Bioactive compounds in human milk and intestinal health and maturity in preterm newborn: an overview.

Premature births are increasing worldwide (about 15 millions per year) due to several reasons (an advanced maternal age, fertility treatments, stress, smoking, nutritional deficiencies) and lead to a high societal overall cost. Among neonatal care procedures, the clinical nutrition practices are essential to promote the development and to minimize the sequelae. Premature newborns are at major risk of death by infections due to the immaturity of their intestine. Human milk provides not only nutrients but also a plethora of biologically active components that are tailored to contribute to the development of the intestinal tract early in postnatal life. Among them, some bioactive molecules exhibit trophic effects (LC­PUFA, sphingomyelin, IGF­I and IGF­II, EGF, insulin, leptin, adiponectin, lactoferrin, lactadherin, probiotics, prebiotics, miRNA) or are part of the intestinal cell membranes (PUFA, LC­PUFA, phospholipids, sphingolipids, cholesterol), others educate the intestine for innate microbial recognition (sCD14, sTLR­2, miRNA), many of them display direct fighting against pathogens (some fatty acids and monoglycerides, some phospholipids and sphingolipids, BSSL, insulin, lactoferrin, sIgAs, MUC­1, lactadherin, probiotics, prebiotics), or contribute to establish the gut microbiota (LC­PUFA, lactoferrin, probiotics, prebiotics). A synergetic action exists between several bioactive molecules. All together these precious agents regulate the maturation of the intestinal mucosal barrier, and might program early in postnatal life the future adult intestinal health. This review lists the main bioactive compounds and addresses their plausible roles and mechanisms of action.

Adult CNP::EGFP transgenic mouse shows pronounced hypomyelination and an increased vulnerability to cuprizone-induced demyelination.

CNP::EGFP transgenic mice, genetically engineered to express the enhanced green fluorescent protein (EGFP) under the control of the 2-3-cyclic nucleotide 3-phosphodiesterase (CNPase) promoter in oligodendroglial and Schwann cells, constitute a very important and widely used tool for the study of oligodendrocyte (OLG) development and function in young mice. Our results showed that CNP::EGFP mice were significantly more susceptible to CPZ-induced demyelination, as evaluated by MBP immunostaining, oligodendroglial progenitor cell (OPC) recruitment and astroglial, microglial and nestin response. This enhanced vulnerability was a consequence of their hypomyelination. CNP::EGFP control mice also displayed a significant decrease in corpus callosum (CC) thickness and MBP immunoreactivity. Morphometric analysis further showed a significant decrease in the frequency of myelinated axons, myelin turns (lamellae) and g-ratio carried out in the optic nerve (ON) and CC of CNP::EGFP, as compared to WT mice. Moreover, our results showed a decrease in the number of axons of small caliber, concomitantly with an increase in the number of axons of bigger size with more and enlarged mitochondria, which suggests a high energy demand. These findings and those displaying that MBP+ cells and NF200 staining in the CNP::EGFP cortex were more sparsely distributed provide evidence of axonal loss, which was supported by a decreased number of NeuN+ cells in the CA3 fields of the hippocampus. Transgenic mice also showed an increase in microglial and astroglial activation, accompanied by enhanced lipid peroxidation and recruitment of morphologically altered OPC. Finally, CNPase protein levels proved to be lower than MBP in the CC, which might indicate an altered pattern in myelin proteins with a CNPase deficiency. Behavioral analysis of adult CNP::EGFP transgenic mice supported our results, as it revealed a decrease in locomotion, exploratory activity and motor impairment, as compared to their WT littermates. Our data highlight the relevance of confronting results obtained in adult CNP::EGFP mice with those observed in WT mice. According to our findings, CNP::EGFP hypomyelination might be triggered by the cellular stress induced by the high level of EGFP expression in mature OLG. Adult CNP::EGFP mice could be considered a useful tool to evaluate future therapies for demyelinating diseases such as multiple sclerosis (MS), since these animals present chronic demyelination with axonal degeneration, a characteristic of such pathologies.

[Adult respiratory sequelae of premature birth]. / Devenir respiratoire à l'âge adulte de la prématurité et de la dysplasie bronchopulmonaire.

INTRODUCTION: Between 5 and 7% of babies are born prematurely. In the paediatric age group, the respiratory morbidity of these patients is well known, particularly in cases of bronchopulmonary dysplasia (BPD). On the other hand, very few data are available concerning their adult respiratory status. BACKGROUND: There are currently three different groups of ex-premature babies: (1) those with no BPD who are usually not considered as respiratory high-risk adults but have not been well studied; (2) ex-premature babies with BPD who have an increased risk of asthma, respiratory infections, bronchial obstruction aggravated by smoking, and non-atopic bronchial hyperreactivity; this group has been well studied but not beyond 30 years of age; (3) the babies born very prematurely and affected with a new form of BPD due to neonatal intensive care at a very immature stage of pulmonary development, and for whom the future in adult life is unknown but worrying because of reduced lung volumes since birth. VIEWPOINTS AND CONCLUSIONS: The respiratory physician must be aware of these groups of adults who he may encounter and who may develop, sooner or later, a certain type of chronic obstructive pulmonary disease.

Galectin-3 drives oligodendrocyte differentiation to control myelin integrity and function.

Galectins control critical pathophysiological processes, including the progression and resolution of central nervous system (CNS) inflammation. In spite of considerable progress in dissecting their role within lymphoid organs, their functions within the inflamed CNS remain elusive. Here, we investigated the role of galectin-glycan interactions in the control of oligodendrocyte (OLG) differentiation, myelin integrity and function. Both galectin-1 and -3 were abundant in astrocytes and microglia. Although galectin-1 was abundant in immature but not in differentiated OLGs, galectin-3 was upregulated during OLG differentiation. Biochemical analysis revealed increased activity of metalloproteinases responsible for cleaving galectin-3 during OLG differentiation and modulating its biological activity. Exposure to galectin-3 promoted OLG differentiation in a dose- and carbohydrate-dependent fashion consistent with the 'glycosylation signature' of immature versus differentiated OLG. Accordingly, conditioned media from galectin-3-expressing, but not galectin-3-deficient (Lgals3(-/-)) microglia, successfully promoted OLG differentiation. Supporting these findings, morphometric analysis showed a significant decrease in the frequency of myelinated axons, myelin turns (lamellae) and g-ratio in the corpus callosum and striatum of Lgals3(-/-) compared with wild-type (WT) mice. Moreover, the myelin structure was loosely wrapped around the axons and less smooth in Lgals3(-/-) mice versus WT mice. Behavior analysis revealed decreased anxiety in Lgals3(-/-) mice similar to that observed during early demyelination induced by cuprizone intoxication. Finally, commitment toward the oligodendroglial fate was favored in neurospheres isolated from WT but not Lgals3(-/-) mice. Hence, glial-derived galectin-3, but not galectin-1, promotes OLG differentiation, thus contributing to myelin integrity and function with critical implications in the recovery of inflammatory demyelinating disorders.

Economic evaluation of immunoglobulin replacement in patients with primary antibody deficiencies.

Lifelong immunoglobulin replacement is the standard, expensive therapy for severe primary antibody deficiencies. This treatment can be administrated either by intravenous immunoglobulin (IVIG) or subcutaneous infusions (SCIG) and delivered at home or in an out-patient setting. This study aims to determine whether SCIG is cost-effective compared with IVIG from a French social insurance perspective. Because both methods of administration provide similar efficacies, a cost-minimization analysis was performed. First, costs were calculated through a simulation testing different hypothesis on costs drivers. Secondly, costs were estimated on the basis of field data collected by a questionnaire completed by a population of patients suffering from agammaglobulinaemia and hyper-immunoglobulin (Ig)M syndrome. Patients' satisfaction was also documented. Results of the simulation showed that direct medical costs ranged from 19 484 euro for home-based IVIG to 25 583 euro for hospital-based IVIG, with home-based SCIG in between at 24 952 euro per year. Estimations made from field data were found to be different, with significantly higher costs for IVIG. This result was explained mainly by a higher immunoglobulin mean dose prescribed for IVIG. While the theoretical model showed very little difference between SCIG and hospital-based IVIG costs, SCIG appears to be 25% less expensive with field data because of lower doses used in SCIG patients. The reality of the dose difference between both routes of administration needs to be confirmed by further and more specific studies.

[Fibrate-induced deterioration of renal function]. / Deterioro de la función renal inducido por fibratos.

INTRODUCTION: Fibrates represent one of the medications used to treat patients with hyperlipemia. Deterioration in renal function is not a very known adverse effect of fibric acid derivates. In the last 26 months we have detected thirteen patients with acute renal failure associated to fibrates in our outpatients' clinic. SUBJECTS AND METHODS: The aim of our study is to analyze our experience in deterioration in renal function associated to fibrates use. This is a retrospective charts review. RESULTS: From the thirteen patients (8 males/5 females) with mean age of 65.5 +/- 12.2 years, ten received Fenofibrate (FN), one Bezafibrate (BZ) and two Gemfibrozil (GF). Six cases had previously normal renal function and the seven remaining had mild chronic renal failure (CRF). The increase of serum Creatinine (Crs) value was higher than 74%. Acute renal failure was reversible in 9 patients (group 1), but the other 4 did not recover their previous renal function (group 2). The average of Crs before fibrate treatment was 1.33 +/- 0.36 mg/dl (Creatinine clearance 63.2 +/- 26.6 ml/min) and the highest average of Crs during the treatment was 2.22 +/- 0.49 mg/d (Creatinine clearance 37.3 +/- 11.9 ml/min). The average time until acute renal failure diagnosis was 6.7 +/- 5.8 months and the recovery of renal function was delayed an average of 3.8 +/- 3.5 months after fibrates withdrawn. Group 2 patients had a higuer Crs and longer time with fibrates than group 1 patients. CPK values were normal in all cases. In two patients renal biopsy was performed and no significant lesions were detected. CONCLUSION: The fibrate treatment can induce an acute renal failure. Four patients (30.8%) did not recover their basal renal function. When fibrate treatment begins a renal function should be monitored specially in patients with CRF.

Deterioro de la función renal inducido por fibratos / No disponible

Introducción: Los fibratos representan uno de los grupos de fármacos indicados para el tratamiento de la hiperlipidemia. Uno de sus efectos secundarios, aún poco conocido, es el deterioro agudo de la función renal. En los últimos 26 meses hemos objetivado en nuestra consulta externa de Nefrología un total de13 pacientes con deterioro de la función renal asociado al uso de fibratos. Material y métodos: El objetivo de nuestro estudio es evaluar nuestra experiencia en el incremento de Creatinina sérica (Crs) inducido por fibratos. Se trata de una revisión retrospectiva de una serie de casos. Resultados: De los 13 pacientes (8 hombres/5 mujeres) con edad media de 65,5 ± 12,2 años, diez fueron tratados con fenofibrato, uno con bezafibrato y dos con gemfibrozilo. Seis pacientes partían de una función renal normal y los otros siete presentaban una Insuficiencia Renal Crónica (IRC) leve-moderada previamente al inicio del tratamiento. El incremento de creatinina con respecto a la basal expresado en porcentaje fue superior al 74%. En nueve de los pacientes el deterioro de función renal fue completamente reversible (grupo 1), mientras que en cuatro de ellos la recuperación fue parcial (grupo 2). La media de creatinina antes de recibir tratamiento con fibratos fue de 1,33 ± 0,36 mg/dl (aclaramiento de creatinina 63,2 ± 26,6 ml/min) y la media de la creatinina máxima durante el tratamiento fue de 2,22± 0,49 mg/dl (aclaramiento de creatinina 33,4 ± 8,1 ml/min). El tiempo medio de evolución hasta objetivarse el incremento de creatinina fue de 6,7 ± 5,8 meses y la recuperación de la función renal ocurrió a los 3,8 ± 3,5 meses de la suspensión del tratamiento con fibratos. En los pacientes del grupo 2 se objetivó un mayor incremento de Crs y un tiempo de tratamiento confibratos más prolongado. En los pacientes en los que se obtuvieron niveles de CPK, éstos fueron normales. En dos de nuestros (..) (AU)

Introduction: Fibrates represent one of the medications used to treat patients with hyperlipemia. Deterioration in renal function is not a very known adverse effect of fibric acid derivates . In the last 26 months we have detected thirteen patient s with acute renal failure associated to fibrates in our outpatients’ clinic. Subjects and methods : The aim of our study is to analyze our experience in deterioration in renal function associated to fibrates use. This is a retrospective char t s review. Results: From the thirteen patients (8 males/5 females) with mean age of 65.5 ± 12.2 year s , ten received Fenofibrate (FN) , one Beza fibrate (BZ) and two Gemfibrozil (GF). Six cases had previously normal renal function and the seven remaining had mi ld chronicrenal failure (CRF) . The increase of serum Creatinine (Cr s ) value was higher than 74%. (..) (AU)

Partial inhibition of proteasome activity enhances remyelination after cuprizone-induced demyelination.

We have previously demonstrated that addition of low concentrations of lactacystin (a specific inhibitor of the proteasome) to oligodendroglial cell cultures containing a high percentage of precursor cells induces their exit from the cell cycle and their differentiation. On the other hand, we have recently shown that the mechanism of cuprizone toxicity on oligodendroglial cells involves the recruitment of microglia and their secretion of pro-inflammatory cytokines and in the increased production of oxidant species, which results in a decrease in the activities of the mitochondrial respiratory chain. In the present paper we investigated the effect of a decrease in proteasome activity induced by the injection of lactacystin in the corpus callosum in the remyelination process that normally occurs after cuprizone-induced demyelination. This treatment markedly improves the remyelination process that normally occurs in cuprizone-induced demyelination. It also attenuates the activation of NFkappaB and the recruitment of microglia and astrocytes, thus helping in the recovery of the mitochondrial respiratory chain activities that are affected by cuprizone treatment.

Renal effects of ibuprofen for the treatment of patent ductus arteriosus in premature infants.

In recent years ibuprofen has been proposed for the treatment of patent ductus arteriosus (PDA) as it has been proved to be equally as effective as indomethacin and shows fewer cerebral blood flow, intestinal and renal hemodynamic effects. A number of studies and several meta-analyses comparing both drugs are now available that debate whether indomethacin or ibuprofen should be used for PDA prophylaxis or closure. This review examines the available knowledge on the specific issue of the effects of ibuprofen on kidney function, as improved renal tolerance is a major argument in favor of its use in the routine treatment of PDA. There is sufficient evidence to consider that ibuprofen, at the currently proposed dosing regimen, has a similar efficacy to indomethacin but is better tolerated by the neonatal kidney when employed for the treatment of established PDA. However, adverse effects of ibuprofen have been evidenced both in trials on the use of ibuprofen for the prevention of PDA and of intraventricular hemorrhage-periventricular hemorrhage (IVH-PVH), and in experimental studies on a neonatal, anesthetized animal model. Thus ibuprofen, as with other cyclooxygenase (COX) inhibitors, may not be exempt from causing renal adverse effects, especially in circumstances when renal prostaglandin activation is maximal (i.e., when administrated early after birth, in more immature patients and in certain situations such as in the anesthetized rabbit). However, although the issue has been addressed extensively in the last decades, there is insufficient evidence that therapeutic intervention in PDA is beneficial in terms of mortality or clinically significant morbidity outcomes. Studies aimed at resolving this key issue are still needed.

The neurotoxic effect of cuprizone on oligodendrocytes depends on the presence of pro-inflammatory cytokines secreted by microglia.

In order to further characterize the still unknown mechanism of cuprizone-induced demyelination, we investigated its effect on rat primary oligodendroglial cell cultures. Cell viability was not significantly affected by this treatment. However, when concentrations of IFNgamma and/or TNFalpha having no deleterious effects per se on cell viability were added together with cuprizone, cell viability decreased significantly. In mitochondria isolated from cuprizone-treated glial cells, we observed a marked decrease in the activities of the various complexes of the respiratory chain, indicating a disruption of mitochondrial function. An enhancement in oxidant production was also observed in cuprizone and/or TNFalpha-treated oligodendroglial cells. In in vivo experiments, inhibition of microglial activation with minocycline prevented cuprizone-induced demyelination. Based on the above-mentioned results we suggest that these microglial cells appear to have a very active role in cuprizone-induced oligodendroglial cell death and demyelination, through the production and secretion of pro-inflammatory cytokines.

[Patients with a complete or partial remission of Major Depressive Episode as part of Recurrent Major Depressive Disorder: description of ECLAIR study population]. / Patients en rémission partielle ou totale d'un Episode Dépressif Majeur dans le cadre d'un trouble dépressif récurrent: description de la population incluse dans l'étude ECLAIR.

Some guidelines and expert consensus consider the way of care management practices for the recurrent depressive disorder, particularly according to different identified risk factors for recurrence. But, few data are available about the way that these risk factors influence the care management of depressive recurrent patients during the partial or complete remission phase. Eclair study is a longitudinal observatory multicentric and national study, which describes the different risk factors that influence the psychiatrist decision about the following of patients suffering form Major Depressive Disorder (at least 3 Major Depressive Episode (MDE) according to DSM IV). This article presents the inclusion data (V0) of patients, with a focus on their demography characteristics and history of trouble, diagnosis, symptomatology evaluation (with CGI-S, HAM-D, Carroll scale and Sheehan scale) and Cloninger's personality questionnaire (TCI). A total of 596 patients with a recurrent depression either on partial remission (PaR) or complete remission (ToR) to their last episode at the selection, have been included. Complete remission was defined by the presence of a maximum of two criteria of MDE (according to DSM IV) excepted depressed mood and diminished interest or pleasure during at least two months with a HAM-D (17 items) score < 7 and partial remission was defined by the persistence of depressed symptoms but not sufficient to complete a diagnosis of MDE (according to DSM IV) associated with a HAM-D (17 items) score between 8 and 13 included. Mean HAM-D scores at V0 were 10.3 +/- 1.6 for PaR group and 4.0 +/- 1.9 for the ToR group. Free time since last episode was 6.5 +/- 10.5 months in ToR group and 11.2 +/- 16.9 months in PaR group (n = 385). Residual symptomatology between prior episodes was systematically present for 47.6% patients in PaR group, and for 26.7% patients ToR group. The feel to have a stressful daily life persisted for 62.5% of patient in PaR group and 34.3% in ToR group; 70.3% patients in PaR group and 57.9% patients in ToR group reported persistence of causal factor. The main collected risk factors for recurrence were the number of prior depressive episodes (64.9%), familial conflict existence (52.9%) and recent events of life (45.1%). In the TCI, a significant difference in comparison with the French normative data has been found for 3 dimensions: Harm Avoidance, Cooperativeness and Self-Directedness. Some differences were obtained for Novelty Seeking, Reward Dependence, and Self-Transcendence, but without sufficient clinical significance.This study confirms various characteristics about the unipolar depressive disorder, particularly the high risk of recurrence in patients with high number of previous episodes. In the research of predictive depressive recurrence signs, it would be interesting to focus on discriminating elements between complete remitted patients and partial remitted patients.

Antioxidant status of neonates exposed in utero to tobacco smoke.

To investigate the influence of maternal smoke exposure on neonatal and maternal antioxidant status, 39 mothers who were active smokers, 14 mothers exposed to environmental tobacco smoke (ETS), 17 controls, and their newborns were included in a prospective, controlled study. Plasma total antioxidant capacity, measured as total radical-trapping antioxidant parameter (TRAP) and ferric reducing antioxidant power (FRAP), and concentrations of specific antioxidants were measured in cord and in maternal blood. A similar, significant increase in ceruloplasmin concentration was observed in neonates born to actively smoking mothers and in those born to ETS exposed mothers. Uric acid and TRAP concentrations were significantly increased in ETS-exposed newborns and their mothers, compared to newborns and mothers from the active smoking and no-exposure groups with a trend towards increased uric acid, TRAP and FRAP concentrations being observed in the active smokers group. Neonatal and maternal antioxidant concentrations correlated significantly, except for ceruloplasmin. Cord blood vitamin A, E and C concentrations were unaffected by smoke exposure. These results show that maternal active smoking as well as ETS exposure significantly affect neonatal and maternal antioxidant status.

Cushing's syndrome in pregnancy and neonatal hypertrophic obstructive cardiomyopathy.

Cushing's syndrome is rare in pregnancy but can cause spontaneous abortion, stillbirth or premature birth. We report a case of transient hypertrophic obstructive cardiomyopathy in a newborn whose mother had hypercortisolism due to a primary adrenal lesion. There was no family history of hypertrophic obstructive cardiomyopathy. Follow-up revealed complete resolution of the cardiac abnormalities in the infant. Cushing's syndrome in the mother resolved after delivery. Although maternal hypercortisolism seldom results in symptomatic hypercortisolism in the newborn, hypertrophic obstructive cardiomyopathy can occur.

Vanin-1-/- mice exhibit a glutathione-mediated tissue resistance to oxidative stress.

Vanin-1 is an epithelial ectoenzyme with pantetheinase activity and generating the amino-thiol cysteamine through the metabolism of pantothenic acid (vitamin B(5)). Here we show that Vanin-1(-/-) mice, which lack cysteamine in tissues, exhibit resistance to oxidative injury induced by whole-body gamma-irradiation or paraquat. This protection is correlated with reduced apoptosis and inflammation and is reversed by treating mutant animals with cystamine. The better tolerance of the Vanin-1(-/-) mice is associated with an enhanced gamma-glutamylcysteine synthetase activity in liver, probably due to the absence of cysteamine and leading to elevated stores of glutathione (GSH), the most potent cellular antioxidant. Consequently, Vanin-1(-/-) mice maintain a more reducing environment in tissue after exposure to irradiation. In normal mice, we found a stress-induced biphasic expression of Vanin-1 regulated via antioxidant response elements in its promoter region. This process should finely tune the redox environment and thus change an early inflammatory process into a late tissue repair process. We propose Vanin-1 as a key molecule to regulate the GSH-dependent response to oxidative injury in tissue at the epithelial level. Therefore, Vanin/pantetheinase inhibitors could be useful for treatment of damage due to irradiation and pro-oxidant inducers.

[Efficacy of early cerebral MR in the detection of brain lesions in high risk preterm infants compared with conventional US]. / Apporti della Risonanza Magnetica cerebrale precoce rispetto all'ecografia nella sorveglianza neurologica del grande prematuro.

To identify the efficacy of early cerebral MR, performed in the first month of birth, in the detection of brain lesions in high risk preterm infants, compared with conventional US, we recruited into the study a group of 30 preterm infants born at or below a gestational age of 30 weeks, who had a pathologic scan. The findings on US were compared with those of the early MR scan, performed in the same days, the results of which were considered as the final diagnosis. The value of cranial US as a predictor of MR signal intensity was assessed by calculating sensitivity, specificity, positive and negative predictive values. Agreement between two investigations was evaluated by calculating the K coefficient. US showed 33 haemorrhagic lesions in 25 preterms; MR showed 27 haemorrhagic lesions in 22 infants: in 16 cases MR gave the same results of US. Cranial US was reliable in detecting lesions such as GLH and IVH, but less sensitive in the definition of their size and distribution. Sensitivity of US for haemorrhagic lesions was 96.3%, PPV 78.8%, K coefficient 0.55 (p < 0.001). About the White Matter, cranial US demonstrated 20 lesions in 20 preterms; MR showed 16 lesions in 16 infants: in 3 cases MR was agree to US. US showed high reliability in the detection of cystic lesions, but significant limitations in the demonstration of non-cystic injury. We founded that normal WM echogenicity on US is not a good predictor of normal WM signal intensity on MR (30%). Sensitivity of US for WM lesions was 81.3%, PPV 65%, K coefficient 0.23 (p = 0.04). Finally US showed 4 lesions in other brain locations, MR confirmed 3 of them and discovered other 10. Sensitivity of US for these lesions was 23.1%, PPV 75%, K coefficient 0.21 (p = 0.11). We founded that cranial US is a good method for detecting GLH, IVH, HPI and severe WM lesions (cystic PVL), but it can miss non-cystic PVL, punctate haemorrhages, WMD and lesions in other brain locations, that, on the other hand, MR detects clearly.

[Imaging of neonatal neurological disorders]. / Imagerie des désordres neurologiques néonataux.

Neonatal brain disorders consist of a wide chapter including brain malformations, hypoxic-ischemic encephalopathy, intracranial infections, perinatal trauma and metabolic encephalopathies. The aim of this review paper is to describe the main imaging modalities (ultrasonography, CT, MRI) that are used extensively for the diagnosis of neonatal brain disorders, with their respective advantages and limitations, to illustrate and describe the main brain lesions encountered in the neonatal period, particularly with MRI since its role has increased over the recent years. We will focus on hypoxic-ischemic encephalopathy, materno-fetal infections, metabolic encephalopathies and stroke, those four conditions being the most frequent so far. Imaging modalities, especially MRI, by showing the extent of brain damage, are part of the prognostic factors in cases of infective causes and of hypoxic-ischemic origin. MRI is also very efficient in showing brain damage as atrophy and white matter abnormalities suggestive of an underlying abnormal brain of metabolic origin.

[MRI and in utero ventriculomegaly]. / IRM et ventriculomégalie in utero.

Ventriculomegaly constitutes the major indication of fetal brain MRI. MRI is therefore of utmost importance to look for a cause through the depiction of criteria of malformations and through the definition of criteria of destructive lesions. Malformations and destructive lesions are the most common causes of ventricular dilatation. Some challenging points are worth mentioning in term of mechanism with the challenge of hydrocephalus (in term of increased in intracranial pressure) and of isolated ventriculomegaly. The image itself is also challenging since a similar image may be of different origin. In term of natural history of fetal brain injury an irregular, nodular aspect of the ventricular wall and/or the germinal matrix is often the only pathologic MRI finding that is known to be of clastic origin. In term of prognosis the challenge is represented by the isolated mild ventriculomegaly, the literature being quite confusing. The purpose of this review paper is to highlight the underlying mechanisms and pathophysiology of ventricular dilatation based on results from the literature as well as from personal experience.

Adenovirus-mediated gene transfer of urokinase plasminogen inhibitor inhibits angiogenesis in experimental arthritis.

Plasmin is essential for metalloproteases activation, endothelial cell migration and degradation of the extracellular matrix. The process is common to neoangiogenesis pannus formation and cartilage degradation within arthritic joints. Since 80% of synovial cells express urokinase plasminogen activator receptor (uPAR), we investigated the inhibition of plasmin activation in a collagen-induced arthritis (CIA) mice model, by expressing a uPA/uPAR antagonist molecule (ATF) fused to human serum albumin (HSA) to extend its serum half-life. Overexpression was obtained with an adenoviral vector expressing the chimeric murine ATF-HSA. We showed that the genetic coupling did not significantly reduce the ability of the ATF moiety to interact with its receptor uPAR. The chimeric protein was detectable in the sera of injected mice 7 days following Ad-mATF-HSA injection, then decreased in parallel with the anti-HSA titer increase. Systemic Ad-mATF-HSA injection performed on day 25 following CIA induction decreased the incidence of arthritis and the severity of the disease. Moreover, synovial angiogenesis in arthritic paws was decreased after Ad-mATF-HSA gene transfer, as assessed by smooth muscle actin immunostaining. The preventive effect observed on arthritis was related to the decrease in angiogenesis, rather than inhibition of extracellular matrix degradation.