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Background: Children with biliary atresia rapidly develop liver fibrosis secondary to inflammatory destruction of the biliary tract. Noninvasive detection of liver fibrosis in neonatal/infantile cholestasis is an additional criterion for the diagnosis of biliary atresia, leading to prompt surgical exploration. Objective: To assess the value of US with acoustic radiation force impulse (ARFI) elastography to detect biliary atresia in the workup of neonatal/infantile cholestasis. Materials and methods: In this retrospective study, 20 children with cholestasis suspected of having biliary atresia were investigated by US and ARFI. We evaluated the association between US findings and the diagnosis of biliary atresia and with two scores of liver fibrosis obtained from liver biopsy. Results: In univariate analyses, gallbladder size, triangular cord sign, spleen size and ARFI values were found to be associated with biliary atresia, though only the triangular cord sign remained significant when elevated gamma glutamyltransferase (GGT) was included as a predictor. In contrast, spleen size and ARFI correlated with the degree of liver fibrosis on biopsy (r > 0.70, P

Background: The aim of the present multi-center split-mouth randomized control trial was to investigate the effect on peri-implant tissue of abutment with chromium nitride/ niobium nitride (CrN/NbN) coatings (superlattice) compared to traditional machined surface. Methods: Two adjacent posterior implants were inserted in 20 patients. A machined abutment was randomly screwed on either the mesial or distal implant, while a superlattice abutment was screwed on the other one. Implant survival rate, peri-implant probing depth (PPD), plaque index (PI), and bleeding index (BI) were collected 6 months after surgery, while marginal bone loss (MBL) was evaluated at T0 and T6.; Results: Implant survival rate was 97.7%. A total MBL of 0.77 ± 0.50 mm was recorded for superlattice abutments, while a mean MBL of 0.79 ± 0.40 mm was recorded for the abutment with machined surface. A mean PPD of 1.3 ± 0.23 mm was recorded for the superlattice Group, and a mean PPD of 1.31 ± 0.3 was recorded for the machined surface Group. PI was of 0.55 ± 0.51 for superlattice Group and 0.57 ± 0.50 for machined Group, while BI was of 0.47 ± 0.49 for superlattice Group and of 0.46 ± 0.40 for the machined one. No statistically significant difference was highlighted between the two Groups (p > 0.05). Conclusions: After a 6-month observational period, no statistically significant differences were highlighted between superlattice abutment and traditional machined abutment. Further in vitro studies as well as clinical research with longer follow-ups are required to better investigate the surface properties of the novel abutments’ superlattice coating and its effect on the oral tissues.

Background and purpose Super-resolutionreconstruction (SRR) can be used to reconstruct 3-dimensional (3D) high-resolution (HR) volume from several 2-dimensional (2D) low-resolution (LR) stacks of MRI slices. The purpose is to compare lengthy 2D T2-weighted HR image acquisition of neonatal subjects with 3D SRR from several LR stacks in terms of image quality for clinical and morphometric assessments. Methods LR brain images were acquired from neonatal subjects to reconstruct isotropic 3D HR volumes by using SRR algorithm. Quality assessments were done by an experienced pediatric radiologist using scoring criteria adapted to newborn anatomical landmarks. The Wilcoxon signed-rank test was used to compare scoring results between HR and SRR images. For quantitative assessments, morphology-based segmentation was performed on both HR and SRR images and Dice coefficients between the results were computed. Additionally, simple linear regression was performed to compare the tissue volumes. Results No statistical difference was found between HR and SRR structural scores using Wilcoxon signed-rank test (p = .63, Z = .48). Regarding segmentation results, R2 values for the volumes of gray matter, white matter, cerebrospinal fluid, basal ganglia, cerebellum, and total brain volume including brain stem ranged between .95 and .99. Dice coefficients between the segmented regions from HR and SRR ranged between .83 ± .04 and .96 ± .01. Conclusion Qualitative and quantitative assessments showed that 3D SRR of several LR images produces images that are of comparable quality to standard 2D HR image acquisition for healthy neonatal imaging without loss of anatomical details with similar edge definition allowing the detection of fine anatomical structures and permitting comparable morphometric measurement.

Mosaic somatic mutations in the isocitrate dehydrogenase 1/2 (IDH1/2) genes have been identified in most enchondromas by targeted mutation analysis. Next-generation sequencing (NGS), that may detect even low-level mosaic mutation rates, has not previously been applied to enchondromas. Immunohistochemistry using the H09 clone is routinely used as a surrogate for the common R132H IDH1 mutation in gliomas. We compared immunohistochemistry and NGS results in a series of 13 enchondromas from 8 pediatric patients. NGS identified a heterozygous IDH mutation in all enchondromas, showing identical mutation status in patients with multiple tumors assessed, thereby confirming somatic mosaicism. A majority of the tumors harbored an IDH1 mutation (p.R132H in 3 tumors; p.R132C in 4 tumors from 2 patients; p.R132L and p.R132G in one tumor each). A p.R172S IDH2 mutation was identified in 4 enchondromas, but not in the ependymoma from one patient with Ollier disease, who further displayed a heterozygous STK11 missense mutation. IDH mutation rates varied between 14% (indicative of mutations in 28% of the cells and of intratumoral mosaicism) and 45% (tumor content was close to 100%). Cytoplasmic H09 reactivity was observed as expected in tumors with an IDH1 p.R132H mutation; cross-reactivity was seen with the p.R132L variant. This first NGS study of pediatric enchondromas confirms that IDH mutations may occur in a mosaic fashion. STK11 gene mutations may provide insights in the development of multiple cartilaginous tumors in enchondromatosis, this tumor suppressor gene having been shown in animal models to regulate both chondrocyte maturation and growth plate organization during development.

Sciatic neuropathy (SN) is rarely encountered in the pediatric population. The causes of this mononeuropathy are either infectious, immune mediated, toxic, or infiltrative (tumoral). In this article, we presented the case of a 7.5-year-old male child who presented to the emergency department with a painful right lower limb. Magnetic resonance imaging confirmed the diagnosis of subacute osteomyelitis of the ischium, which extended toward the external hip rotators and infiltrated the tissues around the sciatic nerve. Treatment with intravenous antibiotics (flucloxacillin 50 mg/kg/d and gentamicin 10 mg/kg/d) rapidly improved the child's condition and relieved neurological symptoms within a few days. Traumatic and iatrogenic injuries are the most common causes for SN. To our knowledge, this presented case is the first to describe SN due to an infectious process following subacute osteomyelitis.

BackgroundJoubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation. Over 40 JS-associated genes are known with a diagnostic yield of 60%–75%.In 2018, we reported homozygous hypomorphic missense variants of the SUFU gene in two families with mild JS. Recently, heterozygous truncating SUFU variants were identified in families with dominantly inherited COMA, occasionally associated with mild DD and subtle cerebellar anomalies.MethodsWe reanalysed next generation sequencing (NGS) data in two cohorts comprising 1097 probands referred for genetic testing of JS genes.ResultsHeterozygous truncating and splice-site SUFU variants were detected in 22 patients from 17 families (1.5%) with strong male prevalence (86%), and in 8 asymptomatic parents. Patients presented with COMA, hypotonia, ataxia and mild DD, and only a third manifested intellectual disability of variable severity. Brain MRI showed consistent findings characterised by vermis hypoplasia, superior cerebellar dysplasia and subtle-to-mild abnormalities of the superior cerebellar peduncles. The same pattern was observed in two out of three tested asymptomatic parents.ConclusionHeterozygous truncating or splice-site SUFU variants cause a novel neurodevelopmental syndrome encompassing COMA and mild JS, which likely represent overlapping entities. Variants can arise de novo or be inherited from a healthy parent, representing the first cause of JS with dominant inheritance and reduced penetrance. Awareness of this condition will increase the diagnostic yield of JS genetic testing, and allow appropriate counselling about prognosis, medical monitoring and recurrence risk.

To ensure genome stability, sexually reproducing organisms require that mating brings together exactly 2 haploid gametes and that meiosis occurs only in diploid zygotes. In the fission yeast Schizosaccharomyces pombe, fertilization triggers the Mei3-Pat1-Mei2 signaling cascade, which represses subsequent mating and initiates meiosis. Here, we establish a degron system to specifically degrade proteins postfusion and demonstrate that mating blocks not only safeguard zygote ploidy but also prevent lysis caused by aberrant fusion attempts. Using long-term imaging and flow-cytometry approaches, we identify previously unrecognized and independent roles for Mei3 and Mei2 in zygotes. We show that Mei3 promotes premeiotic S-phase independently of Mei2 and that cell cycle progression is both necessary and sufficient to reduce zygotic mating behaviors. Mei2 not only imposes the meiotic program and promotes the meiotic cycle, but also blocks mating behaviors independently of Mei3 and cell cycle progression. Thus, we find that fungi preserve zygote ploidy and survival by at least 2 mechanisms where the zygotic fate imposed by Mei2 and the cell cycle reentry triggered by Mei3 synergize to prevent zygotic mating., During sexual reproduction, fertilization must happen between exactly two gametes to ensure genome stability. This study shows that two mechanisms – establishment of zygotic fate and re-entry to the cell cycle – combine to prevent fission yeast zygotes fusing with further gametes.

Intramuscular injections of Botulinum Toxin Type A (BoNT-A) in children with spastic cerebral palsy (CP) have been introduced in clinical practice with the aim of reducing muscle tone, preventing muscle contractures and, ultimately, improving function. The aim of this study was to evaluate prospectively the MRI changes in the calf muscles, gastrocnemius (GN) and soleus (S) of two children with unilateral spastic CP (US-CP), prior and more than 1-year following BoNT-A injections. Two male patients with US-CP were injected at the level of the GN and S muscles. Patients underwent a first lower extremity MRI prior to the first BoNT-A injection at the level of GN and S muscles of the affected side. A second MRI was perfomed 34 and 22 months after the index procedure, respectively. Both legs were investigated together symmetrically, to allow a precise comparison between muscles and structures. The MRI protocol included three sequences: axial-T2 weighted tse, SPACE and axial-T1 weighted. We found that BoNT-A injected GN and S muscles had increased signal intensity on the MRI performed 22 and 34 months after index procedure, when compared to the contralateral, not placebo injected (NaCl) leg. To the best of our knowledge, no previous studies have investigated the changes induced in muscle structures in ambulatory children with US-CP managed by BoNT-A injections. Level of evidence: II.

To ensure genome stability, sexually reproducing organisms require that mating brings together exactly two haploid gametes and that meiosis occurs only in diploid zygotes. In the fission yeastSchizosaccharomyces pombe, fertilization triggers the Mei3-Pat1-Mei2 signaling cascade, which represses subsequent mating and initiates meiosis. Here, we establish a degron system to specifically degrade proteins post-fusion and demonstrate that mating blocks not only safeguard zygote ploidy but also prevent lysis caused by aberrant fusion attempts. Using long-term imaging and flow-cytometry approaches, we identify previously unrecognized and independent roles for Mei3 and Mei2 in zygotes. We show that Mei3 promotes premeiotic S-phase independently of Mei2 and that cell cycle progression is both necessary and sufficient to reduce zygotic mating behaviors. Mei2 imposes the meiotic program and promotes the meiotic cycle, but also blocks mating behaviors independently of Mei3 and cell cycle progression. Thus, we find that fungi preserve zygote ploidy and survival by at least two mechanisms where the zygotic fate imposed by Mei2 and the cell cycle re-entry triggered by Mei3 synergize to prevent zygotic mating.

In children older than 5 years with a mild form of Legg–Calve–Perthes disease, the outcome is difficult to predict. In this study, we retrospectively correlated gadolinium-enhanced subtracted (DGS) and diffusion (DWI) MRI findings to the radiographic assessment according to the Catterall and Herring et al. classifications and to the final score according to Stulberg et al.: the aim was to identify a precocious, simple, and objective criterion to differentiate between forms evolving favourably and forms requiring an early surgical treatment in order to avoid femoral head deformity and subsequent osteoarthritis. Twelve boys with unilateral mild femoral head involvement (Catterall grade 2 or grade 3) underwent DSG and DWI MR during the early phase of the disease. The absence of enhancement of the external pillar on DSG MRI and the presence of metaphyseal hyperintensity on DWI were considered to be the signs of poor outcome. These findings were correlated with the Catterall and Herring et al. classifications at the initial sclerotic stage and early fragmentation phase and with the Stulberg et al. classifications at least 5 years after the onset of the disease. DSG MRI findings correctly discriminated three out of four patients with a good outcome but underestimated two out of eight patients with a poor outcome. DWI findings correlated with the Catterall and Herring et al. classifications in 12 out of 12 cases. In only one case, DWI findings did not correlate with the Stulberg et al. classification. DWI MR provides an objective and accurate prognostic criterion that is relatively easy to recognise. DGS MR findings are less accurate, thus underestimating the gravity of the disease in one-fourth of the patients with a poor outcome.

Detection of subclinical hepatic encephalopathy in children is difficult. We aimed to assess the changes in imaging of the central nervous system in children with chronic liver disease using MR imaging, diffusion, and 1H -spectroscopy. Forty three children with chronic liver disease and/or porto-systemic shunting (111.4±56.9 months) and 24 controls (72.0±51.8 months) underwent brain MRI/spectroscopy on a 1.5T to examine T1, T2, ADC, Cho/Cr, ml/Cr, Glx/Cr ratio spectroscopy in the globus pallidus. Patients were divided into 3 groups according to the ratios of globus pallidus/putamen T1 signal : isointense (i), hyperintense (h), much more hyperintense (h+). The relationship with clinical and biological data was analyzed. T1 signal intensity and ml/Cr were significantly different between controls and group h+ (p=0.001). ADC did not differ significantly between groups. Age correlated strongly with the presence of a T1 signal ratio (p > 0.001). There was no correlation between imaging findings and biological parameters. In children with chronic liver disease and/or porto-systemic shunting, the presence of a hyperintense T1 signal in the globus pallidus correlated strongly with age. Biological and clinical parameters were not predictive of these changes. MRI may become a useful screening tool for hepatic encephalopathy in children. • Children with chronic liver disease should undergo brain MRI during their follow-up • T1 hyperintensity of globus pallidus is suggestive of liver-related CNS involvement • MRS mI/Cr is decreased in children with chronic liver disease • Biological parameters (ammonium) were not predictive of hepatic encephalopathy • Duration of chronic liver disease may be causative the hepatic encephalopathy

OBJECTIVES: In this study, we aimed to contrast the bacteriologic epidemiology of osteoarticular infections (OAIs) between 2 patient groups in successive 10-year periods, before and after the extensive use of nucleic acid amplification assays in the diagnostic process. METHODS: Epidemiologic data and bacteriologic etiologies of all children presenting with OAIs on admission to our institution over 20 years (1997–2016) were assessed retrospectively. The population was divided into 2 cohorts, using the standardized use of polymerase chain reaction as the cutoff point (2007). The conventional cohort included children with OAIs mainly investigated by using classic cultures, whereas the molecular cohort referred to patients also investigated by using molecular assays. RESULTS: Kingella kingae was the most frequently isolated pathogen, responsible for 51% of OAIs, whereas other classic pathogens were responsible for 39.7% of cases in the molecular cohort. A statistically significant increase in the mean incidence of OAIs was observed, as was a decrease in the mean age at diagnosis after 2007. After 2007, the pathogen remained unidentified in 21.6% of OAIs in our pediatric population. CONCLUSIONS: Extensive use of nucleic acid amplification assays improved the detection of fastidious pathogens and has increased the observed incidence of OAI, especially in children aged between 6 and 48 months. We propose the incorporation of polymerase chain reaction assays into modern diagnostic algorithms for OAIs to better identify the bacteriologic etiology of OAIs.

Arsenic compounds have been traditionally used to treat a variety of ailments, including skin diseases. Our previous study identified the extract of realgar to possess potent antiproliferative action on HaCaT cells. The present study aimed at evaluating whether several inorganic arsenics found in realgar also possess similar antiproliferative properties. The results showed that arsenic trioxide, arsenic pentoxide, and arsenic iodide had significant antiproliferative action on HaCaT cells, with IC50 values at 2.4, 16, and 6.8 μM, respectively. However, these compounds only modestly inhibited the growth of Hs-68 cells, a normal human skin fibroblast cell line, with IC50 values at 43.4, 223, and 89 μM, respectively, conferring a favorable toxicity profile. In mechanistic studies, all three compounds caused DNA fragmentation as demonstrated by gel electrophoresis and the terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling method. Morphologically, nuclear condensation and DNA fragmentation were observed when the cells were exposed to arsenic compounds. Cell cycle analysis with propidium iodide (PI) staining demonstrated the appearance of sub-G1 peak and cell arrest at the G1 phase in the presence of these compounds. Quantitative analysis by annexin V-PI staining revealed that the arsenic-induced apoptotic event was dose-dependent. Moreover, the arsenic compounds were able to activate caspase-3 expression when examined by Western blot analysis. Our experimental data unambiguously demonstrated that induction of cellular apoptosis was mainly responsible for the observed antiproliferation brought about by the arsenic compounds on HaCaT keratinocytes, suggesting that these arsenic compounds are putative agents from which psoriasis-treating topical formulae could be developed.

Local activity of the small GTPase Cdc42 is critical for cell polarization. Whereas scaffold-mediated positive feedback was proposed to break symmetry of budding yeast cells and produce a single zone of Cdc42 activity, the existence of similar regulation has not been probed in other organisms. Here, we address this problem using rod-shaped cells of fission yeast Schizosaccharomyces pombe, which exhibit zones of active Cdc42-GTP at both cell poles. We implemented the CRY2-CIB1 optogenetic system for acute light-dependent protein recruitment to the plasma membrane, which allowed to directly demonstrate positive feedback. Indeed, optogenetic recruitment of constitutively active Cdc42 leads to co-recruitment of the guanine nucleotide exchange factor (GEF) Scd1 and endogenous Cdc42, in a manner dependent on the scaffold protein Scd2. We show that Scd2 function is dispensable when the positive feedback operates through an engineered interaction between the GEF and a Cdc42 effector, the p21-activated kinase 1 (Pak1). Remarkably, this rewired positive feedback confers viability and allows cells to form 2 zones of active Cdc42 even when otherwise essential Cdc42 activators are lacking. These cells further revealed that the small GTPase Ras1 plays a role in both localizing the GEF Scd1 and promoting its activity, which potentiates the positive feedback. We conclude that scaffold-mediated positive feedback, gated by Ras activity, confers robust polarization for rod-shape formation., The small GTPase Cdc42 is a key regulator of cell polarization. This study uses optogenetic and genetic strategies to show that Cdc42 is under positive feedback regulation potentiated by Ras GTPase activity.

Background: The mean overall survival rate of children with diffuse intrinsic pontine glioma (DIPG) is 9–11 months, with current standard treatment with fractionated radiotherapy and adjuvant chemotherapy. So far, novel therapeutic strategies have not yet resulted in significantly better survival. The main source of energy for glioblastoma cells is glucose. Therefore, metabolic alterations induced by the use of the extremely carbohydrate-restricted ketogenic diet (KD) as adjuvant therapy are subject of interest in cancer research. Procedure: This study explores the safety and feasibility of the KD in children with recurrent DIPG and no remaining treatment options. Safety was defined as the number of adverse effects. Feasibility was defined as the number of patients who were able to use the KD for three months. Coping of patients and parents was measured with questionnaires. Results: Three of 14 children referred to our hospital between 2010 and 2015 were included. Two patients completed the study, and one died before the end of the study. Hospitalizations were needed for placing a nasogastric tube (n = 1) and epileptic seizures (n = 1). Adverse effects related to the diet were mild and transient. Parents were highly motivated during the study. Conclusion: Use of KD is safe and feasible, but the effect on survival has to be proven in a larger cohort of children who start the KD earlier after diagnosis, preferably as adjuvant therapy to fractionated radiotherapy.

This study aims to ascertain the impact of congenital ocular motor apraxia (COMA), alternatively called infantile-onset saccade initiation delay (ISID), on reading acquisition. More specifically, the consequence of defective initiation of horizontal saccades during reading acquisition was investigated. Three siblings (A: male, 11y3m at the first time-point of testing (i.e. T1 hereafter); B: female, 7y3m at T1 and C: male, 5y9m at T1) suffering from ISID were assessed longitudinally over 3 years in various reading tests and their eye movements simultaneously registered. At each time-point, they were compared to control participants matched on reading level. Eye movements during reading tasks were markedly abnormal in children with ISID at the beginning of reading acquisition and their reading scores were poor. With time, the number of fixations, small amplitude saccades and their reading abilities became comparable to those of control children. Despite the abnormal eye movements and difficulties in specifically directing the eyes to the appropriate position, children with ISID do not seem to encounter major difficulties during reading acquisition, although mild delays might be observed during the early stages.

Background This study aimed to describe the spectrum of pediatric primary subacute hematogenous osteomyelitis (PSAHO) and to investigate its bacterial etiology. Methods Sixty-five consecutive cases of PSAHO admitted to our institution over a 16-year period (2000–2015) were retrospectively reviewed to assess their laboratory and radiographic imaging features, as well as their bacteriological etiology. Results On evaluation, white blood cell count and C-reactive protein were normal in 53 (81.5 %) and 34 cases (52.3 %), respectively, whereas the erythrocyte sedimentation rate was superior to 20 mm/h in 44 cases (72.1 %). Blood cultures failed to identify the pathogen in all but one patient, and classic bone sample cultures only managed to isolate the pathogen in five cases (11.6 %). Use of polymerase chain reaction (PCR) assays on bone aspirates or blood allowed the causative microorganism to be isolated in a further 22 cases. Using classic cultures and PCR assays together resulted in pathogen detection in 27 cases (62.8 % of the children bacteriologically investigated), with Kingella kingae being the most frequently reported microorganism. Conclusions Two distinct forms of PSAHO should be distinguished on the basis of age of patients and bacteriological etiology. The infantile form affects children aged between 6 months and 4 years and is predominantly due to K. kingae. The juvenile form involves children aged >4 years and Staphylococcus aureus appears to be the main bacteriological etiology. Appropriate nucleic amplification assays drastically improve the detection rate of the microorganisms responsible for PSAHO. Level of evidence: Case series, level IV.

Purpose: Pseudoprogression is a rare complication of radiation therapy, and discrimination between true progression and pseudoprogression is of paramount importance for further medical care. We present a case of intra-axial pseudoprogression following complementary proton radiation therapy for a choroid plexus carcinoma in a child. We aim to highlight radiological patterns of pseudoprogression after proton beam therapy. Case report: A 6-year-old girl presented with choroid plexus carcinoma, manifesting as change in behavior, tremor, and balance disorder. Partial resection and chemotherapy were performed. Complementary localized proton beam therapy (54Gy) was administered on the residual tumor. Eight month follow-up MRI showed an abnormal, irregular, rim-like enhancement in the pons and both temporal lobes within the field of irradiation. These lesions had a low cerebral blood volume (CBV) on perfusion MR imaging and no restricted diffusion. However, the lesions were hypermetabolic on O-(2-[18F]fluoroethyl)-l-tyrosine (FET)-PET MRI. Follow-up MRI showed disappearance of these lesions confirming the perfusion MR diagnosis of pseudoprogression. Conclusion: Based on this case, radiological patterns of pseudoprogression after proton beam therapy may be a low CBV and no restricted diffusion. Lesions can be hypermetabolic on FET-PET imaging

Perineuroma, rare in children, presents as a painless mononeuropathy of a major nerve trunk. Resection of the lesion with end-to-end sural nerve grafting appears to be the treatment of choice. This technique is not recommended if the unhealthy segment of nerve is too long or if spinal roots are involved. However, in children, reports of direct MR evaluation of nerve trunks and of the exiting nerve roots are limited. We report a 7-year-old girl with an intramural sciatic nerve perineuroma in whom the diagnosis was made by MRI and confirmed by biopsy. The MR protocol combining 3-D T2-W STIR SPACE, fat-saturated gadolinium-enhanced T1-W images, and diffusion tensor imaging with tractography was a valuable tool for depicting peripheral nerve and roots in order to plan surgical treatment.

The ploidy cycle, integral to sexual reproduction, requires not only meiosis to halve the number of chromosomes, but also mechanisms that ensure zygotes are formed by exactly two partners1–5. During sexual reproduction of the fungal model organismSchizosaccharomyces pombe, haploid P- and M-cells normally fuse to form a diploid zygote that immediately enters meiosis6. Here, we reveal that fast post-fusion reconstitution of a bi-partite transcription factor actively blocks re-fertilization. We first identify mutants that undergo transient cell fusion involving cytosol exchange but not karyogamy, and show this drives distinct cell fates in the two gametes: The P-partner undergoes lethal, haploid meiosis while the M-cell persists in mating. Consistently, we find that the zygotic transcription that drives meiosis is initiated rapidly only from the P-parental genome, even in wild type cells. This asymmetric gene expression depends on a bi-partite complex formed post-fusion between the nuclear P-cell-specific homeobox protein Pi and a cytosolic M-specific peptide Mi7,8, which is captured by Pi in the P-nucleus. Zygotic transcription is thus poised to initiate in the P-nucleus as fast as Mi reaches it. The asymmetric nuclear accumulation is inherent to the transcription factor design, and is reconstituted by a pair of synthetic interactors, one localized to the nucleus of one gamete and the other in the cytosol of its partner. Strikingly, imposing a delay in zygotic transcription, by postponing Mi expression or deleting its transcriptional target in the P-genome, leads to zygotes fusing with additional gametes, thus forming polyploids and eventually aneuploid progeny. We further show that the signaling cascade to block re-fertilization shares components with, but bifurcates from, meiotic induction9–11. Thus, cytoplasmic connection upon gamete fusion leads to rapid reconstitution of a bi-partite transcription factor in one partner to block re-fertilization and induce meiosis, thus ensuring genome maintenance during sexual reproduction.

Malignant or nonmalignant lymphoproliferative disorders together with repeated ear, nose, and throat infections should strongly motivate immunologic investigations. Indeed, we report a 7-year-old patient with a history of persistent abdominal symptoms along with recurrent ear, nose, and throat infections, who presented with intra-abdominal masses highly suggestive of a diagnostic of lymphoma, and who was diagnosed with activated-PI3K-delta syndrome, a recently described primary immunodeficiency prone to lymphoproliferation.

Although rare, masses and mass-like lesions of developmental and genetic origin may affect the paediatric craniofacial skeleton. They represent a major challenge in clinical practice because they can lead to functional impairment, facial deformation and disfigurement. The most common lesions include fibrous dysplasia, dermoid cysts, vascular malformations and plexiform neurofibromas. Less common lesions include torus mandibularis and torus palatinus, cherubism, nevoid basal cell carcinoma syndrome, meningoencephalocele and nasal sinus tract. This article provides a comprehensive approach for the evaluation of children with masses or mass-like lesions of developmental and genetic origin affecting the craniofacial skeleton. Typical findings are illustrated and the respective roles of computed tomography (CT), cone beam CT (CBCT), magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) sequences and ultrasonography (US) are discussed for the pre-therapeutic assessment, complex treatment planning and post-treatment surveillance. Key imaging findings and characteristic clinical manifestations are reviewed. Pitfalls of image interpretation are addressed and how to avoid them. • Masses of developmental and genetic origin may severely impair the craniofacial skeleton. • Although rare, these lesions have characteristic imaging features. • CT, MRI and ultrasonography play a key role in their work-up. • Recognition of pivotal imaging pearls and diagnostic pitfalls avoids interpretation errors.

The ploidy cycle, which is integral to sexual reproduction, requires meiosis to halve chromosome numbers as well as mechanisms that ensure zygotes are formed by exactly two partners1-4. During sexual reproduction of the fungal model organism Schizosaccharomyces pombe, haploid P and M cells fuse to form a diploid zygote that immediately enters meiosis5. Here we reveal that rapid post-fusion reconstitution of a bipartite transcription factor blocks re-fertilization. We first identify mutants that undergo transient cell fusion involving cytosol exchange but not karyogamy, and show that this drives distinct cell fates in the two gametes. The P partner undergoes lethal haploid meiosis, whereas the M cell persists in mating. The zygotic transcription that drives meiosis is rapidly initiated first from the P parental genome, even in wild-type cells. This asymmetric gene expression depends on a bipartite complex formed post-fusion between the cytosolic M-cell-specific peptide Mi and the nuclear P-cell-specific homeobox protein Pi6,7, which captures Mi in the P nucleus. Zygotic transcription is thus poised to initiate in the P nucleus as fast as Mi reaches it after fusion, a design that we reconstruct using two synthetic interactors localized to the nucleus and the cytosol of two respective partner cells. Notably, delaying zygotic transcription-by postponing Mi expression or deleting its transcriptional target in the P genome-leads to zygotes fusing with additional gametes, thus forming polyploids and eventually aneuploid progeny. The signalling cascade to block re-fertilization shares components with, but bifurcates from, meiotic induction8-10. Thus, a cytoplasmic connection upon gamete fusion leads to asymmetric reconstitution of a bipartite transcription factor to rapidly block re-fertilization and induce meiosis, ensuring genome maintenance during sexual reproduction.

Although the orbit is a small anatomical space, the wide range of structures present within it are often the site of origin of various tumours and tumour-like conditions, both in adults and children. Cross-sectional imaging is mandatory for the detection, characterization, and mapping of these lesions. This review focuses on multiparametric imaging of orbital tumours. Each tumour is reviewed in relation to its clinical presentation, compartmental location, imaging characteristics, and its histological features. We herein describe orbital tumours as lesions of the globe (retinoblastoma, uveal melanoma), optic nerve sheath complex (meningioma, optic nerve glioma), conal-intraconal compartment (hemangioma), extraconal compartment (dermoid/epidermoid, lacrimal gland tumours, lymphoma, rhabdomysarcoma), and bone and sinus compartment (fibrous dysplasia). Lesions without any typical compartmental localization and those with multi-compartment involvement (veno-lymphatic malformation, plexiform neurofibroma, idiopathic orbital pseudotumour, IgG4 related disease, metastases) are also reviewed. We discuss the role of advanced imaging techniques, such as MR diffusion-weighted imaging (DWI), diffusion tensor imaging, fluoro-2-deoxy-D-glucose positron emission tomography CT (FDG-PET CT), and positron emission tomography MRI (MRI PET) as problem-solving tools in the evaluation of those orbital masses that present with non-specific morphologic imaging findings. Main messages/Teaching points • A compartment-based approach is essential for the diagnosis of orbital tumours. • CT and MRI play a key role in the work-up of orbital tumours. • DWI, PET CT, and MRI PET are complementary tools to solve diagnostic dilemmas. • Awareness of salient imaging pearls and diagnostic pitfalls avoids interpretation errors.

Diffusion tensor imaging has been useful in demonstrating non-decussating corticospinal tract (CST) and superior cerebellar peduncles (SCP) in Joubert syndrome (JS) related disorder and in horizontal gaze palsy with progressive scoliosis (HGPPS). However, measurements of fractional anisotropy (FA) and mean diffusivity (MD) have never been performed in these diseases. The aim of our work was to investigate if FA and MD values in uncrossed white matter bundles due to defective axon guidance are different from normal decussating fibers. Two patients with HGPPS and four with JS were included. FA and MD were measured by region of interest manually placed on the CST, the SCP and the posterior rows (PR) of the pons. The same measurements were performed in 59 control patients. Comparison of these values between patients and controls was performed by graphical inspection. MD values were normal in all cases. In all patients with HGPPS and JS, FA measurements in SCP were not different from normal controls. FA values in PR and in CST were not different in JS patients but higher than in controls in HGPPS patients. This difference was statistically significant. Normal MD values seem to indicate that MD and FA values likely represent two very different processes in the developing brain. High FA values in PRs and CST in HGPPS, implicating micro- scopic deficits of axonal structures, is a unique finding in this disease. Abnormal measurements on PR confirm a role of these fibers in the pathogenesis and clinical presentation of HGPPS.

Zinner syndrome, the association of congenital seminal vesicle cyst and ipsilateral renal agenesis, is more often reported in adults or older adolescents. We present a case of a boy, followed up in our hospital since birth for right renal agenesis who at the age of 4 years presented a right paravesical cyst on ultrasound. The cyst was initially considered as an ureterocele. The diagnosis of Zinner syndrome was made later, at the age of 15 years by ultrasound and magnetic resonance imaging; at that moment the cyst had increased in size and had changed in aspect. This malformation should be considered in the differential diagnosis of a pelvic cyst in male patients with renal agenesis.

Background/purpose Intracranial calcifications have been identified in many neurological disorders. To our knowledge, however, such findings have not been described in cartilage-hair hypoplasia – anauxetic dysplasia spectrum disorders (CHH-AD), a group of conditions characterized by a wide spectrum of clinical manifestations. Methods/results We report a 22-year old female patient, diagnosed with this disorder during her first year of life, and in whom bilateral intracranial calcifications (frontal lobes, basal ganglia, cerebellar dentate nuclei) were discovered by brain MRI at the age of 17 years. Conclusion The etiology of this finding remains unclear. Some causes of such deposits can be of a reversible nature, thus prompting early recognition although their consequences on clinical outcome remain mostly unknown.

The yeast cell wall is digested to allow cell fusion during sexual reproduction. How cells coordinate this process with cell–cell contact to prevent lysis is unclear. Merlini et al. show that the Ras GAP protein Gap1, which is recruited to sites of Ras-GTP, restricts Ras activity and protects cells from lysis due to premature fusion attempts., In the fission yeast Schizosaccharomyces pombe, pheromone signaling engages a signaling pathway composed of a G protein–coupled receptor, Ras, and a mitogen-activated protein kinase (MAPK) cascade that triggers sexual differentiation and gamete fusion. Cell–cell fusion requires local cell wall digestion, which relies on an initially dynamic actin fusion focus that becomes stabilized upon local enrichment of the signaling cascade on the structure. We constructed a live-reporter of active Ras1 (Ras1–guanosine triphosphate [GTP]) that shows Ras activity at polarity sites peaking on the fusion structure before fusion. Remarkably, constitutive Ras1 activation promoted fusion focus stabilization and fusion attempts irrespective of cell pairing, leading to cell lysis. Ras1 activity was restricted by the guanosine triphosphatase–activating protein Gap1, which was itself recruited to sites of Ras1-GTP and was essential to block untimely fusion attempts. We propose that negative feedback control of Ras activity restrains the MAPK signal and couples fusion with cell–cell engagement.

The fission yeast

In fission yeast Schizosaccharomyces pombe, pheromone signalling engages a GPCR-Ras-MAPK cascade to trigger sexual differentiation leading to gamete fusion. Cell-cell fusion necessitates local cell wall digestion, the location of which relies on an initially dynamic actin fusion focus that becomes stabilized upon local enrichment of the signalling cascade. We constructed a live-reporter of active Ras1 (Ras1-GTP), also functional in S. cerevisiae, which revealed Ras activity at polarity sites peaking on the fusion structure before fusion. Remarkably, constitutive Ras1 activation promoted fusion focus stabilization and fusion attempts irrespective of cell-cell pairing, leading to cell lysis. Ras1 activity is restricted by the GTPase activating protein (GAP) Gap1, itself recruited to sites of Ras1-GTP. While the GAP domain on its own does not suffice for this localization, its recruitment to Ras1-GTP sites is essential to block untimely fusion attempts. We conclude that negative feedback control of Ras activity restrains the MAPK signal and couples fusion with cell-cell engagement.

Background:Neonatal thalamic hemorrhagic stroke is related to cerebral sinus venous thrombosis and associated with neurological sequelae. Predicting factors are however lacking.Methods:Clinical and radiological findings at onset and on follow-up of 5 neonates with thalamic hemorrhage stroke are described.Results:All neonates presented with abrupt lethargy, ophistotonos, irritability and/or seizures. The thalamic hemorrhagic stroke was most often unilateral (4/5), involving the posterior/entire thalamus in 3 cases and the anterior thalamus in 2. Cerebral venous thrombosis was identified in a single patient. At follow-up, children with unilateral anterior thalamic hemorrhagic stroke demonstrated thalamic atrophy without neurological symptoms, whereas children whose thalamus lesion was extensive exhibit a porencephalic cavity and presented with late-onset epilepsy.Discussion:Although deep cerebral venous thrombosis is probably the cause of neonatal thalamic hemorrhagic stroke, its radiological evidence is challenging. Outcome seems dependent of the size and location of thalamic hemorrhagic stroke. Epilepsy is a frequent morbidity after thalamic hemorrhagic stroke.

Fucosidosis is a rare lysosomal storage disease. A 14-year-old girl is presented, with recurrent infections, progressive dystonic movement disorder and mental retardation with onset in early childhood. The clinical picture was also marked by mild morphologic features, but absent dysostosis multiplex and organomegaly. MRI images at 6.5 years of age were reminiscent of pallidal iron deposition ("eye-of-the-tiger" sign) seen in neurodegeneration with brain iron accumulation (NBIA) disorders. Progressively spreading angiokeratoma corporis diffusum led to the correct diagnosis. This case extends the scope of clinical and neuroradiological manifestations of fucosidosis.

The assessment of acute vertigo in childhood is often challenging, but fortunately a central cause is rarely identified. We present the case of a 7-year-old boy who developed, after a mild head trauma, a rotary vertigo associated with nausea and vomiting. A posttraumatic peripheral vestibular dysfunction was first suspected but not confirmed by an otoneurological evaluation. When subtle neurological signs were elicited, a brain magnetic resonance imaging was promptly requested. This showed a small infarct on the lateral posterior left part of the medulla oblongata of the brainstem, typical of Wallenberg syndrome. Vascular imaging was normal and no defined etiology was found. The child was started on prophylactic acetylsalicylic acid. The rapid disappearance of vertigo was noted. On follow-up at 6 months, there has been no recurrence and neurological examination was fully normal. Our case extends the differential diagnosis of acute vertigo in childhood that rarely includes the possibility of a brainstem infarct whose recognition through appropriate clinical examination is nevertheless capital for appropriate investigations and management.

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare autosomal recessive disorder characterized by the absence of conjugate horizontal eye movements, and progressive scoliosis developing in childhood and adolescence, caused by mutations in the ROBO3 gene which has an important role in axonal guidance and neuronal migration. We describe two female children aged 12 years and 18 months, with progressive scoliosis, in whom the neurological examination showed absent conjugate horizontal eye movements, but preserved vertical gaze and convergence. Cerebral Magnetic resonance imaging findings included pontine hypoplasia, absent facial colliculi, butterfly configuration of the medulla and a deep midline pontine cleft, while Diffusion tensor imaging (DTI) maps showed the absence of decussating ponto-cerebellar fibers and superior cerebellar peduncles. Somatosensory and motor evoked potential studies demonstrated ipsilateral sensory and motor responses. The diagnosis was confirmed by the identification of bi-allelic mutations in the ROBO3 gene.

INTRODUCTION: Acute fibrinous and organizing pneumonia (AFOP) is a recently described histologic pattern of diffuse pulmonary disease. In children, all cases reported to date have been fatal. In this study, we describe the first nonfatal AFOP in a child and review the literature. DESCRIPTION: A 10-year-old boy developed very severe aplastic anemia (VSAA) after being admitted to our hospital with a fulminant hepatic failure of unknown origin. A chest computed tomography scan revealed multiple lung nodules and a biopsy of a pulmonary lesion showed all the signs of AFOP. Infectious workup remained negative. We started immunosuppressive therapy with antithymocyte globulin and cyclosporine to treat VSAA. Subsequent chest computed tomography scans showed a considerable diminution of the lung lesions but the VSAA did not improve until we performed hematopoietic stem cell transplantation 5 months later. CONCLUSIONS: Aplastic anemia is associated with a variety of autoimmune syndromes. The sequence of events in our patient suggests that the hepatic failure, AFOP, and the VSAA may all have been part of an autoimmune syndrome. AFOP could be the result of immune dysregulation in this pediatric case with favorable outcome after immunosuppressive therapy and hematopoietic stem cell transplantation.

Although genetic defects are the leading cause of central nervous system malformations including in the posterior fossa, specific malformative patterns should alert the clinician to consider rather a teratogenic etiology. We discuss the imaging features of 2 mid-hindbrain malformations consecutive to the intake of isotretinoin (Roaccuatane®; case 1) and misoprostol (Cytotec®; case 2) during pregnancy and review the pertinent literature. We correlate the morphological appearance of the mid-hindbrain malformation, as seen on high-resolution magnetic resonance imaging to possible drug-induced pathogenetical mechanisms. The recognition of characteristic imaging patterns enables diagnosis of and/or confirmation of suspected drug-induced hindbrain malformations. This has important medicolegal implications and also clinical significance to avoid unsuccessful and misleading genetic testing.