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Introduction With increasing automation in clinical laboratories, the requirements for quality control (QC) material have greatly increased in order to monitor performance. The constant use of commercial control material is not economically feasible for many countries because of nonavailability or the high-cost of those materials. Therefore, preparation and use of in-house QC serum will be a very cost-effective measure with respect to laboratory needs. Materials and Methods In-house internal quality control from leftover serum samples of master health checkup subjects, which have been screened negative for HIV, HCV and HBsAg antibodies was pooled in a glass jar with ethanediol as preservative and kept in deep freezer at − 20°C. From the pooled serum, 100 microliter thirty aliquots were prepared. Every day along with commercial internal QC (IQC), one aliquot of pooled serum was analyzed for 30 days for the following parameters: plasma glucose, blood urea, serum creatinine, total cholesterol, triglycerides (TGL), high-density lipoprotein, calcium, total protein, albumin, total bilirubin, AST, ALT, ALP, amylase. After getting 30 values for each parameter, mean, standard deviation (SD) and CV% were calculated for both IQC commercial sample and pooled serum sample. Results The mean, SD, and CV% of glucose, cholesterol, TGL, calcium, alanine aminotransaminase (ALT), aspartate aminotransferase (AST), amylase, and alkaline phosphatase (ALP) were statistically significant between pooled serum and commercial QC. Conclusion In-house QC prepared from pooled serum is better than commercial internal QC. The biochemical parameters were stable in pooled serum due to less matrix effect; also, variation was less in pooled serum IQC.

Objective: Heart failure with preserved ejection fraction is a major health care issue which has been difficult to manage to date, due to its complex and not well understood pathophysiology. Specifically, if a wealth of literature focuses on heart failure with preserved ejection fraction cardiac component, very little information can be found on its vascular component. Our goal is to unravel the critical role of cardiac small vessel disease in the pathophysiology of diastolic dysfunction. Approach and Results: To do so, we used leptin receptor deficient (Lepr db/db ) female mice, a recognized model of diastolic dysfunction. In these mice, the increased end-diastolic pressure signing diastolic dysfunction is associated with vascular leakage, endothelial cell activation, and leucocyte infiltration. Strikingly, a RNA sequencing analysis of the cardiac vascular fraction of both Lepr db/db and control mice confirmed endothelial dysfunction and systemic inflammation, but above all, revealed a strong increase in several mast cell markers (notably FceR1a [high affinity immunoglobulin epsilon receptor subunit α], tryptase, and chymase). We then confirmed this accumulation of activated mast cells in the heart of Lepr db/db mice via histology. Importantly, we found that both mast cell degranulation inhibition and specific histamine blockade reduced vascular leakage, leucocyte infiltration, and subsequently end-diastolic pressure in Lepr db/db mice. This demonstrated, for the first time, that mast cells, via histamine release, participate in the development of cardiac small vessel disease leading to diastolic dysfunction. Conclusions: Cardiac small vessel disease is a key mechanism of heart failure with preserved ejection fraction pathophysiology that can be targeted to prevent the occurrence of diastolic dysfunction, by using both mast cell stabilizers and antihistaminic drugs.

RationalHeart failure with preserved ejection fraction (HFpEF) is a growing epidemiologic issue. However, to date, its pathophysiology remains poorly understood.ObjectiveOur goal was to investigate the role of microvessel disease in the pathophysiology of diastolic dysfunction.FindingsTo do so, we used Leptin receptor deficient (Leprdb/db) female mice as a model of diastolic dysfunction. In these mice, the increased end diastolic pressure (EDP) signing diastolic dysfunction is associated with vascular leakage, endothelial cell activation and leucocyte infiltration. Strikingly, a RNA sequencing analysis of the cardiac vascular fraction of both Leprdb/db and control female mice confirmed endothelial dysfunction and systemic inflammation but also revealed a strong increase in several mast cell markers (notably FceR1a, Tryptase and Chymase). We then histologically confirmed an accumulation of activated mast cells in the heart of Leprdb/db mice. Importantly, mast cell degranulation inhibition reduced EDP, vascular leakage and leucocyte infiltration in Leprdb/db mice.ConclusionMast cells play a critical role in the development of cardiac microvessel disease and diastolic dysfunction.

A variety of animal models exist for the study of cardiovascular function using many approaches from surgically induced ischemia to genetic manipulation. A murine physiological model was recently proposed for the non-invasive study of peripheral circulation and was strengthened by the wavelet transform analysis (WA) of laser Doppler flowmetry (LDF) signals. WA allows the extraction of cardiac, respiratory, sympathetic, endothelial, and myogenic components from the raw LDF signal. The present study was designed to evaluate the discernment capacity of the model through an analysis of the short-term effects of the well-known hypotensive cardiovascular drug, atenolol. Six male C57/BL6 mice (16 weeks old) were included in the study, with each animal serving as its own control. Following anesthesia with ketamine-xylazine, skin perfusions were continuously assessed in both hindlimbs by LDF during baseline and after two sequential atenolol administrations (2.5 and 5.0 mg/kg, as commonly prescribed). Expected atenolol-induced hypotension was present, associated with a significantly increased heart rate and peripheral perfusion with both dosages. Through the application of WA to the LDF signal, we could detail the mechanisms of the atenolol-induced peripheral perfusion modulation: an immediate amplitude decrease of the cardiac LDF spectrum with an amplitude increase of the sympathetic component (p &lt, 0.05) and the endothelial and myogenic components (non-significant). These data suggested a regulatory crosstalk between the peripheral (baroreceptors) and the microcirculatory units, which ultimately resulted in hypotension, inotropic reduction, and tachycardia. In conclusion, WA offered insight that simply could not be seen with only the perfusion curve and, thus, was an effective tool to investigate this cardiovascular mechanism of regulation.

Rationale: Klf (kruppel-like factor) 2 is critical to establish and maintain endothelial integrity. Objective: Therefore, determining upstream and downstream mediators of Klf2 would lead to alternative therapeutic targets in cardiovascular disease management. Methods and Results: Here we identify Dhh (desert hedgehog) as a downstream effector of Klf2, whose expression in endothelial cells (ECs) is upregulated by shear stress and decreased by inflammatory cytokines. Consequently, we show that Dhh knockdown in ECs promotes endothelial permeability and EC activation and that Dhh agonist prevents TNF-α (tumor necrosis factor alpha) or glucose-induced EC dysfunction. Moreover, we demonstrate that human critical limb ischemia, a pathological condition linked to diabetes mellitus and inflammation, is associated to major EC dysfunction. By recreating a complex model of critical limb ischemia in diabetic mice, we found that Dhh-signaling agonist significantly improved EC function without promoting angiogenesis, which subsequently improved muscle perfusion. Conclusion: Restoring EC function leads to significant critical limb ischemia recovery. Dhh appears to be a promising target, downstream of Klf2, to prevent the endothelial dysfunction involved in ischemic vascular diseases.

International audience; This study combines two well-known vascular research models, hyperoxia and hind limb ischemia, aiming to better characterize capacities of the hyperoxia challenge. We studied two groups of C57/BL6 male mice, a control (C) and a hind limb ischemia (HLI) group. Perfusion from both limbs was recorded in all animals by laser Doppler techniques under an oxygen (O 2) saturated atmosphere, once for control and, during 35 days for the HLI group. We used a third set of normoxic animals for HLI morphometric control. The expected variability of responses was higher for the younger animals. In the HLI group, capillary density normalized at Day 21 as expected, but not microcirculatory physiology. In the operated limb, perfusion decreased dramatically following surgery (Day 4), as a slight reduction in the non-operated limb was also noted. Consistently, the response to hyperoxia was an increased perfusion in the ischemic limb and decreased perfusion in the contralateral limb. Only at Day 35, both limbs exhibited similar flows, although noticeably lower than Day 0. These observations help to understand some of the functional variability attributed to the hyperoxia model, by showing (i) differences in the circulation of the limb pairs to readjust a new perfusion set-point even after ischemia, an original finding implying that (ii) data from both limbs should be recorded when performing distal measurements in vivo. Our data demonstrate that the new vessels following HLI are not functionally normal, and this also affects the non-operated limb. These findings confirm the discriminative capacities of the hyperoxia challenge and suggest its potential utility to study other pathologies with vascular impact.

Rationale: Tamoxifen prevents the recurrence of breast cancer and is also beneficial against bone demineralization and arterial diseases. It acts as an ER (estrogen receptor) α antagonist in ER-positive breast cancers, whereas it mimics the protective action of 17β-estradiol in other tissues such as arteries. However, the mechanisms of these tissue-specific actions remain unclear. Objective: Here, we tested whether tamoxifen is able to accelerate endothelial healing and analyzed the underlying mechanisms. Methods and Results: Using 3 complementary mouse models of carotid artery injury, we demonstrated that both tamoxifen and estradiol accelerated endothelial healing, but only tamoxifen required the presence of the underlying medial smooth muscle cells. Chronic treatment with 17β-estradiol and tamoxifen elicited differential gene expression profiles in the carotid artery. The use of transgenic mouse models targeting either whole ERα in a cell-specific manner or ERα subfunctions (membrane/extranuclear versus genomic/transcriptional) demonstrated that 17β-estradiol-induced acceleration of endothelial healing is mediated by membrane ERα in endothelial cells, while the effect of tamoxifen is mediated by the nuclear actions of ERα in smooth muscle cells. Conclusions: Whereas tamoxifen acts as an antiestrogen and ERα antagonist in breast cancer but also on the membrane ERα of endothelial cells, it accelerates endothelial healing through activation of nuclear ERα in smooth muscle cells, inviting to revisit the mechanisms of action of selective modulation of ERα.

Introduction Endothelium integrity is critical to vascular homeostasis, as failure of this system results in serious consequences such as hemorrhage, edema, inflammation and tissue ischemia. We recently identified Desert Hedgehog (DHH) as a critical regulator of endothelium integrity, downstream of KLF2. Objective The purpose of the present study was to characterize signaling pathways mediating Dhh-regulation of endothelium integrity. Methods We used BioGRID database to identify possible interactors of the DHH receptor, Patched-1 (PTCH1). Among these we chose to test the role of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) starting with in vitro assays including co-immunoprecipitation, western blot, immunofluorescence and endothelium permeability assays. Results First, we confirmed ADAM17 interaction with PTCH1 via co-immunoprecipitation assays in HeLa cells. Then, we showed that either DHH overexpression in HeLa cells or treatment of cultured endothelial cells (ECs) with soluble DHH induces ADAM17 protein degradation. By using either lysosome (Bafilomycin A1 and chloroquine) or proteasome inhibitors (MG132), we found that DHH induces ADAM17 degradation via the lysosome. To test whether DHH promotes adherens junction integrity by degrading ADAM17, cultured EC were either transfected with DHH siRNA alone, or with both DHH and ADAM17 siRNAs. We found that while DHH siRNA alone induces Cdh5 junction destabilization and increases endothelial permeability, these effects were prevented in the presence of ADAM17 siRNA, demonstrating DHH knockdown promotes Cdh5 junction destabilization and increased endothelial permeability via ADAM17. Conclusion Altogether, these results demonstrate that DHH promotes endothelium integrity by inducing ADAM17 degradation. We will soon verify these results in vivo in Dhh endothelial specific KO mice treated or not with the ADAM17 inhibitor Aderbasib.

Introduction While the critical role of pericytes in maintaining vascular integrity has been extensively demonstrated in the brain and in the retina, very little is known about their role in the heart. Objective To investigate the cardiac structural and functional consequences of partial pericyte depletion (about 60%) in adult mice. Method To deplete pericytes in adult mice, Pdgfrb-Cre/ERT2; RosaDTA mice were administered with tamoxifen at 8 weeks of age and again at 10 weeks of age for 5 consecutive days. Control mice were RosaDTA mice chosen among their littermates and administered with tamoxifen following the same protocol. Cardiac function was assessed via echocardiography and left ventricle (LV) catheterization at 14 weeks of age. Immediately after, mice were sacrificed for histological analyses. Results Mice depleted with pericytes had a reduced LV ejection fraction (43,9 ± 0,7% vs. 77,6 ± 3,2 in control mice) and an increased end-diastolic pressure (11,12 ± 0,8282 mmHg vs. 5,730 ± 0,9524 in control mice) demonstrating systolic dysfunction. Accordingly, mice depleted with pericytes presented a decreased LV contractility (dP/dtmax) (3500 ± 387 mmHg/s vs. 5086 ± 157 in control mice) and an increased LV relaxation time (dP/dtmin) (−2664 ± 360,3 mmHg/s vs. −4557 ± 192,9 in control mice). Morphologically, the heart of mice depleted with pericytes did not show hypertrophy, however, it presented signs of fibrosis with increased perivascular type I collagen levels and inflammation with an increased CD45 + cell infiltration and endothelial ICAM-1 expression. Conclusion Cardiac pericyte depletion induces heart failure with reduced ejection fraction demonstrating that cardiac pericytes are critical for cardiac function. This result suggests that pericyte dysfunction could contribute to the onset of heart failure.

Introduction Heart Failure with Preserved Ejection Fraction is proposed to be caused by endothelial dysfunction in cardiac small vessels. Objective Our goal is to demonstrate that endothelial dysfunction is sufficient to induce diastolic dysfunction by using a mouse model with genetically-induced endothelial dysfunction. Methods We used Desert Hedgehog (Dhh) endothelial deficient mice as such a model. Indeed, we recently demonstrated that Dhh is a downstream target of Klf2 critical for endothelial integrity. Practically, Cdh5-Cre/ERT2; Dhhflox/flox (DhhECKO) and their control (Dhhflox/flox) littermates were administered with tamoxifen at 8 weeks of age to induce Dhh KO and endothelial dysfunction. Cardiac function was assessed one month later via echocardiography and hemodynamic measurements. Immediately after, mice were sacrificed for gene expression and histological analyses. Results As expected, DhhECKO mice exhibited phenotypic changes in their cardiac small vessels characterized by a pro-inflammatory and a pro-thrombotic phenotype, an increased endothelium permeability to albumin, IgG and fibrinogen and perivascular fibrosis. Notably, we found that these changes are sufficient to induce diastolic dysfunction since DhhECKO mice presented significantly increased end-diastolic pressures (8.05 ± 1.11 mmHg vs. 4.69 ± 1.69 in control mice, P = 0.02) while their left ventricular ejection fraction was comparable to that of control mice. Moreover, DhhECKO had a reduced exercise tolerance in the treadmill test, (running time: 13.28 ± 4.62 min vs. 24.97 ± 4.27 in control mice, P = 0.01) suggesting that they do present heart failure. Diastolic dysfunction in these mice is more likely due to an increased cardiomyocyte passive stiffness since DhhECKO heart display an increased Tcap mRNA expression while the minimum dP/dt and the relaxation time constant Tau were not modified. Conclusion Altogether, these results strongly support that endothelial dysfunction is sufficient to HFPEF.

Introduction In 2019, Schiattarella et al introduced a new mouse model mimicking heart failure with preserved ejection fraction (HFpEF). In this model, diastolic dysfunction is induced by a high fat diet (HFD) regimen together with L-NAME treatment. Even though small vessel disease is currently proposed to be responsible for HFpEF, the phenotype of the cardiac microvasculature has not been described in this model. Objective To characterize the phenotype of the cardiac microvasculature in this model. Method Ovariectomized C57Bl6/J female mice were fed with HFD (60% kCal from fat) from 8 weeks of age. Discontinuous L-NAME (1 g/L in the drinking water, 4 days a week) treatment was initiated 2 week later. Cardiac function was assessed via echocardiography and left ventricle (LV) catheterization at 20 weeks of age. Immediately after, mice were sacrificed for histological and gene expression analyses. Results Consistently with Schiattarella et al data, HDF + L-NAME treated mice displayed increased end diastolic pressure [12.8 ± 0,9 mmHg vs. 4.0 ± 0,6 in control mice (P Conclusion Diastolic dysfunction observed in HFD + L-NAME treated mice is associated with endothelial dysfunction supporting that small vessel disease especially increased endothelial permeability and or activation could play a central role in the pathophysiology of HFpEF.

Ovarian cancers diagnosed between 2000 and 2013 were examined and cases with and without endometriosis compared. Among 139 epithelial ovarian, there were 49 (35%) with endometriosis and 90 (65%) without endometriosis. Endometriosis associated ovarian cancers were more likely to be confined to the pelvis (54% vs. 9%, p < 0.0001) and lower grade (51% vs. 29%, p = 0.014). Younger age and earlier stage independently predicted the presence of endometriosis (p = 0.0011 and p < 0.0001, respectively). Ovarian cancer patients with endometriosis had improved PFS and OS [(HR = 0.20; 95% CI, 0.09-0.43), (HR = 0.18; 95% CI, 0.04-0.81)], compared to patients without endometriosis; however, endometriosis had no independent prognostic significance.

Introduction Heart failure with preserved ejection fraction (HFpEF) is a growing epidemiologic problem and a major source of morbidity and mortality. However, to date, there are no therapies available to treat HFpEF mainly because of its poorly understood pathophysiology. Objective The purpose of this study is to investigate whether Leptin receptor deficient (Leprdb/db) female mice can be used as an appropriate mouse model of HFpEF to investigate its pathophysiology. Notably, Leprdb/db female mice exhibit 3 risk factors for HFpEF i.e. diabetes, obesity and female gender. Methods We assessed cardiac function, heart structure and heart microvessel phenotype in both leprdb/db female mice and their control Leprdb/+ littermates at 3, 6 and 12 months of age. Results From 3 months of age, Leprdb/db female mice present an elevated end-diastolic pressure (EDP) compared to their age-matched controls while their ejection fraction (EF) remain above 50% which indicate diastolic dysfunction with preserved EF. In addition, Leprdb/db mice have a significant cardiac hypertrophy characterized by an increased heart weight/tibia length ratio, increased left ventricular wall thickness and increased cardiomyocyte size. While both quantification of fibrosis after Picrosirius red staining and qPCR analysis and Col1a1 and Col3a1 mRNA expression did not reveal any significant changes is collagen amount, Lysyl oxidase mRNA was significantly increased in Leprdb/db female mice after 6 months of age indicating a probable increased collagen cross linking. The cardiac microvessel phenotype of these mice is characterized by an increased endothelium permeability (albumin extravasation) and activation (increased ICAM-1 and E-Selectin) while capillary density is not changed. This is associated with an increased macrophage infiltration. Conclusion Leprdb/db mice recapitulate most features of HFpEF including increased EDP, unchanged EF, cardiac hypertrophy, EC activation and cardiac inflammation.

Introduction Sonic Hedgehog (Shh), when administered as recombinant protein or via gene therapy was shown to be proangiogenic. However, studies performed in mice deficient for Hedgehog (Hh) signaling pathway elements have revealed that, on the contrary, endogenous Hh signaling is necessary for endothelium integrity and limits angiogenesis, suggesting that Hh ligands may have antagonistic effects. Notably, we recently demonstrated that endothelium integrity depends on endothelial cell (EC)-derived Desert Hedgehog (Dhh). Objective We wish to clarify mechanisms underlying regulation of angiogenesis and vascular barrier integrity by Hh ligands. Methods and results First we confirmed that Shh recombinant protein induces angiogenesis in the mouse corneal angiogenesis model. Then, we investigated the role of EC-derived Dhh in the same model, and found that, unexpectedly, VEGFA-induced angiogenesis was significantly increased in the absence of EC-derived Dhh suggesting that endogenous Dhh is anti-angiogenic. Besides, we administered Shh-encoding lentiviruses in the brain of WT mice and found that ectopic Shh, on the contrary to EC-derived Dhh disrupts blood brain barrier integrity, demonstrating, once again, that EC-derived Dhh and ectopic Shh have antagonistic effects. We then performed in vitro experiments in cultured ECs and confirmed that both treatment of ECs by Shh recombinant protein and Dhh KD in ECs disrupt intercellular junction integrity and promote EC migration. Notably, Smoothened inhibition recapitulates the phenotype of Dhh deficiency both in vivo and in vitro suggesting that Dhh autocrinally activates Hh signaling in ECs while ectopic Shh inhibits it. Finally, we performed immunoprecipitation assays and found that Dhh binding to Patched-1 is decreased in the presence of Shh. Conclusion Altogether these results suggest for the first time that Shh, when administered ectopically may counteract Dhh-induced blood vessel integrity and quiescence.

Objective— Chronic nonhealing wounds are a substantial medical concern and are associated with morbidity and mortality; thus, new treatment strategies are required. The first step toward personalized/precision medicine in this field is probably in taking sex differences into account. Impaired wound healing is augmented by ischemia, and we previously demonstrated that 17β-estradiol exerts a major preventive effect against ischemia-induced skin flap necrosis in female mice. However, the equivalent effects of testosterone in male mice have not yet been reported. We then investigated the role of steroid hormones in male mice using a skin flap ischemia model. Approach and Results— Castrated male mice developed skin necrosis after ischemia, whereas intact or castrated males treated with testosterone were equally protected. Testosterone can (1) activate the estrogen receptor after its aromatization into 17β-estradiol or (2) be reduced into dihydrotestosterone, a nonaromatizable androgen that activates the androgen receptor. We found that dihydrotestosterone protected castrated wild-type mice by promoting skin revascularization, probably through a direct action on resistance arteries, as evidenced using a complementary model of flow-mediated outward remodeling. 17β-estradiol treatment of castrated male mice also strongly protected them from ischemic necrosis through the activation of estrogen receptor-α by increasing skin revascularization and skin survival. Remarkably, 17β-estradiol improved skin survival with a greater efficiency than dihydrotestosterone. Conclusions— Testosterone provides males with a strong protection against cutaneous necrosis and acts through both its estrogenic and androgenic derivatives, which have complementary effects on skin survival and revascularization.

Key features of asthma include bronchial hyperresponsiveness (BHR), eosinophilic airway inflammation, and bronchial remodeling, characterized by subepithelial collagen deposition, airway fibrosis, and increased bronchial smooth muscle (BSM) mass. The calcium-activated K(+) channel K(Ca)3.1 is expressed by many cells implicated in the pathogenesis of asthma, and is involved in both inflammatory and remodeling responses in a number of tissues. The specific K(Ca)3.1 blocker 5-[(2-chlorophenyl)(diphenyl)methyl]-1H-pyrazole (TRAM-34) attenuates BSM cell proliferation, and both mast cell and fibrocyte recruitment in vitro. We aimed to examine the effects of K(Ca)3.1 blockade on BSM remodeling, airway inflammation, and BHR in a murine model of chronic asthma. BALB/c mice were sensitized with intraperitoneal ovalbumin (OVA) on Days 0 and 14, and then challenged with intranasal OVA during Days 14-75. OVA-sensitized/challenged mice received TRAM-34 (120 mg/kg/day, subcutaneous) from Days -7 to 75 (combined treatment), Days -7 to 20 (preventive treatment), or Days 21 to 75 (curative treatment). Untreated mice received daily injections of vehicle (n = 8 per group). Bronchial remodeling was assessed by histological and immunohistochemical analyses. Inflammation was evaluated using bronchoalveolar lavage and flow cytometry. We also determined BHR in both conscious and anesthetized mice via plethysmography. We demonstrated that curative treatment with TRAM-34 abolishes BSM remodeling and subbasement collagen deposition, and attenuates airway eosinophilia. Although curative treatment alone did not significantly reduce BHR, the combined treatment attenuated nonspecific BHR to methacholine. This study indicates that K(Ca)3.1 blockade could provide a new therapeutic strategy in asthma.

To assess the feasibility and safety of concomitant intra-articular (IA) knee injection of mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP) under fluoroscopic guidance to treat patellofemoral osteoarthritis (OA).This prospective study included 19 consecutive patients referred for fluoroscopically guided IA MSC and PRP injection for symptomatic patellofemoral chondropathy in which conservative treatment had failed. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score and magnetic resonance (MR) data, including T2 mapping sequence, were prospectively collected before and 6 months after treatment. Clinical data without MR imaging were collected until 12 months after the procedure.WOMAC scores were significantly lower after IA injection of MSCs and PRP at 6 months and during 12-months follow-up compared with baseline (mean score decreased from 34.3 to 14.2; P.0018). Patients reported no complications. Concerning MR imaging follow-up, there were no significant differences in grade, surface, or T2 value of the chondral lesions (P.375).IA injection of MSCs and PRP in early patellofemoral OA appears to allow functional improvement.

Local shape descriptors can be used for a variety of tasks, from registration to comparison to shape analysis and retrieval. There have been a variety of local shape descriptors developed for these tasks, which have been evaluated in isolation or in pairs, but not against each other. We provide a survey of existing descriptors and a framework for comparing them. We perform a detailed evaluation of the descriptors using real data sets from a variety of sources. We first evaluate how stable these metrics are under changes in mesh resolution, noise, and smoothing. We then analyze the discriminatory ability of the descriptors for the task of shape matching. Finally, we compare the descriptors on a shape classification task. Our conclusion is that sampling the normal distribution and the mean curvature, using 25 samples, and reducing this data to 5–10 samples via Principal Components Analysis, provides robustness to noise and the best shape discrimination results. For shape classification, mean curvature sampled at the vertex or averaged, and the more global Shape Diameter Function, performed the best.

Epilepsy surgery has gained a large role in the treatment of intractable seizures in the last few decades because of the development of operative techniques and better identification of the cerebral anomalies using electrophysiological recordings and neuroimaging. A series of 419 children, aged from five months to 15 years, with epilepsy (medically refractory in 85.5% of them) associated with focal cortical lesions, who underwent surgery between 1986 and 2006 was analyzed to identify the factors that correlated with outcome. Mean follow-up was 5.2 years. According to Engel's classification; 75.8% of the children were seizure-free. When the lesion was well defined, correlations between clinical data, radiological features and electrophysiological features, suggesting a zone of seizure onset around (or even in) the lesion, was the best guarantee of achieving good seizure control by lesionectomy. Nevertheless, seizure outcome was also determined by other factors: the duration of the epilepsy and the surgery. Persistence of seizures was found to be significantly associated with the preoperative duration of epilepsy, the completeness of the lesional resection and de novo brain damage induced by the surgical procedure itself. Early surgery must be considered in children because of the benefits of seizure control on the developing brain and the risk of secondary epileptogenesis.

International audience; AIMS:Microangiopathy, i.e. endothelial dysfunction, has long been suggested to contribute to the development of diabetic neuropathy, although this has never been fully verified. In the present paper, we have identified the role of Hedgehog (Hh) signalling in endoneurial microvessel integrity and evaluated the impact of impaired Hh signalling in endothelial cells (ECs) on nerve function.METHODS AND RESULTS:By using Desert Hedgehog (Dhh)-deficient mice, we have revealed, that in the absence of Dhh, endoneurial capillaries are abnormally dense and permeable. Furthermore, Smoothened (Smo) conditional KO mice clarified that this increased vessel permeability is specifically due to impaired Hh signalling in ECs and is associated with a down-regulation of Claudin5 (Cldn5). Moreover, impairment of Hh signalling in ECs was sufficient to induce hypoalgesia and neuropathic pain. Finally in Lepr(db/db) type 2 diabetic mice, the loss of Dhh expression observed in the nerve was shown to be associated with increased endoneurial capillary permeability and decreased Cldn5 expression. Conversely, systemic administration of the Smo agonist SAG increased Cldn5 expression, decreased endoneurial capillary permeability, and restored thermal algesia to diabetic mice, demonstrating that loss of Dhh expression is crucial in the development of diabetic neuropathy.CONCLUSION:The present work demonstrates the critical role of Dhh in maintaining blood nerve barrier integrity and demonstrates for the first time that endothelial dysfunction is sufficient to induce neuropathy.

Background In elderly and diabetic patients, the increased risk of developing ischemic disease is associated with impaired regenerative properties of most tissues including skeletal muscle, which make those patients a challenging population to treat. We recently demonstrated that in skeletal muscle, Hedgehog (Hh) signaling promotes ischemia-induced angiogenesis by maintaining peripheral nerve and by promoting myogenesis. The objective of this study is to investigate the functionality of Hh dependent regulation of peripheral nerve survival and myogenesis in aged mice. Methods and Results In the present study, we used 12 week old (young mice) and 20 to 24 month old C57BL/6 mice (old mice) to investigate the activity of Hh signaling in the setting of ischemic skeletal muscle regeneration. In this model, delayed ischemic muscle repair observed in old mice was associated with an impaired upregulation of Gli1. Sonic Hedgehog expression was not different in old mice compared to young mice while Desert Hedgehog (Dhh) expression was downregulated in skeletal muscle of old mice both in healthy and ischemic conditions. Rescue of Dhh expression by gene therapy in old mice increased nerve density and promoted ischemia-induced angiogenesis, nevertheless it failed to promote myogenesis. After further investigation, we found that, in addition to Dhh knockdown, Smoothened (Smo) expression was significantly downregulated in old mice. We used mice in which Hh signaling is specifically disrupted in myocytes (HSA Cre:Smoflox/flox) and demonstrated that Smo knockdown is sufficient to impair ischemiainduced myogenesis. Conclusion The present study demonstrates that Hh signaling is impaired in aged mice which leads to impaired peripheral nerve survival and myogenesis in acute ischemic stress condition. Moreover, this study brings the new concept that it is necessary to restore both peripheral nerve integrity and myogenesis in elderly to promote revascularisation of ischemic tissues.

The aim of this review is to summarize our knowledge about Dandy-Walker malformation (DWM) and introduce recent notions about its prognosis. DWM is a malformation associating hypoplasia of the vermis, pseudocystic fourth ventricle, upward displacement of the tentorium, torcular and lateral sinuses and anterio-posterior enlargement of the posterior fossa. It is frequently associated with genetic anomalies, brain malformations (anomalies of gyration, grey matter heterotopias, meningoceles, corpus callosum agenesis...) or systemic malformations (heart, orthopedic, intestinal, urogenital and facial anomalies). It is also part of many syndromes. Its rarity, the difficulty of its diagnosis, the fact that the malformation is mainly known through hospitalized patients, mainly from neurosurgical departments, have made its definition variable and prevents us from having an accurate knowledge of its natural history and prognosis. Hydrocephalus, so frequent in neurosurgical series that some have included it in the definition, is actually rare as has been seen in prenatal series. Treatment, when necessary, is still controversial, the main options remaining cyst fenestration, ventriculo- and/or cystoperitoneal shunts and more recently endoscopic third ventriculostomy. The prognosis, commonly said to be unpredictable, is actually foreseeable after scrutinous observation of the brain anatomy, and mainly of the vermis. A cerebellar vermis with three groups of lobes and two main fissures, as identified on MRI T2 sagittal views, not only has the greatest chance to not be associated with other malformation but also to have a favorable neurocognitive outcome. On the contrary, a deeply dysgenetic vermis with only two or one recognizable lobes is not only constantly associated with other brain malformation but also with poor prognosis. This is a recent advance that may be important for those involved in prenatal counselling.

Object. The authors of this retrospective review and analysis of the literature cover an institutional series of neurenteric cysts of the central nervous system in children treated in the magnetic resonance imaging era during a 14-year period. Methods. Sixteen patients 20 days to 14 years of age are described. The most frequent signs and symptoms at presentation were acute spinal cord compression (11 patients), paresis of a cranial nerve (two patients), meningitis or infection (two patients), and intracranial hypertension (one patient). The locations of the cysts were as follows: in the spinal canal in 12 patients (75%), the clivus in two (12.5%), the cavernous sinus in one (6%), and the craniocervical junction in one (6%). The most common location was the ventral aspect of the spinal canal (seven patients). Associated spinal deformities were found in five patients. All patients underwent surgery, with a posterior approach used in all of the spinal cases. Total resection was achieved in 12 of the 16 cases and partial resection in four. Of the four patients who underwent subtotal resection, the cyst recurred in three, requiring further surgery. Conclusions. Neurenteric cysts are uncommon congenital anomalies that can present acutely in the pediatric population. Total removal is usually possible and is associated with a good prognosis.

A prospective study on childhood craniopharyngiomas (CPs) was conducted from 1994 to 1998 to appreciate the pre- and postoperative clinical, endocrine, mental, and intellectual status of the patients and to determine the incidence and severity of the postoperative hypothalamic syndrome. The series included 14 consecutive CPs. Twelve were retrochiasmatic and intraventricular, and two were partly prechiasmatic and extraventricular. All were treated with the aim of “total” removal. The removal was “total” in nine cases but incomplete in the other five. Immediate postoperative follow-up was uncomplicated in all cases. At 2-year follow-up, the two children with an extraventricular CP and a “total” tumor removal were intellectually normal, had no hypothalamic syndrome, and attended normal school with good results. The 12 others, although still intellectually normal, were more or less severely affected by a hypothalamic syndrome which altered their social insertion and caused academic failure. The authors conclude from this study that radical surgery should be reserved to extraventricular CPs only.

The tremendous increase in chemical structure and biological activity data brought about through combinatorial chemistry and high-throughput screening technologies has created the need for sophisticated graphical tools for visualizing and exploring structure-activity data. Visualization plays an important role in exploring and understanding relationships within such multidimensional data sets. Many chemoinformatics software applications apply standard clustering techniques to organize structure-activity data, but they differ significantly in their approaches to visualizing clustered data. Molecular Property eXplorer (MPX) is unique in its presentation of clustered data in the form of heatmaps and tree-maps. MPX employs agglomerative hierarchical clustering to organize data on the basis of the similarity between 2D chemical structures or similarity across a predefined profile of biological assay values. Visualization of hierarchical clusters as tree-maps and heatmaps provides simultaneous representation of cluster members along with their associated assay values. Tree-maps convey both the spatial relationship among cluster members and the value of a single property (activity) associated with each member. Heatmaps provide visualization of the cluster members across an activity profile. Unlike a tree-map, however, a heatmap does not convey the spatial relationship between cluster members. MPX seamlessly integrates tree-maps and heatmaps to represent multidimensional structure-activity data in a visually intuitive manner. In addition, MPX provides tools for clustering data on the basis of chemical structure or activity profile, displaying 2D chemical structures, and querying the data based over a specified activity range, or set of chemical structure criteria (e.g., Tanimoto similarity, substructure match, and "R-group" analysis).

OBJECTIVE The natural history of spinal lipomas of the conus (SLCs) has not been well studied. Because of disappointing long-term results with early surgical treatment of asymptomatic children with SLCs, we have followed a protocol of conservative management for these patients. The results are presented in this report. METHODS Since 1994, all asymptomatic children with SLCs who were examined at Necker-Enfants Malades Hospital were subject to a protocol of conservative management. The records for those patients were reviewed, to determine the incidence and timing of neurological deterioration. The findings were compared with those for a previously reported historical cohort of asymptomatic patients who underwent early surgery at our institution. RESULTS Fifty-three asymptomatic children (35 girls and 18 boys) with SLCs were monitored, with conservative management. During a mean follow-up period of 4.4 years (range, 12 mo to 9 yr), 13 patients (25%) exhibited neurological deterioration. At 9 years, the actuarial risks of deterioration, as determined with the Kaplan-Meier method, were 33% for the conservatively treated patients and 46% for the surgically treated patients. With a Cox proportional-hazards model, there was no significant difference in the risks of neurological deterioration for patients who were treated conservatively and those who underwent early surgery. CONCLUSION The incidences and patterns of neurological deterioration seemed to be very similar, regardless of whether early surgery was performed. These results suggest that conservative treatment of asymptomatic patients is a reasonable option. A more definitive randomized study will be required to clarify the relative efficacy of early surgery for SLCs among asymptomatic patients.

Purpose Shaken baby syndrome consists of intracranial and intraocular hemorrhages in young children in the absence of signs of direct head trauma. Because it has major medicolegal implications, it must be distinguished from accidental trauma. This study aimed to determine the ophthalmologic manifestations and their natural course in child abuse victims and whether ophthalmologic examination can help to distinguish shaken babies from children with accidental impact head trauma. Design Prospective comparative observational case series. Methods A prospective study was conducted from January 1996 to September 2001 on 241 consecutive infants hospitalized for a subdural hematoma to determine the frequency and the type of ocular abnormalities encountered. At admission, 186 children were highly presumed to have been shaken (group 1), 38 children had signs of direct head trauma without any relevant history of trauma (group 2), some of them having been possibly shaken, whereas 7 children had proven severe accidental head trauma (group 3). Results Intraocular hemorrhages were the main finding. Their shape, laterality, and size were not significantly different in groups 1 and 2. However they were significantly more frequent in nonaccidental head trauma than in infants with head impact (77.5% versus 20%). None of the group 3 children had intraocular hemorrhage. Eighty-two percent of intraocular hemorrhages resolved within 4 weeks. Conclusions Intraocular hemorrhages are frequent in shaken babies but not specific of this syndrome. When associated with a subdural hematoma, they are strongly suggestive of shaken neglect. They are rare in pediatric accidental head trauma.

Object. The aim of this study was to investigate the effect of patient-related factors, extent of surgery, and adjuvant therapy on survival in children presenting with intracranial ependymoma. Methods. Between 1980 and 1999, 83 children (mean age 36 months) underwent surgery for intracranial ependymomas. Complete resection, verified on postoperative computerized tomography scans, was achieved in 73%. Adjuvant therapy modalities have changed over the years: before 1990 all patients received radiotherapy, whereas after 1990 the children younger than 3 years of age and later those younger than 5 years of age were treated first with chemotherapy and received radiotherapy only after their first tumor recurrence. The follow-up period averaged 70 x 49 months. Conclusions. Overall survival, intraoperative deaths excluded, was 73 ± 11% and 51 ± 14% at 5 and 10 years, respectively. The event-free survival rate at 5 and 10 years was 48 ± 12% and 46 ± 12%, respectively. Most of the events were local recurrences. Despite multiple reinterventions, the overall survival rate in this group dropped to 14%. On univariate analysis, the only significant prognostic factors were complete resection and radiotherapy. Both of these factors combined increased the 5- and 10-year survival rates to 93 and 75%, respectively. Age of the patients was not a statistically independent prognostic factor. The patients in the chemotherapy group did not fare as well as those in the radiotherapy group. A subgroup (36%) within the chemotherapy group, however, survived tumor free after a mean follow-up period of 67 months. It is not clear whether this subgroup either responded well to chemotherapy or needed no adjuvant therapy. Further research is warranted to answer this question.

PI3Kγ plays a major role in the initiation and progression of intimal hyperplasia by specifically modulating Th1 cytokines leading to CXCL10 and RANTES production by smooth muscle cells., Interventional strategies to treat atherosclerosis, such as transluminal angioplasty and stent implantation, often cause vascular injury. This leads to intimal hyperplasia (IH) formation that induces inflammatory and fibroproliferative processes and ultimately restenosis. We show that phosphoinositide 3-kinase γ (PI3Kγ) is a key player in IH formation and is a valid therapeutic target in its prevention/treatment. PI3Kγ-deficient mice and mice expressing catalytically inactive PI3Kγ (PI3Kγ KD) showed reduced arterial occlusion and accumulation of monocytes and T cells around sites of vascular lesion. The transfer of PI3Kγ KD CD4+ T cells into Rag2-deficient mice greatly reduced vascular occlusion compared with WT cells, clearly demonstrating the involvement of PI3Kγ in CD4+ T cells during IH formation. In addition we found that IH is associated with increased levels of Th1 and Th17 cytokines. A specific decrease in the Th1 response was observed in the absence of PI3Kγ activity, leading to decreased CXCL10 and RANTES production by smooth muscle cells. Finally, we show that treatment with the PI3Kγ inhibitor AS-605240 is sufficient to decrease IH in both mouse and rat models, reinforcing the therapeutic potential of PI3Kγ inhibition. Altogether, these findings demonstrate a new role for PI3Kγ activity in Th1-controlled IH development.

PURPOSE: To evaluate a strategy that avoids radiotherapy in first-line treatment in children under 5 years of age with brain or posterior fossa ependymoma, by exclusively administering 16 months of adjuvant multiagent chemotherapy after surgery. PATIENTS AND METHODS: Between June 1990 and October 1998, 73 children with ependymoma (82% with high-grade tumors) were enrolled onto this multicenter trial. Children received adjuvant conventional chemotherapy after surgery consisting of seven cycles of three courses alternating two drugs at each course (procarbazine and carboplatin, etoposide and cisplatin, vincristine and cyclophosphamide) over a year and a half. Systematic irradiation was not envisaged at the end of chemotherapy. In the event of relapse or progression, salvage treatment consisted of a second surgical procedure followed by local irradiation with or without second-line chemotherapy. RESULTS: Conventional chemotherapy was well tolerated and could be administered in outpatient clinics. No radiologically documented response to chemotherapy more than 50% was observed. With a median follow-up of 4.7 years (range, 5 months to 8 years), the 4-year progression-free survival rate in this series was 22% (95% confidence interval [CI], 13% to 43%) and the overall survival rate was 59% (95% CI, 47% to 71%). Overall, 40% (95% CI, 29% to 51%) of the patients were alive having never received radiotherapy 2 years after the initiation of chemotherapy and 23% (95% CI, 14% to 35%) were still alive at 4 years without recourse to this modality. In the multivariate analysis, the two factors associated with a favorable outcome were a supratentorial tumor location (P = .0004) and complete surgery (P = .0009). Overall survival at 4 years was 74% (95% CI, 59% to 86%) for the patients in whom resection was radiologically complete and 35% (95% CI, 18% to 56%) for the patients with incomplete resection. CONCLUSION: A significant proportion of children with ependymoma can avoid radiotherapy with prolonged adjuvant chemotherapy. Deferring irradiation at the time of relapse did not compromise overall survival of the entire patient population.

Progression patterns of optic pathway tumours (OPT) need to be precisely defined for treatment planning. In patients with neurofibromatosis type 1 (NF1), this disease is usually indolent and the available literature rarely reports progression after the age of 6 years. In patients without NF1, the disease course seems to be less favourable. We reviewed the clinical and radiological files of 106 children referred to our institution for the treatment of a symptomatic OPT since 1980. NF1 was present in 51 of them. Progression patterns in children with NF1 differed markedly from those in the other patients. A total of 83 children had tumour extension beyond the chiasm (Dodge type III). Children with NF1 had progressive tumours later during follow-up (47% after the age of 6 years), had more often proptosis and infiltrating tumours but less frequently nystagmus or increased intracranial pressure. 32 children were not treated at diagnosis because they had only mild symptoms related to the OPT. In these patients, progression occurred more often in children without than with NF1 (12/12 versus 12/20 respectively, P = 0.04). A high number of patients needed treatment for progression or severe symptoms after 6 years of age. Of the patients, 33% needed treatment for progression or severe symptoms after 6 years of age.Progression patterns of optic pathway tumours in children with neurofibromatosis type 1 differ markedly from those in other patients. This study emphasises the need for prolonged follow-up of children with optic pathway tumours, especially in neurofibromatosis type 1.

A suprasellar arachnoid cyst may cause disorders of growth, puberty and hypothalamic-pituitary function, due to the proximity of the cyst to the hypothalamic-pituitary area. A total of 30 patients (17 boys) with cyst diagnosed at 4.3 +/- 1 years were routinely evaluated at 5.4 +/- 1 years; 24 of them had one or multiple cyst derivations. Some 23 cases had an abnormal height, weight or puberty: short (-2SD, 5 cases) or tall (2SD, 10 cases) stature, overweight (body mass index, BMI,2SD, 6 cases), central precocious puberty (10 cases) and/or no progression of pubertal development (3 cases). The growth hormone (GH) peaks after pharmacological stimulation test were low (10 MICROg/L) in 16 patients, confirmed by a second evaluation in 8/11 of them. The plasma free thyroxine was low in five patients, prolactin was high in two and the cortisol and concomitant plasma and urinary osmolalities were normal. BMI was correlated negatively with the GH peaks (r = -0.37, P0.01) and positively with the plasma leptin concentrations (r = 0.55, P0.01). The plasma fasting insulin concentrations were also correlated negatively with the GH peaks (r = -0.55, P0.02) and positively with the plasma insulin-like growth factor I concentrations (r = 0.64, P0.002). The adult height (12 cases) was at 4SD in 1 and-2SD in 4 patients, two of whom had precocious puberty untreated with gonadotropin releasing hormone (GnRH) analogue, and two had untreated GH deficiency. The adult height of those treated was normal. One girl had primary amenorrhoea and two boys had low plasma testosterone, despite a normal gonadotropin response to a GnRH test.Suprasellar arachnoid cysts may cause deficiencies of growth hormone and thyrotropin, stimulation of the hypothalamic-pituitary-gonadal axis, tall stature and/or overweight. These last two disorders may be due to hyperinsulinism, itself due to suprasellar arachnoid cyst.

The authors report on the clinicopathological aspects of and management strategies for the group of rare, large hemispheric childhood tumours recently classified as desmoplastic infantile ganglioglioma (DIGG), desmoplastic astrocytoma of infancy (DACI) and pleomorphic xanthoastrocytoma (PXA). Between 1985 and 1997, ten children (4 with DACIs, 4 with DIGGs and 2 with PXAs) with a median age of 9.5 months were operated on. All these patients had complete surgical resections, with two having a preoperative biopsy. This led to an erroneous diagnosis in both cases of malignant grade 4 astrocytoma. As a result, one patient had preoperative chemotherapy with no effect. There was one perioperative death. Histology revealed heterogeneous tumours with malignant looking areas in 8 of the specimens. None of the patients has had any postoperative adjuvant treatment. All surviving patients are alive at follow-up (median 4.2 years). Despite their often malignant appearance, these tumours have an excellent prognosis, but they can present formidable surgical challenges when they occur in very young age patients. We believe that surgical excision can offer a cure and that adjuvant treatment is not necessary. Finally, biopsy is of little value and may even lead to an erroneous diagnosis and subsequent mismanagement.

The clinical, radiologic, and pathologic data from a series of 234 patients hospitalized in the Pediatric Neurosurgical Department of the Necker–Enfants Malades Hospital, Paris, for congenital intraspinal lipomas and operated on from 1976 to 1995 were examined. Histological studies showed that these lesions may be simple lipomas, similar to those developing elsewhere in the body, or they may be more complex forms including in addition to the lipomatous component a variety of unusual ectopic tissues of ectodermal, mesodermal, and/or endodermal origin. These complex forms indica te the malformative nature of these tumors. When they contain elements that are truly foreign to the region, the possibility of teratoma with a tumoral potential should be considered. Data found in the literature and from Necker–Enfants Malades Hospital are discussed.

Purpose: To review the outcome and quality of life at 5 years and more of 37 children treated with radiation therapy combined or not with surgical resection for a craniopharyngioma in a single institution. Methods and Materials: From January 1969 through December 1992, 37 children received external therapy at the Institut Gustave Roussy (Villejuif, France). Age ranged between 1 and 15 years (mean 7.4), M/F sex ratio was 0.76. In approximately one-half of the cases (18/37), radiation therapy was applied in conjunction with a surgical resection, and in almost one-half of the cases (18/37) as part of a salvage program following local failure. Total dose ranged between 45 and 56 Gy (median 50) given with a conventional fractionation in most children. Survival (S), event-free survival (EFS) were computerized according to the Kaplan-Meier method and prognostic factors for local failure and functional status analyzed. Functional outcome was evaluated according to the Wen score in 4 grades (gr 1: normal with/without hormonal replacement, gr 4: totally dependent, gr 2 and 3: intermediate disabilities). Results: At the time of analysis, 24 children (65%) were alive with NED, 4 (11%) alive after failure, and 9 (24%) dead of various causes. Following therapy, S and EFS regularly degraded and didn't seem to reach a plateau before 9 years (5 and 10 year S and EFS, respectively, 91, 65, and 78 and 56.5%). This was due to the occurrence of late failures (5 and 8.5 years) and late lethal complications (1 in-field glioblastoma multiforme at 9 years). A significant gain on EFS followed the introduction of modern imaging ( p = 0.03), the association of surgical resection with RT ( p = 0.01) and of higher doses of radiation superior or equal to 55 Gy ( p = 0.05); a similar gain on S was observed in patients with a good initial performance status ( p = 0.05). It is remarkable that surgical salvage of local failures following RT could induce prolonged remission in 4 children. Functional outcome was impaired in all but 5 children out of 35 fully evaluable (86%) and related with the initial symptomatology and/or therapy. Endocrinological, visual, neurological functions were affected in 97, 34, and 40%, respectively. It appeared correlated with the initial performance status ( p = 0.02) and possibly with a younger age at treatment ( p = 0.07). Conclusions: Long-term follow-up beyond 5 years is warranted in craniopharyngioma to assess tumor control and functional outcome after radiation therapy. Although this therapeutical modality provides a high cure rate alone or in combination with surgery and even though at the time of failure, further strategies should aim to limit the severe toxicity ( i.e. , Wen gr 3 + 4) that was observed in more than one-third of our patients.

Object. The goal of this study was to analyze the types of failure and long-term efficacy of third ventriculostomy in children.Methods. The authors retrospectively analyzed clinical data obtained in 213 children affected by obstructive triventricular hydrocephalus who were treated by third ventriculostomy between 1973 and 1997. There were 120 boys and 93 girls. The causes of the hydrocephalus included: aqueductal stenosis in 126 cases; toxoplasmosis in 23 cases, pineal, mesencephalic, or tectal tumor in 42 cases; and other causes in 22 cases. In 94 cases, the procedure was performed using ventriculographic guidance (Group I) and in 119 cases by using endoscopic guidance (Group II). In 19 cases (12 in Group I and seven in Group II) failure was related to the surgical technique. Three deaths related to the technique were observed in Group I. For the remaining patients, Kaplan—Meier survival analysis showed a functioning third ventriculostomy rate of 72% at 6 years with a mean follow-up period of 45.5 months (range 4 days–17 years). No significant differences were found during long-term follow up between the two groups. In Group I, a significantly higher failure rate was seen in children younger than 6 months of age, but this difference was not observed in Group II. Thirty-eight patients required reoperation (21 in Group I and 17 in Group II) because of persistent or recurrent intracranial hypertension. In 29 patients shunt placement was necessary. In nine patients in whom there was radiologically confirmed obstruction of the stoma, the third ventriculostomy was repeated; this was successful in seven cases. Cine phase-contrast (PC) magnetic resonance (MR) imaging studies were performed in 15 patients in Group I at least 10 years after they had undergone third ventriculostomy (range 10–17 years, median 14.3 years); this confirmed long-term patency of the stoma in all cases.Conclusions. Third ventriculostomy effectively controls obstructive triventricular hydrocephalus in more than 70% of children and should be preferred to placement of extracranial cerebrospinal shunts in this group of patients. When performed using ventriculographic guidance, the technique has a higher mortality rate and a higher failure rate in children younger than 6 months of age and is, therefore, no longer preferred. When third ventriculostomy is performed using endoscopic guidance, the same long-term results are achieved in children younger than 6 months of age as in older children and, thus, patient age should no longer be considered as a contraindication to using the technique. Delayed failures are usually secondary to obstruction of the stoma and often can be managed by repeating the procedure. Midline sagittal T2-weighted MR imaging sequences combined with cine PC MR imaging flow measurements provide a reliable tool for diagnosis of aqueductal stenosis and for ascertaining the patency of the stoma during follow-up evaluation.

Object. Cerebellar astrocytomas are benign tumors of childhood known to be associated with excellent long-term survival in patients in whom complete surgical resection is possible. However, the roles of other factors—clinical, radiological, histological, and therapeutic—in the survival of the patient, tumor recurrence, and long-term patient outcome remain imprecise. The goal of this study was to examine these factors and their relationships.Methods. To clarify these issues a retrospective review was conducted of 168 children who were surgically treated for a cerebellar astrocytoma at Hôpital Necker—Enfants Malades between 1955 and 1995. These patients' clinical files were examined, the histological characteristics of their tumors were reviewed, and their outcomes were assessed according to Bloom's scale and the Wechsler intelligence quotient test.Of the 168 patients in the study, 91 were male and 77 were female with a mean age of 6.9 years and a mean follow up lasting 7.7 years. Tumors were identified as being strictly located in the cerebellum in 76.2% of the patients and as involving the brainstem (referred to as the “transitional form”) in 23.8% of the patients. Complete surgical excision was possible in 88.7% of cases. There was a total mortality rate of 4.2% and a tumor recurrence rate of 9.5%. Fifty-eight percent of the patients had no neurological sequelae at follow-up evaluation.Pejorative factors that were discovered by multivariate analysis to be important included: a long preoperative duration of symptoms and the transitional form of tumor with respect to survival; incomplete tumor excision with respect to an increased risk of recurrence; and a long preoperative duration of symptoms, an early epoch during which surgery was performed (1955–1974), severe ventricular dilation, and the transitional form of tumor with respect to a poorer long-term patient outcome.Conclusions. The presence of brainstem involvement (tumor in the transitional form) emerged as a significant negative prognostic factor and should be treated as a distinct nosological entity. The extent of surgical excision has a significant bearing on the risk of tumor recurrence.

BACKGROUND Factors that could optimize the management of pediatric spinal cord astrocytoma remain unclear and controversial. METHODS To determine the factors that influence the prognosis of pediatric patients with spinal cord astrocytomas, a series of 73 consecutive patients at 13 French treatment centers with histologically proven spinal cord astrocytomas was retrospectively reviewed. Hospital records, operative records, and results of radiologic investigations were available in all cases. Follow-up was achieved in 94% of cases. RESULTS Seventy percent of the patients had low grade (1 or 2) tumors. Total or subtotal surgical resection was achieved in 43%. Thirty-six patients were irradiated following surgery. Fifty-one patients were alive at a median follow-up of 54 months. Twenty-three patients relapsed. Univariate analysis showed that good outcome was correlated with male gender, age younger than 7 years, duration of presenting symptoms longer than 2 months, the presence of spinal deformities, and low grade histology, whereas sensory loss was associated with decreased survival. Multivariate analysis using the Cox proportional hazards model confirmed that histology (relative risk [RR] = 7.69) and the interval between first symptoms and diagnosis (RR = 4.93) were significant independent prognostic factors. The extent of surgery or radiotherapy had no clear influence on survival. CONCLUSIONS This review sheds light on the prognoses of pediatric patients with spinal cord astrocytomas and may help to determine therapeutic strategies based on patients' clinical, radiologic, and pathologic features. Cancer 1998;83:2391-2399. © 1998 American Cancer Society.

Object. Choroid plexus tumors are rare intraventricular tumors (1% of all intracranial tumors) that occur mainly in children. The pathophysiological characteristics of associated hydrocephalus, surgical management, and oncological issues related to these tumors remain a matter of debate. To understand more about these tumors, the authors have reviewed their experience with the management of 38 children with choroid plexus tumors.Methods. There were 25 cases of papilloma and 13 of carcinoma. The mean age of the patients at presentation was 22.5 months, and one-half of the patients were younger than 2 years of age. Hydrocephalus was present in 33 patients and poorly correlated with the size, site, and pathological characteristics of the tumor. In nine children, a ventriculoperitoneal shunt was required after tumor excision, calling into question the notion that cerebrospinal fluid oversecretion is the only cause of hydrocephalus.Complete excision was achieved in 96% of the cases of papilloma and 61.5% of the cases of carcinoma. These surgical procedures were complicated by the risks of intraoperative hemorrhage, which proved to be fatal in two cases, and postoperative brain collapse, which led to subdural fluid collections requiring subdural shunt placement in six patients. Preoperative embolization was partially successful in four cases and significantly assisted surgery. Preoperative controlled drainage of excessively dilated ventricles and intraoperative gluing of the cortical incision have been used to address the problem of postoperative brain collapse.Patients with carcinomas were treated postoperatively by chemotherapy alone (seven cases), radiotherapy (one case), or chemotherapy plus radiotherapy (one case). The overall 5-year survival rate was 100% for patients with papillomas and 40% for those with carcinomas.Conclusions. Total surgical excision is curative in cases of papillomas. For carcinomas, the most effective treatment remains total surgical excision; however, adjuvant treatment in the form of chemotherapy in patients younger than age 3 years, supplemented by radiation therapy in older children, can moderately reduce the risk of recurrence.

Object. A retrospective study of 1727 cases of craniosynostosis was undertaken to determine the interrelationship between abnormal cerebrospinal fluid (CSF) hydrodynamics and craniosynostosis. Methods. The patients were divided into two groups: nonsyndromic craniosynostosis and syndromic craniosynostosis. Cases of occipital plagiocephaly without suture synostosis and cases of shunt-induced craniosynostosis were excluded from the study. The majority of patients (1297) were treated surgically for their cranial deformity; 95% of these patients had a postoperative follow-up review period lasting 5 years. Clinical and radiographic charts covering the time from presentation through the follow-up period were reviewed. Conclusions. Abnormal intracranial CSF hydrodynamics was found in 8.1% of the patients (3.4% of whom had received shunts and 4.5% of whom had not). Three types of CSF hydrodynamic disturbance were observed: progressive hydrocephalus with ventricular dilation, nonprogressive ventriculomegaly, and dilation of the subarachnoid spaces. Hydrocephalus occurred much more frequently in patients with syndromic craniosynostosis (12.1%) than in those with isolated craniosynostosis (0.3%). In fact, patients with kleeblattschädel exhibited hydrocephalus as a constant feature and patients with Crouzon's syndrome were far more likely to have hydrocephalus than those with other syndromes. In Apert's syndrome, ventricular dilation occurred very frequently, but it was almost always nonprogressive in nature. In most cases of syndromic craniosynostosis, venous sinus obstruction and/or chronic tonsillar herniation were found. Their role in the pathophysiology of hydrocephalus in craniosynostosis is discussed.

Resume Le pronostic mental des scaphocephalies est encore controverse. La question de savoir si les indications chirurgicales sont d'ordre fonctionnel ou seulement esthetique reste discutee. Le but de ce travail est de tenter de clarifier ce probleme. Patients et methodes. — L'evolution intellectuelle de 396 enfants atteints de scaphocephalie a ete analysee et correlee a l'âge, la pression intracrânienne (PIC) et le devenir mental. Avant tout traitement, la PIC etait enregistree (systematiquement durant la premiere partie de l'etude); le niveau mental etait evalue initialement, et apres 5 ans d'evolution en moyenne. Les evolutions intellectuelles etaient comparees selon qu'une intervention etait pratiquee ou non. Resultats. — L'evolution intellectuelle des enfants etait normale dans la grande majorite des cas, avec ou sans intervention. Le niveau mental des enfants de moins de 1 an etait significativement plus souvent normal que celui des enfants de plus de 1 an (p Conclusions. — Dans cette serie, le niveau mental initial apparait comme le facteur pronostique principal du devenir mental. Dans la mesure ou le niveau mental final est le reflet du niveau initial, et ou enfants les plus âges ont statistiquement un niveau plus faible que les plus jeunes, on peut envisager l'indication de cette intervention a visee esthetique sous un angle preventif.

✓ The incidence of chronic tonsillar herniation (CTH) was evaluated with magnetic resonance imaging in 44 patients with Crouzon's syndrome and 51 with Apert's syndrome; the incidence was 72.7% in Crouzon's syndrome and 1.9% in Apert's syndrome. All the patients with Crouzon's syndrome and progressive hydrocephalus had CTH, but of 32 individuals with Crouzon's syndrome and CTH, only 15 had progressive hydrocephalus. Five patients with Apert's syndrome were treated for progressive hydrocephalus; none had CTH. The patterns of suture closure in these two groups of patients were studied, and significant differences in coronal, sagittal, and lambdoid sutures were found between patients with Crouzon's and Apert's syndromes. In Crouzon's syndrome, significant differences in the pattern of lambdoid suture closure were found between the groups with and without CTH; in the group with CTH, the lambdoid closure appeared earlier. The authors propose that the high incidence of individuals with CTH who have Crouzon's syndrome is related to the premature synostosis of the lambdoid suture in the first 24 months of age.

3D imaging of biological structures is now ubiquitous. From these images it is possible to extract surface models of developing structures, gather examples of both healthy and diseased or injured populations, and track changes in structure due to disease over time. To make full use of these data sets we need tools to establish correspondences between surfaces with similar structures and quantitative measures of changes to local and global shape. A key requirement for both of these tasks is the ability to locally compare shape. More formally, the goal is to create a local shape descriptor which maps local shape to an n dimensional number. This descriptor can then be used for many downstream applications, such as comparing or quantifying shape change or automatically determining feature correspondences for registration.

A study was made of 75 children treated between 1970 and 1990, with partial, subtotal, or total removal of three intrinsic and 72 exophytic or surface brain-stem tumors. In all cases, the goal of surgery was to remove as much tumor as possible. Extent of removal was defined according to data obtained from postoperative computerized tomography or magnetic resonance imaging, and was considered partial when only a small amount of tumor was removed, subtotal when a few cubic millimeters of tumor was left, and total when no residual tumor was seen on postoperative radiological investigations. An ultrasonic aspirator was used for the 43 most recent operations. Among tumor removals without the aspirator, 24 (75%) were partial, eight (25%) subtotal, and none total; with the use of the aspirator, the number of partial removals decreased to 44.5% while that of subtotal and total removals increased to 32% and 23.5%, respectively. There were 69 gliomas (92%) and 47 benign tumors (62.6%). Forty-nine patients were irradiated postoperatively, and 14 of the 23 patients whose benign tumors were removed totally or subtotally did not undergo irradiation. This study showed that: 1) the overall prognosis of patients with malignant tumors was poor and was not improved by surgery; 2) the survival rate of those with benign tumors was significantly (p < 0.01) lower after partial removal than after total or subtotal removal (52% and 94%, respectively, at 5 years); 3) comparison of means and proportions (Student's and chi-squared tests) between benign and malignant tumors showed a significant difference relating to patient age (p < 0.03), peritumoral hypodensity (p < 0.001), and preoperative duration of symptoms (p < 0.001); 4) stepwise logistic regression analysis confirmed that two of these three variables were related to malignancy: namely, patient age at surgery (p < 0.03) and presence of peritumoral hypodensity (p < 0.001); and 5) routine postoperative irradiation was contraindicated after total or subtotal removal of benign tumors.

Background— Inflammatory processes play a critical role in myocarditis, dilated cardiomyopathy, and heart failure. The expression of the inflammatory chemokine osteopontin (OPN) is dramatically increased in cardiomyocytes and inflammatory cells during myocarditis and heart failure in human and animals. However, its role in the development of heart diseases is not known. Methods and Results— To understand whether OPN is involved in cardiomyopathies, we generated a transgenic mouse (MHC-OPN) that specifically overexpresses OPN in cardiomyocytes with cardiac-specific promoter-directed OPN expression. Young MHC-OPN mice were phenotypically indistinguishable from their control littermates, but most of them died prematurely with a half-life of 12 weeks of age. Electrocardiography revealed conduction defects. Echocardiography showed left ventricular dilation and systolic dysfunction. Histological analysis revealed cardiomyocyte loss, severe fibrosis, and inflammatory cell infiltration. Most of these inflammatory cells were activated T cells with Th1 polarization and cytotoxic activity. Autoantibodies against OPN, cardiac myosin, or troponin I, were not found in the serum of MHC-OPN mice. Conclusions— These data show that OPN expression in the heart induces in vivo T-cell recruitment and activation leading to chronic myocarditis, the consequence of which is myocyte destruction and hence, dilated cardiomyopathy. Thus, OPN might therefore constitute a potential therapeutic target to limit heart failure.