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Background: The safety of gadolinium-based contrast agents is a hot topic in radiology. Purpose: To evaluate the safety profile of gadobutrol during routine use. Material and Methods: Prospective, non-interventional study in 80 centers in Germany. The primary outcome was the number of adverse drug reactions (ADR) following gadobutrol administration. Results: A total of 3710 patients were included in the analysis, including 404 children (10.9%). A total of 6026 magnetic resonance imaging examinations of organs/organ systems and 872 magnetic resonance angiography examinations were performed. A total of 22 (0.59%) patients experienced at least one ADR. Nausea and vomiting were the most frequent ADRs, experienced by nine (0.24%) and three (0.08%) patients, respectively. One serious ADR was recorded (anaphylactoid reaction). No deaths were reported. Conclusion: This non-interventional study in 3710 patients confirmed gadobutrol as a safe and reliable contrast agent in adults and children. [ABSTRACT FROM AUTHOR]

Human cytomegalovirus (HCMV), a ubiquitous human pathogen, is the leading cause of birth defects and morbidity in immunocompromised patients and a potential trigger for vascular disease. HCMV replicates in vascular endothelial cells and drives leukocyte-mediated viral dissemination through close endothelium-leukocyte interaction. However, the genetic basis of HCMV growth in endothelial cells and transfer to leukocytes is unknown. We show here that the UL131-128 gene locus of HCMV is indispensable for both productive infection of endothelial cells and transmission to leukocytes. The experimental evidence for this is based on both the loss-of-function phenotype in knockout mutants and natural variants and the gain-of-function phenotype by trans-complementation with individual UL131, UL130, and UL128 genes. Our findings suggest that a common mechanism of virus transfer may be involved in both endothelial cell tropism and leukocyte transfer and shed light on a crucial step in the pathogenesis of HCMV infection. [ABSTRACT FROM AUTHOR]

The 230-kb human cytomegalovirus genome is among the largest of the known viruses. Experiments to determine the genetic determinants of attenuation, pathogenesis, and tissue tropism are underway; however, a lack of complete sequence data for multiple strains and substantial problems with genetic instability during in vitro propagation create serious complications for such studies. For example, recent findings suggest that common laboratory strains Towne and AD169 passaged in cultured human fibroblasts are missing up to 15 kb of genetic information relative to clinical isolates. To establish standard, genetically stable genomes that can be sequenced, disseminated, and repeatedly reconstituted to produce virus stocks, we have undertaken to clone two variants of Towne, designated Townelong and Towneshort (referred to asTownevarRIT3) (A. , Proc. Natl. Acad. Sci. USA 98, 7829–7834), and the pathogenic strain Toledo into bacterial artificial chromosomes (BACs). We further demonstrate the ease with which mutagenesis can be achieved by deleting 13.5 kb from the Toledo genome using a PCR-based technique. [Copyright &y& Elsevier]

Our basic understanding of how viruses infect, replicate, and cause disease has been largely derived from genetic approaches in which viral sequences have been mutated and the consequences of those mutations determined. In the herpesvirus field, deletions or insertions that preclude expression of specific viral proteins or remove critical cis elements have been invaluable in identifying their overall functions. We are now ready to move to a new level of detail—mapping functional domains within viral proteins or defining cis elements to the nucleotide level. This level of detail will require mutagenesis on a new scale, with recombinant viruses containing mutations within a given locus perhaps numbering in the hundreds. Mutagenesis on this scale would be greatly facilitated by more rapid methods of recombinant virus construction. In this report, we adapted a technology employing Tn7-mediated site-specific transposition [J. Virol. 67 (1993) 4566] as a rapid and highly reliable method to introduce novel sequences into bacmid-cloned herpesvirus genomes. We show that recombinant viruses can be rapidly created and that a deletion of the human cytomegalovirus (HCMV) essential gene ie2 can be complemented in cis by reintroduction, via transposition, of an ie2 cDNA; detailed mutagenesis of the complementing ie2 gene can now follow. Tn7-mediated transposition should accelerate greatly the pace at which recombinant herpesviruses can be constructed and, thus, facilitate the use of recombinant viruses for detailed mutagenic studies of both cis- and trans-acting genetic elements. [Copyright &y& Elsevier]

Presents a study on the role played by hematopoietic cells and their progenitors in human cytomegalovirus latency and reactivation. Materials and methods used; Evaluation of latent infection in defined populations of myeloid-lineage-committed progenitor cells; Results and discussion.

Magnetic resonance (MR) imaging is widely used for assessing infant head and brain development and for diagnosing pathologies. The main goal of this work is the development of a segmentation framework to create patient-specific head and brain anatomical models from MR images for clinical evaluation. The proposed strategy consists of a fusion-based Deep Learning (DL) approach that combines the information of different image sequences within the MR acquisition protocol, including the axial T1w, sagittal T1w, and coronal T1w after contrast. These image sequences are used as input for different fusion encoder–decoder network architectures based on the well-established U-Net framework. Specifically, three different fusion strategies are proposed and evaluated, namely early, intermediate, and late fusion. In the early fusion approach, the images are integrated at the beginning of the encoder–decoder architecture. In the intermediate fusion strategy, each image sequence is processed by an independent encoder, and the resulting feature maps are then jointly processed by a single decoder. In the late fusion method, each image is individually processed by an encoder–decoder, and the resulting feature maps are then combined to generate the final segmentations. A clinical in-house dataset consisting of 19 MR scans was used and divided into training, validation, and testing sets, with 3 MR scans defined as a fixed validation set. For the remaining 16 MR scans, a cross-validation approach was adopted to assess the performance of the methods. The training and testing processes were carried out with a split ratio of 75% for the training set and 25% for the testing set. The results show that the early and intermediate fusion methodologies presented the better performance (Dice coefficient of 97.6 ± 1.5% and 97.3 ± 1.8% for the head and Dice of 94.5 ± 1.7% and 94.8 ± 1.8% for the brain, respectively), whereas the late fusion method generated slightly worst results (Dice of 95.5 ± 4.4% and 93.8 ± 3.1% for the head and brain, respectively). Nevertheless, the volumetric analysis showed that no statistically significant differences were found between the volumes of the models generated by all the segmentation strategies and the ground truths. Overall, the proposed frameworks demonstrate accurate segmentation results and prove to be feasible for anatomical model analysis in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Juvenile dermatomyositis (jDM) is the most common idiopathic inflammatory myopathy of childhood. Amyopathic or hypomyopathic courses have been described. Case presentation: We present the case of a 4-year-old patient with MDA5 antibody positive jDM and interstitial lung disease. In our patient, typical symptoms of jDM with classical skin lesions, arthritis, proximal muscle weakness, and ulcerative calcifications were observed. Due to the severity of the disease and the pulmonary changes, therapy with the Janus kinase (JAK) inhibitor ruxolitinib was added to the therapy with corticosteroids, intravenous immunoglobulins (IVIG) and hydroxychloroquine leading to a fast and sustained remission. Conclusion: While there is growing evidence that JAK inhibition is a promising therapeutic option in jDM our case report shows that this approach may also be effective in MDA5-positive jDM with high risk features. [ABSTRACT FROM AUTHOR]

Background: Neurological development is determined by brain growth. Methods to measure total brain volume (TBV) in clinical settings are limited. MR-imaging represents the gold-standard.Aims: The present study tests the hypotheses that in infants without any brain pathology, TBV - as determined by MRI - can be accurately estimated by cranial volume (CrV), measured by 3D-laser scanning. In case of good correlation of CrV with TBV it was further tested, whether CrV can be also estimated by (I) head circumference (HC) or (II) by other technology than laser scanning.Study Design& Subjects: To test the hypothesis, that TBV can be reliably estimated by CrV-measurement, data from routine MRI and 3D-laser-scanner measurements were analyzed in infants if no major structural brain anomaly was found in MR-imaging. To test whether CrV can be predicted by HC-measurements during infancy, data from routine follow-up visits were used from preterms born in a two year period. Preterms are invited for a routine follow-up visit (which includes laser scanning of the head) at an age of 3 months and, for further follow-ups at 6, 9 or 12 months. To compare accuracy of CrV measurement by other techniques, a puppet head was measured, using different 3D-measurement principles: (i) Structured light projection system, (ii) The non-invasive laser-shape-digitizer, and (iii) Structure-from-motion (SFM) technique.Outcome Measures: TBV was compared with CrV using a Passing-Bablok-Regression. To determine how well HC predicts CrV, the coefficient of determinant (R2) was calculated for each age group.Results: CrV and TBV of 25 infants (median age 19 month, body weight of 11 kg) showed a median bias of -86.7 mm3 with a slightly smaller TBV (median of 1034.1 mm3, IQR 875.9 … 1179.8 mm3) than CrV (median 1092.2, IQR 950.5 … 1258.4 mm3). CrV was poorly estimated by HC, with R2 between 0.79 and 0.87 at 3 and 9 month of age respectively. For the non-invasive laser-shape-digitizer and the SFM-technique the accuracy was good (radial coordinate differences ±0.3 vs. ±0.5 mm).Conclusion: The present study provides convincing evidence that CrV can be used to estimate TBV in routine care, whereas HC is a poor predictor of individual CrV. [ABSTRACT FROM AUTHOR]

Autosomal dominantly inherited mutations of BICD2 are associated with congenital-onset spinal muscular atrophy characterised by lower limb predominance. A few cases have also showed upper motor neuron pathology, including presenting with features resembling hereditary spastic paraplegia. The age-of-onset for the published families is usually at birth but also included cases with childhood- and adult-onset disease. In this report we described two isolated probands that presented in utero with features associated with reduced fetal movements. Both cases were diagnosed at birth with arthrogryposis multiplex congenita (AMC) and hypotonia. Other variable features included congenital fractures, hip dislocation, micrognathia, respiratory insufficiency, microcephaly and bilateral perisylvian polymicrogyria. Patient 1 is 4 years of age and stable, but shows significant motor developmental delay and delayed speech. Patient 2 passed away at 7 weeks of age. Through next generation sequencing we identified the same missense substitution in BICD2 (p.Arg694Cys) in both probands. Sanger sequencing showed that in both cases the mutation arose de novo . The in utero onset in both cases suggests that the p.Arg694Cys substitution may have a more deleterious effect on BICD2 function than previously described mutations. Our results broaden the phenotypes associated with BICD2 mutations to include AMC and cortical malformations and therefore to a similar phenotypic spectrum to that associated with its binding partner DYNC1H1. [ABSTRACT FROM AUTHOR]

Acute necrotizing encephalopathy (ANE) is a rare disease presenting with rapidly progressing encephalopathy. It usually occurs in otherwise healthy children after common viral infections. The hallmarks of ANE are the neuroradiological findings of multiple symmetric lesions in the thalami, midbrain, pons and brainstem. Most cases are sporadic and non recurrent. However, recurrent or familial forms of ANE due to mutations in RANBP2 gene have been reported. It has been suggested to give these cases the term ANE1. We report the clinical course in two male infants (P1, P2) with ANE1 and a variable clinical course and outcome. One patient is heterozygous for the most common RANBP2 missense mutation p.Thr585Met. In the other patient we observed a novel de novo missense mutation p.Trp681Cys in the RANBP2 gene causing recurrent ANE. Clinical and radiological features are presented and differential diagnoses are discussed. This report adds to the current knowledge of the phenotype in ANE, caused by mutations in RANBP2 gene. [ABSTRACT FROM AUTHOR]

Background: Gadobutrol is a gadolinium-based contrast agent, uniquely formulated at 1.0 mmol/ml. Although there is extensive safety evidence on the use of gadobutrol in adults, few studies have addressed the safety and tolerability of gadobutrol in pediatric patients.Objective: This subanalysis of data from the GARDIAN study evaluated the safety and use of gadobutrol in pediatric patients (age <18 years).Materials and Methods: The GARDIAN study was a large phase IV non-interventional prospective multicenter post-authorization safety study performed in Europe, Asia, North America and Africa. A total of 23,708 patients were included who were scheduled to undergo cranial or spinal MRI, liver or kidney MRI, or MR angiography with gadobutrol enhancement. The primary study endpoint was the overall incidence of adverse drug reactions (ADRs) and serious adverse events (SAEs) following gadobutrol administration.Results: The GARDIAN study included 1,142 children (age <18 years) who received gadobutrol at a mean dose of 0.13 (range 0.04-0.50) mmol/kg body weight. Gadobutrol was well tolerated in these children, with low rates of ADRs (0.5%) and no SAEs, consistent with results in adults enrolled in the GARDIAN study. Rates of adverse events and ADRs were unrelated to pediatric age or gadobutrol weight-adjusted dose. There were no symptoms suggestive of nephrogenic systemic fibrosis. Investigators rated the contrast quality of gadobutrol-enhanced images as good or excellent in 97.8% of pediatric patients, similar to the main study population.Conclusion: Gadobutrol is very well tolerated and provides excellent contrast quality at the recommended weight-adjusted dose in children (age <18 years), similar to the profile in adults. [ABSTRACT FROM AUTHOR]

Chronic nonbacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO) is a non-bacterial osteitis of yet unknown origin. Secondary to the absence of both high-titer autoantibodies and autoreactive T lymphocytes, and the association with other autoimmune diseases, it was recently reclassified as an autoinflammatory disorder of the musculoskeletal system. Since its etiology is largely unknown, the diagnosis is based on clinical criteria, and treatment is empiric and not always successful. In this paper, we summarize recent advances in the understanding of possible etiopathogenetic mechanisms in CNO. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The purpose of this study was to assess the apparent diffusion coefficient (ADC) of neuroblastic tumours and to evaluate if the ADC can enable differentiation of neuroblastoma and ganglioneuroma/ganglioneuroblastoma. Patients and methods: 16 histologically classified tumours (10 neuroblastomas and 6 ganglioneuroma/ganglioneuroblastoma) were investigated in 15 children. Diffusion-weighted echo-planar imaging was performed with a b-value of 800s/mm2. The contrast of tumour tissue depicted with T2-weighted images and diffusion-weighted images was evaluated by means of region-of-interest (ROI) measurements and a calculation of the ADC by a software tool. The ADC of the psoas-muscle was measured to establish an internal standard, too. Results: The mean ADC of the 10 neuroblastomas was 0.81×10−3 mm2/s (SD 0.29×10−3 mm2/s, range 0.39–1.47×10−3 mm2/s). The mean ADC of the four ganglioneuroma and two ganglioneuroblastoma was 1.6×10−3 mm2/s (SD 0.340×10−3 mm2/s, range 1.13–1.99)×10−3 mm2/s. The difference was significant in the t-test (p =0.01). We found no ganglioneuroma or ganglioneuroblastoma with an ADC below 1.1×10−3 mm2/s. Discussion: There is a significant difference of the ADC of neuroblastoma compared to the ADC of ganglioneuroma/ganglioneuroblastoma. These first results suggest that the diffusion-weighted imaging could differentiate neuroblastoma and ganglioneuroma/ganglioneuroblastoma by calculating the ADC. [Copyright &y& Elsevier]

Juvenile scleroderma is a rare connective tissue disease that involves the skin and subcutaneous tissue. Among all presentations of juvenile scleroderma, localized scleroderma (JLSc) is the most frequent, followed by systemic disease (JSSc) and eosinophilic fasciitis (EF). In posttransplantation chronic graft-versus-host disease (GvHD), scleroderma-like skin involvement can occur. Systemic forms of juvenile scleroderma and GvHD can affect the internal organs, such as the lungs, the gastrointestinal tract, the heart, and kidneys and cause disability and severe, sometimes lethal, complications. Here, the authors give an overview of different presentations of juvenile scleroderma. They report their experience with the different forms and presentations of scleroderma, diagnostic workups, treatment, and outcome of all forms of childhood scleroderma in the context of the existing literature. [ABSTRACT FROM PUBLISHER]

Abstract: The class E genome of human cytomegalovirus (HCMV) contains long and short segments that invert due to recombination between flanking inverted repeats, causing the genome to isomerize into four distinct isomers. To determine if isomerization is important for HCMV replication, one copy of each repeat was deleted. The resulting virus replicated in cultured human fibroblasts with only a slight growth impairment. Restriction and Southern analyses confirmed that its genome is locked in the prototypic arrangement and unable to isomerize. We conclude that efficient replication of HCMV in fibroblasts does not require (i) the ability to undergo genome isomerization, (ii) genes that lie partially within the deleted repeats, or (iii) diploidy of genes that lie wholly within repeats. The simple genomic structure of this virus should facilitate studies of genome circularization, latency or persistence, and concatemer packaging as such studies are hindered by the complexities imposed by isomerization. [Copyright &y& Elsevier]

Tuberous sclerosis complex is an autosomal dominant disorder affecting primarily the central nervous system, skin, and kidney caused by mutations in the TSC1 and TSC2 genes. Diagnosis is established with the identification of various neurocutaneous symptoms and multiple organ system hamartomas. The authors report on a 9-year-old patient with episodes of vertigo and headache followed by full spontaneous recovery. There was no history of seizures, mental retardation, or other neurologic sequelae, and psychomotor development was normal. Magnetic resonance imaging revealed pial angiomatosis of the left cerebellum and calcifications in the left parieto-occipital lobe consistent with the diagnosis of Sturge-Weber syndrome. At the age of 13, multiple renal angiomyolipomas and a single hypomelanotic macule were found, and subsequent imaging revealed several cortical tuberi. The diagnosis was confirmed by sequence analysis, which identified a novel missense mutation p.Ala460Thr in exon 13 of the TSC2 gene. Thus, mild tuberous sclerosis due to a hypomorphic mutation in TSC2 may present with isolated leptomeningeal angiomatosis. [ABSTRACT FROM AUTHOR]

Activation of the IKK/NF-κB signalling pathway is a hallmark of human cytomegalovirus (HCMV) infection. However, its role in regulating major immediate-early promoter (MIEP)-dependent transcription and HCMV replication remains controversial. This study uses a combination of genetic approaches to investigate the effects of cell culture conditions on the importance of virus-induced NF-κB activation during the infection of endothelial cells or fibroblasts. Adenoviral-mediated expression of a dominant-negative mutant of IKK2 kinase (dnIKK2) in human umbilical vein endothelial cells resulted in a strong reduction of IκBα degradation and NF-κB activation following infection with an HCMV clinical isolate. Viral replication was impaired in dnIKK2-expressing cells that were growth-arrested before infection, but not in replicating cells. The inhibitory effect of dnIKK2 was independent from the virus strain and the cell type used, because replication of the laboratory AD169 strain was impaired as well in dnIKK2-expressing quiescent fibroblasts. Moreover, progressive disruption of NF-κB response elements within the MIEP in recombinant HCMV viruses derived from the clinical isolate prevented their replication in quiescent cells but not in actively growing cells. These results demonstrate an essential role of virus-induced IKK/NF-κB activity to trigger both viral IE gene expression and productive replication in quiescent cells. [ABSTRACT FROM AUTHOR]

Early spinal rigidity is a nonspecific feature reported in diseases such as neuromuscular and central movement disorders. We present a male patient with rigid spine muscular dystrophy caused by newly identified compound heterozygote mutations of the seleno-protein N gene and discuss this disease as a possible differential diagnosis for early-onset reduced spine mobility. Rigid spine muscular dystrophy is a rare myopathy presenting in childhood with a typical combination of stable or slowly progressive mild to moderate muscle weakness, limitation in flexion of the spine, and progressive restrictive ventilatory disorder. The clinical features of our patient include early-onset rigidity of his spine, scoliosis, mild muscular weakness predominantly of neck and trunk flexors, and restrictive ventilatory disorder. Biopsy of the biceps muscle revealed nonspecific myopathic changes, and molecular analysis confirmed the diagnosis of rigid spine muscular dystrophy. Thus, neuromuscular diseases such as muscular dystrophy must be considered in all patients presenting with early spinal rigidity, and genetic determination is a possible way to determine the diagnosis. [ABSTRACT FROM AUTHOR]

The Human Cytomegalovirus (HCMV) UL72 gene is considered to be the equivalent of the dUTPase gene of the Alpha- and Gamma-herpesviruses. To characterize its function, the expression profiles of UL72 at both the RNA and the protein level were determined. The gene is expressed with a late kinetics and the corresponding UL72 46-kDa protein accumulates late during infection in the cytoplasm of infected cells. The pUL72 was expressed in E. coli and the purified recombinant protein did not display a detectable dUTPase activity. The viral yields of reconstituted HCMV RVΔUL72 viruses carrying a deletion within the UL72 ORF demonstrated a moderate growth defect following low MOI infections, whereas their DNA synthesis profiles were not significantly different from those of the parental HCMV RVAD169. These results demonstrate that the UL72 gene product is not a dUTPase and is not essential for replication in human fibroblasts. [Copyright &y& Elsevier]

Notably, all 14/14 LOTS patients described by Jahnova et al I . i as well as all 18/18 LOTS patients reported by Neudorfer et al I . i exhibit the clinical finding of cerebellar atrophy [[4], [7]]. On physical examination the patient exhibited cachexia, dysarthria, scoliosis, generalized muscular atrophy, bilateral symmetric hyperreflexia, a mild ataxic gait as well as subtle bilateral action tremor. Magnetic resonance imaging (MRI) of the brain at the age of 16 years showed moderate diffuse cerebellar atrophy without supratentorial cerebral atrophy (Fig. [Extracted from the article]

IgG4-related disease (IgG4-RD) is an inflammatory disorder characterized by tumor-like swelling in one or more organs, elevated serum IgG4 levels, and histological alterations with infiltration of IgG4-positive plasma cells. IgG4-RD is rare and likely underdiagnosed in children. We report a case of a 16-year-old girl with IgG4-positive colitis that developed weeks after IgG4-related ophthalmic disease and discuss diagnosis and treatment in the context of the literature available. Since the pathophysiology of IgG4-RD is unknown, treatment options are empiric and, for the most part, untargeted. Systemic corticosteroid treatment is the basis of anti-inflammatory treatment in IgG4-RD and induced early remission in our patient. During corticosteroid taper, the patient developed weight loss and intestinal inflammation. Histopathological assessment of the intestinal walls confirmed IgG4-positive colitis. Immune-modulating treatment with non-biologic (e.g., methotrexate (MTX) and mycophenolate mofetil) or biologic (rituximab) disease-modifying antirheumatic drugs has been reported in treatment refractory or corticosteroid-dependent patients. The patient responded to treatment with anti-inflammatory therapy with food rich in TGF-β2 (modulen) and MTX. This is one of the first pediatric patients reported with IgG4-related colitis extending the phenotype of pediatric IgG4-RD. International collaboration to prospectively document clinical presentation and treatment responses may help to further establish the phenotype and treatment options and to raise awareness for IgG4-RD. [ABSTRACT FROM AUTHOR]

The article presents a case report of a 14-year-old boy with anti-nuclear matrix protein-2 (NXP2) positive juvenile dermatomyositis (JDM). Examinations showed pronounced symmetrical muscular weakness leaving him bedridden with elevated levels of creatinine kinase activity, myoglobin, and von-Willebrand antigen among other conditions. Treatment with ruxolitinib resulted in the patient's clinical improvement, normalization of inflammatory markers and increased mobility.

Background: Growth hormone (GH) has been used to treat children with GH deficiency (GHD) since 1966. Aims: Using a combined retrospective and cross-sectional approach, we explored the long-term outcomes of patients with GHD, analysed factors influencing therapeutic response, determined persistence into adulthood, investigated pituitary morphology, and screened for mutations in causative genes. Methods: The files of 96 GH-deficient children were reviewed. In a subset of 50 patients, re-assessment in adulthood was performed, including GHRH-arginine testing, pituitary magnetic resonance imaging (MRI), and mutational screening for the growth hormone-1 gene (GH1) and the GHRH receptor gene (GHRHR) in isolated GHD (IGHD), and HESX1, PROP1, POU1F1, LHX3, LHX4, and GLI2 in multiple pituitary hormone deficiency (MPHD) patients. Results: GH was started at a height SDS of -3.2 ± 1.4 in IGHD patients and of -4.1 ± 2.1 in MPHD patients. Relative height gain was 0.3 SDS/year, absolute gain 1.6 SDS, and 1.2/2.6 SDS in IGHD/MPHD, respectively. Mid-parental target height was reached in 77%. Initial height SDS, bone age retardation and duration of GH replacement were correlated with height SDS gain. GHD persisted into adulthood in 19 and 89% of subjects with IGHD and MPHD, respectively. In 1/42 IGHD patients a GH1 mutation was detected; PROP1 mutations were found in 3/7 MPHD subjects. Anterior pituitary hypoplasia, combined with posterior pituitary ectopy and pituitary stalk invisibility on MRI, was an exclusive finding in MPHD patients. Conclusions: GH replacement successfully corrects the growth deficit in children with GHD. While the genetic aetiology remains undefined in most cases of IGHD, PROP1 mutations constitute a major cause for MPHD. Persistence of GHD into adulthood is related to abnormal pituitary morphology. [ABSTRACT FROM AUTHOR]

Primarymicrocephaly and severe developmental delay are complex but unspecific signs pointing to various genetic or acquired diseases. A concomitant finding of hematological failure may lead to the differential diagnosis of rare genetic diseases such as chromosome breakage disorders or diseases associated with telomere dysfunction. X-linked Hoyeraal-Hreidarsson syndrome (HHS) is a rare heterogenic disorder characterized by severe neurological impairment and progressive bone marrow failure. The latter represents the main cause of mortality, usually in early childhood. We report on the clinical course of an infant with HHS due to a novel mutation in the DKC1 gene and the particular finding of pontocerebellar hypoplasia. [ABSTRACT FROM AUTHOR]

Background: Only a few cases have been previously published about clear cell meningiomas in children, the majority of them in the location of the spine. We describe an unusual case of clear cell meningioma occurring at the petro-clival region in a 5-year-old child. We further seek to determine the impact of several growth factors as well as the AKT1 mutation on the tumor growth pattern. Case presentation: A five-year-old girl was presented with a one-week history of cephalgia, ataxia, and left sided torticollis. Magnetic resonance imaging (MRI) revealed a dumbbell-shaped homogeneously petro-clival gadolinium-enhancing mass. A staged operative approach was chosen, and a complete removal of the tumor was achieved. Due to recurrent tumor progression, the child underwent several tumor surgeries and two cranial radiations. None of the treatments were able to stop tumor progression. Consequently, the child died at the age of 14 after further extensive intracranial and extracranial tumor progression. The initial histological examination revealed a clear cell meningioma WHO grade II with an MIB-1 labeling index of <1 %, which gradually increased with every recurrence up to 10 % by the last progression at the age of 13 years. Analogically, an increasing overexpression of epidermal growth factor receptor (EGFR), the platelet-derived growth factor receptor (PDGFR), and the vascular endothelial growth factor receptor (VEGFR) was observed with each recurrence. The AKT1 (E17K) mutation in the tumor was not detectable in all investigated specimens. Conclusion: Pediatric clear cell meningiomas WHO grade II are very rare. Our data demonstrate the progressive overexpression of EGF-, PDGF-, and VEGF-receptors in each recurrence, providing one of these receptors as targeted therapy in such cases. Further evaluation of these growth factors in clear cell meningioma is required to establish the optimal treatment of these aggressive tumors. [ABSTRACT FROM AUTHOR]

Background: In cases of suspected mastoiditis, imaging is used to evaluate the extent of mastoid destruction and possible complications. The role of magnetic resonance imaging (MRI) in mastoiditis has not been systematically evaluated. Purpose: To assess the diagnostic performance of MRI in patients with suspected acute mastoiditis. Material and Methods: Twenty-three patients with suspected acute mastoiditis were included in this retrospective study (15 boys, 8 girls; mean age, 2 years 11 months). All patients were examined on a 1.5 T MRI system. The MRI examination included both enhanced and non-enhanced turbo spin echo (TSE), diffusion-weighted images, and venous time-of-flight magnetic resonance angiography (TOF MRA) for the evaluation of the venous sinuses. Surgical findings, as well as clinical and imaging follow-up were used as the standard of reference. The sensitivity and accuracy of MRI for mastoiditis and subperiosteal abscesses was calculated. Results: Twenty (87%) of 23 patients had mastoiditis, and 12 (52%) of 23 patients had a subperiosteal abscess in addition to mastoiditis. Mastoiditis and subperiosteal abscesses were identified by MRI in all cases. Sensitivity for mastoiditis was 100%, specificity was 66%, and accuracy was 86%. Sensitivity for subperiosteal abscesses was 100% and accuracy was 100%. Conclusion: Multiparametric MRI has high accuracy for mastoiditis and subperiosteal abscesses. [ABSTRACT FROM AUTHOR]

Juvenile systemic lupus erythematosus is a rare multisystemic autoimmune disease with variable clinical manifestations, and disease onset before 16 years of age. Patients younger than 5 years are rarely affected and the age of onset may contribute to the course of disease in terms of clinical presentation, organ involvement, and serological findings. Here, we report two exemplary early-onset SLE patients, a 28-month-old patient with WHO class IIB kidney disease, arthritis, and a typical antibody constellation and an 11-month-old infant that presented with microcytic anemia, leukocytosis, arthritis, fasciitis, fatty liver disease, protein losing enteropathy, edema, and minimal change glomerulonephritis. Epidemiologic and clinical features of early-onset SLE compared to other forms of SLE are given and differential diagnoses and treatment options are discussed. [ABSTRACT FROM AUTHOR]

Abstract: A HCMV mutant of endothelial- and DC-tropic strain TB40/E lacking the described MHC downregulating genes US2–6 and US11 (RVTB40/E4ΔUS11) was generated. We analyzed the susceptibility of DC to RVTB40/E4ΔUS11 and subsequently studied antigen presentation and T-cell stimulation. Wildtype TB40/E- and RVTB40/E4ΔUS11 showed no significant difference in the efficiency of infection of DC. Whereas infection with TB40/E induced downregulation of MHC I, no significant MHC I downregulation was observed on RVTB40/E4ΔUS11-infected DC, indicating that the US2–6, US11 region encodes for the major genes relevant for MHC I downregulation. However, both viruses induced downregulation of MHC II, as well as CD40, CD80, CD86 and CD83 to the same levels. Stimulation of IFN-γ production by HCMV-specific CD8+ T-cells by infected autologous DC correlated with the modulation of MHC expression. While TB40/E-infected DC did not efficiently stimulate IFN-γ production, RVTB40/E4ΔUS11-infected DC efficiently stimulated CD8+ T-cells to produce IFN-γ. [ABSTRACT FROM AUTHOR]

Objectives: To compare MRI-based functional pulmonary and cardiac measurements in the long-term follow-up of children operated on for left-sided congenital diaphragmatic hernia (CDH) with age- and body size-matched healthy controls.Methods: Twelve children who received immediate postnatal surgery for closure of isolated left-sided CDH were included and received basic medical examinations, pulmonary function testing and echocardiography. MRI included measurement of lung volume, ventricular function assessment and velocity-encoded imaging of the pulmonary arteries and was compared with the data for 12 healthy children matched for age and body size.Results: While patients' clinical test results were not suspicious, comparison between the MRI data for patients and those for healthy controls revealed significant differences. In patients, the volumes of the left lungs were increased and the tidal volume was larger on the right side. While the stroke volumes of both ventricles were reduced, heart rate and ejection fraction were increased. Flow, acceleration time and cross-sectional area of the left pulmonary artery were reduced.Conclusion: Functional MRI detected pulmonary and cardiac findings in the late follow-up of CDH children which may be missed by standard clinical methods and might be relevant for decisions regarding late outcome and treatment. [ABSTRACT FROM AUTHOR]

The major transactivator protein IE2p86 of human cytomegalovirus (HCMV) has previously been shown to undergo posttranslational modification by the covalent attachment of SUMO proteins, termed SUMOylation, which occurs at two lysine residues located at amino acid positions 175 and 180. Mutation of the acceptor lysines resulted in the abrogation of IE2p86 SUMOylation in mammalian cells and a strong reduction of IE2p86-mediated transactivation. In this paper, we identify an additional SUMO interaction motif (SIM) within IE2p86, which mediates noncovalent binding to SUMO, as shown by yeast two-hybrid analyses. Transient-expression experiments revealed that an IE2p86 SIM mutant exhibited significantly reduced SUMOylation, strongly suggesting that noncovalent SUMO interactions affect the efficacy of covalent SUMO coupling. In order to define the relevance of IE2p86 SUMO interactions for viral replication, recombinant viruses originating from two different HCMV strains (AD169 and VR1814) were generated. Analysis of viruses expressing SUMOylation-negative IE2p86 revealed strongly impaired replication due to reduced viral DNA and protein accumulation, as well as diminished initiation of immediate-early gene expression. The additional introduction of the SIM mutation into the viral genome did not further compromise viral replication but resulted in altered expression of viral proteins at late times postinfection. In summary, this paper clearly shows that IE2p86 SUMOylation is necessary for efficient replication of the HCMV laboratory strain AD169 and the clinical isolate VR1814 and thus for the in vivo function of this viral transcription factor. [ABSTRACT FROM AUTHOR]

Virally encoded microRNAs (miRNAs) have recently been discovered in herpesviruses. However, their biological roles are mostly unknown. We developed an algorithm for the prediction of miRNA targets and applied it to human cytomegalovirus miRNAs, resulting in the identification of the major histocompatibility complex class I-related chain B (MICB) gene as a top candidate target of hcmv-miR-UL112. MICB is a stress-induced ligand of the natural killer (NK) cell activating receptor NKG2D and is critical for the NK cell killing of virus-infected cells and tumor cells. We show that hcmv-miR-UL112 specifically down-regulates MICB expression during viral infection, leading to decreased binding of NKG2D and reduced killing by NK cells. Our results reveal a miRNA-based immunoevasion mechanism that appears to be exploited by human cytomegalovirus. [ABSTRACT FROM AUTHOR]

Replication of human cytomegalovirus (CMV) requires the expression of the viral mitochondria-localized inhibitor of apoptosis (vMIA). vMIA inhibits apoptosis by recruiting Bax to mitochondria, resulting in its neutralization. We show that vMIA decreases cell size, reduces actin polymerization, and induces cell rounding. As compared with vMIA-expressing CMV, vMIA-deficient CMV, which replicates in fibroblasts expressing the adenoviral apoptosis suppressor E1B19K, induces less cytopathic effects. These vMIA effects can be separated from its cell death-inhibitory function because vMIA modulates cellular morphology in Bax-deficient cells. Expression of vMIA coincided with a reduction in the cellular adenosine triphosphate (ATP) level, vMIA selectively inhibited one component of the ATP synthasome, namely, the mitochondrial phosphate carrier. Exposure of cells to inhibitors of oxidative phosphorylation produced similar effects, such as an ATP level reduced by 30%, smaller cell size, and deficient actin polymerization. Similarly, knockdown of the phosphate carrier reduced cell size. Our data suggest that the cytopathic effect of CMV can be explained by vMIA effects on mitochondrial bioenergetics. [ABSTRACT FROM AUTHOR]

Background Chronic granulomatous disease (CGD) patients are susceptible to recurrent opportunistic infections and to recurrent or chronic inflammations of presumably non-infectious origin. Both types of manifestations are often accompanied by granuloma formation. Both can remain unnoticed until they deteriorate considerably and can become life-threatening if not treated in time. Objective To evaluate the effectiveness of regular follow-up visits in CGD patients. Methods Findings of imaging (ultrasound, radiographs, computer-tomography, magnetic resonance imaging), lung function tests, histopathological and microbiological assessments of biopsies have been reviewed. Results A total of 32 CGD patients have been evaluated within 15 years. Of these eight patients have been checked regularly for more than 5 years. Early detection prior to specific clinical signs and consecutive treatment of six lung manifestations and one liver manifestation such as interstitial pneumonia with formation of small granulomas, formation of large granulomas, fibrosis, Aspergillus infections, and abscesses could presumably prevent considerable aggravation in seemingly healthy or mildly symptomatic patients. In contrast, patients without surveillance who presented with severe symptoms (seven manifestations) often had irreversible organ damage or even died. Conclusions Regular follow-up visits can help prevent or mitigate clinical manifestations, improve life quality and expectancy and weigh indication for bone marrow transplantation in CGD patients. [ABSTRACT FROM AUTHOR]

Tuberous sclerosis (TSC) is an autosomal dominantly inherited multisystemic disease characterized by the development of hamartomas predominantly in brain and kidneys. The TSC2 gene for tuberous sclerosis is localized on chromosome 16p13.3 immediately adjacent to PKDI, the gene for autosomal dominant polycystic kidney disease (ADPKD). A TSC2-PKDI contiguous gene syndrome caused by chromosomal microdeletions disrupting both the TSC2 and PKDI genes has been identified in patients with TSC and early-onset severe ADPKD. We report a 3-month-old Caucasian girl of non- consanguineous parents with TSC and early manifestation of ADPKD. She presented with right-sided focal seizures, two small hypopigmented areas on the left flank, and elevated blood pressure requiring antihypertensive treatment. Brain magnetic resonance imaging revealed typical signs of tuberous sclerosis and abdominal ultrasonography showed bilaterally enlarged kidneys with multiple cysts resembling those seen in ADPKD. There was no family history of renal disease or of tuberous sclerosis. Findings were highly suspicious of TSC2-PKD1 contiguous gene syndrome. Using fluorescence in situ hybridization and plasmid probe CW23, which spans the adjacent 3' regions of TSC2 and PKD1 genes, we identified a submicroscopic deletion on only one of the chromosomes 16p13.3, thus permitting the diagnosis of the TSC2-PKD1 contiguous gene syndrome. [ABSTRACT FROM AUTHOR]

Six strains of human cytomegalovirus have been sequenced, including two laboratory strains (AD169 and Towne) that have been extensively passaged in fibroblasts and four clinical isolates that have been passaged to a limited extent in the laboratory (Toledo, FiX, PH, and TR). All of the sequenced viral genomes have been cloned as infectious bacterial artificial chromosomes. A total of 252 ORFs with the potential to encode proteins have been identified that are conserved in all four clinical isolates of the virus. Multiple sequence alignments revealed substantial variation in the amino acid sequences encoded by many of the conserved ORFs. [ABSTRACT FROM AUTHOR]