgium) and 180 same-age controls in randomly selected French schools. Children's QoL was self-reported with the KIDSCREEN-52 questionnaire and reported by parents with the KIDSCREEN-27. QoL scores of each dimension were compared between CHD and controls and between the classes of disease severity. Both centers were comparable for most demographic and clinical data. Age- and gender-adjusted self-reported QoL scores were lower in CHD children than in controls for physical well-being (mean ± SEM 45.97 ± 0.57 vs 50.16 ± 0.71, p < 0.0001), financial resources (45.72 ± 0.70 vs 48.85 ± 0.87, p = 0.01), peers/social support (48.01 ± 0.72 vs 51.02 ± 0.88, p = 0.01), and autonomy in the multivariate analysis (47.63 ± 0.69 vs 49.28 ± 0.85, p = 0.04). Parents-reported scores were lower in CHD children for physical (p < 0.0001), psychological well-being (p = 0.04), peers/social support (p < 0.0001), and school environment (p < 0.0001) dimensions. Similarly, the disease severity had an impact on physical well-being (p < 0.001), financial resources (p = 0.05), and peers/social support (p = 0.01) for self-reported dimensions, and on physical well-being (p < 0.001), psychological well-being (p < 0.01), peers/social support (p < 0.001), and school environment (p < 0.001) for parents-reported dimensions. However, in multivariate analysis on self-reported QoL, disease severity was significantly associated with the self-perception dimension only. Self-reported QoL of CHD children was similar to that of same-age healthy children in seven of 10 dimensions, but parents-reported QoL was impaired in four of five dimensions.

Multiscale modeling of trabecular bone marrow: understanding the micromechanical environment of mesenchymal stem cells during osteoporosis.

Mechanical loading directs the differentiation of mesenchymal stem cells (MSCs) in vitro and it has been hypothesized that the mechanical environment plays a role in directing the cellular fate of MSCs in vivo. However, the complex multicellular composition of trabecular bone marrow means that the precise nature of mechanical stimulation that MSCs experience in their native environment is not fully understood. In this study, we developed a multiscale model that discretely represents the cellular constituents of trabecular bone marrow and applied this model to characterize mechanical stimulation of MCSs in vivo.We predicted that cell-level strains in certain locations of the trabecular marrow microenvironment were greater in magnitude (maximum e12»24,000 le) than levels that have been found to result in osteogenic differentiation of MSCs in vitro (>8000 le),which may indicate that the native mechanical environment of MSCs could direct cellular fate in vivo. The results also showed that cell­cell adhesions could play an important role in mediating mechanical stimulation within the MSC population in vivo. The model was applied to investigate how changes that occur during osteoporosis affected mechanical stimulation in the cellular microenvironment of trabecular bone marrow. Specifically,a reduced bone volume (BV) resulted in an overall increase in bone deformation, leading to greater cell-level mechanical stimulation in trabecular bone marrow (maximume12»48,000 le). An increased marrow adipocyte content resulted in slightly lower levels of stimulation within the adjacent cell population due to a shielding effect caused by the more compliant behavior of adipocytes (maximum e12»41,000 le). Despite this reduction, stimulation levels in trabecular bone marrow during osteoporosis remained much higher than those predicted to occur under healthy conditions. It was found that compensatory mechanobiological responses that occur during osteoporosis, such as increased trabecular stiffness and axial alignment of trabeculae, would be effective in returning MSC stimulation in trabecular marrow to normal levels. These results have provided novel insight into the mechanical stimulation of the trabecular marrow MSC population in both healthy and osteoporotic bone, and could inform the design three dimensional(3D) in vitro bioreactor strategies techniques, which seek to emulate physiological conditions.

Cell morphology and focal adhesion location alters internal cell stress.

Extracellular mechanical cues have been shown to have a profound effect on osteogenic cell behaviour. However, it is not known precisely how these cues alter intracellular mechanics to initiate changes in cell behaviour. In this study, a combination of in vitro culture of MC3T3-E1 cells and finite-element modelling was used to investigate the effects of passive differences in substrate stiffness on intracellular mechanics. Cells on collagen-based substrates were classified based on the presence of cell processes and the dimensions of various cellular features were quantified. Focal adhesion (FA) density was quantified from immunohistochemical staining, while cell and substrate stiffnesses were measured using a live-cell atomic force microscope. Computational models of cell morphologies were developed using an applied contraction of the cell body to simulate active cell contraction. The results showed that FA density is directly related to cell morphology, while the effect of substrate stiffness on internal cell tension was modulated by both cell morphology and FA density, as investigated by varying the number of adhesion sites present in each morphological model. We propose that the cells desire to achieve a homeostatic stress state may play a role in osteogenic cell differentiation in response to extracellular mechanical cues.

The melanocortin MC(1) receptor agonist BMS-470539 inhibits leucocyte trafficking in the inflamed vasculature.

BACKGROUND AND PURPOSE: Over three decades of research evaluating the biology of melanocortin (MC) hormones and synthetic peptides, activation of the MC type 1 (MC(1)) receptor has been identified as a viable target for the development of novel anti-inflammatory therapeutic agents. Here, we have tested a recently described selective agonist of MC(1) receptors, BMS-470539, on leucocyte/post-capillary venule interactions in murine microvascular beds. EXPERIMENTAL APPROACH: Intravital microscopy of two murine microcirculations were utilized, applying two distinct modes of promoting inflammation. The specificity of the effects of BMS-470539 was assessed using mice bearing mutant inactive MC(1) receptors (the recessive yellow e/e colony). KEY RESULTS: BMS-470539, given before an ischaemia-reperfusion protocol, inhibited cell adhesion and emigration with no effect on cell rolling, as assessed 90 min into the reperfusion phase. These properties were paralleled by inhibition of tissue expression of both CXCL1 and CCL2. Confocal investigations of inflamed post-capillary venules revealed immunostaining for MC(1) receptors on adherent and emigrated leucocytes. Congruently, the anti-inflammatory properties of BMS-470539 were lost in mesenteries of mice bearing the inactive mutant MC(1) receptors. Therapeutic administration of BMS-470539 stopped cell emigration, but did not affect cell adhesion in the cremasteric microcirculation inflamed by superfusion with platelet-activating factor. CONCLUSIONS AND IMPLICATIONS: Activation of MC(1) receptors inhibited leucocyte adhesion and emigration. Development of new chemical entities directed at MC(1) receptors could be a viable approach in the development of novel anti-inflammatory therapeutic agents with potential application to post-ischaemic conditions.

[Respiratory function testing in infants: recommendations on normal values]. / EFR du nourrisson: le point sur les valeurs normales.

The present document is being produced on behalf of the French Society of the Physiology Task Force on standards for Infant Respiratory Function Testing whose aim is to provide guidelines for good laboratory practices according to the latest international recommendations. Application of such recommendations could be of particular value when attempting to develop standardized protocols in the scope of multi-centre trials. The first part resume these recommendations about apparatus, acquisition system and software for Infant Respiratory Function Testing. The second part focuses on physiological principles and practical considerations: calibration procedure, infant conditioning, tidal breathing measurements, and occlusion techniques for assessing passive respiratory mechanics, plethysmographic measurements of lung volume and airway resistance and forced expiratory flows measurements. The major problem when collecting lung function data is that of predicted values. Valid reference data, set up according to these recommendations, are, to date, still to be established. The last part of the document provides a review of the literature concerning infant respiratory function reference data and a resume of the most used of them. This document will clearly need to be updated regularly in response to advances in knowledge in this field.

Role of neutrophil elastase in LTB4-induced neutrophil transmigration in vivo assessed with a specific inhibitor and neutrophil elastase deficient mice.

BACKGROUND AND PURPOSE: The serine protease neutrophil elastase (NE) appears to regulate inflammatory responses at multiple levels but its role in leukocyte transmigration in vivo remains unclear. The present study aimed to address this issue by using both an NE inhibitor (ONO-5046) and NE deficient (NE(-/-)) mice. EXPERIMENTAL APPROACH: A number of inflammatory mediators (LTB(4), KC and PAF) were investigated in vitro for their ability to stimulate the release and the surface expression of NE by neutrophils. In addition, the role of NE in leukocyte migration elicited by topical LTB(4) was investigated in vivo in mouse cremasteric venules as observed by intravital microscopy. KEY RESULTS: Amongst the mediators tested in vitro, LTB(4) was found to be a highly potent and efficacious inducer of NE cell surface expression on murine neutrophils. Furthermore, in wild-type mice (WT), LTB(4)-induced leukocyte transmigration was reduced by intravenous ONO-5046 (66% inhibition), an effect that appeared to occur at the level of the perivascular basement membrane. Interestingly, LTB(4)-induced responses were normal in NE(-/-) mice and, while ONO-5046 had no inhibitory effect in these animals, the broad-spectrum serine protease inhibitor aprotinin suppressed leukocyte transmigration in both WT and NE(-/-) mice. CONCLUSIONS AND IMPLICATIONS: The findings demonstrate the potent ability of LTB(4) to induce cell-surface expression of NE and provide evidence for the involvement of NE in LTB(4)-induced neutrophil transmigration in vivo. The results also suggest the existence of compensatory mechanisms in NE(-/-) mice, highlighting the added value of investigating pharmacological blockers in parallel with genetic deletion.

[Medium and long-term results of anatomical correction of transposition of the great arteries in Marseille]. / Résultats à moyen et long terme de la correction anatomique de la transposition des gros vaisseaux à Marseille.

The object of this study was to evaluate the results of anatomical correction of transposition of the great arteries (TGA) in an inter-regional centre. The characteristics of 220 patients operated between 1985 and 2002 were analysed. Prenatal diagnosis of TGA was made in 38 patients (17%) including 36 of the 109 patients operated since 1995 (33%) and leading to earlier atrial septostomy in this situation (p= 0.046). Since 1995, the global early mortality of 12.3% has been significantly reduced to 5.5% (N= 6) including 4.4% (3/68 cases) of simple TGA (p= 0.002). In multivariate analysis, the only independent risk factor for early mortality was the occurrence of a major per-operative complication (p< 0.0001). The average follow-up was 4.8 +/- 4.5 years with an 86% survival at 5, 10 and 15 years and 97% survival at 5 years for patients operated after 1995. There were 22 reoperations including 14 on the right ventricular outflow tract. The non-reoperation rate at 10 years was 80% for simple TGA versus 70% in complex TGA (p= 0.0001). Survivors are asymptomatic with a normal ECG and normal LV function on echocardiography. Five patients have significant pulmonary stenosis and 4 have mild aortic regurgitation. The exercise stress tests performed between the ages of 7 and 10 were all normal. The authors conclude that that modern and reproducible management of TGA is possible in an inter-regional centre with results comparable to those of surgical centres of reference.

[Physical fitness in children with asthma]. / Aptitude à l'effort de l'enfant asthmatique.

The exercise limitation in a child with asthma is the result of several factors: the lack of ventilatory reserve, muscle deconditioning, and cardiac limitation. The severity of the airway obstruction is a major determinant of physical fitness. Aerobic and anaerobic fitness are equally affected. Both types of fitness can be improved by specific training programs.

Genetic clines in the Bay of Biscay provide estimates of migration for Sardina pilchardus.

Nine allozymic loci in 1,635 individuals of Sardina pilchardus obtained at 33 sites ranging from the North to the South limits of the Bay of Biscay were analyzed to provide a description of the genetic structure of the sardine population. Individual body size and age were also recorded and analyzed. In the study population, weak but significant genetic differences were found, and a cline was observed between multilocus heterozygosity and longitude. The cline was predominantly driven by allelic frequencies of two loci, PGM-1* and PEP-lt*, and using a cline model, we estimated a migration rate of 103.1 km/gen (dispersal distance per generation). In addition, we observed that the cline was linked to biological data such as mean length and mean age of the fish. Two hypotheses may explain this cline: mixing of two different populations in the Bay of Biscay or a selective process. The weak genetic differences, the important dispersal distance per generation, and the link between genetic and biological data suggest that selection is likely to be the primary factor that maintains the cline.

[Histological lesions of supraspinatus tendons in full thickness tears of the rotator cuff]. / Les lésions histologiques des tendons des supraspinatus dans les ruptures transfixiantes de la coiffe des rotateurs.

PURPOSE OF THE STUDY: Iterative tears after simple tendon bone suture of transfixiant ruptures of the rotator cuff are frequent. The frequency of iterative ruptures had seemed to be correlated to the importance of the preoperative fatty degenerations of the cuff muscles. But fatty degeneration cannot account for iterative ruptures occurring with no or little preoperative muscle fatty degeneration. The authors have tried to know if iterative ruptures could also be accounted for by the presence on repaired tendinous stumps of histological lesions which are known to lower their mechanical quality, and if such was the case, they have tried to know what could be the impact of these lesions on the repairing technique by suturing cuff ruptures. MATERIAL AND METHOD: Thirty-two distal stumps of ruptured supraspinatus, resected on more than 1 cm to eliminate macroscopic tendinous lesions (thin, lacerated, cleaved, hardened or whitish tendons) and to reach a new stump, slightly bleeding and thick enough to hold the stitches correctly, have been studied on longitudinal histological slides. RESULTS: All the tendinous resected stumps had histological anomalies: dilacerations lesions of the conjunctive tissue, fatty infiltrations, necrosis, scar lesions and micro calcifications were found. The histological lesions were often associated. The histological lesions were an average 4 mm shorter than those of the tendinous resection. In 18 cases however the whole of the resected tendon was histologically abnormal. DISCUSSION: Tendinous histological lesions found on the whole or almost the whole length of the macroscopically abnormal tendinous stumps diminish the mechanical quality of the tendons. Insufficient resection of the tendinous stumps leaving macroscopical lesions and therefore histological lesions could account for iterative ruptures in the first post operative year. Yet complete resection of the macroscopically abnormal tendinous stump does not entail that the neo tendinous stump to be repaired is histologically normal. This encourages to put the stitches well within the zone of the tendinous resection and to bury the tendinous stumps into a highly vascular bony trough. But tendinous resection although logical from the histological and mechanical point of view widens the rupture of the cuff to be repaired. It can make sutures under tension, which can entail iterative ruptures. Musculo-tendinoplasty appears then necessary to perform sutures without tension. CONCLUSION: Histological lesions of tendinous stumps of cuff ruptures correspond roughly to tendinous macroscopic lesions. They could be at the origin of iterative ruptures that take place after simple tendon-bone sutures of ruptured cuffs which are not accounted for by muscular fatty degeneration. They could also partly account for iterative ruptures taking place when pre operative fatty degeneration is evident. It seems logical to resect macroscopically abnormal tendinous stumps before performing a suture. But the tendon-bone suture without tension is then often possible only with musculo-tendinoplasties.

Haemodynamic features during high-frequency oscillatory ventilation in preterms.

AIM: To compare the haemodynamic status during high-frequency oscillatory ventilation and conventional mechanical ventilation in very preterm infants with respiratory distress syndrome. METHODS: Thirty-two neonates of less than 30 wk gestation randomly assigned to high-frequency oscillatory ventilation (n = 15) or conventional mechanical ventilation (n = 17) had three echocardiographies and one cerebral Doppler-echography under the same ventilation during the first 48 h of life. RESULTS: Mean airway pressure was 2 cm H2O higher in infants ventilated with high-frequency oscillatory ventilation at the different echocardiographies. Comparable right ventricular indexes were observed in the two groups. Reduction of the ductus arteriosus diameter and ductal closure were significant only in neonates ventilated conventionally. Left ventricular performance and left ventricular contractility did not differ between the groups. The high-frequency group had lower end diastolic velocity and a higher resistance index in the anterior cerebral artery. CONCLUSION: Compared with conventional mechanical ventilation, high-frequency oscillatory ventilation was achieved without altering cardiac function. However, the inability of the left ventricle to improve its performance in the presence of a significant ductal shunt suggests a narrow range of optimal pressures under this ventilatory mode.

Hemarthrosis: an unusual complication of type 1 neurofibromatosis.

Type 1 neurofibromatosis is one of the most common autosomal-dominant disorders and often includes orthopedic manifestations. We report the case of a 48-year-old woman with hemarthrosis caused by a popliteal cyst infiltrated by a diffuse neurofibroma associated with angiodysplasia. Surgical resection of this tumor was followed by postoperative hemorrhagic complications.

Macroscopic and histological assessments of the cruciate ligaments in arthrosis of the knee.

We examined the macroscopic appearance of both cruciate ligaments in 52 knees during knee replacement. It was classsified as normal, abnormal or ruptured. The ligaments were also evaluated histologically: stage 0 (normal), stage I (degeneration of < 1/3 of the collagen fibers), stage 2 (degeneration of 1/3-2/3) and stage 3 (> 2/3). 17 anterior cruciate ligaments (ACL) were normal, 14 were abnormal and 21 ruptured. All the posterior cruciate ligaments (PCL) were normal. 14 ACL were stage 0, 6 stage 1, 8 stage 2 and 24 were stage 3. 22 PCL were stage 0, 14 stage 1, 13 stage 2 and 3 were stage 3. When the ACL was abnormal or ruptured, the PCL was stage 0 only in one fourth of the cases. The long-term results of TKR retaining the PCL should be better if the ligament is strong. The intraoperative assessment of the macroscopic appearance of the ACL reflects the histological state of the PCL.

Malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1: a clinicopathologic and molecular study of 17 patients.

OBJECTIVE: To identify potential prognostic factors and criteria for early detection of malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1 (NF1). DESIGN: Retrospective study of malignant peripheral nerve sheath tumors in a cohort of 395 patients with NF1 followed up between October 1, 1988, and January 1, 1999; review of the clinical and histological characteristics of treatment and course; and analysis of p53 mutations and overexpression in tumors. SETTING: Teaching hospital referral neurofibromatosis center for adults. PATIENTS: Seventeen patients with NF1 (9 males and 8 females). Mean +/- SD patient age at diagnosis was 32 +/- 14 years. MAIN OUTCOME MEASURES: (1) Clinical symptoms, (2) comparison of p53 mutations and overexpression in benign vs malignant tumors; and (3) median survival. RESULTS: Twelve patients had high-grade tumors. All tumors except 1 developed on preexisting nodular or plexiform neurofibromas. Pain and enlarging mass were the first and predominant signs. None of the benign tumors displayed significant p53 staining or p53 mutations. Six of 12 malignant tumors significantly overexpressed p53, and 4 of 6 harbored p53 missense mutations. Median survival was 18 months overall, 53 months in peripheral locations, and 21 months in axial locations. CONCLUSIONS: Malignant peripheral nerve sheath tumors are highly aggressive in NF1. They mostly arise from plexiform or nodular neurofibromas. Investigations and deep biopsy of painful and enlarging nodular or plexiform neurofibromas should be considered in patients with NF1. Late appearance of p53 mutations and overexpression precludes their use as predictive markers of malignant transformation.

[Rehabilitation of hypoplastic pulmonary arteries and anatomic correction of pulmonary atresia with interventricular communication]. / Réhabilitation des artères pulmonaires hypoplasiques et correction anatomique des atrésies pulmonaires avec communication interventriculaire.

Conventional treatment of pulmonary atresia with ventricular septal defect (VSD), hypoplastic pulmonary arteries (PA) and major aorto-pulmonary collaterals (MAPCAs) is controversial: from symptomatic and palliative treatment for some authors to surgery with unifocalisation of collaterals for others. These treatments never use native pulmonary arteries as only source of pulmonary flow, but create "neo-pulmonary arteries". Nine cases of pulmonary atresia with VSD, hypoplastic PA and MAPCAs were treated by rehabilitation of native PA through a staged approach: 1) surgical neonatal connection between right ventricule (RV) and hypoplastic PA, 2) evaluation and interventionnal catheterism with angioplasty of PA stenosis and closure of collaterals, 3) complete surgical correction with reconstruction of right outflow track and PA and closure of VSD. After first surgical stage of RV-PA connection at the mean age of 4.8 months (+/- 5.6 months), 8 patients were alive and underwent 22 cardiac catheterisms (mean of 2.7 per patient), with angioplasty of PA, and occlusion of MAPCAs in 6 and 2 patients respectively. Seven patients underwent complete anatomical correction at the mean age of 28.8 months (+/- 17.7 months) with one late death. The 6 remaining patients had encouraging hemodynamic status (RV pressure/LV pressure ratio at 0.6 +/- 0.26; mean left and right distal pulmonary pressure at 15.2 mmHg (+/- 9.1 mmHg)), and good functionnal status (3 in NYHA functionnal class 1, and 3 in class 2), for a mean follow-up of 79.5 months (+/- 41.4 months). One patient had reoperation on right outflow track stenosis, 6 years after correction. This small series enhances the feasibility of a staged approach with rehabilitation of small PA, allowing complete surgical correction with the native PA with good hemodynamic and functional results in pulmonary atresia, with VSD, hypoplastic PA and MAPCAs.